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bioRxiv2017

Therapeutic importance of timely immunophenotyping of breast cancer in a resource-constrained setting: a retrospective hospital-based cohort study

BackgroundOrganizations that issue guidance on breast cancer recommend the use of immunohistochemistry (IHC) for providing appropriate and precise care. However, little focus has been directed to the identification of maximum allowable turnaround times for IHC, which is necessary given the diversity of hospital settings in the world. Much less effort has been committed to the development of digital tools that allow hospital administrators to monitor service utilization histories of their patients.\n\nMethodsIn this retrospective cohort study, we reviewed electronic and paper medical records of all suspected breast cancer patients treated at one secondary-care hospital of the Mexican Institute of Social Security (IMSS), located in western Mexico. We then followed three years of medical history of those patients with IHC testing.\n\nResultsIn 2014, there were 402 breast cancer patients, of which 30 were tested for some IHC biomarker (ER, PR, HER2). The subtyping allowed doctors to adjust (56.7 %) or confirm (43.3 %) the initial therapeutic regimen. The average turnaround time was 56 days. Opportune IHC testing was found to be beneficial when it was available before or during the first rounds of chemotherapy.\n\nConclusionsThe use of data mining tools applied to health record data revealed that there is an association between timely immunohistochemistry and improved outcomes in breast cancer patients. Based on this finding, inclusion of turnaround time in clinical guidelines is recommended. As much of the health data in the country becomes digitized, our visualization tools allow a digital dashboard of the hospital service utilization histories.

epidemiology↗

bioRxiv2017

Improving the visualisation, interpretation and analysis of two-sample summary data Mendelian randomization via the radial plot and radial regression

BackgroundSummary data furnishing a two-sample Mendelian randomization study are often visualized with the aid of a scatter plot, in which single nucleotide polymorphism (SNP)-outcome associations are plotted against the SNP-exposure associations to provide an immediate picture of the causal effect estimate for each individual variant. It is also convenient to overlay the standard inverse variance weighted (IVW) estimate of causal effect as a fitted slope, to see whether an individual SNP provides evidence that supports, or conflicts with, the overall consensus. Unfortunately, the traditional scatter plot is not the most appropriate means to achieve this aim whenever SNP-outcome associations are estimated with varying degrees of precision and this is reflected in the analysis.\n\nMethodsWe propose instead to use a small modification of the scatter plot - the Galbraith radial plot - for the presentation of data and results from an MR study, which enjoys many advantages over the original method. On a practical level it removes the need to recode the genetic data and enables a more straightforward detection of outliers and influential data points. Its use extends beyond the purely aesthetic, however, to suggest a more general modelling framework to operate within when conducting an MR study, including a new form of MR-Egger regression.\n\nResultsWe illustrate the methods using data from a two-sample Mendelian randomization study to probe the causal effect of systolic blood pressure on coronary heart disease risk, allowing for the possible effects of pleiotropy. The radial plot is shown to aid the detection of a single outlying variant which is responsible for large differences between IVW and MR-Egger regression estimates. Several additional plots are also proposed for informative data visualisation.\n\nConclusionThe radial plot should be considered in place of the scatter plot for visualising, analysing and interpreting data from a two-sample summary data MR study. Software is provided to help facilitate its use.

epidemiology↗

bioRxiv2017

Pneumococcal phenotype and interaction with nontypeable Haemophilus influenzae as determinants of otitis media progression

BackgroundAll-cause otitis media (OM) incidence has declined in numerous settings following introduction of pneumococcal conjugate vaccines (PCVs) despite increases in carriage of non-vaccine pneumococcal serotypes escaping immune pressure. To understand the basis for declining incidence, we assessed the intrinsic capacity of pneumococcal serotypes to cause OM independently and in polymicrobial infections involving nontypeable Haemophilus influenzae (NTHi) using samples obtained from middle ear fluid and nasopharyngeal cultures before PCV7/13 rollout.\n\nMethodsData included OM episodes (11,811) submitted for cultures during a 10-year prospective study in southern Israel and nasopharyngeal samples (1588) from unvaccinated asymptomatic children in the same population. We compared pneumococcal serotype diversity across carriage and disease isolates with and without NTHi co-isolation. We also measured associations between pneumococcal phenotype and rate of progression from colonization to OM in the presence and absence of NTHi.\n\nResultsWhereas pneumococcal serotype diversity in single-species OM is lower than in single-species colonization, serotype diversity does not differ significantly between colonization and OM in mixed-species episodes. Serotypes differed roughly 100-fold in progression rates, and these differences were attenuated in polymicrobial episodes. Vaccine-serotype pneumococci had higher rates of progression than non-vaccine serotypes. While serotype invasiveness was a weak predictor of OM progression rate, efficient capsular metabolic properties--traditionally thought to serve as an advantage in colonization--predicted an enhanced rate of progression to complex OM.\n\nConclusionsThe lower capacity of non-vaccine serotypes to cause OM may partially account for reductions in all-cause OM incidence despite serotype replacement in carriage following rollout of PCVs.

