Relationship between antihypertensive medications and cognitive impairment: Part I. review of human studies and clinical trials

Purpose of review: There is an established association between hypertension and increased risk of poor cognitive performance and dementia including Alzheimer’s disease; however, associations between antihypertensive medications (AHMs) and dementia risk are less consistent. An increased interest in AHM has resulted in expanding publications; however, none of the recent reviews are comprehensive. Our extensive review includes 15 observational and randomized controlled trials (RCTs) published over the last 5 years, assessing the relationship between AHM and cognitive impairment. Recent findings: All classes of AHM showed similar result patterns in human studies with the majority of study results reporting point estimates below one and only a small number of studies (N = 15) reporting statistically significant results in favor of a specific class. Summary: Only a small number of studies reported statistically significant results in favor of a specific class of AHM. Methodological limitations of the studies prevent definitive conclusions. Further work is now needed to evaluate the class of AHM and cognitive outcomes in future RCTs, with a particular focus on the drugs with the promising results in both animals and human observational studies

The Effect of Diabetes Medication on Cognitive Function: Evidence from the PATH Through Life Study

Objective. To examine the effect of diabetes treatment on change of measures of specific cognitive domains over 4 years. Research Design and Methods. The sample was drawn from a population-based cohort study in Australia (the PATH Through Life Study) and comprised 1814 individuals aged 65-69 years at first measurement, of whom 211 were diagnosed with diabetes. Cognitive function was measured using 10 neuropsychological tests. The effect of type of diabetes treatment (diet, oral hypoglycemic agents, and insulin) on measures of specific cognitive domains was assessed using Generalized Linear Models adjusted for age, sex, education, smoking, physical activity level, BMI, and hypertension. Results. Comparison of cognitive function between diabetes treatment groups showed no significant effect of type of pharmacological treatment on cognitive function compared to diet only group or no diabetes group. Of those on oral hypoglycaemic treatment only, participants who used metformin alone had better cognitive function at baseline for the domains of verbal learning, working memory, and executive function compared to participants on other forms of diabetic treatment. Conclusion. This study did not observe significant effect from type of pharmacological treatment for diabetes on cognitive function except that participants who only used metformin showed significant protective effect from metformin on domain of verbal learning, working memory, and executive function.The PATH Through Life Study was funded by National Health and Medical Research Council (NHMRC) Grants (973302, 179805, and 350833). Kaarin J. Anstey and Nicolas Cherbuin were supported by NHMRC Fellowships (002560 and 1063907, resp.). Pushpani M. Herath was supported by Australian National University International Student Scholarship and Australian Research Council Centre for Excellence in Population Ageing Research (CEPAR)

Individual-level factors associated with the risk of acquiring human Plasmodium knowlesi malaria in Malaysia: a case-control study

