Citations

ABSTRACT Background Membranous nephropathy (MN) is a leading cause of nephrotic syndrome (NS). Since the identification of anti–phospholipase A2 receptor (anti-PLA2R) antibodies in 2009, the use of laser microdissection and tandem mass spectrometry (LMD/MS) has allowed the discovery of several target antigens in MN. Methods In this retrospective cohort study, adult patients evaluated at the Division of Nephrology at Brotzu Hospital (Cagliari, Italy) with biopsy-proven MN and a negative serological test for anti-PLA2R antibody underwent LMD/MS, performed at the Department of Laboratory Medicine and Pathology of Mayo Clinic (Rochester, MN, USA). Results Twenty-four cases of biopsy-proven MN were available for antigen detection by LMD/MS studies. High total spectral counts of PLA2R were detected in 12 out of 24 (50%) cases. In addition, high spectral counts of THSD7A and NELL1 were detected in two cases each, and EXT1/EXT2 and NCAM1 in one case each. Five putative antigens have been detected: SULF1, PGLYRP, HYAL1, THBS and SEZ6L2. Conclusions Our study highlights at least two interesting considerations. First, the determination of PLA2R on renal tissue in the diagnosis of PLA2R-associated MN is emphasized since 50% of our cases were falsely diagnosed with PLA2R-negative MN based on the serum anti-PLA2R antibodies determination. Second, our study shows six patients with MN likely associated with putative antigens, two of them showing new antigens never described before in literature (HYAL1 and THBS1). This high prevalence of putative antigens in our cohort is not easily explainable and paves the way for evaluating specific factors in the Sardinian population that could explain this evidence.

Background: Deciding to use oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF) is complex. For many, the decision between treatment and non-treatment requires a primary tradeoff between the risks of potential stroke and increased bleeding. Hypothesis: We hypothesized that patient values and empiric stroke risk measured by CHA 2 DS 2 -VASc score would influence OAC decisions. Methods: We conducted a secondary analysis of a randomized clinical trial where eligible clinicians and patients were independently randomized to one of two decision aids (DAs) – a patient decision aid and/or an encounter decision aid. Eligible patients were adults with AF with CHA 2 DS 2 -VASc≥1 for men or ≥2 for women. Patients newly prescribed (OAC-naive subgroup) or already taking OAC (OAC-experienced subgroup) were included. We assessed patient values using a 5-point Likert scale between stroke prevention and bleeding risk after SDM during a clinical encounter. We report preliminary results using descriptive statistics and adjusted analysis to investigate the effects of CHA 2 DS 2 -VASc and expressed values on OAC use. Results: 1005 patients were included in the analysis. 828 (82%) patients valued stroke prevention over bleeding risk. Among the OAC-naive group, 175 (63%) valued stroke prevention more than bleed avoidance, 58 (20%) valued bleed avoidance more than stroke prevention, and 47 (17%) were neutral. In the unadjusted analysis, patients were more likely to value stroke prevention if they were OAC-experienced (p<0.001), older (p<0.001), female (p< 0.001), had patient-reported bleeding (p=0.003), or if CHA 2 DS 2 -VASc ≥ 2 if male, ≥3 if female (p<0.001) Table 1 . After adjustments, there were significant associations for OAC use among patients who valued stroke prevention (OR 5.35, 95%CI 3.13-9.13, p<0.001) or had higher CHA 2 DS 2 -VASc (OR 2.03, 95%CI 1.26-3.27, p=0.004). Patients who valued bleed avoidance had an opposing association not to use OAC (OR 0.23, 95%CI 0.11-0.48, p<0.001). Conclusions: Patients with elevated risk (CHA 2 DS 2 -VASc score, age, and female), and those who reported a prior bleeding event valued stroke prevention more than bleeding avoidance. Both empiric stroke risk and patient values were associated with the decision to use OAC. While the tradeoff between stroke prevention and bleeding risk is only one aspect of the decision-making process, these results indicate variability in patient values may influence OAC use.

