A systematic review of the clinical impact of small colony variants in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a life-limiting disorder that is characterised by respiratory tract inflammation that is mediated by a range of microbial pathogens. Small colony variants (SCVs) of common respiratory pathogens are being increasingly recognised in CF. The aim of this systematic review is to investigate the prevalence of SCVs, clinical characteristics and health outcomes for patients with CF, and laboratory diagnostic features of SCVs compared to non-small colony variants (NCVs) for a range of Gram-positive and Gram-negative respiratory pathogens. METHODS: A literature search was conducted (PubMed, Web of Science, Embase and Scopus) in April 2020 to identify articles of interest. Data pertaining to demographic characteristics of participants, diagnostic criteria of SCVs, SCV prevalence and impact on lung function were extracted from included studies for analysis. RESULTS: Twenty-five of 673 studies were included in the systematic review. Individuals infected with SCVs of Staphylococcus aureus (S. aureus) were more likely to have had prior use of the broad-spectrum antibiotic trimethoprim sulfamethoxazole (p < 0.001), and the prevalence of SCVs in patients infected with S. aureus was estimated to be 19.3% (95% CI: 13.5% to 25.9%). Additionally, patients infected with SCVs of Gram-negative and Gram-positive pathogens were identified to have a lower forced expiratory volume in one second percentage predicted (-16.8, 95% CI: -23.2 to -10.4) than those infected by NCVs. Gram-positive SCVs were commonly described as small and non-haemolytic, grown on Mannitol salt or blood agar for 24 h at 35°C and confirmed using tube coagulase testing. CONCLUSION: The findings of this systematic review demonstrate that SCVs of S. aureus have a high prevalence in the CF community, and that the occurrence of SCVs in Gram-positive and Gram-negative pathogens is linked to poorer respiratory function. Further investigation is necessary to determine the effect of infection by SCVs on the CF population.

MicroRNAs control the apoptotic threshold in primed pluripotent stem cells through regulation of BIM.

Mammalian primed pluripotent stem cells have been shown to be highly susceptible to cell death stimuli due to their low apoptotic threshold, but how this threshold is regulated remains largely unknown. Here we identify microRNA (miRNA)-mediated regulation as a key mechanism controlling apoptosis in the post-implantation epiblast. Moreover, we found that three miRNA families, miR-20, miR-92, and miR-302, control the mitochondrial apoptotic machinery by fine-tuning the levels of expression of the proapoptotic protein BIM. These families therefore represent an essential buffer needed to maintain cell survival in stem cells that are primed for not only differentiation but also cell death.

Exceptional longevity in a lightly exploited, semi-anadromous clupeid (Perth herring Nematalosa vlaminghi) within a degraded estuarine environment.

Many anadromous (and semi-anadromous) fish species, which migrate from marine to freshwater ecosystems to spawn and to complete their life cycle, are currently threatened by habitat degradation in the upper parts of estuaries and rivers, where spawning and juvenile nursery areas occur. This situation pertains to Nematalosa vlaminghi, a semi-anadromous gizzard shad (Clupeidae: Dorosomatinae) endemic to south-western Australia. More information on the biology of N. vlaminghi is required for its effective management and conservation. This study estimated growth, longevity and natural mortality of N. vlaminghi. Ages were determined by counting validated annual growth increments in thin sections of sagittal otoliths. Fish were sampled in the Swan-Canning Estuary, which historically hosted the main commercial fishery for N. vlaminghi. Since the late 1990s, however, only very minor catches of this species have been taken from this estuary and none since 2007. Given the essentially unexploited state of the current population, the estimate of total mortality (Z, y-1 ) from the catch curve analysis in this study provides a direct estimate of natural mortality (M, y-1 ) for N. vlaminghi. Somatic growth during this study was substantially slower than that historically reported for N. vlaminghi. Various processes operating in this estuary since the 1970s may have contributed to slower growth, including increased hypoxia, higher primary productivity due to eutrophication and cessation of fishing for N. vlaminghi. The maximum observed age of 19.8 years for N. vlaminghi is the highest reported for any gizzard shad globally and one of the highest reported for any clupeid species. This exceptional longevity is likely part of a life-history strategy that allows N. vlaminghi, which exhibits substantial variation in annual recruitment success, to persist in the intermittently closed estuaries of south-western Australia where environmental factors, including low flow and hypoxia, can create unfavourable conditions for reproduction for extended periods.

