tbuckley/cabot-search huggingface dataset:
Ascertainment Bias in the Genomic Test of Positive Selection on Regulatory Sequences
Authors: Daohan Jiang, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2023)

Abstract Evolution of gene expression mediated by cis-regulatory changes is thought to be an important contributor to organismal adaptation, but identifying adaptive cis-regulatory changes is challenging due to the difficulty in knowing the expectation under no positive selection. A new approach for detecting positive selection on transcription factor binding sites (TFBSs) was recently developed, thanks to the application of machine learning in predicting transcription factor (TF) binding affinities of DNA sequences. Given a TFBS sequence from a focal species and the corresponding inferred ancestral sequence that differs from the former at n sites, one can predict the TF-binding affinities of many n-step mutational neighbors of the ancestral sequence and obtain a null distribution of the derived binding affinity, which allows testing whether the binding affinity of the real derived sequence deviates significantly from the null distribution. Applying this test genomically to all experimentally identified binding sites of 3 TFs in humans, a recent study reported positive selection for elevated binding affinities of TFBSs. Here, we show that this genomic test suffers from an ascertainment bias because, even in the absence of positive selection for strengthened binding, the binding affinities of known human TFBSs are more likely to have increased than decreased in evolution. We demonstrate by computer simulation that this bias inflates the false positive rate of the selection test. We propose several methods to mitigate the ascertainment bias and show that almost all previously reported positive selection signals disappear when these methods are applied.
RSV Prevention — Breakthroughs and Challenges
Authors: Natasha B. Halasa
Journal: New England Journal of Medicine (2023)

Since the discovery of respiratory syncytial virus (RSV) in 1956, the pathogen has become well recognized as a leading cause of acute respiratory illness worldwide. By 2 years of age, most children have been infected with RSV, with illnesses ranging from mild upper respiratory tract infection to severe and sometimes fatal lower respiratory tract infection. In 2019, there were an estimated 33 million cases of acute lower respiratory tract infection due to RSV, resulting in 3.6 million hospitalizations and 26,300 in-hospital deaths among children younger than 5 years of age worldwide.1 In addition, 101,400 deaths were attributable to RSV.1 However, . . .
Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke
Authors: Ying Gao, Weiqi Chen, Yuesong Pan, Jing Jing, Chunjuan Wang, S. Claiborne Johnston, Pierre Amarenco, Philip M. Bath, Lingling Jiang, Yingying Yang, Tingting Wang, Shangrong Han, Xia Meng, Jinxi Lin, Xingquan Zhao, Liping Liu, Jinguo Zhao, Ying Li, Yingzhuo Zang, Shuo Zhang, Hongqin Yang, Jianbo Yang, Yuanwei Wang, Dali Li, Yanxia Wang, Dongqi Liu, Guangming Kang, Yongjun Wang, Yilong Wang
Journal: New England Journal of Medicine (2023)

Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied.
Nirsevimab for Prevention of Hospitalizations Due to RSV in Infants
Authors: Simon B. Drysdale, Katrina Cathie, Florence Flamein, Markus Knuf, Andrea M. Collins, Helen C. Hill, Friedrich Kaiser, Robert Cohen, Didier Pinquier, Christian T. Felter, Natalya C. Vassilouthis, Jing Jin, Mathieu Bangert, Karine Mari, Rapi Nteene, Sophie Wague, Michelle Roberts, Pierre Tissières, Simon Royal, Saul N. Faust
Journal: New England Journal of Medicine (2023)

