Citations

Abstract Introduction: Recruitment for rare disease studies is challenging due to small eligible populations. Traditional clinical research management systems often lack tools to track recruitment contacts prior to enrollment. The NET-PRO study, focused on neuroendocrine tumors (NETs), implemented a participation monitoring system to enhance recruitment efficiency and representativeness. Methods: NET-PRO is a multicenter cohort study of 2538 adults diagnosed with gastroenteropancreatic (GEP) or lung NETs between January 2018 and September 2024. Recruitment occurred from January 2022 to February 2025 across 14 U.S. medical centers. Sites used flexible recruitment methods (email, mail, phone, in-clinic) and tracked contacts using REDCap-based tools. Participant characteristics were analyzed by enrollment mode (online or mail) and recruitment difficulty (number of contacts required prior to enrollment) using standardized mean differences, chi-square tests, and ANOVA. Results: Of 9279 contacted patients, 2675 consented (28.8%) and 2538 enrolled (27.4%). Most enrolled online (83.2%), while 16.8% enrolled by mail. Mail respondents were older, had lower education and income, and more comorbidities. Among those enrolled, recruitment difficulty was associated with older age, lower education and income, but not comorbidity. Over half of the most difficult-to-recruit participants enrolled online. Contact methods varied by attempt, with email dominating early contacts and phone/mail used more in later attempts. Conclusions: A participation monitoring tool supported flexible, multimodal recruitment and improved sample representativeness in a rare cancer study. Tracking recruitment contacts enabled adaptive strategies and may reduce bias in observational research by enabling better outreach to harder-to-reach populations.

OBJECTIVES: Current research does not address the existence and impact of structured tele-critical care (TCC) training on the delivery of care in the ICU. This pilot study aimed to evaluate the association between on boarding elements focused on training and clinicians perceptions of delivery of care. DESIGN: Cross-sectional survey study. SETTING AND PARTICIPANTS: Critical Care professionals at four U.S. hospitals, professional meetings and Society of Critical Care Medicine’s International Membership base. Participants were active clinicians who practice in the TCC setting. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 432 participants responded to the survey, 227 met the eligibility criteria (52.5%) and were included in the analysis. Respondents were a multi-professional group of TCC clinicians aged between 35–55 years of age (56.4%). Seventy-four percent of respondents reported having orientation before providing TCC, 46% reported having formal mentorship, and 66% reported formal training on their institutional platform. Provision of orientation before participating in a TCC program was associated with higher ratings of feeling prepared (odds ratio [OR], 3.52; p < 0.001) and feeling accepted as part of the ICU team (OR, 2.21; p = 0.008). Mentorship was associated with feeling more prepared (OR, 8.2; p < 0.001) and higher comfort in delivering care (OR, 2.78; p = 0.016). Platform training was associated with feeling more prepared (OR, 4.66; p < 0.001), comfortable in delivering care (OR, 3.6; p = 0.002), feeling accepted as part of the team (OR, 3.18; p < 0.001), and more likely to participate in quality improvement (OR, 2.51; p = 0.001). A site visit also made a positive impact in feeling prepared (OR, 2.86; p < 0.001), comfortable (OR, 4.95; p = 0.002), feeling like recommendations were accepted (OR, 3.73; p < 0.001), more likely to recommend TCC (OR, 3.18; p = 0.001), and participating in quality improvement (OR, 3.24; p < 0.001). CONCLUSIONS: In this pilot study, structured training utilizing orientation, mentorship, and platform training as surrogates, along with a site visit before beginning delivery of care in a TCC setting, were associated with more positive perceptions in the delivery of care domains assessed. We highlight potentially important factors that warrant further evaluation and assessment of the need for standardization across TCC programs.

