Miracle-dz/UniFAR-FTUs huggingface dataset:
Participation of keratinocyte‐ and fibroblast‐derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders

Human epidermal melanocytes play a central role in sensing the environment and protecting the skin from the drastic effects of solar ultraviolet radiation and other environmental toxins or inflammatory agents. Melanocytes survive in the epidermis for decades, which subjects them to chronic environmental insults. Melanocytes have a poor self‐renewal capacity; therefore, it is critical to ensure their survival with genomic stability. The function and survival of melanocytes is regulated by an elaborate network of paracrine factors synthesized mainly by epidermal keratinocytes and dermal fibroblasts. A symbiotic relationship exists between epidermal melanocytes and keratinocytes on the one hand, and between melanocytes and dermal fibroblasts on the other hand. Melanocytes protect epidermal keratinocytes and dermal fibroblasts from the damaging effects of solar radiation, and the latter cells synthesize biochemical mediators that maintain the homeostasis, and regulate the stress response of melanocytes. Disruption of the paracrine network results in pigmentary disorders, due to abnormal regulation of melanin synthesis, and compromise of melanocyte survival or genomic stability. This review provides an update of the current knowledge of keratinocyte‐ and fibroblast‐derived paracrine factors and their contribution to melanocyte physiology, and how their abnormal production is involved in the pathogenesis of common pigmentary disorders.
The Transposable Element Environment of Human Genes Differs According to Their Duplication Status and Essentiality

Abstract Transposable elements (TEs) are major components of eukaryotic genomes and represent approximately 45% of the human genome. TEs can be important sources of novelty in genomes and there is increasing evidence that TEs contribute to the evolution of gene regulation in mammals. Gene duplication is an evolutionary mechanism that also provides new genetic material and opportunities to acquire new functions. To investigate how duplicated genes are maintained in genomes, here, we explored the TE environment of duplicated and singleton genes. We found that singleton genes have more short-interspersed nuclear elements and DNA transposons in their vicinity than duplicated genes, whereas long-interspersed nuclear elements and long-terminal repeat retrotransposons have accumulated more near duplicated genes. We also discovered that this result is highly associated with the degree of essentiality of the genes with an unexpected accumulation of short-interspersed nuclear elements and DNA transposons around the more-essential genes. Our results underline the importance of taking into account the TE environment of genes to better understand how duplicated genes are maintained in genomes.
Coronary plaque composition influences biomechanical stress and predicts plaque rupture in a morpho-mechanic OCT analysis

Plaque rupture occurs if stress within coronary lesions exceeds the protection exerted by the fibrous cap overlying the necrotic lipid core. However, very little is known about the biomechanical stress exerting this disrupting force. Employing optical coherence tomography (OCT), we generated plaque models and performed finite-element analysis to simulate stress distributions within the vessel wall in 10 ruptured and 10 non-ruptured lesions. In ruptured lesions, maximal stress within fibrous cap (peak cap stress [PCS]: 174 ± 67 vs. 52 ± 42 kPa, p<0.001) and vessel wall (maximal plaque stress [MPS]: 399 ± 233 vs. 90 ± 95 kPa, p=0.001) were significantly higher compared to non-ruptured plaques. Ruptures arose in the immediate proximity of maximal stress concentrations (angular distances: 21.8 ± 30.3° for PCS vs. 20.7 ± 23.7° for MPS); stress concentrations excellently predicted plaque rupture (area under the curve: 0.940 for PCS, 0.950 for MPS). This prediction of plaque rupture was superior to established vulnerability features such as fibrous cap thickness or macrophage infiltration. In conclusion, OCT-based finite-element analysis effectively assesses plaque biomechanics, which in turn predicts plaque rupture in patients. This highlights the importance of morpho-mechanic analysis assessing the disrupting effects of plaque stress.
Male Circumcision Reduces Penile HPV Incidence and Persistence: A Randomized Controlled Trial in Kenya

