Citations

Objective To evaluate the clinical effectiveness of sodium glucose cotransporter 2 (SGLT2) inhibitors in reducing the risk of hospital admission for heart failure and mortality in a contemporary nationwide cohort of patients with heart failure with preserved ejection fraction (HFpEF). Design Nationwide cohort study (REFINE-HFpEF). Setting 170 veteran health medical centres across the US, 1 January 2014 to 31 December 2021. Participants 2177 patients with type 2 diabetes and HFpEF; 1129 patients were newly prescribed SGLT2 inhibitors and 1048 were newly prescribed dipeptidyl peptidase 4 (DPP4) inhibitors or sulfonylureas. Main outcome measures The primary outcome was a composite of all cause mortality and hospital admission for heart failure. Secondary outcomes included all cause mortality only and serial changes in body weight. Hazard ratios were derived from Cox proportional hazards models, incorporating inverse probability of treatment weighting based on propensity scores to account for confounding. Results From a validated cohort of 179 288 patients with type 2 diabetes and HFpEF, the study included 1129 new users of SGLT2 inhibitors (active treatment) and 1048 new users of DPP4 inhibitors or sulfonylureas (comparators). After a median follow-up of 2.63 years, 46.4% of the study population had at least one hospital admission for heart failure (n=1011) and the overall mortality rate was 45.9% (n=1000). Use of SGLT2 inhibitors was associated with a relative risk reduction in the primary composite outcome of 18% compared with the use of DPP4 inhibitors or sulfonylureas (hazard ratio 0.82, 95% confidence interval 0.70 to 0.96; P=0.01). The adjusted hazard ratio for all cause mortality only was 0.73 (0.60 to 0.89; P=0.002). Weight loss was similar in the two groups. Conclusions In this large, contemporary, nationwide cohort of patients with HFpEF, type 2 diabetes, and high event rates, starting SGLT2 inhibitors was associated with a significantly lower risk of hospital admission for heart failure and all cause mortality compared with starting treatment with DPP4 inhibitors or sulfonylureas.

Background New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms. Methods The American Heart Association convened 75 multidisciplinary experts for the Amyloid‐Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β‐Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus‐based guidance for clinicians. Results This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co‐occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision‐making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions. Conclusions Building on lessons learned from the establishment of stroke systems of care, the consensus‐based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground‐breaking therapies.

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received <7/8 MMUD grafts; 82.4% of the <7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the <7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the <7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

Introduction Allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) entails prolonged recovery, serious complications, functional limitations, psychological distress, and extended isolation to prevent infection. During the peak of the COVID-19 pandemic, treatment disruptions, restricted caregiver access, and intensified isolation compounded these transplant-specific burdens. The longer-term influence of the pandemic experience on HCT recovery and survivorship remains poorly understood. Methods In this qualitative descriptive study, adults with AML who underwent allogeneic HCT from March through September 2020 participated in virtual semi-structured interviews from July 2022 through April 2023, approximately two years post-transplant. Participants were identified through the Center for International Blood and Marrow Transplant Research registry. Zoom or phone interviews were recorded, transcribed verbatim, and analyzed using inductive qualitative content analysis to describe survivorship experiences and opportunities to improve supportive care. Results A total of 25 AML survivors (ages 24-78, 56% male) were interviewed approximately two years post-transplant. Three themes were found: (1) Transplant is an arduous journey; (2) The COVID-19 pandemic shaped the transplant experience in complex and far-reaching ways; (3) Transplant demands sustained personal and relational investment throughout the transplant journey. Conclusions This study enhances our understanding of the stressors associated with transplantation during periods of heightened adversity, while also identifying opportunities to strengthen healthcare systems and supportive care services for this population. Situating these experiences within the context of a global health emergency offers a rare lens into how external stressors can exacerbate the already demanding nature of HCT survivorship. By understanding survivors’ experiences, healthcare systems can better anticipate and address the evolving needs of transplant survivors.

Aneuploidy is a hallmark of cancer often associated with inferior prognosis. Copy number gains of chromosome 8 (chr8) are recurrent in multiple cancers, including breast, prostate, colorectal cancers, and sarcomas such as malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are aggressive, hard-to-treat sarcomas frequently linked to the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. To investigate the role of chr8 gain in MPNST pathogenesis, we performed a CRISPR knockout screen and identified 58 essential genes on chr8, including PTK2, which encodes focal adhesion kinase (FAK). We evaluated FAK as a therapeutic target and tested small-molecule FAK inhibitors (FAKi) alone or combined with RAF/MEK inhibitors (RAF/MEKi), a class of agents relevant to NF1-deficient tumors with ERK pathway hyperactivation. Both pharmacological and genetic inhibition of FAK reduced MPNST cell proliferation in vitro and tumor growth in vivo. Combined FAKi and RAF/MEKi treatment further suppressed phosphorylation of FAK, STAT3, and AKT while increasing cleaved caspase-3 and PARP-1, indicating enhanced apoptosis. In MPNST patient-derived xenograft (PDX) models, combination therapy significantly reduced tumor growth, showing superior efficacy, particularly in chr8 gain MPNST-PDX. These results support FAK/RAF/MEK co-targeting as a promising therapeutic strategy for chr8 gain MPNST and related tumors.

Abstract Although the human genome encodes a vast repertoire of noncoding RNAs that regulate gene expression, the noncoding genome remains underexplored due to technical challenges. Specifically, during transcriptomic sequencing data alignment, the overlap between noncoding and coding loci can create ambiguous read alignments that are subsequently discarded from downstream analysis. For this reason, most of the noncoding genome is excluded from standard genomic annotations used for sequencing alignment. To address this challenge and enable concurrent profiling of the coding and noncoding transcriptome, we systematically integrated standard coding (GENCODE) and noncoding (LncBook) genome annotations, preserving coding gene annotations and removing overlapping noncoding regions. The resulting integrated genome annotation expanded the number of annotated noncoding genes from 40,785 to 138,296 while preserving all coding genes and reducing ambiguous read assignment. To evaluate the utility of our integrated genome annotation for uncovering novel, biologically relevant noncoding RNAs (ncRNAs), we realigned CD138-positive bulk RNA-seq (N = 942) and CD138-negative single-cell RNA-seq (N = 478) data from the MMRF CoMMpass study, generating a comprehensive coding-noncoding atlas of the myeloma bone marrow microenvironment with noncoding genes representing 51% of highly variable genes and displaying significant cell type specificity. Tumor expression profiling based on this integrated profiling identified 15 clusters, including two enriched for amp(1q21) or t(4;14) and associated with shorter progression-free survival (PFS). Differential expression and systematic filtering yielded 19 candidate high-risk ncRNAs, including previously uncharacterized ENSG00000310209 , which was associated with poor PFS (HR = 1.141, P = 0.0025), increased IRF4 activity, Wnt pathway activation, CCL5 signaling, and the accumulation of anergic-like CD8+ T cells. These findings establish integrated coding-noncoding analysis as a strategic approach for discovering functional ncRNAs from transcriptomic sequencing data.