Miracle-dz/UniFAR-FTUs huggingface dataset:
High-throughput screening yields several small-molecule inhibitors of repeat-associated non-AUG translation

Repeat-associated non-AUG (RAN) translation is a noncanonical translation initiation event that occurs at nucleotide-repeat expansion mutations that are associated with several neurodegenerative diseases, including fragile X–associated tremor ataxia syndrome (FXTAS), ALS, and frontotemporal dementia (FTD). Translation of expanded repeats produces toxic proteins that accumulate in human brains and contribute to disease pathogenesis. Consequently, RAN translation constitutes a potentially important therapeutic target for managing multiple neurodegenerative disorders. Here, we adapted a previously developed RAN translation assay to a high-throughput format to screen 3,253 bioactive compounds for inhibition of RAN translation of expanded CGG repeats associated with FXTAS. We identified five diverse small molecules that dose-dependently inhibited CGG RAN translation, while relatively sparing canonical translation. All five compounds also inhibited RAN translation of expanded GGGGCC repeats associated with ALS and FTD. Using CD and native gel analyses, we found evidence that three of these compounds, BIX01294, CP-31398, and propidium iodide, bind directly to the repeat RNAs. These findings provide proof-of-principle supporting the development of selective small-molecule RAN translation inhibitors that act across multiple disease-causing repeats.
Articular cartilage surgery for the athlete

Purpose of review Current management of articular cartilage injuries has become one of the best examples of the translational relationship between technology, science, and surgery. In this review, we discuss the newest developments in this area over the past year with special emphasis on the implications for athletes. Recent findings Recent developments have been helpful in elucidating the important differences among techniques for articular cartilage injury management. The best results with microfracture and osteochondral autografts seem to be obtained with small lesions (<2 cm2), whereas larger lesions require autologous chondocyte implantation and osteochondral allografts. The results of microfracture seem to diminish over time whereas those of autologous chondrocyte implantations do not seem to change. Articular cartilage lesions seem to do better when treated early (within 12 months of injury). Comparative outcomes studies have shown little statistically significant differences in the different methods of achieving cartilage repair; however, second-generation autologous chondrocyte implantation has shown promise. Although the recent data are applicable to athletes, data that focuse on the topic of articular cartilage surgery in athletes are limited. Summary Articular cartilage repair techniques have become important tools that enable today's orthopedic surgeons to optimize outcomes for patients. A rapidly growing database is yielding better understanding of the short-term and long-term outcomes of available treatment options.
Plasma sCD36 as non-circadian marker of chronic circadian disturbance in shift workers

Shift work induces chronic circadian disturbance, which might result in increased health risks, including cardio-metabolic diseases. Previously, we identified sCD36 as a potential non-circadian biomarker of chronic circadian disturbance in mice. The aim of the current study (n = 232 individuals) was to identify whether sCD36 measured in plasma can be used as a non-circadian marker of chronic circadian disturbance in humans, which would allow its use to measure the effects of interventions and monitoring in large-scale studies. We compared levels of plasma sCD36 of day workers with recent (< 2 years) and experienced (> 5 years) night-shift workers within the Klokwerk study. We detected no differences in sCD36 levels between day workers and recent or experienced night-shift workers, measured during a day or afternoon shift. In addition, sCD36 levels measured directly after a night shift were not different from sCD36 levels measured during day or afternoon shifts, indicating no acute effect of night shifts on sCD36 levels in our study. In summary, our study does not show a relation between night-shift work experience (recent or long-term) and plasma levels of sCD36. Since we do not know if and for which time span night-shift work is associated with changes in sCD36 levels, and our study was relatively small and cross-sectional, further evidence for an association between chronic circadian disruption and this candidate biomarker sCD36 should be gathered from large cohort studies.
Scientific rigor in qualitative research

