Miracle-dz/UniFAR-FTUs huggingface dataset:
Is there any contribution of bronchial washing to biopsy in the diagnosis of patients with endobronchial pathology in the era of personalized medicine?

Introduction Bronchoscopic biopsies and bronchial washings (BW) are commonly used together for the diagnosis of centrally located tumors. This study aimed to investigate the clinical relevance of routinely collecting BWs in patients who simultaneously had biopsies for visible endobronchial lesions in the current molecular analysis-driven personalized medicine era. Materials and Methods We retrospectively reviewed the patients who underwent fiberoptic bronchoscopy (FOB) between October 2011 and December 2016. Patients who had both BW and biopsy specimens (EBB: endobronchial forceps biopsy and/or EBNA: endobronchial needle aspiration biopsy) for visible endobronchial lesions were included in this study. Demographic and clinical data, macroscopic findings during FOB, pathology results, and final diagnoses were collected from the hospital database. Result The study included 269 patients (220 males/49 females) with a mean age of 61.6 ± 10.6 years. While the overall diagnostic yield of FOB was 71.4%, the diagnostic yields of bronchoscopic procedures were 68.2% for EBB, 83.3% for EBNA, and 19.7% for BW. Only three patients (1.1%) with undiagnostic biopsies had positive BW cytology revealing merely malignant epithelial cells. Conclusions BW provided a negligible diagnostic contribution in 1.1% (n= 3) of the patients. These three patients had undergone further diagnostic procedures for making a proper therapeutic management plan. In the era of personalized therapy, it is logical to obtain more biopsy in the time spent for BWs.
Distinct antibody profiles in HLA-B∗57+, HLA-B∗57− HIV controllers and chronic progressors

Objective: Spontaneous control of HIV replication without treatment in HIV-1 controllers (HICs) was associated with the development of an efficient T-cell response. In addition, increasing data suggest that the humoral response participates in viral clearance. Design: In-depth characterization of Ab response in HICs may help to define new parameters associated with this control. Methods: We assessed the levels of total and HIV-specific IgA and IgG subtypes induction and their functional potencies – that is, neutralization, phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), according to the individual's major histocompatibility complex class I (HLA)-B∗57 status, and compared it with nontreated chronic progressors. Results: We found that despite an undetectable viral load, HICs displayed HIV-specific IgG levels similar to those of chronic progressors. Interestingly, our compelling multifunctional analysis demonstrates that the functional Ab profile, by itself, allowed to discriminate HLA-B∗57+ HICs from HLA-B∗57− HICs and chronic progressors. Conclusion: These results show that HICs display a particular HIV-specific antibody (Ab) profile that may participate in HIV control and emphasize the relevance of multifunctional Ab response analysis in future Ab-driven vaccine studies.
Effects of combined treatment with blood flow restriction and low-current electrical stimulation on capillary regression in the soleus muscle of diabetic rats.

To clarify the preventive effects of low-current electrical stimulation (ES) under blood flow restriction (Bfr) on diabetes-associated capillary regression in skeletal muscles, we assessed the changes in three-dimensional capillary architecture and angiogenic factors. Twenty-four Goto-Kakizaki rats were randomly divided into four groups: the sedentary diabetes mellitus (DM), Bfr (DM + Bfr), electrical stimulation (DM + ES), and Bfr plus ES (DM + Bfr + ES) groups. Six healthy Wistar rats were used as age-matched controls. Bfr was performed using pressure cuffs (80 mmHg) around the thighs of the rats, and low-current ES was applied to the calf muscles of the rats. The current intensity was set at 30% of the maximal isometric contraction (24-30 mA). The treatments were delivered three times a week for 8 wk. In the DM group, the capillary diameter and volume of the soleus muscle decreased, and, the antiangiogenic factor level increased. Furthermore, DM caused an increase in the hypoxia-inducible factor. Individually, Bfr or ES treatments failed to inhibit the DM-associated capillary regression and increase in antiangiogenic factor. However, combined treatment with Bfr and ES prevented DM-associated capillary regression via inhibition of the increased antiangiogenic factor and enhancement of interleukin-15 expression, mitochondrial biogenesis factors, and a proangiogenic factor. Therefore, DM-associated capillary regression inhibited by the combined treatment may prevent the effects of the increased antiangiogenic factor and enhance the proangiogenic factor.NEW & NOTEWORTHY The combined treatment of blood flow restriction and low intensity electrical stimulation attenuated type 2 diabetes (T2D)-associated capillary regression in the skeletal muscles. The treatment inhibits the T2D-associated increase in antiangiogenic factors via inhibition of intramuscular chronic hypoxia; it can inhibit intramuscular chronic hypoxia by enhancing proangiogenic factors. These results suggest that the combined treatment may be an effective therapeutic intervention for the prevention of T2D-associated capillary regression in the skeletal muscles.
The impact of race and comorbid conditions on adult liver transplant outcomes in obese recipients

