Citations

AbstractSynucleinopathies‐related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA‐DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27–1.93, p = 2.70e‐05). We also discovered associations between iRBD and HLA‐DRB1 70D (OR = 1.26, 95%CI = 1.12–1.41, p = 8.76e‐05), 70Q (OR = 0.81, 95%CI = 0.72–0.91, p = 3.65e‐04) and 71R (OR = 1.21, 95%CI = 1.08–1.35, p = 1.35e‐03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

Objective Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer‐term relapse risk is unknown. Here, we investigate whether early relapses increase longer‐term relapse risk in patients with MOGAD. Methods A retrospective analysis of 289 adult‐ and pediatric‐onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. “Early relapses” were defined as attacks within the first 12 months from onset, with “very early relapses” defined within 30 to 90 days from onset and “delayed early relapses” defined within 90 to 365 days. “Long‐term relapses” were defined as relapses beyond 12 months. Cox regression modeling and Kaplan–Meier survival analysis were used to estimate the long‐term relapse risk and rate. Results Sixty‐seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long‐term relapses if any “early relapses” were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long‐term relapses (HR = 2.64, p = 0.026). Interpretation The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long‐term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric‐onset disease. ANN NEUROL 2023;94:508–517

ObjectivesTo 1) determine the types and frequency of complications within 3 months following ultrasound‐guided surgical procedures, and 2) identify any patient demographics, co‐morbidities, or procedural characteristics that were associated with an increased risk of complications.MethodsA retrospective chart review was performed at six Sports Medicine clinics across the United States. The Clavien‐Dindo classification was used to categorize procedural complications on a 5‐point scale from 1, representing any deviation in post‐procedure care without requiring pharmacological or invasive treatment to 5, representing death. Generalized Estimating Equations for binomial outcomes with a logit link were used to estimate the overall and procedure‐specific 3‐month complication rates.ResultsAmong 1902 patients, 8.1% (n = 154) had diabetes and 6.3% (n = 119) were current smokers. The analysis included 2,369 procedures, which were performed in either the upper extremity (44.1%, n = 1045) or lower extremity (55.2%, n = 1308) regions. The most common procedure was ultrasound‐guided tenotomy (69.9%, n = 1655). Additional procedures included, trigger finger release (13.1%, n = 310), tendon scraping (8.0%, n = 189), carpal tunnel release (5.4%, n = 128), soft tissue release (2.1%, n = 50), and compartment fasciotomy (1.6%, n = 37). Overall, there was a complication rate of 1.2% (n = 29 complications; 95% CI: 0.8–1.7%). Individual procedures had complication rates that ranged from 0 to 2.7%. There were 13 Grade I complications in 13 patients, 12 Grade II complications in 10 patients, 4 Grade III complications in 4 patients, and 0 Grade IV or V complications. No associations between complication risk and any patient demographics (age, sex, BMI), co‐morbidities (diabetes, smoker), or procedure characteristics (type, region) were identified.ConclusionThis retrospective review provides an evidence‐based estimate supporting the low level of risk associated with ultrasound‐guided surgical procedures for patients from a variety of geographical settings who are seeking care at private and academic‐affiliated clinics.

Abstract Exonic variants present some of the strongest links between genotype and phenotype. However, these variants can have significant inter-individual pathogenicity differences, known as variable penetrance. In this study, we propose a model where genetically controlled mRNA splicing modulates the pathogenicity of exonic variants. By first cataloging exonic inclusion from RNA-sequencing data in GTEx V8, we find that pathogenic alleles are depleted on highly included exons. Using a large-scale phased whole genome sequencing data from the TOPMed consortium, we observe that this effect may be driven by common splice-regulatory genetic variants, and that natural selection acts on haplotype configurations that reduce the transcript inclusion of putatively pathogenic variants, especially when limiting to haploinsufficient genes. Finally, we test if this effect may be relevant for autism risk using families from the Simons Simplex Collection, but find that splicing of pathogenic alleles has a penetrance reducing effect here as well. Overall, our results indicate that common splice-regulatory variants may play a role in reducing the damaging effects of rare exonic variants.

