Development, implementation, and evaluation of an innovative clinical trial operations training program for Africa (ClinOps).

Background: Africa's involvement in clinical trials remains very low. Although the crucial role of training initiatives in building clinical trial capacity in Africa has been documented, current efforts fall short as they lack alignment with local contexts. This study aimed to design, develop, implement, and evaluate an innovative clinical trial operations training program for Africa.

Defining Hyperphagia for Improved Diagnosis and Management of MC4R Pathway-Associated Disease: A Roundtable Summary.

Purpose Of Review: Hyperphagia is a condition associated with rare obesity-related diseases, presenting as a pathologic, insatiable hunger accompanied by abnormal food-seeking behaviors. In October 2023, a group of researchers and clinicians with expert knowledge on hyperphagia convened at the annual ObesityWeek meeting to discuss the need for a unified definition of hyperphagia and key items necessary to improve the identification, assessment, and treatment of hyperphagia in patients with melanocortin 4 receptor (MC4R) pathway-associated diseases.

Recent Findings: The definition of hyperphagia proposed by this group is a pathologic, insatiable hunger accompanied by abnormal food-seeking behaviors.

Antimicrobial Resistance in Curable Sexually Transmitted Infections.

Purpose Of Review: Antimicrobial resistance in sexually transmitted infections (STIs) has become an urgent global public health threat, raising the specter of untreatable infections. This review summarizes the determinants of resistance among the five most common curable STIs Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Treponema pallidum, and Trichomonas vaginalis, as well as strategies to mitigate the spread of resistance.

Recent Findings: Genetic mutations are key drivers of resistance for N.

Dual anti-CTLA-4 and anti-PD-1 blockade in metastatic basal cell carcinoma.

We report the basal cell cancer (BCC) cohort of the SWOG/NCI 1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART), a phase II prospective, multicenter basket trial of nivolumab and ipilimumab. The primary endpoint was objective response rate (ORR) (RECIST v1.1).

Immune infiltrate populations within distinct tumor immune microenvironments predictive of immune checkpoint treatment outcome.

Understanding the dynamic tumor immune microenvironment (TIME) is important in guiding immunotherapy. We have previously validated signatures predictive of checkpoint inhibitor efficacy which distinguish immunomodulatory, mesenchymal stem-like, and mesenchymal phenotypes. Here we use twenty tumor types (7162 samples) to identify potentially conserved immune biology within these TIME spaces, genes co-expressed across distinct cell types involved these immune processes, and the association of these signatures with ICI response.

Unraveling complexity and leveraging opportunities in uncommon breast cancer subtypes.

Special histologic subtypes of breast cancer (BC) exhibit unique phenotypes and molecular profiles with diagnostic and therapeutic implications, often differing in behavior and clinical trajectory from common BC forms. Novel methodologies, such as artificial intelligence may improve classification. Genetic predisposition plays roles in a subset of cases.

Broad substrate scope C-C oxidation in cyclodipeptides catalysed by a flavin-dependent filament.

Cyclic dipeptides are produced by organisms across all domains of life, with many exhibiting anticancer and antimicrobial properties. Oxidations are often key to their biological activities, particularly C-C bond oxidation catalysed by tailoring enzymes including cyclodipeptide oxidases. These flavin-dependent enzymes are underexplored due to their intricate three-dimensional arrangement involving multiple copies of two distinct small subunits, and mechanistic details underlying substrate selection and catalysis are lacking.

Mechanical thrombectomy in elderly stroke patients with low ASPECTS: insights from STAR.

Background: The elderly population (≥80 years) were underrepresented in recent trials of endovascular thrombectomy (EVT) for anterior circulation large vessel occlusion acute ischemic stroke (LVO-AIS) with low Alberta Stroke Program Early CT Score (ASPECTS) (≤5).

Methods: This study analyzed data from a prospectively maintained database of 37 thrombectomy centers. The primary cohort of the study comprised patients with LVO-AIS aged ≥80 who underwent EVT with ASPECTS≤5 from 2013 to 2023.

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for children with chronic GVHD after Hematopoietic Cell Transplantation.

While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplant (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD, and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms.

TET2-loss enhances immediate and time-resolved IFNγ signaling responses across myeloid differentiation.

Signaling responses to cytokines are disrupted in clonal hematopoiesis and myeloid malignancies. To better identify specific signaling response alterations in the presence or absence of TET2, we developed a 36-parameter CyTOF panel of both surface marker and phosphoprotein antigens in murine BM. We show diverse, cell-type specific inflammatory cytokine responses in healthy hematopoietic cells.

Clinical Care Pathways for Second and Third Trimester Termination of Pregnancy for Medical Reasons in Canada.

Objective: Termination of pregnancy in the 2/3 trimester for fetal or maternal complications (i.e., for medical reasons) is an essential health service.

Radiation Segmentectomy for Early Hepatocellular Carcinoma is Curative.