epidemiology↗

bioRxiv2017

Antenatal Screening for Group B Streptococcus in the Setting of Preterm Premature Rupture of Membranes: Empiric versus Culture-based Prophylaxis

Introduction Introduction Methods Results Discussion References Group B streptococcus (GBS) bacteria colonizes the genital tract in 10-30% of pregnant women.1,2 GBS colonization during pregnancy is the primary risk factor for neonatal GBS infection with its accompanying risks of significant infant morbidity and mortality.3-5 Over the last several decades, intrapartum intravenous administration of antibiotics to women at risk for transmitting GBS has greatly reduced neonatal disease.3,6,7 Current CDC guidelines recommend routine screening for GBS at 35-37 weeks gestation and subsequent administration of intrapartum antibiotics if the GBS screen is positive (universal culture-base ...

epidemiology↗

bioRxiv2017

Target immunity levels for achieving and maintaining measles elimination

BackgroundVaccination has reduced the global incidence of measles to the lowest rates in history. However, local interruption of measles virus transmission requires sustained high levels of population immunity that can be challenging to achieve and maintain. The herd immunity threshold for measles is typically stipulated at 90-95%. This figure does not easily translate into age-specific immunity levels required to interrupt transmission. Previous estimates of such levels were based on speculative contact patterns based on historical data from high-income countries. The aim of this study was to determine age-specific immunity levels that would ensure elimination of measles when taking into account empirically observed contact patterns.\n\nMethodsWe combined estimated immunity levels from serological data in 17 countries with studies of age-specific mixing patterns to derive contact-adjusted immunity levels. We then compared these to case data from the 10 years following the seroprevalence studies to establish a contact-adjusted immunity threshold for elimination. We lastly combined a range of hypothetical immunity profiles with contact data from a wide range of socioeconomic and demographic settings to determine whether they would be sufficient for elimination.\n\nResultsWe found that contact-adjusted immunity levels were able to predict whether countries would experience outbreaks in the decade following the serological studies in about 70% of countries. The corresponding threshold level of contact-adjusted immunity was found to be 93%, corresponding to an average basic reproduction number of approximately 14. Testing different scenarios of immunity with this threshold level using contact studies from around the world, we found that 95% immunity would have to be achieved by the age of five and maintained across older age groups to guarantee elimination. This reflects a greater level of immunity required in 5-9 year olds than established previously.\n\nConclusionsThe immunity levels we found necessary for measles elimination are higher than previous guidance. The importance of achieving high immunity levels in 5-9 year olds presents both a challenge and an opportunity. While such high levels can be difficult to achieve, school entry provides an opportunity to ensure sufficient vaccination coverage. Combined with observations of contact patterns, further national and sub-national serological studies could serve to highlight key gaps in immunity that need to be filled in order to achieve national and regional measles elimination.

epidemiology↗

bioRxiv2018

Ebola outbreak brings to light an unforeseen impact of tsetse control on sleeping sickness transmission in Guinea.

In addition to the thousands of deaths due the unprecedented ebola outbreak that stroke West Africa (2014-2016), national health systems in affected countries were deeply challenged impacting a number of diseases control programs. Here we describe the case of Human African Trypanosomiasis (HAT), a deadly neglected tropical disease due to a trypanosome transmitted by tsetse flies for which no vaccine nor chemoprophylaxis exists. Data are presented for the disease focus of Boffa in Guinea where a pilot elimination project combining medical screening and vector control was launched in 2012. During ebola, HAT active screening activities were postponed and passive surveillance also was progressively impaired. However, tsetse control using small insecticide impregnated targets could be maintained. The over two years disruption of screening activities led to a dramatic increase of HAT prevalence, from 0.7% in 2013 (21/2885) to 2% (69/3448) in 2016, reaching epidemic levels (>5%) in some villages. In deep contrast, control levels reached in 2013 (0.1%; 7/6564) were maintained in areas covered with impregnated targets as no cases were found in 2016 (0/799). In Boffa, ebola has thus incidentally provided a unique framework to assess the impact of current HAT control strategies. A first lesson is that the \"screen and treat\" strategy is fragile as rapid bursts of the disease may occur in case of disruption. A second lesson is that vector control reducing human-tsetse contacts, even implemented alone, is effective in providing a good level of protection against infection. This advocates for a greater attention being paid to the combination of tsetse control together with medical activities in aiming to reach the HAT elimination objective in Africa.

