Miracle-dz/UniFAR-FTUs huggingface dataset:
Evaluating Industry Payments Among Dermatology Clinical Practice Guidelines Authors

Importance It is well documented that financial conflicts of interest influence medical research and clinical practice. Prior to the Open Payments provisions of the Affordable Care Act, financial ties became apparent only through self-disclosure. The nature of financial interests has not been studied among physicians who develop dermatology clinical practice guidelines. Objective To evaluate payments received by physicians who author dermatology clinical practice guidelines, compare disclosure statements for accuracy, determine whether pharmaceutical companies from which the authors received payments manufactured products related to the guidelines, and examine the extent to which the American Academy of Dermatology enforced their Administrative Regulations for guideline development. Design, Setting, and Participants Three American Academy of Dermatology guidelines published from 2013 to 2016 were retrieved. Double data extraction was used to record financial payments received by 49 guideline authors using the Open Payments database. Payments received by the authors from the date of the initial literature search to the date of publication were used to evaluate disclosure statement accuracy, detail the companies providing payments, and evaluate Administrative Regulations enforcement. This study is applicable to clinical practice guideline panels drafting recommendations, physicians using clinical practice guidelines to inform patient care, and those establishing policies for guideline development. Main Outcomes and Measures Our main outcomes are the monetary values and types of payments received by physicians who author dermatology guidelines and the accuracy of disclosure statements. Data were collected from the Open Payments database and analyzed descriptively. Results Of the 49 authors evaluated, 40 received at least 1 reported industry payment, 31 accepted more than $1000, 25 accepted more than $10 000, and 18 accepted more than $50 000. Financial payments amounted to a mean of $157 177 per author. The total reimbursement among the 49 authors from 2013 to 2015 was $7 701 681. Of the 40 authors receiving payments, 22 did not accurately disclose industry relationships. Authors received payments from companies with products directly related to the guideline topic. Violations to the Administrative Regulations were found. Conclusions and Relevance Dermatology clinical practice guideline authors received sizable industry payments and did not completely disclose these payments. The American Academy of Dermatology policies may benefit from stricter enforcement or the adoption of new standards.
Experiences of hospital-based multidisciplinary team meetings in oncology: An interview study among participating general practitioners

Abstract Background: Cancer care has become complex, requiring healthcare professionals to collaborate to provide high-quality care. Multidisciplinary oncological team (MDT) meetings in the hospital have been implemented to coordinate individual cancer patients’ care. General practitioners (GPs) are invited to join, but their participation is minimal. Objectives: Aim of this study is to explore participating GPs’ perceptions of their current role and to understand their preferences towards effective role execution during MDT meetings. Methods: In May to June 2014, semi-structured interviews (n = 16) were conducted involving GPs with MDT experience in Belgium. The analysis was done according to qualitative content analysis principles. Results: Attendance of an MDT meeting is perceived as part of the GP’s work, especially for complex patient care situations. Interprofessional collaborative relationships and the GP’s perceived benefit to the MDT meeting discussions are important motivators to participate. Enhanced continuity of information flow and optimized organizational time management were practical aspects triggering the GP’s intention to participate. GPs valued the communication with the patient before and after the meeting as an integral part of the MDT dynamics. Conclusion: GPs perceive attendance of the MDT meeting as an integral part of their job. Suggestions are made to enhance the efficiency of the meetings.
Determinants of retinal microvascular features and their relationships in two European populations

