Venous Endothelial Cell Transcriptomic Profiling Implicates METAP1 in Preeclampsia.

Background: Preeclampsia is a hypertensive disorder of pregnancy characterized by systemic endothelial dysfunction. The pathophysiology of preeclampsia remains incompletely understood. This study used human venous endothelial cell (EC) transcriptional profiling to investigate potential novel mechanisms underlying EC dysfunction in preeclampsia.

Leveraging Language Model Multitasking To Predict C-H Borylation Selectivity.

C-H borylation is a high-value transformation in the synthesis of lead candidates for the pharmaceutical industry because a wide array of downstream coupling reactions is available. However, predicting its regioselectivity, especially in drug-like molecules that may contain multiple heterocycles, is not a trivial task. Using a data set of borylation reactions from Reaxys, we explored how a language model originally trained on USPTO_500_MT, a broad-scope set of patent data, can be used to predict the C-H borylation reaction product in different modes: product generation and site reactivity classification.

Impact of smoking status on clinical outcomes in patients with metastatic renal cell carcinoma treated with first-line immune checkpoint inhibitor-based regimens.

Background: Current tobacco smoking is independently associated with decreased overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) treated with targeted monotherapy (VEGF-TKI). Herein, we assess the influence of smoking status on the outcomes of patients with mRCC treated with the current first-line standard of care of immune checkpoint inhibitor (ICI)-based regimens.

Materials And Methods: Real-world data from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were collected retrospectively.

Self-Expanding or Balloon-Expandable TAVR in Patients with a Small Aortic Annulus.

Background: Patients with severe aortic stenosis and a small aortic annulus are at risk for impaired valvular hemodynamic performance and associated adverse cardiovascular clinical outcomes after transcatheter aortic-valve replacement (TAVR).

Methods: We randomly assigned patients with symptomatic severe aortic stenosis and an aortic-valve annulus area of 430 mm or less in a 1:1 ratio to undergo TAVR with either a self-expanding supraannular valve or a balloon-expandable valve. The coprimary end points, each assessed through 12 months, were a composite of death, disabling stroke, or rehospitalization for heart failure (tested for noninferiority) and a composite end point measuring bioprosthetic-valve dysfunction (tested for superiority).

The Advantages of Flexibility: The Role of Entropy in Crystal Structures Containing C-H···F Interactions.

Molecular crystal structures are often interpreted in terms of strong, structure directing, intermolecular interactions, especially those with distinct geometric signatures such as H-bonds or π-stacking interactions. Other interactions can be overlooked, perhaps because they are weak or lack a characteristic geometry. We show that although the cumulative effect of weak interactions is significant, their deformability also leads to occupation of low energy vibrational energy levels, which provides an additional stabilizing entropic contribution.

The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

Background: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples.

Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.

Introduction: Here we set out to create a symptom-led staging system for the canonical semantic and non-fluent/agrammatic variants of primary progressive aphasia (PPA), which present unique diagnostic and management challenges not well captured by functional scales developed for Alzheimer's disease and other dementias.

Methods: An international PPA caregiver cohort was surveyed on symptom development under six provisional clinical stages and feedback was analyzed using a mixed-methods sequential explanatory design.

Results: Both PPA syndromes were characterized by initial communication dysfunction and non-verbal behavioral changes, with increasing syndromic convergence and functional dependency at later stages.

Risk of COVID-19 in people with multiple sclerosis who are seronegative following vaccination.

Background: People with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs) have attenuated IgG response following COVID-19 vaccination; however, the clinical consequences remain unclear.

Objective: To report COVID-19 rates in pwMS according to vaccine serology.

Methods: PwMS with available (1) serology 2-12 weeks following COVID-19 vaccine 2 and/or vaccine 3 and (2) clinical data on COVID-19 infection/hospitalisation were included.

Improved semi-experimental equilibrium structure and high-level theoretical structures of ketene.

The millimeter-wave rotational spectrum of ketene (H2C=C=O) has been collected and analyzed from 130 to 750 GHz, providing highly precise spectroscopic constants from a sextic, S-reduced Hamiltonian in the Ir representation. The chemical synthesis of deuteriated samples allowed spectroscopic measurements of five previously unstudied ketene isotopologues. Combined with previous work, these data provide a new, highly precise, and accurate semi-experimental (reSE) structure for ketene from 32 independent moments of inertia.