epidemiology↗

bioRxiv2017

Plasmodium falciparum infection during pregnancy impairs fetal head growth: prospective and populational-based retrospective studies

BackgroundMalaria in pregnancy is associated with adverse effects on the fetus and newborns. However, the outcome on a newborns head circumference (HC) is still unclear. Here, we show the relation of malaria during pregnancy with fetal head growth.\n\nMethodsClinical and anthropometric data were collected from babies in two cohort studies of malaria-infected and non-infected pregnant women, in the Brazilian Amazon. One enrolled prospectively (PCS, Jan. 2013 to April 2015) through volunteer sampling, and followed until delivery, 600 malaria-infected and non-infected pregnant women. The other assembled retrospectively (RCS, Jan. 2012 to Dec. 2013) clinical and malaria data from 4697 pregnant women selected through population-based sampling. The effects of malaria during pregnancy in the newborns were assessed using a multivariate logistic regression. According with World Health Organization guidelines babies were classified in small head (HC < 1 SD below the median) and microcephaly (HC < 2 SD below the median) using international HC standards.\n\nResultsAnalysis of 251 (PCS) and 232 (RCS) malaria-infected, and 158 (PCS) and 3650 (RCS) non-infected women with clinical data and anthropometric measures of their babies was performed. Among the newborns, 70 (17.1%) in the PCS and 934 (24.1%) in the RCS presented with a small head (SH). Of these, 15 (3.7%) and 161 (4.2%), respectively, showed microcephaly (MC). The prevalence of newborns with a SH (30.7% in PCS and 36.6% in RCS) and MC (8.1% in PCS and 7.3% in RCS) was higher among babies born from women infected with Plasmodium falciparum during pregnancy. Multivariate logistic regression analyses revealed that P. falciparum infection during pregnancy represents a significant increased odds for the occurrence of a SH in newborns (PCS: OR 3.15, 95% CI 1.52-6.53, p=0.002; RCS: OR 1.91, 95% CI 1.21-3.04, p=0.006). Similarly, there is an increased odds of MC in babies born from mothers that were P. falciparum-infected (PCS: OR 5.09, 95% CI 1.12-23.17, p=0.035). Moreover, characterization of placental pathology corroborates the association analysis, particularly through the occurrence of more syncytial nuclear aggregates and inflammatory infiltrates in placentas from babies with the reduced head circumference.\n\nConclusionsThis work indicates that falciparum-malaria during pregnancy presents an increased likelihood of occurring reduction of head circumference in newborns, which is associated with placental malaria.\n\nTrial Registrationregistered as RBR-3yrqfq in the Brazilian Clinical Trials Registry

epidemiology↗

bioRxiv2017

Diabetes mellitus is associated with increased prevalence of latent tuberculosis infection: Results from the National Health and Nutrition Examination Survey

AimsWe aimed to determine the association between prediabetes and diabetes with latent TB using National Health and Nutrition Examination Survey data.\n\nMethodsWe performed a cross-sectional analysis of 2011-2012 National Health and Nutrition Examination Survey data. Participants [≥]20 years were eligible. Diabetes was defined by glycated hemoglobin (HbA1c) as no diabetes ([≤]5.6% [38 mmol/mol]), prediabetes (5.7-6.4% [3946mmol/mol]), and diabetes ([≥]6.5% [48 mmol/mol]) combined with self-reported diabetes. Latent TB infection was defined by the QuantiFERON(R)-TB Gold In Tube (QFT-GIT) test. Adjusted odds ratios (aOR) of latent TB infection by diabetes status were calculated using logistic regression and accounted for the stratified probability sample.\n\nResultsDiabetes and QFT-GIT measurements were available for 4,958 (89.2%) included participants. Prevalence of diabetes was 11.4% (95%CI 9.8-13.0%) and 22.1% (95%CI 20.523.8%) had prediabetes. Prevalence of latent TB infection was 5.9% (95%CI 4.9-7.0%). After adjusting for age, sex, smoking status, history of active TB, and foreign born status, the odds of latent TB infection were greater among adults with diabetes (aOR 1.90, 95%CI 1.15-3.14) compared to those without diabetes. The odds of latent TB in adults with prediabetes (aOR 1.15, 95%CI 0.90-1.47) was similar to those without diabetes.\n\nConclusionsDiabetes is associated with latent TB infection among adults in the United States, even after adjusting for confounding factors. Given diabetes increases the risk of active TB, patients with co-prevalent diabetes and latent TB may be targeted for latent TB treatment.

