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Motor and cognitive aging can severely affect life quality of elderly people and burden health care systems. In search for diagnostic behavioral biomarkers, it has been suggested that walking speed can predict forms of cognitive decline, but in humans, it remains challenging to separate the effects of biological aging and lifestyle. We examined a possible association of motor and cognitive decline in Drosophila, a genetic model organism of healthy aging. Long term courtship memory is present in young male flies but absent already during mid life (4-8 weeks). By contrast, courtship learning index and short term memory (STM) are surprisingly robust and remain stable through mid (4-8 weeks) and healthy late life (>8 weeks), until courtship performance collapses suddenly at ~4.5 days prior to death. By contrast, climbing speed declines gradually during late life (>8 weeks). The collapse of courtship performance and short term memory close to the end of life occur later and progress with a different time course than the gradual late life decline in climbing speed. Thus, during healthy aging in male Drosophila, climbing and courtship motor behaviors decline differentially. Moreover, cognitive and motor performances decline at different time courses. Differential behavioral decline during aging may indicate different underlying causes, or alternatively, a common cause but different thresholds for defects in different behaviors.

BackgroundAnticholinergic burden has been associated with adverse outcomes such as falls. To date, no gold standard measure has been identified to assess anticholinergic burden, and no conclusion has been drawn on which of the different measure algorithms best predicts falls in older patients from general practice. This study compared the ability of five measures of anticholinergic burden to predict falls. To account for patients' individual susceptibility to medications, the added predictive value of typical anticholinergic symptoms was further quantified in this context.Methods and findingsTo predict falls, models were developed and validated based on logistic regression models created using data from two German cluster-randomized controlled trials. The outcome was defined as "≥ 1 fall" vs. "no fall" within a 6-month follow-up period. Data from the RIME study (n = 1,197) were used in model development, and from PRIMUM (n = 502) for external validation. The models were developed step-wise in order to quantify the predictive ability of anticholinergic burden measures, and anticholinergic symptoms. In the development set, 1,015 patients had complete data and 188 (18.5%) experienced ≥ 1 fall within the 6-month follow-up period. The overall predictive value of the five anticholinergic measures was limited, with neither the employed anticholinergic variable (binary / count / burden), nor dose-dependent or dose-independent measures differing significantly in their ability to predict falls. The highest c-statistic was obtained using the German Anticholinergic Burden Score (0.73), whereby the optimism-corrected c-statistic was 0.71 after interval validation using bootstrapping and 0.63 in the external validation. Previous falls and dizziness / vertigo had the strongest prognostic value in all models.ConclusionsThe ability of anticholinergic burden measures to predict falls does not appear to differ significantly, and the added value they contribute to risk classification in fall-prediction models is limited. Previous falls and dizziness / vertigo contributed most to model performance.

Both the natural and the social sciences are currently facing a deep "reproducibility crisis". Two important factors in this crisis have been the selective reporting of results and methodological problems. In this article, we examine a fusion of these two factors. More specifically, we demonstrate that the uncritical import of Boolean optimization algorithms from electrical engineering into some areas of the social sciences in the late 1980s has induced algorithmic bias on a considerable scale over the last quarter century. Potentially affected are all studies that have used a method nowadays known as Qualitative Comparative Analysis (QCA). Drawing on replication material for 215 peer-reviewed QCA articles from across 109 high-profile management, political science and sociology journals, we estimate the extent this problem has assumed in empirical work. Our results suggest that one in three studies is affected, one in ten severely so. More generally, our article cautions scientists against letting methods and algorithms travel too easily across disparate disciplines without sufficient prior evaluation of their suitability for the context in hand.