Incidence of falls among adults with cerebral palsy: a cohort study using primary care data.

AIM: To compare the rate of falls between adults with and without cerebral palsy (CP). METHOD: We used primary care data on 1705 adults with CP and 5115 adults without CP matched for age, sex, and general practice attended. We compared odds of experiencing a fall between adults with and without CP using conditional logistic regression. We compared the rate of falls using a negative binomial model. RESULTS: Participants were 3628 males (53%) and 3192 females (47%) (median age 29y, interquartile range 20-42y) at the start of follow-up. Follow-up was 14 617 person-years for adults with CP and 56 816 person-years for adults without CP. Of adults with CP, 15.3% experienced at least one fall compared to 5.7% of adults without CP. Adults with CP had 3.64 times (95% confidence interval [CI] 2.98-4.45) the odds of experiencing a fall compared to adults without CP. The rate of falls was 30.5 per 1000 person-years and 6.7 per 1000 person-years for adults with and without CP respectively (rate ratio 5.83, 95% CI 4.84-7.02) INTERPRETATION: Adults with CP are more likely to fall, and fall more often, than adults without CP. The causes and consequences of falls in adults with CP need examination. WHAT THIS PAPER ADDS: Twenty adults with CP and 5.3 adults without CP experienced at least one fall per 1000 person-years. Adults with CP experienced 30.5 falls per 1000 person-years compared to 6.7 falls per 1000 person-years among adults without CP. Adults with CP had 3.64 times the odds of experiencing a fall compared to adults without CP. Adults with CP experienced 5.83 times more falls than adults without CP.

Modeling tails for collinear data with outliers in the English Longitudinal Study of Ageing: Quantile profile regression.

Research has shown that high blood glucose levels are important predictors of incident diabetes. However, they are also strongly associated with other cardiometabolic risk factors such as high blood pressure, adiposity, and cholesterol, which are also highly correlated with one another. The aim of this analysis was to ascertain how these highly correlated cardiometabolic risk factors might be associated with high levels of blood glucose in older adults aged 50 or older from wave 2 of the English Longitudinal Study of Ageing (ELSA). Due to the high collinearity of predictor variables and our interest in extreme values of blood glucose we proposed a new method, called quantile profile regression, to answer this question. Profile regression, a Bayesian nonparametric model for clustering responses and covariates simultaneously, is a powerful tool to model the relationship between a response variable and covariates, but the standard approach of using a mixture of Gaussian distributions for the response model will not identify the underlying clusters correctly, particularly with outliers in the data or heavy tail distribution of the response. Therefore, we propose quantile profile regression to model the response variable with an asymmetric Laplace distribution, allowing us to model more accurately clusters that are asymmetric and predict more accurately for extreme values of the response variable and/or outliers. Our new method performs more accurately in simulations when compared to Normal profile regression approach as well as robustly when outliers are present in the data. We conclude with an analysis of the ELSA.

Risk of dementia associated with cardiometabolic abnormalities and depressive symptoms: a longitudinal cohort study using the English longitudinal study of ageing.

OBJECTIVES: Depression and cardiometabolic abnormalities are independently associated with a high risk of dementia. This study aimed to examine the association of comorbid depressive symptoms and cardiometabolic abnormalities with risk of dementia. METHODS: The sample comprised 4859 participants aged 50 or older without baseline dementia who took part in the English Longitudinal Study of Ageing (waves 2-7). Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression tool. Cardiometabolic abnormalities were defined as three or more cardiometabolic risk factors (inflammation, central obesity, raised triglycerides, low high-density lipoprotein [HDL] cholesterol, hypertension, and hyperglycaemia or diabetes). Participants were classified into four groups based on presence of depressive symptoms and cardiometabolic abnormalities. Results were analysed using the Cox proportional hazards regression adjusted for covariates. RESULTS: A total of 216 cases of incident dementia were reported over 10 years of follow-up. The group with high depressive symptoms only had an increased hazard of developing incident dementia during follow-up (HR = 2.68; 95%CI, 1.70-4.23), which was attenuated after adjustment for baseline cognition. No evidence was found for an association of overall cardiometabolic abnormalities with incident dementia; though hyperglycaemia, hypertension, and abdominal obesity with depressive symptoms had an unadjusted association with incident dementia. Only low-HDL cholesterol with depressive symptoms had an adjusted association with incident dementia (HR = 0.18; 95%CI, 0.04-0.75). CONCLUSIONS: This work confirms depressive symptoms as a risk factor for incident dementia. However, low HDL-cholesterol with depressive symptoms may be protective against dementia, though more work is required to confirm this association.

