Miracle-dz/UniFAR-FTUs huggingface dataset:
Usefulness of methylthioadenosine phosphorylase and BRCA‐associated protein 1 immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens

The separation of benign from malignant mesothelial proliferations on effusion cytology can be difficult. Loss of methylthioadenosine phosphorylase (MTAP) by immunohistochemistry is an established marker of malignancy in mesothelial proliferations, but to the authors' knowledge largely has been applied only to biopsies. The current study was conducted to determine the usefulness of MTAP immunohistochemistry in the diagnosis of malignant mesothelioma in effusion cytology specimens.
Effects of Mg Content on Hydrogen Content and Melt Quality of Al-Mg Alloys

In Al-Mg alloys with Mg content 0 ≤ XMg ≤ 6 wt. %, the effects of XMg on dissolved hydrogen content ([H]) and melt quality were investigated. [H] was measured using the Closed-Loop Recirculation method, and the melt quality was quantified using the density index (DI), bifilm index (BI), and porosity measurement. [H] in the molten alloys increased with increasing XMg and melt temperature TMelt; these trends agree with theoretical calculations for hydrogen solubility. The tendency of melt quality vs XMg was similar in DI, BI, and porosity measurements, and the poorest melt quality was observed in the Al-4Mg alloy that had XMg = 4 wt. %, whereas the highest [H] was obtained in the Al-6Mg alloy melt that had XMg = 6 wt. % Mg. During thermogravimetric/differential thermal analysis, rapid oxidation occurred in the Al-4Mg alloy melt during the holding time between 45 and 60 min at 800 °C. , i.e., just before the molten metal was cast. The inferior melt quality of Al-4Mg alloy may have been caused by high-temperature oxidation.
Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study

Background Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk. Methods and findings We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m2 BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m2 BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12–1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m2) without a family history of diabetes, similar to that in obese individuals (BMI ≥ 30 kg/m2) with a family history (1.21-fold reduction, 95% CI 1.13–1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual’s entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life. Conclusions In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk.
Authentic leadership in healthcare organizations: A study of 14 chief executive officers and 70 direct reports

There is limited research on authentic leadership in senior leaders of healthcare organizations. The purpose of this study was to investigate authentic leadership from the perspectives of 14 healthcare Chief Executive Officers (CEOs) and 70 senior-level direct reports using the validated Authentic Leadership Questionnaire (ALQ) and one-on-one interviews. CEOs also completed a 20-hour leadership curriculum focusing on authentic leadership. Although CEOs rated themselves higher than their direct reports on the total ALQ, it only approached significance (P = .060). Ratings on the four component parts of the ALQ were also higher, but only one was significant (P = .025) with a trend toward significance on another (P = .61). The CEOs’ scores were slightly higher after their self-directed study but only one component was significant (P = .040). Interviews with the CEOs and direct reports underscore how healthcare leadership and authentic leadership specifically is viewed depending on organizational roles.
Peer Mentorship via Mobile Phones for Newly Diagnosed HIV-Positive Youths in Clinic Care in Khayelitsha, South Africa: Mixed Methods Study

Background Youths in South Africa are poor utilizers of HIV health services. Medecins Sans Frontieres has been piloting youth-adapted services at a youth clinic in Khayelitsha, including a peer virtual mentorship program over mobile phones, piloted from March 2015 to May 2016. Objective The objective of this study was to evaluate the effect of the peer mentorship program on youth engagement with HIV services and explore the acceptability of the program to both mentors and mentees. Methods Antiretroviral initiation, retention in care (RIC), and viral load suppression were compared between youths engaged in the virtual mentorship program and two matched controls. In-depth interviews were also conducted for 5 mentors and 5 mentees to explore acceptability and impact of the program. Results A total of 40 youths were recruited into the virtual mentorship program over the study period. Of these, data were obtained for 35 and 2 matched controls were randomly sampled for each. There was no difference in baseline demographics (eg, age, gender, and CD4 count). Mentees had increased antiretroviral initiation (28/35, 80% vs 30/70, 42% in matched controls) and viral load completion (28/35, 80% vs 32/70, 45%); however, no differences were found in viral load suppression or RIC at 6 or 12 months. Mentors reported being motivated to participate in the program because of previous personal struggles with HIV and a desire to help their peers. Mentees reported fears of disclosure and lack of acceptance of their status as barrier to accessing services, but they felt free to talk to their mentors, valued the mentorship program, and indicated a preference for phone calls. Conclusions Peer mentorship in youths is acceptable to both mentors and mentees and appears to increase linkage to care and viral load completion rates.
Mitochondrial DNA Haplogroups and Frailty in Adults Living with HIV.