Background: The emergence of human malaria due to the monkey parasite Plasmodium knowlesi threatens elimination efforts in southeast Asia. Changes in land use are thought to be driving the rise in reported P knowlesi cases, but the role of individual-level factors is unclear. To address this knowledge gap we assessed human and environmental factors associated with zoonotic knowlesi malaria risk. Methods: We did this population-based case-control study over a 2 year period in the state of Sabah in Malaysia. We enrolled cases with microscopy-positive, PCR-confirmed malaria who presented to two primary referral hospitals serving the adjacent districts of Kudat and Kota Marudu. We randomly selected three malaria-negative community controls per case, who were matched by village within 2 weeks of case detection. We obtained questionnaire data on demographics, behaviour, and residential malaria risk factors, and we also assessed glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. We used conditional logistic regression models to evaluate exposure risk between P knowlesi cases and controls, and between P knowlesi and human-only Plasmodium spp malaria cases. Findings: From Dec 5, 2012, to Jan 30, 2015, we screened 414 patients and subsequently enrolled 229 cases with P knowlesi malaria mono-infection and 91 cases with other Plasmodium spp infection. We enrolled 953 matched controls, including 683 matched to P knowlesi cases and 270 matched to non-P knowlesi cases. Age 15 years or older (adjusted odds ratio [aOR] 4·16, 95% CI 2·09–8·29, p<0·0001), male gender (4·20, 2·54–6·97, p<0·0001), plantation work (3·50, CI, 1·34–9·15, p=0·011), sleeping outside (3·61, 1·48–8·85, p=0·0049), travel (2·48, 1·45–4·23, p=0·0010), being aware of the presence of monkeys in the past 4 weeks (3·35, 1·91–5·88, p<0·0001), and having open eaves or gaps in walls (2·18, 1·33–3·59, p=0·0021) were independently associated with increased risk of symptomatic P knowlesi infection. Farming occupation (aOR 1·89, 95% CI 1·07–3·35, p=0·028), clearing vegetation (1·89, 1·11–3·22, p=0·020), and having long grass around the house (2·08, 1·25–3·46, p=0·0048) increased risk for P knowlesi infection but not other Plasmodium spp infection. G6PD deficiency seemed to be protective against P knowlesi (aOR 0·20, 95% CI 0·04–0·96, p=0·045), as did residual insecticide spraying of household walls (0·52, 0·31–0·87, p=0·014), with the presence of young sparse forest (0·35, 0·20–0·63, p=00040) and rice paddy around the house (0·16, 0·03–0·78, 0·023) also associated with decreased risk. Interpretation: Adult men working in agricultural areas were at highest risk of knowlesi malaria, although peri-domestic transmission also occurrs. Human behavioural factors associated with P knowlesi transmission could be targeted in future public health interventions

A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: The ANU-ADRI

Background and Aims: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts. Methods: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index. Results: For the ANU-ADRI using available data, the MAP study c-statistic was 0.637 (95% CI 0.596-0.678), for the KP study it was 0.740 (0.712-0.768) and for the CVHS it was 0.733 (0.691-0.776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625). Conclusion: A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up. © 2014 Anstey et al

Longitudinal associations between activity and cognition vary by age, activity type, and cognitive domain

The demonstration of correlated change is critical to understanding the relationship between activity engagement and cognitive functioning in older adulthood. Changes in activity have been shown to be related to changes in cognition, but little attention has been devoted to how this relationship may vary between specific activity types, cognitive domains, and age groups. Participants initially aged 65−98 years (M = 77.46 years) from the Australian Longitudinal Study of Ageing (n = 1,321) completed measurements of activity (i.e., cognitive, group social, one-on-one social, and physical) and cognition (i.e., perceptual speed, and immediate and delayed episodic memory) at baseline, 2, 8, 11, and 15 years later. Bivariate latent growth curve models covarying for education, sex, and baseline age and medical conditions revealed multiple positive-level relations between activity and cognitive performance, but activity level was not related to later cognitive change. Change in perceptual speed over 15 years was positively associated with change in cognitive activity, and change in immediate episodic memory was positively associated with change in one-on-one social activity. Old-old adults showed a stronger change−change covariance for mentally stimulating activity in relation to perceptual speed than did young-old adults. The differentiation by activity type, cognitive domain, and age contributes to the growing evidence that there is variation in the way cognitive ability at different ages is related to activity.NHMRC Fellowship No. 1002560 and the ARC Centre of Excellence in Population Ageing Research (project # CE110001029)

Long term outcomes following hospital admission for sepsis using relative survival analysis: a prospective Cohort study of 1,092 patients with 5 year follow up

Background: Sepsis is a leading cause of death in intensive care units and is increasing in incidence. Current trials of novel therapeutic approaches for sepsis focus on 28-day mortality as the primary outcome measure, but excess mortality may extend well beyond this time period.Methods: We used relative survival analysis to examine excess mortality in a cohort of 1,028 patients admitted to a tertiary referral hospital with sepsis during 2007–2008, over the first 5 years of follow up. Expected survival was estimated using the Ederer II method, using Australian life tables as the reference population. Cumulative and interval specific relative survival were estimated by age group, sex, sepsis severity and Indigenous status.Results: Patients were followed for a median of 4.5 years (range 0–5.2). Of the 1028 patients, the mean age was 46.9 years, 52% were male, 228 (22.2%) had severe sepsis and 218 (21%) died during the follow up period. Mortality based on cumulative relative survival exceeded that of the reference population for the first 2 years post admission in the whole cohort and for the first 3 years in the subgroup with severe sepsis. Independent predictors of mortality over the whole follow up period were male sex, Indigenous Australian ethnicity, older age, higher Charlson Comorbidity Index, and sepsis-related organ dysfunction at presentation.Conclusions: The mortality rate of patients hospitalised with sepsis exceeds that of the general population until 2 years post admission. Efforts to improve outcomes from sepsis should examine longer term outcomes than the traditional primary endpoints of 28-day and 90-day mortality

