Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.

Gene-Environment Interactions for Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology. Multiple genetic and environmental factors have been associated with PD, but most PD risk remains unexplained. The aim of this study was to test for statistical interactions between PD-related genetic and environmental exposures in the 23andMe, Inc. research dataset. METHODS: Using a validated PD polygenic risk score and common PD-associated variants in the GBA gene, we explored interactions between genetic susceptibility factors and 7 lifestyle and environmental factors: body mass index (BMI), type 2 diabetes (T2D), tobacco use, caffeine consumption, pesticide exposure, head injury, and physical activity (PA). RESULTS: We observed that T2D, as well as higher BMI, caffeine consumption, and tobacco use, were associated with lower odds of PD, whereas head injury, pesticide exposure, GBA carrier status, and PD polygenic risk score were associated with higher odds. No significant association was observed between PA and PD. In interaction analyses, we found statistical evidence for an interaction between polygenic risk of PD and the following environmental/lifestyle factors: T2D (p = 6.502 × 10-8), PA (p = 8.745 × 10-5), BMI (p = 4.314 × 10-4), and tobacco use (p = 2.236 × 10-3). Although BMI and tobacco use were associated with lower odds of PD regardless of the extent of individual genetic liability, the direction of the relationship between odds of PD and T2D, as well as PD and PA, varied depending on polygenic risk score. INTERPRETATION: We provide preliminary evidence that associations between some environmental and lifestyle factors and PD may be modified by genotype. ANN NEUROL 2024;95:677-687.

Size thresholds for repair of abdominal aortic aneurysms warrant reconsideration.

BACKGROUND: The historical size threshold for abdominal aortic aneurysm (AAA) repair is widely accepted to be 5.5 cm for men and 5.0 cm for women. However, contemporary AAA rupture risks may be lower than historical benchmarks, which has implications for when AAAs should be repaired. Our objective was to use contemporary AAA rupture rates to inform optimal size thresholds for AAA repair. METHODS: We used a Markov chain analysis to estimate life expectancy for patients with AAA. The primary outcome was AAA-related mortality. We estimated survival using Social Security Administration life tables and published contemporary AAA rupture estimates. For those undergoing repair, we modified survival estimates using data from the Vascular Quality Initiative and Medicare on complications, late rupture, and open conversion. We used this model to estimate the AAA repair size threshold that minimizes AAA-related mortality for 60-year-old average-health men and women. We performed a sensitivity analysis of poor-health patients and 70- and 80-year-old base cases. RESULTS: The annual risk of all-cause mortality under surveillance for a 60-year-old woman presenting with a 5.0 cm AAA using repair thresholds of 5.5 cm, 6.0 cm, 6.5 cm, and 7.0 cm was 1.7%, 2.3%, 2.7%, and 2.8%, respectively. The corresponding risk for a man was 2.3%, 2.9%, 3.3%, and 3.4% for the same repair thresholds, respectively. For a 60-year-old average-health woman, an AAA repair size of 6.1 cm was the optimal threshold to minimize AAA-related mortality. Life expectancy varied by <2 months for repair at sizes from 5.7 cm to 7.1 cm. For a 60-year-old average-health man, an AAA repair size of 6.9 cm was the optimal threshold to minimize AAA-related mortality. Life expectancy varied by <2 months for repair at sizes from 6.0 cm to 7.4 cm. Women in poor health, at various age strata, had optimal AAA repair size thresholds that were >6.5 cm, whereas men in poor health, at all ages, had optimal repair size thresholds that were >8.0 cm. CONCLUSIONS: The optimal threshold for AAA repair is more nuanced than a discrete size. Specifically, there appears to be a range of AAA sizes for which repair is reasonable to minmized AAA-related mortality. Notably, they all are greater than current guideline recommendations. These findings would suggest that contemporary AAA size thresholds for repair should be reconsidered.

Comparative outcomes of open mesenteric bypass after a failed endovascular or open mesenteric revascularization for chronic mesenteric ischemia.

