Citations

Background: Carpal tunnel syndrome (CTS) is the most common peripheral nerve entrapment syndrome. The thread carpal tunnel release (TCTR) is an incision-less ultrasound-guided approach to divide the transverse carpal ligament. This retrospective case series aims to identify and assess the bleeding risks associated with continuing anticoagulation or antiplatelet therapy during TCTR. Methods: Retrospective chart review with follow-up questionnaires/surveys. One hundred and fourteen adult patients who were using antiplatelet or anticoagulation medication underwent 164 TCTR procedures during 2018 to 2023 at a single institution (tertiary care hospital) from June 29, 2018, and August 11, 2023. A chart review was performed to identify patients on antiplatelets or anticoagulants at the time of the procedure and to determine if there were any adverse events associated with continuing or holding their antiplatelet or anticoagulant therapy. Results: There were no significant complications associated with continuing or holding anticoagulation or antiplatelet therapy during TCTR. Conclusions: Continuing antiplatelet therapy during TCTR appears safe. The decision to continue antiplatelet or anticoagulation therapy should be made on a case-by-case basis.

Study Design Retrospective Cohort. Objectives Craniovertebral instability can arise from various congenital or acquired conditions, but definitive management often requires craniocervical fusion. This study evaluates whether postoperative clivo-axial angle (CXA) can predict distal junctional failure in patients undergoing craniocervical fusion. While postoperative alignment of the head and cervical spine can be quantified via the CXA, it is unclear whether the CXA can predict distal junctional failure. Methods All patients undergoing craniocervical decompression and fusion (CCF) for craniovertebral instability between 2012 and 2023 at a single institution were identified. Patients experiencing adjacent segment disease (ASD) were identified and compared to those without said pathology based on CXA, Grabb-Oakes line (pBC2), and the presence of cervical kyphosis, cervical disc degeneration, or subluxation on pre- and postoperative imaging. Statistical analysis included Shapiro-Wilk tests for normality, followed by independent t-tests or Mann-Whitney U tests with FDR adjusted P values as appropriate, and univariable logistic regression. Results 71 patients were included, of whom ten (14.3%) developed distal junctional kyphosis and 3 (4.3%) developed cervical spondylolisthesis. The median postoperative CXA was significantly lower in non-ASD patients (144° [IQR: 140-148°] vs 158° [IQR: 153-162°]; P < .001) and logistic regression showed that each 10° degree increase in CXA was associated with a 6.7-fold higher odds of ASD. Conclusions We found craniocervical alignment, as assessed by CXA, independently predicted distal junctional disease in patients undergoing craniocervical fusion, possibly due to low preoperative CXA in these patients. Large increases in CXA may contribute to postoperative instrumentation failure.

Abstract INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized cohorts (LEADS and ADNI). METHODS We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early‐stage AD), along with cognitively unimpaired participants. RESULTS After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION Our findings point to the clinical utility of MRI‐based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

ABSTRACT Background The continuum of metabolic syndrome encompasses a spectrum of dysfunctions impacting obesity‐linked insulin resistance, glucose homeostasis, lipid metabolism and pro‐inflammatory immune responses. The global prevalence of metabolic diseases, including diabetes, chronic liver disease, cardiometabolic disease and kidney disease, has surged in recent decades, contributing significantly to population mortality. Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as non‐alcoholic fatty liver disease, is a leading cause of liver disease worldwide. MASLD poses a significant global health challenge with its rising prevalence, placing a substantial burden on healthcare systems, impacts patient well‐being and incurs significant economic costs. Addressing MASLD requires a comprehensive understanding of its interconnected factors, including its prevalence, healthcare burden and economic implications. Lack of awareness, imprecise non‐invasive diagnostic methods and ineffective preventive interventions are core components of the MASLD‐related problem. Aim The aim of this article was to summarise the global burden of MASLD from the payer's perspective. Methods We carried out a review of the global comprehensive burden of MASLD. These topics led to discussions and insights by an expert panel during the 7th Metabolic Continuum Roundtable meeting, which took place in November 2023. This meeting focused on the burden, patient‐reported outcomes and health economics, from payor and societal perspectives, and aimed to identify opportunities for improving patient care, optimise resource allocation and mitigate the overall impact on individuals and society related to MASLD. During the roundtable, an emphasis emerged on the need for greater awareness and strategic deployment of diagnostic, therapeutic and preventative measures to address MASLD effectively. Conclusion The global burden of MASLD is high and growing. Prioritising the prevention of metabolic dysregulation and timely therapeutic interventions can yield a holistic strategy to combat MASLD, its progression and potentially lower disease costs. Trial Registration: NCT06309992

