Miracle-dz/UniFAR-FTUs huggingface dataset:
Macitentan Improves Risk Categorization for Liver Transplant Mortality in Patients With Portopulmonary Hypertension: A PORTICO Study Post Hoc Analysis

Portopulmonary hypertension (PoPH) is pulmonary arterial hypertension (PAH) associated with portal hypertension, usually caused by liver cirrhosis. Prognosis is poor for patients with PoPH and liver transplant (LT) can be life-saving; however, pre- and post-transplant outcomes depend on pre-LT cardiopulmonary hemodynamics. The recently-completed PORTICO study evaluated the effects of macitentan, an endothelin receptor antagonist, in PoPH patients and was the first randomized controlled trial of a PAH therapy specifically conducted in this patient population. In PORTICO, 85 participants were randomized to receive either macitentan (n=43) or placebo (n=42). The study showed that macitentan significantly improved pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (mPAP) as compared with placebo, was generally well tolerated and did not lead to further adverse liver conditions. Here we report a post-hoc analysis of the PORTICO study, evaluating whether changes in PVR and mPAP could improve risk categorization for LT mortality. Based on hemodynamic criteria and changes achieved after 12 weeks, treatment with macitentan improved patients' risk category for both LT perioperative mortality (odds ratio: 4.9; 95% confidence interval: 1.6, 17.7) and waitlist mortality (odds ratio: 10.5; 95% confidence interval: 2.4, 66.8). In conclusion, macitentan treatment could potentially decrease the risk of LT-related death in PoPH patients; however, further research is required to establish if these changes translate into improvements in survival in a real-world setting.
Updated National Estimates of Disparities in Physical Activity and Sports Participation Experienced by Children and Adolescents With Disabilities: NSCH 2016-2017.

BACKGROUND Children and adolescents with disabilities often report low levels of physical activity (PA). Estimating the magnitude of PA disparities has been previously challenged by underreporting and variability in subsampling of disability. Using the National Survey of Children's Health, this study estimated the population-level PA disparities experienced and the association between disability status and PA engagement. METHODS Weighted prevalence of PA engagement (National Physical Activity Guidelines for Americans (2nd edition) and sports participation) was compared across disability groups for children (n = 20,867, 6-11 y) and adolescents (n = 28,651, 12-17 y) and found to be 12%. Age-stratified multivariable logistic regressions estimated the likelihood of PA engagement as a function of disability status and type, after adjusting for child and household factors. RESULTS Children, but not adolescents, with disabilities had significantly lower odds of being sufficiently active compared with peers without disabilities (adjusted odds ratio = 0.75; 95% confidence interval, 0.60-0.94). Across age groups, the lowest prevalence rates were observed among those experiencing function and mobility disabilities. Children and adolescents were significantly less likely to participate in sports compared with peers. CONCLUSION Children with function and mobility disabilities were identified as priority subpopulations least likely to be sufficiently active. The disparity in sports participation highlights a critical intervention point for increasing PA among children with disabilities.
Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD

Background Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described. Methods Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation. Results Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1). Conclusions Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.
Have We Looked in the Wrong Direction for More Than 100 Years? Delayed Onset Muscle Soreness Is, in Fact, Neural Microdamage Rather Than Muscle Damage

According to our hypothesis, delayed onset muscle soreness (DOMS) is an acute compression axonopathy of the nerve endings in the muscle spindle. It is caused by the superposition of compression when repetitive eccentric contractions are executed under cognitive demand. The acute compression axonopathy could coincide with microinjury of the surrounding tissues and is enhanced by immune-mediated inflammation. DOMS is masked by sympathetic nervous system activity at initiation, but once it subsides, a safety mode comes into play to prevent further injury. DOMS becomes manifest when the microinjured non-nociceptive sensory fibers of the muscle spindle stop inhibiting the effects of the microinjured, hyperexcited nociceptive sensory fibers, therefore providing the ‘open gate’ in the dorsal horn to hyperalgesia. Reactive oxygen species and nitric oxide play a cross-talking role in the parallel, interlinked degeneration–regeneration mechanisms of these injured tissues. We propose that the mitochondrial electron transport chain generated free radical involvement in the acute compression axonopathy. ‘Closed gate exercises’ could be of nonpharmacological therapeutic importance, because they reduce neuropathic pain in addition to having an anti-inflammatory effect. Finally, DOMS could have an important ontogenetical role by not just enhancing ability to escape danger to survive in the wild, but also triggering muscle growth.
Immunogenicity, Safety, and Efficacy of a Standalone Universal Influenza Vaccine, FLU-v, in Healthy Adults