Bi-allelic Single Nucleotide Polymorphism (SNP) markers are widely used in population genetic studies. In most studies, sequences either side of the SNPs remain unused, although these sequences contain information beyond that used in population genetic studies. In this study, we show how these sequence tags either side of a single nucleotide polymorphism can be used for comparative genome analysis. We used DArTseq (Diversity Array Technology) derived SNP data for a non-model Australian native freshwater fish, Macquaria ambigua, to identify genes linked to SNP associated sequence tags, and to discover homologies with evolutionarily conserved genes and genomic regions. We concatenated 6,776 SNP sequence tags to create a hypothetical genome (representing 0.1-0.3% of the actual genome), which we used to find sequence homologies with 12 model fish species using the Ensembl genome browser with stringent filtering parameters. We identified sequence homologies for 17 evolutionarily conserved genes (cd9b, plk2b, rhot1b, sh3pxd2aa, si:ch211-148f13.1, si:dkey-166d12.2, zgc:66447, atp8a2, clvs2, lyst, mkln1, mnd1, piga, pik3ca, plagl2, rnf6, sec63) along with an ancestral evolutionarily conserved syntenic block (euteleostomi Block_210). Our analysis also revealed repetitive sequences covering approximately 12% of the hypothetical genome where DNA transposon, LTR and non-LTR retrotransposons were most abundant. A hierarchical pattern of the number of sequence homologies with phylogenetically close species validated the approach for repeatability. This new approach of using SNP associated sequence tags for comparative genome analysis may provide insight into the genome evolution of non-model species where whole genome sequences are unavailable.

PURPOSE:Acute lung injury is a life threatening condition often requiring mechanical ventilation. Lung-protective ventilation with tidal volumes of 6 mL/kg predicted body weight (PBW, calculated on the basis of a patient's sex and height), is part of current recommended ventilation strategy. Hence, an exact height is necessary to provide optimal mechanical ventilation. However, it is a common practice to visually estimate the body height of mechanically ventilated patients and use these estimates as a reference size for ventilator settings. We aimed to determine if the common practice of estimating visual height to define tidal volume reduces the possibility of receiving lung-protective ventilation. METHODS:In this prospective observational study, 28 mechanically ventilated patients had their heights visually estimated by 20 nurses and 20 physicians. All medical professionals calculated the PBW and a corresponding tidal volume with 6 ml/kg/PBW on the basis of their visual estimation. The patients' true heights were measured and the true PBW with a corresponding tidal volume was calculated. Finally, estimates and measurements were compared. RESULTS:1033 estimations were undertaken by 153 medical professionals. The majority of the estimates were imprecise and resulting data comprised taller body heights, higher PBW and higher tidal volumes (all p≤0.01). When estimates of patients´ heights are used as a reference for tidal-volume definition, patients are exposed to mean tidal volumes of 6.5 ± 0.4 ml/kg/PBW. 526 estimation-based tidal volumes (51.1%) did not provide lung-protective ventilation. Shorter subjects (

In Vietnam, rabies has been a notifiable disease for more than 40 years. Over the last five years, on average, more than 350,000 people per year have been bitten by dogs and cats while more than 80 human deaths have been reported yearly. No studies have been conducted to evaluate the geographical and temporal patterns of rabies in humans in Vietnam. Therefore, the main objective of this study was to assess the geographical and temporal distributions of rabies post exposure prophylaxis (PEP) incidence in humans in Vietnam from 2005 to 2015.Average incidence rabies (AIR) PEP rates for every 3 or 4 years (2005-2008, 2009-2012 and 2013-2015) were calculated to describe the spatial distribution of rabies PEP. Hotspot analysis was implemented to identify patterns of spatial significance using the Getis-Ord Gi statistic. For temporal pattern analysis, two regions [Mekong River Delta (MRD) and Southeast Central Coast (SCC)], with the highest incidence rates, and the seasonal-decomposition procedure based on loess (STL), were compared to assess their temporal patterns of rabies PEP.We found hotspots in southern Vietnam and coldspots in northern Vietnam during the study period. Rabies cases were limited to specific areas. In addition, the hotspot analysis showed that new risk areas were identified in each period which were not observed in incidence rate maps. The seasonal plots showed seasonal patterns with a strong peak in February/July and a minor peak in October/December in the MRD region. However, in the SCC, a small peak was detected at the early part of each year and a strong peak in the middle of each year.Our findings provide insight into understanding the geographical and seasonal patterns of rabies PEP in Vietnam. This study provides evidence to aid policy makers when making decisions and investing resources. Such information may also be utilized to raise public awareness to prevent rabies exposures and reduce unnecessary PEP.

