Effect of clinical signs, endocrinopathies, timing of surgery, hyperlipidemia, and hyperbilirubinemia on outcome in dogs with gallbladder mucocele

Gallbladder mucocele (GBM) is a common extra-hepatic biliary syndrome in dogs with death rates ranging from 7 to 45%. Therefore, the aim of this study was to identify the association of survival with variables that could be utilized to improve clinical decisions. A total of 1194 dogs with a gross and histopathological diagnosis of GBM were included from 41 veterinary referral hospitals in this retrospective study. Dogs with GBM that demonstrated abnormal clinical signs had significantly greater odds of death than subclinical dogs in a univariable analysis (OR, 4.2; 95% CI, 2.14–8.23; P < 0.001). The multivariable model indicated that categorical variables including owner recognition of jaundice (OR, 2.12; 95% CI, 1.19–3.77; P = 0.011), concurrent hyperadrenocorticism (OR 1.94; 95% CI, 1.08–3.47; P = 0.026), and Pomeranian breed (OR, 2.46; 95% CI 1.10–5.50; P = 0.029) were associated with increased odds of death, and vomiting was associated with decreased odds of death (OR, 0.48; 95% CI, 0.30–0.72; P = 0.001). Continuous variables in the multivariable model, total serum/plasma bilirubin concentration (OR, 1.03; 95% CI, 1.01–1.04; P < 0.001) and age (OR, 1.17; 95% CI, 1.08–1.26; P < 0.001), were associated with increased odds of death. The clinical utility of total serum/plasma bilirubin concentration as a biomarker to predict death was poor with a sensitivity of 0.61 (95% CI, 0.54–0.69) and a specificity of 0.63 (95% CI, 0.59–0.66). This study identified several prognostic variables in dogs with GBM including total serum/plasma bilirubin concentration, age, clinical signs, concurrent hyperadrenocorticism, and the Pomeranian breed. The presence of hypothyroidism or diabetes mellitus did not impact outcome in this study.Supplemental Table S1. Number of dogs included from each institution and years reviewed.Supplemental Table S2. Included breeds.Supplemental Table S3. Distribution of various reasons given for performing cholecystectomy in the 179 subclinical dogs with gallbladder mucocele (GBM).Supplemental Table S4. Distribution of clinical signs associated with systemic illness in 982 dogs with gallbladder mucocele.Supplemental Table S5. Distribution of reasons for death in-hospital (i.e. euthanized and died) in 179 dogs with gallbladder mucocele that underwent cholecystectomy.http://www.elsevier.com/locate/tvjlhj2020Companion Animal Clinical Studie

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Reversible tonic pupils

A 36-year-old man with a remote history of Hodgkin lymphoma and a recent history of non-Hodgkin lymphoma (NHL) developed tonic pupils and absent deep tendon reflexes in the lower extremities. One year later, pupils were normal except for slight iris segmental contraction to light. Over the next 2 years, the patient remained asymptomatic, and pupils remained unchanged. The NHL went into remission, and no other neurologic manifestations appeared. This is the first report of reversible tonic pupils. They may have a pathogenesis different from that typically seen in irreversible tonic pupil

Value of routine funduscopy in patients with hypertension: systematic review

Objective To evaluate the additional value of funduscopy in the routine management of patients with hypertension. Design Systematic review. Participants Adults aged 19 or more with hypertensive retinopathy. Data sources Medline, Embase, and the Cochrane Library from 1990. Review methods Studies were included that assessed hypertensive retinopathy with blinding for blood pressure and cardiovascular risk factors. Studies on observer agreement had to be assessed by two or more observers and expressed as a K statistic. Studies on the association between hypertensive retinopathy and hypertensive organ damage were carried out in patients with hypertension. The association between hypertensive retinopathy and cardiovascular risk was carried out in unselected normotensive and hypertensive people without diabetes mellitus. Results The assessment of microvascular changes in the retina is limited by large variation between observers. The positive and negative predictive values for the association between hypertensive retinopathy and blood pressure were low (47% to 72% and 32% to 67%, respectively). Associations between retinal microvascular changes and cardiovascular risk were inconsistent, except for retinopathy and stroke. The increased risk of stroke, however, was also present in normotensive people with retinopathy. These studies did not adjust for other indicators of hypertensive organ damage. Conclusion Evidence is lacking that routine funduscopy is of additional value in the management of hypertensive patient

Blood pressure, arterial stiffness, and open-angle glaucoma: the Rotterdam study

OBJECTIVE: To investigate cross-sectional associations among blood pressures (BPs), arterial stiffness, and open-angle glaucoma (OAG). METHODS: Study participants came from the population-based Rotterdam Study. The baseline examination phase took place after an extensive home interview from March 20, 1990, to June 17, 1993, and the third phase between March 19, 1997, and December 16, 1999. Cases were classified into high-tension OAG (htOAG) and normal-tension OAG (ntOAG), according to an intraocular pressure greater than 21 mm Hg or 21 mm Hg or less. Pulse pressure was the difference between systolic and diastolic BP. Diastolic perfusion pressure was the difference between diastolic BP and the intraocular pressure; indicators of arterial stiffness were carotid-femoral pulse wave velocity and carotid distensibility. Associations were evaluated with logistic regression analysis, adjusted for age, sex, body mass index, smoking, diabetes mellitus, serum cholesterol level, and BP-lowering treatment. RESULTS: A total of 5317 participants were included in this study. In participants with a higher pulse pressure, the prevalence of htOAG was elevated (odds ratio [OR] per standard deviation, 1.32; 95% confidence interval [CI], 1.03-1.69). In persons treated for systemic hypertension, low diastolic perfusion pressure ( <50 mm Hg) was inversely associated with ntOAG (OR, 0.25; 95% CI, 0.10-0.63) and positively associated with htOAG (OR, 4.68; 95% CI, 1.29-17.01). The lowest tertile of carotid distensibility compared with the highest had an OR for htOAG of 2.84 (95% CI, 0.99-8.10; P=.05). CONCLUSIONS: We found that htOAG was associated with high pulse pressure, possibly with increased carotid arterial stiffness, and, only in persons treated for systemic hypertension, with low diastolic perfusion pressure. In these persons, ntOAG was associated with high diastolic BP, whereas the association between ntOAG and low diastolic perfusion pressure was inverte