Miracle-dz/UniFAR-FTUs huggingface dataset:
A single bout of coordination training does not lead to EIH in young healthy men – a RCT

Abstract Objectives Physical activity can lead to hypoalgesic effects and is often recommended as part of multidisciplinary pain management. Based on the idea, that in future specific and more differentiated sports therapeutic interventions could be used for a multidisciplinary pain management, various type of sports and their effects on pain sensitivity should be analysed. Whereas endurance as well as strengthening exercises are associated with a decrease in pain sensitivity in healthy people as well as people with chronic pain states, the effects of a specific coordination training (CT) on pain sensitivity have not yet been sufficiently investigated. Therefore, aim of the present study was to examine if a single bout of CT leads to exercised-induced hypoalgesia in young healthy men. Methods Thirty five healthy men (mean age 27 ± 3 years) were examined in a randomised crossover design before and after a single bout of 45-min CT and a 45-min resting session as control condition by means of Quantitative Sensory Testing (QST). The QST is a validated instrument to assess the function of the somatosensory system, by applying thermal and mechanical stimuli. By doing so, various detection and pain thresholds were determined at the dorsum of one foot. Exercises of CT were chosen to generate high proprioceptive input for the ankle joints. Results Analysis of the QST data in respect of the factors group (CT/control condition), time (pre/post) and stimuli (parameter of QST) revealed no statistically significant main effects of a single bout of CT on somatosensory system, neither for the factors group*time (p=0.51), nor the factors group*time*stimuli (p=0.32). All stimuli remained constant in the course of both conditions (e.g. mean ± sd of heat pain threshold pre/post in °C: coordination: 44.7 ± 3.1/44.8 ± 2.9; rest: 45.5 ± 3.0/44.9 ± 3.0). Conclusions In this setting, a single bout of CT had no effect on the somatosensory system in young healthy men. Therefore, this specific CT did not lead to an exercised-induced hypoalgesia in healthy people. Intensity of sensory input during training intervention might be too low to generate analgesic effects in a non-pathological altered somatosensory system of young healthy men. Further research is needed to clarify if a CT can induce exercised-induced hypoalgesia in people with pathological alterations of the somatosensory system. In addition, it has to examined if analgesic effects can be induced by changing the intensity of CT in healthy people. Detailed knowledge regarding the effects of different training interventions on pain modulation is needed to completely understand the mechanism of exercised-induced hypoalgesia.
Stress-related cognitive style is related to volumetric change of the hippocampus and FK506 binding protein 5 polymorphism in post-traumatic stress disorder

Abstract Background Patients with post-traumatic stress disorder (PTSD) show a different stress-related cognitive style compared with healthy controls (HC). The FK506 binding protein 5 gene (FKBP5), one of the PTSD known risk factors, is involved in the stress response through the hypothalamic-pituitary-adrenal axis and brain volumetric alterations. The present study aimed to uncover the neural correlates of stress-related cognitive styles through the analysis of the regional brain volumes and FKBP5 genotype in patients with PTSD compared with HC. Methods In this study, 51 patients with PTSD and 94 HC were assessed for stress-related cognitive styles, PTSD symptoms severity, and genotype of FKBP5 single nucleotide polymorphisms, and underwent T1-weighted structural magnetic resonance imaging. Diagnosis-by-genotype interaction for regional brain volumes was examined in 16 brain regions of interest. Results Patients with PTSD showed significantly higher levels of catastrophizing, ruminative response, and repression, and reduced distress aversion and positive reappraisal compared with HC (p < 0.001). Significant diagnosis-by-genotype interactions for regional brain volumes were observed for bilateral hippocampi and left frontal operculum. A significant positive correlation between the severity of the repression and left hippocampal volume was found in a subgroup of patients with PTSD with FKBP5 rs3800373 (AA genotype) or rs1360780 (CC genotype). Conclusions The present study showed the influences of FKBP5 genotype on the distorted cognitive styles in PTSD by measuring the volumetric alteration of hippocampal regions, providing a possible role of the hippocampus and left frontal operculum as significant neurobiological correlates of PTSD.
Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity

Manganese (Mn)-induced neurotoxicity resembles Parkinson's disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week–old YY1flox/flox mice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. 3 weeks after adeno-associated viral (AAV) infusion, mice were exposed to 330 μg of Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by Western blotting, quantitative PCR, and immunohistochemistry to assess YY1, TH, GLAST, and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced impairment of motor functions, reduction of TH-expressing cells in SN, and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with histone deacetylases in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.
Potential of Liver T1 Mapping for the Detection of Fontan-associated Liver Disease in Adults