The allocation of time and energy to different behaviours can impact survival and fitness, and ultimately influence population dynamics. Intrinsically, the rate at which animals expend energy is a key component in understanding how they interact with surrounding environments. Activity, derived through locomotion and basic metabolism, represents the principal energy cost for most animals, although it is rarely quantified in the field. We examined some abiotic drivers of variability in locomotor activity of a free-ranging freshwater predatory fish, Murray cod (Maccullochella peelii), for six months using tri-axial accelerometers. Murray cod (n = 20) occupied discrete river reaches and generally exhibited small-scale movements (

Stroke incidence data with methodologically acceptable design in Southeast Asia countries is limited. This study aimed to determine incidence of age-, sex- and subtype-specific first-ever stroke (FES) in Vietnam.We conducted a hospital-based retrospective study, targeting all stroke cases hospitalized at a solo-provider hospital in our study site of Nha Trang from January 2009 to December 2011 with International Classification of Diseases, 10th revision (ICD-10) codes I60-69. We calculated positive predictive values (PPVs) of each ICD-10-coded stroke by conducting a detailed case review of 190 randomly selected admissions with ICD-10 codes of I60-I69. These PPVs were then used to estimate annual incident stroke cases from the computerized database. National census data in 2009 was used as a denominator.2,693 eligible admissions were recorded during the study period. The crude annual incidence rate of total FES was 90.2 per 100,000 population (95% CI 81.1-100.2). The age-adjusted incidence of FES was 115.7 (95% CI 95.9-139.1) when adjusted to the WHO world populations. Importantly, age-adjusted intracerebral hemorrhage was as much as one third of total FES: 36.9 (95% CI 26.1-51.0).We found a considerable proportion of FES in Vietnam to be attributable to intracerebral hemorrhage, which is as high or exceeding levels seen in high-income countries. A high prevalence of improperly treated hypertension in Vietnam may underlie the high prevalence of intracerebral hemorrhagic stroke in this population.

Fishways have been developed to restore longitudinal connectivity in rivers. Despite their potential for aiding fish passage, fishways may represent a source of significant energetic expenditure for fish as they are highly turbulent environments. Nonetheless, our understanding of the physiological mechanisms underpinning fishway passage of fish is still limited. We examined swimming behaviour and activity of silver redhorse (Moxostoma anisurum) during its upriver spawning migration in a vertical slot fishway. We used an accelerometer-derived instantaneous activity metric (overall dynamic body acceleration) to estimate location-specific swimming activity. Silver redhorse demonstrated progressive increases in activity during upstream fishway passage. Moreover, location-specific passage duration decreased with an increasing number of passage attempts. Turning basins and the most upstream basin were found to delay fish passage. No relationship was found between basin-specific passage duration and activity and the respective values from previous basins. The results demonstrate that successful fishway passage requires periods of high activity. The resultant energetic expenditure may affect fitness, foraging behaviour and increase susceptibility to predation, compromising population sustainability. This study highlights the need to understand the physiological mechanisms underpinning fishway passage to improve future designs and interpretation of biological evaluations.

BACKGROUND:The rise in dengue fever cases and the absence of dengue vaccines will likely cause governments to consider various types of effective means for controlling the disease. Given strong public interests in potential dengue vaccines, it is essential to understand the private economic benefits of dengue vaccines for accelerated introduction of vaccines into the public sector program and private markets of high-risk countries. METHODOLOGY/PRINCIPAL FINDINGS:A contingent valuation study for a hypothetical dengue vaccine was administered to 400 households in a multi-country setting: Vietnam, Thailand, and Colombia. All respondents received a description of the hypothetical dengue vaccine scenarios of 70% or 95% effectiveness for 10 or 30 years with a three dose series. Five price points were determined after pilot tests in order to reflect different local situations such as household income levels and general perceptions towards dengue fever. We adopted either Poisson or negative binomial regression models to calculate average willingness-to-pay (WTP), as well as median WTP. We found that there is a significant demand for dengue vaccines. The parametric median WTP is $26.4 ($8.8 per dose) in Vietnam, $70.3 ($23.4 per dose) in Thailand, and $23 ($7.7 per dose) in Colombia. Our study also suggests that respondents place more value on vaccinating young children than school age children and adults. CONCLUSIONS/SIGNIFICANCE:Knowing that dengue vaccines are not yet available, our study provides critical information to both public and private sectors. The study results can be used to ensure broad coverage with an affordable price and incorporated into cost benefit analyses, which can inform prioritization of alternative health interventions at the national level.

