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Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.
, , Luo, J, Thomassen, JQ, Bellenguez, C, Grenier-Boley, B, de Rojas, I, Castillo, A, Parveen, K, Küçükali, F, Nicolas, A, et al
JAMA network open. 2023;(5):e2313734
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Abstract
IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
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Pooled Phase 2 and 3 Efficacy and Safety Data on Budesonide Oral Suspension in Adolescents with Eosinophilic Esophagitis.
Mukkada, VA, Gupta, SK, Gold, BD, Dellon, ES, Collins, MH, Katzka, DA, Falk, GW, Williams, J, Zhang, W, Boules, M, et al
Journal of pediatric gastroenterology and nutrition. 2023;(6):760-768
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Abstract
OBJECTIVES The objective of this study was to evaluate the efficacy and safety of budesonide oral suspension (BOS) in adolescents with eosinophilic esophagitis (EoE). METHODS This post hoc analysis pooled data from two 12-week, randomized, double-blind, placebo-controlled studies of BOS 2.0 mg twice daily (b.i.d.) (phase 2, NCT01642212; phase 3, NCT02605837) in patients aged 11-17 years with EoE and dysphagia. Efficacy endpoints included histologic (≤6, ≤1, and <15 eosinophils per high-power field [eos/hpf]), dysphagia symptom (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] scores from baseline), and clinicopathologic (≤6 eos/hpf and ≥30% reduction in DSQ scores from baseline) responses at week 12. Change from baseline to week 12 in peak eosinophil counts, DSQ scores, EoE Histology Scoring System (EoEHSS) grade (severity) and stage (extent) total score ratios (TSRs), and total EoE Endoscopic Reference Scores (EREFS) were assessed. Safety outcomes were also examined. RESULTS Overall, 76 adolescents were included (BOS, n = 45; placebo, n = 31). Significantly more patients who received BOS than placebo achieved histologic responses (≤6 eos/hpf: 46.7% vs 6.5%; ≤1 eos/hpf: 42.2% vs 0.0%; <15 eos/hpf: 53.3% vs 9.7%; P < 0.001) and a clinicopathologic response (31.1% vs 3.2%; P = 0.003) at week 12. More BOS-treated than placebo-treated patients achieved a dysphagia symptom response at week 12 (68.9% vs 58.1%; not statistically significant P = 0.314). BOS-treated patients had significantly greater reductions in EoEHSS grade and stage TSRs ( P < 0.001) and total EREFS ( P = 0.021) from baseline to week 12 than placebo-treated patients. BOS was well tolerated, with no clinically meaningful differences in adverse events versus placebo. CONCLUSIONS BOS 2.0 mg b.i.d. significantly improved most efficacy outcomes in adolescents with EoE versus placebo.
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Qualitative assessment of the suitability of the Dysphagia Symptom Questionnaire to monitor dysphagia in children aged 7-10 years with eosinophilic esophagitis.
Pokrzywinski, RM, Goodwin, B, Dellon, ES, Kodroff, E, Brooks, A, Bailey, A, Williams, J, Desai, NK
Journal of patient-reported outcomes. 2023;(1):110
Abstract
BACKGROUND The Dysphagia Symptom Questionnaire (DSQ) is a patient-reported outcome measure that assesses the frequency and severity of dysphagia in patients with eosinophilic esophagitis (EoE); however, it has only been validated for use in patients with EoE aged 11-40 years. This study examined the content validity of the DSQ and its usability on an electronic handheld device in children aged 7-10 years with EoE. METHODS In this qualitative, observational cohort study, participants were recruited to partake in two rounds of interviews. During visit 1, a cognitive interview examined EoE-associated concepts and the appropriateness of the DSQ for assessing dysphagia. Participants completed the DSQ daily for 2 weeks, and DSQ scores were calculated. After 2 weeks, a second interview assessed the usability of the DSQ on the electronic device and the burden associated with completing it daily. RESULTS Overall, 16 participants were included (aged 7-8 years: n = 8; aged 9-10 years: n = 8); most were male (75%) and white (81%), and the mean (standard deviation [SD]) age was 8.4 (1.3) years. The most commonly reported EoE-associated concept was 'trouble with swallowing' (63% [10/16]). Most participants reported that the questions were 'easy to complete' and 'relevant to someone with EoE and dysphagia'. Overall, participants reported understanding the questions and associated responses; however, further probing demonstrated inconsistent comprehension. Key challenging concepts included 'solid food', 'trouble swallowing', 'vomit', and 'relief'; some participants also reported difficulty differentiating between pain levels (31% [4/13]). Most caregivers reported that their child had experienced dysphagia (94% [15/16]); however, mean (SD) DSQ scores over the study period were low (7.3 [7.4]), suggesting infrequent and mild dysphagia, or a lack of comprehension of the questions. Most participants reported that completing the DSQ on the electronic device was easy (93% [14/15]) and they would be willing to complete it for longer than 2 weeks (73% [11/15]). CONCLUSIONS Difficulties with comprehension and comprehensiveness suggest that the DSQ may not be sufficiently comprehensive for use in all patients in this population, and wording/phrasing changes are required before use in a clinical trial setting.