Mortality due to cardiovascular disease, respiratory disease, and cancer in adults with cerebral palsy.

AIM: To compare mortality rates for cardiovascular disease, cancer, and respiratory disease between adults with cerebral palsy (CP) and the general population. METHOD: A cohort study was conducted using data from adults with CP in England, identified through a primary care data set (the Clinical Practice Research Datalink), with linked data on death registrations from the Office for National Statistics. Cause of death was categorized according to International Classification of Diseases codes. Standardized mortality ratios (SMRs) were calculated to compare mortality rates between adults with CP and the general population, adjusted for age, sex, and calendar year. RESULTS: Nine hundred and fifty-eight adults with CP were identified (52.5% males, 47.5% females; median age at start of follow-up 31y [interquartile range 22-43y]) and followed for a total of 7693 person-years. One hundred and forty-two patients (15%) died during follow-up. Adults with CP had an increased risk of death due to cardiovascular disease (SMR: 3.19, 95% confidence interval [CI] 2.20-4.62) and respiratory disease (SMR: 13.59, 95% CI 9.89-18.67), but not from malignant neoplasms (SMR: 1.42, 95% CI 0.83-2.45). INTERPRETATION: We found that adults with CP in England have increased risk of death due to diseases of the circulatory and respiratory systems, supporting findings from two studies that compared cause-specific mortality rates between adults with CP in the USA and the general population. Further research is required into primary and secondary prevention of cardiovascular and respiratory disease in people with CP worldwide. WHAT THIS PAPER ADDS: Adults with cerebral palsy (CP) in England have 14-fold increased risk of mortality due to diseases of the respiratory system. They have a 3-fold increased risk of mortality due to diseases of the circulatory system. Adults with CP had an increased risk of death due to cerebrovascular disease and ischaemic heart disease. The elevated risk of ischaemic heart disease, however, did not reach statistical significance at the 5% per cent level.

MORTALIDAD POR ENFERMEDAD CARDIOVASCULAR, ENFERMEDAD RESPIRATORIA Y CÁNCER EN ADULTOS CON PARÁLISIS CEREBRAL: OBJETIVO: Comparar tasas de mortalidad por enfermedad cardiovascular, cáncer y enfermedad respiratoria entre adultos con parálisis cerebral (PC) y la población general. MÉTODO: Se llevó a cabo un estudio de cohorte utilizando datos de adultos con PC en Inglaterra, identificados a través de un set de datos de atención primaria (the Clinical Practice Research Datalink) con datos vinculados sobre los registros de defunciones de la Oficina Nacional de Estadísticas. Las causas de muertes fueron categorizadas de acuerdo con los códigos de la Clasificación Internacional de Enfermedades. Las tasas de mortalidad estandarizadas (TME) fueron calculadas a fin de comparar las tasas de mortalidad entre adultos con PC y la población general, ajustadas por edad, sexo y año calendario. RESULTADOS: Se identificaron 958 adultos con PC (52,5% varones, 47,5% mujeres; edad mediana al comienzo del seguimiento 31 años [rango intercuartilo 22-43 años] y fueron seguidos por un total de 7.693 años-persona. Ciento cuarenta y dos pacientes (15%) fallecieron durante el seguimiento. Los adultos con PC tuvieron un mayor riesgo de muerte por enfermedad cardiovascular (TME:3,19, 95% intervalo de confidencia [IC] 2,20-4,62) y enfermedad respiratoria (TME:13,59,95% IC 9,89-18,67), pero no tuvieron mayor riesgo de neoplasias malignas (TME:1,42, 95% IC 0,83-2,45). INTERPRETACIÓN: Encontramos que los adultos con PC en Inglaterra tienen un riesgo incrementado de muerte por enfermedades de los sistemas circulatorio y respiratorio, sosteniendo los hallazgos con dos estudios que compararon tasas de mortalidad causa-específicas entre adultos con PC en los EEUU y la población general. Se necesita avanzar con la investigación hacia prevención primaria y secundaria de enfermedades cardiovascular y respiratoria en personas con PC en todo el mundo.

