Miracle-dz/UniFAR-FTUs huggingface dataset:
Time spent walking and disability‐free survival in older Japanese: The Ohsaki Cohort 2006 Study

The extent to which long disability‐free survival (DFS) time can be extended according to the amount of time spent walking has not been investigated. The aim of this study was to examine the association between time spent walking per day and DFS time in older adults. We conducted a cohort study of 14 342 disability‐free individuals (aged ≥ 65 years) living in Ohsaki City, Japan. The amount of time spent walking per day (<0.5 h, 0.5–1 h, ≥1 h) by each individual in 2006 was assessed by a self‐reported questionnaire. Data on 11‐year incident functional disability were retrieved from the public Long‐Term Care Insurance database. After estimating the multivariable‐adjusted hazard ratios (HRs) of the composite outcome (incident functional disability or death), the multivariable‐adjusted 50th percentile differences (50th PDs; difference in the period until the first 50% of the composite outcome occurred) were estimated according to time spent walking. Among 114 764 person‐years, the composite outcome occurred in 7761 persons (67.6 per 1000 person‐years). The HRs (95% confidence intervals) of the composite outcome were 1.00 (reference) for <0.5 h, 0.84 (0.79, 0.88) for 0.5–1 h, and 0.78 (0.74, 0.83) for ≥1 h (p‐trend < 0.001). The 50th PDs (95% confidence intervals) of DFS time were 238 (155, 322) days longer for 0.5–1 h and 360 (265, 454) days longer for ≥1 h, in comparison with <0.5 h. The results suggest that longer time spent walking per day contributes to longer DFS time.
Prevalence and haemodynamic profiles of pulmonary hypertension in cardiac amyloidosis

Objectives While cardiac amyloidosis (CA) classically involves the left ventricle (LV), less is known about its impact on the right ventricle (RV) and pulmonary vasculature. We performed a retrospective analysis to identify the prevalence and types of pulmonary hypertension (PH) profiles in CA and to determine haemodynamic and cardiovascular magnetic resonance (CMR) predictors of major adverse cardiovascular events (MACE). Methods Patients with CA who underwent CMR and right heart catheterisation (RHC) within 1 year between 2010 and 2019 were included. Patients were assigned the following haemodynamic profiles based on RHC: no PH, precapillary PH, isolated postcapillary PH (IPCPH), or combined precapillary and postcapillary PH (CPCPH). The relationship between PH profile and MACE (death, heart failure hospitalisation) was assessed using survival analysis. CMR and RV parameters were correlated with MACE using Cox-regression analysis. Results A total of 52 patients were included (age 69±9 years, 85% men). RHC was performed during biopsy in 44 (85%) and for clinical indications in 8 (15%) patients. Rates of no PH, precapillary PH, IPCPH and CPCPH were 5 (10%), 3 (6%), 29 (55%) and 15 (29%), respectively. Haemodynamic PH profile did not correlate with risk of death (p=0.98) or MACE (p=0.67). Transpulmonary gradient (TPG) (HR 0.88, CI 0.80 to 0.97), RV, (HR 0.95, CI 0.92 to 0.98) and LV ejection fraction (HR 0.95, CI 0.92 to 0.98) were significantly associated with MACE. Conclusions PH is highly prevalent in CA, even at the time of diagnosis. While IPCPH was most common, CPCPH is not infrequent. TPG and RV ejection fraction (RVEF) are prognostic markers in this population.
Molnupiravir and Nirmatrelvir-Ritonavir: Oral COVID Antiviral Drugs

