Miracle-dz/UniFAR-FTUs huggingface dataset:
Power analysis for cluster randomized trials with multiple binary co‐primary endpoints

Cluster randomized trials (CRTs) are widely used in different areas of medicine and public health. Recently, with increasing complexity of medical therapies and technological advances in monitoring multiple outcomes, many clinical trials attempt to evaluate multiple co‐primary endpoints. In this study, we present a power analysis method for CRTs with K≥2 binary co‐primary endpoints. It is developed based on the GEE (generalized estimating equation) approach, and three types of correlations are considered: inter‐subject correlation within each endpoint, intra‐subject correlation across endpoints, and inter‐subject correlation across endpoints. A closed‐form joint distribution of the K test statistics is derived, which facilitates the evaluation of power and type I error for arbitrarily constructed hypotheses. We further present a theorem that characterizes the relationship between various correlations and testing power. We assess the performance of the proposed power analysis method based on extensive simulation studies. An application example to a real clinical trial is presented.
Second language learning induces grey matter volume increase in people with multiple sclerosis

Background Grey matter volume (GMV) decline is a frequent finding in multiple sclerosis (MS), the most common chronic neurological disease in young adults. Increases of GMV were detected in language related brain regions following second language (L2) learning in healthy adults. Effects of L2 learning in people with MS (pwMS) have not been investigated so far. Methods This study prospectively evaluated the potential of an eight-week L2 training on grey matter plasticity measured by 3T-MRI, L2 proficiency and health-related quality of life (HRQoL) in people with relapsing-remitting MS (pwMS, n = 11) and healthy, sex- and age-matched controls (HCs; n = 12). Results Categorical voxel-based analysis revealed significantly less GMV bilaterally of the insula extending to the temporal pole in pwMS at baseline. Following L2 training, significant increases of GMV were evident in the right hippocampus, parahippocampus and putamen of pwMS and in the left insula of HCs. L2 training resulted in significant improvements of listening comprehension, speaking fluency and vocabulary knowledge in both pwMS and HCs. GMV increases of right hippocampus and parahippocampus significantly correlated with vocabulary knowledge gain and L2 learning was associated with a significant increase of HRQoL in pwMS. Conclusion Our findings demonstrate distinct patterns of GMV increases of language related brain regions in pwMS and HCs and indicate disease-related compensatory cortical and subcortical plasticity to acquire L2 proficiency in pwMS.
Can mindfulness overcome the effects of workplace ostracism on job performance?

ABSTRACT With a basis in the transactional theory of stress and coping, this study investigates the relationship between employees’ exposure to workplace ostracism and their job performance, while also considering the mediating role of acquiescence silence and the moderating role of mindfulness. Multisource, three-wave data from employees and their peers in Pakistani organizations reveal that ostracism in the workplace hinders job performance because employees passively withhold relevant ideas about their work due to feelings of acquiescence. The mediating role of acquiescence silence is mitigated if employees can draw from their mindfulness trait. This study accordingly identifies a key mechanism – the passive withholding of pertinent ideas, based on submission – by which workplace ostracism hampers job performance, and it reveals how this process might be contained by encouraging employees’ receptive attention and awareness focused on present experiences.
Delays in Diagnosis and Treatment of Breast Cancer and the Pathways of Care: A Mixed Methods Study from a Tertiary Cancer Centre in North East India

Introduction: In India, mortality rate in breast cancer is high because more than half are diagnosed late at locally advanced or metastatic stages. This might be due to presentation delay (recognition of symptoms to first provider consultation) and treatment delay (first provider consultation to initiation of treatment), together known as overall delay. We aimed to estimate the overall delay in diagnosis and treatment in breast cancer and the associated factors, describe pathway of care and explore the reasons for delay from a patients’ and providers’ perspective. Methods: Explanatory sequential mixed-methods study with a quantitative component (retrospective cohort study including breast cancer patients registered at Dr. Borooah Cancer Institute (BBCI), Guwahati during February-June 2019) followed by descriptive qualitative component (in-depth interviews with 15 patients and 10 care providers). Results: Of 269 breast cancer patients, median (Inter Quartile Range) overall delay was 203 (110-401) days, presentation delay was 35 (10-112) days and treatment delay was 130 (75-258) days. Majority of patients approached private sector (190, 70.6%) as the first care provider. Nearly half of all patients (136, 50.6%) visited one health care provider before reaching the BBCI and another one-third (90, 33.5%) visited two providers. Reasons for presentation delay were misconception about the disease, perceived stigma, fear and denial of cancer, attribution of symptoms to trivial conditions, family responsibilities and embarrassment of breast examination by a male doctor. Treatment delay was due to initial visit to, misclassification of disease severity, dissatisfaction with care at public facilities, poor accessibility and affordability, fear of treatment and its side effects. Conclusion: Treatment delay was the major contributor to overall delay. Private providers need to be sensitized and trained in screening of breast cancer and referral of suspected cases of cancer. More awareness is needed about warning symptoms of breast cancer and misconceptions regarding the disease.
Culture and personality revisited: Behavioral profiles and within-person stability in interdependent (vs. independent) social orientation and holistic (vs. analytic) cognitive style.

