Palo Alto Veterans Institute for Research

Drusen are subretinal pigment epithelium extracellular matrix deposits. This study compared histomorphometric characteristics of age-related and atypical drusen found in an eye of a young woman with chronic retinal detachment (RD). We conducted a histomorphometric examination of drusen identified in 3 eyes: an eviscerated eye from a 35-year-old woman with chronic RD, and 2 specimens of 2 patients, aged 91 and 77years, with typical age-related drusen. Sections of formalin-fixed tissue stained with hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), Masson trichrome, luxol fast blue (LFB), and Von Kossa were evaluated using light microscopy. Drusen dimensions were quantified using Philips Digital Pathology Software. Atypical drusen identified in the RD eye (n=25) displayed spheroidal shape with peripherally radiating fibrils. There were foci of dystrophic calcification and localized chronic choroidal inflammation and within some drusen. Age-related drusen (n=29) had a typical dome-shaped appearance. Atypical drusen had significantly larger (P<0.001) average circumference (278 vs. 52µm), diameter (96 vs. 20µm), and area (0.006 vs. 0.00022mm2) than age-related drusen, respectively. Both groups stained positively with PAS, negatively with LFB and Von Kossa, and blue on Masson Trichrome. Atypical drusen found in this RD case display significant differences in morphometric parameters compared to age-related drusen but similar histochemical staining patterns, suggesting a similar macromolecular composition. Further investigations are needed to inform drusen pathogenesis, morphology, and associations with sex, age, or long-standing RD. This case adds to the limited body of evidence on drusen in younger patients and suggests that atypical drusen may form in association with RD.

BACKGROUNDSnare polypectomy and endoscopic mucosal resection (EMR) are effective and widely utilized for treating duodenal adenomas. However, circumferential, recurrent and fibrotic adenomas can be challenging to treat with these techniques.AIMTo develop a safe and effective treatment for these challenging lesions.METHODSBetween 2022 and 2024, a retrospective review was performed for all patients treated with cryoballoon for duodenal adenomas at two institutions. Cryoballoon focal ablation was performed using nitrous oxide, in which a 1-second “pre-puff” of nitrous oxide was performed, followed by delivery for 10 seconds to 14 seconds. Repetition was performed as needed. Surveillance endoscopy was performed at 3 months to 12 months post-ablation to assess efficacy.RESULTSA total of ten individuals were treated, including six patients with recurrent adenomas following previous incomplete endoscopic resections, one patient with an extensive flat adenoma surrounding an ampullary polyp that could not be resected with a snare, and two patients with circumferential sessile duodenal adenomas longer than 5 cm that were considered unresectable by EMR. Follow-up endoscopy demonstrated no efficacy (< 20% improvement) in the two patients with circumferential sessile adenomas. Of the eight patients with non-circumferential adenomas, three had no residual adenoma. Five had significant improvement with < 40% of the adenoma remaining and were treated again with cryoballoon (3) or cold snare (2). Three of the five patients had no recurrence following the second treatment. The remainder are awaiting repeat endoscopy. Seven patients were treated as outpatients and had no adverse events. Two patients undergoing concomitant snare ampullectomy were hospitalized for observation; one developed mild pancreatitis and was discharged following a 48-hour admission, and the second patient was asymptomatic.CONCLUSIONCryoballoon treatment may be effective for non-circumferential flat duodenal adenomas that are not amenable to snare polypectomy or EMR, such as those with severe fibrosis from prior treatment. More than one treatment may be required. However, the treatments are safe and well-tolerated. Limited experience in two patients suggests that cryotherapy is not an effective treatment for bulky circumferential adenomas.