INTRODUCTION: Clinical practice guidelines have recommended an endovascular-first approach (ENDO) for the management of patients with chronic mesenteric ischemia (CMI), whereas an open mesenteric bypass (OMB) is proposed for subjects deemed to be poor ENDO candidates. However, the impact of a previous failed endovascular or open mesenteric reconstruction on a subsequent OMB is unknown. Accordingly, this study was designed to examine the results of a remedial OMB (R-OMB) after a failed ENDO or a primary OMB (P-OMB) for patients with recurrent CMI. METHODS: All patients who underwent an OMB from 2002 to 2022 at the University of Florida were reviewed. Outcomes after an R-OMB (ie, history of a failed ENDO or P-OMB) and P-OMB were compared. The primary end point was 30-day mortality, whereas secondary outcomes included complications, reintervention, and survival. The Kaplan-Meier methodology was used to estimate freedom from reintervention and all-cause mortality, whereas multivariable Cox proportional hazards modeling identified predictors of death. RESULTS: A total of 145 OMB procedures (R-OMB, n = 48 [33%]; P-OMB, n = 97 [67%]) were analyzed. A majority of R-OMB operations were performed for a failed stent (prior ENDO, n = 39 [81%]; prior OMB, n = 9 [19%]). R-OMB patients were generally younger (66 ± 9 years vs P-OMB, 69 ± 11 years; P = .09) and had lower incidence of smoking exposure (29% vs P-OMB, 48%; P = .07); however, there were no other differences in demographics or comorbidities. R-OMB was associated with less intraoperative transfusion (0.6 units vs P-OMB, 1.4 units; P = .01), but there were no differences in conduit choice or bypass configuration.The overall 30-day mortality and complication rates were 7% (n = 10/145) and 53% (n = 77/145), respectively, with no difference between the groups. Notably, R-OMB had decreased cardiac (6% vs P-OMB, 21%; P < .01) and bleeding complication rates (2% vs P-OMB, 15%; P = .01). The freedom from reintervention (1 and 5 years: R-OMB: 95% ± 4%, 83% ± 9% vs P-OMB: 97% ± 2%, 93% ± 5%, respectively; log-rank P = .21) and survival (1 and 5 years: R-OMB: 82% ± 6%, 68% ± 9% vs P-OMB: 84% ± 4%, 66% ± 7%; P = .91) were similar. Independent predictors of all-cause mortality included new postoperative hemodialysis requirement (hazard ratio [HR], 7.4, 95% confidence interval [CI], 3.1-17.3; P < .001), pulmonary (HR, 2.7, 95% CI, 1.4-5.3; P = .004) and cardiac (HR, 2.4, 95% CI, 1.1-5.1; P = .04) complications, and female sex (HR, 2.1, 95% CI, 1.03-4.8; P = .04). Notably, R-OMB was not a predictor of death. CONCLUSIONS: The perioperative and longer-term outcomes for a remedial OMB after a failed intraluminal stent or previous open bypass appear to be comparable to a P-OMB. These findings support the recently updated clinical practice guideline recommendations for an endovascular-first approach to treating recurrent CMI due to the significant perioperative complication risk of OMB. However, among the subset of patients deemed ineligible for endoluminal reconstruction after failed mesenteric revascularization, R-OMB results appear to be acceptable and highlight the utility of this strategy in selected patients.

Neuroanatomical and prognostic associations of depression in Parkinson's disease.

BACKGROUND: Depression is reported as a risk factor, prodromal feature and late consequence of Parkinson's disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD. METHODS: We used data from 434 023 participants from UK Biobank with 14.1 years of follow-up. Multivariable regression models established associations of depression with incident PD and regional brain volumes. Cox proportional hazards models assessed prognostic associations of depression in PD with incident dementia and all-cause mortality. RESULTS: Of 2632 individuals with incident PD, 539 (20.5%) were diagnosed with depression at some point. Depression was associated with an increased risk of subsequent PD (risk ratio 1.53, 95% CI 1.37 to 1.72). Among incident PD cases, depression prevalence rose progressively from 10 years pre-PD diagnosis (OR 2.10, 95% CI 1.57 to 2.83) to 10 years postdiagnosis (OR 3.51, 95% CI 1.33 to 9.22). Depression severity in PD was associated with reduced grey matter volume in structures including the thalamus and amygdala. Depression prior to PD diagnosis increased risk of dementia (HR 1.47, 95% CI 1.05 to 2.07) and mortality (HR 1.30, 95% CI 1.07 to 1.58). CONCLUSIONS: This large-scale prospective study demonstrated that depression prevalence increases from 10 years before PD diagnosis and is a marker of cortical and subcortical volume loss. Depression before PD diagnosis signals a worse prognosis in terms of dementia and mortality. This has clinical implications in stratifying people with poorer cognitive and prognostic trajectory in PD.

The relationship between ethnicity and multiple sclerosis characteristics in the United Kingdom: A UK MS Register study.