Background FLU-v is a broad-spectrum influenza vaccine that induces antibodies and cell-mediated immunity. Objective To compare the safety, immunogenicity, and exploratory efficacy of different formulations and dosing regimens of FLU-v versus placebo. Design Randomized, double-blind, placebo-controlled, single-center phase 2b clinical trial. (ClinicalTrials.gov: NCT02962908; EudraCT: 2015-001932-38). Setting The Netherlands. Participants 175 healthy adults aged 18 to 60 years. Intervention 0.5-mL subcutaneous injection of 500 µg of adjuvanted (1 dose) or nonadjuvanted (2 doses) FLU-v (A-FLU-v or NA-FLU-v) or adjuvanted or nonadjuvanted placebo (A-placebo or NA-placebo) (2:2:1:1 ratio). Measurements Vaccine-specific cellular responses at days 0, 42, and 180 were assessed via flow cytometry and enzyme-linked immunosorbent assay. Solicited information on adverse events (AEs) was collected for 21 days after vaccination. Unsolicited information on AEs was collected throughout the study. Results The AEs with the highest incidence were mild to moderate injection site reactions. The difference between A-FLU-v and A-placebo in the median fold increase in secreted interferon-γ (IFN-γ) was 38.2-fold (95% CI, 4.7- to 69.7-fold; P = 0.001) at day 42 and 25.0-fold (CI, 5.7- to 50.9-fold; P < 0.001) at day 180. The differences between A-FLU-v and A-placebo in median fold increase at day 42 were 4.5-fold (CI, 2.3- to 9.8-fold; P < 0.001) for IFN-γ-producing CD4+ T cells, 4.9-fold (CI, 1.3- to 40.0-fold; P < 0.001) for tumor necrosis factor-α (TNF-α), 7.0-fold (CI, 3.5- to 18.0-fold; P < 0.001) for interleukin-2 (IL-2), and 1.7-fold (CI, 0.1- to 4.0-fold; P = 0.004) for CD107a. At day 180, differences were 2.1-fold (CI, 0.0- to 6.0-fold; P = 0.030) for IFN-γ and 5.7-fold (CI, 2.0- to 15.0-fold; P < 0.001) for IL-2, with no difference for TNF-α or CD107a. No differences were seen between NA-FLU-v and NA-placebo. Limitation The study was not powered to evaluate vaccine efficacy against influenza infection. Conclusion Adjuvanted FLU-v is immunogenic and merits phase 3 development to explore efficacy. Primary Funding Source SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project.
Thromboprophylaxis in the End-of-Life Cancer Care: The Update

Cancer patients are at increased risk for venous thromboembolism (VTE), which further increases with advanced stages of malignancy, prolonged immobilization, or prior history of thrombosis. To reduce VTE-related mortality, many official guidelines encourage the use of thromboprophylaxis (TPX) in cancer patients in certain situations, e.g., during chemotherapy or in the perioperative period. TPX in the end-of-life care, however, remains controversial. Most recommendations on VTE prophylaxis in cancer patients are based on the outcomes of clinical trials that excluded patients under palliative or hospice care. This translates to the paucity of official guidelines on TPX dedicated to this group of patients. The problem should not be underestimated as VTE is known to be associated with symptoms adversely impacting the quality of life (QoL), i.e., limb or chest pain, dyspnea, hemoptysis. In end-of-life care, where the assurance of the best possible QoL should be the highest priority, VTE prophylaxis may eliminate the symptom burden related to thrombosis. However, large randomized studies determining the benefits and risks profiles of TPX in patients nearing the end of life are lacking. This review summarized available data on TPX in this population, analyzed potential tools for VTE risk prediction in the view of this group of patients, and summarized the most current recommendations on TPX pertaining to terminal care.
Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice

Background Apixaban and rivaroxaban are the most commonly prescribed direct oral anticoagulants for adults with atrial fibrillation, but head-to-head data comparing their safety and effectiveness are lacking. Objective To compare the safety and effectiveness of apixaban versus rivaroxaban for patients with nonvalvular atrial fibrillation. Design New-user, active-comparator, retrospective cohort study. Setting A U.S. nationwide commercial health care claims database from 28 December 2012 to 1 January 2019. Patients Adults newly prescribed apixaban (n = 59 172) or rivaroxaban (n = 40 706). Measurements The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial hemorrhage or gastrointestinal bleeding. Results 39 351 patients newly prescribed apixaban were propensity score matched to 39 351 patients newly prescribed rivaroxaban. Mean age was 69 years, 40% of patients were women, and mean follow-up was 288 days for new apixaban users and 291 days for new rivaroxaban users. The incidence rate of ischemic stroke or systemic embolism was 6.6 per 1000 person-years for adults prescribed apixaban compared with 8.0 per 1000 person-years for those prescribed rivaroxaban (hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.98]; rate difference, 1.4 fewer events per 1000 person-years [CI, 0.0 to 2.7]). Adults prescribed apixaban also had a lower rate of gastrointestinal bleeding or intracranial hemorrhage (12.9 per 1000 person-years) compared with those prescribed rivaroxaban (21.9 per 1000 person-years), corresponding to an HR of 0.58 (CI, 0.52 to 0.66) and a rate difference of 9.0 fewer events per 1000 person-years (CI, 6.9 to 11.1). Limitation Unmeasured confounding, incomplete laboratory data. Conclusion In routine care, adults with atrial fibrillation prescribed apixaban had a lower rate of both ischemic stroke or systemic embolism and bleeding compared with those prescribed rivaroxaban. Primary Funding Source Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital.
Hyperpolarized 13C MRI: A novel approach for probing cerebral metabolism in health and neurological disease

Cerebral metabolism is tightly regulated and fundamental for healthy neurological function. There is increasing evidence that alterations in this metabolism may be a precursor and early biomarker of later stage disease processes. Proton magnetic resonance spectroscopy (1H-MRS) is a powerful tool to non-invasively assess tissue metabolites and has many applications for studying the normal and diseased brain. However, the technique has limitations including low spatial and temporal resolution, difficulties in discriminating overlapping peaks, and challenges in assessing metabolic flux rather than steady-state concentrations. Hyperpolarized carbon-13 magnetic resonance imaging is an emerging clinical technique that may overcome some of these spatial and temporal limitations, providing novel insights into neurometabolism in both health and in pathological processes such as glioma, stroke and multiple sclerosis. This review will explore the growing body of pre-clinical data that demonstrates a potential role for the technique in assessing metabolism in the central nervous system. There are now a number of clinical studies being undertaken in this area and this review will present the emerging clinical data as well as the potential future applications of hyperpolarized 13C magnetic resonance imaging in the brain, in both clinical and pre-clinical studies.
One‐carbon metabolism, folate, zinc and translation

The translation process, central to life, is tightly connected to the one‐carbon (1‐C) metabolism via a plethora of macromolecule modifications and specific effectors. Using manual genome annotations and putting together a variety of experimental studies, we explore here the possible reasons of this critical interaction, likely to have originated during the earliest steps of the birth of the first cells. Methionine, S‐adenosylmethionine and tetrahydrofolate dominate this interaction. Yet, 1‐C metabolism is unlikely to be a simple frozen accident of primaeval conditions. Reactive 1‐C species (ROCS) are buffered by the translation machinery in a way tightly associated with the metabolism of iron–sulfur clusters, zinc and potassium availability, possibly coupling carbon metabolism to nitrogen metabolism. In this process, the highly modified position 34 of tRNA molecules plays a critical role. Overall, this metabolic integration may serve both as a protection against the deleterious formation of excess carbon under various growth transitions or environmental unbalanced conditions and as a regulator of zinc homeostasis, while regulating input of prosthetic groups into nascent proteins. This knowledge should be taken into account in metabolic engineering.
Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia.

Background The newly identified 2019-nCoV, which appears to have originated in Wuhan, the capital city of Hubei province in central China, is spreading rapidly nationwide. A number of cases of neonates born to mothers with 2019-nCoV pneumonia have been recorded. However, the clinical features of these cases have not been reported, and there is no sufficient evidence for the proper prevention and control of 2019-nCoV infections in neonates. Methods The clinical features and outcomes of 10 neonates (including 2 twins) born to 9 mothers with confirmed 2019-nCoV infection in 5 hospitals from January 20 to February 5, 2020 were retrospectively analyzed. Results Among these 9 pregnant women with confirmed 2019-nCoV infection, onset of clinical symptoms occurred before delivery in 4 cases, on the day of delivery in 2 cases, and after delivery in 3 cases. In most cases, fever and a cough were the first symptoms experienced, and 1 patient also had diarrhea. Of the newborns born to these mothers, 8 were male and 2 were female; 4 were full-term infants and 6 were born premature; 2 were small-for-gestational-age (SGA) infants and 1 was a large-for-gestational-age (LGA) infant; there were 8 singletons and 2 twins. Of the neonates, 6 had a Pediatric Critical Illness Score (PCIS) score of less than 90. Clinically, the first symptom in the neonates was shortness of breath (n=6), but other initial symptoms such as fever (n=2), thrombocytopenia accompanied by abnormal liver function (n=2), rapid heart rate (n=1), vomiting (n=1), and pneumothorax (n=1) were observed. Up to now, 5 neonates have been cured and discharged, 1 has died, and 4 neonates remain in hospital in a stable condition. Pharyngeal swab specimens were collected from 9 of the 10 neonates 1 to 9 days after birth for nucleic acid amplification tests for 2019-nCoV, all of which showed negative results. Conclusions Perinatal 2019-nCoV infection may have adverse effects on newborns, causing problems such as fetal distress, premature labor, respiratory distress, thrombocytopenia accompanied by abnormal liver function, and even death. However, vertical transmission of 2019-nCoV is yet to be confirmed.
miR‐152‐5p suppresses glioma progression and tumorigenesis and potentiates temozolomide sensitivity by targeting FBXL7