The safety of the monoclonal antibody nirsevimab and the effect of nirsevimab on hospitalizations for respiratory syncytial virus (RSV)–associated lower respiratory tract infection when administered in healthy infants are unclear. Download a PDF of the Research Summary. In a pragmatic trial, we randomly assigned, in a 1:1 ratio, infants who were 12 months of age or younger, had been born at a gestational age of at least 29 weeks, and were entering their first RSV season in France, Germany, or the United Kingdom to receive either a single intramuscular injection of nirsevimab or standard care (no intervention) before or during the RSV season. The primary end point was hospitalization for RSV-associated lower respiratory tract infection, defined as hospital admission and an RSV-positive test result. A key secondary end point was very severe RSV-associated lower respiratory tract infection, defined as hospitalization for RSV-associated lower respiratory tract infection with an oxygen saturation of less than 90% and the need for supplemental oxygen. A total of 8058 infants were randomly assigned to receive nirsevimab (4037 infants) or standard care (4021 infants). Eleven infants (0.3%) in the nirsevimab group and 60 (1.5%) in the standard-care group were hospitalized for RSV-associated lower respiratory tract infection, which corresponded to a nirsevimab efficacy of 83.2% (95% confidence interval [CI], 67.8 to 92.0; P<0.001). Very severe RSV-associated lower respiratory tract infection occurred in 5 infants (0.1%) in the nirsevimab group and in 19 (0.5%) in the standard-care group, which represented a nirsevimab efficacy of 75.7% (95% CI, 32.8 to 92.9; P=0.004). The efficacy of nirsevimab against hospitalization for RSV-associated lower respiratory tract infection was 89.6% (adjusted 95% CI, 58.8 to 98.7; multiplicity-adjusted P<0.001) in France, 74.2% (adjusted 95% CI, 27.9 to 92.5; multiplicity-adjusted P=0.006) in Germany, and 83.4% (adjusted 95% CI, 34.3 to 97.6; multiplicity-adjusted P=0.003) in the United Kingdom. Treatment-related adverse events occurred in 86 infants (2.1%) in the nirsevimab group. Nirsevimab protected infants against hospitalization for RSV-associated lower respiratory tract infection and against very severe RSV-associated lower respiratory tract infection in conditions that approximated real-world settings. (Funded by Sanofi and AstraZeneca; HARMONIE ClinicalTrials.gov number, NCT05437510). QUICK TAKE VIDEO SUMMARYNirsevimab for Preventing RSV Hospitalizations in Infants 02:23
Highly efficient bi-allelic correction of homozygous <i>COL7A1</i> mutation using ABE8e adenine base editor
Authors: Imogen R Brooks, Yara Alrokh, Aidin Kazemizadeh, Katarzyna Balon, Gregory Newby, David R Liu, Łukasz Łaczmański, John A McGrath, Joanna Jacków-Malinowska
Journal: British Journal of Dermatology (2023)

Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic skin disorder characterized by severe skin blistering. With no cure at present, we have pursued a gene repair approach using base editing of COL7A1. Following on from our previous report of highly efficient base editing using the novel base editor, ABE8e, here we explore the use of lipid nanoparticle (LNP)-based delivery systems instead of electroporation to effect base editing in RDEB fibroblasts and correct a missense G &amp;gt; A mutation. We demonstrate increasingly high editing efficiencies, averaging 90%, which vary with the ABE8e dosage. We then demonstrate the viability of topical delivery of mRNA encapsulated in an LNP. Our work underscores the translational potential of this therapeutic route for DEB.
Microarchitected Compliant Scaffolds of Pyrolytic Carbon for 3D Muscle Cell Growth
Authors: Mohammadreza Taale, Barbara Schamberger, Miguel A. Monclus, Christian Dolle, Fereydoon Taheri, Dario Mager, Yolita M. Eggeler, Jan G. Korvink, Jon M. Molina‐Aldareguia, Christine Selhuber‐Unkel, Andrés Díaz Lantada, Monsur Islam
Journal: Advanced Healthcare Materials (2023)

The integration of additive manufacturing technologies with the pyrolysis of polymeric precursors enables the design-controlled fabrication of architected 3D pyrolytic carbon (PyC) structures with complex architectural details. Despite great promise, their use in cellular interaction remains unexplored. This study pioneers the utilization of microarchitected 3D PyC structures as biocompatible scaffolds for the colonization of muscle cells in a 3D environment. PyC scaffolds are fabricated using micro-stereolithography, followed by pyrolysis. Furthermore, an innovative design strategy using revolute joints is employed to obtain novel, compliant structures of architected PyC. The pyrolysis process results in a pyrolysis temperature- and design-geometry-dependent shrinkage of up to 73%, enabling the geometrical features of microarchitected compatible with skeletal muscle cells. The stiffness of architected PyC varies with the pyrolysis temperature, with the highest value of 29.57 ± 0.78 GPa for 900 °C. The PyC scaffolds exhibit excellent biocompatibility and yield 3D cell colonization while culturing skeletal muscle C2C12 cells. They further induce good actin fiber alignment along the compliant PyC construction. However, no conclusive myogenic differentiation is observed here. Nevertheless, these results are highly promising for architected PyC scaffolds as multifunctional tissue implants and encourage more investigations in employing compliant architected PyC structures for high-performance tissue engineering applications.
Extending Dual Antiplatelet Therapy for TIA or Stroke
Authors: Anthony S. Kim
Journal: New England Journal of Medicine (2023)

