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

Supplementary Material for: Trends and Outcomes of Severe Sepsis in Patients on Maintenance Dialysis

<b><i>Background:</i></b> Though the incidence of severe sepsis is rising, there is a lack of contemporary information regarding the epidemiology and outcomes of severe sepsis in those on maintenance dialysis. The objectives of this study were to measure the incidence and outcomes of severe sepsis in those on maintenance dialysis. <b><i>Methods:</i></b> Using data from Nationwide Inpatient Sample database from 2005 to 2010, we included all hospitalizations of adults with severe sepsis based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Those on maintenance dialysis were identified by ICD-9-CM codes. We calculated incidence of severe sepsis and mortality. We used logistic regression to assess independent effect of maintenance dialysis status on mortality. <b><i>Results:</i></b> Of the estimated 5,000,152 hospitalizations with severe sepsis, 322,734 (6.4%) were on maintenance dialysis. The unadjusted incidence of severe sepsis was 145.4 per 1,000 in those on maintenance dialysis in comparison to 3.5 per 1,000 in the general population. Mortality was higher in those with severe sepsis (30.3 vs. 26.2%; p < 0.001). Maintenance dialysis is an independent predictor of death in those with severe sepsis (OR 1.26; 95% CI 1.23-1.29). <b><i>Conclusions:</i></b> Hospitalizations with severe sepsis are more prevalent and associated with poor outcomes in those on maintenance dialysis

PowerPoint Slides for: National Impact of Maintenance Dialysis or Renal Transplantation on Outcomes Following ST Elevation Myocardial Infarction

<i>Background:</i> Though cardiovascular disease is an important cause of mortality in patients with end-stage renal disease, epidemiology of ST-elevation myocardial infarction (STEMI) is less well described in this population. <i>Methods:</i> This study included STEMI hospitalizations in patients aged ≥20 using Nationwide Inpatient Sample Database from 2006 to 2010. Primary outcomes were incidence and trends of STEMI hospitalizations based on renal function status. We also looked at utilization of revascularization procedures, all-cause-hospital mortality and predictors of mortality.<i>Results:</i> Of the estimated 882,447 STEMI hospitalizations, 11,383 were on maintenance dialysis and 1,076 had renal transplants. The incidence of STEMI was over 7 times in patients on maintenance dialysis and 1.73 times in renal transplant recipients compared to the general population. This incidence has however declined in those on maintenance dialysis (p for trend <0.001) to a greater extent than the general population and patients with renal transplant. Utilization of revascularization procedures was lowest in patients on maintenance dialysis (51.6 vs. 73.3% in renal transplant recipients and 77.0% in general population; p < 0.001) and mortality was highest (21.6 vs. 10.9 vs. 6.8%; p < 0.001). Being on maintenance dialysis or having a renal transplant were both independent predictors of mortality in patients hospitalized with STEMI. There was a differential effect of cardiac catheterization on odds of mortality with lesser impact in patients on maintenance dialysis. <i>Conclusions:</i>STEMI hospitalizations are more common in patients on maintenance dialysis and with renal transplants. The utilization of revascularizations procedures remains low and mortality high in these patients

Supplementary Material for: National Impact of Maintenance Dialysis or Renal Transplantation on Outcomes Following ST Elevation Myocardial Infarction

<p><b><i>Background:</i></b> Though cardiovascular disease is an important cause of mortality in patients with end-stage renal disease, epidemiology of ST-elevation myocardial infarction (STEMI) is less well described in this population. <b><i>Methods:</i></b> This study included STEMI hospitalizations in patients aged ≥20 using Nationwide Inpatient Sample Database from 2006 to 2010. Primary outcomes were incidence and trends of STEMI hospitalizations based on renal function status. We also looked at utilization of revascularization procedures, all-cause-hospital mortality and predictors of mortality. <b><i>Results:</i></b> Of the estimated 882,447 STEMI hospitalizations, 11,383 were on maintenance dialysis and 1,076 had renal transplants. The incidence of STEMI was over 7 times in patients on maintenance dialysis and 1.73 times in renal transplant recipients compared to the general population. This incidence has however declined in those on maintenance dialysis (p for trend <0.001) to a greater extent than the general population and patients with renal transplant. Utilization of revascularization procedures was lowest in patients on maintenance dialysis (51.6 vs. 73.3% in renal transplant recipients and 77.0% in general population; p < 0.001) and mortality was highest (21.6 vs. 10.9 vs. 6.8%; p < 0.001). Being on maintenance dialysis or having a renal transplant were both independent predictors of mortality in patients hospitalized with STEMI. There was a differential effect of cardiac catheterization on odds of mortality with lesser impact in patients on maintenance dialysis. <b><i>Conclusions:</i></b> STEMI hospitalizations are more common in patients on maintenance dialysis and with renal transplants. The utilization of revascularizations procedures remains low and mortality high in these patients.</p

