Miracle-dz/UniFAR-FTUs huggingface dataset:
Keytruda and PD-L1: a Real-World Example of Co-development of a Drug with a Predictive Biomarker

Pembrolizumab, an anti–programmed death 1 monoclonal antibody, underwent a rapid clinical development program for the treatment of patients with malignancies in parallel to the development of a companion diagnostic for detecting programmed death ligand 1 (PD-L1) expression, which was considered to be a likely biomarker for response and cancer outcome. When investigating outcomes in patients with non–small cell lung cancer (NSCLC) treated with pembrolizumab, PD-L1 tumor proportion score (TPS) was initially identified as a marker of clinical efficacy, with a cutoff of ≥ 50%. This threshold was later reduced to TPS ≥ 1%, which demonstrated that pembrolizumab offered a clinical benefit in a broader population of patients with PD-L1–expressing tumors. As new evidence emerged, it also became clear that immune cell PD-L1 expression has an important role in predicting tumor response in patients treated with pembrolizumab; the combined positive score (CPS), which accounts for both tumor and immune cell PD-L1 expression, was then applied in clinical studies for indications outside of NSCLC. This review summarizes the outcomes of landmark studies in the KEYNOTE clinical development program that investigated the efficacy of pembrolizumab in patients with a variety of malignancies, the relative outcomes when patients were stratified by PD-L1 status, and how these observations have influenced the approved indications for pembrolizumab.
Establishment of Aedes (Ochlerotatus) scapularis (Diptera: Culicidae) in Mainland Florida, With Notes on the Ochlerotatus Group in the United States

Abstract Aedes scapularis (Rondani), a widespread neotropical vector mosquito species, has been included in the mosquito fauna of Florida on the basis of just three larval specimens that were collected in the middle Florida Keys in 1945. Here, we report numerous recent collections of immature and adult Ae. scapularis from multiple locations in two counties of southern Florida. These specimens represent the first records of Ae. scapularis from mainland Florida and the first records of the species in the state since the initial detection of the species 75 yr ago. Collections of both larvae and adults across several years indicate that Ae. scapularis is now established in Broward and Miami-Dade Counties. These contemporary records of this species in Florida may represent novel dispersal and subsequent establishment events from populations outside the United States or a recent reemergence of undetected endemic populations. To confirm morphological identification of Ae. scapularis specimens from Florida, the DNA barcoding region of the cytochrome c oxidase subunit I gene (COI) was sequenced and compared to all other Ochlerotatus Group species from the United States, specifically Aedes condolescens Dyar and Knab (Diptera: Culicidae), Aedes infirmatus Dyar and Knab (Diptera: Culicidae), Aedes thelcter Dyar (Diptera: Culicidae), Aedes tortilis (Theobald) (Diptera: Culicidae), and Aedes trivittatus (Coquillett) (Diptera: Culicidae). Molecular assays and sequencing confirm morphological identification of Ae. scapularis specimens. Maximum likelihood phylogenetic analysis of COI and ITS2 sequences place Florida Ae. scapularis in a distinct clade, but was unable to produce distinct clades for Florida specimens of Ae. condolescens and Ae. tortilis. Graphical Abstract
Analyse des mouvements des granules de sécrétion à proximité de la membrane plasmique par microscopie de fluorescence à excitation par onde évanescente

La secretion regulee d'hormones est un processus decomposable en plusieurs etapes. Les granules de secretion (GS) contenant ces hormones sont formes au niveau du reseau trans-golgien puis migrent jusqu'a la peripherie de la cellule. Ces hormones sont liberees dans le milieu exterieur par exocytose en cas de stimulation de la cellule. Grâce a l'observation des GS situes dans la region juxta-membranaire par microscopie de fluorescence a excitation par onde evanescente, les mouvements de ces organites ont ete etudies a l'echelle du granule unique. Une methode d'analyse permettant la mise en evidence de comportements transitoires au sein des trajectoires tridimensionnelles des GS a ete mise au point. Grâce a son application a l'etude des effets de drogues du cytosquelette et a des observations en double marquage, nous avons pu associer chaque type de mouvements decrit par les GS a un environnement particulier (GS lie a la membrane plasmique, au cytosquelette d'actine ou de microtubules). Nous avons de plus etudie le role du complexe proteique Rab27A/MyRIP/Myosine Va lors de la capture des GS en peripherie de la cellule et leur accrochage aux filaments d'actine.
Intra-operative neurophysiological monitoring in patients with dystrophic neurofibromatosis type 1 scoliosis