Many prior studies comparing liver transplant outcomes between obese and nonobese recipients found no significant differences in survival. However, obesity is intrinsically associated with demographic factors such as race and comorbidities. Thus, this work aimed to analyze the effects of obesity, in conjunction with these factors, on liver transplant outcomes. OPTN data was analyzed to identify adult‐only, first‐time liver transplants between 1995 and 2019. Obesity was defined by the CDC obesity classification. Race, insurance status, age, and comorbidities were analyzed together with patient survival and graft survival using a multivariable Cox Proportional‐Hazards model and long‐term survival with Kaplan–Meier curves. The multivariable models found that being black, older than 50 years, having diabetes, or having nonprivate insurance were all risk factors for both patient survival and graft survival after liver transplant. Adjusting for obesity class, black recipients had a 20% lower patient survival and 23% lower graft survival compared with nonblack recipients. Survival curves verified that obese black liver transplant recipients had poorer long‐term patient survival and graft survival compared with both obese nonblack and nonobese recipients. In conclusion, obesity compounds known factors associated with poor outcomes after liver transplantation. Further work is critical to understand why these discrepancies persist.
Improved Growth of Escherichia coli in Aminoglycoside Antibiotics by the zor-orz Toxin-Antitoxin System

Bacterial species can harbor gene pairs known as type I toxin-antitoxin systems, in which one gene encodes a small protein that is toxic to the bacteria producing it and a second gene that encodes a small RNA antitoxin to prevent toxicity. While artificial overproduction of type I toxin proteins can lead to cell growth inhibition and cell lysis, the endogenous translation of type I toxins appears to be tightly regulated. ABSTRACT Type I toxin-antitoxin systems consist of a small protein (under 60 amino acids) whose overproduction can result in cell growth stasis or death, and a small RNA that represses translation of the toxin mRNA. Despite their potential toxicity, type I toxin proteins are increasingly linked to improved survival of bacteria in stressful environments and antibiotic persistence. While the interaction of toxin mRNAs with their cognate antitoxin sRNAs in some systems are well characterized, additional translational control of many toxins and their biological roles are not well understood. Using an ectopic overexpression system, we show that the efficient translation of a chromosomally encoded type I toxin, ZorO, requires mRNA processing of its long 5′ untranslated region (UTR; Δ28 UTR). The severity of ZorO-induced toxicity on growth inhibition, membrane depolarization, and ATP depletion was significantly increased if expressed from the Δ28 UTR versus the full-length UTR. ZorO did not form large pores, as was evident via a liposomal leakage assay, in vivo morphological analyses, and measurement of ATP loss. Further, increasing the copy number of the entire zor-orz locus significantly improved the growth of bacterial cells in the presence of kanamycin and increased the minimum inhibitory concentration (MIC) against kanamycin and gentamicin; however, no such benefit was observed against other antibiotics. This supports a role for the zor-orz locus as a protective measure against specific stress agents and is likely not part of a general stress response mechanism. Combined, these data shed more insights into the possible native functions for type I toxin proteins. IMPORTANCE Bacterial species can harbor gene pairs known as type I toxin-antitoxin systems, in which one gene encodes a small protein that is toxic to the bacteria producing it and a second gene that encodes a small RNA antitoxin to prevent toxicity. While artificial overproduction of type I toxin proteins can lead to cell growth inhibition and cell lysis, the endogenous translation of type I toxins appears to be tightly regulated. Here, we show that translational regulation controls production of the ZorO type I toxin and prevents subsequent negative effects on the cell. Further, we demonstrate a role for zorO and its cognate antitoxin in the improved growth of Escherichia coli in the presence of aminoglycoside antibiotics.
Botulinum toxin A promotes the transdifferentiation of primary keloid myofibroblasts into adipocyte‐like cells