Abstract Rationale Pulmonary arterial hypertension (PAH) is associated with significant morbidity and mortality. The extent of medication nonadherence in PAH is uncertain and may be linked to adverse outcomes. There has been a lack of multicenter, registry-based studies assessing medication nonadherence and patient-centered outcomes in PAH. Objectives To determine the prevalence of self-reported nonadherence in Pulmonary Hypertension Association Registry (PHAR) participants with PAH or chronic thromboembolic pulmonary hypertension and the relationship of nonadherence with several patient-centered outcomes (mortality, hospitalization rates, emergency department visits, and health-related quality of life). Methods Self-reported PAH medication nonadherence was captured at PHAR enrollment and during follow-up visits. Predictors of nonadherence were modeled using generalized estimating equations assuming a binary distribution. Outcomes associated with nonadherence were modeled using generalized estimating equations with a Poisson distribution. Results A total of 1,543 patients were included, of whom 1,092 (70.8%) were female and 1,340 (86.8%) had PAH. The overall rate of any self-reported nonadherence was 6.1% (95% confidence interval [CI], 5.3–6.9). Predictors of nonadherence included self-reported male sex at birth (odds ratio [OR], 1.4; 95% CI, 1.0–1.9; P = 0.02), poverty (OR, 1.6; 95% CI, 1.2–2.3; P = 0.01), not being married or partnered (OR, 1.5; 95% CI, 1.1–1.9; P = 0.01), having Medicaid or no health insurance (OR, 2.1; 95% CI, 1.5–2.9; P &lt; 0.001), and having completed high school but not having a college degree (OR, 1.7; 95% CI, 1.1–2.9; P &lt; 0.001). PHAR participants who reported any nonadherence had 50.0% more emergency department visits (P &lt; 0.001), 13.3% more hospital admissions (P = 0.03), and 61.9% more days hospitalized (P = 0.01). No relationship was observed between nonadherence and the type or number of PAH therapies or all-cause mortality. Participants reporting nonadherence had worse mean Short Form-12 scores (P &lt; 0.001) and worse emPHasis-10 scores (P = 0.02). Conclusions The rate of self-reported nonadherence in PHAR registrants was low but was associated with male sex and several social determinants of health. Although the complexity or type of PAH regimen did not appear to influence nonadherence, nonadherence was associated with numerous adverse patient-centered outcomes, including greater healthcare use and worse health-related quality of life. Because of limitations in the structure of the gathered data, relationships between exposure and outcomes were not temporally definitive; these observations warrant additional prospective studies.

686 Background: Blue-light cystoscopy (BLC) is an established procedure for use in the diagnosis and surveillance of patients with non-muscle-invasive bladder cancer (NMIBC). It is associated with improved detection rates compared to white light cystoscopy (WLC); however, limited data is available regarding its role in upstaging and/or upgrading when used alongside WLC. The aim of this study is to assess the incidence and features of patients undergoing upstaging and/or risk-group migration with the implementation of BLC. Methods: Using data from the prospective multi-institutional Cysview Registry (2014-2024), patients with NMIBC who underwent transurethral resection or biopsy of bladder tumors were identified. The patients in whom malignant lesions were exclusively detected by BLC, as well as those experiencing an upward change in risk category (as defined by the American Urological Association [AUA] classification) based on BLC findings, were documented. The clinical features of these patients were subsequently reviewed. Results: In this study, 2,854 patients were enrolled, who collectively underwent 4,158 resections and provided 6,432 separate pathology samples. A total of 201 (7%) patients had at least one malignant lesion detected exclusively by BLC while having negative WLC. These lesions (total 335) included carcinoma in-situ (CIS) in 145 (43%), low-grade Ta in 53 (16%), high-grade Ta in 95 (28%), high-grade T1 in 37 (11%), and high-grade T2 in 5 (1%). In patients with multifocal disease, BLC resulted in AUA risk-group upward migration in 66 (2.3%) patients.Theclinical features of these two groups are presented in the table. Taken together, the total rate of upgrading or upstaging using BLC was 9.3%, including migration to low-risk in 1.2%, intermediate-risk in 2.1%, and high-risk in 6%. Conclusions: Using BLC during transurethral resection or biopsy of bladder tumors results in risk group migration in over 9% of patients with NMIBC. This impacts patient management, including the administration of intravesical therapy when it was not initially planned, an extension in the duration of therapy, or the decision to proceed with radical cystectomy. Clinical features of patients with malignant lesions detected by BLC only (A) and those with risk group migration (B). Clinical features A B Age, median (IQR), year 71 (63-76) 71 (61-77) Gender, n (%) Male Female 140 (74)49 (26) 54 (82)12 (18) History of smoking, n (%) 117 (62) 40 (61) Primary occurrence, n (%) 65 (34) 14 (21) History on intravesical therapy, n (%) 92 (49) 40 (61) Urine cytology * , n (%) Positive Suspicious Atypical Negative/NA 33 (17)21 (10)41 (20)106 (53) 13 (20)7 (11)10 (15)36 (54) IQR: interquartile range; NA: not available. *Detected by either voided urine or bladder wash.