Objectives: To examine factors influencing retinal vasculature in two environmentally contrasted, cross-sectional studies of adult participants of European descent and to estimate the extent and specificity of genetic contributions to each retinal vasculature feature. Methods: Retinal images from 1088 participants in the Orkney Complex Disease Study and 387 in the CROATIA-Korčula study, taken using the same nonmydriatic camera system and graded by the same person, were evaluated. Using general linear models, we estimated the influence of an extensive range of systemic risk factors, calculated retinal traits heritabilities and genetic correlations. Main results: Systemic covariates explained little (<4%) of the variation in vessel tortuosity, substantially more (>10%, up to 31.7%) of the variation in vessel width and monofractal dimension. Suggestive not well trodden associations of biological interest included that of urate, tissue plasminogen activator and cardiac PR interval with arteriolar narrowing, that of carotid intima–media thickness with less-tortuous arterioles and of cardiac QT interval with more tortuous venules. The genetic underpinning of tortuosity is largely distinct from that of the other retinal vascular features, whereas that of fractal dimension and vessel width greatly overlaps. The previously recognized influence of ocular axial length on vessel widths was high and can be expected to lead to artefactual genetic associations [genetic correlation with central retinal arteriolar equivalent: −0.53 (standard error 0.11)]. The significant genetic correlation between SBP and central retinal arteriolar equivalent, −0.53 (standard error 0.22) (after adjusting for age, sex and axial length of the eye), augurs more favourably for the discovery of genetic variants relevant to vascular physiology.
Peptidoglycan in obligate intracellular bacteria

Peptidoglycan is the predominant stress‐bearing structure in the cell envelope of most bacteria, and also a potent stimulator of the eukaryotic immune system. Obligate intracellular bacteria replicate exclusively within the interior of living cells, an osmotically protected niche. Under these conditions peptidoglycan is not necessarily needed to maintain the integrity of the bacterial cell. Moreover, the presence of peptidoglycan puts bacteria at risk of detection and destruction by host peptidoglycan recognition factors and downstream effectors. This has resulted in a selective pressure and opportunity to reduce the levels of peptidoglycan. In this review we have analysed the occurrence of genes involved in peptidoglycan metabolism across the major obligate intracellular bacterial species. From this comparative analysis, we have identified a group of predicted ‘peptidoglycan‐intermediate’ organisms that includes the Chlamydiae, Orientia tsutsugamushi, Wolbachia and Anaplasma marginale. This grouping is likely to reflect biological differences in their infection cycle compared with peptidoglycan‐negative obligate intracellular bacteria such as Ehrlichia and Anaplasma phagocytophilum, as well as obligate intracellular bacteria with classical peptidoglycan such as Coxiella, Buchnera and members of the Rickettsia genus. The signature gene set of the peptidoglycan‐intermediate group reveals insights into minimal enzymatic requirements for building a peptidoglycan‐like sacculus and/or division septum.
The Congenital Heart Disease Genetic Network Study: Cohort description

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010–2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.
Simulating EGFR-ERK Signaling Control by Scaffold Proteins KSR and MP1 Reveals Differential Ligand-Sensitivity Co-Regulated by Cbl-CIN85 and Endophilin

ERK activation is enhanced by the scaffolding proteins KSR and MP1, localized near the cell membrane and late endosomes respectively, but little is known about their dynamic interplay. We develop here a mathematical model with ordinary differential equations to describe the dynamic activation of EGFR-ERK signaling under a conventional pathway without scaffolds, a KSR-scaffolded pathway, and an MP1-scaffolded pathway, and their impacts were examined under the influence of the endosomal regulators, Cbl-CIN85 and Endophilin A1. This new integrated model, validated against experimental results and computational constraints, shows that changes of ERK activation and EGFR endocytosis in response to EGF concentrations (i.e ligand sensitivity) depend on these scaffold proteins and regulators. The KSR-scaffolded and the conventional pathways act synergistically and are sensitive to EGF stimulation. When the KSR level is high, the sensitivity of ERK activation from this combined pathway remains low when Cbl-CIN85 level is low. But, such sensitivity can be increased with increasing levels of Endophilin if Cbl-CIN85 level becomes high. However, reduced KSR levels already present high sensitivity independent of Endophilin levels. In contrast, ERK activation by MP1 is additive to that of KSR but it shows little ligand-sensitivity under high levels of EGF. This can be partly reversed by increasing level of Endophilin while keeping Cbl-CIN85 level low. Further analyses showed that high levels of KSR affect ligand-sensitivity of EGFR endocytosis whereas MP1 ensures the robustness of endosomal ERK activation. These simulations constitute a multi-dimensional exploration of how EGF-dependent EGFR endocytosis and ERK activation are dynamically affected by scaffolds KSR and MP1, co-regulated by Cbl-CIN85 and Endophilin A1. Together, these results provide a detailed and quantitative demonstration of how regulators and scaffolds can collaborate to fine-tune the ligand-dependent sensitivity of EGFR endocytosis and ERK activation which could underlie differences during normal physiology, disease states and drug responses.
Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study