Abstract Rationale Increased risk of coronavirus disease (COVID-19) hospitalization and death has been reported among patients with clinical lung disease. Objectives To test the association of objective measures of prepandemic lung function and structure with COVID-19 outcomes in U.S. adults. Methods Prepandemic obstruction (FEV1/FVC &lt; 0.70) and restriction (FEV1/FVC ⩾ 0.7, FVC &lt; 80%) were defined based on the most recent spirometry exam conducted in 11 prospective U.S. general population–based cohorts. Severe obstruction was classified by FEV1 &lt; 50%. Percentage emphysema, percentage high-attenuation areas, and interstitial lung abnormalities were defined on computed tomography in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020 to 2023 and classified as severe (hospitalized or fatal) or nonsevere. Cause-specific hazard models were adjusted for sociodemographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status. Measurements and Main Results Among 29,323 participants (mean age, 67 yr), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs. normal; adjusted hazard ratio [aHR], 2.11; 95% confidence interval [CI], 1.02–1.27), restriction (vs. normal; aHR, 1.40; 95% CI, 1.12–1.76), and percentage emphysema (highest vs. lowest quartile; aHR, 1.64; 95% CI, 1.03–2.61), but not greater high-attenuation areas or interstitial lung abnormalities. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease. Conclusions Prepandemic severe spirometric obstruction, spirometric restriction, and greater percentage emphysema lung on computed tomography were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses.

AbstractBackgroundTandem mass spectrometry (MS/MS) has become a common clinical laboratory testing modality has demonstrated success in distinguishing between small protein variations in transthyretin amyloidosis. Since many common clinically significant RBC antigens are also small protein variations, this study aimed to determine if MS/MS could correctly detect common RBC antigens within the Rh, Kell, Duffy, MNS, Kidd, Diego, and Lutheran blood group systems.Study Design and MethodsResidual samples from serotyped/genotyped blood donors at a hospital‐based blood donation center from February to August 2021 were analyzed. RBC membrane protein preparations underwent protease digestion prior to MS/MS analysis for RhD, RhCE, Kell, atypical chemokine receptor 1 (Duffy), glycophorin A (MNS), glycophorin B (MNS), urea transporter 1 (Kidd), band 3 anion transport protein (Diego), and basal cell adhesion molecule (Lutheran). Untargeted liquid chromatography (LC)‐MS/MS detected protein‐specific peptides, while targeted LC‐selected reaction monitoring (LC‐SRM) detected RBC antigen‐containing peptides.ResultsThrough the use of multiple proteases, untargeted LC–MS/MS detected protein‐specific peptides in all but glycophorin B, with band 3 anion transport protein, basal cell adhesion molecule, Kell, and glycophorin A having the greatest protein sequence coverage. Targeted LC‐SRM detected antigen‐specific peptides for Cw, Dia/Dib, Kpb, and Wra/Wrb, which agreed with the donors' previous typing results.DiscussionMS/MS can successfully detect peptides from several blood group systems but only detected a subset of their common RBC antigens. Further sample enrichment and MS/MS detection improvements will need to occur before MS/MS could be considered a clinical RBC phenotyping modality.

We aimed to describe outcomes, including shoulder motion, deltoid strength and Disabilities of Arm, Shoulder and Hand scores, in 19 patients with terrible triad shoulder injuries (anterior shoulder dislocation, rotator cuff tear or greater tuberosity fracture, and axillary nerve injury) who required axillary nerve reconstruction. The type of nerve surgery (grafting vs. nerve transfer), demographic factors and injury characteristics were not significantly associated with outcomes. The mean postoperative abduction and Disabilities of Arm, Shoulder and Hand score were 95° and 28, respectively. Patients with rotator cuff tears had a higher Disabilities of Arm, Shoulder and Hand score (more disability) than those with isolated greater tuberosity fractures. We conclude that spontaneous recovery of the axillary nerve may not occur in patients with a terrible triad injury. Functional outcomes after axillary nerve repair are poor with respect to motion, strength and patient-reported outcomes compared with reported results for axillary nerve reconstruction in the absence of rotator cuff injury. Level of evidence: IV

Abstract INTRODUCTION β‐synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear. METHODS We investigated serum β‐synuclein in 69 cognitively unimpaired mutation non‐carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network. RESULTS β‐synuclein levels were already higher in asymptomatic AD mutation carriers compared to non‐carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β‐synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β‐synuclein levels were associated with cognitive impairment and gradually increased with declining cognition. DISCUSSION Our study supports the use of blood β‐synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials. Highlights Blood β‐synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β‐synuclein levels were highest in symptomatic AD mutation carriers. Blood β‐synuclein levels start to rise 11 years before symptom onset. Rise of β‐synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β‐synuclein levels gradually increased with declining cognition.