For research methodology scholars, rigor issues related to the qua­lity of the research is a core issue. The objective of this article is to show the status of rigor in qualitative research, its main criteria, the differences in its interpretation and application, ethics and the researchers’ social commitment. For such purpose, issues related to the instrument, field work, analysis and theoretical sampling, theoretical saturation and researcher’s integrity, are analyzed. Vali­dity, reliability, objectivity versus subjectibity, credibility, confirma­bility and transferability concepts, as well as evaluation guidelines, are reviewed. Those are necessary elements to all the ones who are involved in research from different perspectives and interests.
Salivary Pepsin as an Intrinsic Marker for Diagnosis of Sub-types of Gastroesophageal Reflux Disease and Gastroesophageal Reflux Disease-related Disorders

Background/Aims To determine the value of salivary pepsin in discriminating sub-types of gastroesophageal reflux disease (GERD) and GERD-related disorders. Methods Overall, 322 patients with different sub-types of GERD and 45 healthy controls (HC) were studied. All patients took Gastroesophageal Reflux Disease Questionnaire (GerdQ) and underwent endoscopy and 24-hour esophageal pH monitoring and manometry. Salivary pepsin concentration (SPC) was detected by using colloidal gold double-antibody immunological sandwich assay. Oral esomeprazole treatment was administrated in the patients with non-erosive reflux disease (NERD) and extra-esophageal symptoms (EES). Results Compared to HC, patients with erosive esophagitis, NERD, EES, EES plus typical GERD symptoms, or Barrett’s esophagus had a higher prevalence of saliva and SPC (all P < 0.001). There was no significant difference in the positive rate for pepsin in patients with functional heartburn or GERD with anxiety and depression, compared to HC. After esomeprazole treatment, the positive rate and SPC were significantly reduced in NERD (both P < 0.001) and in EES (P = 0.001 and P = 0.002, respectively). Of the 64 NERD patients, 71.9% (n = 46) were positive for salivary pepsin, which was significantly higher than the rate (43.8%, n = 28) of pathological acid reflux as detected by 24-hour esophageal pH monitoring (P = 0.002). Conclusions Salivary pepsin has an important significance for the diagnosis of GERD and GERD-related disorders. Salivary pepsin and 24-hour esophageal pH monitoring may complement with each other to improve the diagnostic efficiency.
Roles of leptin in the recovery of muscle and bone by reloading after mechanical unloading in high fat diet-fed obese mice

Muscle and bone masses are elevated by the increased mechanical stress associated with body weight gain in obesity. However, the mechanisms by which obesity affects muscle and bone remain unclear. We herein investigated the roles of obesity and humoral factors from adipose tissue in the recovery phase after reloading from disuse-induced muscle wasting and bone loss using normal diet (ND)- or high fat diet (HFD)-fed mice with hindlimb unloading (HU) and subsequent reloading. Obesity did not affect decreases in trabecular bone mineral density (BMD), muscle mass in the lower leg, or grip strength in HU mice. Obesity significantly increased trabecular BMD, muscle mass in the lower leg, and grip strength in reloading mice over those in reloading mice fed ND. Among the humoral factors in epididymal and subcutaneous adipose tissue, leptin mRNA levels were significantly higher in reloading mice fed HFD than in mice fed ND. Moreover, circulating leptin levels were significantly higher in reloading mice fed HFD than in mice fed ND. Leptin mRNA levels in epididymal adipose tissue or serum leptin levels positively correlated with the increases in trabecular BMD, total muscle mass, and grip strength in reloading mice fed ND and HFD. The present study is the first to demonstrate that obesity enhances the recovery of bone and muscle masses as well as strength decreased by disuse after reloading in mice. Leptin may contribute to the recovery of muscle and bone enhanced by obesity in mice.
Studies of fall risk and bone morphology in older women with low bone mass

