tbuckley/cabot-search huggingface dataset:
Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation
Authors: Benjamin E. Mead, Kazuki Hattori, Lauren Levy, Shinya Imada, Norihiro Goto, Marko Vukovic, Daphne Sze, Conner Kummerlowe, Juan D. Matute, Jinzhi Duan, Robert Langer, Richard S. Blumberg, Jose Ordovas-Montanes, Ömer H. Yilmaz, Jeffrey M. Karp, Alex K. Shalek
Journal: Nature Biomedical Engineering (2022)

Abstract The cellular composition of barrier epithelia is essential to organismal homoeostasis. In particular, within the small intestine, adult stem cells establish tissue cellularity, and may provide a means to control the abundance and quality of specialized epithelial cells. Yet, methods for the identification of biological targets regulating epithelial composition and function, and of small molecules modulating them, are lacking. Here we show that druggable biological targets and small-molecule regulators of intestinal stem cell differentiation can be identified via multiplexed phenotypic screening using thousands of miniaturized organoid models of intestinal stem cell differentiation into Paneth cells, and validated via longitudinal single-cell RNA-sequencing. We found that inhibitors of the nuclear exporter Exportin 1 modulate the fate of intestinal stem cells, independently of known differentiation cues, significantly increasing the abundance of Paneth cells in the organoids and in wild-type mice. Physiological organoid models of the differentiation of intestinal stem cells could find broader utility for the screening of biological targets and small molecules that can modulate the composition and function of other barrier epithelia.
Genomic Signatures of Sexual Selection on Pollen-Expressed Genes in <i>Arabis alpina</i>
Authors: Juanita Gutiérrez-Valencia, Marco Fracassetti, Robert Horvath, Benjamin Laenen, Aurélie Désamore, Andreas D Drouzas, Magne Friberg, Filip Kolář, Tanja Slotte
Journal: Molecular Biology and Evolution (2021)

Abstract Fertilization in angiosperms involves the germination of pollen on the stigma, followed by the extrusion of a pollen tube that elongates through the style and delivers two sperm cells to the embryo sac. Sexual selection could occur throughout this process when male gametophytes compete for fertilization. The strength of sexual selection during pollen competition should be affected by the number of genotypes deposited on the stigma. As increased self-fertilization reduces the number of mating partners, and the genetic diversity and heterozygosity of populations, it should thereby reduce the intensity of sexual selection during pollen competition. Despite the prevalence of mating system shifts, few studies have directly compared the molecular signatures of sexual selection during pollen competition in populations with different mating systems. Here we analyzed whole-genome sequences from natural populations of Arabis alpina, a species showing mating system variation across its distribution, to test whether shifts from cross- to self-fertilization result in molecular signatures consistent with sexual selection on genes involved in pollen competition. We found evidence for efficient purifying selection on genes expressed in vegetative pollen, and overall weaker selection on sperm-expressed genes. This pattern was robust when controlling for gene expression level and specificity. In agreement with the expectation that sexual selection intensifies under cross-fertilization, we found that the efficacy of purifying selection on male gametophyte-expressed genes was significantly stronger in genetically more diverse and outbred populations. Our results show that intra-sexual competition shapes the evolution of pollen-expressed genes, and that its strength fades with increasing self-fertilization rates.
The effect of two midwives during the second stage of labour to reduce severe perineal trauma (Oneplus): a multicentre, randomised controlled trial in Sweden
Authors: Malin Edqvist, Hannah G Dahlen, Cecilia Häggsgård, Helena Tern, Karin Ängeby, Pia Teleman, Gunilla Ajne, Christine Rubertsson
Journal: The Lancet (2022)
BASELINE LEFT VENTRICULAR CONTRACTILE STATE IS THE STRONGEST DETERMINANT OF FUTURE DROPS IN EJECTION FRACTION FROM CARDIOTOXIC CHEMOTHERAPY: A MACHINE LEARNING BASED CMR STUDY
Authors: Dina Labib, Alessandro Satriano, Steven Dykstra, Yoko Mikami, Easter Prosia, Patricia Feuchter, Jacqueline A. Flewitt, Sandra Rivest, Rosa Sandonato, Andrew G. Howarth, Carmen Lydell, Robert Miller, Louis R. Kolman, Ian Paterson, Gavin Oudit, Edith Pituskin, Winson Y. Cheung, Joon Lee, James White
Journal: Journal of the American College of Cardiology (2022)
HEART FAILURE IN THE ELDERLY: CARDIAC AMYLOIDOSIS AS AN UNDERDIAGNOSED CAUSE
Authors: Camila Almeida, Luiz Bortolotto, Fernanda Colombo, Fabio Fernandes, Fernanda Soares, Renan Oliveira, Matheus Luan Cunha, Bruno Fuzissima, Henrique Souza, André Palone, Renan Perycles Figueiredo
Journal: Journal of the American College of Cardiology (2022)
Superior Efficacy of Midostaurin Over Cladribine in Advanced Systemic Mastocytosis: A Registry-Based Analysis
Authors: Johannes Lübke, Juliana Schwaab, Nicole Naumann, Hans-Peter Horny, Christel Weiß, Georgia Metzgeroth, Sebastian Kreil, Nicholas C.P. Cross, Karl Sotlar, Alice Fabarius, Wolf-Karsten Hofmann, Peter Valent, Jason Gotlib, Mohamad Jawhar, Andreas Reiter
Journal: Journal of Clinical Oncology (2022)