Keloid is a type of unusually raised scar. Botulinum toxin A (BTX‐A) has a great application potential in keloids treatment. Here, we investigated the functional role of BTX‐A in keloids. We separated keloid tissues and normal skin tissues from keloid patients and found that the expression of myofibroblast markers, α‐SMA, Collagen I, and Collagen III was increased in the keloid tissues as compared with normal skin tissues. Keloid fibroblasts derived from keloid tissues were treated with TGF‐β1 to induce the differentiation of fibroblasts into myofibroblasts. The keloid myofibroblasts displayed a significant up‐regulation of α‐SMA. BTX‐A enhanced the expression of adipocyte markers, PPARγ and C/EBPα, and increased the accumulation of lipid droplets, and reduced the expression of α‐SMA, Collagen I, and Collagen III in the keloid myofibroblasts. Moreover, BTX‐A enhanced the expression of BMP4 and p‐smad1/5/8. Noggin (BMP4 antagonist) treatment reversed BTX‐A‐mediated increase of PPARγ and C/EBPα expression and lipid droplets, and down‐regulation of α‐SMA, Collagen I, and Collagen III in primary keloid myofibroblasts. In conclusion, BTX‐A promoted the transdifferentiation of primary keloid myofibroblasts into adipocyte‐like cells, which may attribute to activate BMP4/Smad signalling pathway. Thus, this study provides new insights into the mechanism of BTX‐A in keloid.
Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome

Epilepsy Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. CNKSR2 is a strong X-linked candidate gene implicated in EAS; however, there have been no studies of genetic models to dissect how its absence may lead to EAS. Here we develop a novel Cnksr2 KO mouse line and show that male mice exhibit increased neural activity and have spontaneous electrographic seizures. Cnksr2 KO mice also display significantly increased anxiety, impaired learning and memory, and a progressive and dramatic loss of ultrasonic vocalizations. We find that Cnksr2 is expressed in cortical, striatal, and cerebellar regions and is localized at both excitatory and inhibitory postsynapses. Proteomics analysis reveals Cnksr2 anchors key binding partners at synapses, and its loss results in significant alterations of the synaptic proteome, including proteins implicated in epilepsy disorders. Our results validate that loss of CNKSR2 leads to EAS and highlights the roles of Cnksr2 in synaptic organization and neuronal network activity. SIGNIFICANCE STATEMENT Epilepsy Aphasia Syndromes (EAS) are at the severe end of a spectrum of cognitive-behavioral symptoms seen in childhood epilepsies, and they remain an inadequately understood disorder. The prognosis of EAS is frequently poor, and patients have life-long language and cognitive disturbances. Here we describe a genetic mouse model of EAS, based on the KO of the EAS risk gene Cnksr2. We show that these mice exhibit electrophysiological and behavioral phenotypes similar to those of patients, providing an important new model for future studies of EAS. We also provide insights into the molecular disturbances downstream of Cnksr2 loss by using in vivo quantitative proteomics tools.
Phenotype and pathology of the dilated cardiomyopathy with ataxia syndrome in children

The dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive mitochondrial disease caused by mutations in the DnaJ heat shock protein family (Hsp40) member C19 (DNAJC19) gene. DCMA or 3‐methylglutaconic aciduria type V is globally rare, but the largest number of patients in the world is found in the Hutterite population of southern Alberta in Canada. We provide an update on phenotypic findings, natural history, pathological findings, and our clinical experience. We analyzed all available records for 43 patients diagnosed with DCMA between 2005 and 2015 at the Alberta Children's Hospital. All patients studied were Hutterite and homozygous for the causative DNAJC19 variant (c.130‐1G>C, IVS3‐1G>C) and had elevated levels of 3‐methyglutaconic acid. We calculated a birth prevalence of 1.54 cases per 1000 total births in the Hutterite community. Children were small for gestational age at birth and frequently required supplemental nutrition (63%) or surgical placement of a gastrostomy tube (35%). Early mortality in this cohort was high (40%) at a median age of 13 months (range 4‐294 months). Congenital anomalies were common as was dilated cardiomyopathy (50%), QT interval prolongation (83%), and developmental delay (95%). Tissue pathology was analyzed in a limited number of patients and demonstrated subendocardial fibrosis in the heart, macrovesicular steatosis and fibrosis in the liver, and structural abnormalities in mitochondria. This report provides clinical details for a cohort of children with DCMA and the first presentation of tissue pathology for this disorder. Despite sharing common genetic etiology and environment, the disease is highly heterogeneous for reasons that are not understood. DCMA is a clinically heterogeneous systemic mitochondrial disease with significant morbidity and mortality that is common in the Hutterite population of southern Alberta.
Trust in scientists in times of pandemic: Panel evidence from 12 countries

Significance During the COVID-19 pandemic, support for nonpharmaceutical interventions (NPIs) and compliant behavior changed substantially over time. Using a large-scale, longitudinal, and representative survey for 12 countries from March to December 2020 (n = 54,000), combined with experimental data, we show that trust in scientists is the critical determinant of societies’ resilience in their fight against the pandemic. Yet, this trust has eroded dramatically in some countries such as France. Individuals and countries for which trust in scientists has declined have experienced fading support for and compliance with NPIs. In countries where trust in government is low, the independence of scientists and scientific institutions is essential to obtain citizen’s support for measures necessary to protect public health. This article analyzes the specific and critical role of trust in scientists on both the support for and compliance with nonpharmaceutical interventions (NPIs) during the COVID-19 pandemic. We exploit large-scale, longitudinal, and representative surveys for 12 countries over the period from March to December 2020, and we complement the analysis with experimental data. We find that trust in scientists is the key driving force behind individual support for and compliance with NPIs and for favorable attitudes toward vaccination. The effect of trust in government is more ambiguous and tends to diminish support for and compliance with NPIs in countries where the recommendations from scientists and the government were not aligned. Trust in others also has seemingly paradoxical effects: in countries where social trust is high, the support for NPIs is low due to higher expectations that others will voluntary social distance. Our individual-level longitudinal data also allows us to evaluate the effects of within-person changes in trust over the pandemic: we show that trust levels and, in particular, trust in scientists have changed dramatically for individuals and within countries, with important subsequent effects on compliant behavior and support for NPIs. Such findings point out the challenging but critical need to maintain trust in scientists during a lasting pandemic that strains citizens and governments.
Etiological spectrum of irreversible blindness in Kashmir in North India

Purpose: To determine the etiological spectrum of irreversible blindness in Kashmir Valley in India. Methods: Patients presenting to a tertiary care hospital in Kashmir, India, with unilateral or bilateral blindness from April 2019 to March 2020 were included in this cross-sectional study. Blindness was defined using the World Health Organization (WHO) criteria. All subjects had a complete ophthalmologic examination and information was gathered regarding their demographic profile, nature of ocular disorder whether primary or secondary and laterality, if the ocular involvement was unilateral. Results: 248 patients were enrolled in the study. The mean age of the patients was 57.17 years. The male: female ratio was 2.17:1. The commonest cause of unilateral or bilateral blindness was glaucoma (22.58%) followed by diabetic retinopathy (DR) (17.74%). Unilateral blindness was seen in 78.62% of the patients. Unilateral blindness occurred mainly due to glaucoma (16.41%), DR (14.87%), age-related macular degeneration (13.33%), and trauma (pellet injury: 10.76%, non-pellet injury: 10.25%). The major causes of bilateral blindness were glaucoma (45.28%), DR (28.30%), and hereditary/congenital retinal diseases (16.98%). Socioeconomic status and educational status were significantly associated (P < 0.05 each) while age, gender, place of residence, and occupation were not significantly associated (P > 0.05 each) with the number of eyes affected by blindness. Conclusion: Glaucoma and DR are the foremost causes of irreversible blindness in Kashmir. Public health plans aimed at encouraging good health education of patients should be developed in this region. Moreover, patients should be screened effectively for glaucoma and diabetes at the level of primary health care facilities.
A parameter-free statistical test for neuronal responsiveness

