Citations

AbstractBackgroundVEXAS syndrome is an autoinflammatory disease caused by somatic UBA1 mutations on the X chromosome, predominantly affecting men.ObjectiveTo characterize VEXAS syndrome in women and to compare the features of VEXAS syndrome between sexes.MethodsWe conducted an international, multicenter study, including 12 women and 301 men with genetically confirmed VEXAS syndrome. Data were collected using a standardized case report form. Bone marrow analyses and molecular investigations were performed locally.ResultsClinical features, age at onset, UBA1 mutation type, variant allele frequency, and mortality were comparable between sexes. Acquired X monosomy was found in 6/8 tested women. Additional clonal mutations were present in 3/5 tested women. Three additional UBA1‐mutated women without typical inflammation are described separately.ConclusionVEXAS syndrome affects women with clinical features similar to men, supporting the need for UBA1 testing in women with compatible presentations. X monosomy is common but not universal, suggesting alternative pathogenic mechanisms.

Summary We investigated the outcomes of patients with advanced systemic mastocytosis (AdvSM) undergoing allogeneic haematopoietic cell therapy (alloHCT) in the US. Twenty‐seven adult (median age, 58 years) patients with AdvSM received alloHCT from 2014 to 2021. Most patients were white (93%), male (63%) and had systemic mastocytosis (SM) with associated haematological neoplasm (SM‐AHN, 70%), received peripheral blood grafts (89%) and non‐myeloablative regimens. KIT mutation was detected in 14 of the reported 16 patients (87.5%). Post‐transplantation cyclophosphamide (PTCy) was used in approximately 50% of the cohort. Approximately 1 year after alloHCT, median bone marrow mast cell burden decreased from 15% pre‐alloHCT to 1.5% (range 0–8) at 1 year post‐alloHCT. The median serum tryptase decreased from 55 ng/mL (range 3–400 ng/mL) pre‐alloHCT to 18 ng/mL (range 0–481 ng/mL) at 1 year post‐alloHCT. At 1 year, progression‐free survival (PFS) and overall survival (OS) were 59% (95% confidence interval [CI], 41%–77%) and 74% (95% CI, 56%–89%) respectively. In the subset of patients with SM‐AHN, 1‐year PFS and OS were 74% (52%–91%) and 79% (95% CI, 58%–94%) respectively. The cumulative incidence of relapse/progression for the entire population of patients with SM ( n = 27) was 4% (95% CI, 0–14) at 100 days and 15% (95% CI, 4–31) at 1 year. For the subset of patients with AHN, the cumulative incidence was 11% (95% CI, 1–28) at 100 days and 21% (95% CI, 6–42) at 1 year. Relapse/progression was the cause of death in six of 12 patients (5 died of AHN and 1 died of SM progression). Eighteen and nine patients received a KIT inhibitor before alloHCT and after alloHCT respectively. In addition, six patients received a KIT inhibitor for the treatment of relapse/progression of SM after alloHCT. Although it is difficult to delineate the exact effect of alloHCT and KIT inhibitors because of the size of the study in this era, the use of alloHCT and KIT inhibitors pre‐ and post‐ alloHCT is increasing. In the near future, larger studies are required to provide further insights into this subject.

Abstract Objective Increased frequency of neuroimaging has led to enhanced identification of small nonfunctioning pituitary adenomas (NFPAs) leading, in many cases, to extensive follow-up. However, the value of ongoing monitoring of these incidental lesions remains unclear. The study aims to determine the need for surgical intervention and assess the risks of developing new endocrinopathies during follow-up in patients with conservatively treated micro-NFPAs. Design A systematic review and individual participant data (IPD) meta-analysis. Methods We conducted a bibliographical search of PubMed and EMBASE to identify relevant studies. Authors of eligible studies were invited to share IPD. Cohort studies including patients with conservatively treated micro-NFPAs with at least 1 follow-up magnetic resonance imaging were considered eligible. Fourteen studies met inclusion criteria. Six authors provided IPD (N = 647). Data were reanalyzed for verification. In cases of discrepancies the original authors were contacted for authentication. Results Risk estimates were reported as number of events per 100 person-years (PYs). Estimates were pooled using the 2-step approach. Overall probability of surgery was 0.2/100 PYs (95% CI: 0.0-0.4; I2 = 28%). Probability of surgery due to visual impairment was 0.1/100 PYs (95% CI: 0.0-0.2; I2 = 0%). Both were independent of baseline tumor size (≥6 or <6 mm), sex, or age (P values >.40). Risk of developing a new endocrinopathy was 1.0/100 PYs (95% CI: 0.4-1.6; I2 = 0%). Data for classical meta-analysis were available for 7 studies (N = 1089) and supported the IPD results. Conclusions These data suggest that routine follow-up of micro-NFPAs can be reduced significantly and that available guidelines should be revisited.

