Miracle-dz/UniFAR-FTUs huggingface dataset:
Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A: a population pharmacokinetic model

During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. However, maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and information on bleeding from patients’ diaries. Each patient’s time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and number of bleeds (from the patients’ diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (n=187 patients; 815 patient-years’ exposure), factor VIII activity was predicted to be >1% for 85.64% of the time. The annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. When making decisions regarding target trough levels and the prophylactic regimen, the patients’ age, joint disease activity, and other bleeding risk determinants should be taken into consideration. Clinical trial registration numbers: NCT00840086; NCT01138501; NCT00984126
Stress-Induced Morphological, Cellular and Molecular Changes in the Brain—Lessons Learned from the Chronic Mild Stress Model of Depression

Major depressive disorder (MDD) is a severe illness imposing an increasing social and economic burden worldwide. Numerous rodent models have been developed to investigate the pathophysiology of MDD. One of the best characterized and most widely used models is the chronic mild stress (CMS) model which was developed more than 30 years ago by Paul Willner. More than 2000 published studies used this model, mainly to assess novel compounds with potential antidepressant efficacy. Most of these studies examined the behavioral consequences of stress and concomitant drug intervention. Much fewer studies focused on the CMS-induced neurobiological changes. However, the stress-induced cellular and molecular changes are important as they may serve as potential translational biomarkers and increase our understanding of the pathophysiology of MDD. Here, we summarize current knowledge on the structural and molecular alterations in the brain that have been described using the CMS model. We discuss the latest neuroimaging and postmortem histopathological data as well as molecular changes including recent findings on microRNA levels. Different chronic stress paradigms occasionally deliver dissimilar findings, but the available experimental data provide convincing evidence that the CMS model has a high translational value. Future studies examining the neurobiological changes in the CMS model in combination with clinically effective antidepressant drug intervention will likely deliver further valuable information on the pathophysiology of MDD.
Aerobic Exercise Training Inhibits Neointimal Formation via Reduction of PCSK9 and LOX-1 in Atherosclerosis

The purpose of this study was to investigate whether aerobic exercise training inhibits atherosclerosis via the reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) expression in balloon-induced common carotid arteries of a high-fat-diet rats. Male SD (Sprague Dawley) rats fed an eight-weeks high-fat diet were randomly divided into three groups; these were the sham-operated control (SC), the balloon-induced control (BIC) and the balloon-induced exercise (BIE). The aerobic exercise training groups were performed on a treadmill. The major findings were as follows: first, body weight gain was significantly decreased by aerobic exercise training compared to the BIC without change of energy intake. Second, neointimal formation was significantly inhibited by aerobic exercise training in the balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. Third, low-density lipoprotein (LDL) receptor (LDLr) expression was significantly increased by aerobic exercise training in the livers of the high-fat diet group compared to the BIC, but not the proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Fourth, aerobic exercise training significantly decreased the expression of PCSK9, the lectin-like oxidized LDL receptor-1 (LOX-1), and vascular cell adhesion molecule-1 (VCAM-1) in balloon-induced common carotid arteries of high-fat-diet rats compared to the BIC. In conclusion, our results suggest that aerobic exercise training increases LDLr in the liver and inhibits neointimal formation via the reduction of PCSK9 and LOX-1 in balloon-induced common carotid arteries of high-fat-diet-induced rats.
Acute and episodic vestibular syndromes caused by ischemic stroke: predilection sites and risk factors

Objective This study was performed to investigate the predilection sites of acute vestibular syndrome (AVS) and episodic vestibular syndrome (EVS) caused by acute infarcts. Methods This retrospective cohort study was performed at a stroke center in a tertiary teaching hospital. We diagnosed patients with AVS/EVS caused by acute ischemic stroke using diffusion-weighted imaging (DWI) and magnetic resonance angiography. Results Among all patients with AVS/EVS, 68 had DWI-positive ischemic events and 113 had DWI-negative ischemic events. Of the 68 patients with positive DWI findings, 42.6% had acute infarcts in the anterior circulation and 41.2% had acute infarcts in the posterior circulation. The main stroke predilection sites were the insular cortex (22.1%) and posterior thalamus (11.8%). Large vessel stenosis/occlusion (odds ratio, 0.12; 95% confidence interval, 0.04–0.36) and focal neurological symptoms/signs (odds ratio, 0.27; 95% confidence interval, 0.10–0.72) were significantly associated with the risk of AVS/EVS in patients with acute ischemic stroke. Conclusions The main predilection sites of AVS/EVS caused by ischemic stroke are the insular cortex and posterior thalamus. The risk of AVS/EVS is associated with large vessel stenosis and focal symptoms.
Perceived Knowledge of HIV-Negative Status Increases Condom Use Among Female Sex Workers in Zambian Transit Towns

