Volunteer-led physical activity interventions to improve health outcomes for community-dwelling older people: a systematic review.

BACKGROUND: Physical activity (PA) is important for older people to maintain functional independence and healthy ageing. There is strong evidence to support the benefits of physical activity interventions on the health outcomes of older adults. Nonetheless, innovative approaches are needed to ensure that these interventions are practical and sustainable. AIM: This systematic review explores the effectiveness of volunteer-led PA interventions in improving health outcomes for community-dwelling older people. METHODS: Five databases (MEDLINE, Embase, CINAHL, PEDro, Cochrane library) were systematically searched for studies using trained volunteers to deliver PA interventions for community-dwelling older people aged ≥ 65 years. Meta-analysis was not conducted due to included study heterogeneity. RESULTS: Twelve papers describing eight studies (five papers reported different outcomes from the same study) were included in the review. All eight studies included strength and balance exercises and frequency of PA ranged from weekly to three times a week. Volunteer-led exercises led to improvements in functional status measured using the short physical performance battery, timed up and go test, Barthel Index, single leg stand, step touch test, chair stand test, and functional reach. Frailty status identified by grip strength measurement or the use of long-term care insurance improved with volunteer-led exercises. Interventions led to improvement in fear of falls and maintained or improved the quality of life. The impact on PA levels were mixed. CONCLUSION: Limited evidence suggests that volunteer-led PA interventions that include resistance exercise training, can improve outcomes of community-dwelling older adults including functional status, frailty status, and reduction in fear of falls. More high-quality RCTs are needed to investigate the effects of volunteer-led PA interventions among older people.

Guidelines for investigating causality of sequence variants in human disease.

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

Rapid, climate-driven changes in outlet glaciers on the Pacific coast of East Antarctica.

Observations of ocean-terminating outlet glaciers in Greenland and West Antarctica indicate that their contribution to sea level is accelerating as a result of increased velocity, thinning and retreat. Thinning has also been reported along the margin of the much larger East Antarctic ice sheet, but whether glaciers are advancing or retreating there is largely unknown, and there has been no attempt to place such changes in the context of localized mass loss or climatic or oceanic forcing. Here we present multidecadal trends in the terminus position of 175 ocean-terminating outlet glaciers along 5,400 kilometres of the margin of the East Antarctic ice sheet, and reveal widespread and synchronous changes. Despite large fluctuations between glaciers--linked to their size--three epochal patterns emerged: 63 per cent of glaciers retreated from 1974 to 1990, 72 per cent advanced from 1990 to 2000, and 58 per cent advanced from 2000 to 2010. These trends were most pronounced along the warmer western South Pacific coast, whereas glaciers along the cooler Ross Sea coast experienced no significant changes. We find that glacier change along the Pacific coast is consistent with a rapid and coherent response to air temperature and sea-ice trends, linked through the dominant mode of atmospheric variability (the Southern Annular Mode). We conclude that parts of the world's largest ice sheet may be more vulnerable to external forcing than recognized previously.

Transcriptomic variation of pharmacogenes in multiple human tissues and lymphoblastoid cell lines.

Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.

Pharmacogenomic variants have larger effect sizes than genetic variants associated with other dichotomous complex traits.

It has been suggested that pharmacogenomic phenotypes are influenced by genetic variants with larger effect sizes than other phenotypes, such as complex disease risk. This is presumed to reflect the fact that relevant environmental factors (drug exposure) are appropriately measured and taken into account. To test this hypothesis, we performed a systematic comparison of effect sizes between pharmacogenomic and non-pharmacogenomic phenotypes across all genome-wide association studies (GWAS) reported in the NHGRI GWAS catalog. We found significantly larger effect sizes for studies focused on pharmacogenomic phenotypes, as compared with complex disease risk, morphological phenotypes and endophenotypes. We found no significant differences in effect sizes between pharmacogenomic studies focused on adverse events versus those focused on drug efficacy. Furthermore, we found that this pattern persists among sample size-matched studies, suggesting that this pattern does not reflect overestimation of effect sizes due to smaller sample sizes in pharmacogenomic studies.The Pharmacogenomics Journal advance online publication, 7 July 2015; doi:10.1038/tpj.2015.47.

Establishment of CYP2D6 reference samples by multiple validated genotyping platforms.

