tbuckley/cabot-search huggingface dataset:
School-based interventions modestly increase physical activity and cardiorespiratory fitness but are least effective for youth who need them most: an individual participant pooled analysis of 20 controlled trials
Authors: Timothy Bryan Hartwig, Taren Sanders, Diego Vasconcellos, Michael Noetel, Philip D Parker, David Revalds Lubans, Susana Andrade, Manuel Ávila-García, John Bartholomew, Sarahjane Belton, Naomi E Brooks, Anna Bugge, Iván Cavero-Redondo, Lars Breum Christiansen, Kristen Cohen, Tara Coppinger, Sindre Dyrstad, Vanessa Errisuriz, Stuart Fairclough, Trish Gorely, Francisco Javier Huertas-Delgado, Johann Issartel, Susi Kriemler, Silje Eikanger Kvalø, Pedro Marques-Vidal, Vicente Martinez-Vizcaino, Niels Christian Møller, Colin Moran, John Morris, Mary Nevill, Angélica Ochoa-Avilés, Mai O'Leary, Louisa Peralta, Karin A Pfeiffer, Jardena Puder, Andrés Redondo-Tébar, Lorraine B Robbins, Mairena Sanchez-Lopez, Jakob Tarp, Sarah Taylor, Pablo Tercedor, Mette Toftager, Emilio Villa-González, Niels Wedderkopp, Kathryn Louise Weston, Zenong Yin, Zhou Zhixiong, Chris Lonsdale, Borja del Pozo Cruz
Journal: British Journal of Sports Medicine (2021)

Objectives To determine if subpopulations of students benefit equally from school-based physical activity interventions in terms of cardiorespiratory fitness and physical activity. To examine if physical activity intensity mediates improvements in cardiorespiratory fitness. Design Pooled analysis of individual participant data from controlled trials that assessed the impact of school-based physical activity interventions on cardiorespiratory fitness and device-measured physical activity. Participants Data for 6621 children and adolescents aged 4–18 years from 20 trials were included. Main outcome measures Peak oxygen consumption (VO 2Peak mL/kg/min) and minutes of moderate and vigorous physical activity. Results Interventions modestly improved students’ cardiorespiratory fitness by 0.47 mL/kg/min (95% CI 0.33 to 0.61), but the effects were not distributed equally across subpopulations. Girls and older students benefited less than boys and younger students, respectively. Students with lower levels of initial fitness, and those with higher levels of baseline physical activity benefitted more than those who were initially fitter and less active, respectively. Interventions had a modest positive effect on physical activity with approximately one additional minute per day of both moderate and vigorous physical activity. Changes in vigorous, but not moderate intensity, physical activity explained a small amount (~5%) of the intervention effect on cardiorespiratory fitness. Conclusions Future interventions should include targeted strategies to address the needs of girls and older students. Interventions may also be improved by promoting more vigorous intensity physical activity. Interventions could mitigate declining youth cardiorespiratory fitness, increase physical activity and promote cardiovascular health if they can be delivered equitably and their effects sustained at the population level.
Molecular epidemiology and mortality of group B streptococcal meningitis and infant sepsis in the Netherlands: a 30-year nationwide surveillance study
Authors: Merel N van Kassel, Gregory de Boer, Samira A F Teeri, Dorota Jamrozy, Stephen D Bentley, Matthijs C Brouwer, Arie van der Ende, Diederik van de Beek, Merijn W Bijlsma
Journal: The Lancet Microbe (2021)