epidemiology↗

bioRxiv2017

Small-scale field testing of Alpha-cypermethrin water-dispersible granules in comparison with the recommended wettable powder formulation for indoor residual spraying against malaria vectors in Benin

BackgroudPyrethroids are the most common class of insecticide used worldwide for indoor residual spraying (IRS) against malaria vectors. Water-dispersible granules (WG) are a pyrethroid formulation to be applied after disintegration and dispersion in water with less risks of inhalation than using the usual wettable powder (WP) formulation. The objective of this small-scale field study was to evaluate efficacy and duration of insecticidal action of a new alpha-cypermethrin WG (250g a.i./Kg) against susceptible Anopheles gambiae in comparison with the WHO reference product (alpha-cypermethrin WP, 50g a.i./Kg) on the most common indoor surfaces in Benin.\n\nMethodsBoth formulations were applied at two target-dose concentrations in houses made of mud and cement in the Tokoli village in southern Benin. We measured the applied dose of insecticide by chemical analysis of filter paper samples collected from the sprayed inner walls. We recorded An. gambiae mortality and knock-down rates every 15 days during 6 months using standard WHO bioassays.\n\nResultsThe alpha-cypermethrin WG formulation did not last as long as the WP formulation on both surfaces. The difference is higher with the 30mg/m2 concentration for which the WP formulation reached the 80% mortality threshold during 2 months on the mud-plastered walls (3 months on cement) whereas the WG formulation last only one month (2 months on cement).\n\nConclusionsThe new WG formulation has a shorter efficacy than the WHO recommended WP formulation. In this trial, both the WG and WP formulations had low durations of efficacy that would need at least two rounds of spray to cover the entire transmission season.

epidemiology↗

bioRxiv2017

Long-Term Leisure-Time Physical Activity and Other Health Habits as Predictors of Objectively Monitored Late-Life Physical Activity: A 40-Year Twin Study

IMPORTANCEModerate-to-vigorous physical activity (MVPA) in old age is an important indicator of good health and functional capacity enabling independent living.\n\nOBJECTIVETo investigate whether physical activity and other health habits at ages 31-48 years predict objectively measured MVPA decades later.\n\nDESIGN, SETTING, AND PARTICIPANTSThis prospective twin cohort study in Finland comprised 616 individuals (197 complete twin pairs, including 91 monozygotic pairs, born 1940-1944), who responded to baseline questionnaires in 1975, 1981, and 1990, and participated in accelerometer monitoring at follow-up (mean age, 73 years).\n\nEXPOSURESPrimary exposure was long-term leisure-time physical activity, 1975-1990 (LT-mMET index). Covariates were body mass index (BMI), work-related physical activity, smoking, heavy alcohol use and health status in 1990, and socioeconomic status.\n\nMAIN OUTCOMES AND MEASURESPhysical activity was measured with a waist-worn triaxial accelerometer (at least 10 hours per day for at least 4 days) to obtain daily mean MVPA values.\n\nRESULTSHigh baseline LT-mMET index predicted higher amounts of MVPA (increase in R2 of 6.9% after age and sex adjustment, P<.001) at follow-up. After addition of BMI to the regression model, the R2 value of the whole multivariate model was 17.2%, and with further addition of baseline smoking, socioeconomic status, and health status, the R2 increased to 20.3%. In pairwise analyses, differences in MVPA amount were seen only among twin pairs who were discordant at baseline for smoking (n=40 pairs, median follow-up MVPA 25 vs. 35 min, P=.037) or for health status (n=69 pairs, 30 vs. 44 min, P=.014). For smoking, the difference in MVPA also was seen for monozygotic pairs, but for health status, it was seen only for dizygotic pairs. Mediation analysis showed that shared genetic factors explained 82% of the correlation between LT-mMET and MVPA.\n\nCONCLUSIONS AND RELEVANCELow leisure-time physical activity at younger age, overweight, smoking, low socioeconomic status, and health problems predicted low MVPA in old age in individual-based analyses. However, based on the pairwise analyses and quantitative trait modeling, genetic factors and smoking seem to be important determinants of later-life MVPA.