Background: Male circumcision reduces the risk of human immunodeficiency virus infection in men. We assessed the effect of male circumcision on the incidence and natural history of human papillomavirus (HPV) in a randomized clinical trial in Kisumu, Kenya. Methods: Sexually active, 18- to 24-year-old men provided penile exfoliated cells for HPV DNA testing every 6 months for 2 years. HPV DNA was detected via GP5+/6+ PCR in glans/coronal sulcus and in shaft samples. HPV incidence and persistence were assessed by intent-to-treat analyses. Results: A total of 2,193 men participated (1,096 randomized to circumcision; 1,097 controls). HPV prevalence was 50% at baseline for both groups and dropped to 23.7% at 24 months in the circumcision group, and 41.0% in control group. Incident infection of any HPV type over 24 months was lower among men in the circumcision group than in the control group [HR = 0.61; 95% confidence interval (CI), 0.52–0.72]. Clearance rate of any HPV infection over 24 months was higher in the circumcision group than in the control group (HR = 1.87; 95% CI, 1.49–2.34). Lower HPV point-prevalence, lower HPV incidence, and higher HPV clearance in the circumcision group were observed in glans but not in shaft samples. Conclusion: Male circumcision reduced the risk of HPV acquisition and reinfection, and increased HPV clearance in the glans. Impact: Providing voluntary, safe, and affordable male circumcision should help reduce HPV infections in men, and consequently, HPV-associated disease in their partners.
Population pharmacokinetics of raxibacumab in healthy adult subjects

Raxibacumab is a fully humanized monoclonal antibody that blocks the interaction of Bacillus anthracis toxins, thereby protecting target cells from its effects. Raxibacumab is approved in the USA for the treatment of adults and children with inhalational anthrax in combination with antibiotics, and for prophylaxis of inhalational anthrax. The aim of this investigation was to characterise the population pharmacokinetics and assess the effect of baseline demographic covariates on the disposition of raxibacumab.
Computational investigation of phytochemicals from Withania somnifera (Indian ginseng/ashwagandha) as plausible inhibitors of GluN2B-containing NMDA receptors

Abstract N-Methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Owing to dearth of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies acting like salutary agents is a dynamic expanse of investigation to contest neurodegenerative disease. Withania somnifera (W. somnifera) has been used since antiquity as a nerve tonic and nootropic agents in Ayurveda, an old Indian system of medicine. In the present study, we have explored phytochemicals from Ayurvedic herb W. somnifera as an inhibitor of NMDA receptor-mediated excitotoxicity through allosteric reticence of the GluN1-GluN2B encompassing NMDARs by dint of molecular docking and dynamics studies. Thus, steering and constraining GluN1-GluN2B may be effective in the management of neurodegenerative diseases including Alzheimer’s disease. Out of the curtained phytochemicals, chlorogenic acid revealed significant docking scores of –8.856 and –8.645 kcal/mol and free binding energies of –49.84 and –50.67 kcal/mol in Chain AB and Chain CD of NMDARs, respectively. Chlorogenic acid in AB chain forms four hydrogen bonding with Glu110, Arg115, Leu135 and Asp136 amino acid residues and five hydrogen bond with Glu106, Ala107, Ile133, Ile335and Arg155 amino acid residues of CD chain. To further validate the interaction of top scored molecule chlorogenic acid, molecular dynamics study of 100 ns was carried out. It indicated that the protein–ligand complex was stable throughout the simulation period, and minimal backbone fluctuations have ensued in the system. In silico pharmacokinetic predictions of the screened phytochemicals were within the defined range described for human use. Communicated by Ramaswamy H. Sarma
Deletion of a putative promoter-proximal Tnfsf11 regulatory region in mice does not alter bone mass or Tnfsf11 expression in vivo