Importance Lensectomy with primary intraocular lens (IOL) implantation is often used in the management of nontraumatic pediatric cataract, but long-term data evaluating the association of age and IOL location with the incidence of complications are limited. Objective To describe the incidence of complications and additional eye surgeries through 5 years following pediatric lensectomy with primary IOL implantation and association with age at surgery and IOL location. Design, Setting, and Participants This prospective cohort study used Pediatric Eye Disease Investigator Group cataract registry data from 61 institution- and community-based practices over 3 years (June 2012 to July 2015). Participants were children younger than 13 years without baseline glaucoma who had primary IOL implantation (345 bilateral and 264 unilateral) for nontraumatic cataract. Data analysis was performed between September 2021 and January 2023. Exposures Lensectomy with primary IOL implantation. Main Outcome and Measures Five-year cumulative incidence of complications by age at surgery (&amp;lt;2 years, 2 to &amp;lt;4 years, 4 to &amp;lt;7 years, and 7 to &amp;lt;13 years) and by IOL location (sulcus vs capsular bag) were estimated using Cox proportional hazards models. Results The cohort included 609 eyes from 491 children (mean [SD] age, 5.6 [3.3] years; 261 [53%] male and 230 [47%] female). Following cataract extraction with primary IOL implantation, a frequent complication was surgery for visual axis opacification (VAO) (cumulative incidence, 32%; 95% CI, 27%-36%). Cumulative incidence was lower with anterior vitrectomy at the time of IOL placement (12%; 95% CI, 8%-16%) vs without (58%; 95% CI, 50%-65%), and the risk of undergoing surgery for VAO was associated with not performing anterior vitrectomy (hazard ratio [HR], 6.19; 95% CI, 3.70-10.34; P &amp;lt; .001). After adjusting for anterior vitrectomy at lens surgery, there were no differences in incidence of surgery for VAO by age at surgery (&amp;lt;2 years, HR, 1.35 [95% CI, 0.63-2.87], 2 to &amp;lt;4 years, HR, 0.86 [95% CI, 0.44-1.68], 4 to &amp;lt;7 years, HR, 1.06 [95% CI, 0.72-1.56]; P = .74) or by capsular bag vs sulcus IOL fixation (HR, 1.22; 95% CI, 0.36-4.17; P = .75). Cumulative incidence of glaucoma plus glaucoma suspect by 5 years was 7% (95% CI, 4%-9%), which did not differ by age after controlling for IOL location and laterality. Conclusions and Relevance In this cohort study, a frequent complication following pediatric lensectomy with primary IOL was surgery for VAO, which was associated with primary anterior vitrectomy not being performed but was not associated with age at surgery or IOL location. The risk of glaucoma development across all ages at surgery suggests a need for long-term monitoring.