epidemiology↗

bioRxiv2017

Impact of global change on future Ebola emergence and epidemic potential in Africa

Animal-borne or zoonotic human diseases (e.g., SARS, Rabies) represent major health and economic burdens throughout the world, disproportionately impacting poor communities. In 2013-2016, an outbreak of the Ebola virus disease (EVD), a zoonotic disease spread from animal reservoirs caused by the Zaire Ebola virus (EBOV), infected approximately 30,000 people, causing considerable negative social and economic impacts in an unexpected geographical location(Sierra Leone, Guinea, and Liberia). It is not known whether the spatial distribution of this outbreak and unprecedented severity was precipitated by environmental changes and, if so, which areas might be at risk in the future. To better address the major health and economic impacts of zoonotic diseases we develop a system-dynamics approach to capture the impact of future climate, land use and human population change on Ebola (EVD). We create future risk maps for affected areas and predict between a 1.75-3.2 fold increase in EVD outbreaks per year by 2070. While the best case future scenarios we test saw a reduction in the likelihood of epidemics, other future scenarios with high human population growth and low rates of socioeconomic development saw a fourfold increase in the risk of epidemics occurring and almost 50% increase in the risk of catastrophic epidemics. As well as helping to target where health infrastructure might be further developed or vaccines best deployed, our modelling framework can be used to target global interventions and forecast risk for many other zoonotic diseases.\n\nSignificance StatementDespite the severe health and economic impacts of outbreaks of diseases like SARS or Zika, there has been surprisingly little progress in predicting where and when human infectious disease outbreaks will occur next. By modelling the impacts of future climate, land use and human population change on one particular disease Ebola, we develop future risk maps for the affected areas and predict 1.7-3.2 times as many human Ebola outbreaks per year by 2070, and a 50% increase in the chance that these outbreaks will become epidemics. As well as helping to target where health infrastructure might be further developed or vaccines deployed, our approach can also be used to target actions and predict risk hotspots for many other infectious diseases.

epidemiology↗

bioRxiv2017

Delirium symptoms are associated with decline in cognitive function between ages 53 to 69: findings from a British birth cohort study.

INTRODUCTIONFew population studies have investigated whether longitudinal decline after delirium in mid-to-late life might affect specific cognitive domains.\n\nMETHODSParticipants from a birth cohort completing assessments of search speed, verbal memory and the Addenbrookes Cognitive Examination at age 69 were asked about delirium symptoms between ages 60-69. Linear regression models estimated associations between delirium symptoms and cognitive outcomes.\n\nRESULTSPeriod prevalence of delirium between 60 and 69 was 4% (95% CI 3.2%,4.9%). Self-reported symptoms of delirium over the seventh decade were associated with worse scores in the Addenbrookes Cognitive Examination (-1.7 points, 95% CI -3.2, -0.1, p=0.04). In association with delirium symptoms, verbal memory scores were initially lower, with subsequent decline in search speed by age 69. These effects were independent of other Alzheimers risk factors.\n\nDISCUSSIONDelirium symptoms may be common even at relatively younger ages, and their presence may herald cognitive decline, particularly in search speed, over this time period.

epidemiology↗

bioRxiv2017

Enumerating the Economic Cost of Antimicrobial Resistance Per Antibiotic Consumed to Inform the Evaluation of Interventions Affecting their Use