Cytochrome P450 2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6)), a highly polymorphic drug-metabolizing enzyme, is involved in the metabolism of one-quarter of the most commonly prescribed medications. Here we have applied multiple genotyping methods and Sanger sequencing to assign precise and reproducible CYP2D6 genotypes, including copy numbers, for 48 HapMap samples. Furthermore, by analyzing a set of 50 human liver microsomes using endoxifen formation from N-desmethyl-tamoxifen as the phenotype of interest, we observed a significant positive correlation between CYP2D6 genotype-assigned activity score and endoxifen formation rate (rs = 0.68 by rank correlation test, P = 5.3 × 10(-8)), which corroborated the genotype-phenotype prediction derived from our genotyping methodologies. In the future, these 48 publicly available HapMap samples characterized by multiple substantiated CYP2D6 genotyping platforms could serve as a reference resource for assay development, validation, quality control and proficiency testing for other CYP2D6 genotyping projects and for programs pursuing clinical pharmacogenomic testing implementation.

Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

Genome-wide meta-analysis identifies variants associated with platinating agent susceptibility across populations.

Platinating agents are used in the treatment of many cancers, yet they can induce toxicities and resistance that limit their utility. Using previously published and additional world population panels of diverse ancestry totaling 608 lymphoblastoid cell lines (LCLs), we performed meta-analyses of over 3 million single-nucleotide polymorphisms (SNPs) for both carboplatin- and cisplatin-induced cytotoxicity. The most significant SNP in the carboplatin meta-analysis is located in an intron of NBAS (neuroblastoma amplified sequence; P=5.1 × 10(-7)). The most significant SNP in the cisplatin meta-analysis is upstream of KRT16P2 (P=5.8 × 10(-7)). We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Most of the variants that associate with platinum-induced cytotoxicity are polymorphic across multiple world populations; therefore, they could be tested in follow-up studies in diverse clinical populations. Seven genes previously implicated in platinating agent response, including BCL2 (B-cell CLL/lymphoma 2), GSTM1 (glutathione S-transferase mu 1), GSTT1, ERCC2 and ERCC6, were also implicated in our meta-analyses.

Genome wide association studies for diabetes: perspective on results and challenges.

Recent results of genome wide association study (GWAS) for diabetes genes, while reaching impressive technical milestones and implicating new findings for research, have been uniformly disappointing in terms of immediate clinical utility. The relative risk associated with any of the newly reported genetic loci, or even considering all of them together, is far less than simply that which can be obtained by taking a history and a physical exam. For type 2 diabetes (T2D), GWAS have implicated novel pathways, supported previously known associations, and highlighted the importance of the beta cell and insulin secretion. Monogenic forms of diabetes, on the other hand, continue to yield interesting insights into genes controlling human beta cell function but most cases of monogenic diabetes are simply not diagnosed. Here, we briefly review recent results related to type 1, type 2 and maturity onset diabetes of youth (MODY) diabetes and suggest that future studies emphasizing quantitative traits are likely to yield even more insights.

Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans.

Complex disorders such as diabetes, cardiovascular disease, asthma, hypertension and psychiatric illnesses account for a large and disproportionate share of health care costs, but remain poorly characterized with respect to aetiology. The transmission of such disorders is complex, reflecting the actions and interactions of multiple genetic and environmental factors. Genetic analyses that allow for the simultaneous consideration of susceptibility from multiple regions may improve the ability to map genes for complex disorders, but such analyses are currently computationally intensive and narrowly focused. We describe here an approach to assessing the evidence for statistical interactions between unlinked regions that allows multipoint allele-sharing analysis to take the evidence for linkage at one region into account in assessing the evidence for linkage over the rest of the genome. Using this method, we show that the interaction of genes on chromosomes 2 (NIDDM1) and 15 (near CYP19) makes a contribution to susceptibility to type 2 diabetes in Mexican Americans from Starr County, Texas.

A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens and studies focused on candidate genes have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15. We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.

Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus.

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.

Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism.

Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA(A) receptor ß3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant ß3 subunit-containing α1ß3γ2 or α3ß3γ2 GABA(A) receptors shows reduced whole-cell current and decreased ß3 subunit protein on the cell surface due to impaired intracellular ß3 subunit processing. We thus provide the first evidence of an association between a specific GABA(A) receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.

Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals.