BackgroundStreptococcus agalactiae (group B streptococcus) causes invasive disease in all age groups. In the Netherlands, the incidence of group B streptococcal sepsis in early infancy is increasing because of a specific genetic subtype, clonal complex (CC) 17-A1. We assessed the molecular epidemiology, incidence, and mortality of group B streptococcal meningitis in the Netherlands over 30 years.MethodsWe used nationwide surveillance data from Jan 1, 1987, to Dec 31, 2016, on all group B streptococcal meningitis and sepsis cases. The surveillance database of the Netherlands Reference Laboratory for Bacterial Meningitis—which receives approximately 90% of cerebrospinal fluid isolates from all patients with bacterial meningitis in the Netherlands—was the data source for the study. All patients with group B streptococcus-positive cerebrospinal fluid cultures (meningitis) and infants (0–89 days) with group B streptococcus-positive blood cultures (sepsis) were included. Patients with missing date of birth were excluded. Multi-locus sequence typing and clade profiles were extracted from whole genome sequences. Serotyping was done by latex agglutination and genome sequencing. Survival data was obtained through Municipal Personal Records.Findings1501 episodes in 1490 patients were identified: 626 meningitis cases (in patients of all ages) and 875 sepsis cases (in patients aged 0–89 days). Mean annual group B streptococcal meningitis incidence was 1·32 per 1 000 000 population. CC17-A1 caused 16 (5%) of 307 meningitis cases in the first half of the study and 77 (26%) of 296 meningitis cases in the second half of the observation period (p<0·0001). Because of a simultaneous decline in CC19, the overall meningitis incidence remained stable. 27 (8%) of 323 patients with meningitis younger than 3 months died and 14 (21%) of 66 patients older than 3 months died. Patients older than 65 years with sequence type (ST) 24 disease were independently associated with death. Serotype III and ST17 were associated with meningitis in early infancy, serotype III remained associated with meningitis in children younger than 3 months after correcting for ST17 (odds ratio 3·71, 95%CI 2·75–5·01). Serotype Ia, Ib, II, III, and V accounted for 98% of the meningitis cases in patients younger than 3 months and 92% cases in patients older than 3 months.InterpretationCC17-A1 is an increasing cause of group B streptococcal meningitis in all age groups. A pentavalent polysaccharide vaccine would cover most meningitis cases.FundingNetherlands Organization for Health Research and Development and Amsterdam University Medical Centres.
Covid-19: Controversial rapid test policy divides doctors and scientists
Authors: Zosia Kmietowicz
Journal: BMJ (2021)

The UK government’s new policy of distributing rapid coronavirus tests to local authorities in England has divided the medical and scientific community, with some calling for the tests to be halted because they could falsely reassure people and increase the spread of covid-19.

Critics are also concerned that the policy, announced on Sunday 10 January, was being rolled out without sufficient provision for people who test positive, such as putting them in hotels and compensating them financially. Supporters say the tests are a valuable additional tool in public health interventions to identify new cases and suppress further transmission.

Launching the new testing drive, England’s health and social care secretary, Matt Hancock, said, “With roughly a third of people who have coronavirus not showing symptoms, targeted asymptomatic testing and subsequent isolation is highly effective in breaking chains of transmission. Rapid, regular testing is led by local authorities who design programmes based on their in-depth knowledge of the local populations, so testing can have the greatest impact.”

As many as 131 local authorities have signed up to the initiative, and 107 have begun testing, Hancock said. Many areas, including Essex and Milton Keynes, were carrying out tests among critical workers and people who have to leave home for essential reasons. The government said that the tests, which provide results in 30 minutes, are accurate and reliable and have helped to identify more than 14 800 covid-19 cases …
Targeting the histone demethylase LSD1 prevents cardiomyopathy in a mouse model of laminopathy
Authors: Anne-Claire Guénantin, Imen Jebeniani, Julia Leschik, Erwan Watrin, Gisèle Bonne, Nicolas Vignier, Michel Pucéat
Journal: Journal of Clinical Investigation (2021)

LMNA mutations in patients are responsible for a dilated cardiomyopathy. Molecular mechanisms underlying the origin and development of the pathology are unknown. Herein, using mouse pluripotent embryonic stem cells (ESCs) and a mouse model both harboring the p.H222P Lmna mutation, we found early defects in cardiac differentiation of mutated ESCs and dilatation of mutated embryonic hearts at E13.5, pointing to a developmental origin of the disease. Using mouse ESCs, we demonstrated that cardiac differentiation of LmnaH222P/+ was impaired at the mesodermal stage. Expression of Mesp1, a mesodermal cardiogenic gene involved in epithelial-to-mesenchymal transition of epiblast cells, as well as Snai1 and Twist expression, was decreased in LmnaH222P/+ cells compared with WT cells in the course of differentiation. In turn, cardiomyocyte differentiation was impaired. ChIP assay of H3K4me1 in differentiating cells revealed a specific decrease of this histone mark on regulatory regions of Mesp1 and Twist in LmnaH222P/+ cells. Downregulation or inhibition of LSD1 that specifically demethylated H3K4me1 rescued the epigenetic landscape of mesodermal LmnaH222P/+ cells and in turn contraction of cardiomyocytes. Inhibition of LSD1 in pregnant mice or neonatal mice prevented cardiomyopathy in E13.5 LmnaH222P/H222P offspring and adults, respectively. Thus, LSD1 appeared to be a therapeutic target to prevent or cure dilated cardiomyopathy associated with a laminopathy.
MO01.31 Durability of Clinical Benefit and Biomarkers in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Sotorasib, a KRAS(G12C) Inhibitor
Authors: D.S. Hong, Y.-J. Bang, F. Barlesi, G. Durm, G. Falchook, R. Govindan, G. Dy, K. Park, J. Strickler, T. Burns, J. Kim, A. Ang, J.R. Lipford, G. Ngarmchamnanrith, A. Anderson, B.T. Li
Journal: Journal of Thoracic Oncology (2021)
Cardioprotection with Yet Another SGLT2 Inhibitor — An Embarrassment of Riches
Authors: Frank C. Brosius, Per O. Vandvik
Journal: New England Journal of Medicine (2021)

