How do potentially inappropriate medications and polypharmacy affect mortality in frail and non-frail cognitively impaired older adults?:A cohort study

OBJECTIVES: To test whether the use of potentially inappropriate central nervous system acting medications, proton pump inhibitors (PPIs) or polypharmacy are associated with mortality in cognitively impaired older adults and whether frailer people are at greater risk of harm. SETTING: A cohort study nested within the Cognitive Function and Ageing Study II, a population representative cohort study of the older population in Cambridgeshire, Nottingham and Newcastle, UK. PARTICIPANTS: A total of 1154 cognitively impaired participants, aged 65 years or older. EXPOSURES: Any use of antipsychotics, antidepressants, other anticholinergic medication, benzodiazepines or PPIs, polypharmacy (5-9) and hyperpolypharmacy (≥10 reported medications) were ascertained at baseline. Frailty was assessed using the Fried criteria. PRIMARY OUTCOME: Mortality up to 8 years follow-up. HRs associated with potentially inappropriate medication (PIM), frailty and their interaction were estimated adjusting for covariates. RESULTS: Within the sample, 44% were taking one or more PIM. Apart from antipsychotics (adjusted HR=3.24, 95% CI 1.83 to 5.73), use of specific PIM was not associated with greater subsequent mortality. Polypharmacy (HR=1.17, 95% CI 0.95 to 1.45) and hyperpolypharmacy were associated with mortality (HR=1.60, 95% CI 1.16 to 2.22). Being frail (HR=1.90, 95% CI 1.32 to 2.72) or prefrail (HR=1.56, 95% CI 1.10 to 2.20) was associated with increased mortality. There was some evidence that the HR for polypharmacy on mortality was lower among frailer individuals, but the overall polypharmacy by frailty interaction was not statistically significant (p=0.102). CONCLUSIONS: For those with cognitive impairment, greater concern should be afforded to the number of medications than the prescription of specific classes. Frailer individuals may have a lower relative risk of mortality associated with polypharmacy than less frail individuals

Роль корпоративной культуры в системе мотивации труда

OBJECTIVES: Multimorbidity is common in the older population, but the impact of combinations of chronic conditions on disability and quality of life (QoL) is not well known. This analysis explores the effect of specific combinations of chronic diseases on disability, QoL and self-rated health (SRH). DESIGN: We used data from two population representative cross-sectional studies, the Northern Ireland Health and Social Wellbeing Survey (NIHSWS) 2005 and the Survey of Lifestyle, Attitudes and Nutrition (SLAN) 2007 (conducted in the Republic of Ireland). SETTING: Randomly selected community-living participants were interviewed at home. PARTICIPANTS: A total of 6159 participants aged 50 years and older were included in the analysis. OUTCOME MEASURES: Chronic conditions were classified as cardiovascular disease, chronic pain, diabetes or respiratory disease. Interaction terms estimated by logistic regression were used to examine the effects of multiple chronic conditions on disability, SRH and QoL. RESULTS: Each chronic condition group was correlated with each of the others after adjusting for sociodemographic factors. Those from Northern Ireland were more likely to report a limitation in daily activities (45%) compared to those from the Republic of Ireland (21%). Each condition had an independent effect on disability, SRH and QoL, and those with multiple chronic conditions reported the worst outcomes. However, there were no statistically significant positive interactions between chronic condition groups with respect to any outcome. CONCLUSIONS: Chronic conditions affect individuals largely independent of each other with respect to their effect on disability, SRH and QoL. However, a significant proportion of the population aged 50 years and over across the island of Ireland lives with multimorbidity, and this group is at the highest risk of disability, poor SRH and poor QoL

Impaired Orthostatic Blood Pressure Recovery is associated with Unexplained and Injurious Falls