MORTALIDADE DEVIDO A DOENÇA CARDIOVASCULAR, RESPIRATÓRIA, E CÂNCER EM ADULTOS COM PARALISIA CEREBRAL: OBJETIVO: Comparar as taxas de mortalidade por doença cardiovascular, câncer, e doença respiratória em adultos com paralisia cerebral (PC) e a população em geral. MÉTODO: Um estudo de coorte foi realizado usando dados de adultos com PC na Inglaterra, identificados por meio de um conjunto de dados de atenção primária (o Datalink Pesquisa em Prática Clínica,), com dados sobre registros de óbitos do Escritório Nacional de Estatística. A causa da morte foi categorizada de acordo com os códigos da Classificação Internacional de Doenças. Taxas de mortalidade padronizadas (TMPs) foram calculadas para comparar as taxas de mortalidade entre adultos com PC e a população em geral, ajustadas por idade, sexo e ano calendário. RESULTADOS: Novecentos e cinquenta e oito adultos com PC foram identificados (52,5% do sexo masculino, 47,5% do sexo feminino; idade mediana no início do acompanhamento 31a [intervalo interquartil 22-43a]) e acompanhados por um total de 7,693 anos-pessoa. Cento e quarenta e dois pacientes (15%) morreram durante o acompanhamento. Adultos com PC tiveram risco aumentado de morte por doença (TMP: 3,19, intervalo de confiança [IC] a 95% 2,20-4,62) e doença respiratória (TMP: 13,59, IC 95% 9,89-18,67), mas não por neoplasias malignas (TMP: 1,42, IC 95% 0,83-2,45). INTERPRETAÇÃO: Observamos que adultos com PC na Inglaterra têm risco aumentado de more por doenças dos sistemas circulatório e respiratório, o que apóia achados de dois estudos qu compararam taxas de mortalidade causa-específica em adultos com PC nos EUA e na população em geral. Mais pesquisas são necessárias sobre a prevenção primária e secundária de doenças cardiovasculares e respiratórias em pessoas com PC em todo o mundo.

Evaluating lifestyle and health-related characteristics of older adults with co-occurring depressive symptoms and cardiometabolic abnormalities.

OBJECTIVE: Comorbid depression and cardiometabolic abnormalities might represent an important subgroup of depression. The aim of the present study was to evaluate lifestyle and health-related characteristics of individuals with both depressive symptoms and cardiometabolic abnormalities. METHODS: Data were from the English Longitudinal Study of Ageing. The sample was comprised of 5365 adults aged 50-80 years. High depressive symptoms were based on the eight-item Center for Epidemiologic Studies - Depression scale. Cardiometabolic abnormalities were defined as having ≥3 cardiometabolic risk factors (hypertension, impaired glycemic control, systemic inflammation, low high-density lipoprotein cholesterol, hypertriglyceridemia, and central obesity). Four groups were created based on Center for Epidemiologic Studies - Depression scores and cardiometabolic abnormalities: those with (i) comorbid depressive symptoms and cardiometabolic abnormalities (DCM); (ii) depressive symptoms only (DnoCM); (iii) cardiometabolic abnormalities only; and (iv) neither depressive symptoms nor cardiometabolic abnormalities. Lifestyle and health-related characteristics of the four groups were compared using chi-square tests. A modified Poisson regression analysis was performed to compare the DCM and the DnoCM groups with respect to lifestyle and health-related characteristics. RESULTS: Those in the DCM group were significantly less physically active (p = 0.003), had poorer self-rated health (p < 0.001), had lower income (p = 0.001), and were more likely to be retired (p < 0.001) than those in the DnoCM group. The pattern of results remained after controlling for other lifestyle and health-related factors. CONCLUSION: These results provide support for a cardiometabolic subgroup of depression that is associated with physical inactivity, poorer self-rated health, lower income, and retirement. Copyright © 2015 John Wiley & Sons, Ltd.