Knowledge of HIV status is a necessary pre-condition for most HIV interventions, including treatment as well as biomedical and behavioral prevention interventions. We used data from a female sex worker (FSW) cohort in three Zambian transit towns to understand the effect that knowledge of HIV status has on FSWs' HIV risk-related sexual behaviors with clients. The cohort was formed from an HIV self-testing trial that followed participants for 4 months. Participants completed three rounds of data collection at baseline, 1 month, and 4 months where they reported their perceived knowledge of HIV status, number of clients on an average working night, and consistent condom use with clients. We measured the effect of knowledge of HIV status on participants' sexual behaviors by using linear regression models with individual fixed effects. The majority of the 965 participants tested for HIV at least once during the observation period (96%) and changed their knowledge of HIV status (79%). Knowledge of HIV status did not affect participants' number of clients, but it did affect their consistency of condom use. Compared with unknown HIV status, knowledge of HIV-negative status significantly increased participants' consistent condom use by 8.1% points [95% confidence interval (CI): 2.7–13.4, p = 0.003] and knowledge of HIV-positive status increased participants' consistent condom use by 6.1% points (95% CI: −0.1 to 12.9, p = 0.08); however, this latter effect was not statistically significant. FSWs in Zambia engaged in safer sex with clients when they learned their HIV status. The expansion of HIV testing programs may serve as a behavioral HIV prevention measure among FSWs.
Development of a Rapid Mass Spectrometric Determination of AMP and Cyclic AMP for PDE3 Activity Study: Application and Computational Analysis for Evaluating the Effect of a Novel 2-oxo-1,2-dihydropyridine-3-carbonitrile Derivative as PDE-3 Inhibitor

A simple, quick, easy and cheap tandem mass spectrometry (MS/MS) method for the determination of adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP) has been newly developed. This novel MS/MS method was applied for the evaluation of the inhibitory effect of a novel 2-oxo-1,2-dihydropyridine-3-carbonitrile derivative, also named DF492, on PDE3 enzyme activity in comparison to its parent drug milrinone. Molecule DF492, with an IC50 of 409.5 nM, showed an inhibition of PDE3 greater than milrinone (IC50 = 703.1 nM). To explain the inhibitory potential of DF492, molecular docking studies toward the human PDE3A were carried out with the aim of predicting the binding mode of DF492. The presence of different bulkier decorating fragments in DF492 was pursued to shift affinity of this novel molecule toward PDE3A compared to milrinone in accordance with both the theoretical and experimental results. The described mass spectrometric approach could have a wider potential use in kinetic and biomedical studies and could be applied for the determination of other phosphodiesterase inhibitor molecules.
Facilitators and Barriers to Chronic Disease Self-Management and Mobile Health Interventions for People Living With Diabetes and Hypertension in Cambodia: Qualitative Study

Background In many low- and middle-income countries (LMICs), heart disease and stroke are the leading causes of death as cardiovascular risk factors such as diabetes and hypertension rapidly increase. The Cambodian nongovernmental organization, MoPoTsyo, trains local residents with diabetes to be peer educators (PEs) to deliver chronic disease self-management training and medications to 14,000 people with hypertension and/or diabetes in Cambodia. We collaborated with MoPoTsyo to develop a mobile-based messaging intervention (mobile health; mHealth) to link MoPoTsyo’s database, PEs, pharmacies, clinics, and people living with diabetes and/or hypertension to improve adherence to evidence-based treatment guidelines. Objective This study aimed to understand the facilitators and barriers to chronic disease management and the acceptability, appropriateness, and feasibility of mHealth to support chronic disease management and strengthen community-clinical linkages to existing services. Methods We conducted an exploratory qualitative study using semistructured interviews and focus groups with PEs and people living with diabetes and/or hypertension. Interviews were recorded and conducted in Khmer script, transcribed and translated into the English language, and uploaded into Atlas.ti for analysis. We used a thematic analysis to identify key facilitators and barriers to disease management and opportunities for mHealth content and format. The information-motivation-behavioral model was used to guide data collection, analysis, and message development. Results We conducted six focus groups (N=59) and 11 interviews in one urban municipality and five rural operating districts from three provinces in October 2016. PE network participants desired mHealth to address barriers to chronic disease management through reminders about medications, laboratory tests and doctor’s consultations, education on how to incorporate self-management into their daily lives, and support for obstacles to disease management. Participants preferred mobile-based voice messages to arrive at dinnertime for improved phone access and family support. They desired voice messages over texts to communicate trust and increase accessibility for persons with limited literacy, vision, and smartphone access. PEs shared similar views and perceived mHealth as acceptable and feasible for supporting their work. We developed 34 educational, supportive, and reminder mHealth messages based on these findings. Conclusions These mHealth messages are currently being tested in a cluster randomized controlled trial (#1R21TW010160) to improve diabetes and hypertension control in Cambodia. This study has implications for practice and policies in Cambodia and other LMICs and low-resource US settings that are working to engage PEs and build community-clinical linkages to facilitate chronic disease management.
Epigenetic Clock and Leukocyte Telomere Length are Associated with Vitamin D Status, but not with Functional Assessments and Frailty in the Berlin Aging Study II.