First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis

Background: Polycystic ovary syndrome (PCOS) is the most frequent cause of anovulatory infertility. In women with PCOS, effective ovulation induction serves as an important first-line treatment for anovulatory infertility. Individual participant data (IPD) meta-analysis is considered as the gold standard for evidence synthesis which provides accurate assessments of outcomes from primary randomised controlled trials (RCTs) and allows additional analyses for time-to-event outcomes. It also facilitates treatment-covariate interaction analyses and therefore offers an opportunity for personalised medicine. Objective and Rationale: We aimed to evaluate the effectiveness of different ovulation induction agents, in particular letrozole alone and clomiphene citrate (CC) plus metformin, as compared to CC alone, as the first-line choice for ovulation induction in women with PCOS and infertility, and to explore interactions between treatment and participant-level baseline characteristics. Search Methods: We searched electronic databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials up to 20 December 2018. We included RCTs comparing the following interventions with each other or placebo/no treatment in women with PCOS and infertility: CC, metformin, CC plus metformin, letrozole, gonadotrophin and tamoxifen. We excluded studies on treatment-resistant women. The primary outcome was live birth. We contacted the investigators of eligible RCTs to share the IPD and performed IPD meta-analyses. We assessed the risk of bias by using the Cochrane risk of bias tool for RCTs. Outcomes: IPD of 20 RCTs including 3962 women with PCOS were obtained. Six RCTs compared letrozole and CC in 1284 women. Compared with CC, letrozole improved live birth rates (3 RCTs, 1043 women, risk ratio [RR] 1.43, 95% confidence interval [CI] 1.17-1.75, moderate-certainty evidence) and clinical pregnancy rates (6 RCTs, 1284 women, RR 1.45, 95% CI 1.23-1.70, moderate-certainty evidence) and reduced time-to-pregnancy (6 RCTs, 1235 women, hazard ratio [HR] 1.72, 95% CI 1.38-2.15, moderate-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline serum total testosterone levels and treatment effects on live birth (interaction RR 1.29, 95% CI 1.01-1.65). Eight RCTs compared CC plus metformin to CC alone in 1039 women. Compared with CC alone, CC plus metformin might improve clinical pregnancy rates (8 RCTs, 1039 women, RR 1.18, 95% CI 1.00-1.39, low-certainty evidence) and might reduce time-to-pregnancy (7 RCTs, 898 women, HR 1.25, 95% CI 1.00-1.57, low-certainty evidence), but there was insufficient evidence of a difference on live birth rates (5 RCTs, 907 women, RR 1.08, 95% CI 0.87-1.35, low-certainty evidence). Meta-analyses of effect modifications showed a positive interaction between baseline insulin levels and treatment effects on live birth in the comparison between CC plus metformin and CC (interaction RR 1.03, 95% CI 1.01-1.06). Wider Implications: In women with PCOS, letrozole improves live birth and clinical pregnancy rates and reduces time-to-pregnancy compared to CC and therefore can be recommended as the preferred first-line treatment for women with PCOS and infertility. CC plus metformin may increase clinical pregnancy and may reduce time-to-pregnancy compared to CC alone, while there is insufficient evidence of a difference on live birth. Treatment effects of letrozole are influenced by baseline serum levels of total testosterone, while those of CC plus metformin are affected by baseline serum levels of insulin. These interactions between treatments and biomarkers on hyperandrogenaemia and insulin resistance provide further insights into a personalised approach for the management of anovulatory infertility related to PCOS.Rui Wang, Wentao Li, Esmée M. Bordewijk, Richard S. Legro, Heping Zhang, Xiaoke Wu, Jingshu Gao, Laure Morin-Papunen, Roy Homburg, Tamar E. König, Etelka Moll, Sujata Kar, Wei Huang, Neil P. Johnson, Saad A. Amer, Walter Vegetti, Stefano Palomba, Angela Falbo, Ülkü Özmen, Hakan Nazik, Christopher D. Williams, Grasso Federica, Jonathan Lord, Yilmaz Sahin, Siladitya Bhattacharya, Robert J. Norman, Madelon van Wely, Ben Willem Mol, Reproductive Medicine Network, the International Ovulation Induction IPDMA Collaboratio