Abstract Objective To analyse the intra-operative neurophysiological monitoring (IONM) data in patients with dystrophic neurofibromatosis type 1 (NF1) associated scoliosis, and to investigate the possible risk factors for failed IONM monitoring. Methods Patients undergoing posterior spinal fusion from September 2015 to December 2019 were retrospectively reviewed. The latency (P37, N50) and amplitude of somatosensory evoked potentials (SEP) in bilateral lower extremities, latency and amplitude of motor evoked potentials (MEP) in bilateral lower extremities and unilateral upper extremity were recorded. The neurological status, curve pattern, Cobb angle of main curve, vertebral rotatory subluxation and dystrophic features at pre-operation were assessed for each patient. The failed IONM monitoring was defined as no reliable SEP or MEP waveforms of all monitored muscles. Results A total of 92 patients (53 M, 39 F) with an average age of 14.1 ± 2.7 years were included. Failed IONM monitoring was identified in 17 patients with overall success rates being 87.0 and 94.6% for SEP and MEP. The average P37 latency, N50 latency, SEP amplitude and MEP latency showed no significant difference between concave and convex sides (p > 0.05 for all). The MEP amplitudes of lower extremities were lower on concave side than convex side (334.5 ± 291.9 µV VS 417.5 ± 380.5 µV, p = 0.030). Higher risk of failed IONM monitoring was found in patients with neurological deficit (p = 0.014) and more dystrophic features (p = 0.002) at pre-operation. Conclusions The overall success rates were 87.0% for SEP and 94.6% for MEP in patients with NF1-associated scoliosis. Neurological deficit and more dystrophic features at pre-operation indicated higher risk of failed IONM monitoring.
Eight-season epidemiological study of match injuries in women’s international rugby sevens

ABSTRACT This study aimed to describe anthropometry and incidence, nature and causes of match injuries in women’s international rugby sevens and to compare these with results reported previously for men’s international rugby sevens. The study comprised an 8-season, prospective study of World Rugby’s women’s Sevens World Series. Over the eight seasons, the overall incidence of injury was 105.6 (95% CI: 96.0 to 116.3) injuries/1000 player-match-hours with a mean injury severity of 53.4 (95% CI: 46.9 to 59.9) days-absence. There were no statistically significant trends for backs or forwards in the incidence (backs: p = 0.470; forwards: p = 0.242) or mean severity (backs: p = 0.098; forwards: p = 0.544) of injuries sustained over the 8-season period. Head/face (20.8%), knee (19.7%), ankle (11.3%) and shoulder/clavicle (8.4%) were the most common injury locations while ligament sprain (31.7%), concussion (15.6%), haematoma/bruise (11.5%) and fracture (11.5%) were the most common types of injury sustained. Being-tackled (35.4%), tackling (26.3%), collisions (13.8%) and rucks (8.8%) were the match events responsible for most injuries. The study indicates that injury burden in women’s international rugby sevens (5,640 days-absence/1000 player-match-hours; 95% CI: 5,123 to 6,209) is similar to that reported previously for men’s international rugby sevens (5,263 days-absence/1000 player-match-hours; 95% CI: 5,000 to 5,540).
The effect of ursodeoxycholic acid on indirect hyperbilirubinemia in neonates treated with phototherapy: a randomized clinical trial

Abstract Objectives Indirect hyperbilirubinemia during neonatal period is a common problem, and most preterm and more than half of the term neonates find this problem. Ursodeoxycholic acid (UDCA) protects the liver against oxidative stresses and prevents cellular apoptosis. In addition, it causes stimulation of bile flow, is well tolerated by the patient, and has limited side effects. Thus, the aim of this study was to investigate the effect of UDCA in treating neonates with unconjugated hyperbilirubinemia undergoing phototherapy. Methods In this randomized clinical trial, 220 neonates with unconjugated hyperbilirubinemia who referred to Amir-Kabir Hospital, Arak, Iran in 2017–2018, were randomly assigned to phototherapy group (Control group) and phototherapy plus UDCA group (Intervention group) as 10 mg/kg/day. The level of total bilirubin was measured at the baseline, and after 12, and 24 h using spectrophotometric, and the duration of receiving phototherapy was also measured in both groups. Results The mean age of included neonates in the control and intervention group was 5.3 and 4.9 days, respectively. The results revealed that after 12 h of treatment, the total bilirubin level in the control group had diminished by 2.70 mg/dL on average while, in the intervention group, the reduction was 3.7 md/dL (p = .001) and after 24 h of treatment, the total bilirubin level in the control group had diminished by 5.22 mg/dL on average and in the intervention group, the reduction was 6.54 md/dL (p = .001). It was also observed that there is no significant difference between groups in terms of the mean of the duration required for phototherapy (p = .63). Conclusions UDCA combined with phototherapy enhances TSB decrease, but this effect is not relevant from a clinical point of view because it does not decrease phototherapy and hospital stay duration. Thus, this study does not support the UDCA use in the clinical practice Trial registration IRCT, IRCT2017071515511N2. Registered 21 Aug 2017 – Retrospectively registered, https://en.irct. ir/trial/14763.
RAB5A is associated with genes involved in exosome secretion: Integration of bioinformatics analysis and experimental validation