Background/Objectives: Cardiovascular disorders are recognised as important modifiable risk factors for falls. However the association between falls and orthostatic hypotension (OH) remains ambivalent, particularly because of poor measurement methods of previous studies. Our goal was to determine for the first time to what extent OH (and variants) are risk factors for incident falls, unexplained falls (UF), injurious falls (IF) and syncope using dynamic blood pressure (BP) measurements in a population study. Design: Nationally Representative Longitudinal Cohort Study - The Irish Longitudinal Study on Ageing (TILDA) – wave 1 (2009-2011) with 2 year follow-up at wave 2 (2012-2013). Setting: Community dwelling adults. Participants: 4127 participants were randomly sampled from the population of older adults aged ≥50 years resident in Ireland. Measurements: Continuous BP recordings measured during active stands were analysed. OH and variants (initial OH and impaired orthostatic BP stabilisation OH(40)) were defined using dynamic BP measurements. Associations with the number of falls, UF, IF and syncope reported two years later were assessed using negative binomial and modified Poisson regression. Results: Participants had a mean age 61.5(8.2) years (54.2% female). OH(40) was associated with increased relative risk of UF (RR:1.52 95%CI:1.03-2.26). OH was associated with all-cause falls (IRR:1.40 95%CI:1.01-1.96), UF(RR:1.81 95%CI:1.06-3.09), and IF(RR:1.58 95%CI:1.12-2.24). IOH was not associated with any outcome. Conclusion: With the exception of initial orthostatic hypotension, beat-to-beat measures of impaired orthostatic BP recovery (delayed or incomplete stabilisation) are independent risk factors for future falls, unexplained falls, and injurious falls

Undiagnosed dementia in primary care: A record linkage study

BackgroundThe number of people living with dementia is greater than the number with a diagnosis of dementia recorded in primary care. This suggests that a significant number are living with dementia that is undiagnosed. Little is known about this group and there is little quantitative evidence regarding the consequences of diagnosis for people with dementia.ObjectivesThe aims of this study were to (1) describe the population meeting the criteria for dementia but without diagnosis, (2) identify predictors of being diagnosed and (3) estimate the effect of diagnosis on mortality, move to residential care, social participation and well-being.DesignA record linkage study of a subsample of participants (n = 598) from the Cognitive Function and Ageing Study II (CFAS II) (n = 7796), an existing cohort study of the population of England aged ≥ 65 years, with standardised validated assessment of dementia and consent to access medical records.Data sourcesData on dementia diagnoses from each participant’s primary care record and covariate and outcome data from CFAS II.SettingA population-representative cohort of people aged ≥ 65 years from three regions of England between 2008 and 2011.ParticipantsA total of 598 CFAS II participants, which included all those with dementia who consented to medical record linkage (n = 449) and a stratified sample without dementia (n = 149).Main outcome measuresThe main outcome was presence of a diagnosis of dementia in each participant’s primary care record at the time of their CFAS II assessment(s). Other outcomes were date of death, cognitive performance scores, move to residential care, hospital stays and social participation.ResultsAmong people with dementia, the proportion with a diagnosis in primary care was 34% in 2008–11 and 44% in 2011–13. In both periods, a further 21% had a record of a concern or a referral but no diagnosis. The likelihood of having a recorded diagnosis increased with severity of impairment in memory and orientation, but not with other cognitive impairment. In multivariable analysis, those aged ≥ 90 years and those age

Functional and emotional outcomes after transient ischaemic attack: A 12-month prospective controlled cohort study

Background: Symptoms of transient ischemic attack are believed to fully resolve within 24 h of onset. Emerging evidence suggests that there may be prolonged functional and psychological impact, although studies have not been able to robustly identify whether these are the effect of transient ischemic attack or changes usually associated with ageing. We describe trajectories of disability and risk of anxiety and depression among patients seen at transient ischemic attack clinics over 12 months, compared to healthy controls. Methods: Thirty transient ischemic attack clinics across England participated. A total of 1320 participants were included: 373 diagnosed with transient ischemic attack, 186 with minor stroke, 310 with “possible transient ischemic attack,” 213 with another condition mimicking a transient ischemic attack and 238 controls recruited from primary care providers. Participants completed questionnaires after diagnosis then after 3, 6 and 12 months. Outcomes were the Nottingham Extended Activities of Daily Living Scale and the Hospital Anxiety and Depression Scale. Mixed effects regression was used to estimate group differences and trajectories. Results: At baseline, confirmed transient ischemic attack patients scored 1.31 HADS-Anxiety points (s.e. = 0.28; p < 0.001), 0.51 HADS-Depression points (s.e. = 0.26; p = 0.056), and 2.6 NEADL points (s.e. = 1.1; p = 0.020) worse than controls. At 12 months, the deficits were 0.78 (s.e. = 0.30; p = 0.008), 0.97 (s.e. = 0.23; p < 0.001), and 0.96 (s.e. = 0.92; p = 0.294) respectively. Differences among patients diagnosed with minor stroke were like or worse than transient ischemic attack patients. Conclusions: Transient ischemic attack clinic patients may have functional and emotional impairments compared to the general population irrespective of final diagnosis. The presence of emotional symptoms or risk of developing anxiety or depression did not always fully recover and may increase

