Integrative proteogenomic analysis identifies COL6A3-derived endotrophin as a mediator of the effect of obesity on coronary artery disease.

Obesity strongly increases the risk of cardiometabolic diseases, yet the underlying mediators of this relationship are not fully understood. Given that obesity strongly influences circulating protein levels, we investigated proteins mediating the effects of obesity on coronary artery disease, stroke and type 2 diabetes. By integrating two-step proteome-wide Mendelian randomization, colocalization, epigenomics and single-cell RNA sequencing, we identified five mediators and prioritized collagen type VI α3 (COL6A3).

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).

Transforming diagnosis through artificial intelligence.

Artificial intelligence (AI) is increasingly permeating the fabric of medicine, but getting full benefits will likely require fundamental changes in practice. Accepting this will be challenging for many clinicians. However, it may be necessary to ensure that AI’s ambitious promises translate into real-life improvement.

Transposon mediated functional genomic screening for BRAF inhibitor resistance reveals convergent Hippo and MAPK pathway activation events.

Genotype-informed anticancer therapies such as BRAF inhibitors can show remarkable clinical efficacy in BRAF-mutant melanoma; however, drug resistance poses a major hurdle to successful cancer treatment. Many resistance events to targeted therapies have been identified, suggesting a complex path to improve therapeutics. Here, we showed the utility of a piggyBac transposon activation mutagenesis screen for the efficient identification of genes that are resistant to BRAF inhibition in melanoma.

V3+ extends the V3 framework to ensure user-centricity and scalability of sensor-based digital health technologies.

We propose the addition of usability validation to the extended V3 framework, now "V3+", and describe a pragmatic approach to ensuring that sensor-based digital health technologies can be used optimally at scale by diverse users. Alongside the original V3 components (verification; analytical validation; clinical validation), usability validation will ensure user-centricity of digital measurement tools, paving the way for more inclusive, reliable, and trustworthy digital measures within clinical research and clinical care.

Composite cardiac computed tomography angiography score for improved risk assessment in chronic coronary syndromes.

Agatston score, the degree of lumen narrowing categorized by CAD-RADS, high-risk atherosclerotic plaque features and pericoronary adipose tissue attenuation (PCAT) are parameters, which can be assessed non-invasively by coronary computed tomography angiography (CCTA) and aid risk stratification in patients with chronic coronary syndromes (CCS). However, few studies have so far compared the prognostic value of all those parameters together. To develop and test the prognostic value of a composite CCTA score, derived from Agatston score, CAD-RADS, high-risk plaques and PCAT in patients undergoing CCTA due to CCS.

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.

SLC25A38 is required for mitochondrial pyridoxal 5'-phosphate (PLP) accumulation.

Many essential proteins require pyridoxal 5'-phosphate, the active form of vitamin B6, as a cofactor for their activity. These include enzymes important for amino acid metabolism, one-carbon metabolism, polyamine synthesis, erythropoiesis, and neurotransmitter metabolism. A third of all mammalian pyridoxal 5'-phosphate-dependent enzymes are localized in the mitochondria; however, the molecular machinery involved in the regulation of mitochondrial pyridoxal 5'-phosphate levels in mammals remains unknown.

A Call for a Neoadjuvant Kidney Cancer Consortium: Lessons Learned from Other Cancer Types.

Neoadjuvant systemic treatment strategies have improved outcomes in several solid tumour types. This success has not yet been replicated in renal cell carcinoma (RCC). A consensus and international collaboration are urgently needed for the development of adaptive perioperative immunotherapy strategies for patients with RCC at high risk of recurrence.

Using artificial intelligence to optimize anti-seizure treatment and EEG-guided decisions in severe brain injury.

Electroencephalography (EEG) is invaluable in the management of acute neurological emergencies. Characteristic EEG changes have been identified in diverse neurologic conditions including stroke, trauma, and anoxia, and the increased utilization of continuous EEG (cEEG) has identified potentially harmful activity even in patients without overt clinical signs or neurologic diagnoses. Manual annotation by expert neurophysiologists is a major resource limitation in investigating the prognostic and therapeutic implications of these EEG patterns and in expanding EEG use to a broader set of patients who are likely to benefit.

Age Self Care-Resilience, a medical group visit program targeting pre-frailty: A mixed methods pilot clinical trial.