AIMS/HYPOTHESIS: We conducted genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) analyses to identify and characterise risk loci for type 2 diabetes in Mexican-Americans from Starr County, TX, USA. METHOD: Using 1.8 million directly interrogated and imputed genotypes in 837 unrelated type 2 diabetes cases and 436 normoglycaemic controls, we conducted Armitage trend tests. To improve power in this population with high disease rates, we also performed ordinal regression including an intermediate class with impaired fasting glucose and/or glucose tolerance. These analyses were followed by meta-analysis with a study of 967 type 2 diabetes cases and 343 normoglycaemic controls from Mexico City, Mexico. RESULT: The top signals (unadjusted p value <1 × 10(-5)) included 49 single nucleotide polymorphisms (SNPs) in eight gene regions (PER3, PARD3B, EPHA4, TOMM7, PTPRD, HNT [also known as RREB1], LOC729993 and IL34) and six intergenic regions. Among these was a missense polymorphism (rs10462020; Gly639Val) in the clock gene PER3, a system recently implicated in diabetes. We also report a second signal (minimum p value 1.52 × 10(-6)) within PTPRD, independent of the previously implicated SNP, in a population of Han Chinese. Top meta-analysis signals included known regions HNF1A and KCNQ1. Annotation of top association signals in both studies revealed a marked excess of trans-acting eQTL in both adipose and muscle tissues. CONCLUSIONS/INTERPRETATION: In the largest study of type 2 diabetes in Mexican populations to date, we identified modest associations of novel and previously reported SNPs. In addition, in our top signals we report significant excess of SNPs that predict transcript levels in muscle and adipose tissues.

Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas.

AIMS/HYPOTHESIS: We report a genome-wide association study of type 2 diabetes in an admixed sample from Mexico City and describe the results of a meta-analysis of this study and another genome-wide scan in a Mexican-American sample from Starr County, TX, USA. The top signals observed in this meta-analysis were followed up in the Diabetes Genetics Replication and Meta-analysis Consortium (DIAGRAM) and DIAGRAM+ datasets. METHODS: We analysed 967 cases and 343 normoglycaemic controls. The samples were genotyped with the Affymetrix Genome-wide Human SNP array 5.0. Associations of genotyped and imputed markers with type 2 diabetes were tested using a missing data likelihood score test. A fixed-effects meta-analysis including 1,804 cases and 780 normoglycaemic controls was carried out by weighting the effect estimates by their inverse variances. RESULTS: In the meta-analysis of the two Hispanic studies, markers showing suggestive associations (p < 10(-5)) were identified in two known diabetes genes, HNF1A and KCNQ1, as well as in several additional regions. Meta-analysis of the two Hispanic studies and the recent DIAGRAM+ dataset identified genome-wide significant signals (p < 5 × 10(-8)) within or near the genes HNF1A and CDKN2A/CDKN2B, as well as suggestive associations in three additional regions, IGF2BP2, KCNQ1 and the previously unreported C14orf70. CONCLUSIONS/INTERPRETATION: We observed numerous regions with suggestive associations with type 2 diabetes. Some of these signals correspond to regions described in previous studies. However, many of these regions could not be replicated in the DIAGRAM datasets. It is critical to carry out additional studies in Hispanic and American Indian populations, which have a high prevalence of type 2 diabetes.

Detecting 2009 pandemic influenza A (H1N1) virus infection: availability of diagnostic testing led to rapid pandemic response.

Diagnostic tests for detecting emerging influenza virus strains with pandemic potential are critical for directing global influenza prevention and control activities. In 2008, the Centers for Disease Control and Prevention received US Food and Drug Administration approval for a highly sensitive influenza polymerase chain reaction (PCR) assay. Devices were deployed to public health laboratories in the United States and globally. Within 2 weeks of the first recognition of 2009 pandemic influenza H1N1, the Centers for Disease Control and Prevention developed and began distributing a new approved pandemic influenza H1N1 PCR assay, which used the previously deployed device platform to meet a >8-fold increase in specimen submissions. Rapid antigen tests were widely used by clinicians at the point of care; however, test sensitivity was low (40%-69%). Many clinical laboratories developed their own pandemic influenza H1N1 PCR assays to meet clinician demand. Future planning efforts should identify ways to improve availability of reliable testing to manage patient care and approaches for optimal use of molecular testing for detecting and controlling emerging influenza virus strains.

Interaction of prenatal exposure to cigarettes and MAOA genotype in pathways to youth antisocial behavior.