PURPOSE On the basis of data from the German Registry on Disorders of Eosinophils and Mast Cells, we compared the efficacy of midostaurin and cladribine in patients with advanced systemic mastocytosis (AdvSM). PATIENTS AND METHODS Patients with AdvSM (n = 139) were treated with midostaurin only (n = 63, 45%), cladribine only (n = 23, 17%), or sequentially (midostaurin-cladribine, n = 30, 57%; cladribine-midostaurin, n = 23, 43%). Prognosis was assessed through the Mutation-Adjusted Risk Score (MARS). Besides the comparison of efficacy between midostaurin and cladribine on response (eg, organ dysfunction, bone marrow mast cell [MC] infiltration, and tryptase), overall survival (OS), and leukemia-free survival, we focused on the impact of treatment on involved non-MC lineages, for example, monocytes or eosinophils, and the KIT D816V expressed allele burden. RESULTS Midostaurin only was superior to cladribine only with effects from responses on MC and non-MC lineages conferring on a significantly improved OS (median 4.2 v 1.9 years, P = .033) and leukemia-free survival (2.7 v 1.3 years, P = .044) on the basis of a propensity score–weighted analysis of parameters included in MARS. Midostaurin compensated the inferior efficacy of cladribine in first- and second-line treatment. On midostaurin in any line, response of eosinophilia did not improve its baseline adverse prognostic impact, whereas response of monocytosis proved to be a positive on-treatment parameter. Multivariable analysis allowed to establish three risk categories (low/intermediate/high) through the combination of MARS and the reduction of the KIT D816V expressed allele burden of ≥ 25% at month 6 (median OS not reached v 3.0 years v 1.0 year; P &lt; .001). CONCLUSION In this registry-based analysis, midostaurin revealed superior efficacy over cladribine in patients with AdvSM. In midostaurin-treated patients, the combination of baseline MARS and molecular response provided a compelling three-tier risk categorization (MARSv2.0) for OS.
IMPELLA 5.5 MECHANICAL CIRCULATORY SUPPORT AS A BRIDGE TO HEART TRANSPLANTATION FOR REFRACTORY VENTRICULAR TACHYCARDIA
Authors: Pujan Patel, Sanjana Bhatia-Patel, Bianca Yoo, Annie van Beuningen, Kunal Bhatt, Sonjoy Raja Laskar, David Vega, Mani A. Daneshmand, Divya Gupta
Journal: Journal of the American College of Cardiology (2022)
How data from the United Kingdom has guided covid-19 vaccine policies
Authors: Azeem Majeed, Elise Tessier, Julia Stowe, Ali H. Mokdad
Journal: BMJ (2022)

Throughout the pandemic, the UK's covid-19 data systems have been guiding global as well as local policies.The well established health information systems combined with the more recently established National Immunisation Management System in England provided timely information on infections, emergence of new variants, and the value of different interventions.But one of the most important contributions from the UK came from the ability to rapidly track vaccine effectiveness.Vaccination is the best method for societies to reduce the severity of illness and number of deaths from covid-19; and to start to return to a more normal way of living, working, and studying. 1But vaccination programmes need to be evidence based, so that vaccines and healthcare resources are used appropriately, and there is equitable vaccine delivery.The covid-19 pandemic has shown the importance of data from medical records and the National Immunisation Management System in guiding national vaccination policies.Clinical trials can provide initial data on the efficacy and safety of vaccines.However, because of their relatively small size and short duration of follow-up, they cannot provide longer term data on vaccine effectiveness or on rare adverse events. 2 Furthermore, because covid-19 vaccines were designed to target the original strain of SARS-CoV-2, the trials are also unable to provide data on protection against new variants that emerged after the trials were completed.Nor were they able to provide data on the need for booster doses of vaccines to maintain protection from serious illness and death.
Early versus delayed lengthening exercises for acute hamstring injury in male athletes: a randomised controlled clinical trial
Authors: Robin Vermeulen, Rod Whiteley, Anne D van der Made, Nicol van Dyk, Emad Almusa, Celeste Geertsema, Stephen Targett, Abdulaziz Farooq, Roald Bahr, Johannes L Tol, Arnlaug Wangensteen
Journal: British Journal of Sports Medicine (2022)