Abstract Prostate cancer (CaP) significantly affects black men causing highermortality rates especially within African and Caribbean countries. The Prostate Cancer Transatlantic Consortium (CaPTC) is a 10 year longitudinal study aimed at studying environmental, epidemiological and prostate cancer associated risk factors within black men of West African descent living in the United States (US), Cameroon, and Nigeria. Methods: Men ages 35- 70 years old, who identified as a US Black male or West African Black male immigrant in the US, were recruited from community-based organizations. Community- based organizations include local churches, health fairs and socialorganizations. Anthropometric, environmental, and epidemiological variables measures were collected via survey questions. Saliva samples were collected using Salimetrics. Mean and range from the survey questions were categorized and a logistical regression model was used to determine associations between variables. Results: Logistical analysis output for analysis of pesticide exposure and cancer diagnosis within the three countries, found participants in Nigeria who were exposed to pesticide use, to be a significant predictor of cancer diagnosis (p 0.013). The age of exposure was another variable analyzed to see whether there was a correlation between age of exposure in pesticide use and cancer diagnosis. No significant predictors were determined yet a reasoning to why a significance is not yet found could be due to many participants needing a closer examination into the consequences of early exposure to known carcinogens. Conclusion: Significant data was found between pesticide exposure and cancer diagnosis between the US, Cameroon, and Nigeria in West African Black men. Regarding age of pesticide exposure and the relation between cancer diagnosis, more data needs to be collected regarding these variables. Significance in determining pesticide use as a predictor for cancer diagnosis in black males, can lead to increased efforts in pesticide exposure education in addition to possible government reformation on laws regarding pesticide use. Citation Format: Emelina Asto-Flores, Iweala Emeka, Popoola Ademola, Paul Jibrin, Mohammed Faruk, Anthonia Sowumi, Omolara Fatiregun, Nkegoum Blaise, Catherine Oladoyinbo, Ifeoma Okoye, Abdulkadir Ayo Salako, Abidemi Omonisi, Iya Eze Bassey, Kayode Adeniji, Nggada Haruna Asura, Ernest Kaninjing, Oluwole Kukoyi, Parisa Fathi, Ruth Enuka, Oluwaseyi Toye, Jennifer Crook, CaPTC Investigators, Folakemi Odedina. Impact of pesticide exposure in West African Black men within the United States, Cameroon, and Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1213.

e15640 Background: The standard management of locally advanced rectal cancer (LARC) is neo-adjuvant concurrent chemo radiation (CCRT) followed by total meso-rectal excision. Recently there is an increased interest in total neo-adjuvant treatment (TNT). Most patients with rectal cancer in developing countries present in advanced stage for several reasons including lack of resources and delayed health seeking behavior. Most patients are not able to get standard management. This study tries to assess treatment patterns and outcomes in LARC. Methods: A cross-sectional study was conducted in patients with LARC that are treated at TASH from Jan 1, 2020 up to Sept. 2022. The data was collected from Patient’s cards using a pre-structured format that included demographic data, laboratory, pathological and imaging information. Data analysis was conducted by using IBM SPSS version 25. Results: 100 patients were included in the study, 51% were male. The median (range) age at diagnosis was 45.5 (20-86) years. 81% of patients came to our center without getting any oncologic treatment and 75.3% of them were presented on a multi-disciplinary tumor board for their treatment decision. Upfront surgery was decided in 48.1% (39/81) of patients. Standard neo-adjuvant treatment of either TNT or CCRT was decided in 23.4% (19/81) and 8.6% (7/81) of patients respectively. There is no significant association between tumor location, TNM stage, mesorectal fascia status and first treatment decision. Only 12 (14.8%) patients were able to finish their whole treatment plan. The most common reason for not finishing all treatment was prolonged radiation waiting time, with the median (range) waiting time of 10 ± 7.1 (1-26) months. From 81 treatment naive patients, 79 were decided to have surgery; and 59.5% (47/79) underwent the planned surgery with 89.9% R0 resection rate. R0 resection rate in patients who undergo upfront surgery was 91.2% (31/34). Neo-adjuvant chemotherapy was given to 34.6% (28/81); and only 18% (5/28) underwent subsequent surgery. The most common reason for not undergoing subsequent surgery was disease progression 43.5% (10/23) during or after finishing the neo-adjuvant chemotherapy. Only 24% of the study participants received radiotherapy. From the patients who took radiotherapy, only two patients received short course radiotherapy. Conclusions: Treatment decisions for rectal cancer in our study did not conform to standard treatment recommendations. Upfront surgery maybe a better option than neoadjuvant chemotherapy, since timely administration of standard neoadjuvant treatment is not possible. Alternative radiotherapy treatment options like short course radiotherapy may be better in resource limited setting to alleviate the longer radiotherapy waiting time.

PURPOSE Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS This retrospective study included PWH treated with anti–PD-1- or anti–PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti–PD-1/anti–PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was –0.06 months (95% CI, –5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, –4.02 to 8.48; P = .48) for OS. CONCLUSION Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.