ABSTRACT Background Chronic gastroduodenal symptoms arise from heterogeneous gastric motor dysfunctions. This study applied multimodal physiological testing using gastric emptying scintigraphy (GES) with intragastric meal distribution (IMD) and Gastric Alimetry body surface gastric mapping (BSGM) to define motility and symptom associations. Methods Patients with chronic gastroduodenal symptoms underwent simultaneous supine GES and BSGM with a 30 m baseline, 99mTC‐labeled egg meal, and 4 h postprandial recording. IMD (ratio of counts in the proximal half of the stomach to the total gastric counts) was calculated immediately after the meal (IMD0), with < 0.568 defining abnormal IMD. BSGM phenotyping followed a consensus approach, based on normative spectral reference intervals. Results Among 67 patients (84% female, median age 40 years, median BMI 24 kg/m 2 ), median IMD0 was 0.76 (IQR: 0.69–0.86) with 5 (7.5%) meeting abnormal IMD criteria. Delayed gastric emptying ( n = 18) was associated with higher IMD0 (median 0.9 vs. 0.7, p = 0.004). On BSGM, 15 patients had abnormal spectrograms (5 [7.5%] high frequency and 10 [14.9%] low rhythm stability and/or amplitude); and in these patients, higher IMD0 (proximal retention) strongly correlated to delayed BSGM meal responses ( R = −0.71, p = 0.003). Lower IMD, indicating antral distribution, correlated with higher gastric frequencies ( R = −0.27, p = 0.03). BSGM abnormalities paired with abnormal IMD were associated with worse dyspeptic symptoms. Conclusion Proximal retention of food as assessed by IMD correlated with delayed emptying, and in the presence of neuromuscular spectral abnormalities (abnormal frequencies or rhythms), delayed motility responses on BSGM. Patients with multiple motor abnormalities experience worse dyspeptic symptoms.

Background: Patients with acute ischemic stroke secondary to distal and medium vessel occlusion (AIS-DMVO) and minor strokes present a challenge in determining the most appropriate emergent treatment. Factors leading to early neurological deterioration (END) in this patient population are understudied, but END is known to result in poor functional outcomes. Therefore, we aimed to investigate the factors contributing to END in minor AIS-DMVO cases. Methods: We included patients with AIS-DMVO and minor strokes from 37 sites across North America, Asia, and Europe. Minor stroke was defined as a baseline National Institutes of Health Stroke Scale (NIHSS) score of ⩽5. The primary outcome measure, END, was defined as a shift of ⩾4 points in the NIHSS score at day one after treatment compared to baseline. Univariable and multivariable logistic regression analyses were performed to identify factors associated with END. Results: Among 559 consecutive patients with DMVO and minor strokes, END was reported in 68 patients. In multivariable analysis, mechanical thrombectomy (MT) was independently associated with higher odds of END (adjusted odds ratio [aOR] 2.37, 95% CI 1.12–5.02, p = 0.02), while intravenous thrombolysis (IVT) was associated with lower odds of END (aOR 0.46, 95% CI 0.26–0.81, p = 0.008). However, the association between MT and END was no longer statistically significant in the IPTW-adjusted analysis (OR 1.65, 95% CI 0.69–3.98, p = 0.26). Hypertension and antiplatelet use at baseline were also independently associated with END. Among MT-treated patients, successful and excellent recanalization and first-pass effect were protective against END. Conclusion: MT was associated with END in patients with minor AIS-DMVO, although this association was not significant after IPTW adjustment. IVT was independently associated with reduced risk of END. These findings support careful patient selection and further study in randomized trials.