Background- Antimicrobial resistance (AMR) poses a colossal threat to global health and incurs high economic costs to society. Economic evaluations of antimicrobials and interventions such as diagnostics and vaccines that affect their consumption rarely include the costs of AMR, resulting in sub-optimal policy recommendations. We estimate the economic cost of AMR per antibiotic consumed, stratified by drug class and national income level.\n\nMethods- The model is comprised of three components: correlation coefficients between human antibiotic consumption and subsequent resistance; the economic costs of AMR for five key pathogens; and consumption data for antibiotic classes driving resistance in these organisms. These were used to calculate the economic cost of AMR per antibiotic consumed for different drug classes, using data from Thailand and the United States (US) to represent low/middle and high-income countries.\n\nResults- The correlation coefficients between consumption of antibiotics that drive resistance in S. aureus, E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa and resistance rates were 0.37, 0.27, 0.35, 0.45, and 0.52, respectively. The total economic cost of AMR due to resistance in these five pathogens was $0.5 billion and $2.8 billion in Thailand and the US, respectively. The cost of AMR associated with the consumption of one standard unit (SU) of antibiotics ranged from $0.1 for macrolides to $0.7 for quinolones, cephalosporins and broad-spectrum penicillins in the Thai context. In the US context, the cost of AMR per SU of antibiotic consumed ranged from $0.1 for carbapenems to $0.6 for quinolones, cephalosporins and broad spectrum penicillins.\n\nConclusion- The economic costs of AMR per antibiotic consumed were considerable, often exceeding their purchase cost. Differences between Thailand and the US were apparent, corresponding with variation in the overall burden of AMR and relative prevalence of different pathogens. Notwithstanding their limitations, use of these estimates in economic evaluations can make better-informed policy recommendations regarding interventions that affect antimicrobial consumption and those aimed specifically at reducing the burden of AMR.

epidemiology↗

bioRxiv2017

Agent-based network model predicts strong benefits to youth-centered HIV treatment-as-prevention efforts

We used an agent-based network model to examine the effect of targeting different risk groups with unsuppressed HIV viral load for linkage or re-linkage to HIV-related treatment services in a heterosexual population with annual testing. Our model identifies prevention strategies that can reduce incidence to negligible levels (i.e., less than 0.1 infections per 100 person-years) 20 years after a targeted Treatment-as-Prevention (TasP) campaign. The model assumes that most (default 95%) of the population is reachable (i.e., could, in principle, be linked to effective care) and a modest (default 5% per year) probability of a treated person dropping out of care. Under random allocation or CD4-based targeting, the default version of our model predicts that the TasP campaign would need to suppress viral replication in ~80% of infected people to halt the epidemic. Under age-based strategies, by contrast, this percentage drops to 50% to 60% (for strategies targeting those <30 and <25, respectively). Age-based targeting did not need to be highly exclusive to yield significant benefits; e.g. the scenario that targeted those <25 years old saw ~80% of suppressed individuals fall outside the target group. This advantage to youth-based targeting remained in sensitivity analyses in which key age-related risk factors were eliminated one by one. As testing rates increase in response to UNAIDS 90-90-90 goals, we suggest that efforts to link all young people to effective care could be an effective long-term method for ending the HIV epidemic. Linking greater numbers of young people to effective care will be critical for developing countries in which a demographic \"youth bulge\" is starting to increase the number of young people at risk for HIV infection.

epidemiology↗

bioRxiv2017

Apolipoprotein-E (ApoE) ϵ4 and cognitive decline over the adult life course

We tested the association between APOE-{varepsilon}4 and processing speed and memory between ages 43 and 69 in a population-based birth cohort. Analyses of processing speed (using a timed letter search task) and episodic memory (a 15-item word learning test) were conducted at ages 43, 53, 60-64 and 69 years using linear and multivariable regression, adjusting for gender and childhood cognition. Linear mixed models, with random intercepts and slopes, were conducted to test the association between APOE and the rate of decline in these cognitive scores from age 43 to 69. Model fit was assessed with the Bayesian Information Criterion. A cross-sectional association between APOE-{varepsilon}4 and memory scores was detected at age 69 for both heterozygotes and homozygotes ({beta}=-0.68 & {beta}=-1.38 respectively, p=.03) with stronger associations in homozygotes; no associations were observed before this age. Homozygous carriers of APOE-{varepsilon}4 had a faster rate of decline in memory between ages 43 and 69, when compared to noncarriers, after adjusting for gender and childhood cognition ({beta}=-0.05, p=.04). There were no cross-sectional or longitudinal associations between APOE-{varepsilon}4 and processing speed. We conclude that APOE-{varepsilon}4 is associated with a subtly faster rate of memory decline from midlife to early old age; this may be due to effects of APOE-{varepsilon}4 becoming manifest around the latter stage of life. Continuing follow-up will determine what proportion of this increase will become clinically significant.