OBJECTIVE We test the proposition that both social orientation and cognitive style are constructs consisting of loosely related attributes. Thus, measures of each construct should weakly correlate among themselves, forming intra-individually stable profiles across measures over time. METHOD Study 1 tested diverse samples of Americans (N = 233) and Japanese (N = 433) with a wide range of measures of social orientation and cognitive style to explore correlations among these measures in a cross-cultural context, using demographically heterogeneous samples. Study 2 recruited a new sample of 485 Americans and Canadians and examined their profiles on measures of social orientation and cognitive style twice, one month apart, to assess the stability of individual profiles using these variables. RESULTS Despite finding typical cross-cultural differences, Study 1 demonstrated negligible correlations both among measures of social orientation and among measures of cognitive style. Study 2 demonstrated stable intra-individual behavioral profiles across measures capturing idiosyncratic patters of social orientation and cognitive style, despite negligible correlations among the same measures. CONCLUSION The results provide support for the behavioral profile approach to conceptualizing social orientation and cognitive style, highlighting the need to assess intra-individual stability of psychological constructs in cross-cultural research.
Effects of exercise training on serum preptin, undercarboxylated osteocalcin and high molecular weight adiponectin in adults with metabolic syndrome

What is the central question of this study? Are the advantages of aerobic interval exercise, resistance exercise and concurrent exercise on the metabolic profile mediated in part through preptin and undercarboxylated osteocalcin (ucOCN)? What is the main finding and its importance? Glucose was significantly lowered after concurrent exercise and aerobic interval exercise, but serum preptin and insulin were significantly lowered in all three training groups. By contrast, ucOCN and high molecular weight adiponectin increased significantly in all three training groups. These findings support the possible cross‐talk between bone, pancreatic β‐cells and energy metabolism in humans and suggest that preptin and ucOCN may potentially serve as markers of exercise‐induced improvement of metabolism.
SPA: a peptide antagonist that acts as a cell-penetrating peptide for drug delivery

Abstract Although cell-penetrating peptides (CPPs) has been proven to be efficient transporter for drug delivery, ideal peptide vectors for tumor therapy are still being urgently sought. Peptide antagonists have attracted substantial attention as targeting molecules because of their high tumor accumulation and antitumor activity compared with agonists. SPA, a derivative of substance P, is a potent antagonist that exhibits antitumor activity. Based on the amino acid composition of SPA, we speculate that it can translocate across cell membranes as CPPs do. In this study, our results demonstrated that SPA could enter cells similarly to a CPP. As a vector, SPA could efficiently deliver camptothecin and plasmids into cells. In addition, our results showed that SPA exhibited low toxicity to normal cells and high enzymatic stability. Taken together, our results validated the ability of SPA for efficient drug delivery. More importantly, our study opens a new avenue for designing ideal CPPs based on peptide antagonists.
Low retinal toxicity of intravitreal carboplatin associated with good retinal tumour control in transgenic murine retinoblastoma

Retinoblastoma is a rare intraocular malignancy in children. Current treatments have many adverse effects. New therapeutic approaches like intravitreal injections of chemotherapies are currently being developed but their toxicities need to be evaluated on animal models. This study compares the efficacy and toxicity of intravitreal melphalan, topotecan and carboplatin, alone or in combination (sequential administration), in the LHBetaTag retinoblastoma mice.
Seasonality of Pulmonary Tuberculosis in Sousse (Tunisia).