202 Background: While several PARP inhibitors are approved in combination with hormonal therapies for metastatic castrate resistant prostate cancer (CRPC), their use in castrate sensitive prostate cancer (CSPC) is understudied. We previously reported that olaparib monotherapy (without ADT) shows significant clinical activity in BRCA2 -altered patients with biochemically recurrent (BCR) prostate cancer. Here, we explored prognostic and predictive PARP-related mRNA biomarkers derived from primary prostate tumors. Methods: We characterized the expression of 16 PARP transcripts using a cohort of 52,266 radical prostatectomy (RP) specimens (2016-2024) undergoing Decipher prostate genomic classifier testing (Veracyte Inc). Transcriptome-wide mRNA expression data as well as baseline clinical/pathologic factors were retrieved from the Decipher GRID database (NCT02609269). Associations between high PARP expression (top 25%), baseline factors, and gene signatures were examined using logistic regression. We assessed the association between PARP expression and distant metastases in 3 retrospective cohorts (n= 545, 855, and 325). Finally, we evaluated PARP expression in our prior phase II trial (NCT03047135, n=39) of olaparib monotherapy in the setting of BCR following RP. Results: Higher mRNA levels of PARP1 , 2 , 8 and 14 showed strong associations (all P <0.001) with known adverse prognostic factors such as very-high Decipher score (>0.85), high Gleason grade (GG5) and non-organ confined disease (EPE, SVI and LNI), while higher PARP6 and 7 expression were associated with more favorable disease characteristics. High PARP1 expression was positively correlated with DNA-repair deficiency (r=0.77) and tumor immune microenvironment (r=0.62) signatures. In 3 independent retrospective cohorts of intermediate-high risk PCa patients, higher PARP1 expression was strongly associated with development of distant metastases after RP (HR 1.70, 1.81, and 1.67 respectively; all P <0.05). Finally, in our phase II trial of patients with BCR who received olaparib monotherapy, PARP1 (but not PARP2 ) expression from RP was 1.5-fold higher in samples with BRCA2 mutations (median 0.416 vs 0.276, P =0.01) and was associated with overall improved PSA progression-free survival (continuous variable, HR 0.55, P =0.01) and longer time to next systemic treatment (continuous variable, HR 0.66, P =0.02). Conclusions: High PARP1 mRNA expression, measured at RP, is associated with aggressive disease biology and greater risk of metastasis. However, high PARP1 (but not PARP2 ) levels are associated with improved response to PARP inhibition in the setting of BCR prostate cancer. Future trials testing PARP (including PARP1-selective) inhibitors in the CSPC space should consider measuring PARP1 mRNA levels in addition to BRCA1/2 mutation status. Clinical trial information: NCT02609269 , NCT03047135 .