The longitudinal associations between C-reactive protein and depressive symptoms: evidence from the English Longitudinal Study of Ageing (ELSA).

OBJECTIVES: The inflammatory marker C-reactive protein (CRP) is associated with depression. We examined the directional relations between CRP and symptoms of depression among older adults. METHOD: The sample consisted of 3397 participants from the English Longitudinal Study of Ageing, a prospective study of community-dwelling older adults. CRP and depressive symptoms were measured at baseline and follow-up. A high CRP level was dichotomized as >3 mg/L. Elevated depressive symptomatology was defined as ≥4 using the 8-item Center for Epidemiologic Studies Depression Scale. Logistic regressions computed the association between high CRP levels at baseline with elevated depressive symptoms at follow-up, and vice versa. RESULTS: After adjusting for baseline depressive symptoms, baseline high CRP levels were associated with subsequent elevated symptoms of depression (OR = 1.49; 95% CI, 1.19-1.88). This relationship was no longer significant after simultaneous adjustments for metabolic and health variables. In the other direction, after adjusting for baseline CRP levels, baseline elevated depressive symptoms was not associated with subsequent high CRP levels (OR = 1.12; 95% CI, 0.88-1.42). CONCLUSION: High CRP levels at baseline are related to elevated depressive symptomatology at follow-up due to clinical factors. No association was found in the opposite direction.

Pharmaceutical Opioid Use and Dependence among People Living with Chronic Pain: Associations Observed within the Pain and Opioids in Treatment (POINT) Cohort.

OBJECTIVE: There is increasing concern about the appropriateness of prescribing pharmaceutical opioids for chronic non-cancer pain (CNCP), given the risks of problematic use and dependence. This article examines pharmaceutical opioid dose and dependence and examines the correlates of each. DESIGN: Baseline data were obtained from a national sample of 1,424 people across Australia (median 58 years, 55% female and experiencing pain for a median of 10 years), who had been prescribed opioids for CNCP. Current opioid consumption was estimated in oral morphine equivalent (OME; mg per day), and ICD-10 pharmaceutical opioid dependence was assessed using the Composite International Diagnostic Interview. RESULTS: Current opioid consumption varied widely: 8.8% were taking <20 mg OME per day, 52.1% were taking 21-90 mg OME, 24.3% were taking 91-199 mg OME, and 14.8% were taking >= 200 mg OME. Greater daily OME consumption was associated with higher odds of multiple physical and mental health issues, aberrant opioid use, problems associated with opioid medication and opioid dependence. A significant minority, 8.5%, met criteria for lifetime ICD-10 pharmaceutical opioid dependence and 4.7% met criteria for past year ICD-10 pharmaceutical opioid dependence. Multivariate analysis found past-year dependence was independently associated with being younger, exhibiting more aberrant behaviors and having a history of benzodiazepine dependence. CONCLUSIONS: In this population of people taking opioids for CNCP, consumption of higher doses was associated with increased risk of problematic behaviors, and was more likely among people with a complex profile of physical and mental health problems.

Longitudinal relationships between depression and functioning in people with type 2 diabetes.

BACKGROUND: The reciprocal relationship between depression and functioning in people with chronic conditions is poorly understood. PURPOSE: The aim of the present study was to analyze the dynamic relationship between depression and functioning in a community sample of people with diabetes. METHODS: Participants with diabetes were assessed at baseline and three yearly follow-up assessments (n = 1,403). Depression was assessed using the Patient Health Questionnaire. Global functioning was assessed using the World Health Organization Disability Assessment Schedule II. RESULTS: Path analysis suggested a reciprocal relationship between depression and functioning. Baseline depression was associated with functioning at 3 years follow-up through depression and functioning at 1 and 2 years follow-up assessments. CONCLUSIONS: Depression and functioning might interact with each other in a dynamic way: depression at one assessment point might predict poor functioning at the next assessment point, which in turn might predict depression at the next assessment point. This should be taken into account in both treatment and research programs.

Association of depression and anxiety symptoms with functional disability and disability days in a community sample with type 2 diabetes.