Abstract Background Primary CNS lymphoma (PCNSL) is a rare, aggressive diffuse large B-cell lymphoma confined to the CNS, with poor outcomes. Virally associated PCNSL, including AIDS-related PCNSL (AR-PCNSL) and CNS post-transplant lymphoproliferative disorder (CNS-PTLD) accounts for ~10% of cases and is strongly linked to EBV infection and poor prognosis. In our prior Blood (Gandhi et al. 2021) study, targeted sequencing showed that EBV⁺ PCNSL lacks canonical MYD88, CD79B, and PIM1 mutations and retains intact HLA class I/II, suggesting distinct immunobiology. However, questions remain regarding the immune microenvironment, broad mutational landscape, and intratumoral heterogeneity. Here, we present the first large-scale comprehensive integrated analysis of virally associated PCNSL to define subtype-specific vulnerabilities and therapeutic implications. Methods FFPE brain biopsies from 72 PCNSL patients (40 EBV- de novo PCNSL, 32 EBV+ PCNSL including 18 AR-PCNSL and 14 CNS-PTLD) were analyzed. Immune gene expression was profiled using the NanoString PanCancer Immune Panel. Whole exome sequencing (WES) defined recurrent driver mutations, tumor mutational burden (TMB), and LymphGen classification (excluding A53 subtype). Single nuclei RNA sequencing (snRNA-seq) using the 10x Genomics Chromium Flex platform characterized cellular heterogeneity. Results WES demonstrated a marked reduction in canonical mutations (MYD88L265P, CD79B, PIM1, CARD11) in CNS-PTLD (0%) and AR-PCNSL (29%) vs. de novo PCNSL (87.5%; p&lt;0.0001). AR-PCNSL had a distinct mutational signature when compared with CNS-PTLD and de novo PCNSL. NOTCH1/2 mutations were significantly enriched in AR-PCNSL (71%) vs. CNS-PTLD (9%) and de novo PCNSL (33%) (p&lt;0.01). NLRC5 mutations were present in 64% of AR-PCNSL cases, higher than the 25% observed in de novo PCNSL and were absent in CNS-PTLD. TMB was significantly elevated in AR-PCNSL (mean 26.27 mutations/Mb) vs. de novo PCNSL (17.22) and CNS-PTLD (11.01; p=0.0018) underscoring pronounced genomic instability and suggesting HIV may exert a mutagenic influence beyond immunosuppression. EBV driven subtypes lacked MCD features and were more often classified as ST2 or unassigned. Despite NOTCH2 mutations, AR-PCNSL cases were not classified under the BN2 subtype, further highlighting limitations in current molecular classification systems to accurately stratify virally associated PCNSL. Immune transcriptomic profiling revealed further distinctions within EBV+ PCNSL. CNS-PTLD showed increased expression of genes related to antigen presentation (p&lt;0.0001), cytotoxicity (p=0.0019), and T cell function (p&lt;0.0001), suggesting retained immune responsiveness. AR-PCNSL exhibited significant suppression of HLA class I/II genes (p=0.0027 and p&lt;0.0001 respectively), despite intact genomic loci, implicating post-transcriptional or epigenetic silencing. Immune cell composition revealed reduced macrophage infiltration and suppressed CD4 expression in AR-PCNSL. CNS-PTLD showed higher expression of checkpoint molecules LAG3, TIM3, and CTLA4, consistent with T cell exhaustion. snRNA-seq profiling of AR-PCNSL identified distinct malignant and non-malignant cell populations, including a reduced CD4⁺ compartment and altered microglial/macrophage populations and cell states compared to de novo PCNSL, corroborating bulk transcriptomic data, amongst other ongoing analysis. Conclusion This study represents the largest and most comprehensive immunogenomic investigation of virally associated PCNSL. AR-PCNSL and CNS-PTLD lack canonical PCNSL driver mutations and instead harbor distinct mutational signatures, including NOTCH pathway alterations in AR-PCNSL. These findings underscore divergent pathogenic mechanisms and support tailored therapies. AR-PCNSL is marked by high TMB, suppressed antigen presentation, and reduced CD4⁺ infiltration, indicating profound immune dysfunction. CNS-PTLD retains immune functionality but shows checkpoint upregulation and T cell exhaustion. Despite both being EBV-driven and CNS-restricted, they display distinct molecular and immunological programs, suggesting context specific EBV mechanisms. These findings challenge existing classification systems and support CNS-specific molecular frameworks to guide therapeutic interventions including BTK inhibition for NOTCH-mutated lymphoma. They lay the foundation for precision approaches in EBV⁺ PCNSL, including immune restoration, antigen-specific T cell therapy, and epigenetic modulation.