Exosomes, as cell–cell communicators with an endosomal origin, are involved in the progression of various diseases. RAB5A, a member of the small Rab GTPases family, which is well known as a key regulator of cellular endocytosis, is expected to be involved in exosome secretion. Here, we found the impact of RAB5A on exosome secretion from human hepatocellular carcinoma cell line using a rapid yet reliable bioinformatics approach followed by experimental analysis. Initially, RAB5A and exosome secretion‐related genes were gathered from bioinformatics tools, namely, CTD, COREMINE, and GeneMANIA; and published papers. Protein–protein interaction (PPI) was then constructed by the Search Tool for Retrieval of Interacting Genes (STRING) database. Among them, several genes with different combined scores were validated by the real‐time quantitative polymerase chain reaction (RT‐qPCR) in stable RAB5A knockdown cells. Thereafter, to validate the bioinformatics results functionally, the impact of RAB5A knockdown on exosome secretion was evaluated. Bioinformatics analysis showed that RAB5A interacts with 37 genes involved in exosome secretion regulatory pathways. Validation by RT‐qPCR confirmed the association of RAB5A with candidate interacted genes and interestingly showed that even medium to low combined scores of the STRING database could be experimentally valid. Moreover, the functional analysis demonstrated that the stable silencing of RAB5A could experimentally decrease exosome secretion. In conclusion, we suggest RAB5A as a regulator of exosome secretion based on our bioinformatics approach and experimental analysis. Also, we propose the usage of PPI‐derived from the STRING database regardless of their combined scores in advanced bioinformatics analysis.
Vγ9γδ T Cell Induction by Human Umbilical Cord Blood Monocytes-Derived, Interferon-α-Stimulated Dendritic Cells

Dendritic cells (DC) are professional antigen-presenting cells that activate T cells to kill cancer cells. The extracellular products of DCs have also been reported to perform the same function. In this study, we examined the in vitro differentiation of umbilical cord blood monocytes into DCs in the presence of GM-CSF, and interferon (IFN)-α. The resulting DC population (called IFN-DCs) were then matured in the presence of TNF-α, and pulsed with total protein extracted from A549 cancer cell line. The pulsed DCs and their conditioned medium were then used to stimulate allogeneic lymphocytes (alloLym). The proliferation and cytotoxicity of alloLym were then determined. The results showed that after 5 days of differentiation, the stimulated monocytes had the typical morphology and characteristic surface markers of DCs. Both unpulsed and pulsed IFN-DCs can induce the proliferation of alloLym, especially Vγ9γδ T cells. The conditioned medium from pulsed and unpulsed IFN-DCs culture also prompted the growth of Vγ9γδ T cells. Moreover, alloLym stimulated with pulsed DCs and their conditioned medium had a greater cytotoxic effect on A549 cells than the ones that were not stimulated. Our results indicated that IFN-DCs and their conditioned medium could induce the anti-tumor immunity in vitro, providing evidence for application of cord blood monocytes-derived, interferon-α- stimulated dendritic cells and their extracellular products in anti-cancer therapy.
Mutational spectra induced by flavonoid extracts from pepper tree (Schinus terebinthifolius, Raddi) stem bark