BACKGROUND: There is a well-documented association between depression and disability in people with diabetes. However, less is known about the possible association of co-occurring anxiety on these associations. OBJECTIVE: The objective of this study was to assess the association of elevated anxiety or depression symptoms or both with functional disability and frequent disability days in a community sample with type 2 diabetes. METHODS: The participants were 1999 people with diabetes who completed the baseline portion of the Evaluation of Diabetes Treatment study. Functional disability was assessed using the World Health Organization Disability Assessment Schedule II. Frequent disability days were assessed using a cutoff score ≥14 on a question assessing functional disability in the past month from the Healthy Days Core Module. Depression and anxiety were assessed with the Patient Health Questionnaire and General Anxiety Questionnaire with cutoff scores ≥10 applied to create groups. Additional questions examined diabetes complications, chronic conditions, and sociodemographic characteristics. RESULTS: Fully adjusted logistic regression analyses demonstrated an increased likelihood of reporting functional disability for all groups with high anxiety or depressive symptoms or both. Groups with high depressive symptoms with and without high anxiety symptoms were also more likely to report frequent disability days. CONCLUSIONS: Results indicate that elevated anxiety and depression symptoms are important factors associated with increased functional disability and frequent disability days in people with diabetes.

Global analysis of the regulon of the transcriptional repressor LexA, a key component of SOS response in Mycobacterium tuberculosis.

The DNA damage response is crucial for bacterial survival. The transcriptional repressor LexA is a key component of the SOS response, the main mechanism for the regulation of DNA repair genes in many bacteria. In contrast, in mycobacteria gene induction by DNA damage is carried out by two mechanisms; a relatively small number of genes are thought to be regulated by LexA, and a larger number by an alternate, independent mechanism. In this study we have used ChIP-seq analysis to identify 25 in vivo LexA-binding sites, including nine regulating genes not previously known to be part of this regulon. Some of these binding sites were found to be internal to the predicted open reading frame of the gene they are thought to regulate; experimental analysis has confirmed that these LexA-binding sites regulate the expression of the expected genes, and transcriptional start site analysis has found that their apparent relative location is due to misannotation of these genes. We have also identified novel binding sites for LexA in the promoters of genes that show no apparent DNA damage induction, show positive regulation by LexA, and those encoding small RNAs.

Exploring the association of psychological status with self-rated diabetes control: results from the Montreal evaluation of diabetes treatment study.

AIMS: There is an increasing interest in single-item self-rated indicators of perceived health and control status in people with chronic illnesses such as diabetes. However, self-rated measures can be associated with indicators of psychological status. The aim of this paper is to explore the association of anxiety, depression, and diabetes distress with self-rated diabetes control. METHODS: Telephone interviews were conducted with 1,787 people with type 2 diabetes taking oral hypoglycemic medication. Diabetes control, health behaviors, and outcomes, anxiety, depression, and diabetes distress were assessed by standardized questionnaires. Self-reported diabetes control was modeled using logistic regression. RESULTS: The best fit logistic regression model for self-rated poor diabetes control was a model that incorporated diabetes distress. When adjusted for age, sex, and all other health behaviors and outcomes, poor diabetes control was most associated with diabetes distress, physical inactivity, being overweight, and poor eating habits. CONCLUSIONS: Results from this study indicate that poor self-rated diabetes control shares the strongest associations with diabetes-specific distress along with perceptions of diabetes-specific healthcare behaviors and outcomes.

"It's Still in the Test Tube and Finding out How the Experiment Ends ". A Qualitative Study on Health and Aging in Older Gay Males Living with HIV in England.

This paper highlights experiences and perceptions of older gay males living with Human Immunodeficiency Virus (HIV) in relation to age, sexual orientation, HIV status and how they perceive health. Participants were gay males aged 50 and over living in England, diagnosed with HIV for longer than 2 years. In total, 19 interviews were conducted between March 2020 and March 2021. Data were analysed using thematic analysis. Three major themes were generated: 1.) Health as holistic and as a balance; 2.) The impact of HIV on people's lives; 3.) The Intersectionality of stigma: a lifetime of discrimination. Participants highlighted the changing nature of the concept of health through their lifespan while the intersectionality of stigma in different contexts is examined considering the personal journey of living with HIV. The implications of health as a complex concept and intersectional stigma on the planning and delivering of care in this population are discussed.