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Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2023;(1):716
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Management of adults with diabetes on dialysis: Summary of recommendations of the Joint British Diabetes Societies guidelines 2022.
Frankel, AH, Wahba, M, Ashworth, V, Bedi, R, Berrington, R, Buckley, M, Chandrasekharan, L, Doyle, F, Duval, D, Game, F, et al
Diabetic medicine : a journal of the British Diabetic Association. 2023;(4):e15027
Abstract
Diabetes is the commonest cause of end-stage kidney disease in many parts of the world, and many people on dialysis programmes live with diabetes. Such people are vulnerable to complications from their diabetes, and their care may be fragmented due to the many specialists involved. This updated guidance from the Joint British Diabetes Societies aims to review and update the 2016 guidance, with particular emphasis on glycaemic monitoring in the light of recent advances in this area. In addition, the guidance covers clinical issues related to the management of diabetes in people on peritoneal dialysis, along with acute complications such as hypoglycaemia and ketoacidosis, and chronic complications such as foot and eye disease.
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Trends in direct oral anticoagulant (DOAC) prescribing in English primary care (2014-2019).
Joy, M, Williams, J, Emanuel, S, Kar, D, Fan, X, Delanerolle, G, Field, BC, Heiss, C, Pollock, KG, Sandler, B, et al
Heart (British Cardiac Society). 2023;(3):195-201
Abstract
BACKGROUND In England, most prescribing of direct-acting oral anticoagulants for atrial fibrillation (AF) is in primary care. However, there remain gaps in our understanding of dosage and disparities in use. We aimed to describe trends in direct oral anticoagulant (DOAC) prescribing, including dose reduction in people with renal impairment and other criteria, and adherence. METHODS Using English primary care sentinel network data from 2014 to 2019, we assessed appropriate DOAC dose adjustment with creatinine clearance (CrCl). Our primary care sentinel cohort was a subset of 722 general practices, with 6.46 million currently registered patients at the time of this study. RESULTS Of 6 464 129 people in the cohort, 2.3% were aged ≥18 years with a diagnosis of AF, and 30.8% of these were prescribed vitamin K antagonist and 69.1% DOACs. Appropriate DOAC prescribing following CrCl measures improved between 2014 and 2019; dabigatran from 21.3% (95% CI 15.1% to 28.8%) to 48.7% (95% CI 45.0% to 52.4%); rivaroxaban from 22.1% (95% CI 16.7% to 28.4%) to 49.9% (95% CI 48.5% to 53.3%); edoxaban from 10.0% (95% CI 0.3% to 44.5%) in 2016 to 57.6% (95% CI 54.5% to 60.7%) in 2019; apixaban from 30.8% (95% CI 9.1% to 61.4%) in 2015 to 60.5% (95% CI 57.8% to 63.2%) in 2019.Adherence was highest for factor Xa inhibitors, increasing from 50.1% (95% CI 47.7% to 52.4%) in 2014 to 57.8% (95% CI 57.4% to 58.2%) in 2019. Asian and black/mixed ethnicity was associated with non-adherence (OR 1.81, 95% CI 1.56 to 2.09) as was male gender (OR 1.19, 95% CI 1.15 to 1.22), higher socioeconomic status (OR 1.60, 95% CI 1.52 to 1.68), being an ex-smoker (OR 1.12, 95% CI 1.06 to 1.19) and hypertension (OR 1.07, 95% CI 1.03 to 1.17). CONCLUSIONS The volume and quality of DOAC prescribing has increased yearly. Future interventions to augment quality of anticoagulant management should target disparities in adherence.
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Effects of GLP-1 Infusion Upon Whole-body Glucose Uptake and Skeletal Muscle Perfusion During Fed-state in Older Men.
Abdulla, H, Phillips, B, Wilkinson, D, Gates, A, Limb, M, Jandova, T, Bass, J, Lewis, J, Williams, J, Smith, K, et al
The Journal of clinical endocrinology and metabolism. 2023;(4):971-978
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Abstract
INTRODUCTION Ageing skeletal muscles become both insulin resistant and atrophic. The hormone glucagon-like peptide 1 (GLP-1) facilitates postprandial glucose uptake as well as augmenting muscle perfusion, independent of insulin action. We thus hypothesized exogenous GLP-1 infusions would enhance muscle perfusion and positively affect glucose metabolism during fed-state clamps in older people. METHODS Eight men (71 ± 1 years) were studied in a randomized crossover trial. Basal blood samples were taken before postprandial (fed-state) insulin and glucose clamps, accompanied by amino acid infusions, for 3 hours. Reflecting this, following insertions of peripheral and femoral vessels cannulae and baseline measurements, peripheral IV infusions of octreotide, insulin (Actrapid), 20% glucose, and mixed amino acids; Vamin 14-EF with or without a femoral arterial GLP-1 infusion were started. GLP-1, insulin, and C-peptide were measured by ELISA. Muscle microvascular blood flow was assessed via contrast enhanced ultrasound. Whole-body glucose handling was assayed by assessing glucose infusion rate parameters. RESULTS Skeletal muscle microvascular blood flow significantly increased in response to GLP-1 vs feeding alone (5.0 ± 2.1 vs 1.9 ± 0.7 fold-change from basal, respectively; P = 0.008), while also increasing whole-body glucose uptake (area under the curve 16.9 ± 1.7 vs 11.4 ± 1.8 mg/kg-1/180 minutes-1, P = 0.02 ± GLP, respectively). CONCLUSIONS The beneficial effects of GLP-1 on whole-body glycemic control are evident with insulin clamped at fed-state levels. GLP-1 further enhances the effects of insulin on whole-body glucose uptake in older men, underlining its role as a therapeutic target. The effects of GLP-1 in enhancing microvascular flow likely also affects other glucose-regulatory organs, reflected by greater whole-body glucose uptake.