Neurophysiological studies depend on a reliable quantification of whether and when a neuron responds to stimulation. Simple methods to determine responsiveness require arbitrary parameter choices, such as binning size, while more advanced model-based methods require fitting and hyperparameter tuning. These parameter choices can change the results, which invites bad statistical practice and reduces the replicability. New recording techniques that yield increasingly large numbers of cells would benefit from a test for cell-inclusion that requires no manual curation. Here, we present the parameter-free ZETA-test, which outperforms t-tests, ANOVAs, and renewal-process-based methods by including more cells at a similar false-positive rate. We show that our procedure works across brain regions and recording techniques, including calcium imaging and Neuropixels data. Furthermore, in illustration of the method, we show in mouse visual cortex that (1) visuomotor-mismatch and spatial location are encoded by different neuronal subpopulations and (2) optogenetic stimulation of VIP cells leads to early inhibition and subsequent disinhibition.
Amateur antigen‐presenting cells in the tumor microenvironment

Presentation of tumor antigens is a critical step in producing a robust antitumor immune response. Classically tumor antigens are thought to be presented to both CD8 and CD4 T cells by professional antigen‐presenting cells (pAPCs) like dendritic cells using major histocompatibility complexes (MHC) I and II. But recent evidence suggests that in the tumor microenvironment (TME) cells other than pAPCs are capable of presenting tumor antigens on both MHC I and II. The evidence currently available on tumor antigen presentation by epithelial cells, vascular endothelial cells (VECs), fibroblasts, and cancer cells is reviewed herein. We refer to these cell types in the TME as “amateur” APCs (aAPCs). These aAPCs greatly outnumber pAPCs in the TME and could, potentially, play a significant role in priming an antitumor immune response. This new evidence supports a different perspective on antigen presentation and suggests new approaches that can be taken in designing immunotherapies to increase T cell priming.
Sexual Minority Status and Age of Onset of Adolescent Suicide Ideation and Behavior

BrightcoveDefaultPlayer 10.1542/6259330343001 PEDS-VA_2020-034900 Video Abstract OBJECTIVES To determine if sexual minority adolescents have earlier onset of suicidality and faster progressions from ideation to plan and attempt than heterosexual adolescents. METHODS A population-based longitudinal cohort of 1771 adolescents participated in the NEXT Generation Health Study. Participants reported sexual minority status (defined by sexual attraction) in 2010–2011 and retrospectively reported age at onset of suicidality in 2015–2016. RESULTS Sexual minority adolescents (5.8% of weighted sample) had higher lifetime risk of suicide ideation (26.1% vs 13.0%), plan (16.6% vs 5.4%), and attempt (12.0% vs 5.4%) than heterosexual adolescents. Survival analyses adjusted for demographic characteristics and depressive symptoms revealed positive associations of sexual minority status with time to first onset of suicide ideation (hazard ratio [HR] = 1.77; 95% confidence interval [CI] 1.03–3.06) and plan (HR = 2.69; 95% CI 1.30–5.56). The association between sexual minority status and age at onset of suicide attempt was stronger at age <15 (HR = 3.26; 95% CI 1.25–8.47) than age ≥15 (HR = 0.59; 95% CI 0.21–1.66). The association between sexual minority status and progression from ideation to plan was stronger in the same year of first ideation (HR = 2.01; 95% CI 1.07–3.77) than ≥1 year after first ideation (HR = 1.33; 95% CI 0.26–6.77). CONCLUSIONS Sexual minority adolescents had earlier onset of suicidality and faster progression from suicide ideation to plan than heterosexual adolescents. The assessment of sexual minority status in routine pediatric care has the potential to inform suicide risk screening, management, and intervention efforts among early sexual minority adolescents.