Flavonoids are a diverse family of plant compounds that are involved in pigmentation, protection, and endogenous regulation. Flavonoids also have medicinal applications, suggesting that they may exert chemoprotective effects. However, some studies have shown, that some plant flavonoids have oxidative and toxic effects, including those produced by Schinus terebinthifolius. In Brazil, extracts of this plant are widely used for medical purposes. In this study, we analyzed the mutagenic potential of two flavonoid‐enriched fractions from Brazilian pepper tree stem bark using Escherichia coli CC strains deficient and proficient in enzymes involved in the DNA repair of oxidative lesions. The highest mutagenic response was detected in the CC104mutMmutY strain but CC104mutY showed a higher mutation frequency than CC104mutM. The spectrum of mutations induced in plasmid DNA is composed of mutations typically caused by oxidative lesions. However, a new type of lesion must be occurred to explain the cytotoxicity, higher mutation rates in the CC104mutY strain, and the rare A:T → T:A and G:C → C:G transversions found in this work.
Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study.

BACKGROUND Coronavirus disease 2019 (COVID-19) is a global public health event without specific therapeutic agents till now. We aim to determine if high dose intravenous vitamin C (HDIVC) was effective for COVID-19 patients in severe condition. METHODS COVID-19 patients admitted in Shanghai Public Health Clinical Center from January 22, 2020 to April 11, 2020 were retrospectively scrolled. The enrolled patients were those with confirmed diagnosis of severe or critical COVID-19 pneumonia, who received HDIVC within 24 hours after disease aggravation. Main clinical outcomes obtained from 3-5 days (day 3) and 7-10 days (day 7) after HDIVC were compared to the ones just before (day 0) HDIVC. RESULTS Totally, twelve patients were enrolled including six severe [age of mean, 56; interquartile range (IQR), 32-65 years, 3 men] and six critical (age of mean, 63; IQR, 60-82 years, 4 men) patients. The dosage of vitamin C [median (IQR), mg/kg (body weight)/day] were [162.7 (71.1-328.6)] for severe and [178.6 (133.3-350.6)] for critical patients. By Generalized estimating equation (GEE) model, C-reactive protein (CRP) was found to decrease significantly from day 0 to 3 and 7 (severe: 59.01±37.9, 12.36±22.12, 8.95±20.4; critical: 92.5±41.21, 33.9±30.2, 59.56±41.4 mg/L). Lymphocyte and CD4+ T cell counts in severe patients reached to normal level since day 3. Similar improving trends were observed for PaO2/FiO2 (severe: 209.3±111.7, 313.4±146, 423.3±140.8; critical: 119.9±52.7, 201.8±86.64, 190.5±51.99) and sequential organ failure assessment score (severe: 2.83±1.72, 1.33±1.63, 0.67±1.03; critical: 6.67±2.34, 4.17±2.32, 3.83±2.56). Better improving effect was observed in severe than critical patients after HDIVC. CONCLUSIONS HDIVC might be beneficial in aspects of inflammatory response, immune and organ function for aggravation of COVID-19 patients. Further clinical trials are in warrant. TRIAL REGISTRATION This trial has been retrospectively registered in Chinese Clinical Trail Registry (ChiCTR2000032716) on May 8, 2020. http://www.chictr. org.cn/showproj.aspx? proj=53389.
How Effective Are Dementia Caregiver Interventions? An Updated Comprehensive Meta-Analysis.

BACKGROUND AND OBJECTIVES Caring for a person with dementia places a significant burden upon informal caregivers and leads to decreased psychological and physical health, which is why dementia caregiver interventions have been developed. However, empirical evidence for the efficacy of those interventions is inconclusive and the last comprehensive meta-analysis (Pinquart & Sörensen. Helping caregivers of persons with dementia: Which interventions work and how large are their effects? International Psychogeriatrics. 2006;18(4), 577-595. ) was published more than 10 years ago. RESEARCH DESIGN AND METHOD This meta-analysis aims to update the meta-analysis conducted by Pinquart and Sörensen. Based on a systematic search in electronic data bases, effects of 282 controlled studies were integrated. The effectiveness of different intervention types and influences of study characteristics were evaluated. RESULTS Interventions had, on average, a significant, small-to-moderate effect on the improvement of ability/knowledge, subjective well-being, burden, depression, and the caregiver's anxiety as well as symptoms of the care recipient. No mean effect was found in regard to reducing the risk of institutionalization. Most intervention types had an effect on the reduction of burden as well as on other outcomes. Psychoeducation and multicomponent interventions affected most outcomes, whereas the efficacy of other intervention types was domain-specific. DISCUSSION AND IMPLICATIONS There is evidence for the efficacy of dementia caregiver interventions, though due to having predominantly small effect sizes, there is still room for improvement. Interventions should be tailored to the desired outcome. More research on long-term effects, effects on anxiety and institutionalization, efficacy of respite and support interventions, care recipient training, and the intervention process is needed.
Predictors of recovery in children aged 6–59 months with uncomplicated severe acute malnutrition: a multicentre study

