Differential Infiltration of Key Immune T-Cell Populations Across Malignancies Varying by Immunogenic Potential and the Likelihood of Response to Immunotherapy.

Solid tumors vary by the immunogenic potential of the tumor microenvironment (TME) and the likelihood of response to immunotherapy. The emerging literature has identified key immune cell populations that significantly impact immune activation or suppression within the TME. This study investigated candidate T-cell populations and their differential infiltration within different tumor types as estimated from mRNA co-expression levels of the corresponding cellular markers.

Azithromycin to Reduce Mortality - An Adaptive Cluster-Randomized Trial.

Background: Twice-yearly mass distribution of azithromycin to children is a promising intervention to reduce childhood mortality in sub-Saharan Africa. The World Health Organization recommended restricting distribution to infants 1 to 11 months of age to mitigate antimicrobial resistance, although this more limited treatment had not yet been tested.

Methods: We randomly assigned rural communities in Niger to four twice-yearly distributions of azithromycin for children 1 to 59 months of age (child azithromycin group), four twice-yearly distributions of azithromycin for infants 1 to 11 months of age and placebo for children 12 to 59 months of age (infant azithromycin group), or placebo for children 1 to 59 months of age.

Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study.

Background: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation.

Methods: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma.

The Equipoise Ruler: A National Survey on Surgeon Judgment About the Value of Surgery.

Objective: To understand professional norms regarding the value of surgery.

Background: Agreed-upon professional norms may improve surgical decision-making by contextualizing the nature of surgical treatment for patients. However, the extent to which these norms exist among surgeons practicing in the United States is not known.

Automated Assessment of the DWI-FLAIR Mismatch in Patients with Acute Ischemic Stroke: Added Value to Routine Clinical Practice.

Background And Purpose: The DWI-FLAIR mismatch is used to determine thrombolytic eligibility in patients with acute ischemic stroke when the time since stroke onset is unknown. Commercial software packages have been developed for automated DWI-FLAIR classification. We aimed to use e-Stroke software for automated classification of the DWI-FLAIR mismatch in a cohort of patients with acute ischemic stroke and in a comparative analysis with 2 expert neuroradiologists.

Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the HTT gene. In addition to germline CAG expansions, somatic repeat expansions in neurons also contribute to HD pathogenesis. The DNA mismatch repair gene, MSH3, identified as a genetic modifier of HD onset and progression, promotes somatic CAG expansions, and thus presents a potential therapeutic target.

Azithromycin during Routine Well-Infant Visits to Prevent Death.

Background: Mass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear.

Methods: We conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age).

Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in CSF.

In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to the propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for the aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients.

The T Cell Immunoscore as a Reference for Biomarker Development Utilizing Real-World Data from Patients with Advanced Malignancies Treated with Immune Checkpoint Inhibitors.

Background: We aimed to determine the prognostic value of an immunoscore reflecting CD3+ and CD8+ T cell density estimated from real-world transcriptomic data of a patient cohort with advanced malignancies treated with immune checkpoint inhibitors (ICIs) in an effort to validate a reference for future machine learning-based biomarker development.

Methods: Transcriptomic data was collected under the Total Cancer Care Protocol (NCT03977402) Avatar project. The real-world immunoscore for each patient was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells utilizing CIBERSORTx and the LM22 gene signature matrix.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes.

Safety and Outcome of Revascularization Treatment in Patients With Acute Ischemic Stroke and COVID-19: The Global COVID-19 Stroke Registry.

Background And Objectives: COVID-19-related inflammation, endothelial dysfunction, and coagulopathy may increase the bleeding risk and lower the efficacy of revascularization treatments in patients with acute ischemic stroke (AIS). We aimed to evaluate the safety and outcomes of revascularization treatments in patients with AIS and COVID-19.

Methods: This was a retrospective multicenter cohort study of consecutive patients with AIS receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021 tested for severe acute respiratory syndrome coronavirus 2 infection.

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.

Intervention Codesign in the Pediatric Cardiac Intensive Care Unit to Improve Family Meetings.

Context: Family meetings are encouraged in the pediatric cardiac intensive care unit (CICU) with the expectation of supporting parental shared decision-making (SDM). However, they often fall short of this goal. Additionally, interprofessional team and family meetings are dominated by input from physicians, under-utilizing the skillset of the full clinical team.

Five ways to improve international comparisons of cancer survival: lessons learned from ICBP SURVMARK-2.

Background: Comparisons of population-based cancer survival between countries are important to benchmark the overall effectiveness of cancer management. The International Cancer Benchmarking Partnership (ICBP) Survmark-2 study aims to compare survival in seven high-income countries across eight cancer sites and explore reasons for the observed differences. A critical aspect in ensuring comparability in the reported survival estimates are similarities in practice across cancer registries.

A way to explore the existence of "immortals" in cancer registry data - An illustration using data from ICBP SURVMARK-2.

Background: Accurately recorded vital status of individuals is essential when estimating cancer patient survival. When deaths are ascertained by linkage with vital statistics registers, some may be missed, and such individuals will wrongly appear to be long-term survivors, and survival will be overestimated. Interval-specific relative survival that levels off above one indicates that the survival among the cancer patients is better than expected, which could be due to the presence of immortals.

Age-Stratified Risk of Cerebral Venous Sinus Thrombosis After SARS-CoV-2 Vaccination.

Background And Objectives: Cerebral venous sinus thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) vaccination. Estimated background rate of CVST with thrombocytopenia is 0.1 per million per month.

Transcatheter Treatment of Secondary Tricuspid Regurgitation With Direct Annuloplasty: Results From a Multicenter Real-World Experience.

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Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning.

T-cell-redirecting bispecific antibodies have emerged as a new class of therapeutic agents designed to simultaneously bind to T cells via CD3 and to tumor cells via tumor-cell-specific antigens (TSA), inducing T-cell-mediated killing of tumor cells. The promising preclinical and clinical efficacy of TSAxCD3 antibodies is often accompanied by toxicities such as cytokine release syndrome due to T-cell activation. How the efficacy and toxicity profile of the TSAxCD3 bispecific antibodies depends on the binding affinity to CD3 remains unclear.

Type 2 diabetes and heart failure: insights from the global DISCOVER study.

Aims: Heart failure (HF) is increasingly recognized as a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), but the global epidemiology and treatment of HF in T2D are not well defined. This study aimed to examine the global prevalence of HF and the incidence of HF over 3 years of follow-up in patients with T2D [by presence and absence of co-existing coronary artery disease (CAD)].

Methods And Results: DISCOVER was a 3 year, prospective, observational study of T2D patients enrolled at initiation of second-line glucose-lowering therapy.