OBJECTIVE Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine if haplogroup is associated with frailty and its components among older PWH. METHODS A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, sex, education, smoking, hepatitis C, and prior use of didanosine/stavudine. RESULTS Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (SD 7.5) years and median nadir CD4 count 212 (IQR 72, 324) cells/L; 6% were frail, 7% had slow gait and 21% weak grip. H haplogroup participants were more likely to be frail/pre-frail (p=0.064), have slow gait (p=0.09), or weak grip (p=0.017) compared to non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail vs non-frail (OR 4.0 [95% CI 1.0, 15.4]) and having weak grip (OR 2.1 [1.1, 4.1]), but not slow gait (OR 1.6 [0.5, 5.0]) compared to non-H. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. CONCLUSIONS Among ART-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.
Performance of Afinion HbA1c measurements in general practice as judged by external quality assurance data

Abstract Background It has been debated whether point-of care (POC) glycated hemoglobin (HbA1c) measurements methods can be used for diagnosing persons with diabetes mellitus. The aim of this study was to evaluate the analytical performance of the POC Afinion HbA1c system in the hands of the users, and to investigate which predictors that were associated with good participant performance. Methods External quality assurance (EQA) data from seven surveys in 2017–2018 with a total of 5809 Afinion participants from a POC total quality system in Norway were included in this study (response rate 90%). The control materials were freshly drawn pooled EDTA whole blood. Each participant was evaluated against the analytical performance specification of ±6% from the target value, while the Afinion system was evaluated against the pooled within-laboratory CV <2%, the between-laboratory CV <3.5%, and bias <0.3%HbA1c. Logistic regression analyses were used to investigate which factors were associated with good participant performance. Results The participant pass rates for each survey varied from 98.2% to 99.7%. The pooled within-laboratory CV varied from 1.3% to 1.5%, the between-laboratory CV varied from 1.5% to 2.1%, and bias varied between −0.17 and −0.01 %HbA1c in all surveys. Reagent lot was the only independent factor to predict good participant performance. Conclusions Afinion HbA1c fulfilled the analytical performance specifications and is robust in the hands of the users. It can therefore be used both in diagnosing and monitoring persons with diabetes mellitus, given that the instrument is monitored by an EQA system.
LRRK2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK‐mediated ubiquitination pathway

Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Impaired mitochondrial function is suspected to play a major role in PD. Nonetheless, the underlying mechanism by which impaired LRRK2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK2 in endoplasmic reticulum (ER)–mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK2 regulated the activities of E3 ubiquitin ligases MARCH5, MULAN, and Parkin via kinase‐dependent protein–protein interactions. Kinase‐active LRRK2(G2019S) dissociated from these ligases, leading to their PERK‐mediated phosphorylation and activation, thereby increasing ubiquitin‐mediated degradation of ER–mitochondrial tethering proteins. By contrast, kinase‐dead LRRK2(D1994A)‐bound ligases blocked PERK‐mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER–mitochondrial tethering proteins. Thus, the role of LRRK2 in the ER–mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD.
Investigation into the properties of evaporated Gd-Co films

INVESTIGATION INTO THE PROPERTIES OF EVAPORATED GD-CO FILMS Robert Zwingman Dual source evaporated gadolinium-cobalt thin films have been prepared with compositions between 70 and 90 atomic percent cobalt. The magnetization and coercivity versus composition characteristics of these films indicate that the cobalt magnetic moments are antiferromagnetically coupled to the gadolinium moments. The anisotropy mechanisms are found to be shape anisotropy due to columar growths and anisotropy due to directional ordering. A prefered anisotropy direction can be formed in some of these films during fabrication or by annealing. The magnetization structure in some of these films is of a radial nature. A discussion of radially magnetized films 1s presented. The films are found to be amorphous and non-magnetostr1cti Oxidation effects are also studied.
Associations of Vestibular Tests With Penn Acoustic Neuroma Quality of Life Scores After Resection of Vestibular Schwannoma.