Introduction Osteoporotic fractures are a major health care problem. Fracture risk can be largely divided into two domains: fall risk and bone health, and both can be influenced by exercise. Purpose 1) To examine the role of different types of exercise on both fall risk and bone health in older women with low bone mass. 2) To explore fall risk factors that may be unique to women with low bone mass. Methods Subjects: Women aged 65 to 75 years with osteoporosis for Parts I and II. Women aged 75 to 85 years with low bone mass (i.e. osteoporosis or osteopenia) for Parts III, IV, and V. Study Design: Parts I and II are cross-sectional studies. Parts III, IV, and V involved a 25-week randomized controlled trial of resistance training, agility training, and stretching (sham exercise). Results Parts I & II: Back pain was negatively associated with both postural stability (r2 = 0.09, p = 0.04) and functional mobility (r2 = 0.12, p = 0.001). Compared to their counterparts without osteoporosis, older women with osteoporosis had 11 to 18% greater fall risk by composite balance score and quadriceps strength (both p < 0.03). Part III to V: Both high-intensity resistance training and agility training significantly reduced fall risk compared to a general stretching program (both p < 0.01). The resistance training program reduced fall risk by 57% and the agility training program reduced fall risk by 48% without any serious adverse effects. Both exercise programs also significantly increased cortical bone density (by pQCT) in the appendicular skeleton. Fear of falling was also reduced after 13 weeks of participating in both exercise programs. Conclusions The cross-sectional studies suggest that back pain may warrant scrutiny as a fall risk factor in older women with osteoporosis and that older women with osteoporosis may be at greater risk of falls than is often recognised. The RCT indicates that in women aged 75 to 85 years with low bone mass both high-intensity resistance training and agility training reduce fall risk compared to general stretching. Also, both types of training have the potential to increase cortical bone density in a site-specific manner despite the population being elderly. Change in balance confidence may not correlate closely with changes in physiological measures of fall risk. Further studies in high-risk populations should be powered for falls as the primary outcome.
Unexpected high seroprevalence of hepatitis E virus in patients with alcohol-related cirrhosis

Introduction Little is known about hepatitis E virus (HEV) infection in patients with cirrhosis. The aim of the present study was to describe the frequency of HEV infection and associated risk factors in patients with cirrhosis from Argentina. Materials and methods We evaluated HEV seroprevalence (IgG anti-HEV) and acute infections (IgM and RNA) in patients with cirrhosis (n = 140) vs. healthy controls (n = 300). Additionally, we compared the same outcomes in individuals with alcohol-related cirrhosis (n = 43) vs. patients with alcohol use disorder (without cirrhosis, n = 72). Results The overall HEV seroprevalence in the cohort of subjects with cirrhosis was 25% (35/140), compared to 4% in the healthy control group [12/300; OR = 8; (95% CI = 4–15.99); p<0.05]. HEV seropositivity was significantly higher in alcohol-related cirrhosis compared to other causes of cirrhosis [39.5% vs. 12.4%; OR = 4.71; (95% CI = 1.9–11.6); p<0.05] and to healthy controls [OR = 15.7; (95% CI = 6.8–36.4); p = 0.0001]. The HEV seroprevalence in alcoholic-related cirrhosis vs. with alcohol use disorder was 39.5% vs. 12.5% [OR = 4.58; (95% CI = 1.81–11.58); p<0.001]. Conclusion We found a high seroprevalence of HEV in patients with cirrhosis and in individuals with alcohol use disorder. The simultaneous presence of both factors (cirrhosis + alcohol) showed more association to HEV infection. Larger studies with prospective follow up are needed to further clarify this interaction.
Vitamin D insufficiency increases risk of chronic pain among African Americans experiencing motor vehicle collision.