Background: Pre-frailty is highly prevalent and multimodal lifestyle interventions are effective for preventing transition to frailty. However, little is known about the potential for medical group visits (MGV) to prevent frailty progression.

Objectives: To assess the feasibility and acceptability of the MGV Age Self Care-Resilience.

Patient-reported outcomes in sarcopenia: An ICFSR task force report.

The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force convened in March 2024 to address patient-reported outcomes measures (PROMs) in the field of sarcopenia. PROMs are crucial to enhance healthcare services at both individual and societal levels. PROMs complement objective outcome measures by capturing insights that patients are best suited to judge.

Heart rate variability as a digital biomarker for frailty in cardiovascular patients.

Background: Frailty is a syndrome associated with age-related impairments in multiple organ systems, of which the autonomic nervous system plays a fundamental role. Measurement of heart rate variability (HRV) is a non-invasive method to evaluate the autonomic activity and gain insights into cardiovascular health and potentially, frailty. A few small studies have explored the relationship between HRV and frailty, with promising but conflicting results.

Characteristics of children and adolescents with multidrug-resistant and rifampicin-resistant tuberculosis and their association with treatment outcomes: a systematic review and individual participant data meta-analysis.

Background: There are few data on the treatment of children and adolescents with multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis, especially with more recently available drugs and regimens. We aimed to describe the clinical and treatment characteristics and their associations with treatment outcomes in this susceptible population.

Methods: We conducted a systematic review and individual participant data meta-analysis.

Clinical outcomes of patients with unsuccessful mechanical thrombectomy versus best medical management of medium vessel occlusion stroke in the middle cerebral artery territory.

Background: Current randomized controlled trials are investigating the efficacy and safety of mechanical thrombectomy (MT) in patients with medium vessel occlusion (MeVO) stroke. Whether best medical management (MM) is more efficient than unsuccessful vessel recanalization during MT remains unknown.

Methods: This was a retrospective cohort study using data from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021.

US children from non-English-speaking households are less likely to undergo vision testing.

Purpose: To investigate the association between primary household language and vision testing among children living in the United States from 2016 to 2020.

Methods: This analysis used data for children aged 3-17 years from the National Survey of Children's Health (NSCH), combining survey responses from 2016 to 2020. Primary household language and whether vision testing occurred were determined by survey responses.

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.

Implantable Cardioverter-Defibrillators and Cardiovascular Resynchronization Therapy with Left Ventricular Assist Devices: A MOMENTUM 3 Trial Analysis.

Background: The benefit of implantable cardioverter-defibrillators (ICD) and cardiovascular resynchronization therapy (CRT-D) in patients supported with a HeartMate 3 left ventricular assist device (LVAD) remains uncertain.

Methods: An analysis of the MOMENTUM 3 randomized clinical trial and the first 1000 patients in the Continued Access Protocol trial. Patients were divided into three groups based on the presence of ICD and/or CRT-D: No device (n=153, 11%), ICD only (n=699, 50.

Targeting alarmins in asthma- From the bench to the clinic.

Over the past two decades, mechanistic studies of allergic and type 2 (T2)-mediated airway inflammation have led to multiple approved therapies for the treatment of moderate-to-severe asthma. The approval and availability of these monoclonal antibodies targeting immunoglobulin E, a type 2 cytokine (IL-5) and/or cytokine receptors (IL-5Rα, IL-4Rα) has been central to the progresses made in the management of moderate-to-severe asthma over this period. However, there are persistent gaps in clinician's ability to provide precise care given that many patients with type 2-high asthma do not respond to the IgE or T2 cytokine-targeting therapies and patients with type 2-low asthma have limited therapeutic options.

Long term outcomes post-ICD in Chagas cardiomyopathy and non-ischemic cardiomyopathy: A comparative analysis.

Background: Chagas cardiomyopathy (CCM) is a significant cause of ventricular arrhythmias and sudden cardiac death (SCD). Although, implantable cardiac defibrillators (ICD) have been used for all forms of non-ischemic cardiomyopathy (NICM), studies on ICD efficacy in CCM are scarce.

Objective: The present study aims to compare the long-term outcomes, mortality rates, and the occurrence of tachycardia therapies after ICD implantation in patients with CCM and NICM.

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.