BackgroundAt low levels of kidney function, uremic symptoms prompt the initiation of dialysis. Peritoneal dialysis can continue to relieve these symptoms even when patients become anuric. To accomplish this, dialysis must maintain the plasma levels of solutes which cause symptoms lower than they were when dialysis was initiated. This study examined kinetic properties that solutes must possess for peritoneal dialysis to accomplish this. We sought further to identify solutes that possess these properties.MethodsMathematical modeling analyzed kinetic properties that determine a solute's plasma level in an anuric dialysis patient relative to its level when symptoms prompt dialysis initiation. The predictions of modeling were compared to the observed behavior of the solutes methylurea, guanidine, and phenylacetylglutamine measured in 22 patients on peritoneal dialysis and 22 patients with advanced chronic kidney disease using liquid chromatography tandem mass spectrometry.ResultsModeling showed that peritoneal dialysis can effectively control the plasma levels only of solutes which have a high dialytic clearance relative to their native kidney clearance. Chemical measurements showed that the dialytic clearance of methylurea was close to that of urea while the dialytic clearances of guanidine and phenylacetylglutamine were lower. Comparison of these dialytic clearances with residual native kidney clearances suggested that if their generation rates remained stable, peritoneal dialysis could control the levels of methylurea but not guanidine or phenylacetylglutamine in anuric patients.ConclusionA search for solutes whose properties include a high dialytic clearance and a relatively low native kidney clearance could identify solutes that contribute to uremic symptoms.

The U.S. Preventive Services Task Force expanded lung cancer (LC) screening eligibility in 2021 (USPSTF-2021) by decreasing the minimum number of smoking pack-years from 30 to 20. Underrepresented minorities still experience disparities in screening eligibility. To evaluate screening eligibility and prognostic performance of alternative smoking duration-based criteria versus USPSTF-2021 (primary outcome) and risk-based screening using the recalibrated Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012update) model (secondary outcome) across diverse racial and ethnic groups. Prospective, population-based Multiethnic Cohort linked to SEER (Surveillance, Epidemiology, and End Results) registries. California and Hawai'i, with recruitment from 1993 to 1996. 105 261 adults aged 45 to 75 years with a history of smoking. Hypothetical eligibility and prognostic performance (sensitivity and specificity) in detecting 6-year LC. Under USPSTF-2021, 24.0% of the cohort would be eligible for screening; a 30-year smoking duration yielded the closest eligibility rate (27.5%). Compared with USPSTF-2021, the 30-year duration criteria would reduce eligibility gaps across all races relative to Whites, most notably in African Americans (30.4% vs. 28.8% for Whites under duration-based; 21.4% vs. 30.2% for Whites under USPSTF-2021) and Latinos (25.1% vs. 28.8% for Whites under duration-based; 15.7% vs. 30.2% for Whites under USPSTF-2021). Prognostic sensitivity to identify LC within 6 years increased across all races under the 30-year duration criteria, although specificity decreased commensurately. At matched overall eligibility (27.5%), a risk-based PLCOm2012update 6-year threshold of 1.1% improved both sensitivity and specificity in the overall cohort. However, it widened the eligibility gap between Latinos and Whites (14.4% vs. 31.3%) and demonstrated lower sensitivity in Latinos than duration-based criteria (59.7% vs. 69.8%). Cohort geography and enrollment period may limit generalizability. Overdiagnosis was not measured. Compared with USPSTF-2021, the 30-year duration-based criteria could reduce the eligibility gaps among African Americans and Latinos relative to Whites while improving 6-year LC detection sensitivity across all races. National Institutes of Health.