BackgroundHierarchical spatial models enable the geographic and ecological analysis of health data thereby providing useful information for designing effective health interventions. In this study, we used a Bayesian hierarchical spatial model to evaluate mortality data in Vietnam. The model enabled identification of socio-ecological risk factors and generation of risk maps to better understand the causes and geographic implications of prime-age (15 to less than 45 years) adult death.Methods and findingsThe study was conducted in two sites: Nha Trang and Hue in Vietnam. The study areas were split into 500×500 meter cells to define neighborhoods. We first extracted socio-demographic data from population databases of the two sites, and then aggregated the data by neighborhood. We used spatial hierarchical model that borrows strength from neighbors for evaluating risk factors and for creating spatially smoothed risk map after adjusting for neighborhood level covariates. The Markov chain Monte Carlo procedure was used to estimate the parameters. Male mortality was more than twice the female mortality. The rates also varied by age and sex. The most frequent cause of mortality was traffic accidents and drowning for men and traffic accidents and suicide for women. Lower education of household heads in the neighborhood was an important risk factor for increased mortality. The mortality was highly variable in space and the socio-ecological risk factors are sensitive to study site and sex.ConclusionOur study suggests that lower education of the household head is an important predictor for prime age adult mortality. Variability in socio-ecological risk factors and in risk areas by sex make it challenging to design appropriate intervention strategies aimed at decreasing prime-age adult deaths in Vietnam.

It is challenging to find genes with stable transcripts for use as reference genes for quantitative realtime polymerase chain reaction (qRT-PCR) during viral infection. Autographa californica nucleopolyhedrovirus (AcMNPV) is known to globally shut off host gene transcription in Sf21 cells and to modify their cytoskeletons. In this study, seven host genes were selected for validation as references for gene expression experiments using qRT-PCR. Two of them, ecdysoneless (ECD) and myosin showed stable RNA levels in our previous microarray study at 6, 12, and 24 hpi for both genes and 48 hpi for ECD. The others, actin, tubulin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and 28S ribosome (28S), are commonly employed as reference genes for qRT-PCR. Ribosomal protein L35 (L35) gene was selected to test if ribosomal protein genes show stable RNA transcript levels similar to 28S and 18S rRNA and to validate the microarray data. In addition to 28S, previously known to have stable transcript levels, qRT-PCR showed that ECD transcript levels remained constant throughout the time course of AcMNPV infection. Transcripts of cytoskeleton genes such as actin, tubulin, and myosin declined dramatically as the infection progressed. GAPDH and L35 transcripts also declined over time. These results indicate that ECD is a reliable reference gene for qRT-PCR experiments during AcMNPV infection of Spodoptera frugiperda cells. Although 28S could be used as a reference gene for these experiments, it is less useful than ECD because of its abundance, which might make it difficult to establish an accurate baseline value for data analysis.

BACKGROUND: Pain and musculoskeletal complaints are among the most common symptoms in the general population. Despite their epidemiological, clinical and health economic importance, prevalence data on pain and musculoskeletal complaints for Germany are scarce. METHODS: A cross-sectional survey of a random sample of citizens of Herne, Germany, aged ≥ 40 years was performed. A detailed self-complete postal questionnaire was used, followed by a short reminder questionnaire and telephone contacts for those not responding. The questionnaire contained 66 items, mainly addressing pain of any site, musculoskeletal complaints of any site and of knee and hip, pain intensities, the Western Ontario MacMaster Universities (WOMAC) index, medication, health care utilization, comorbidities, and quality of life. RESULTS: The response rate was 57.8% (4,527 of 7,828 individuals). Survey participants were on average 1.3 years older, and the proportion of women among responders tended to be greater than in the population sample. There was no age difference between the population sample and 2,221 participants filling out the detailed questionnaire. The following standardized prevalences were assessed: current pain: 59.7%, pain within the past four weeks: 74.5%, current joint complaints: 49.3%, joint complaints within the past four weeks and twelve month: 62.8% and 67.4%, respectively, knee as the site predominantly affected: 30.9%, knee bilateral: 9.7%, hip: 15.2%, hip bilateral: 3.5%, knee and hip: 5.5%. Pain and musculoskeletal complaints were significantly more often reported by women. A typical relationship of pain and joint complaints to age could be found, i.e. increasing prevalences with increasing age categories, with a drop in the highest age groups. In general, pain and joint pain were associated with comorbidity and body mass index as well as quality of life. CONCLUSIONS: Our data confirm findings of other recent national as well as European surveys. The high site specific prevalences of knee and hip complaints underline the necessity to further investigate characteristics and consequences of pain and symptomatic osteoarthritis of these joints in adults in Germany.