Abstract Introduction: The ZRSR2 gene, located at Xp22.2, encodes a protein component of the RNA spliceosome. Alterations in ZRSR2 have been reported in various myeloid neoplasms (MN) and their precursors. They are frequently accompanied by other co-mutations, most commonly TET2. Isolated ZRSR2 mutations, however, are less commonly encountered and their clinicopathologic features have not been well documented. Aim: To describe the clinicopathologic features of MN and their precursors with isolated ZRSR2 mutations. Methods: Next-generation sequencing (NGS) was performed on peripheral blood (PB) or bone marrow (BM) samples from patients with confirmed/suspected MN using a 35-47 gene MN-targeting NGS panel. MN and clonal cytopenia of undetermined significance (CCUS) cases with isolated likely pathogenic/pathogenic (LP/P) ZRSR2 mutations were identified. Pathology diagnoses were rendered following the 2022 WHO/ICC classification and the slides were reviewed by three pathologists. Electronic medical records were reviewed for collection of relevant laboratory data. This study was approved by our institution's Institutional Review Board. Results: Of 164 ZRSR2-mutated cases, 10 cases with isolated LP/P mutations in ZRSR2 were identified. Patients were all male, with a median age 69.5 years. Three patients were diagnosed with CCUS, five with myelodysplastic syndrome (MDS), one with chronic myelomonocytic leukemia (CMML, MDS/MPN) and one with mixed phenotype acute leukemia (MPAL). Six patients had additional variants of undetermined significance (VUS) detected in ASXL1, CALR, EZH2, IDH2 and TET2. The other four patients had no additional variants identified by NGS but had cytogenetic abnormalities. One patient with MPAL had MECOM and IGH gene rearrangements detected on cytogenetic analysis. All patients had macrocytic anemia. One CMML patient with accompanying VUS in TET2 also had absolute monocytosis. BM cellularity and erythroid and granulocytic morphology were variable, ranging from unremarkable to left-shifted and dysplastic morphology. Nine (90%) cases showed atypical megakaryocyte morphology, characterized by hypolobated forms and osteoclast-like forms with separated and eccentrically located nuclear lobes. Interestingly, this megakaryocytic morphology was also observed in CCUS cases, albeit with lower frequency, below the 10% threshold necessary for the diagnosis of MDS. Megakaryocyte distribution was normal. Conclusions: Isolated LP/P ZSRS2 mutations are seen in a spectrum of myeloid neoplasms, including CCUS. They show a strong association with macrocytic anemia and megakaryocytic atypia/dysplasia. The presence of additional cytogenetic alterations and variants of undetermined significance is a confounding factor in determining the role of ZRSR2 mutations in driving the pathogenesis and morphologic features of these diseases.

This Viewpoint discusses care denial for transgender youth forced by law and how health systems will need to invest resources to adjust to the expected emergence of mental health concerns, for which psychiatrists can play a key role in developing and implementing such programs locally.

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). Objective To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). Design, Setting, and Participants This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. Interventions Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. Main Outcomes and Measures All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. Results Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. Conclusions and Relevance The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. Trial Registration ClinicalTrials.gov Identifiers: NCT03860935 ; NCT04988386