A generally used chemotherapeutic drug for glioma, a frequently diagnosed brain tumour, is temozolomide (TMZ). Our study investigated the activity of FBXL7 and miR‐152‐5p in glioma. Levels of microRNA‐152‐5p (miR‐152‐5p) and the transcript and protein of FBXL7 were assessed by real‐time PCR and Western blotting, respectively. The migratory and invasive properties of cells were measured by Transwell migration and invasion assay and their viability were examined using CCK‐8 assay. Further, the putative interaction between FBXL7 and miR‐152‐5p were analysed bioinformatically and by luciferase assay. The activities of FBXL7, TMZ and miR‐152‐5p were analysed in vivo singly or in combination, on mouse xenografts, in glioma tumorigenesis. The expression of FBXL7 in glioma tissue is significantly up‐regulated, which is related to the poor prognosis and the grade of glioma. TMZ‐induced cytotoxicity, proliferation, migration and invasion in glioma cells were impeded by the knock‐down of FBXL7 or overexpressed miR‐152‐5p. Furthermore, the expression of miR‐152‐5p reduced remarkably in glioma cells and it exerted its activity through targeted FBXL7. Overexpression of miR‐152‐5p and knock‐down of FBXL7 in glioma xenograft models enhanced TMZ‐mediated anti‐tumour effect and impeded tumour growth. Thus, the miR‐152‐5p suppressed the progression of glioma and associated tumorigenesis, targeted FBXL7 and increased the effect of TMZ‐induced cytotoxicity in glioma cells, further enhancing our knowledge of FBXL7 activity in glioma.
Gastric Cancer with Radiographically Occult Metastatic Disease: Biology, Challenges, and Diagnostic Approaches

Gastric adenocarcinoma is an aggressive cancer that demonstrates heterogeneous biology depending on patient ethnicity, tumor location, tumor type, and genetic profile. It remains the third leading cause of cancer deaths worldwide and was estimated to result in 782,000 deaths in 2018. Challenges exist in accurately assessing the disease burden, as available radiological staging often underestimates metastatic disease. This diagnostic handicap, along with the poor understanding of the heterogeneous biology of gastric cancer, has hindered the development of effective therapeutic solutions and thus halted improvement in patient outcomes over the last few decades. The management of occult peritoneal disease is complicated, as most patients are understaged by standard imaging studies and therefore thought to have local diseases. In this article, we systematically review recent literature on the limitations that are associated with standard radiographic staging, discuss recent molecular biology advances to better identify and diagnose occult peritoneal disease, and propose possible management strategies to approach this complicated clinical problem.
New Perspectives Related to the Bioluminescent System in Dinoflagellates: Pyrocystis lunula, a Case Study

Pyrocystis lunula is considered a model organism due to its bioluminescence capacity linked to circadian rhythms. The mechanisms underlying the bioluminescent phenomenon have been well characterized in dinoflagellates; however, there are still some aspects that remain an enigma. Such is the case of the presence and diversity of the luciferin-binding protein (LBP), as well as the synthesis process of luciferin. Here we carry out a review of the literature in relation to the molecular players responsible for bioluminescence in dinoflagellates, with particular interest in P. lunula. We also carried out a phylogenetic analysis of the conservation of protein sequence, structure and evolutionary pattern of these key players. The basic structure of the luciferase (LCF) is quite conserved among the sequences reported to date for dinoflagellate species, but not in the case of the LBP, which has proven to be more variable in terms of sequence and structure. In the case of luciferin, its synthesis has been shown to be complex process with more than one metabolic pathway involved. The glutathione S-transferase (GST) and the P630 or blue compound, seem to be involved in this process. In the same way, various hypotheses regarding the role of bioluminescence in dinoflagellates are exposed.