Background To evaluate the efficacy of early versus delayed introduction of lengthening (ie, eccentric strengthening) exercises in addition to an established rehabilitation programme on return to sport duration for acute hamstring injuries in a randomised controlled superiority trial. Methods 90 male participants (age: 18–36 years, median 26 years) with an MRI-confirmed acute hamstring injury were randomised into an early lengthening (at day 1 of rehabilitation) group or a delayed lengthening (after being able to run at 70% of maximal speed) group. Both groups received an established rehabilitation programme. The primary outcome was time to return to sport (ie, time from injury to full unrestricted training and/or match play). The secondary outcome was reinjury rate within 12 months after return to sport. Other outcomes at return to sport included the Askling H-test, hamstring strength, clinical examination and readiness questions. Results The return to sport in the early lengthening group was 23 (IQR 16–35) days and 33 (IQR 23–40) days in the delayed lengthening group. For return to sport (in days), the adjusted HR for the early lengthening group compared with the delayed lengthening group was 0.95 (95% CI 0.56 to 1.60, p=0.84). There was no significant difference between groups for reinjury rates within 2 months (OR=0.94, 95% CI 0.18 to 5.0, p=0.94), from 2 to 6 months (OR=2.00, 95% CI 0.17 to 23.3, p=0.58), and 6 to 12 months (OR=0.57, 95% CI 0.05 to 6.6, p=0.66). Conclusion Accelerating the introduction of lengthening exercises in the rehabilitation of hamstring injury in male athletes did not improve the time to return to sport nor the risk of reinjury.
Therapeutic and Prognostic Significance of Arachidonic Acid in Heart Failure
Authors: Ke Ma, Jie Yang, Yihui Shao, Ping Li, Hongchang Guo, Jianing Wu, Yi Zhu, Hui Zhang, Xu Zhang, Jie Du, Yulin Li
Journal: Circulation Research (2022)

Accurate prediction of death is an unmet need in patients with acute decompensated heart failure (HF). Arachidonic acid (AA) metabolites play an important role in the multiple pathophysiological processes. We aimed to develop an AA score to accurately predict mortality in patients with acute decompensated HF and explore the causal relationship between the AA predictors and HF.The serum AA metabolites was measured in patients with acute decompensated HF (discovery cohort n=419; validation cohort n=386) by mass spectroscopy. We assessed the prognostic importance of AA metabolites for 1-year death using Cox regression and machine learning approaches. A machine learning-based AA score for predicting 1-year death was created and validated. We explored the mechanisms using transcriptome and functional experiments in a mouse model of early ischemic cardiomyopathy.Among the 27 AA metabolites, elevated 14,15-DHET/14,15-EET ratio was the strongest predictor of 1-year death (hazard ratio, 2.10, P=3.1×10-6). Machine learning-based AA score using a combination of the 14,15-DHET/14,15-EET ratio, 14,15-DHET, PGD2, and 9-HETE performed best (area under the curve [AUC]: 0.85). The machine learning-based AA score provided incremental information to predict mortality beyond BNP (B-type natriuretic peptide; ΔAUC: 0.19), clinical score (ΔAUC: 0.09), and preexisting Acute Decompensated Heart Failure National Registry, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, and Get With The Guidelines Heart Failure scores (ΔAUC: 0.17, 0.17, 0.15, respectively). In the validation cohort, the AA score accurately predicted mortality (AUC:0.81). False-negative and false-positive findings, as classified by the BNP threshold, were correctly reclassified by the AA score (46.2% of false-negative and 84.5% of false-positive). In a murine model, the expression and enzymatic activity of sEH (soluble epoxide hydrolase) increased after myocardial infarction. Genetic deletion of sEH improved HF and the blockade of 14,15-EET abolished this cardioprotection. We mechanistically revealed the beneficial effect of 14,15-EET by impairing the activation of monocytes/macrophages.Our studies propose that the AA score predicts death in patients with acute decompensated HF and inhibiting sEH serves as a therapeutic target for treating HF.URL: https://www.gov; Unique identifier: NCT04108182.
More efforts are needed for background surveys of zoonotic coronaviruses in animals
Authors: Liang Wang, Jing Yang, Kangtai Sun, Yuhai Bi, George F. Gao
Journal: Cell Reports Medicine (2022)