INTRODUCTION Seasonal variation of Pulmonary tuberculosis (TB) has attracted the attention in several regions of the world. AIM To explore the relationship between variations of mean meteorological parameters (temperature, atmospheric pressure, relative humidity and duration of sunshine) and the occurrence of cases of pulmonary TB. METHODS This is a retrospective descriptive study of two-time series (meteorological data, case of pulmonary TB) from 1th January 2010 to 31th December 2014.Meteorological data were collected throughout the 5-year period. RESULTS We collected 180 cases confirmed by direct examination. The relationship between seasonality and the occurrence of TB cases was addressed in two ways considering either the date of the bacteriological diagnosis or the date date of onset of symptoms of TB as the date of the census of cases. Taking into account the date of bacteriological diagnosis, it appeared that spring (33.7%) and summer (25.9%) had the most days with positive diagnosis (p = 0.012). However, considering the date of onset of symptoms of TB , it appeared that winter (34.2%) and spring (28%) had the most days with positive diagnosis with a significant difference. The comparison of the mean of meteorological parameters between days with and without bacteriological diagnosis showed that only the mean duration of sunshine was significatively associated with more cases(p=0.002). This same comparison between the days with and without TB according to the date of onset of symptoms of TB showed significant difference only for mean temperatures which were lower during the days when patients présented symptoms of TB (p=0.013). CONCLUSION Our results have highlighted the possible implication of meteorological parameters in the occurrence of pulmonary TB cases.
Carboxylesterase 1 and Precision Pharmacotherapy: Pharmacogenetics and Nongenetic Regulators

Carboxylesterase (CES) 1 is the most abundant drug-metabolizing enzyme in human livers, comprising approximately 1% of the entire liver proteome. CES1 is responsible for 80%–95% of total hydrolytic activity in the liver and plays a crucial role in the metabolism of a wide range of drugs (especially ester-prodrugs), pesticides, environmental pollutants, and endogenous compounds. Expression and activity of CES1 vary markedly among individuals, which is a major contributing factor to interindividual variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs metabolized by CES1. Both genetic and nongenetic factors contribute to CES1 variability. Here, we discuss genetic polymorphisms, including single-nucleotide polymorphisms (SNPs), and copy number variants and nongenetic contributors, such as developmental status, genders, and drug-drug interactions, that could influence CES1 functionality and the PK and PD of CES1 substrates. Currently, the loss-of-function SNP G143E (rs71647871) is the only clinically significant CES1 variant identified to date, and alcohol is the only potent CES1 inhibitor that could alter the therapeutic outcomes of CES1 substrate medications. However, G143E and alcohol can only explain a small portion of the interindividual variability in the CES1 function. A better understanding of the regulation of CES1 expression and activity and identification of biomarkers for CES1 function in vivo could lead to the development of a precision pharmacotherapy strategy to improve the efficacy and safety of many CES1 substrate drugs. SIGNIFICANCE STATEMENT The clinical relevance of CES1 has been well demonstrated in various clinical trials. Genetic and nongenetic regulators can affect CES1 expression and activity, resulting in the alteration of the metabolism and clinical outcome of CES1 substrate drugs, such as methylphenidate and clopidogrel. Predicting the hepatic CES1 function can provide clinical guidance to optimize pharmacotherapy of numerous medications metabolized by CES1.
Systemic Evaluation of Chimeric LNA/2′-O-Methyl Steric Blockers for Myotonic Dystrophy Type 1 Therapy

Myotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystemic disorder characterized clinically by delayed muscle relaxation and weakness. The disease is caused by a CTG repeat expansion in the 3′ untranslated region (3′ UTR) of the DMPK gene, which leads to the expression of a toxic gain-of-function mRNA. The expanded CUG repeat mRNA sequesters the MBNL1 splicing regulator in nuclear-retained foci structures, resulting in loss of protein function and disruption of alternative splicing homeostasis. In this study, we used CAG repeat antisense oligonucleotides (ASOs), composed of locked nucleic acid (LNA)- and 2′-O-methyl (2′OMe)-modified bases in a chimeric design, to alleviate CUGexpanded-mediated toxicity. Chimeric 14–18mer LNA/2′OMe oligonucleotides, exhibiting an LNA incorporation of ∼33%, significantly ameliorated the misregulated alternative splicing of Mbnl1-dependent exons in primary DM1 mouse myoblasts and tibialis anterior muscles of DM1 mice. Subcutaneous delivery of 14mer and 18mer LNA/2′OMe chimeras in DM1 mice resulted in high levels of accumulation in all tested skeletal muscles, as well as in the diaphragm and heart tissue. Despite the efficient delivery, chimeric LNA/2′OMe oligonucleotides were not able, even at a high-dosage regimen (400 mg/kg/week), to correct the misregulated splicing of Serca1 exon 22 in skeletal muscles. Nevertheless, oligonucleotide doses were well-tolerated as determined by histological and plasma biochemistry analyses. Our results provide proof of concept that inhibition of MBNL1 sequestration by systemic delivery of a steric-blocking ASO is extremely challenging, considering the large number of target sites that need to be occupied per RNA molecule. Although not suitable for DM1 therapy, chimeric LNA/2′OMe oligonucleotides could prove to be highly beneficial for other diseases, such as Duchenne muscular dystrophy, that require inhibition of a single target site per RNA molecule.
Rate of Programs Affected by Resident Attrition and Program Factors Associated With Attrition in Emergency Medicine.