DNA methylation (DNAm) age acceleration, a parameter derived via the epigenetic clock, has recently been suggested as a biomarker of aging. We hypothesized that accelerated biological aging, measured by both this new and the established biomarker of aging, relative leukocyte telomere length (rLTL), are associated with vitamin D deficiency. Moreover, we tested for an association between rLTL/DNAm age acceleration and different clinical assessments for functional capacity, including the Fried frailty score. Cross-sectional data of 1,649 participants of the Berlin Aging Study II was available (∼50% female, age: 22-37 and 60-84 years). A seven cytosine-phosphate-guanine clock was estimated to calculate the DNAm age acceleration. rLTL was measured by quantitative real-time PCR. 25-hydroxyvitamin D (25(OH)D) serum levels <25 nmol/L was defined as vitamin D deficiency and <50 nmol/L as vitamin Dinsufficiency. Vitamin D-sufficient individuals had a 1.4 years lower mean DNAm age acceleration (p<0.05, ANOVA) and a 0.11 longer rLTL (p<0.001, ANOVA) than vitamin D-deficient participants. Likewise, vitamin D sufficient participants had lower DNAm age acceleration (β=1.060, p=0.001) and longer rLTL (β=-0.070; p<0.001) than vitamin D non-sufficient subjects in covariate adjusted analysis. Neither DNAm age acceleration nor rLTL were significantly associated with the Fried frailty score or the functional assessments. Only the clock drawing test was associated with DNAm age acceleration (subgroup of older men: β=1.898, p=0.002). Whether the analyzed biomarkers of aging can be used to predict an individual's functional capacity or will be associated with frailty in the advanced course of aging, will be clarified by future longitudinal analyses.
Quantum-Chemical Design of Molecular Structures of Tetra-, Penta- and Hexanuclear Metal Clusters Containing Aluminum and 3d-Element Atoms

Various data on the structural and thermodynamic characteristics of polynuclear metal clusters containing atoms of aluminum and various d-elements with the general formula AlnMm where (n + m) is 4, 5, or 6, and which can be precursors for the formation of nanoparticles of elemental metals or intermetallic compounds, have been systematized and discussed. It has been noted that each of these metal clusters in principle is able to exist in very diverse structural isomers, differing significantly among themselves in terms of the total energy and spin multiplicity of the ground state, the number of which is determined by both the specific values of n and m, and the nature of d-elements in their compositions. The presence of very complex dynamics with respect to the changes of the individual thermodynamic characteristics of the metal clusters under consideration as well as the thermodynamic parameters of the reactions of their formation, depending on the nature of the d-element, were also ascertained. In the main, the given review is devoted to the authors’ works published over the last 10 years. Bibliography – 96 references.
COVID-19 transforms health care through telemedicine: Evidence from the field

Abstract This study provides data on the feasibility and impact of video-enabled telemedicine use among patients and providers and its impact on urgent and nonurgent healthcare delivery from one large health system (NYU Langone Health) at the epicenter of the coronavirus disease 2019 (COVID-19) outbreak in the United States. Between March 2nd and April 14th 2020, telemedicine visits increased from 102.4 daily to 801.6 daily. (683% increase) in urgent care after the system-wide expansion of virtual urgent care staff in response to COVID-19. Of all virtual visits post expansion, 56.2% and 17.6% urgent and nonurgent visits, respectively, were COVID-19–related. Telemedicine usage was highest by patients 20 to 44 years of age, particularly for urgent care. The COVID-19 pandemic has driven rapid expansion of telemedicine use for urgent care and nonurgent care visits beyond baseline periods. This reflects an important change in telemedicine that other institutions facing the COVID-19 pandemic should anticipate.
A distinct role for recombination repair factors in an early cellular response to transcription–replication conflicts