Abstract Objective: To identify predictors of recovery in children with uncomplicated severe acute malnutrition (SAM). Design: This is a secondary data analysis from an individual randomised controlled trial, where children with uncomplicated SAM were randomised to three feeding regimens, namely ready-to-use therapeutic food (RUTF) sourced from Compact India, locally prepared RUTF or augmented home-prepared foods, under two age strata (6–17 months and 18–59 months) for 16 weeks or until recovery. Three sets of predictors that could influence recovery, namely child, family and nutritional predictors, were analysed. Setting: Rural and urban slum areas of three states of India, namely Rajasthan, Delhi and Tamil Nadu. Participants: In total, 906 children (age: 6–59 months) were analysed to estimate the adjusted hazard ratio (AHR) using the Cox proportional hazard ratio model to identify various predictors. Results: Being a female child (AHR: 1·269 (1·016, 1·584)), better employment status of the child’s father (AHR: 1·53 (1·197, 1·95)) and residence in a rental house (AHR: 1·485 (1·137, 1·94)) increased the chances of recovery. No hospitalisation (AHR: 1·778 (1·055, 2·997)), no fever, (AHR: 2·748 (2·161, 3·494)) and ≤ 2 episodes of diarrhoea (AHR: 1·579 (1·035, 2·412)) during the treatment phase; availability of community-based peer support to mothers for feeding (AHR: 1·61 (1·237, 2·097)) and a better weight-for-height Z-score (WHZ) at enrolment (AHR: 1·811 (1·297, 2·529)) predicted higher chances of recovery from SAM. Conclusion: The probability of recovery increases in children with better WHZ and with the initiation of treatment for acute illnesses to avoid hospitalisation, availability of peer support and better employment status of the father.
Long-term Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin-containing Mushrooms

ABSTRACT Obsessive Compulsive Disorder (OCD) is a chronic neuropsychiatric condition, characterized by obsessions and compulsions, which is usually disabling for the suffering individual. The first-line treatment is not effective in all patients. There is evidence showing the effectiveness of psilocybin and psilocybin-containing mushrooms in the treatment of OCD symptoms. We present the case of a male adult with OCD who showed a clinically meaningful reduction of his OCD symptomatology after the consumption of psilocybin-containing mushrooms. Future research will determine if psilocybin and other psychoactive compounds of psilocybin-containing mushrooms are effective and safe for the treatment of OCD.
Nurses' assessments of staffing adequacy in care services for older patients following hospital discharge

Abstract Aims To explore community nurses' assessments of staffing adequacy in care provision for older patients following hospital discharge and analyse the extent to which their assessments are associated with characteristics of the system level of municipality and vertical coordination between hospital and community care services. Design Nation‐wide cross‐sectional survey. Methods Web‐based survey conducted in 2017 among 3,461 nurses working with older persons (65+) in homecare services, residential care and nursing homes in Norway. Responses from individual homecare nurses were linked with municipal‐level register data (age structure, economic flexibility, service profiles). Stratified multilevel analyses were used to analyse the association of staffing adequacy with municipal characteristics and perceived quality of vertical coordination. Results Almost half of the nurses experienced inadequate staffing in general, whereas a similar share indicated that staffing was adequate. Nursing home nurses showed the least positive ratings of staffing adequacy. Most nurses indicated that there were too many unqualified care workers at their workplace. More positive assessments of staffing adequacy were associated with better vertical coordination. Average ratings of staffing adequacy were lower in larger municipalities and municipalities with an older population. Conclusion Healthcare providers, nurse managers and policy makers may benefit from a stronger focus on rebalancing skill‐mix and on new models of vertical coordination in addressing current and future nurse staffing shortages in care services for older people following hospital discharge. Impact statement This study adds to the scarce national and international research literature on nurse staffing in community care services, addressing the pressing challenges of staffing and skill‐ mix in long‐term care provision. Findings support the development of nurse‐led models of care coordination for older patients following hospital discharge and stimulate future research on the effects of recruitment and retainment strategies in different municipalities and different models of vertical coordination.