The fluid management of adults with severe malaria

Fluid resuscitation has long been considered a key intervention in the treatment of adults with severe falciparum malaria. Profound hypovolemia is common in these patients and has the potential to exacerbate the acidosis and acute kidney injury that are independent predictors of death. However, new microvascular imaging techniques have shown that disease severity correlates more strongly with obstruction of the microcirculation by parasitized erythrocytes - a process termed sequestration. Fluid loading has little effect on sequestration and increases the risk of complications, particularly pulmonary edema, a condition that can develop suddenly and unpredictably and that is frequently fatal in this population. Accordingly, even if a patient is clinically hypovolemic, if there is an adequate blood pressure and urine output, there may be little advantage in infusing intravenous fluid beyond a maintenance rate of 1 to 2 mL/kg per hour. The optimal agent for fluid resuscitation remains uncertain; significant anemia requires blood transfusion, but colloid solutions may be associated with harm and should be avoided. The preferred crystalloid is unclear, although the use of balanced solutions requires investigation. There are fewer data to guide the fluid management of severe vivax and knowlesi malaria, although a similar conservative strategy would appear prudent

Pulmonary tuberculosis in outpatients in Sabah, Malaysia: Advanced disease but low incidence of HIV co-infection

BackgroundTuberculosis (TB) is generally well controlled in Malaysia, but remains an important problem in the nation’s eastern states. In order to better understand factors contributing to high TB rates in the eastern state of Sabah, our aims were to describe characteristics of patients with TB at a large outpatient clinic, and determine the prevalence of HIV co-infection. Additionally, we sought to test sensitivity and specificity of the locally-available point-of-care HIV test kits.MethodsWe enrolled consenting adults with smear-positive pulmonary TB for a 2-year period at Luyang Clinic, Kota Kinabalu, Malaysia. Participants were questioned about ethnicity, smoking, prior TB, disease duration, symptoms and comorbidities. Chest radiographs were scored using a previously devised tool. HIV was tested after counselling using 2 point-of-care tests for each patient: the test routinely in use at the TB clinic (either Advanced Quality™ Rapid Anti-HIV 1&2, FACTS anti-HIV 1/2 RAPID or HIV (1 + 2) Antibody Colloidal Gold), and a comparator test (Abbott Determine™ HIV-1/2, Inverness Medical). Positive tests were confirmed by enzyme immunoassay (EIA), particle agglutination and line immunoassay.Results176 participants were enrolled; 59 (33.5%) were non-Malaysians and 104 (59.1%) were male. Smoking rates were high (81/104 males, 77.9%), most had cavitary disease (51/145, 64.8%), and 81/176 (46.0%) had haemoptysis. The median period of symptoms prior to treatment onset was 8 weeks. Diabetes was present in 12. People with diabetes or other comorbidities had less severe TB, suggesting different healthcare seeking behaviours in this group. All participants consented to HIV testing: three (1.7%) were positive according to Determine™ and EIA, but one of these tested negative on the point-of-care test available at the clinic (Advanced Quality™ Rapid Anti-HIV 1&2). The low number of positive tests and changes in locally-available test type meant that accurate estimates of sensitivity and specificity were not possible.ConclusionPatients had advanced disease at diagnosis, long diagnostic delays, low HIV co-infection rates, high smoking rates among males, and migrants may be over-represented. These findings provide important insights to guide local TB control efforts. Caution is required in using some point-of-care HIV tests, and ongoing quality control measures are of major importance