Abstract At a crucial time with rapid spread of Omicron SARS-CoV-2 virus variant globally, the United States Food and Drug Administration has issued an emergency use authorization for two oral antivirals molnupiravir (>18 years) and nirmatrelvir-ritonavir (Paxlovid) (≥12 years; >40kg ) for the outpatient treatment of mild to moderate COVID–19 patients who are at risk for progression. Molnupiravir is a nucleoside analogue, whereas nirmatrelvir is a SARS-CoV-2 main protease inhibitor, and ritonavir is an HIV-1 protease inhibitor. Drug interactions are a major concern for nirmatrelvir-ritonavir. Nirmatrelvir-ritonavir demonstrated a greater risk reduction in hospitalization and death than molnupiravir compared to placebo. Both drugs need to be started within five days of symptoms onset and given for five days duration. This article will review the two oral COVID-19 antiviral drugs including the mechanisms of action, antiviral activity, pharmacokinetics, drug interactions, clinical experience including trials, adverse events, recommended indications, and formulary considerations.
Prevalence of Suicidality and its Association with Quality of Life in Older Patients with Clinically Stable Psychiatric Disorders in China During the COVID-19 Pandemic

Aims The pattern of suicidality in older patients with psychiatric disorders during the COVID-19 pandemic is not clear. This study examined the prevalence of suicidality and its association with quality of life (QOL) among older clinically stable patients with psychiatric disorders during the COVID-19 pandemic. Methods A multicenter, cross-sectional study was conducted from May 22 to July 15, 2020, among four major tertiary psychiatric hospitals in China. Suicidality was assessed by asking 3 standardized questions. Depressive symptoms, pain, and QOL were assessed with the 9-item Patient Health Questionnaire (PHQ-9), the numeric pain rating scale (NPRS), and the World Health Organization Quality of Life Questionnaire-brief version, respectively. Results A total of 1063 clinically stable patients participated and completed the assessment. The prevalence of suicidality was 11.8% (95% CI: 9.9%–13.7%) during the COVID-19 pandemic. Multiple logistic regression analysis revealed that poor treatment adherence (P = .009, OR = 1.86, 95% CI: 1.17–2.96) and perceived illness worsening during the COVID-19 outbreak (P = .02, OR = 2.07, 95% CI: 1.15–3.73), being diagnosed with major depressive disorder (P < .001, OR = 2.79, 95% CI: 1.68–4.64), PHQ-9 total score (P < .001, OR = 1.20, 95% CI: 1.15–1.24) and NPRS total score (P = .002, OR = 1.17, 95% CI: 1.06–1.29) were associated with higher risk of suicidality. After controlling for covariates, older psychiatric patients with suicidality had lower QOL compared to those without (F(1, 1063) =16.5, P<. 001). Conclusions Suicidality was common in older patients with clinically stable psychiatric disorders during the COVID-19 pandemic. Considering its negative impact on QOL and personal suffering, routine screening and preventive suicide measures should be implemented for older psychiatric patients.
A null founder variant in NPNT, encoding nephronectin, causes autosomal recessive renal agenesis

Congenital anomalies of the kidney and urinary tract (CAKUT) are a spectrum of abnormalities affecting morphogenesis of the kidneys and other structures of the urinary tract. Bilateral renal agenesis (BRA) is the most severe presentation of CAKUT. Loss of either nephronectin (NPNT) or its receptor ITGA8 leads to failure of metanephric kidney development with resulting renal agenesis in murine models. Very recently, a single family with renal agenesis and a homozygous truncating variant in NPNT was reported. We report two families in whom genome‐wide linkage analysis showed an autozygous locus linked to BRA (at least one member has unilateral renal agenesis) at 4q24, with an LOD score of ~3. Exome sequencing detected a nonsense variant in NPNT in both families within the linkage interval. The pathogenicity of this variant was supported by reverse transcription polymerase chain reaction data showing complete nonsense‐mediated decay of the NPNT transcript. Our report confirms the candidacy of NPNT in renal agenesis in humans and shows that even complete loss of function can be compatible with the formation of a single kidney.
Alternative LIM homeodomain splice variants are dynamically regulated at key developmental steps in vertebrates

Alternative splicing provides a broad strategy to amplify the genome. Yet how alternative splicing influences neurodevelopment or indeed which variants are translated at developmental choice points remains poorly explored. Here we focused on a gene important for neurodevelopment, the Lim homeodomain transcription factor, Lhx9. Lhx9 has two noncanonical splice variants, Lhx9a and Lhx9b which compared with the canonical variant Lhx9c have a truncated homeodomain and an alternative C‐terminal sequence, suggesting that, if translated, these variants could differently impact on cellular function.
Adult Vaccine Hesitancy Scale in Arabic and French: Protocol for Translation and Validation in the World Health Organization Eastern Mediterranean Region