The cytokine RANKL is essential for osteoclast formation during physiological and pathological bone resorption. RANKL also contributes to lymphocyte production, development of lymph nodes and mammary glands, as well as other biological activities. Transcriptional control of the Tnfsf11 gene, which encodes RANKL, is complex and involves distant regulatory regions. Nevertheless, cell culture studies suggest that an enhancer region near the transcription start site is involved in the control of Tnfsf11 expression by hormones such as 1,25-(OH)2 vitamin D3 and parathyroid hormone, as well as the sympathetic nervous system. To address the significance of this region in vivo, we deleted the sequence between -510 to -1413 bp, relative to Tnfsf11 exon 1, from mice using CRISPR-based gene editing. MicroCT analysis of the femur and fourth lumbar vertebra of enhancer knockout mice showed no differences in bone mass compared to wild type littermates at 5 weeks and 6 months of age, suggesting no changes in osteoclast formation. RNA extracted from the tibia, fifth lumbar vertebra, thymus, and spleen at 6 months of age also showed no reduction in Tnfsf11 mRNA abundance between these groups. However, maximal stimulation of Tnfsf11 mRNA abundance in cultured stromal cells by PTH was reduced approximately 40% by enhancer deletion, while stimulation by 1,25-(OH)2 vitamin D3 was unaffected. The abundance of B and T lymphocytes in the bone marrow did not differ between genotypes. These results demonstrate that the region between -510 and -1413 does not contribute to Tnfsf11 expression, osteoclast support, or lymphocyte production in mice under normal physiological conditions but may be involved in situations of elevated parathyroid hormone.
Electronic Health Records As a Platform for Audiological Research: Data Validity, Patient Characteristics, and Hearing-Aid Use Persistence Among 731,213 U.S. Veterans

Supplemental Digital Content is available in the text. Objectives: This article presents a summary of audiological, general health, and hearing aid (HA) outcome data in a large sample of U.S. Veterans receiving HAs. The current article also provides the foundation for a series of papers that will explore relationships between a wide range of factors and HA outcomes. Design: The patient sample is all (n = 731,213) patients for whom HAs were ordered between April 2012 and October 2014 through the U.S. Veterans Health Administration Remote Order Entry System. For these patients, Veterans Affairs electronic health records (EHRs) stored in various databases provided data on demographics, received diagnostic and procedure codes (2007 to 2017), audiometry, self-reported outcomes up to 6 months postfitting, and HA battery orders (to 2017). Data cleaning and preparation was carried out and is discussed with reference to insights that provide potential value to other researchers pursuing similar studies. HA battery order data over time was used to derive a measure of long-term HA use persistence. Descriptive statistics were used to characterize the sample, comparative analyses against other data supported basic validity assessment, and bivariate analyses probed novel associations between patient characteristics and HA use persistence at 2 years postfitting. Results: Following extensive cleaning and data preparation, the data show plausible characteristics on diverse metrics and exhibit adequate validity based on comparisons with other published data. Further, rates of HA use persistence are favorable when compared against therapy persistence data for other major chronic conditions. The data also show that the presence of certain comorbid conditions (Parkinson’s disease, diabetes, arthritis, and visual impairment) are associated with significantly lower HA use persistence, as are prior inpatient admissions (especially among new HA recipients), and that increasing levels of multimorbidity, in general, are associated with decreasing HA use persistence. This is all despite the fact that deriving relevant audiological care-process variables from the available records was not straightforward, especially concerning the definition of the date of HA fitting, and the use of battery ordering data to determine long-term HA use persistence. Conclusions: We have shown that utilizing EHRs in audiology has the potential to provide novel insights into clinical practice patterns, audiologic outcomes, and relations between factors pertaining to hearing and to other health conditions in clinical populations, despite the potential pitfalls regarding the lack of control over the variables available and limitations on how the data are entered. We thus conclude that research using EHRs has the potential to be an integral supplement to population-based and epidemiologic research in the field of audiology.
Sociodemographic Characteristics and Physical Activity in Patients with COPD: A 3-Month Cohort Study