African Americans experience an increased burden of motor vehicle collision (MVC), post-MVC musculoskeletal pain (MSP) and Vitamin D insufficiency. In this prospective multicenter study, we tested the hypothesis that African Americans (n=133) presenting to the ED after MVC with low peritraumatic Vitamin D levels would have worse chronic MSP outcomes compared to individuals with sufficient Vitamin D. Vitamin D levels were assessed in the early aftermath of MVC via enzyme-linked immunosorbent assay, and pain severity was assessed via the 0-10 numeric rating scale at 6 weeks, 6 months and 1 year. In repeated-measures analysis, African American MVC survivors with vitamin D insufficiency experienced more severe chronic pain (β=1.18, p=0.031). In secondary analyses, we assessed for evidence that the effect of Vitamin D on post-MVC pain outcomes is mediated, at least in part, by the influence of Vitamin D on genetic variants in genes involved in immune system regulation (IL-10 and NLRP3). Genotyping was performed using a genome-wide microarray using collected DNA samples. Secondary analyses suggest that the effect of Vitamin D on post-MVC pain outcomes may be influenced by genetic variation in IL-10 and NLRP3. Further studies are needed to assess the impact of Vitamin D insufficiency on pain outcomes in African Americans experiencing MVC and other common trauma exposures, to assess factors affecting this relationship, and to assess the efficacy of administering Vitamin D in the immediate aftermath of MVC to prevent chronic pain. Such low-cost, non-opioid interventions are urgently needed to address chronic pain development following MVC.
Next-of-Kin Involvement in Regulatory Investigations of Adverse Events That Caused Patient Death: A Process Evaluation (Part II: The Inspectors’ Perspective)

Objective The aim of the study was to explore regulatory inspectors’ experiences with a new method for next-of-kin involvement in investigation of adverse events causing patient death. A resilient healthcare perspective is used as the theoretical foundation. Methods The study design was a qualitative process evaluation of the new involvement method in 2 Norwegian counties. Next of kin, who had lost a close family member in an adverse event, were invited to a 2-hour face-to-face meeting with the inspectors. Data collection involved 3 focus group interviews with regulatory inspectors and observation (20 hours) of the meetings (2017–2018). Data were analyzed by a thematic content analysis. Results Next-of-kin involvement informed the investigations by additional and new information about the adverse events and by different versions of the investigators’ earlier obtained information, such as time sequences, what happened and how, and who were involved. Inspectors considered next of kin as a key source of information that contributed to improve the quality of the investigation. The downside was that the involvement method increased work load and could challenge the principle of equal treatment in regulatory practice. Conclusions Involvement of next of kin in regulatory investigation of adverse events causing patient death contributes to a better understanding of work as done in clinical practice and contributes to strengthen the learning potential in resilience.
A RAPGEF6 variant constitutes a major risk factor for laryngeal paralysis in dogs

Laryngeal paralysis (LP) is the inability to abduct the arytenoid cartilages during inspiration, resulting in a partial to complete airway obstruction and consequent respiratory distress. Different forms of LP with varying age of onset exist in dogs. Hereditary early onset forms were reported in several dog breeds. In most breeds, hereditary LP is associated with other neurologic pathologies. Using a genome-wide association study and haplotype analyses, we mapped a major genetic risk factor for an early onset LP in Miniature Bull Terriers to a ~1.3 Mb interval on chromosome 11. Whole genome sequencing of an affected Miniature Bull Terrier and comparison to 598 control genomes revealed a 36 bp insertion into exon 15 of the RAPGEF6 gene (c.1793_1794ins36). The imperfect genotype-phenotype correlation suggested a complex mode of inheritance with a major genetic risk factor involving a recessive risk allele. Homozygosity for the insertion was associated with a 10- to 17-fold increased risk for LP. The insertion allele was only found in Miniature Bull Terriers and Bull Terriers. It was absent from >1000 control dogs of other dog breeds. The insertion sequence contains a splice acceptor motif leading to aberrant splicing in transcripts originating from the mutant allele (r.1732_1780del). This leads to a frameshift and a premature stop codon, p.(Ile587ProfsTer5), removing 64% of the open reading frame. Our results suggest an important role of RAPGEF6 in laryngeal nerve function and provide new clues to its physiological significance.
Consideration of a Credibility Assessment Framework in Model‐Informed Drug Development: Potential Application to Physiologically‐Based Pharmacokinetic Modeling and Simulation