Recently, a novel dog-origin coronavirus has been found in humans. The low similarity between the receptor-binding domain from this novel virus and other human-infecting coronaviruses in genus Alphacoronavirus suggests it might use a novel receptor or mechanism to enter human cells and also might trigger a novel immune response.
ATYPICAL NON-PULMONARY VEIN TRIGGER FOR ATRIAL FIBRILLATION - THE RIGHT ATRIAL APPENDAGE
Authors: Nikita Nand, Mohamed Diab, Sarath Lal Mannumbeth Renjithlal, Chloe Deng, Mohan Rao, Saumya Sharma
Journal: Journal of the American College of Cardiology (2022)
ADVERSE CARDIAC REMODELLING BY ECHOCARDIOGRAPHY FOLLOWING HYPERTENSIVE DISORDERS OF PREGNANCY
Authors: Esther Davis, Henrietta Afari, Kaitlyn James, Tanayott Thaweethai, Michael Honigberg, Judy W. Hung, Malissa J. Wood, Camille E. Powe, Amy Sarma
Journal: Journal of the American College of Cardiology (2022)
From child institutions to family reunification: challenges and opportunities in building family-centred care
Authors: Lauren Beard, Leyla Ismayilova, Emily Claypool, Emma Heidorn, Narmin Guliyeva
Journal: The Lancet Global Health (2022)

At least 2·7 million children worldwide are estimated to live in institutional care, with former Soviet Union countries having the highest rates of child institutionalisation in the world. In response, many countries are supporting family reunification as a primary de-institutionalisation strategy. Previous literature shows that the family offers a better environment for children and adolescents, yet little is known about the challenges and opportunities encountered by families upon reintegration. Research on how traumatic experiences associated with institutionalisation and de-institutionalisation affect family reunification is also scarce.Children and adolescents aged 8-16 years and their parents or next of kin (n=47) were recruited through five child institutions in Azerbaijan. Semi-structured interviews included questions about children's and caregiver's experiences during the readjustment process. Four coders thematically coded the interviews.Both adolescents and caregivers emphasised a desire to be reunited. Conversely, young people often manifested behavioural issues (ie, social withdrawal, emotional dysregulation, and overtly aggressive behaviours) after reunification; caregivers further struggled to respond to these reactions. Accordingly, family members discussed their goals and challenges associated with reunification, primarily focusing on a desire to build a better sense of familial trust and communication. Family members also highlighted the importance of learning to manage unexpected role conflicts and contradictory conceptions of authority, particularly among male adolescents.To improve the emotional and psychosocial wellbeing of reunifying children and their caregivers, deinstitutionalisation strategies can incorporate culturally responsive, trauma-informed, and attachment-based interventions, which can heal relational traumas and further equip children and caregivers with coping, stress management, and emotional regulation skills.The study was funded by the Center for Health Administration Studies at the University of Chicago.
Association Between Childhood Body Size and Premenstrual Disorders in Young Adulthood
Authors: Donghao Lu, Jurate Aleknaviciute, Astrid M. Kamperman, Rulla M. Tamimi, Jonas F. Ludvigsson, Unnur A. Valdimarsdóttir, Elizabeth R. Bertone-Johnson
Journal: JAMA Network Open (2022)

Emerging data suggest that more than two-thirds of premenstrual disorders (PMDs), including premenstrual syndrome and premenstrual dysphoric disorder, have symptom onset during the teen years. Adulthood adiposity has been associated with PMDs; however, the association with childhood and adolescent body size is unknown.To examine the association between childhood and adolescent body size and risk of PMDs in young adulthood.This prospective cohort study included 6524 US female participants from the Growing Up Today Study (1996-2013). Data were analyzed from February 26, 2020, to June 23, 2021.Body mass index (BMI) was estimated using self-reported height and weight through adolescence and converted to BMI for age (z score).In 2013, premenstrual symptoms and identified PMDs were assessed with a validated scale based on the Calendar of Premenstrual Experiences. The associations of BMI for age with PMDs and premenstrual symptoms were examined using log-binomial and linear regressions, respectively.Among 6524 participants (mean [SD] age, 26 [3.5] years; 6108 [93.6%] White), 1004 (15.4%) met the criteria for a PMD. Baseline BMI for age reported at a mean (SD) age of 12.7 (1.1) years was associated with increased risk of PMDs (confounding-adjusted relative risk, 1.09 per unit of z score; 95% CI, 1.03-1.15) and higher burden of premenstrual symptoms (β = 0.06; 95% CI, 0.04-0.08). Associations were particularly pronounced for premenstrual dysphoric disorder and for PMDs with symptom onset before 20 years of age and remained in the absence of psychiatric comorbidities, including depression, anxiety, and disordered eating behavior. When analyzing BMI change over time, individuals with high BMI throughout adolescence had a higher burden of premenstrual symptoms (β = 0.17; 95% CI, 0.08-0.27) compared with those with normal BMI throughout adolescence. Individuals with high BMI early followed by a mild decrease later did not report higher premenstrual symptoms (β = 0.06; 95% CI, 0.00-0.12).In this cohort study, childhood body size was associated with PMD risk and premenstrual symptoms in young adulthood. These findings suggest that maintaining a normal body mass in childhood may be considered for lowering the burden of PMDs in adulthood.
Orbital Metastasis
Authors: David Morland, Lucas Jallet, Sophie Deguelte, Guillaume Cadiot, Dimitri Papathanassiou
Journal: Clinical Nuclear Medicine (2022)