Abstract Decreased physical activity (PA) is associated with morbidity and mortality in COPD patients. In this secondary analysis of data from a 12-week longitudinal study, we describe factors associated with PA in COPD. Participants completed the Physical Activity Checklist (PAC) daily for a 7- to 8-day period. PA was measured monthly using the Physical Activity Scale for the Elderly (PASE). At three different time points, daily step count was measured for one week with an Omron HJ-720ITC pedometer. The 35 participants were primarily male (94%) and White (91%), with an average age of 66.5 years and FEV1 44.9% predicted. Common activities reported on the PAC were walking (93%), preparing a meal (89%), and traveling by vehicle (96%). PA measured by both PASE score (p = 0.01) and average daily step count (p = 0.04) decreased during follow-up. In repeated measures multivariable modeling, participants living with others had a higher daily step count (ß = 942 steps, p = 0.01) and better PASE scores (ß = 46.4, p < 0.001). Older age was associated with decreased step count (ß = −77 steps, p < 0.001) whereas White race was associated with lower PASE scores (ß = −55.4, p < 0.001) compared to non-White race. Other demographic factors, quality of life, and medications were not associated with PA. A better understanding of the role of social networks and social support may help develop interventions to improve PA in COPD.
Monitoring muscle mass using ultrasound: a key role in critical care

Purpose of review The loss of muscle mass in critically ill patients contributes to morbidity and mortality, and results in impaired recovery of physical functioning. The number of publications on the topic is increasing. However, there is a lack of consistent methodology and the most optimal methodology remains unclear, hampering its broad use in clinical practice. Recent findings There is a large variety of studies recently published on the use of ultrasound for assessment of muscle mass. A selection of studies has been made, focusing on monitoring of muscle mass (repeated measurements), practical aspects, feasibility and possible nutrition and physical therapy interventions. In this review, 14 new small (n = 19–121) studies are categorized and reviewed as individual studies. Summary The use of ultrasound in clinical practice is feasible for monitoring muscle mass in critically ill patients. Assessment of muscle mass by ultrasound is clinically relevant and adds value for guiding therapeutic interventions, such as nutritional and physical therapy interventions to maintain muscle mass and promote recovery in critically ill patients.
Epidemiology of Carbapenem Resistance Determinants Identified in Meropenem-Nonsusceptible Enterobacterales Collected as Part of a Global Surveillance Program, 2012 to 2017

To estimate the incidence of carbapenem-resistant Enterobacterales (CRE), a global collection of 81,781 surveillance isolates of Enterobacterales collected from patients in 39 countries in five geographic regions from 2012 to 2017 was studied. Overall, 3.3% of isolates were meropenem-nonsusceptible (MIC ≥2 μg/ml), ranging from 1.4% (North America) to 5.3% (Latin America) of isolates by region. Klebsiella pneumoniae accounted for the largest number of meropenem-nonsusceptible isolates (76.7%). ABSTRACT To estimate the incidence of carbapenem-resistant Enterobacterales (CRE), a global collection of 81,781 surveillance isolates of Enterobacterales collected from patients in 39 countries in five geographic regions from 2012 to 2017 was studied. Overall, 3.3% of isolates were meropenem-nonsusceptible (MIC ≥2 μg/ml), ranging from 1.4% (North America) to 5.3% (Latin America) of isolates by region. Klebsiella pneumoniae accounted for the largest number of meropenem-nonsusceptible isolates (76.7%). The majority of meropenem-nonsusceptible Enterobacterales carried KPC-type carbapenemases (47.4%), metallo-β-lactamases (MBLs; 20.6%) or OXA-48-like β-lactamases (19.0%). Forty-three carbapenemase sequence variants (8 KPC-type, 4 GES-type, 7 OXA-48-like, 5 NDM-type, 7 IMP-type, and 12 VIM-type) were detected, with KPC-2, KPC-3, OXA-48, NDM-1, IMP-4, and VIM-1 identified as the most common variants of each carbapenemase type. The resistance mechanisms responsible for meropenem-nonsusceptibility varied by region. A total of 67.3% of all carbapenemase-positive isolates identified carried at least one additional plasmid-mediated or intrinsic chromosomally encoded extended-spectrum β-lactamase, AmpC β-lactamase, or carbapenemase. The overall percentage of meropenem-nonsusceptible Enterobacterales increased from 2.7% in 2012 to 2014 to 3.8% in 2015 to 2017. This increase could be attributed to the increasing proportion of carbapenemase-positive isolates that was observed, most notably among isolates carrying NDM-type MBLs in Asia/South Pacific, Europe, and Latin America; OXA-48-like carbapenemases in Europe, Middle East/Africa, and Asia/South Pacific; VIM-type MBLs in Europe; and KPC-type carbapenemases in Latin America. Ongoing CRE surveillance combined with a global antimicrobial stewardship strategy, sensitive clinical laboratory detection methods, and adherence to infection control practices will be needed to interrupt the spread of CRE.
Brief Self-Report Measure of Agitation: A Psychometric Investigation in a German Sample