BACKGROUND: Previous studies have suggested differences in multiple sclerosis (MS) severity according to ethnicity. METHODS: Data were obtained from the UK MS Register, a prospective longitudinal cohort study of persons with MS. We examined the association between self-reported ethnic background and age at onset, symptom of onset and a variety of participant-reported severity measures. We used adjusted multivariable linear regression models to explore the association between ethnicity and impact of MS, and Cox proportional hazards models to assess disability progression. RESULTS: We analysed data from 17,314 people with MS, including participants from self-reported Black (n = 157) or South Asian (n = 230) ethnic backgrounds. Age at MS onset and diagnosis was lower in those of South Asian (median 30.0) and Black (median 33.0) ethnicity compared with White ethnicity (median 35.0). In participants with online MS severity measures available, we found no statistically significant evidence for an association between ethnic background and physical disability in MS in both cross-sectional and longitudinal analyses. CONCLUSION: We found no association between ethnic background and MS severity in a large, diverse UK cohort. These findings suggest that other factors, such as socioeconomic status and structural inequalities, may explain previous findings.

Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors.

OBJECTIVE: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available. METHODS: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses. RESULTS: A higher polygenic resilience score was associated with a lower risk for PD (ß = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2  = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. INTERPRETATION: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.

The Contemporary Impact of Body Mass Index on Open Aortic Aneurysm Repair.

INTRODUCTION: The Centers for Disease Control and Prevention (CDC) has deemed obesity a national epidemic and contributor to other leading causes of death including heart disease, stroke, and diabetes. Accordingly, the role of body mass index (BMI) and its impact on surgical outcomes has been a focus of persistent investigation. The purpose of this study was to quantify the effect of BMI on open abdominal aortic aneurysm repair (oAAA) outcomes in contemporary practice. METHODS: All elective oAAAs in the VQI (2010-2021) were identified. End-points included 30-day death, in-hospital complications and 1-year mortality. Patients were stratified into four BMI cohorts (BMI<18.5, 18.5≤BMI<25, 25≤BMI<30, BMI≥30). Spline interpolation was used to explore a potential non-linear association between BMI and perioperative mortality. Mixed-effects Cox regression was used to assess the association between BMI and 1-year survival. RESULTS: 9,479 patients underwent oAAA over the study interval (median age-70, 74%-male, BMI 27±6). Lower BMI patients(<18.5) compared to higher BMI(>30) patients were more likely to be women (53% vs. 32%;p<.0001), current smokers(65% vs. 50%;p<.0001), and have COPD(58% vs. 37%;p<.0001). In contrast, an increased BMI was associated with a greater prevalence of diabetes and CAD (DM-26% vs. 6%;p<.0001; CAD-27% vs. 20%;p=.01). There was no difference in cross-clamp position or visceral/renal bypass between groups, though low BMI patients necessitated more frequent infrainguinal bypass(5% vs. 2%;p=.0002). 30-day mortality and in-hospital complications were greater among low BMI patients(30-day mortality:12% vs. 4%;p<.0001;complications-47% vs. 37%;p<.0001). Interestingly, low BMI conferred a nearly 2-fold increase in observed pulmonary complications(18% vs. 11%;p<.0001). Surgical site infections were twice as common among the lowest and highest BMI groups(4% vs. 2%;p<.0001). 1-year mortality was greatest among low BMI patients(23% vs. 9%;p<.0001). Adjusted spline-fit analysis demonstrated increased mortality among patients with BMI<21 or >34(BMI<18.5-HR 2.1, 95%CI 1.6-2.8;p<.0001; BMI>34-HR 1.3, 95%CI 1.1-1.6;p=.009). CONCLUSION: Both low (<18.5) and high (>34) BMI were associated with increased oAAA mortality in current practice. Despite the perception that obesity confers substantial surgical risk during oAAA, diminished BMI was associated with a 3-fold increase in 30-day and 1-year mortality. It appears that BMI extremes are distinct proxies for differential clinical phenotypes and should inform risk stratification for oAAA repair.

Adverse childhood experiences and prescription opioid use during pregnancy: an analysis of the North and South Dakota PRAMS, 2019-2020.