OBJECTIVE Determine associations between preoperative caloric testing and video head impulse testing (vHIT) with baseline and postoperative Penn Acoustic Neuroma Quality of Life (PANQOL) scores following resection of vestibular schwannoma (VS). STUDY DESIGN Retrospective case series. SETTING Two tertiary referral hospitals. PATIENTS Adult patients with unilateral VS, preoperative calorics, vHIT, and dizziness handicap inventory (DHI) score. INTERVENTIONS Surgical resection of VS and postoperative surveys. MAIN OUTCOME MEASURES PANQOL scores. RESULTS Forty-three patients were included (58.1% women) with a median age of 54 years (range, 28-82). Mean tumor size was 14.8 mm (σ=8.6), and 28 (65.1%) were right-sided. Average preoperative vHIT gain was 0.7 (σ = 0.3). Covert and overt saccades were present in 8 (25%) and 14 (42.4%) patients, respectively. Average preoperative unilateral weakness was 47% (σ = 33.2). Translabyrinthine approach was performed in 26 (60.5%) patients. No significant difference of PANQOL scores was noted at baseline or over time between patients with normal (>0.8) or abnormal (<0.8) gain. Patients with more unilateral weakness (>50%) had significantly higher baseline PANQOL scores compared with those with < 25% or 25 to 50% (p = 0.02), but had significant improvement in scores over time (p = 0.01). Higher preoperative DHI preoperatively was significantly associated with worse PANQOL scores at all timepoints (β=0.57, p = 0.0064). No differences in PANQOL scores amongst surgical approaches were observed. CONCLUSION Preoperative vestibular testing with vHIT, calorics, DHI, and baseline PANQOL surveys may allow for patient counseling regarding postoperative quality of life over time.
Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

Duchenne muscular dystrophy (DMD) is a severe childhood muscle disease primarily caused by the lack of functional dystrophin at the muscle fiber membranes. Multiple therapeutic approaches are currently in (pre)clinical development, aimed at restoring expression of (truncated) dystrophin. Key questions in this phase relate to route of drug administration, dose regimen, and levels of dystrophin required to improve muscle function. A series of studies applying antisense oligonucleotides (AONs) in the mdx mouse model for DMD has been reported over the last two decades, claiming a variable range of exon skipping and increased dystrophin levels correlated to some functional improvement. The aim of this study was to compare the efficacy of subcutaneous (SC) versus intravenous (IV) dosing routes of an mdx-specific AON at both the molecular and functional level, using state-of-the-art quantitative technologies, including digital droplet polymerase chain reaction, capillary Western immunoassay, magnetic resonance imaging, and automated kinematic analysis. The majority of all readouts we quantified, both molecular and functional, showed that IV dosing of the AON had a more pronounced beneficial effect than SC dosing in mdx mice. Last, but not least, the more quantitative molecular and functional data obtained in this study suggest that low levels of dystrophin protein of at least 2.5% of wild type may already have a beneficial effect on muscle leakiness and may improve motor performance of mdx mice.
Integrated lipidomic and transcriptomic analyses identify altered nerve triglycerides in mouse models of prediabetes and type 2 diabetes