SummaryStrong sex differences exist in sleep phenotypes and also cardiovascular diseases (CVDs). However, sex-specific causal effects of sleep phenotypes on CVD-related outcomes have not been thoroughly examined. Mendelian randomization (MR) analysis is a useful approach for estimating the causal effect of a risk factor on an outcome of interest when interventional studies are not available. We first conducted sex-specific genome-wide association studies (GWASs) for suboptimal-sleep phenotypes (insomnia, obstructive sleep apnea [OSA], short and long sleep durations, and excessive daytime sleepiness) utilizing the Million Veteran Program (MVP) dataset. We then developed a semi-empirical Bayesian framework that (1) calibrates variant-phenotype effect estimates by leveraging information across sex groups and (2) applies shrinkage sex-specific effect estimates in MR analysis to alleviate weak instrumental bias when sex groups are analyzed in isolation. Simulation studies demonstrate that the causal effect estimates derived from our framework are substantially more efficient than those obtained through conventional methods. We estimated the causal effects of sleep phenotypes on CVD-related outcomes using sex-specific GWAS data from the MVP and All of Us. Significant sex differences in causal effects were observed, particularly between OSA and chronic kidney disease, as well as long sleep duration on several CVD-related outcomes. By applying shrinkage estimates for instrumental variable selection, we identified multiple sex-specific significant causal relationships between OSA and CVD-related phenotypes. The method is generalizable and can be used to improve power and alleviate weak instrument bias when only a small sample is available for a specific condition or group.

The paucity of health economics studies on traumatic brain injury (TBI) was highlighted in a recent report from the National Academies of Sciences, Engineering, and Medicine. Resource and cost modeling of acute hospitalizations for Service Members and Veterans (SMVs) can be used to inform Department of Defense (DoD) and Department of Veterans Affairs (VA) policy. The objective of this study was to compare intensive care unit (ICU) utilization, length of stay (LOS), and cost between DoD and VA facility hospitalizations for SMVs with a primary diagnosis of TBI. A unique database of ICU utilization, LOS, cost, and demographic variables was created from DoD and VA administrative databases for hospitalizations with a primary diagnosis code for TBI. Logistic and generalized linear models were used to estimate the adjusted differences in ICU utilization, LOS, and hospitalization cost between DoD and VA. All models were first adjusted for age, sex, and specific TBI diagnosis and then for clinical severity, as measured by the Medicare Severity Diagnosis-Related Group (MS-DRG). SMVs hospitalized in DoD facilities were younger (median age 44 vs 73) and more than double were female (10.7% vs 3.5%), relative to VA facilities. The most frequent diagnosis for SMVs in both systems was traumatic subdural hemorrhage without loss of consciousness (LOC) (15.2% in DoD vs 47.8% in VA). DoD-treated SMVs had a much higher frequency of LOC diagnoses: traumatic subdural hemorrhage with LOC, unspecified duration (14.4% vs 8.1%), traumatic subarachnoid hemorrhage with LOC, unspecified duration (11.5% vs 4.1%), and concussion with LOC, unspecified duration (8.2% vs 1.1%). The most frequent MS-DRG in DoD facilities was concussion without complications/comorbidities or major complications/comorbidities (16.1%), and traumatic stupor and coma <1 hour with complications/comorbidities in VA facilities (27.5%). In diagnosis-adjusted models, the odds of ICU utilization were higher (OR 2.19, 95% CI 1.47, 3.25), although LOS was lower (-3.67, 95% CI -5.43, -1.9) for SMVs treated in DoD facilities. Female SMVs had significantly lower diagnosis-adjusted LOS (-1.88, 95% CI -3.69, -.07). Unadjusted total hospitalization cost ($13,548 vs $23,084) was statistically significantly lower in DoD than VA facilities, but neither total nor daily marginal cost was statistically significantly different between the two systems in diagnosis-adjusted models. Similar results were found for MS-DRG adjusted models. This study found that DoD facilities treat SMVs with TBI more intensively and rapidly than the VA. SMVs hospitalized in DoD facilities were younger, more likely to be female, and had diagnoses associated with LOC. In contrast, SMVs hospitalized in VA facilities had much higher rates of MS-DRGs with complications and comorbidities. Female SMVs were found to have lower LOS, consistent with civilian hospitalizations. These findings are limited in that Service Members and Veterans are distinct groups in terms of the mechanism of injury and non-hospitalization comorbidities, which are not accounted for in hospitalization data. Despite limitations, the findings suggest that the DoD and VA, as two government systems, have similar marginal costs for treating TBI. Future studies should include SMV cohorts with data on the mechanism of injury, military characteristics, and non-hospitalization comorbidities.