What determines the self-rated health of older individuals with stroke compared to other older individuals? A cross-sectional analysis of the Medical Research Council Cognitive Function and Aging Study.

BACKGROUND: Poor self-rated health has been associated with poorer objective health outcomes across a range of conditions including stroke. Identification of factors associated with poor self-rated health in stroke survivors has received little attention compared to that in other older individuals. This study identifies determinants of self-rated health in older individuals with or without a history of stroke participating in the population-representative MRC Cognitive Function and Aging Study (MRC CFAS). METHODS: The MRC CFAS is a multicentred longitudinal survey of a population representative sample of people in their 65th year and older at baseline. Baseline interview included questions about functional disability, psychiatric history, independent living status, social interactions, and cognitive function. Multiple logistic regression was used to determine associations between demographic, physical, cognitive, psychological and social factors with poor self-rated health among those with and without stroke. RESULTS: After excluding those with impaired cognitive function, 776 individuals out of 11,957 reported a stroke. Factors associated with self-rated health were similar between those with or without a stroke in older individuals. Poorer self-rated health in those who had suffered a stroke was associated predominantly with the presence of comorbidity with diabetes (OR 3.5; 95% CI 1.5-8.1) and not "getting out and about" (OR 2.6; 95% CI 1.7-4.1) even after adjustment for disability levels and for depression. In those without a stroke the most important determinants were disability (OR 3.9; 95% CI 3.2-4.8) and not "getting out and about" (OR 2.9; 95% CI 2.5-3.3). The presence of disability was less strongly associated with poor self-rated health in those with a history of stroke than those without due to a substantially higher reporting of poor self-rated health in the non-disabled stroke group than the non-disabled stroke-free group, while those with disabilities reported poor self-rated health irrespective of stroke status. CONCLUSIONS: Self-rated health is determined by a range of psychological and social factors in addition to disability in older patients with stroke. Addressing social integration and mobility out of the home is an important element of rehabilitation for older people with stroke as well as those without

Incidence of necrotising enterocolitis before and after introducing routine prophylactic Lactobacillus and Bifidobacterium probiotics

Objective: To compare rates of necrotising enterocolitis (NEC), late-onset sepsis, and mortality in 5-year epochs before and after implementation of routine daily multistrain probiotics administration in high-risk neonates. Design: Single-centre retrospective observational study over the 10-year period from 1 January 2008 to 31 December 2017. Setting: Level 3 neonatal intensive care unit (NICU) of the Norfolk and Norwich University Hospital, UK. Patients: Preterm neonates at high risk of NEC: Admitted to NICU within 3 days of birth at <32 weeks' gestation or at 32-36 weeks' gestation and of birth weight <1500 g. Intervention: Prior to 1 January 2013 probiotics were not used. Thereafter, dual-species Lactobacillus acidophilus and Bifidobacterium bifidum combination probiotics were routinely administered daily to high-risk neonates; from April 2016 triple-species probiotics (L.acidophilus,B.bifidum, and B.longum subspecies infantis) were used. Main outcome measures: Incidence of NEC (modified Bell's stage 2a or greater), late-onset sepsis, and mortality. Results: Rates of NEC fell from 7.5% (35/469 neonates) in the pre-implementation epoch to 3.1% (16/513 neonates) in the routine probiotics epoch (adjusted sub-hazard ratio=0.44, 95% CI 0.23 to 0.85, p=0.014). The more than halving of NEC rates after probiotics introduction was independent of any measured covariates, including breast milk feeding rates. Cases of late-onset sepsis fell from 106/469 (22.6%) to 59/513 (11.5%) (p<0.0001), and there was no episode of sepsis due to Lactobacillus or Bifidobacterium. All-cause mortality also fell in the routine probiotics epoch, from 67/469 (14.3%) to 47/513 (9.2%), although this was not statistically significant after multivariable adjustment (adjusted sub-hazard ratio=0.74, 95% CI 0.49 to 1.12, p=0.155). Conclusions: Administration of multispecies Lactobacillus and Bifidobacterium probiotics has been associated with a significantly decreased risk of NEC and late-onset sepsis in our neonatal unit, and no safety issues. Our data are consistent with routine use of Lactobacillus and Bifidobacterium combination probiotics having a beneficial effect on NEC prevention in very preterm neonates