Genetic susceptibility to antisocial behavior may increase fetal sensitivity to prenatal exposure to cigarette smoke. Testing putative gene x exposure mechanisms requires precise measurement of exposure and outcomes. We tested whether a functional polymorphism in the gene encoding the enzyme monoamine oxidase A (MAOA) interacts with exposure to predict pathways to adolescent antisocial behavior. We assessed both clinical and information-processing outcomes. One hundred seventy-six adolescents and their mothers participated in a follow-up of a pregnancy cohort with well-characterized exposure. A sex-specific pattern of gene x exposure interaction was detected. Exposed boys with the low-activity MAOA 5' uVNTR (untranslated region variable number of tandem repeats) genotype were at increased risk for conduct disorder (CD) symptoms. In contrast, exposed girls with the high-activity MAOA uVNTR genotype were at increased risk for both CD symptoms and hostile attribution bias on a face-processing task. There was no evidence of a gene-environment correlation (rGE). Findings suggest that the MAOA uVNTR genotype, prenatal exposure to cigarettes and sex interact to predict antisocial behavior and related information-processing patterns. Future research to replicate and extend these findings should focus on elucidating how gene x exposure interactions may shape behavior through associated changes in brain function.

Can probiotics, prebiotics and synbiotics improve functional outcomes for older people: a systematic review.

PURPOSE: Research evaluating the effect of probiotics, prebiotics and synbiotics (PPS) on laboratory markers of health (such as immunomodulatory and microbiota changes) is growing but it is unclear whether these markers translate to improved functional outcomes in the older population. This systematic review evaluates the effect of PPS on functional outcomes in older people. METHODS: We conducted a systematic review of the effect of PPS in older adults on functional outcomes (physical strength, frailty, mood and cognition, mortality and receipt of care). Four electronic databases were searched for studies published since year 2000. RESULTS: Eighteen studies (including 15 RCTs) were identified. One of five studies evaluating physical function reported benefit (improved grip strength). Two analyses of one prebiotic RCT assessed frailty by different methods with mixed results. Four studies evaluated mood with no benefit reported. Six studies evaluated cognition: four reported cognitive improvement in participants with pre-existing cognitive impairment receiving probiotics. Seven studies reported mortality as a secondary outcome with a trend to reduction in only one. Five studies reported length of hospital stay but only two peri-operative studies reported shorter stays. CONCLUSION: There is limited evidence that probiotics may improve cognition in older people with pre-existing cognitive impairment but no clear evidence of benefit of PPS on physical function, frailty, mood, length of hospitalisation and mortality. Larger studies with more homogenous interventions, accounting for confounding factors, such as diet, co-morbidities and medications, are required. There is currently inadequate evidence to recommend PPS use to older people in general. PROSPERO REGISTRATION NUMBER: PROSPERO registration number is CRD42020173417. Date of PROSPERO registration: 01/05/20.

Poor Appetite Is Associated with Six Month Mortality in Hospitalised Older Men and Women.

OBJECTIVES: Appetite loss is common in hospitalised older individuals but not routinely assessed. Poor appetite in hospital has previously been identified as predictive of greater mortality in the six months following discharge in a single study of female patients. The present study aimed to assess this association in a larger sample including both hospitalised men and women. DESIGN: Longitudinal observational study with six month follow up. SETTING: Acute hospital wards in a single large hospital in England. PARTICIPANTS: Older inpatients aged over 70 years. MEASUREMENTS: Appetite was assessed using the Simplified Nutritional Appetite Questionnaire (SNAQ) during hospital stay. Deaths during six month follow-up period were recorded. Association between SNAQ score during hospital admission and death 6 months post-discharge was assessed using binary logistic regression in unadjusted and adjusted analysis. RESULTS: 296 participants (43% female, mean age 83 years (SD 6.9)) were included in this study. Prevalence of poor appetite (SNAQ score <14) was 41%. In unadjusted analysis a SNAQ score of <14 was associated with a 2.47 increase in odds of mortality at six months (OR 2.47 (95% CI 1.27,4.82)). This association remained after adjusting for number of comorbidities (Charlson index), length of stay and gender (OR 2.62 (95% CI 1.30, 5.27)). In unadjusted continuous analysis, every one point decrease in SNAQ score led to a 1.20 fold increase in odds of mortality at six months (OR 1.20 (95% CI 1.06-1.36)). This association remained in adjusted analysis (OR 1.22 (95% CI 1.07-1.39)). CONCLUSION: Poor appetite is common in hospitalised older people. We have confirmed the association, previously reported in older women, between poor appetite during hospital stay and greater mortality at six months post-discharge but in a larger study including older men and women. Further research is needed to understand the mechanisms of poor appetite, which lead to increased mortality.