Peracid Oxidation of Unactivated sp C-H Bonds: An Important Solvent Effect.

The peracid oxidation of hydrocarbons in chlorinated solvents is a low yielding and poorly selective process. Through a combination of DFT calculations, spectroscopic studies, and kinetic measurement it is shown that the origin of this is electronic in nature and can be influenced through the addition of hydrogen bond donors (HBD) and hydrogen bond acceptors (HBA). Performing the reaction of a cycloalkane with mCPBA in a fluorinated alcohol solvent such as nonafluoro-tert-butanol (NFTB) or hexafluoroisopropanol (HFIP), which act as strong HBD and poor HBA, leads to significantly higher yields and selectivities being observed for the alcohol product.

Quantification of Liver Iron Overload with MRI: Review and Guidelines from the ESGAR and SAR.

Accumulation of excess iron in the body, or systemic iron overload, results from a variety of causes. The concentration of iron in the liver is linearly related to the total body iron stores and, for this reason, quantification of liver iron concentration (LIC) is widely regarded as the best surrogate to assess total body iron. Historically assessed using biopsy, there is a clear need for noninvasive quantitative imaging biomarkers of LIC.

Predictors of Driving Cessation in Older Adults: A 12-year Population-based Study.

Background: Changes in physical health and cognition during aging can result in some older adults to stop driving. In this population-based longitudinal study, we describe potential predictors of driving cessation in older adults.

Methods: Age-stratified random population cohort of 1982 adults aged 65 years and older drawn from voter registration lists.

Secondary prevention in diabetic and nondiabetic coronary heart disease patients: Insights from the German subset of the hospital arm of the EUROASPIRE IV and V surveys.

Background: Patients with coronary heart disease (CHD) with and without diabetes mellitus have an increased risk of recurrent events requiring multifactorial secondary prevention of cardiovascular risk factors. We compared prevalences of cardiovascular risk factors and its determinants including lifestyle, pharmacotherapy and diabetes mellitus among patients with chronic CHD examined within the fourth and fifth EUROASPIRE surveys (EA-IV, 2012-13; and EA-V, 2016-17) in Germany.

Methods: The EA initiative iteratively conducts European-wide multicenter surveys investigating the quality of secondary prevention in chronic CHD patients aged 18 to 79 years.

Perceptions, Coping Strategies, and Mental Health of Residents during COVID-19.

Objectives: Since the inception of the coronavirus disease 2019 (COVID-19) pandemic, the United States has been the leader in cases and deaths. Healthcare workers treating these severely ill patients are at risk of many deleterious consequences. Residents, in particular, may be affected by physical as well as psychological consequences.

A systematic review and network meta-analysis of topical pharmacological, oral pharmacological, physical and combined treatments for acne vulgaris.

Background: Various treatments for acne vulgaris exist, but little is known about their comparative effectiveness in relation to acne severity.

Objectives: To identify best treatments for mild-to-moderate and moderate-to-severe acne, as determined by clinician-assessed morphological features.

Methods: We undertook a systematic review and network meta-analysis of randomized controlled trials (RCTs) assessing topical pharmacological, oral pharmacological, physical and combined treatments for mild-to-moderate and moderate-to-severe acne, published up to May 2020.

The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment.

Proof of concept of peptide-linked blockmiR-induced MBNL functional rescue in myotonic dystrophy type 1 mouse model.

Myotonic dystrophy type 1 is a debilitating neuromuscular disease causing muscle weakness, myotonia, and cardiac dysfunction. The phenotypes are caused by muscleblind-like (MBNL) protein sequestration by toxic RNA in the DM1 protein kinase () gene. DM1 patients exhibit a pathogenic number of repetitions in , which leads to downstream symptoms.

Federated learning for predicting clinical outcomes in patients with COVID-19.

Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.

Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the gene. CUG expansions in mutant transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration.

Optimization of brain-penetrant picolinamide derived leucine-rich repeat kinase 2 (LRRK2) inhibitors.

The discovery of potent, kinome selective, brain penetrant LRRK2 inhibitors is the focus of extensive research seeking new, disease-modifying treatments for Parkinson's disease (PD). Herein, we describe the discovery and evolution of a picolinamide-derived lead series. Our initial optimization efforts aimed at improving the potency and CLK2 off-target selectivity of compound by modifying the heteroaryl C-H hinge and linker regions.