Background Resident attrition negatively affects residents and programs. The incidence of attrition in emergency medicine (EM) and program-specific factors associated with attrition remain unclear. Objective We quantified the percentage of EM residencies affected by attrition between 2007 and 2016 and identified program-specific factors associated with attrition. Methods We performed a retrospective analysis of data derived from the American Medical Association National Graduate Medical Education Census. We defined attrition as any postgraduate who left their residency training program prior to completion. We calculated the percentage of residency programs that experienced attrition and the overall incidence of attrition. We used Fisher's exact tests, Wilcoxon rank sum tests, and t tests, as well as multivariable logistic regression, to identify program-specific factors associated with attrition. Results Between 2007 and 2016, 139 EM residency programs (82%) experienced attrition of at least 1 resident. An average of 23% of EM training programs experienced attrition annually. The incidence of EM resident attrition averaged 0.85% per year. Program-specific factors associated with attrition include 4-year residencies (P = .031), programs with medium class size (P = .0003), more female residents (P = .002), and more female faculty (P = .003). After analysis, only medium class size (compared to small) was associated with attrition (odds ratio = 4.96, 95% confidence interval 1.65-14.91). Conclusions Between 2007 and 2016, while the incidence of resident attrition in EM was low (< 1%), the majority of programs experienced resident attrition. Medium class size (7 to 12 residents) was the only program-specific factor associated with increased attrition.
Validation of self-reported measures of periodontitis in a Spanish Population.

BACKGROUND AND OBJECTIVE Use of self-reported questionnaires in Dentistry may be useful to estimate the prevalence of periodontitis in epidemiological studies. This study aims to assess the accuracy of self-reporting for predicting the prevalence of periodontitis in a Spanish population participating in a diabetes incidence study. MATERIALS AND METHODS Data were collected from 231 patients participating in the Di@bet.es study. Eight questions about periodontal health were included in a health patient-reported questionnaire. The outcomes from self-reporting were validated against a full-mouth periodontal examination. Multivariable logistic regression predictive modeling was used to determine the sensitivity, specificity, and area under the receiver operator characteristic curve (AUROCC). RESULTS Self-reported gum health, loose teeth, tooth appearance, and use of dental floss were associated with different definitions of severe periodontitis. Correlations between responses to the questions were weak. The question "Do you think you might have gum disease? " combined with demographic and well-established risk factors resulted in an AUC value of 0.75, sensitivity of 75.2%, and specificity of 60.6% for severe periodontitis. The answer to 4 questions combined with age, educational level, smoking status, and tooth loss was 76.4% sensitive and 63.5% specific, with an AUC of 0.75 in predicting prevalence of ≥25% of teeth with probing pocket depth (PPD) ≥6 mm. CONCLUSION Predictive models, combining self-reporting on oral health status with demographic and risk factors, were useful for estimating the prevalence of severe periodontitis in the Spanish population.
Elaboration of a spontaneous gluten-free sourdough with a mixture of amaranth, buckwheat, and quinoa flours analyzing microbial load, acidity, and pH

Pseudocereals are gluten-free, nutrient-dense raw materials that are being considered for the production of gluten-free products, especially bread. This study proposes a gluten-free sourdough formula based on equal amounts of amaranth, buckwheat, and quinoa with a dough yield of 250, and an elaboration method to obtain ripe sourdough. Sourdough was characterized in terms of microbiology, pH, and total titratable acidity. The established protocol made it possible to obtain a spontaneous ripe sourdough with lactic acid bacteria populations of 9.60 ± 0.02 log CFU/g and total yeasts and non-Saccharomyces yeast populations (lysine positive) of 7.91 ± 0.15 and 7.52 ± 0.10 log CFU/g, respectively. Great pH stability and total titratable acidity were maintained in the ripe sourdough phase, with values of 4.04 ± 0.02 and 18.39 ± 0.56 ml NaOH 0.1 M/10 g, respectively, at the time of the next refreshment. The use of this sourdough could be an interesting alternative for the production of not only gluten-free bread but also other gluten-free products.
A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients

The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. ABSTRACT The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 μg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level β-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 μg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against β-lactamase-producing Gram-negative bacteria.