Abstract Transcription–replication (T–R) conflicts are profound threats to genome integrity. However, whilst much is known about the existence of T–R conflicts, our understanding of the genetic and temporal nature of how cells respond to them is poorly established. Here, we address this by characterizing the early cellular response to transient T–R conflicts (TRe). This response specifically requires the DNA recombination repair proteins BLM and BRCA2 as well as a non-canonical monoubiquitylation-independent function of FANCD2. A hallmark of the TRe response is the rapid co-localization of these three DNA repair factors at sites of T–R collisions. We find that the TRe response relies on basal activity of the ATR kinase, yet it does not lead to hyperactivation of this key checkpoint protein. Furthermore, specific abrogation of the TRe response leads to DNA damage in mitosis, and promotes chromosome instability and cell death. Collectively our findings identify a new role for these well-established tumor suppressor proteins at an early stage of the cellular response to conflicts between DNA transcription and replication.
Finite-Time Tracking Control for Nonlinear Systems via Adaptive Neural Output Feedback and Command Filtered Backstepping

This article is concerned with the tracking control problem for uncertain high-order nonlinear systems in the presence of input saturation. A finite-time control strategy combined with neural state observer and command filtered backstepping is proposed. The neural network models the unknown nonlinear dynamics, the finite-time command filter (FTCF) guarantees the approximation of its output to the derivative of virtual control signal in finite time at the backstepping procedure, and the fraction power-based error compensation system compensates for the filtering errors between FTCF and virtual signal. In addition, the input saturation problem is dealt with by introducing the auxiliary system. Overall, it is shown that the designed controller drives the output tracking error to the desired neighborhood of the origin at a finite time and all the signals in the closed-loop system are bounded at a finite time. Two simulation examples are given to demonstrate the control effectiveness.
Molecular Mechanisms, Diagnostic Aspects and Therapeutic Opportunities of Micro Ribonucleic Acids in Atrial Fibrillation

Micro ribonucleic acids (miRNAs) are short non-coding RNA molecules responsible for regulation of gene expression. They are involved in many pathophysiological processes of a wide spectrum of diseases. Recent studies showed their involvement in atrial fibrillation. They seem to become potential screening biomarkers for atrial fibrillation and even treatment targets for this arrhythmia. The aim of this review article was to summarize the latest knowledge about miRNA and their molecular relation to the pathophysiology, diagnosis and treatment of atrial fibrillation.
Taming the flagellar motor of pseudomonads with a nucleotide messenger.

Pseudomonads rely on the flagellar motor to rotate a polar flagellum for swimming and swarming, and to sense surfaces for initiating the motile-to-sessile transition to adopt a surface-dwelling lifestyle. Deciphering the function and regulation of the flagellar motor is of paramount importance for understanding the behaviours of environmental and pathogenic pseudomonads. Recent studies disclosed the preeminent role played by the messenger c-di-GMP in controlling the real-time performance of the flagellar motor in pseudomonads. The studies revealed that c-di-GMP controls the dynamic exchange of flagellar stator units to regulate motor torque/speed and modulates the frequency of flagellar motor switching via the chemosensory signalling pathways. Apart from being a rotary motor, the flagellar motor is emerging as a mechanosensor that transduces surface-induced mechanical signals into an increase of cellular c-di-GMP concentration to initiate the cellular programs required for long-term colonization. Collectively, the studies generate long-awaited mechanistic insights into how c-di-GMP regulates bacterial motility and the motile-to-sessile transition. The new findings also raise the fundamental questions of how cellular c-di-GMP concentrations are dynamically coupled to flagellar output and the proton-motive force, and how c-di-GMP signalling is coordinated spatiotemporally to fine-tune flagellar response and the behaviour of pseudomonads in solutions and on surfaces. This article is protected by copyright. All rights reserved.
The Evolving AML Genomic Landscape: Therapeutic Implications.

Improved understanding of the genomic and molecular landscape of acute myeloid leukemia (AML) has resulted in significant evolution of our understanding of AML biology and allows refined prognostication for those receiving standard combination chemotherapy induction. This dramatic increase in knowledge preceded, and was somewhat responsible for, at least some of eight new FDA drug approvals for AML. This review discusses the impact of genomics on clinical care of AML patients and highlights newly approved FDA drugs. Despite these recent clinical advances, however, the outcome for most patients diagnosed with AML remains dire. Thus, we describe here some of the challenges identified with treating AML including off-target toxicity, drug transporters, clonal heterogeneity, and adaptive resistance, and some of the most promising opportunities for improved therapy.