ABSTRACT Peripheral neuropathy (PN) is a complication of prediabetes and type 2 diabetes (T2D). Increasing evidence suggests that factors besides hyperglycaemia contribute to PN development, including dyslipidaemia. The objective of this study was to determine differential lipid classes and altered gene expression profiles in prediabetes and T2D mouse models in order to identify the dysregulated pathways in PN. Here, we used high-fat diet (HFD)-induced prediabetes and HFD/streptozotocin (STZ)-induced T2D mouse models that develop PN. These models were compared to HFD and HFD-STZ mice that were subjected to dietary reversal. Both untargeted and targeted lipidomic profiling, and gene expression profiling were performed on sciatic nerves. Lipidomic and transcriptomic profiles were then integrated using complex correlation analyses, and biological meaning was inferred from known lipid-gene interactions in the literature. We found an increase in triglycerides (TGs) containing saturated fatty acids. In parallel, transcriptomic analysis confirmed the dysregulation of lipid pathways. Integration of lipidomic and transcriptomic analyses identified an increase in diacylglycerol acyltransferase 2 (DGAT2), the enzyme required for the last and committed step in TG synthesis. Increased DGAT2 expression was present not only in the murine models but also in sural nerve biopsies from hyperlipidaemic diabetic patients with PN. Collectively, these findings support the hypothesis that abnormal nerve-lipid signalling is an important factor in peripheral nerve dysfunction in both prediabetes and T2D. This article has an associated First Person interview with the joint first authors of the paper. Summary: Mouse models of prediabetes and type 2 diabetes that develop peripheral neuropathy display increased levels of nerve triglycerides, which return to normal upon dietary reversal, suggesting that altered lipids are involved in disease.
Vitamin E sequestration by liver fat in humans.

BACKGROUND We hypothesized that obesity-associated hepato-steatosis served as a pathophysiologic chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were utilized to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepato-steatosis vs healthy controls.METHODS Custom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepato-steatosis under IND guidelines. Serial samples obtained over 72 hours were analyzed by LC/MS. Fluorescent-labelled α-tocopherol was custom-synthesized for cell studies.RESULTS In healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 6-8 hours. d3- and d6-α-Tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1h, indicating a key role of liver in rapid uptake and re-release into the circulation. Compared to healthy subjects, subjects with hepato-steatosis had similar d6-α-tocopherol entry rates into liver, but reduced initial release rates (p<0.001). Similarly, pharmacokinetics parameters of AUC and Maximum Concentration (Cmax) were reduced (AUC0-8 ,p<0.01;Cmax p<0.02) in hepato-steatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reduced kinetics and pharmacokinetics parameters (AUC and Cmax) in hepato-steatosis subjects who received 2 mg were mirrored by similar reductions in healthy subjects when comparing 5 and 2 mg doses. In vitro, fluorescent-labelled α-tocopherol localized specifically to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONS The unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepato-steatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepato-steatosis may similarly alter hepatic physiology of other fat-soluble vitamins.
Tulathromycin treatment does not affect bacterial dissemination or clearance of Brucella melitensis 16M following experimental infection of goats

Brucellosis in sheep and goats, a zoonotic disease primarily associated with Brucella melitensis infections, causes significant economic losses and public health concerns worldwide. Although control measures are effective, economic limitations and nomadic lifestyles may limit vaccination coverage, and test and removal policies may not be feasible. In this study, we evaluated the effects of therapy with a long acting antimicrobial tulathromycin on the pathogenesis of brucellosis. Thirty-five goats were randomly assigned for experimental infection with B. melitensis strain 16M while open or during mid-gestation. Approximately half of the animals in each group were then treated with tulathromycin and subsequently assessed for the development of humoral responses to infection, clinical presentation, and bacterial dissemination and colonization. All animals, regardless of treatment group were successfully challenged with B. melitensis 16M demonstrated by bacterial recovery from conjunctival swabs and development of positive antibody titers. In goats infected while open, no animals aborted and Brucella was recovered from only one animal in tulathromycin-treated and one animal from the untreated group. Tulathromycin treatment of pregnant goats did not prevent abortion nor did it reduce bacterial dissemination, colonization, or shedding. Our data suggests that treatment of goats in mid-gestation with tulathromycin at the labeled dose does not influence disease pathogenesis or tissue colonization after experimental B. melitensis challenge.