Background The world as we know it changed during the COVID-19 pandemic. Hope has emerged with the development of new vaccines against the disease. However, many factors hinder vaccine uptake and lead to vaccine hesitancy. Understanding the factors affecting vaccine hesitancy and how to assess its prevalence have become imperative amid the COVID-19 pandemic. The vaccine hesitancy scale (VHS), developed by the World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization, has been modified to the adult VHS (aVHS) and validated in English and Chinese. To our knowledge, no available aVHS has been designed or validated in Arabic or French. Objective The aim of this research is to translate the aVHS from its original English language to Arabic and French and validate the translations in the WHO Eastern Mediterranean region. Methods The study will follow a cross-sectional design divided into 5 phases. In phase 1, the original aVHS will be forward-translated to Arabic and French, followed by backward translation to English. An expert committee will review and rate all versions of the translations. Expert agreement will then be measured using the Cohen kappa coefficient (k). In phase 2, the translated aVHS will be pilot-tested with 2 samples of participants (n=100): a group that speaks both Arabic and English and another that speaks French and English. Participants’ responses to the English version will also be collected. In phase 3, responses will then be compared. Descriptive statistics and paired t tests or one-way analyses of variance (ANOVA) and Pearson correlation coefficient will be used in the preliminary validation. In phase 4, prefinal versions (Arabic and French) will be tested with larger sample sizes of Arabic speakers (n=1000) and French speakers (n=1000). Sociodemographic information and vaccination status will be collected and used for further analysis. In phase 5, the scale's statistical reliability and internal consistency will be measured using Cronbach alpha. An exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) will be used to examine the model fit resulting from the EFA. ANOVA and regression models will be constructed to control for confounders. All data will be electronically collected. Results As of January 2022, the scale had been translated to Arabic and French and was undergoing the process of back translation. All data collection tools have been prepared (ie, sociodemographics, vaccination status, and open-ended questions) and are ready to go into their electronic formats. We expect to reach the desired sample size in this phase by June 2022. Conclusions This study will provide researchers with a validated tool to assess adult vaccine hesitancy within populations that speak Arabic and/or French and provide a road map to scale translation and ensure cross-cultural adaptation. International Registered Report Identifier (IRRID) PRR1-10.2196/36928
A unimorph nanocomposite dielectric elastomer for large out-of-plane actuation

Dielectric elastomer actuators (DEAs) feature large, reversible in-plane deformation, and stacked DEA layers are used to produce large strokes in the thickness dimension. We introduce an electrophoretic process to concentrate boron nitride nanosheet dispersion in a dielectric elastomer precursor solution onto a designated electrode surface. The resulting unimorph nanocomposite dielectric elastomer (UNDE) has a seamless bilayer structure with 13 times of modulus difference. The UNDE can be actuated to large bending curvatures, with enhanced breakdown field strength and durability as compared to conventional nanocomposite dielectric elastomer. Multiple UNDE units can be formed in a simple electrophoretic concentration process using patterned electrode areas. A disc-shaped actuator comprising six UNDE units outputs large bidirectional stroke up to 10 Hz. This actuator is used to demonstrate a high-speed lens motor capable of varying the focal length of a two-lens system by 40 times.
High-performance manganese and nitrogen codoped carbon (Mn–N–C) oxygen reduction electrocatalyst from Mn2+ coordinated sodium alginate