Importance Advances in Alzheimer disease (AD) have shifted research focus to earlier disease stages, necessitating more scalable approaches to identify cognitively unimpaired individuals with amyloid β (Aβ) pathology. Objective To assess the utility of plasma phosphorylated tau 217 (p-tau217) for classifying Aβ status in cognitively unimpaired individuals, both as a stand-alone test and in a 2-step approach where positive plasma results were confirmed using a second modality (Aβ positron emission tomography [PET] or cerebrospinal fluid [CSF]). Design, Setting, and Participants This cross-sectional cohort study used data collected between June 2009 and March 2024. We included 2916 cognitively unimpaired participants from 12 international independent observational cohorts in the US, Europe, Australia, and Canada with available plasma p-tau217 levels and CSF or PET Aβ biomarkers. Performance comparisons between mass spectrometry and immunoassay-based p-tau217 measurements were also performed (n = 964). Exposures Plasma p-tau217 levels measured by immunoassay. Main Outcome and Measures Aβ status, determined by CSF or Aβ PET biomarkers. Results Participants had a mean (SD) age of 66.9 (9.9) years; 971 (33.3%) were Aβ positive by either CSF or PET, 1667 (57.2%) were women, and 1108 (38.1%) carried at least 1 APOE ε4 allele. As a stand-alone test, plasma p-tau217 achieved a positive predictive value (PPV) of 79% (95% CI, 74-84) and an overall accuracy of 81% (95% CI, 80-82). In a 2-step workflow, the PPV and accuracy significantly increased to 91% (95% CI, 86-95). While this approach required screening of 677 individuals with plasma p-tau217 to identify 100 Aβ-positive individuals, compared to 536 participants when using PET alone, it reduced the need for PET testing to 124. Immunoassays demonstrated comparable PPVs to mass spectrometry (80% [95% CI, 74-86] vs 85% [95% CI, 81-90]; P = .12) but significantly lower overall accuracy (82% [95% CI, 79-84]% vs 88 [95% CI, 86-90]; P &amp;lt; .001) and true Aβ-positive detection rate (49% [95% CI, 43-55] vs 69% [95% CI, 64-75]; P &amp;lt; .001). Conclusions and Relevance The findings highlight the potential of plasma p-tau217 as a stand-alone test—or when used in a sequential 2-step approach alongside PET or CSF testing—as a cost-effective, scalable, and minimally burdensome strategy for identifying preclinical AD. Tailored screening workflows that incorporate p-tau217 can improve efficiency in participant selection for preclinical AD trials and, in the future, help guide access to disease-modifying treatments.

Abstract Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells—a highly dynamic lymphocyte subtype—undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes—FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258—with strong evidence for a causal role in CRC development (FDR-P &lt; 0.05; colocalisation H4 &gt; 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.

OBJECTIVE Degenerative lumbar spondylolisthesis is a common cause of back and leg pain influenced by factors like instability, disc degeneration, facet arthropathy, and psychosocial phenotype. Patients’ experience of high-severity pain is complex, with significant implications for surgical planning. The goal of this study was to assess the impact of back pain catastrophizing on long-term outcomes following lumbar spondylolisthesis surgery. METHODS This study uses the Quality Outcomes Database (QOD) lumbar spondylolisthesis dataset and includes prospectively collected data from the 12 highest-enrolling clinical sites participating in the QOD lumbar module. The authors reviewed patients undergoing single-segment surgery for grade 1 degenerative lumbar spondylolisthesis. Severe baseline numeric rating scale for back pain (NRS-BP) scores (≥ 8) were classified as "catastrophizing," and mild to moderate pain scores (< 8) were classified as "non-catastrophizing." Patient-reported outcomes (PROs) were compared for catastrophizing versus non-catastrophizing patients at 60 months. Univariate and multivariate analyses were conducted to assess the impact of catastrophizing on PROs, with multivariate analysis controlling for variables initially reaching a p value < 0.10. RESULTS Of the 608 patients in this analysis, 260 (42.8%) experienced catastrophizing while 348 (57.2%) did not. Catastrophizing patients were significantly younger (59.9 ± 12.2 years vs 63.9 ± 11.7 years, p < 0.001), less often had ≥ 4 years of college education (31.2% vs 42.5%, p = 0.004), and more often used private insurance (58.8% vs 47.7%, p = 0.01). The catastrophizing cohort also had higher rates of depression (24.6% vs 17.0%, p = 0.02) and back pain predominance (45.4% vs 32.2%, p < 0.001). Surgical and perioperative characteristics did not significantly differ between cohorts. Although catastrophizing patients typically reported worse PRO scores at both baseline and 60 months, they demonstrated significantly greater improvement and minimal clinically important difference (MCID) achievement across almost all PROs at 60 months (p < 0.05). However, North American Spine Society (NASS) satisfaction scores at 60 months did not differ significantly between cohorts. Multivariate analysis found that catastrophizing significantly predicted 60-month NRS-BP change (β −1.45, 95% CI −1.81 to −1.09; p < 0.001) and MCID achievement (OR 1.98, 95% CI 1.52–2.58; p < 0.001) but not mean NRS-BP score or other metrics, including NASS satisfaction. CONCLUSIONS Despite presenting with worse baseline symptoms, patients with pain catastrophizing experienced substantial and clinically meaningful improvement following surgery for degenerative lumbar spondylolisthesis. Patient satisfaction was comparable between cohorts, reflecting a nuanced balance between greater absolute improvement and persistence of residual symptoms. These findings underscore that catastrophizing should not be viewed as a barrier to surgical success, while pointing to the need for proactive expectation setting and shared decision-making.