This study investigates the potential of matrine, a quinolizidine alkaloid, in regulating intraocular pressure (IOP) in normal and corticosteroid-induced ocular hypertension (OHT) mice. Wild-type C57BL/6 mice were randomly divided into normal and OHT groups. The OHT mouse model was established by periocular conjunctival fornix injections of dexamethasone-21-acetate (DEX). IOP was measured at 0.0, 0.5, 1.0, 3.0, and 6.0 hours after matrine treatment in both groups. Aqueous humor (AH) outflow facility was measured using our previously described/validated perfusion system. Anterior segment-optical coherence tomography was used to evaluate morphological changes in the anterior chamber following matrine treatment. Hematoxylin and eosin staining and immunofluorescence staining were used to investigate structural changes. Matrine treatment (50-200µg/g) decreased the IOP in normal mice in a dose-dependent manner. AH outflow facility in normal mice elevated at 0.5 hours after matrine treatment (100 and 200µg/g). Additionally, 100µg/g matrine treatment increased the angle opening distance in the anterior chamber. In DEX-induced OHT mice, matrine (100 and 200µg/g) reduced the elevated IOP and increased the AH outflow facility. Furthermore, 100µg/g matrine treatment increased the angle opening distance compared with that of PBS-treated controls. However, matrine (100µg/g) did not induce significant changes in trabecular meshwork gross morphology or the expression of cell contractility and extracellular matrix markers in OHT mice at 0.5 hours after treatment. Matrine decreased the IOP in the DEX-induced OHT mouse model, highlighting its potential as a therapeutic agent for managing glaucoma, particularly in corticosteroid-associated secondary cases.

Large-scale genetic association studies have identified thousands of trait-associated risk loci, establishing the polygenic basis for common complex traits and diseases. Although prior studies suggest that many trait-associated loci are pleiotropic, the extent to which this pleiotropy reflects shared causal variants or confounding by linkage disequilibrium remains poorly characterized. To define a set of candidate loci with potentially pleiotropic associations, we performed genome-wide association study (GWAS) meta-analyses of up to 1,167 clinically relevant traits and diseases across 1,789,365 diverse individuals genetically similar to Admixed American (AMR, NMax = 60,756), African (AFR, NMax = 128,361), East Asian (EAS, NMax = 307,465), European (EUR, NMax = 1,283,907), and South Asian (SAS, NMax = 8,876) reference populations from the VA Million Veteran Program (MVP), UK Biobank (UKB), FinnGen, Biobank Japan (BBJ), Tohoku Medical Megabank (ToMMo), and Korean Genome and Epidemiology Study (KoGES). We identified 27,193 genome-wide significant locus-trait pairs (1MB region with PGWAMA < 5 × 10−8) in within-population analysis and 29,139 in multi-population analysis (PMR-MEGA < 5 × 10−8). Among these, 11.5% (n = 3,149) of locus-trait pairs in population-wise and 6.4% (n = 1,875) in multi-population analyses did not reach genome-wide significance in previously published GWAS. In aggregate, the genome-wide significant loci fell within 2,624 non-overlapping autosomal genomic windows on average ~600kb in size. Each locus contained genome-wide significant signals for a median of 6 traits (IQR 2 to 18), including 2,110 (80%) pleiotropic loci associated with >1 trait. Multi-trait colocalization identified 1,902 (72%) loci with high-confidence (posterior probability > 0.9) evidence of a shared causal variant across two or more traits. Variants in pleiotropic loci were significantly enriched for a broad spectrum of functional annotations compared to non-pleiotropic counterparts. Polygenic scores (PGS) developed from these data generally improved prediction compared to existing PGS, and were broadly associated with both primary and pleiotropic phenotypes. These results provide a contemporary map of genetic pleiotropy across the spectrum of human traits/diseases and diverse genetic backgrounds.