Clustering of Cardiometabolic Risk Factors and Dementia Incidence in Older Adults: A Cross-Country Comparison in England, the United States, and China.

BACKGROUND: There is mixed evidence for an association between cardiometabolic risk factors and dementia incidence. This study aimed to determine whether different latent classes of cardiometabolic conditions were associated with dementia risk in older adults across England, the United States, and China. METHODS: A total of 4 511 participants aged 50 and older were drawn from the English Longitudinal Study of Ageing (ELSA), 5 112 from Health and Retirement Study (HRS), and 9 022 from China Health and Retirement Longitudinal Study (CHARLS). Latent class analyses were performed across each data set utilizing 7 baseline cardiometabolic conditions: obesity, low high-density lipoprotein cholesterol, systolic and diastolic blood pressure, hyperglycemia, diabetes, and inflammation. Confounder-adjusted Cox proportional hazards regressions were conducted to estimate dementia incidence by cardiometabolic latent classes. RESULTS: Three similar cardiometabolic classes were identified across all countries: (i) "relatively healthy/healthy obesity," (ii) "obesity-hypertension," and (iii) "complex cardiometabolic." Across the 3 samples, a total of 1 230 individuals developed dementia over a median of 6.8-12.2 years. Among ELSA and HRS participants, the "complex cardiometabolic" group had a higher dementia risk when compared to the "healthy obesity" groups (England: adjusted hazard ratio [AdjHR] = 1.62 [95% confidence interval {CI} = 1.11-2.37]; United States: AdjHR = 1.31 [95% CI = 1.02-1.68]). However, in CHARLS participants, the "obesity-hypertension" group had a greater risk of dementia when compared to the "relatively healthy" group (AdjHR = 1.28 [95% CI = 1.04-1.57]). CONCLUSION: This study provides evidence that in western populations, complex cardiometabolic clusters are associated with higher rates of dementia incidence, whereas in a Chinese sample, a different cardiometabolic profile seems to be linked to an increased risk of dementia.

The combined effect of socioeconomic position and C-reactive protein for predicting incident cardiometabolic disease: Findings from a 14-year follow-up study of the English Longitudinal Study of Ageing (ELSA).

Cardiovascular disease and diabetes are leading causes of morbidity and mortality worldwide. Social inequalities in the distribution of these diseases across the population exist. The aim of the current study was to examine the additive effect of socioeconomic position and a known biological risk marker (C-reactive protein [CRP]) for future incident cardiometabolic disease. We used data from the English Longitudinal Study of Ageing (N = 5410). Tertiles of net financial wealth and CRP (>3 mg/L) were measured at wave 2 (2004/05) and disease incidence (coronary heart disease [CHD], stroke, diabetes/high blood glucose) was reported across the subsequent 14 years of follow-up (2006-2019). Individual diseases were modelled as well as cardiometabolic multimorbidity which was defined as 2 or more incident cardiometabolic disease diagnoses over follow-up. Participants were free from the disease of interest at baseline. Cox proportional hazard and logistic regression analyses were used controlling for sociodemographic, lifestyle and health-related covariates. After adjusting for all covariates, the combination of low wealth and elevated CRP was an independent predictor of incident diabetes/high blood glucose (Hazard Ratio (HR) = 2.14; 95% Confidence Interval (C.I.) = 1.49-3.07), CHD (HR = 2.48, 95% C.I. = 1.63-3.76), stroke (HR = 1.55; 95% C.I. = 1.18-2.04), relative to high wealth/low CRP. Low wealth and elevated CRP was also an independent predictor of incident cardiometabolic multimorbidity (Odds Ratio = 2.22, 95% C.I. = 1.16-4.28) in age and sex adjusted models. The presence of both low wealth and elevated CRP was implicated in the onset of CHD, stroke, diabetes/high blood glucose, and cardiometabolic multimorbidity up to 14 years later, reflecting the role of psychobiological processes in predicting disease burden. Our results reinforce calls for efforts to tackle structural inequalities to improve healthy ageing trajectories.

The Association of Loneliness With Health and Social Care Utilization in Older Adults in the General Population: A Systematic Review.