OBJECTIVES: This study assesses the association between adverse childhood experiences (ACEs) and prescription opioid use during pregnancy. METHODS: This study uses data on 2,999 individuals from the 2019 and 2020 Pregnancy Risk Assessment Monitoring System (PRAMS) from North Dakota and South Dakota. The relationship between ACEs and prescription opioid use during pregnancy is examined using multiple logistic regression. RESULTS: The prevalence of prescription opioid use increases alongside more ACE exposure. Compared to those with no ACEs, recent mothers with three or more ACEs have a 2.4 greater odds of prescription opioid use during pregnancy (aOR [adjusted odds ratio] = 2.437; 95% CI [confidence interval] = 1.319, 4.503). CONCLUSION: Exposure to three or more ACEs are associated with a higherrisk of prescription opioid use during pregnancy. Additional research is needed better understand the mechanisms that link ACEs and prescription opioid use during pregnancy, as well as how to best support those with ACEs exposure in a trauma-informed manner to reduce the risk of substance use.

Ventriculo-inferior-venacaval shunt salvage via endovascular surgery.

INTRODUCTION: Hydrocephalus treatment can be very challenging. While some hydrocephalic patients can be treated endoscopically, many will require ventricular shunting. Frequent shunt issues over a lifetime is not uncommon. Although most shunt malfunctions are of the ventricular catheter or valve, distal failures occur as well. A subset of patients will accumulate non-functioning distal drainage sites. CASE DESCRIPTION: We present a 27-year-old male with developmental delay who was shunted perinatally for hydrocephalus from intraventricular hemorrhage of prematurity. After failure of the peritoneum, pleura, superior vena cava (SVC), gallbladder, and endoscopy, an inferior vena cava (IVC) shunt was placed minimally-invasively via the common femoral vein. We believe this is only the eighth reported ventriculo-inferior-venacaval shunt. IVC occlusion years later was successfully treated with endovascular angioplasty and stenting followed by anticoagulation. To our knowledge, a ventriculo-inferior-venacaval shunt salvaged by endovascular surgery has not been previously described in the literature. CONCLUSION: After failure of the peritoneum, pleura, SVC, gallbladder, and endoscopy, IVC shunt placement is an option. Subsequent IVC occlusion can be rescued by endovascular angioplasty and stenting. Anticoagulation after stenting (and potentially after initial IVC placement) is advised.

Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease.

OBJECTIVES: Patients with established Parkinson's disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis. METHODS: We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations. RESULTS: After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1-SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07-1.32, padjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C-reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; ORMR = 1.09, 95% CI = 1.01-1.18, p = 0.02). INTERPRETATION: We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD. ANN NEUROL 2021;89:803-812.

Outcomes of endovascular abdominal aortic aneurysm repair conversion in octogenarians treated at a high-volume aorta center.

BACKGROUND: Endovascular abdominal aortic aneurysm repair (EVAR) has become the dominant treatment strategy for infrarenal abdominal aortic aneurysms but has been especially preferred for octogenarian (age ≥80 years) patients because of concerns surrounding comorbidity severity and physiologic frailty. However, EVAR failure resulting in subsequent open conversion (EVAR-c) has been increasingly reported in older patients, although a paucity of literature focusing on the outcomes in this subgroup is available. The purpose of the present analysis was to evaluate our experience with EVAR-c for octogenarians (age ≥80 years) compared with that for younger patients (age <80 years). METHODS: A retrospective review of all nonmycotic EVAR-c procedures (2002-2020) at a single high-volume academic hospital with a dedicated aorta center (available at: https://www.uf-health-aortic-disease-center) was performed. A total of 162 patients were categorized into octogenarian (age ≥80 years; n = 43) and nonoctogenarian (age <80 years; n = 119) cohorts and compared. The primary end point was 30-day mortality. The secondary end points included complications, 90-day mortality, and overall survival. Cox regression was used to determine the effects of selected covariates on mortality risk. The Kaplan-Meier method was used to estimate survival. RESULTS: No differences in the preadmission EVAR reintervention rates were present (octogenarians, 42%; nonoctogenarians, 43%; P = 1.00) although the interval to the first reintervention was longer for the octogenarians (41 months) than for the nonoctogenarians (15 months; P = .01). In addition, the time to EVAR-c was significantly longer for the octogenarian patients (61 months) than for the nonoctogenarian patients (39 months; P < .01). No difference in rupture presentation was evident (14% vs 10%; P = .6). However, elective EVAR-c occurred less frequently for octogenarians (42%) than for nonoctogenarians (59%; P = .07). The abdominal aortic aneurysm diameter was significantly larger for elective octogenarian EVAR-c (7.8 ± 1.9 cm) than for nonoctogenarian EVAR-c (7.0 ± 1.5 cm; P = .02), and the presence of a type Ia endoleak was the most common indication overall (58%; n = 91). A trend toward greater 30-day mortality was evident for octogenarian patients (16%) compared with nonoctogenarian patients (7%; P = .06). Similarly, the 90-day mortality was greater for the octogenarian patients (26%) than for the nonoctogenarian patients (10%; P = .02). However, the incidence of any complication (56% vs 49%; P = .5), readmission rate (12% vs 6%; P = .3), unplanned reoperation rate (10% vs 5%; P = .5), and length of stay (11 days vs 9 days; P = .3) were not significantly different between the two groups. Age ≥80 years was predictive of short-term mortality after nonelective but not after elective surgery. However, increasing comorbidities, nonelective admission, and renal or mesenteric revascularization showed the strongest association with mortality risk. Survival at 1 and 3 years was not different between the two groups when comparing all patients after the first 90 days postoperatively. CONCLUSIONS: Although the unadjusted perioperative mortality was greater for octogenarian patients, the risk-adjusted elective outcomes were comparable to those for younger EVAR-c patients when treated at a high-volume aortic surgery center. This finding underscores the importance of appropriate patient selection and modulation of operative complexity when feasible to achieve optimal results. Providers caring for octogenarian patients with EVAR failure should consider timely elective referral to high-volume aorta centers to reduce resource usage and the frequency of nonelective presentations.