The use of computational models in drug development has grown during the past decade. These model‐informed drug development (MIDD) approaches can inform a variety of drug development and regulatory decisions. When used for regulatory decision making, it is important to establish that the model is credible for its intended use. Currently, there is no consensus on how to establish and assess model credibility, including the selection of appropriate verification and validation activities. In this article, we apply a risk‐informed credibility assessment framework to physiologically‐based pharmacokinetic modeling and simulation and hypothesize this evidentiary framework may also be useful for evaluating other MIDD approaches. We seek to stimulate a scientific discussion around this framework as a potential starting point for uniform assessment of model credibility across MIDD. Ultimately, an overarching framework may help to standardize regulatory evaluation across therapeutic products (i.e., drugs and medical devices).
Barriers to care in pediatric cancer: The role of illness uncertainty in relation to parent psychological distress

The current study evaluated perceived barriers to care for parents of children with cancer and the mediating effect of illness uncertainty (IU; uncertainty from the ambiguity or unpredictability of the illness) on the relationship between barriers and parental psychological distress. We hypothesized that greater barriers to care would be related to higher levels of IU and, in turn, higher anxiety, depression, and posttraumatic stress symptom (PTSS) ratings.
Economic evaluation of community acquired pneumonia management strategies: A systematic review of literature

Background Community-acquired pneumonia (CAP) is a major cause of mortality and morbidity worldwide. Efficient use of resources is fundamental for best use of money among the available and novel treatment options for the management of pneumonia. The objective of this study was to systematically review the economic analysis of management strategies of pneumonia. Methods A systematic search was performed using Academic Search Complete, MEDLINE, EconLit, Global health, MEDLINE complete and Embase databases using specific subject headings or key words in May 2018 without restricting publication year. All search results were recorded and any type of economic evaluation for management of CAP was included for detailed review. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist was used for quality appraisal. Results Nineteen studies met the inclusion criteria; ten studies were trial based, five conducted analysis using model based techniques and the rest of the studies were either based on observational, record review or pre-post intervention studies. Most of the studies conducted cost-effectiveness analysis (n = 15) and compared different combinations of antimicrobials. Most were based on developed countries (n = 17), considered adult age groups (n = 16) and used a provider perspective (n = 14). Nine studies reported dominant alternatives (lower cost with higher benefit). Sensitivity analysis was performed by the majority of studies (n = 15). Fourteen studies were assessed as either being excellent, very good or good quality, with no relationship found between publication year and study quality. Methodological variation, type of microbial used, perspective, costs and outcome measures limit the compatibility among the results of the included studies. Conclusion Economic evaluation of interventions for management of CAP to date supports cost-effectiveness of studied interventions. However, evidence relates largely to antimicrobials choice in older populations in developed countries. Parallel economic evaluation of different management strategies of CAP is recommended for both developed and developing countries to support rigorous and robust comparative economic analysis within health care systems. PROSPERO registration no: CRD42018097174
The Arteries of the Central Forehead: Implications for Facial Plastic Surgery.

BACKGROUND The forehead has substantial importance as an aesthetic unit. The central and supraorbital parts of this area are supplied by the supratrochlear (ST) and supraorbital (SO) arteries, as well as the recently defined paracentral (PA) and central arteries. OBJECTIVES This study aimed to assess the morphometry of the vessels of the forehead in the context of plastic surgery and minimally invasive cosmetic procedures. METHODS This research included 40 cadavers who were directed for forensic autopsy and subjected to postmortem computed tomography angiography. In total, 75 hemifaces were examined for the course and location of arteries, relative to the bones and surrounding structures. RESULTS The arteries were observed as follow: ST in 97.3%, SO in 89.3% and PA in 44.0%. The PA can be expected in the 13 mm wide zone starting 2 mm laterally from the midline. The ST should be expected in the 10 mm wide area extended laterally from the tenth millimeter from the midline and the SO should be expected in the slightly wider (11 mm) area extending laterally from the 20th millimeter from the midline. For the proximal main trunks of the ST and SO arteries, we observed no overlap between the zones of occurrence, whereas the zones for the PA and ST main proximal trunks did overlap. No distinctive central artery was observed in the midline region of the forehead, but instead, a network of small vessels in the midline region was visible. CONCLUSION The ST is the main and most conservative artery of this region, while the PA is the most variable. A unique and detailed anatomical map was created to better understand the vasculature of the forehead area.