BACKGROUND AND OBJECTIVES: Loneliness is proposed to be linked with increased service use. This review examined the association of loneliness and health and social care utilization (HSCU) in older adults from the general population. RESEARCH DESIGN AND METHODS: Four databases were screened for studies that examined the association of loneliness (predictor) with HSCU (outcome) in older adults (defined as the majority of sample 60 or older). Study quality was assessed with the National Institutes for Health scale for observational cohorts and cross-sectional studies. RESULTS: We identified 32 studies, of which 9 prospective studies were evaluated as being good or good-fair quality. Two good-fair quality studies found that loneliness at baseline was associated with subsequent admission to a residential care home. There was emerging evidence that loneliness was associated with emergency department use (n = 1) and cardiovascular disease-specific hospitalization (n = 1). Once adjusted for confounders, the highest quality studies found no association of baseline loneliness with physician utilization, outpatient service utilization, skilled nursing facility use, and planned or unplanned hospital admissions. The remaining studies were cross-sectional, or of fair to poor quality, and inadequate to reliably determine whether loneliness was associated with a subsequent change in HSCU. DISCUSSION AND IMPLICATIONS: There was heterogeneity in study design, measurement, and study quality. This generated an inconsistent evidence base where we cannot determine clear inferences about the relationship between loneliness and HSCU. Only one consistent finding was observed between 2 good-fair quality studies regarding care home admission. To determine clinical implications and make reliable inferences, additional good quality longitudinal research is needed.

Risk of dementia in adults with cerebral palsy: a matched cohort study using general practice data.

OBJECTIVES: Determine the risk of incident dementia in adults with cerebral palsy (CP) compared with age, sex and general practice (GP) matched controls. DESIGN: Retrospective cohort study. SETTING: UK GPs linked into the Clinical Practice Research Datalink (CPRD). PARTICIPANTS: CPRD data were used to identify adults aged 18 or older with a diagnosis of CP. Each adult with CP was matched to three controls who were matched for age, sex and GP. In total, 1703 adults with CP and 5109 matched controls were included in the analysis. The mean baseline age of participants was 33.30 years (SD: 15.48 years) and 46.8% of the sample were female. PRIMARY OUTCOME: New diagnosis of dementia during the follow-up period (earliest date of 1987 to latest date of 2015). RESULTS: During the follow-up, 72 people were identified with a new diagnosis of dementia. The overall proportion of people with and without CP who developed dementia was similar (CP: n=19, 1.1%; matched controls n=54, 10.0%). The unadjusted HR suggested that people with CP had an increased hazard of being diagnosed with dementia when compared with matched controls (HR 2.69, 95% CI 1.44 to 5.00). This association was attenuated when CP comorbidities (sensory impairment, intellectual disability and epilepsy) were accounted for (HR 1.92, 95% CI 0.92 to 4.02). CONCLUSIONS: There was no difference in the proportion of people with CP and matched controls who were diagnosed with dementia during the follow-up. Furthermore, while there was evidence for an increased hazard of dementia among people with CP, the fact that this association was attenuated after controlling for comorbidities indicates that this association may be explained by comorbidities rather than being a direct result of CP. Findings should be interpreted with caution due to the low number of incident cases of dementia.

Effect of Crizanlizumab, a P-Selectin Inhibitor, in COVID-19: A Placebo-Controlled, Randomized Trial.

COVID-19 is characterized by vascular inflammation and thrombosis, including elevations in P-selectin, a mediator of inflammation released by endothelial cells. We tested the effect of P-selectin inhibition on biomarkers of thrombosis and inflammation in patients with COVID-19. Hospitalized patients with moderate COVID-19 were randomly assigned to receive either placebo or crizanlizumab, a P-selectin inhibitor, in a double-blind fashion. Crizanlizumab reduced P-selectin levels by 89%. Crizanlizumab increased D-dimer levels by 77% and decreased prothrombin fragment. There were no significant differences between crizanlizumab and placebo for clinical endpoints. Crizanlizumab was well tolerated. Crizanlizumab may induce thrombolysis in the setting of COVID-19. (Crizanlizumab for Treating COVID-19 Vasculopathy [CRITICAL]; NCT04435184).