Purpose: The native T1 value at 3T MRI is a sensitive marker for diffuse fibrosis or damage in various organs including the heart, liver, and pancreas. Despite the fact that Fontan-associated liver disease (FALD) is a crucial issue in adults with Fontan circulation, there are only a few studies with liver T1 mapping in children and adolescents. We investigated the potential of the liver native T1 mapping in detecting FALD in adult patients. Methods: We prospectively enrolled 16 consecutive adults with Fontan circulation (age 31.3 ± 8.5 years), who were in New York Heart Association Functional class II–IV. Twenty with tetralogy of Fallot (TOF), and 20 age-matched controls also underwent cardiac magnetic resonance (CMR) imaging at 3T. Myocardial T1 mapping with a Modified Look-Locker Inversion recovery sequence was applied to liver T1 mapping. Patients in the Fontan group underwent the right heart catheter and liver function tests, including those for fibrotic markers. Results: Liver native T1 values in the Fontan group were significantly higher than that in TOF and controls (P < 0.001). In the Fontan group, the liver native T1 value was significantly correlated with age, γ -glutamyltransferase, model for end-stage liver disease XI score, and albumin-bilirubin score (P = 0.01, 0.01, 0.044, 0.001). However, it demonstrated no correlation with central venous pressure, pulmonary vessel resistance, or fibrotic markers. Conclusion: Liver native T1 value derived from CMR may be a non-invasive adjunctive and/or screening marker to detect FALD.
A proton-coupled folate transporter mutation causing hereditary folate malabsorption locks the protein in an inward-open conformation

The proton-coupled folate transporter (PCFT, SLC46A1) is required for folate intestinal absorption and transport across the choroid plexus. Recent work has identified a F392V mutation causing hereditary folate malabsorption. However, the residue properties responsible for this loss of function remains unknown. Using site-directed mutagenesis, we observed complete loss of function with charged (Lys, Asp, and Glu) and polar (Thr, Ser, and Gln) Phe-392 substitutions and minimal function with some neutral substitutions; however, F392M retained full function. Using the substituted-cysteine accessibility method (with N-biotinyl aminoethyl methanethiosulfonate labeling), Phe-392 mutations causing loss of function, although preserving membrane expression and trafficking, also resulted in loss of accessibility of the substituted cysteine in P314C-PCFT located within the aqueous translocation pathway. F392V function and accessibility of the P314C cysteine were restored by insertion of a G305L (suppressor) mutation. A S196L mutation localized in proximity to Gly-305 by homology modeling was inactive. However, when inserted into the inactive F392V scaffold, function was restored (mutually compensatory mutations), as was accessibility of the P314C cysteine residue. Reduced function, documented with F392H PCFT, was due to a 15-fold decrease in methotrexate influx Vmax, accompanied by a decreased influx Kt (4.5-fold) and Ki (3-fold). The data indicate that Phe-392 is required for rapid oscillation of the carrier among its conformational states and suggest that this is achieved by dampening affinity of the protein for its folate substrates. F392V and other inactivating Phe-392 PCFT mutations lock the protein in its inward-open conformation. Reach (length) and hydrophobicity of Phe-392 appear to be features required for full activity.
Sample size determination for Bayesian analysis of small n sequential, multiple assignment, randomized trials (snSMARTs) with three agents

ABSTRACT The small n, Sequential, Multiple Assignment, Randomized Trial (snSMART) is a two-stage clinical trial design for rare diseases motivated by the comparison of three active treatments for isolated skin vasculitis in the ongoing clinical trial ARAMIS (a randomized multicenter study for isolated skin vasculitis, NCT09239573). In Stage 1, all patients are randomized to one of three treatments. In Stage 2, patients who respond to their initial treatment receive the same treatment again, while those who fail to respond are re-randomized to one of the two remaining treatments. A Bayesian method for estimating the response rate of each individual treatment in a three-arm snSMART demonstrated efficiency gains for a given sample size relative to other existing frequentist approaches. However, these efficiency gains are dependent upon knowing how many subjects are required to determine a specific difference in the treatment response rates. Because few sample size calculation methods for snSMARTs exist, we propose a Bayesian sample size calculation for an snSMART designed to distinguish the best treatment from the second-best treatment. Although our methods are based on asymptotic approximations, we demonstrate via simulations that our proposed sample size calculation approach produces the desired statistical power, even in small samples. Moreover, our methods and applet produce sample sizes quickly, thereby saving time relative to using simulations to determine the appropriate sample size. We compare our proposed sample size to an existing frequentist method based upon a weighted -statistic and demonstrate that the Bayesian method requires far fewer patients than the frequentist method for a study with the same design parameters.
Clinical Outcomes and Angiographic Results of Bailout Stenting for Guide Catheter-Induced Iatrogenic Coronary Artery Dissection　- Impact of Stent Type.