382 Background: The natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) is heterogeneous, with most patients not progressing to metastasis. Determining the impact and optimal timing of salvage radiation therapy (SRT) remains challenging, particularly in the absence of prospective randomized trials with a surveillance control arm. Our objective isto quantify the oncologic benefit of SRT among men with BCR after RP. Methods: Patients who underwent RP at Mayo Clinic between 1990 and 2017 and developed BCR (PSA≥0.20ng/mL) were included. Patients treated with SRT were compared to those managed with surveillance using risk-set matching with time-dependent propensity scores, accounting for covariates at BCR and post-BCR. The primary outcome was metastases, analyzed via Kaplan-Meier and Cox proportional hazard models. The number needed to treat (NNT) with SRT to prevent progression was calculated using regression outputs at 5 and 15 years post-BCR. Interaction analyses identified factors modifying SRT’s effect on metastasis. Results: Of 6,881 patients with BCR, 2,109 received SRT. At a median follow-up of 10.2 years, 1,147 patients with BCR developed metastases. After 1:1 matching, SRT was associated with lower metastasis risk than surveillance at 5 years (12.7% vs 19.3%, p<0.0001) and 15 years (28.6% vs. 31.5%, p<0.001). SRT was independently associated with decreased metastasis risk (HR 0.75, 95%CI 0.63–0.90, p=0.002) on multivariable analysis, translating to NNT of 23 and 15 at 5 and 15 years, respectively (Table). Additionally, we noted a significant interaction between PSA at SRT and the association of SRT with metastasis (p-interaction=0.02), such that the reduction in metastatic progression with SRT vs. surveillance was restricted to the cohort of patients who received SRT for PSA>0.40ng/mL (HR 0.66, 95%CI 0.54–0.80, p<0.001). Conclusions: Most patients with BCR post-RP do not develop metastases. Indeed, the NNT with SRT to reduce metastasis versus surveillance indicates a generally indolent disease course. Further, the lack of a significant association of SRT with reduction of metastases in patients with a PSA≤0.40ng/mL underscores the importance of careful patient selection when considering early SRT. Our data establish the rationale for a randomized trial comparing early SRT versus surveillance for appropriately selected patients with BCR after RP. Hazard ratios of SRT after matching by propensity scores, and number needed to treat for systemic progression, prostate cancer specific mortality and overall mortality. DiseaseOutcome Hazard Ratio(95% CI) P value Number Needed to Treat* (95% CI) 5 years 15 years Systemic progression 0.75(0.63 – 0.90) 0.002 23(17 – 41) 15(11 – 27) Prostate cancer mortality 0.81 (0.64 – 1.03) 0.086 103(62 – 494) 26(15 – 124) Overall mortality 0.79 (0.70 – 0.89) 0.0001 38(29 – 62) 12(9 – 20) *Number needed to treat (NNT) calculated using regression based absolute differences in event free survival between salvage radiation therapy (SRT) and observation.

410 Background: Inflammasomes are multiprotein complexes that regulate inflammation-associated signaling pathways. Although inflammation plays a crucial role in cancer cell proliferation, the specific role of inflammasomes in prostate cancer (PCa) remains underexplored. This study aims to elucidate the expression of inflammasome-related genes in PCa and assess their association with clinical outcomes. Methods: De-identified transcriptome data from a cohort of 52,266 radical prostatectomy (RP) samples tested (2016-2024) with the Decipher prostate genomic classifier (Veracyte, San Diego, CA) were retrieved from the GRID registry (NCT02609269). Expression analysis focused on 33 genes involved in inflammatory pathways. Outcomes analysis was conducted on a retrospective cohort of 855 patients treated with RP (META855), using Cox regression analysis, adjusting for baseline pathological characteristics. Results: Analysis of baseline gene expression in the GRID RP cohort revealed that most genes exhibit low baseline expression, whereas HSP90AB1, APP, TXN, and TXNIP demonstrate strong expression signals. Higher expression of most genes was associated with higher rate of Gleason grade group 4 or 5 in the GRID RP cohort. On survival analysis of the META855 cohort, higher expression (top 25%) of AIM2 and HSP90AB1 were associated with worse metastasis-free survival (p<0.05 for both). Conversely, both high and low expression levels of NLRP3 were associated with better metastasis-free survival outcomes following RP compared to average expression (p<0.05). On multivariable Cox regression analysis, adjusting for grade group, seminal vesicle involvement, lymph node involvement, and margin status, higher expression of AIM1 (HR 1.75) and HSP90AB1 (HR 1.60) were significantly associated with shorter time to metastasis following RP (p<0.05 for both). Conclusions: There is a molecular heterogeneity within pro-inflammatory genes among patients with PCa.Our findings showed thathigher expression of HSP90AB1 is linked to poorer oncological outcomes, whereas both high and low expression levels of NLRP3 are associated with better outcomes following RP.Further refinement is required to build a robust signature, along with external validation of these findings in other cohorts.

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510