BACKGROUND: Elevated blood pressure (BP) is a major contributor to coronary artery disease. We explored the impact of life-course BP on later-life normalized stress myocardial blood flow (sMBF N ) and myocardial perfusion reserve by cardiovascular magnetic resonance (CMR). METHODS: MyoFit46 prospectively recruited ≈500 National Survey of Health and Development 1946 birth cohort participants, aged ≈77 years, to undergo stress perfusion and late gadolinium enhancement CMR. Systolic (SBPs) and diastolic BPs were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, the annual rates of BP change (steepness of BP increase) and area under the BP trajectory curve (cumulative life-course BP burden) were derived using mixed-effects models. The associations between BP measures and CMR metrics were tested using generalized linear and additive models, adjusted for antihypertensive use, demographics, lifestyle choices, and comorbidities. Cross-sectional associations between CMR metrics and major adverse cardiovascular events (myocardial infarction, stroke, and heart failure) were also tested. Mediation analyses explored the mechanistic pathways linking life-course BPs, myocardial perfusion, and myocardial fibrosis. RESULTS: Among 459 included MyoFit46 participants, each 10 mm Hg higher SBP at 36 to 69 years was associated with 3% to 6% lower sMBF N by CMR at 77 years. At 43 to 63 years, as SBPs rose from 120 to 140 mm Hg, sMBF N was 18% to 24% lower. Having a sustained higher SBP by 10 mm Hg from 36 to 77 years was associated with 11% (95% CI, 8–14) lower sMBF N at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, 53 to 63, and 63 to 69 years was associated with 2% to 6% lower sMBF N at 77 years, associations not conditional on baseline or final BPs in each age interval. Associations may be clinically relevant as each 1% lower sMBF N was associated with 3% higher odds of major adverse cardiovascular events. sMBF N mediated ≈20% to ≈40% of the associations between life-course SBPs and late gadolinium enhancement at 77 years. Results were similar for diastolic BP, myocardial perfusion reserve, or sMBF (not normalized). CONCLUSIONS: Higher life-course BPs, steeper increases, and greater cumulative BP burden associate with lower myocardial perfusion by CMR at 77 years, which can be linked with higher odds of major adverse cardiovascular events and greater myocardial fibrosis burden. This underscores the importance of early life BP screening and guiding hyperetension treatment based on longitudinal BP trajectories (rather than relying solely on cross-sectional BPs). REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05455125.

Abstract Repetitive head impacts are common in contact and collision sports and are linked to structural brain changes and an elevated risk of neurodegenerative diseases such as Chronic Traumatic Encephalopathy. Identifying early in vivo structural markers remains challenging. Although diagnosis currently requires post-mortem confirmation, clinical symptoms, including cognitive impairment and behavioural changes, are reflected in the diagnosis of Traumatic Encephalopathy Syndrome. These symptoms align with dysfunction in key brain regions—amygdala, hippocampus and thalamus—which support memory, emotion and behaviour and commonly show tau pathology in Chronic Traumatic Encephalopathy. This study uses shape analysis to examine structural differences in these regions between former American football players and unexposed asymptomatic controls and evaluates the influence of age, head impact exposure and clinical diagnosis on brain structure. We analyzed brain morphology in former American football players (n = 163) and unexposed, asymptomatic controls (n = 53). Structural segmentation was performed with FreeSurfer 7.1, and the shape analysis pipeline was used to generate subregional reconstructions. Vertex-level morphometry, based on the logarithm of the Jacobian determinant and radial distance, quantified local surface area dilation and thickness. Group differences were examined with covariate-adjusted linear regression models contrasting football players and controls, as well as participants with and without a Traumatic Encephalopathy Syndrome diagnosis. Partial correlations examined the influence of age, age of first football exposure and cumulative head impact index metrics, including frequency, linear acceleration and rotational force. Models were adjusted accordingly for age, body mass index, education, race, imaging site, apolipoprotein ϵ4 status and total intracranial volume. Former football players exhibited bilateral surface area contractions in the hippocampus and amygdala, along with reduced amygdala thickness, compared to controls. Older age was associated with widespread surface contractions and thinning across all regions, except for preserved thickness in the left hippocampus. An earlier age of first exposure to football correlated with surface contractions in the thalamus and left hippocampus. Greater cumulative linear acceleration was linked to bilateral hippocampal surface contractions and reduced thickness in the left thalamus, while greater rotational force exposure was associated with hippocampal thinning. No significant structural differences were found between players with and without a diagnosis of Traumatic Encephalopathy Syndrome. These findings extend volume-based research by revealing localized alterations in surface area dilation and thickness and emphasize the roles of age and repetitive head impact exposure in long-term brain changes.