Although stroke is typically understood to be a medical emergency, the same pertains when cerebral ischemia produces seemingly mild or transient symptoms. For transient ischemic attack (TIA) and minor stroke, urgent evaluation and treatment are no less important than for larger strokes, given that the risk of recurrent stroke occurs early. Nearly half the 90-day stroke risk occurs within the first 48 hours after an event.1 The risk is modifiable with interventions such as aspirin2 or dual antiplatelet therapy with clopidogrel–aspirin3,4 or ticagrelor–aspirin5 if it is initiated within 24 hours. The trials that established the efficacy of short-term dual antiplatelet . . .
The IARC Perspective on Alcohol Reduction or Cessation and Cancer Risk
Authors: Susan M. Gapstur, Véronique Bouvard, Suzanne T. Nethan, Jo L. Freudenheim, Christian C. Abnet, Dallas R. English, Jürgen Rehm, Silvia Balbo, Penny Buykx, David Crabb, David I. Conway, Farhad Islami, Dirk W. Lachenmeier, Katherine A. McGlynn, Mikko Salaspuro, Norie Sawada, Mary B. Terry, Tatiana Toporcov, Béatrice Lauby-Secretan
Journal: New England Journal of Medicine (2023)

The IARC convened a group of scientists to review the evidence on reduction or cessation of alcohol beverage consumption in relation to alcohol-related cancer incidence or mortality.
Comment on ‘Dupilumab significantly improves sleep in adults with atopic dermatitis: results from the 12-week placebo-controlled period of the 24-week phase IV randomized double-blinded placebo-controlled DUPISTAD study’
Authors: Chandler Johnson, Payton Smith, Kathryn Haran, Allison Kranyak, Wilson Liao, Tina Bhutani
Journal: British Journal of Dermatology (2023)

In this letter to the editor, we respond to the article by Merola et al. titled ‘Dupilumab significantly improves sleep in adults with atopic dermatitis: results from the 12-week placebo-controlled period of the 24-week phase IV randomized double-blinded placebo-controlled DUPISTAD study’. We add to the authors’ discussion on the discrepancy between objective and subjective measures of sleep in people with atopic dermatitis treated with dupilumab.
Topical gene editing therapeutics using lipid nanoparticles: ‘gene creams’ for genetic skin diseases?
Authors: Ina Guri-Lamce, Yara AlRokh, Youngah Kim, Ruhina Maeshima, Carina Graham, Stephen L Hart, John A McGrath, Joanna Jacków-Malinowska
Journal: British Journal of Dermatology (2023)

Patients living with inherited skin diseases have benefited from recent advances in DNA sequencing technologies that provide new or improved diagnostics. However, developing and delivering new treatments for the 'genodermatoses' remains challenging. The goal of creating topical preparations that can recover the inherent gene pathology remains largely aspirational. However, recent progress in two fields - the chemistry of topical delivery formulations (lipid nanoparticles) and the molecular biology of gene repair (CRISPR-Cas9, base and prime editing) - presents new opportunities to address this unmet need. In this review, we discuss how lipid nanoparticle delivery vehicles could be used to deliver gene-editing tools to formulate topical 'gene creams' suitable for the treatment of genodermatoses. We summarize the historical landscape of topical therapeutics and advances in gene editing that may herald an era of new therapies for patients with inherited skin disorders.
Wearable Technology in Clinical Practice for Depressive Disorder
Authors: Szymon Fedor, Robert Lewis, Paola Pedrelli, David Mischoulon, Joshua Curtiss, Rosalind W. Picard
Journal: New England Journal of Medicine (2023)