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Biglycan and reduced glycolysis are associated with breast cancer cell dormancy in the brain.
Sunderland, A, Williams, J, Andreou, T, Rippaus, N, Fife, C, James, F, Kartika, YD, Speirs, V, Carr, I, Droop, A, et al
Frontiers in oncology. 2023;:1191980
Abstract
Exit of quiescent disseminated cancer cells from dormancy is thought to be responsible for metastatic relapse and a better understanding of dormancy could pave the way for novel therapeutic approaches. We used an in vivo model of triple negative breast cancer brain metastasis to identify differences in transcriptional profiles between dormant and proliferating cancer cells in the brain. BGN gene, encoding a small proteoglycan biglycan, was strongly upregulated in dormant cancer cells in vivo. BGN expression was significantly downregulated in patient brain metastases as compared to the matched primary breast tumors and BGN overexpression in cancer cells inhibited their growth in vitro and in vivo. Dormant cancer cells were further characterized by a reduced expression of glycolysis genes in vivo, and inhibition of glycolysis in vitro resulted in a reversible growth arrest reminiscent of dormancy. Our study identified mechanisms that could be targeted to induce/maintain cancer dormancy and thereby prevent metastatic relapse.
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Simply Dinner: A Randomized Controlled Trial of Home Meal Delivery.
Brophy-Herb, HE, Martoccio, TL, Kerver, JM, Choi, HH, Jeanpierre, LA, Williams, J, Mitchell, K, Martin, CK, Sturza, J, Contreras, DA, et al
Academic pediatrics. 2023;(5):952-962
Abstract
OBJECTIVE To determine the effect of a bundled intervention (home meal delivery and provision of cooking/serving resources) on preschoolers' body mass index z-score (BMIz), dietary quality, and family meal frequency. METHODS Participants (299 families; mean child age 4.4 years, 47% male, 55% White, 18% Black, 27% Hispanic or other race and ethnicity, and 25% were overweight or obese) were randomized to a control group or to provision of cooking/serving resources plus home meal delivery for 12 weeks (meals provided by Meals on Wheels [MOW cohort, n = 83] or a commercial service [COM cohort, n = 216]). Outcomes were child dietary quality, family meal frequency, and child BMIz. RESULTS The intervention increased dinnertime intake of red and orange vegetables in the full sample (MOW cohort+COM cohort) (0.10 pre- to 0.15 cup equivalents (CE) post-in the intervention group vs 0.10 pre- to 0.09 post- in the control group; P = .01) and the COM cohort (0.11 pre- to 0.17 CE post- vs 0.11 pre- to 0.09 post-; P = .002), and typical daily dietary intake of fruit and fruit juice in the MOW cohort (1.50 CE pre- to 1.66 post- vs 1.48 pre- to 1.19 post-; P = .05). The intervention did not change meal frequency or BMIz. CONCLUSIONS Short-term home meal delivery with provision of cooking/serving resources improved dietary quality among preschool-aged children but did not change meal frequency or BMIz. Expansion of Meals on Wheels programs to preschool-aged children may be a promising intervention to improve dietary quality. Family meals, when already frequent, are not further increased by reducing the burden of meal preparation.
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Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease.
Sanyal, AJ, Williams, SA, Lavine, JE, Neuschwander-Tetri, BA, Alexander, L, Ostroff, R, Biegel, H, Kowdley, KV, Chalasani, N, Dasarathy, S, et al
Journal of hepatology. 2023;(4):693-703
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BACKGROUND & AIMS Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. METHODS Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4). RESULTS The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified. CONCLUSIONS Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD. CLINICAL TRIAL NUMBER Not applicable. IMPACT AND IMPLICATIONS An aptamer-based protein scan of serum proteins was performed to identify diagnostic signatures of the key histological features of non-alcoholic fatty liver disease (NAFLD), for which no approved non-invasive diagnostic tools are currently available. We also identified specific protein signatures related to the presence and severity of NAFLD and its histological components that were also sensitive to change over time. These are fundamental initial steps in establishing a serum proteome-based diagnostic signature of NASH and provide the rationale for using these signatures to test treatment response and to identify several novel targets for evaluation in the pathogenesis of NAFLD.