BACKGROUND Guide catheter-induced iatrogenic coronary artery dissection is a rare but feared complication. When it occurs, bailout stenting is widely performed; however, its prognosis and the impact of stent type remains unclear.Methods and Results:The study population consisted of 77,257 consecutive patients (coronary angiography, 55,864; percutaneous coronary intervention, 21,393) between 2000 and 2015. We investigated the incidence, clinical outcomes, and angiographic results after bailout stenting and compared by stent type: bare-metal stent (BMS) and drug-eluting stent (DES). Iatrogenic coronary artery dissection occurred in 105 patients (incidence rate, 0.14%). All cases of iatrogenic coronary artery dissection that were recognized as requiring bailout procedure could be managed by stent implantation, and no patients died during bailout procedure. The 5-year cumulative incidences of cardiac death, target lesion revascularization, and major adverse cardiac events were 11.3%, 10.3%, and 21.0%, respectively. The binary restenosis rate was 10.4%, and it was not significantly different between BMS and DES implantation. In lesions with preprocedural stenosis, however, it was significantly lower in the DES group than in the BMS group. On the other hand, coronary artery dissection recurred in 8 patients, which was observed only after DES implantation. CONCLUSIONS The immediate and long-term outcomes of bailout stenting for iatrogenic coronary artery dissection were acceptable. Although DES may be favorable for stenotic lesions, coronary artery dissection can recur after DES implantation.
The response of lianas to 20 years of nutrient addition in a Panamanian forest.

Over the past two decades, liana density and basal area have been increasing in many tropical forests, which has profound consequences for forest diversity and functioning. One hypothesis to explain increasing lianas is elevated nutrient deposition in tropical forests resulting from fossil fuels, agricultural fertilizer, and biomass burning. We tested this hypothesis by surveying all lianas ≥ 1 cm in diameter (n=3967) in 32 plots in a fully factorial nitrogen (N), phosphorus (P) and potassium (K) addition experiment in a mature tropical forest in central Panama. We conducted the nutrient addition experiment from 1998 until present and we first censused lianas in 2013 and then again in 2018. After 20-years of nutrient addition (1998-2018), liana density, basal area, and rarefied species richness did not differ significantly among any of the nutrient addition and control treatments. Moreover, nutrient addition in the most recent five years of the experiment did not change liana relative growth, recruitment, or mortality rates. From 2013 until 2018, liana density, basal area, and species richness increased annually by 1.6%, 1.4%, and 2.4%, respectively. Nutrient addition did not affect these increases. Our findings indicate that nutrient deposition does not explain increasing lianas in this tropical forest. Instead, increases in tree mortality and disturbance, atmospheric carbon dioxide, drought frequency and severity, and hunting pressure are more likely explanations for the increase in lianas in tropical forests.
Survival and predictors of deaths of patients hospitalised due to COVID-19 from a retrospective and multicentre cohort study in Brazil

Abstract This study aimed to analyse the survival of patients admitted to Brazilian hospitals due to the COVID-19 and estimate prognostic factors. This is a retrospective, multicentre cohort study, based on data from 46 285 hospitalisations for COVID-19 in Brazil. Survival functions were calculated using the Kaplan–Meier's method. The log-rank test compared the survival functions for each variable and from that, hazard ratios (HRs) were calculated, and the proportional hazard model was used in Cox multiple regression. The smallest survival curves were the ones for patients at the age of 68 years or more, black/mixed race, illiterate, living in the countryside, dyspnoea, respiratory distress, influenza-like outbreak, O2 saturation <95%, X-ray change, length of stay in the intensive care unit (ICU), invasive ventilatory support, previous heart disease, pneumopathy, diabetes, Down's syndrome, neurological disease and kidney disease. Better survival was observed in the influenza-like outbreak and in an asthmatic patient. The multiple model for increased risk of death when they were admitted to the ICU HR 1.28, diabetes HR 1.17, neurological disease HR 1.34, kidney disease HR 1.11, heart disease HR 1.14, black or mixed race of HR 1.50, asthma HR 0.71 and pneumopathy HR 1.12. This reinforces the importance of socio-demographic and clinical factors as a prognosis for death.
Association of Urinary Matrix Metalloproteinase 7 Levels With Incident Renal Flare in Lupus Nephritis

Flares of lupus nephritis (LN) are frequent and associated with impaired renal prognosis. One major management obstacle in LN flare is the lack of effective methods to identify at‐risk patients earlier in their disease course. This study was undertaken to test the utility of measurement of urinary matrix metalloproteinase 7 (MMP‐7) for the dynamic surveillance of renal disease activity and prediction of renal flares in LN.
Years of life lost associated with COVID-19 deaths in the United States