Sleep patterns and physical activity can be monitored by wearable technology. The authors describe the state of the art for using data from wearable devices in diagnosing and managing depression.
Optimizing Blood Transfusion in Patients with Acute Myocardial Infarction
Authors: Evan M. Bloch, Aaron A.R. Tobian
Journal: New England Journal of Medicine (2023)

Red-cell transfusion is one of the most commonly performed medical procedures. It is also one of the most overused medical procedures, which largely neglects the associated risks, costs, and sustainability of liberal transfusion practices. In 1999, Hébert and colleagues published their findings from the landmark Transfusion Requirements in Critical Care (TRICC) trial, results that challenged the then-standard practice of liberal transfusion.1 The trial showed that 30-day mortality among critically ill patients was not significantly different between those who had been assigned to a restrictive transfusion strategy (hemoglobin trigger, <7 g per deciliter) and those who had been assigned to a . . .
Divergence time shapes gene reuse during repeated adaptation
Authors: Magdalena Bohutínská, Catherine L. Peichel
Journal: Trends in Ecology & Evolution (2023)

When diverse lineages repeatedly adapt to similar environmental challenges, the extent to which the same genes are involved (gene reuse) varies across systems. We propose that divergence time among lineages is a key factor driving this variability: as lineages diverge, the extent of gene reuse should decrease due to reductions in allele sharing, functional differentiation among genes, and restructuring of genome architecture. Indeed, we show that many genomic studies of repeated adaptation find that more recently diverged lineages exhibit higher gene reuse during repeated adaptation, but the relationship becomes less clear at older divergence time scales. Thus, future research should explore the factors shaping gene reuse and their interplay across broad divergence time scales for a deeper understanding of evolutionary repeatability.
Mental health from 5 years before to 10 years after bariatric surgery in adolescents with severe obesity: a Swedish nationwide cohort study with matched population controls
Authors: Gustaf Bruze, Kajsa Järvholm, Mattias Norrbäck, Johan Ottosson, Ingmar Näslund, Jonas Söderling, Johan Reutfors, Torsten Olbers, Martin Neovius
Journal: The Lancet Child & Adolescent Health (2023)
Letter to the Editor: How F to S turned the premature to be mature?
Authors: Yasser Fouad, Mohamed Alboraie, Mortada El-Shabrawi, Ming-Hua Zheng
Journal: Hepatology (2023)

To the editor, We read with great interest the article by Rinella et al1 proposing the redefinition of NAFLD to metabolic dysfunction–associated steatotic liver disease (MASLD). The nomenclature and diagnostic criteria are largely adapted from the metabolic dysfunction–associated fatty liver disease (MAFLD) proposal, which was a game changer when it was put forth in 2020.2 Despite being widely endorsed and supported by a wealth of evidence,3 an editorial was published in this journal that raised various concerns regarding the change from NAFLD to MAFLD, leading to an intense debate.4 The authors questioned the prematurity of the change to MAFLD nomenclature in several aspects, including the vagueness of the word "metabolic" and the need for a full understanding of the disease before making any changes. They also criticized the impact of the new nomenclature on awareness and its confusing effect on the field of pediatric population. Lastly, they criticized the use of data generated under NAFLD under the MAFLD name. What is surprising is that these authors are the same ones who led the team of consensus that is currently proposing the name change from NAFLD to MASLD. This raises a legitimate question: what happened regarding the aforementioned debates with the new proposal MASLD? Did the change of the "F" letter to the "S" letter fill the gap and address the criticism? How can we have already declared that we have a full understanding of the disease? It is difficult for us to reject the notion that the main objective of this consensus statement is actually to resist the initial proposal to adopt MAFLD, as pointed out in another editorial published in this journal.5 For the sake of our field, let the evidence guide our path in a process devoid of emotional aspects. We must ensure that the proposed nomenclature and diagnostic criteria for MASLD are well validated through a deliberate process, including comparative studies with the MAFLD criteria and are not influenced by external factors.
Decreased platelet activation predicts hepatic decompensation and mortality in patients with cirrhosis
Authors: Benedikt S. Hofer, Ksenia Brusilovskaya, Benedikt Simbrunner, Lorenz Balcar, Beate Eichelberger, Silvia Lee, Lukas Hartl, Philipp Schwabl, Mattias Mandorfer, Simon Panzer, Thomas Reiberger, Thomas Gremmel
Journal: Hepatology (2023)