Abstract To perform repeated measurements in clinical practice without putting unnecessary strain on patients, short instruments are needed. The Brief Self-Report Measure of Agitation (BAM) is a short measure assessing agitation, which has been associated with suicidal ideation and behavior. However, its reliability and validity have not been examined in an independent sample. A non-clinical sample of N = 429 participants aged between 18-81 (M = 27.36, SD = 9.67; 82.3% female) was surveyed online. A confirmatory factor analysis was conducted and reliability was investigated. The validity of the BAM was examined by calculating correlations and an ANOVA for differences in BAM scores between subgroups. BAM items significantly loaded onto one factor (factor loadings: ≥ .62) and the measure was found to have good reliability (Cronbach’s α = .83) and convergent/discriminant validity. Participants with recent suicidal ideation and those with recent suicidal ideation and lifetime suicide attempts had significantly higher BAM scores than participants without suicidal ideation/suicide attempt. Results indicate good validity and reliability for the measurement of agitation with the German version of the BAM in the present sample. Thereby, we introduce a brief instrument in German for repeated assessment of agitation in research and clinical practice.
Early Experience with Comaneci, a Newly FDA-Approved Controllable Assist Device for Wide-Necked Intracranial Aneurysm Coiling

Background: Comaneci (Rapid Medical) is a compliant, adjustable mesh that provides temporary scaffolding during coiling of wide-necked intracranial aneurysms (WNAs) that preserves antegrade flow. We report our early multi-institutional experience with the Comaneci device in the USA. Method: We reviewed all patients with WNAs that were treated using the Comaneci device for coil remodeling of ruptured and unruptured aneurysms at 4 institutions between July 2019 and May 2020. Clinical characteristics, angiographic variables, and endovascular results were assessed. Results: A total of 26 patients were included (18 women). The mean age was 62.7 years (range 44–81). Fifteen patients presented with ruptured aneurysms and 11 with unruptured aneurysms. The mean aneurysm neck width was 3.91 mm (range 1.9–6.5) with a mean dome-to-neck ratio of 1.57 (range 0.59–3.39). The mean maximum width was 5.80 mm (range 3.0–9.9) and the mean maximum height was 5.61 mm (range 2.0–11.8). Successful aneurysm occlusion was achieved in 25 of 26 patients. Complete occlusion was achieved in 16 patients, near-complete occlusion was observed in 9 patients, and 1 patient demonstrated residual filling. The mean time of device exposure was 24 min (range 8–76). No vasospasm was observed at the device location. Clot formation on the device was noted in 2 separate cases, but there were no clinical sequelae. There was 1 intraprocedural complication in a case that involved the simultaneous use of 2 Comaneci devices. Conclusions: Our initial experience shows that the Comaneci device is a promising and reliable tool that can safely support coil remodeling of WNAs.