The research on low-cost, high-performance non platinum group metal (PGM) oxygen reduction reaction (ORR) catalysts is of great significance for the rapid promotion of fuel cells’ practical applications. In this work, Mn–N–C catalyst with outstanding activity was prepared through using hydrogel formed by coordination of sodium alginate (SA) and Mn2+ as the precursor. During the preparation process, g-C3N4 was added to improve the surface area enrich the pore structure of catalysts, as well as to function as the nitrogen source. Compare with commercial Pt/C catalyst, the optimum Mn–N–C catalyst possesses extraordinary ORR activity in alkaline electrolytes, with a half-wave potential (E 1/2) of 0.90 V. In addition, the Mn–N–C catalyst also displays exceptional stability in alkaline and acidic electrolytes, much superior to Pt/C catalyst.
Stokowski and the Bell Telephone Laboratories: Collaboration in the Development of High-Fidelity Sound Reproduction

performing artist and an eminent group of research scientists and engineers, the relationship is of considerable intrinsic interest. It also reveals Bell Laboratories' generally unrecognized role in the development of high-fidelity sound reproduction and sheds light on the process of innovation for many modern technologies. Finally, it marks an aesthetic turning point in the relationship between classical music and electronic technology.
Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice

Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor–derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide “proof of principle” that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.
Myoblast 3D bioprinting to burst in vitro skeletal muscle differentiation

Skeletal muscle regeneration is one of the major areas of interest in sport medicine as well as trauma centers. Three‐dimensional (3D) bioprinting (BioP) is nowadays widely adopted to manufacture 3D constructs for regenerative medicine but a comparison between the available biomaterial‐based inks (bioinks) is missing. The present study aims to assess the impact of different hydrogels on the viability, proliferation, and differentiation of murine myoblasts (C2C12) encapsulated in 3D bioprinted constructs aided to muscle regeneration. We tested three different commercially available hydrogels bioinks based on: (1) gelatin methacrylate and alginate crosslinked by UV light; (2) gelatin methacrylate, xanthan gum, and alginate‐fibrinogen; (3) nanofibrillated cellulose (NFC)/alginate‐fibrinogen crosslinked with calcium chloride and thrombin. Constructs embedding the cells were manufactured by extrusion‐based BioP and C2C12 viability, proliferation, and differentiation were assessed after 24 h, 7, 14, 21, and 28 days in culture. Although viability, proliferation, and differentiation were observed in all the constructs, among the investigated bioinks, the best results were obtained by using NFC/alginate‐fibrinogen‐based hydrogel from 7 to 14 days in culture, when the embedded myoblasts started fusing, forming at day 21 and day 28 multinucleated myotubes within the 3D bioprinted structures. The results revealed an extensive myotube alignment all over the linear structure of the hydrogel, demonstrating cell maturation, and enhanced myogenesis. The bioprinting strategies that we describe here denote a strong and endorsed approach for the creation of in vitro artificial muscle to improve skeletal muscle tissue engineering for future therapeutic applications.
Differences in neuroinvasion and protective innate immune pathways between encephalitic California Serogroup orthobunyaviruses

The California serogroup (CSG) of Orthobunyaviruses comprises several members capable of causing neuroinvasive disease in humans, including La Crosse orthobunyavirus (LACV), Jamestown Canyon orthobunyavirus (JCV), and Inkoo orthobunyavirus (INKV). Despite being genetically and serologically closely related, their disease incidences and pathogenesis in humans and mice differ. We have previously shown that following intraperitoneal inoculation of weanling mice, LACV was highly pathogenic while JCV and INKV were not. To determine why there were differences, we examined the ability of these viruses to invade the CNS and compared the host innate immune responses that regulated viral pathogenesis. We found that LACV was always neuroinvasive, which correlated with its high level of neuroinvasive disease. Interestingly, JCV was not neuroinvasive in any mice, while INKV was neuroinvasive in most mice. The type I interferon (IFN) response was critical for protecting mice from both JCV and INKV disease, although in the periphery JCV induced little IFN expression, while INKV induced high IFN expression. Despite their differing neuroinvasive abilities, JCV and INKV shared innate signaling components required for protection. The presence of either cytoplasmic Rig-I-Like Receptor signaling or endosomal Toll-Like Receptor signaling was sufficient to protect mice from JCV or INKV, however, inhibition of both pathways rendered mice highly susceptible to neurological disease. Comparison of IFN and IFN-stimulated gene (ISG) responses to INKV in the brains of resistant wild type (WT) mice and susceptible immune knockout mice showed similar IFN responses in the brain, but WT mice had higher ISG responses, suggesting induction of key ISGs in the brain is critical for protection of mice from INKV. Overall, these results show that the CSG viruses differ in neuroinvasiveness, which can be independent from their neuropathogenicity. The type I IFN response was crucial for protecting mice from CSG virus-induced neurological disease, however, the exact correlates of protection appear to vary between CSG viruses.
Infection History and Current Coinfection With Schistosoma mansoni Decreases Plasmodium Species Intensities in Preschool Children in Uganda