BackgroundAedes aegypti, the major vector of dengue viruses, often breeds in water storage containers used by households without tap water supply, and occurs in high numbers even in dense urban areas. We analysed the interaction between human population density and lack of tap water as a cause of dengue fever outbreaks with the aim of identifying geographic areas at highest risk.Methods and findingsWe conducted an individual-level cohort study in a population of 75,000 geo-referenced households in Vietnam over the course of two epidemics, on the basis of dengue hospital admissions (n = 3,013). We applied space-time scan statistics and mathematical models to confirm the findings. We identified a surprisingly narrow range of critical human population densities between around 3,000 to 7,000 people/km² prone to dengue outbreaks. In the study area, this population density was typical of villages and some peri-urban areas. Scan statistics showed that areas with a high population density or adequate water supply did not experience severe outbreaks. The risk of dengue was higher in rural than in urban areas, largely explained by lack of piped water supply, and in human population densities more often falling within the critical range. Mathematical modeling suggests that simple assumptions regarding area-level vector/host ratios may explain the occurrence of outbreaks.ConclusionsRural areas may contribute at least as much to the dissemination of dengue fever as cities. Improving water supply and vector control in areas with a human population density critical for dengue transmission could increase the efficiency of control efforts. Please see later in the article for the Editors' Summary.

BACKGROUND: Killed oral cholera vaccines (OCVs) are available but not used routinely for cholera control except in Vietnam, which produces its own vaccine. In 2007-2008, unprecedented cholera outbreaks occurred in the capital, Hanoi, prompting immunization in two districts. In an outbreak investigation, we assessed the effectiveness of killed OCV use after a cholera outbreak began. METHODOLOGY/PRINCIPAL FINDINGS: From 16 to 28 January 2008, vaccination campaigns with the Vietnamese killed OCV were held in two districts of Hanoi. No cholera cases were detected from 5 February to 4 March 2008, after which cases were again identified. Beginning 8 April 2008, residents of four districts of Hanoi admitted to one of five hospitals for acute diarrhea with onset after 5 March 2008 were recruited for a matched, hospital-based, case-control outbreak investigation. Cases were matched by hospital, admission date, district, gender, and age to controls admitted for non-diarrheal conditions. Subjects from the two vaccinated districts were evaluated to determine vaccine effectiveness. 54 case-control pairs from the vaccinated districts were included in the analysis. There were 8 (15%) and 16 (30%) vaccine recipients among cases and controls, respectively. The vaccine was 76% protective against cholera in this setting (95% CI 5% to 94%, P = 0.042) after adjusting for intake of dog meat or raw vegetables and not drinking boiled or bottled water most of the time. CONCLUSIONS/SIGNIFICANCE: This is the first study to explore the effectiveness of the reactive use of killed OCVs during a cholera outbreak. Our findings suggest that killed OCVs may have a role in controlling cholera outbreaks.

BACKGROUND:We explore the association between bone T-scores, used in osteoporosis diagnosis, and functional status since we hypothesized that bone health can impact elderly functional status and indirectly independence. METHODS:In a cross-sectional study (2005-2006) on community dwelling elderly (> = 75 years) from Herne, Germany we measured bone T-scores with Dual-energy X-ray Absorptiometry, and functional status indexed by five geriatric tests: activities of daily living, instrumental activities of daily living, test of dementia, geriatric depression score and the timed-up-and-go test, and two pooled indexes: raw and standardized. Generalized linear regression was used to determine the relationship between T-scores and functional status. RESULTS:From 3243 addresses, only 632 (19%) completed a clinical visit, of which only 440 (male:female, 243:197) could be included in analysis. T-scores (-0.99, 95% confidence interval [CI], -1.1-0.9) predicted activities of daily living (95.3 CI, 94.5-96.2), instrumental activities of daily living (7.3 CI, 94.5-96.2), and timed-up-and-go test (10.7 CI, 10.0-11.3) (P < = 0.05). Pooled data showed that a unit improvement in T-score improved standardized pooled functional status (15 CI, 14.7-15.3) by 0.41 and the raw (99.4 CI, 97.8-101.0) by 2.27 units. These results were limited due to pooling of different scoring directions, selection bias, and a need to follow-up with evidence testing. CONCLUSIONS:T-scores associated with lower functional status in community-dwelling elderly. Regular screening of osteoporosis as a preventive strategy might help maintain life quality with aging.

The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia.Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]).Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.