In this Expert Opinion, we provide the rationale for concluding that radiation segmentectomy (using RADSEG method), a technique of administrating ablative, complete necrosis-inducing trans-arterial Yttrium-90 (Y90) radiotherapy in limited-disease burden hepatocellular carcinoma (HCC), is curative. Currently, curative options for early stage and other carefully selected HCC patients include transplantation, resection, and ablation. Because of issues with organ availability, co-morbidities preventing resection, and tumor size and location limiting ablation, other treatments are necessary for this selected patient population.

Characterization of gene-environment interactions for vitamin D through variance quantitative trait loci: a UK Biobank-based genetic epidemiology study.

Background: Understanding gene-environment interactions associated with vitamin D status may refine nutrition and public health strategies for vitamin D deficiency. Recent methodological advances have enabled the identification of variance quantitative trait loci (vQTLs) where gene-environment interactions are enriched.

Objectives: To identify vQTLs for serum 25-hydroxy vitamin D (25OHD) concentrations and characterize potential gene-environment interactions of vQTLs.

Sand and dust storms: a growing global health threat calls for international health studies to support policy action.

Sand and dust storms increasingly threaten global environmental and public health. To date, 150 countries are directly affected, with more than 100 classified as non-dust source regions. With climate change, these storms are expected to become more frequent and severe.

Mapping hotspots of zoonotic pathogen emergence: an integrated model-based and participatory-based approach.

Background: An increase in pandemics of zoonotic origin has led to a growing interest in using statistical prediction to identify hotspots of zoonotic emergence. However, the rare nature of pathogen emergence requires modellers to impose simplifying assumptions, which limit the model's validity. We present a novel approach to hotspot mapping that aims to improve validity by combining model-based insights with expert knowledge.

A novel rapalog shows improved safety vs. efficacy in a human organoid model of polycystic kidney disease.

The mammalian target of rapamycin (mTOR) pathway is a therapeutic target in polycystic kidney disease (PKD), but mTOR inhibitors such as everolimus have failed to show efficacy at tolerated doses in clinical trials. Here, we introduce AV457, a novel rapalog developed to reduce side effects, and assess its dose-dependent safety and efficacy versus everolimus in PKD1 and PKD2 human kidney organoids, which form cysts in a PKD-specific way. Both AV457 and everolimus reduce cyst growth over time.

Paediatric strategy forum for medicinal product development in diffuse midline gliomas in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments.

Antiviral Mx proteins have an ancient origin and widespread distribution among eukaryotes.

Mx proteins, first identified in mammals, encode potent antiviral activity against a wide range of viruses. Mx proteins arose within the Dynamin superfamily of proteins (DSP), which mediate critical cellular processes, such as endocytosis and mitochondrial, plastid, and peroxisomal dynamics. Despite their crucial role, the evolutionary origins of Mx proteins are poorly understood.

Improving Social Determinants of Health via the Workplace.

: Social determinants of health (SDOH), such as food security and healthcare access, are key to maintaining and improving health. Publicly funded safety-net programs, such as Medicaid and the Supplemental Nutrition Assistance Program, address SDOH. Many low-wage employees are program-eligible, but there are substantial participation gaps.

Distributed lag models for retrospective cohort data with application to a study of built environment and body weight.

Distributed lag models (DLMs) estimate the health effects of exposure over multiple time lags prior to the outcome and are widely used in time series studies. Applying DLMs to retrospective cohort studies is challenging due to inconsistent lengths of exposure history across participants, which is common when using electronic health record databases. A standard approach is to define subcohorts of individuals with some minimum exposure history, but this limits power and may amplify selection bias.

Health Care Spending Increases and Value in South Korea.

Importance: Health care spending in South Korea (hereafter Korea) nearly doubled from 2010 to 2019. However, little is known about the drivers and effectiveness of these spending increases in terms of changes in disability-adjusted life-years (DALYs).

Objectives: To evaluate the factors contributing to changes in health care spending and DALYs and estimate the value of health care spending from 2010 to 2019 in Korea.

Incidence Rate Trends of Breast Cancer Overall and by Molecular Subtype by Race and Ethnicity and Age.

Importance: Black and Hispanic women in the US experience higher incidence rates of aggressive molecular subtypes of breast cancer, including triple-negative disease. However, how these rates are changing, particularly across different age groups, has not been well documented.

Objective: To assess changes in overall and subtype-specific breast cancer incidence rates in the US by age and race and ethnicity.

rDNA Copy Number Variation and Methylation During Normal and Premature Aging.

Ribosomal RNA is the main component of the ribosome, which is essential for protein synthesis. The diploid human genome contains several hundred copies of the rDNA transcription unit (TU). Droplet digital PCR and deep bisulfite sequencing were used to determine the absolute copy number (CN) and the methylation status of individual rDNA TU in blood samples of healthy individuals.