Abstract Malaria–schistosomiasis coinfections are common in sub-Saharan Africa but studies present equivocal results regarding the interspecific relationships between these parasites. Through mixed-model analyses of a dataset of Ugandan preschool children, we explore how current coinfection and prior infection with either Schistosoma mansoni or Plasmodium species alter subsequent Plasmodium intensity, Plasmodium risk, and S mansoni risk. Coinfection and prior infections with S mansoni were associated with reduced Plasmodium intensity, moderated by prior Plasmodium infections, wealth, and host age. Future work should assess whether these interactions impact host health and parasite control efficacy in this vulnerable age group.
Small activating RNA activation of ATOH1 promotes regeneration of human inner ear hair cells

ABSTRACT The loss of inner ear hair cells leads to irreversible acoustic injury in mammals, and regeneration of inner ear hair cells to restore hearing loss is challenging. ATOH1 is a key gene in the development and regeneration of hair cells. Small activating RNAs (saRNAs) can target a gene to specifically upregulate its expression. This study aimed to explore whether small activating RNAs could induce the differentiation of human adipose-derived mesenchymal stem cells into hair cell-like cells with a combination of growth factors in vitro and thus provide a new strategy for hair cell regeneration and the treatment of sensorineural hearing loss. Fifteen small activating RNAs targeting the human ATOH1 gene were designed and screened in 293 T and human adipose-derived mesenchymal stem cells, and 3 of these candidates were found to be capable of effectively and stably activating ATOH1 gene expression. The selected small activating RNAs were then transfected into hair cell progenitor cells, and hair cell markers were examined 10 days after transfection. After transfection of the selected small activating RNAs, the expression of the characteristic markers of inner ear hair cells, POU class 4 homeobox 3 (POU4F3) and myosin VIIA (MYO7A), was detected. Human adipose-derived mesenchymal stem cells have the potential to differentiate into human hair cell progenitor cells. In vitro, small activating RNAs were able to induce the differentiation of hair cell progenitor cells into hair cell-like cells. Therefore, RNA activation technology has the potential to provide a new strategy for the regeneration of hair cells. Graphical Abstract
Characterization of More Than a Third of a Million Toy-Related Fractures

Introduction: The toy industry has grown substantially over time, with billions of dollars of toys sold each year in the United States alone. Even after safety considerations, injuries can result. This study examined toy-related fractures in the US Emergency Departments (ED). Methods: The 1999 to 2018 National Electronic Injury Surveillance System from the US Consumer Product Safety Commission was examined data for fractures involving a toy-related injury. The incidence, trends, and anatomic locations for such fractures were assessed. Results: In total, 347,135 toy-related fractures were identified, of which 237,754 (68%) were in patients younger than 18 years, 182,516 (53%) were sustained by male subjects, and a 95% yearly incidence increase was observed over the years of the study. Anatomically, 37% were shoulder/arm/elbow, 24% wrist/hand/finger, 19% ankle/toe/foot, 10% leg/knee, 6% face/neck/head, and 4% trunk/pubic region. Discussion: Despite safety considerations with toy design, more than a third of toy-related fractures were seen in the ED, with a nearly doubling yearly incidence over the study period. This could be contributed to by increased production and prevalence of toys and/or rougher play and increased overall violence. These results are important not only for patient safety but also for orthopaedic surgeons, EDs, toy manufacturers, and policymakers.