Background and Aims: Patients with cirrhosis show alterations in primary hemostasis, yet prognostic implications of changes in platelet activation remain controversial, and assay validity is often limited by thrombocytopenia. We aimed to study the prognostic role of platelet activation in cirrhosis, focusing on bleeding/thromboembolic events, decompensation, and mortality. Approach and Results: We prospectively included 107 patients with cirrhosis undergoing a same-day hepatic venous pressure gradient (HVPG) and platelet activation measurement. Platelet activation was assessed using flow cytometry after protease-activated receptor (PAR)-1, PAR-4, or epinephrine stimulation. Over a follow-up of 25.3 (IQR: 15.7–31.2) months, first/further decompensation occurred in 29 patients and 17 died. More pronounced platelet activation was associated with an improved prognosis, even after adjusting for systemic inflammation, HVPG, and disease severity. Specifically, higher PAR-4–inducible platelet activation was independently linked to a lower decompensation risk [adjusted HR per 100 MFI (median fluorescence intensity): 0.95 (95% CI: 0.90–0.99); p =0.036] and higher PAR-1-inducible platelet activation was independently linked to longer survival [adjusted HR per 100 MFI: 0.93 (95% CI: 0.87–0.99); p =0.040]. Thromboembolic events occurred in eight patients (75% nontumoral portal vein thrombosis [PVT]). Higher epinephrine-inducible platelet activation was associated with an increased risk of thrombosis [HR per 10 MFI: 1.07 (95% CI: 1.02–1.12); p =0.007] and PVT [HR per 10 MFI: 1.08 (95% CI: 1.02–1.14); p =0.004]. In contrast, of the 11 major bleedings that occurred, 9 were portal hypertension related, and HVPG thus emerged as the primary risk factor. Conclusions: Preserved PAR-1- and PAR-4–inducible platelet activation was linked to a lower risk of decompensation and death. In contrast, higher epinephrine-inducible platelet activation was a risk factor for thromboembolism and PVT.
Letter to the Editor: More on Non-Alcohol/Non-Metabolic Dysfunction-Associated Steatohepatitis
Authors: Pietro Vajro, Claudia Mandato
Journal: Hepatology (2023)

To the editor, We read with interest the article by Khan et al1 in Hepatology regarding the specific etiologies that must be considered in the differential diagnosis of nonalcoholic/nonmetabolic dysfunction–associated steatohepatitis. We commend the authors for taking on this huge and timely task, given that not all hepatologists are sufficiently familiar with some of these conditions characterized by systemic and asynchronous symptoms' presentations that might preclude disease-specific management. However, to avoid the risk of their work being a mere list of conditions, we wonder whether the authors' opinion/further elaboration on the following possibly missing or inaccurate general/specific points might help the less expert readers to gain more from the article. The authors did not clearly emphasize that (1) other concurrent causes of liver steatosis should be automatically considered when liver abnormalities persist despite lifestyle interventions,2 and (2) the causative role of an inherited recessive liver disease should not be rejected despite the denied parental consanguinity when the parents come from the same or neighboring small villages where (often unknown) inbreeding occurs due to geographical isolation or cultural origin. The authors (1) do not indicate which conditions the serum creatine kinase measurement included in their Table 2 refers to, and (2) mention this test only in Pediatrics Tier 2 rather than in both age brackets. While this is correct for mitochondrial myopathies, it may be inexact for myotonic dystrophy type 1/Steinert disease and neutral lipid storage disease, which present typically in adults. The latter is of particular interest to hepatologists due to the risk of more severe liver fibrosis.3 The association of celiac disease-liver steatosis despite the gluten-free diet is not as simple as suggested since steatosis has also been reported in a sizeable portion of lean celiacs regardless of typical metabolic risk factors.4 Lastly, early exposure to endocrine-disrupting chemicals has not been mentioned in the article. However, bisphenol A and phthalates have been implicated in the development and progression of liver steatosis, independent of obesity, by directly disrupting lipid metabolism and promoting inflammation and oxidative stress.5