epidemiology↗

bioRxiv2017

Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort

BackgroundFrailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. Younger individuals (under 65 years) typically have low levels of frailty and are less-studied in this respect. Also, the relationship between the Rockwood frailty index (FI) and cause-specific mortality in community settings is understudied.\n\nMethodsWe created and validated a 42-item Rockwood-based FI in The Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks.\n\nResultsOur FI demonstrated construct validity as its associations with age, sex and mortality were similar to the existing literature. The FI was independently associated with increased risk for all-cause mortality in younger (<65 years; HR per increase in one deficit 1.11, 95%CI 1.07-1.17) and older ([≥]65 years; HR 1.07, 95%CI 1.04-1.10) women and in younger men (HR 1.05, 95%CI 1.01-1.10). In cause-specific mortality analysis, the FI was strongly predictive of CVD mortality in women (HR per increase in one deficit 1.13, 95%CI 1.09-1.17), whereas in men the risk was restricted to deaths from other causes (HR 1.07, 95%CI 1.01-1.13).\n\nConclusionsThe FI showed good predictive value for all-cause mortality especially in the younger group. The FI predicted CVD mortality risk in women, whereas in men it captured vulnerability to death from various causes.

epidemiology↗

bioRxiv2017

Socioeconomic Disparities and Sexual Dimorphism in Neurotoxic Effects of Ambient Fine Particles on Youth IQ: A Longitudinal Analysis

Mounting evidence indicates that early-life exposure to particulate air pollutants pose threats to childrens cognitive development, but studies about the neurotoxic effects associated with exposures during adolescence remain unclear. We examined whether exposure to ambient fine particles (PM2.5) at residential locations affects intelligence quotient (IQ) during pre-/early-adolescence (ages 9-11) and emerging adulthood (ages 18-20) in a demographically-diverse population (N = 1,360) residing in Southern California. Increased ambient PM2.5 levels were associated with decreased IQ scores. This association was more evident for Performance IQ (PIQ), but less for Verbal IQ, assessed by the Wechsler Abbreviated Scale of Intelligence. For each inter-quartile (7.73 g/m3) increase in one-year PM2.5 preceding each assessment, the average PIQ score decreased by 3.08 points (95% confidence interval = [-6.04, -0.12]) accounting for within-family/within-individual correlations, demographic characteristics, family socioeconomic status (SES), parents cognitive abilities, neighborhood characteristics, and other spatial confounders. The adverse effect was 150% greater in low SES families and 89% stronger in males, compared to their counterparts. Better understanding of the social disparities and sexual dimorphism in the adverse PM2.5-IQ effects may help elucidate the underlying mechanisms and shed light on prevention strategies.

epidemiology↗

bioRxiv2017

Delirium, frailty and mortality: interactions in a prospective study of hospitalized older people

BackgroundIt is unknown if the association between delirium and mortality is consistent for individuals across the whole range of health states. A bimodal relationship has been proposed, where delirium is particularly adverse for those with underlying frailty, but may have a smaller effect (perhaps even protective) if it is an early indicator of acute illness in fitter people. We investigated the impact of delirium on mortality in a cohort simultaneously evaluated for frailty.\n\nMethodsWe undertook an exploratory analysis of a cohort of consecutive acute medical admissions aged [≥]70. Delirium on admission was ascertained by psychiatrists. A Frailty Index (FI) was derived according to a standard approach. Deaths were notified from linked national mortality statistics. Cox regression was used to estimate associations between delirium, frailty and their interactions on mortality.\n\nResultsThe sample consisted of 710 individuals. Both delirium and frailty were independently associated with increased mortality rates (delirium: HR 2.4, 95%CI 1.8-3.3, p<0.01; frailty (per SD): HR 3.5, 95%CI 1.2-9.9, p=0.02). Estimating the effect of delirium in tertiles of FI, mortality was greatest in the lowest tertile: tertile 1 HR 3.4 (95%CI 2.1-5.6); tertile 2 HR 2.7 (95%CI 1.5-4.6); tertile 3 HR 1.9 (95% CI 1.2-3.0).\n\nConclusionWhile delirium and frailty contribute to mortality, the overall impact of delirium on admission appears to be greater at lower levels of frailty. In contrast to the hypothesis that there is a bimodal distribution for mortality, delirium appears to be particularly adverse when precipitated in fitter individuals.

epidemiology↗