Type 2 Diabetes as a Determinant of Parkinson's Disease Risk and Progression.

BACKGROUND: Type 2 diabetes (T2DM) and Parkinson's disease (PD) are prevalent diseases that affect an aging population. Previous systematic reviews and meta-analyses have explored the relationship between diabetes and the risk of PD, but the results have been conflicting. OBJECTIVE: The objective was to investigate T2DM as a determinant of PD through a meta-analysis of observational and genetic summary data. METHODS: A systematic review and meta-analysis of observational studies was undertaken by searching 6 databases. We selected the highest-quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate the causal effects of genetic liability toward T2DM on PD risk and progression, using summary data derived from genome-wide association studies. RESULTS: In the observational part of the study, pooled effect estimates showed that T2DM was associated with an increased risk of PD (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07-1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (standardized mean difference [SMD] 0.55, 95% CI 0.39-0.72) and cognitive decline (SMD -0.92, 95% CI -1.50 to -0.34). Using MR, we found supportive evidence for a causal effect of diabetes on PD risk (inverse-variance weighted method [IVW] OR 1.08, 95% CI 1.02-1.14; P = 0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01-1.20; P = 0.032) but not on cognitive progression. CONCLUSIONS: Using meta-analyses of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk and new evidence to support a role in PD progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Antiproliferative Effect of Above-Label Doses of Somatostatin Analogs for the Management of Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. OBJECTIVE: To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. METHODS: Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. RESULTS: The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9-33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, p = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. CONCLUSIONS: Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.

Medical Students' Perceptions of American Indian-Focused Educational Experiences.

INTRODUCTION: American Indians are burdened with a myriad of health disparities. As South Dakota's largest minority population, increasing medical students' experiences with the healthcare of American Indians can play a significant role in helping to alleviate American Indians' health disparities as these future physicians will be better able to predict, detect, and treat the health care needs of this population. METHODS: Survey data from 103 medical students at the University of South Dakota Sanford School of Medicine (SSOM) was collected and analyzed. Demographic information and perceived levels of being informed about American Indians and populations on reservations were collected. Furthermore, medical students' insights on how the SSOM can improve its students' educational experiences with American Indian populations were also collected. RESULTS: Compared to their perceived knowledge of American Indians prior to beginning medical school (26.2 percent), responding medical students believe they became more informed regarding American Indians (61.2 percent) as they progressed through medical school. Fifty-one of the 64 students (80 percent) who answered the open-ended question noted that their medical training would benefit from increased opportunities (including required) with American Indian people, culture, and reservation-based communities. CONCLUSION: There is a desire amongst medical students to increase and require more cultural information and clinical experiences with American Indian people and populations on reservations. Future research is needed to obtain medical student feedback on the newly implemented curriculum and elective opportunities.

Parkinson's disease determinants, prediction and gene-environment interactions in the UK Biobank.

OBJECTIVE: To systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson's disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores. METHODS: We identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene-environment interactions and compare predictive models for PD. RESULTS: Strong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes. INTERPRETATION: Here, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene-environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

Systematic review and meta-analysis of the association between Epstein-Barr virus, multiple sclerosis and other risk factors.