Abstract Background The mortality effects of COVID-19 are a critical aspect of the disease’s impact. Years of life lost (YLLs) can provide greater insight than the number of deaths by conveying the shortfall in life expectancy and thus the age profile of the decedents. Methods We employed data regarding COVID-19 deaths in the USA by jurisdiction, gender and age group for the period 1 February 2020 through 11 July 2020. We used actuarial life expectancy tables by gender and age to estimate YLLs. Results We estimated roughly 1.2 million YLLs due to COVID-19 deaths. The YLLs for the top six jurisdictions exceeded those for the remaining 43. On a per-capita basis, female YLLs were generally higher than male YLLs throughout the country. Conclusions Our estimates offer new insight into the effects of COVID-19. Our findings of heterogenous rates of YLLs by geography and gender highlight variation in the magnitude of the pandemic’s effects that may inform effective policy responses.
In Silico Drug Repurposing for SARS-CoV-2 Main Proteinase and Spike Proteins

The pandemic caused by SARS-CoV-2 is currently representing a major health and economic threat to humanity. So far, no specific treatment to this viral infection has been developed and the emergency still requires an efficient intervention. In this work, we used virtual screening to facilitate drug repurposing against SARS-CoV-2, targeting viral main proteinase and spike protein with 3000 existing drugs. We used a protocol based on a docking step followed by a short molecular dynamic simulation and rescoring by the Nwat-MMGBSA approach. Our results provide suggestions for prioritizing in vitro and/or in vivo tests of already available compounds.
Effect of Comorbidity on Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD1 Immunotherapy

Background Comorbidities are reportedly related to the survival of patients with non-small cell lung cancer (NSCLC). The purpose of this study was to explore the impact of comorbidity, assessed by the Charlson comorbidity index (CCI) and the simplified comorbidity scores (SCS) on clinical outcomes of patients with NSCLC treated with immune checkpoint inhibitors. Material/Methods Sixty-six patients with NSCLC who received programmed cell death protein 1 (PD1) inhibitors in our institution in the past 2 years were enrolled in this retrospective study. Data on comorbidity (CCI and SCS) and clinical outcomes, including progression-free survival (PFS), immunotherapy responses, and immunotherapy-related adverse events, were analyzed. Results The disease control rate was obviously higher among patients in the CCI <1 group than the CCI ≥1 group (P<0.001), but were similar between the SCS <8 group and SCS ≥8 group (P=0.585). The median PFS in the CCI <1 group was 271.0 days (95% CI: 214.3–327.7 days) compared with 232.0 days (95% CI: 66.2–397.8 days) for the CCI ≥1 group (P=0.0084). However, the median PFS showed no difference between the groups with SCS <8 at 271.0 days (95% CI: 138.7–403.3 days) versus SCS ≥8 at 222.0 days (95% CI: 196.2–247.8 days), P=0.2106). The incidence of adverse events was similar among patients with high versus low comorbidity indexes (CCI: 35.8% versus 23.6%, P=0.286, respectively; and SCS: 28.0% versus 29.3%, respectively, P=0.912). Conclusions The comorbidity burden might be a predictor for survival in patients with NSCLC undergoing PD1 inhibitor immunotherapy.
Response surface methodology optimization of polyhydroxyalkanoate production by Burkholderia cepacia BPT1213 using waste glycerol from palm oil‐based biodiesel production

The feasibility of using waste glycerol from the biodiesel industry for biosynthesis of polyhydroxyalkanoate (PHA) by Burkholderia cepacia BPT1213 was evaluated. Culture conditions were optimized by growing B. cepacia BPT1213 in mineral salt medium supplemented with 2% waste glycerol in a 2.5 L bioreactor. Response surface methodology was used to determine the influence of aeration rate (0.6–1.8 vvm), agitation speed (100–300 rpm), and cultivation period (48–72 hr) on PHA production. The optimum conditions for the growth and PHA accumulation were 1.5 vvm, 300 rpm, and 72 hr, with predicted values of 5.08 g/L cell dry weight (CDW), 66.07% PHA content, and 3.35 g/L total PHA concentration. Using these conditions, the experimental system produced 5.63 g/L of CDW with 64.00% wt/wt PHA content, which is threefold higher PHA concentration (3.60 g/L) compared to the non‐optimized conditions. The melting temperature (Tm) of purified PHA was 173.45 ± 1.05°C. In conclusion, the statistical approach was significantly increased the PHA production using waste glycerol as the sole carbon source.