Gastric cancer is a significant global health concern, with CDH1-associated gastric cancer representing a small but important subset of cases. Historically, individuals with CDH1 pathogenic germline variants were advised to undergo prophylactic total gastrectomy due to the high reported risk of gastric cancer and the limited sensitivity of upper endoscopy in detecting signet ring cell carcinoma (SRCC). However, emerging data suggest that the cumulative lifetime risk of advanced gastric cancer among CDH1 germline pathogenic variant carriers is lower than previously thought, and early-stage SRCC detected on endoscopy does not necessarily indicate imminent—or even eventual—progression to advanced cancer. The near-universal presence of T1a SRCC in gastrectomy specimens from asymptomatic CDH1 pathogenic variant carriers calls into question the reflexive recommendation for gastrectomy, including upon detection of SRCC during surveillance. Furthermore, the morbidity and quality-of-life impact associated with total gastrectomy require careful consideration. Active endoscopic surveillance has shown promise as an alternative management strategy for gastrectomy in patients lacking indicators of >T1a SRCC, though current data are limited by short follow-up periods and selection bias. This review synthesizes recent findings on the natural history of CDH1-associated gastric cancer and evaluates the risks and benefits of gastrectomy versus active endoscopic surveillance, with the goal of helping clinicians provide personalized and evidence-based recommendations for patients with CDH1 pathogenic variants.

The NCCN Guidelines for Testicular Cancer provide recommendations for the multidisciplinary approach to the diagnostic workup, treatment, and follow-up for testicular germ cell tumors, including both seminoma and nonseminoma. These NCCN Guidelines Insights discuss the current treatment recommendations and supporting clinical data for seminomas as presented in Version 2.2025 of the NCCN Guidelines for Testicular Cancer.

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement–positive cancers are limited. In this study, in a pan-cancer analysis of &gt;46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion–positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14–altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion–positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. Significance: MET rearrangement–positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

ABSTRACT Background The assessment of aortic stenosis (AS) severity remains a challenge in some patients, and hemodynamic exercise testing has been proposed as a diagnostic tool in this population. However, the current understanding of exercise hemodynamics in AS is limited. Methods Retrospective review of 34 adults (aged ≥ 18 years) with ≥ moderate AS and preserved left ventricular ejection fraction (LVEF) undergoing exercise invasive hemodynamics (supine cycle protocol) with simultaneous measurement of aortic and left ventricular pressures. Results Age was 77.1 (IQR 68.6; 84.1) years, and 50% were female. LVEF was 62.1 ± 6.6%. All patients were symptomatic. Resting aortic valve area (AVA) was 1.0 ± 0.2 cm 2 and aortic valve (AV) systolic mean gradient 22.0 ± 7.3 mmHg. At peak exercise (40 [IQR 30; 60] W), AV systolic mean gradient (Δ3 [0.6; 7] mmHg, p < 0.001) and AVA (Δ0.2 [0; 0.6] cm 2 , p = 0.002) significantly increased, while stroke volume (SV) did not (Δ6.8 ± 19.4 ml; p = 0.07). Exercise‐induced changes in AV systolic mean gradient were directly related to changes in cardiac output ( r = 0.53, p = 0.003), being inversely related to exercise systemic vascular resistance ( r = −0.60, p = 0.002). Elevated pulmonary artery wedge pressure was present in 41.2% at rest (≥ 15 mmHg) and 69.7% during exercise (≥ 25 mmHg). Conclusions Symptomatic patients with ≥ moderate AS and preserved LVEF experience small increases in AV mean gradient with exercise, and unlike the normal physiological response to exercise, there was no significant increase in SV. In most patients, AVA rose during exercise. Exercise‐induced elevation in filling pressures was highly prevalent.