To date very few studies with small sample size have compared peroral esophageal myotomy (POEM) with the current surgical standard of care, laparoscopic Heller myotomy (LHM), in terms of efficacy and safety, and no recommendations have been proposed.To investigate the efficacy and safety of POEM compared with LHM, for the treatment of achalasia.The databases of Pubmed, Medline, Cochrane, and Ovid were systematically searched between January 1, 2005 and January 31, 2015, with the medical subject headings (MeSH) and keywords "achalasia," "POEM," "per oral endoscopic myotomy," and "peroral endoscopic myotomy," "laparoscopic Heller myotomy" (LHM), "Heller myotomy."All types of study designs including adult patients with diagnosis of achalasia were selected. Studies that did not report the comparison between endoscopic and surgical treatment, experimental studies in animal models, single case reports, technical reports, reviews, abstracts, and editorials were excluded.The total number of included patients was 486 (196 in POEM group and 290 in LHM group).There were no differences between POEM and LHM in reduction in Eckardt score (MD = -0.659, 95% CI: -1.70 to 0.38, P = 0.217), operative time (MD = -0.354, 95% CI: -1.12 to 0.41, P = 0.36), postoperative pain scores (MD = -1.86, 95% CI: -5.17 to 1.44, P = 0.268), analgesic requirements (MD = -0.74, 95% CI: -2.65 to 1.16, P = 0.445), and complications (OR = 1.11, 95% CI: 0.5-2.44, P = 0.796). Length of hospital stay was significantly lower for POEM (MD = -0.629, 95% CI: -1.256 to -0.002, P = 0.049). There was a trend toward significant reduction in symptomatic gastroesophageal reflux rate in favors of LHM compared to POEM group (OR = 1.81, 95% CI: 1.11-2.95, P = 0.017).All included studied were not randomized. Furthermore all selected studies did not report the results of follow-up longer than 1 year and most of them included patients who were both treatment naive and underwent previous endoscopic or surgical interventions for achalasia.POEM represents a safe and efficacy procedure comparable to the safety profile of LHM for achalasia at a short-term follow-up. Long-term clinical trials are urgently needed.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10^-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10^-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

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We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10^-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10^-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10^-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)_cases = 0.0059, MAF_controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10^-10, OR = 1.43, MAF_cases = 0.011, MAF_controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10^-14, OR = 1.67, MAF_cases = 0.0143, MAF_controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.