Background Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking. Objectives (1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers. Methods Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model. Results Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period. Conclusions Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.
A scalable fabrication process of polymer microneedles

While polymer microneedles may easily be fabricated by casting a solution in a mold, either centrifugation or vacuumizing is needed to pull the viscous polymer solution into the microholes of the mold. We report a novel process to fabricate polymer microneedles with a one-sided vacuum using a ceramic mold that is breathable but water impermeable. A polymer solution containing polyvinyl alcohol and polysaccharide was cast in a ceramic mold and then pulled into the microholes by a vacuum applied to the opposite side of the mold. After cross-linking and solidification through freeze-thawing, the microneedle patch was detached from the mold and transferred with a specially designed instrument for the drying process, during which the patch shrank evenly to form an array of regular and uniform needles without deformation. Moreover, the shrinkage of the patches helped to reduce the needles’ size to ease microfabrication of the male mold. The dried microneedle patches were finally punched to the desired sizes to achieve various properties, including sufficient strength to penetrate skin, microneedles-absorbed water-swelling ratios, and drug-release kinetics. The results showed that the microneedles were strong enough to penetrate pigskin and that their performance was satisfactory in terms of swelling and drug release.
Women with Fibromyalgia Have Lower Levels of Calcium, Magnesium, Iron and Manganese in Hair Mineral Analysis

Little is known about hair mineral status in fibromyalgia patients. This study evaluated the characteristics of hair minerals in female patients with fibromyalgia compared with a healthy reference group. Forty-four female patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria were enrolled as the case group. Ageand body mass index-matched data were obtained from 122 control subjects enrolled during visit for a regular health check-up. Hair minerals were analyzed and compared between the two groups. The mean age was 43.7 yr. General characteristics were not different between the two groups. Fibromyalgia patients showed a significantly lower level of calcium (775 µg/g vs 1,093 µg/g), magnesium (52 µg/g vs 72 µg/g), iron (5.9 µg/g vs 7.1 µg/g), copper (28.3 µg/g vs 40.2 µg/g) and manganese (140 ng/g vs 190 ng/g). Calcium, magnesium, iron, and manganese were loaded in the same factor using factor analysis; the mean of this factor was significantly lower in fibromyalgia group in multivariate analysis with adjustment for potential confounders. In conclusion, the concentrations of calcium, magnesium, iron, and manganese in the hair of female patients with fibromyalgia are lower than of controls, even after adjustment of potential confounders.
Learning to never forget—time scales and specificity of long-term memory of a motor skill

Despite anecdotal reports that humans retain acquired motor skills for many years, if not a lifetime, long-term memory of motor skills has received little attention. While numerous neuroimaging studies showed practice-induced cortical plasticity, the behavioral correlates, what is retained and also what is forgotten, are little understood. This longitudinal case study on four subjects presents detailed kinematic analyses of humans practicing a bimanual polyrhythmic task over 2 months with retention tests after 6 months and, for two subjects, after 8 years. Results showed that individuals not only retained the task, but also reproduced their individual “style” of performance, even after 8 years. During practice, variables such as the two hands' frequency ratio and relative phase, changed at different rates, indicative of multiple time scales of neural processes. Frequency leakage across hands, reflecting intermanual crosstalk, attenuated at a significantly slower rate and was the only variable not maintained after 8 years. Complementing recent findings on neuroplasticity in gray and white matter, our study presents new behavioral evidence that highlights the multi-scale process of practice-induced changes and its remarkable persistence. Results suggest that motor memory may comprise not only higher-level task variables but also individual kinematic signatures.
Impulsive Rats Exhibit Blunted Dopamine Release Dynamics during a Delay Discounting Task Independent of Cocaine History