BACKGROUND: Epstein-Barr virus (EBV) infection is thought to play a central role in the development of multiple sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. OBJECTIVE: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. METHODS: Pubmed was searched using the terms 'multiple sclerosis' AND 'Epstein Barr virus', 'multiple sclerosis' AND EBV, 'clinically isolated syndrome' AND 'Epstein Barr virus' and 'clinically isolated syndrome' AND EBV. All abstracts were reviewed for possible inclusion. RESULTS: A total of 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (attributable proportion due to interaction (AP) = 0.48, p < 1 × 10-4). Previous infectious mononucleosis (IM) was associated with increased odds ratio (OR) of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR = 2.76) but not low anti-EBV antibodies (OR = 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. CONCLUSION: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

Effect of Mentoring on Match Rank of Integrated Vascular Surgery Residents.

BACKGROUND: Mentoring relationships have been encouraged for medical students interested in surgical specialties. We investigated the role of mentoring relationships of integrated vascular surgery residents, while in medical school. We hypothesized that mentoring relationships between medical students and vascular surgeons would have a positive effect on match outcome in the integrated vascular surgery residency match. METHODS: We used an online survey that respondents completed on a smartphone, tablet, or computer. This was created with Qualtrics Software. The survey was circulated to all North American Integrated Vascular Surgery residents, with the support of the Association of Program Directors in Vascular Surgery Recruitment Committee and the Society for Vascular Surgery Resident/Student Outreach Committee. Questions were posed either as Likert Scale or as multiple choice. Data were analyzed in Stata. RESULTS: Response rate (67 total responses of 241 polled residents) was 28%. Earlier postgraduate year residents were more likely to have had vascular surgeon mentors (P = 0.033). There was no association between having a mentor and match rank; however, those with vascular surgeon mentors matched higher on their rank list (P = 0.022). 50% of respondents indicated that mentoring was influential in the choice of integrated residency. Respondents with nonvascular surgeon mentors were more likely to answer negatively regarding their mentor's knowledge about other integrated (P < 0.0001) and traditional programs (P < 0.0001) while residents with a vascular surgeon mentor were more likely to respond positively to this question (P < 0.0001). Regarding the effectiveness of mentorship, 81% indicated their mentor was accessible, 92% responded that their mentor demonstrated professional integrity, and 76% responded that their mentor prioritized their success. CONCLUSIONS: Integrated vascular surgery residents were generally positive about their medical school mentors. Our data indicate that surgical mentorship in medical school is effective, both in influencing medical students to choose the vascular surgery specialty and in improving match rank-vascular surgeons were more knowledgeable and mentees with vascular surgeon mentors tended to be more successful in the match.

Epidemiology of Epstein-Barr virus infection and infectious mononucleosis in the United Kingdom.

BACKGROUND: Epstein-Barr Virus (EBV) is a ubiquitous gamma-herpesvirus with which ~ 95% of the healthy population is infected. EBV infection has been implicated in a range of haematological malignancies and autoimmune diseases. Delayed primary EBV infection increases the risk of subsequent complications. Contemporaneous seroepidemiological data is needed to establish best approaches for successful vaccination strategies in the future. METHODS: We conducted a sero-epidemiological survey using serum samples from 2325 individuals between 0 and 25 years old to assess prevalence of detectable anti-EBV antibodies. Second, we conducted a retrospective review of Hospital Episode Statistics to examine changes in Infectious Mononucleosis (IM) incidence over time. We then conducted a large case-control study of 6306 prevalent IM cases and 1,009,971 unmatched controls extracted from an East London GP database to determine exposures associated with IM. RESULTS: 1982/2325 individuals (85.3%) were EBV seropositive. EBV seropositivity increased more rapidly in females than males during adolescence (age 10-15). Between 2002 and 2013, the incidence of IM (derived from hospital admissions data) increased. Exposures associated with an increased risk of IM were lower BMI, White ethnicity, and not smoking. CONCLUSIONS: We report that overall EBV seroprevalence in the UK appears to have increased, and that a sharp increase in EBV seropositivity is seen in adolescent females, but not males. The incidence of IM requiring hospitalisation is increasing. Exposures associated with prevalent IM in a diverse population include white ethnicity, lower BMI, and never-smoking, and these exposures interact with each other. Lastly, we provide pilot evidence suggesting that antibody responses to vaccine and commonly encountered pathogens do not appear to be diminished among EBV-seronegative individuals. Our findings could help to inform vaccine study designs in efforts to prevent IM and late complications of EBV infection, such as Multiple Sclerosis.