Evidence for the cardiovascular benefits of sodium–glucose cotransporter 2 (SGLT2) inhibitors continues to accumulate. Most recently, Bhatt et al. performed two randomized trials to investigate the cardiovascular effects of sotagliflozin; their findings are now reported in the Journal.1,2 Sotagliflozin, unlike other drugs in this class, also has an inhibitory effect on intestinal SGLT1, a related sodium–glucose cotransporter. The first trial, Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure (SOLOIST-WHF),1 involving 1222 participants with type 2 diabetes who had a very recent episode of decompensated heart failure, was designed to determine the efficacy and safety of sotagliflozin in preventing . . .
Myelodysplastic syndromes with ring sideroblasts ( <scp>MDS‐RS</scp> ) and <scp>MDS</scp> /myeloproliferative neoplasm with <scp>RS</scp> and thrombocytosis ( <scp>MDS/MPN‐RS‐T</scp> ) – “ <scp>2021</scp> update on diagnosis, risk‐stratification, and management”
Authors: Mrinal M. Patnaik, Ayalew Tefferi
Journal: American Journal of Hematology (2021)

Abstract Disease Overview Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T). Diagnosis MDS‐RS is a lower risk MDS, with single or multilineage dysplasia (MDS‐RS‐SLD/MLD), &lt;5% bone marrow (BM) blasts, &lt;1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN‐RS‐T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS‐RS‐SLD, along with a platelet count ≥450 × 10 9 /L and large atypical megakaryocytes. Mutations and Karyotype Mutations in SF3B1 are seen in ≥80% of patients with MDS‐RS‐SLD and MDS/MPN‐RS‐T, and strongly correlate with the presence of BM RS; MDS/MPN‐RS‐T patients also demonstrate JAK2 V617F (50%), DNMT3A , TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both. Risk Stratification Most patients with MDS‐RS‐SLD are stratified into lower risk groups by the revised‐IPSS. Disease outcome in MDS/MPN‐RS‐T is better than that of MDS‐RS‐SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation. Treatment Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first‐in‐class erythroid maturation agent is now approved for the management of anemia in patients with MDS‐RS and MDS/MPN‐RS‐T. Aspirin therapy is reasonable in MDS/MPN‐RS‐T, especially in the presence of JAK2 V617F, but the value of platelet‐lowering drugs remains to be defined.
Use of plasma ctDNA as a potential biomarker for longitudinal monitoring of a patient with metastatic high-risk upper tract urothelial carcinoma receiving pembrolizumab and personalized neoepitope-derived multipeptide vaccinations: a case report
Authors: Carolin Blumendeller, Julius Boehme, Maximilian Frick, Martin Schulze, Antje Rinckleb, Christina Kyzirakos, Simone Kayser, Maria Kopp, Sabine Kelkenberg, Natalia Pieper, Oliver Bartsch, Dirk Hadaschick, Florian Battke, Arnulf Stenzl, Saskia Biskup
Journal: Journal for ImmunoTherapy of Cancer (2021)

Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Only limited data are available concerning therapeutic regimes and potential biomarkers for disease monitoring. Standard therapies often provide only insufficient treatment options. Hence, immunotherapies and complementary approaches, such as personalized neoepitope-derived multipeptide vaccine (PNMV), come into focus. In this context, genetic analysis of tumor tissue by whole exome sequencing represents an essential diagnostic step in order to calculate tumor mutational burden (TMB) and to reveal tumor-specific neoantigens. Furthermore, disease progression is essential to be monitored. Longitudinal screening of individually known mutations in plasma circulating tumor DNA (ctDNA) by the use of next-generation sequencing and digital droplet PCR (ddPCR) might be a promising method to fill this gap.Here, we present the case of a 55-year-old man who was diagnosed with high-risk metastatic UTUC in 2015. After initial surgery and palliative chemotherapy, he developed recurrence of the tumor. Genetic analysis revealed a high TMB of 41.2 mutations per megabase suggesting a potential success of immunotherapy. Therefore, in 2016, off-label treatment with the checkpoint-inhibitor pembrolizumab was started leading to strong regression of the disease. This therapy was then discontinued due to side effects and treatment with a previously produced PNMV was started that induced strong T cell responses. During both treatments, plasma Liquid Biopsies (pLBs) were performed to measure the number of mutated molecules per mL plasma (MM/mL) of a known tumor-specific variant in the MLH1 gene by ddPCR for longitudinal monitoring. Under treatment, MM/mL was constantly zero. A few months after all therapies had been discontinued, an increase of MM/mL was detected that persisted in the following pLBs. When MRI scans proved tumor recurrence, treatment with pembrolizumab was started again leading to a rapid decrease of MM/mL in the pLB to again zero. Treatment response was then also confirmed by MRI.This case shows that use of immunotherapy and PNMV might be a promising treatment option for patients with high-risk metastatic UTUC. Furthermore, measurement of individually known tumor mutations in plasma ctDNA by the use of pLB could be a very sensitive biomarker to longitudinally monitor disease.
Predicting clinical outcomes in chronic liver disease: the ELF test is superior to histology and simple scores
Authors: Katharine Irvine, Leesa F. Wockner, Mihir Shanker, Kevin Fagan, Leigh Horsfall, Linda Fletcher, Jacobus Ungerer, Carel J. Pretorius, Gregory Miller, Andrew D. Clouston, Guy Lampe, Elizabeth E. Powell
Journal: Hepatology (2015)
Abstract 11022: Progressive Thrombocytopenia in Critical Limb Ischemia as a Novel Cardiovascular Rsk
Authors: Kaoru Tateno, Yukiko Toyoda, Masanori Hirose, Naomichi Kondo, Masato Kanda, Yoshio Kobayashi
Journal: Circulation (2019)

Introduction: Cardiovascular events (CVE) severely affect mortality and morbidity of patients with critical limb ischemia (CLI). To identify the most vulnerable cases who might develop CVE remains ...
Scaly Dermatitis and Edema in an Irritable Child
Authors: Markus D. Boos, Shanelle Briggs
Journal: JAMA (2021)

A 19-month-old boy fed a vegan diet after being diagnosed with milk, egg, and peanut allergies developed failure to thrive, speech delay, and acute irritability with widespread dermatitis and edema. What is the diagnosis and what would you do next?
ALKBH5 regulates cardiomyocyte proliferation and heart regeneration by demethylating the mRNA of YTHDF1
Authors: Zhenbo Han, Xiuxiu Wang, Zihang Xu, Yang Cao, Rui Gong, Yang Yu, Ying Yu, Xiaofei Guo, Shenzhen Liu, Meixi Yu, Wenya Ma, Yiming Zhao, Juan Xu, Xingda Li, Shuainan Li, Yan Xu, Ruijie Song, Binbin Xu, Fan Yang, Djibril Bamba, Natalia Sukhareva, Hong Lei, Manqi Gao, Wenwen Zhang, Naufal Zagidullin, Ying Zhang, Baofeng Yang, Zhenwei Pan, Benzhi Cai
Journal: Theranostics (2021)

N6-methyladenosine (m6A) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis. However, the potential involvement of m6A in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear. In this study, we aimed to investigate the essential role of m6A modification in heart regeneration during postnatal and adult injury. Methods and results: In this study, we identified the downregulation of m6A demethylase ALKBH5, an m6A "eraser" that is responsible for increased m6A methylation, in the heart after birth. Notably, ALKBH5 knockout mice exhibited decreased cardiac regenerative ability and heart function after neonatal apex resection. Conversely, forced expression of ALKBH5 via adeno-associated virus-9 (AAV9) delivery markedly reduced the infarct size, restored cardiac function and promoted CM proliferation after myocardial infarction in juvenile (7 days old) and adult (8-weeks old) mice. Mechanistically, ALKBH5-mediated m6A demethylation improved the mRNA stability of YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). The modulation of ALKBH5 and YTHDF1 expression in human induced pluripotent stem cell-derived cardiomyocytes consistently yielded similar results. Conclusion: Taken together, our findings highlight the vital role of the ALKBH5-m6A-YTHDF1-YAP axis in the regulation of CMs to re-enter the cell cycle. This finding suggests a novel potential therapeutic strategy for cardiac regeneration.
MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage
Authors: Peter Kalev, Marc L. Hyer, Stefan Gross, Zenon Konteatis, Chi-Chao Chen, Mark Fletcher, Max Lein, Elia Aguado-Fraile, Victoria Frank, Amelia Barnett, Everton Mandley, Joshua Goldford, Yue Chen, Katie Sellers, Sebastian Hayes, Kate Lizotte, Phong Quang, Yesim Tuncay, Michelle Clasquin, Rachel Peters, Jaclyn Weier, Eric Simone, Joshua Murtie, Wei Liu, Raj Nagaraja, Lenny Dang, Zhihua Sui, Scott A. Biller, Jeremy Travins, Kevin M. Marks, Katya Marjon
Journal: Cancer Cell (2021)
Opsin 5 is a key regulator of ultraviolet radiation‐induced melanogenesis in human epidermal melanocytes*
Authors: Y. Lan, W. Zeng, X. Dong, H. Lu
Journal: British Journal of Dermatology (2021)