Abstract The inability to wait for a large, delayed reward when faced with a small, immediate one, known as delay discounting, has been implicated in a number of disorders including substance abuse. Individual differences in impulsivity on the delay discounting task are reflected in differences in neural function, including in the nucleus accumbens (NAc) core. We examined the role of a history of cocaine self-administration, as well as individual differences in impulsivity, on rapid dopamine (DA) release dynamics in the NAc core. Rats with a history of cocaine or water/saline self-administration were tested on delay discounting while being simultaneously assayed for rapid DA release using electrochemical methods. In controls, we found that cue DA release was modulated by reward delay and magnitude, consistent with prior reports. A history of cocaine had no effect on either delay discounting or DA release dynamics. Nonetheless, independent of drug history, individual differences in impulsivity were related to DA release in the NAc core. First, high impulsive animals exhibited dampened cue DA release during the delay discounting task. Second, reward delay and magnitude in high impulsive animals failed to robustly modulate changes in cue DA release. Importantly, these two DAergic mechanisms were uncorrelated with each other and, together, accounted for a high degree of variance in impulsive behavior. Collectively, these findings demonstrate two distinct mechanisms by which rapid DA signaling may influence impulsivity, and illustrate the importance of NAc core DA release dynamics in impulsive behavior.
The population genomics of rhesus macaques (Macaca mulatta) based on whole-genome sequences

Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research, have the largest natural geographic distribution of any nonhuman primate, and have been the focus of much evolutionary and behavioral investigation. Consequently, rhesus macaques are one of the most thoroughly studied nonhuman primate species. However, little is known about genome-wide genetic variation in this species. A detailed understanding of extant genomic variation among rhesus macaques has implications for the use of this species as a model for studies of human health and disease, as well as for evolutionary population genomics. Whole-genome sequencing analysis of 133 rhesus macaques revealed more than 43.7 million single-nucleotide variants, including thousands predicted to alter protein sequences, transcript splicing, and transcription factor binding sites. Rhesus macaques exhibit 2.5-fold higher overall nucleotide diversity and slightly elevated putative functional variation compared with humans. This functional variation in macaques provides opportunities for analyses of coding and noncoding variation, and its cellular consequences. Despite modestly higher levels of nonsynonymous variation in the macaques, the estimated distribution of fitness effects and the ratio of nonsynonymous to synonymous variants suggest that purifying selection has had stronger effects in rhesus macaques than in humans. Demographic reconstructions indicate this species has experienced a consistently large but fluctuating population size. Overall, the results presented here provide new insights into the population genomics of nonhuman primates and expand genomic information directly relevant to primate models of human disease.
Predictors of Retention among Men Attending STI Clinics in HIV Prevention Programs and Research: A Case Control Study in Pune, India

Background Retention is critical in HIV prevention programs and clinical research. We studied retention in the three modeled scenarios of primary prevention programs, cohort studies and clinical trials to identify predictors of retention. Methodology/Principal Findings Men attending Sexually Transmitted Infection (STI) clinics (n = 10, 801) were followed in a cohort study spanning over a ten year period (1993–2002) in Pune, India. Using pre-set definitions, cases with optimal retention in prevention program (n = 1286), cohort study (n = 940) and clinical trial (n = 896) were identified from this cohort. Equal number of controls matched for age and period of enrollment were selected. A case control analysis using conditional logistic regression was performed. Being employed was a predictor of lower retention in all the three modeled scenarios. Presence of genital ulcer disease (GUD), history of commercial sex work and living away from the family were predictors of lower retention in primary prevention, cohort study and clinical trial models respectively. Alcohol consumption predicted lower retention in cohort study and clinical trial models. Married monogamous men were less likely to be retained in the primary prevention and cohort study models. Conclusions/Significance Predicting potential drop-outs among the beneficiaries or research participants at entry point in the prevention programs and research respectively is possible. Suitable interventions might help in optimizing retention. Customized counseling to prepare the clients properly may help in their retention.