AlbaTraDIS:Comparative analysis of large datasets from parallel transposon mutagenesis experiments

Bacteria need to survive in a wide range of environments. Currently, there is an incomplete understanding of the genetic basis for mechanisms underpinning survival in stressful conditions, such as the presence of anti-microbials. Transposon directed insertion-site sequencing (TraDIS) is a powerful tool to identify genes and networks which are involved in survival and fitness under a given condition by simultaneously assaying the fitness of millions of mutants, thereby relating genotype to phenotype and contributing to an understanding of bacterial cell biology. A recent refinement of this approach allows the roles of essential genes in conditional stress survival to be inferred by altering their expression. These advancements combined with the rapidly falling costs of sequencing now allows comparisons between multiple experiments to identify commonalities in stress responses to different conditions. This capacity however poses a new challenge for analysis of multiple data sets in conjunction. To address this analysis need, we have developed 'AlbaTraDIS'; a software application for rapid large-scale comparative analysis of TraDIS experiments that predicts the impact of transposon insertions on nearby genes. AlbaTraDIS can identify genes which are up or down regulated, or inactivated, between multiple conditions, producing a filtered list of genes for further experimental validation as well as several accompanying data visualisations. We demonstrate the utility of our new approach by applying it to identify genes used by Escherichia coli to survive in a wide range of different concentrations of the biocide Triclosan. AlbaTraDIS identified all well characterised Triclosan resistance genes, including the primary target, fabI. A number of new loci were also implicated in Triclosan resistance and the predicted phenotypes for a selection of these were validated experimentally with results being consistent with predictions. AlbaTraDIS provides a simple and rapid method to analyse multiple transposon mutagenesis data sets allowing this technology to be used at large scale. To our knowledge this is the only tool currently available that can perform these tasks. AlbaTraDIS is written in Python 3 and is available under the open source licence GNU GPL 3 from https://github.com/quadram-institute-bioscience/albatradis

Meta-analysis of the Parkinson’s disease gut microbiome suggests alterations linked to intestinal inflammation

The gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson’s disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients

Loss of microbial diversity and pathogen domination of the gut microbiota in critically ill patients

Among long-stay critically ill patients in the adult intensive care unit (ICU), there are often marked changes in the complexity of the gut microbiota. However, it remains unclear whether such patients might benefit from enhanced surveillance or from interventions targeting the gut microbiota or the pathogens therein. We therefore undertook a prospective observational study of 24 ICU patients, in which serial faecal samples were subjected to shotgun metagenomic sequencing, phylogenetic profiling and microbial genome analyses. Two-thirds of the patients experienced a marked drop in gut microbial diversity (to an inverse Simpson's index of <4) at some stage during their stay in the ICU, often accompanied by the absence or loss of potentially beneficial bacteria. Intravenous administration of the broad-spectrum antimicrobial agent meropenem was significantly associated with loss of gut microbial diversity, but the administration of other antibiotics, including piperacillin/tazobactam, failed to trigger statistically detectable changes in microbial diversity. In three-quarters of ICU patients, we documented episodes of gut domination by pathogenic strains, with evidence of cryptic nosocomial transmission of Enterococcus faecium. In some patients, we also saw an increase in the relative abundance of apparent commensal organisms in the gut microbiome, including the archaeal species Methanobrevibacter smithii. In conclusion, we have documented a dramatic absence of microbial diversity and pathogen domination of the gut microbiota in a high proportion of critically ill patients using shotgun metagenomics