Background Human skin, which is constantly exposed to solar ultraviolet radiation (UVR), has a unique ability to respond by increasing its pigmentation in a protective process driven by melanogenesis in human epidermal melanocytes (HEMs). However, the molecular mechanisms used by HEMs to detect and respond to UVR remain unclear. Objectives To investigate the function and potential mechanism of opsin 5 (OPN5), a photoreceptor responsive to UVR wavelengths, in melanogenesis in HEMs. Methods Melanin content in HEMs was determined using the NaOH method, and activity of tyrosinase (TYR) (a key enzyme in melanin synthesis) was determined by the l-DOPA method. OPN5 expression in UVR-treated vs. untreated HEMs and explant tissues was detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunofluorescence. Short interfering RNA-mediated OPN5 knockdown and a lentivirus OPN5 overexpression model were used to examine their respective effects on TYR, tyrosinase-related protein 1 (TRP1), TRP2 and microphthalmia-associated transcription factor (MITF) expression, under UVR. Changes in expression of TYR, TRP1 and TRP2 caused by changes in OPN5 expression level were detected by RT-qPCR and Western blot. Furthermore, changes in signalling pathway proteins were assayed. Results We found that OPN5 is the key sensor in HEMs responsible for UVR-induced melanogenesis. OPN5-induced melanogenesis required Ca2+-dependent G protein-coupled receptor- and protein kinase C signal transduction, thus contributing to the UVR-induced MITF response to mediate downstream cellular effects, and providing evidence of OPN5 function in mammalian phototransduction. Remarkably, OPN5 activation was necessary for UVR-induced increase in cellular melanin and has an inherent function in melanocyte melanogenesis. Conclusions Our results provide insight into the molecular mechanisms of UVR sensing and phototransduction in melanocytes, and may reveal molecular targets for preventing pigmentation or pigment diseases.
Huriez syndrome caused by a large deletion that abrogates the skin‐specific isoform of <i>SMARCAD1</i>
Authors: A.Y.T. Loh, C.M. Ho, S. Muthiah, B. Venkatesh, S. Zwolinski, A.P.J.J. Bray, B. Reversade, N. Rajan, T.J. Carney
Journal: British Journal of Dermatology (2021)

Huriez syndrome (HRZ ; MIM181600) is a rare autosomal dominant genodermatosis, which is characterised by scleroatrophy of the hands and feet, hypoplasia of the nails and palmoplantar keratoderma1,2 . Approximately 15% of HRZ patients are predisposed to cutaneous squamous cell carcinoma (cSCC) which occurs in affected scleroatrophic skin at an early age of 30 to 40 years. cSCC in HRZ may be aggressive, with metastasis and death reported3 .
MO01.18 An indirect Comparison of Pembrolizumab+Chemo vs Ipilimumab+Nivolumab as First-Line Therapies in Patients with PD-L1 TPS≥1% Metastatic NSCLC
Authors: B. Halmos, T. Burke, C. Kalyvas, R. Insinga, K. Vandormael, A. Frederickson, B. Piperdi
Journal: Journal of Thoracic Oncology (2021)
Covax must go beyond proportional allocation of covid vaccines to ensure fair and equitable access
Authors: Lisa M Herzog, Ole F Norheim, Ezekiel J Emanuel, Matthew S McCoy
Journal: BMJ (2021)

International collaboration is key for the fair and efficient distribution of covid-19 vaccines. <b>Lisa Herzog and colleagues</b>' Fair Priority Model, with its focus on allocating vaccine based on limiting covid-19 harms, realises ethical principles better than Covax's proposal of proportional allocation based on population