Abstract Orbital foci of increased uptake are sometimes visualized on 18 F-FDOPA PET/CT, but the literature remains poor as to their nature. The orbit is indeed a rare site of metastatic involvement. Given this low probability of metastatic location, the question of an incidental benign finding may arise. We reviewed all 18 F-FDOPA PET/CT examinations performed at our institution between January 2015 and May 2021: 4/149 patients presented at least 1 orbital focus of increased uptake, all of them presented a metastatic small intestine neuroendocrine tumor. Somatostatin receptor expression was confirmed using 68 Ga-DOTATOC PET/CT supporting the hypothesis of genuine metastases.
RECURRENT PERICARDITIS FROM POST CARDIAC INJURY SYNDROME: THE CLEVELAND CLINIC EXPERIENCE
Authors: Ankit Agrawal, Felix Berglund, Ashwin Kumar, Abdullah Yesilyaprak, Gauranga Mahalwar, Muhammad Furqan, Beni Verma, Mohamed M. Gad, Nicholas Chan, Vardhmaan Jain, Bryce Montane, Tom Kai Ming Wang, Christine Louise Jellis, Paul Cremer, Allan L. Klein
Journal: Journal of the American College of Cardiology (2022)
The Non-Inferiority Complex: What Do Non-Inferiority Trials Tell Us?
Authors: Magdalene M. Assimon, Gary R. Cutter, Joanne M. Bargman
Journal: Journal of the American Society of Nephrology (2022)

In this issue of the JASN , Fishbane et al. add to the ever-growing noninferiority trial literature in the field of nephrology. They report the results of the ROCKIES trial, an international, phase 3, randomized, open-label, active comparator trial of 2133 dialysis patients evaluating if the hypoxia
Near Complete Response to Trametinib Treatment in Histiocytic Sarcoma Harboring a Somatic KRAS Mutation
Authors: Boyu Hu, Jay L. Patel, Randa Tao, Richard B. Cannon, Marcus Monroe, Gaurav Goyal
Journal: Journal of the National Comprehensive Cancer Network (2022)

Survival outcomes of patients with histiocytic neoplasms are poor, with no standard-of-care treatments available for these malignancies. Recent characterization of the genomic landscape of various histiocytic neoplasms have shown a predominance of activating driver mutations within the MAPK/ERK pathway (ie, BRAF, MEK, KRAS, MAPK, and NRAS). Subsequently, successful treatment of these malignancies with BRAF and MEK inhibitors has been reported. This report presents the first patient with histiocytic sarcoma harboring a somatic KRAS Q61H mutation who was subsequently treated to a near complete response with the MEK inhibitor trametinib. Due to patient preference, lack of standard of care treatments, and associated morbidity from head and neck dissection, initial disease reduction provided by trametinib therapy allowed for a less morbid resection. This case report highlights the utility of up-front next-generation sequencing and the efficacy of MEK inhibition in patients with histiocytic sarcoma harboring activating KRAS mutations.
QT PROLONGATION AND IN-HOSPITAL VENTRICULAR ARRHYTHMIC COMPLICATIONS IN PATIENTS ADMITTED WITH APICAL BALLOONING TAKOTSUBO SYNDROME
Authors: Juan Ignacio Damonte, Marco Giuseppe Del Buono, Pengyang Li, Kunal Kapoor, Yuxuan Mao, Krishna Ravindra, Peter C. Westman, Juan G. Chiabrando, Travis Oakes, Paula Rodriguez-Miguelez, Tamas Gal, Santosh Kumar Padala, Jayanthi N. Koneru, Kenneth A. Ellenbogen, Jordana Kron, Antonio Abbate
Journal: Journal of the American College of Cardiology (2022)