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jtitle_s:("Age (dorer)")
1.  Framingham cardiovascular disease risk scores and incident frailty: The English Longitudinal Study of Ageing 
Age (Dordrecht, Netherlands)  2014;36(4):9692.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95% confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74) respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.
doi:10.1007/s11357-014-9692-6
PMCID: PMC4129936  PMID: 25085033
frailty; cardiovascular risk; cohort; longitudinal study
2.  Framingham cardiovascular disease risk scores and incident frailty: the English longitudinal study of ageing 
Age  2014;36(4):9692.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1,726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95 % confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors, the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74), respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.
doi:10.1007/s11357-014-9692-6
PMCID: PMC4129936  PMID: 25085033
Frailty; Cardiovascular risk; Cohort; Longitudinal study
3.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age (Dordrecht, Netherlands)  2013;36(1):10.1007/s11357-013-9553-8.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick Edinburgh Mental Wellbeing Scale (WEMWBS) five to ten years later. Data were drawn from five British cohorts participating in the HALCyon research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10% of a standard deviation (3 studies, N=3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
physical capability; positive mental wellbeing; grip strength; walking speed; chair rise time
4.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age  2013;36(1):445-456.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9553-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
Physical capability; Positive mental wellbeing; Grip strength; Walking speed; Chair rise time
5.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality; whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in 1 s, height FEV1), walking speed (2.44 m), cognitive function (memory and reasoning) and self-reported physical and mental functioning (SF-36) were available on 4,443 individuals, aged 50–74 years. In models adjusted for age, 1 standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta = 0.16, 95% CI: 0.13, 0.19), memory (beta = 0.09, 95% CI: 0.06, 0.12), reasoning (beta = 0.16, 95% CI: 0.13, 0.19) and self-reported physical functioning (beta = 0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), body mass index (BMI) and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good ‘summary’ measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Ageing; Lung function; Cognitive function; Physical function
6.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality, whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in one second, height FEV1), walking speed (over 2.44 m), cognitive function (memory and reasoning), and self-reported physical and mental functioning (SF-36) were available on 4443 individuals, aged 50–74 years. In models adjusted for age, one standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta=0.16, 95% CI: 0.13, 0.19), memory (beta=0.09, 95% CI: 0.06, 0.12), reasoning (beta=0.16, 95% CI: 0.13, 0.19), and self-reported physical functioning (beta=0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), BMI and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good “summary” measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Aged; Aging; physiology; psychology; Cognition; physiology; Female; Health Status; Humans; Lung; physiology; Male; Middle Aged; Spirometry; Walking; physiology; ageing; lung function; cognitive function; physical function
7.  The importance of cognitive ageing for understanding dementia 
Age  2010;32(4):509-512.
A third of those over 80 years of age are likely to have dementia, the lack of a cure requires efforts directed at prevention and delaying the age of onset. We argue here for the importance of understanding the cognitive ageing process, seen as the decline in various cognitive functions from adulthood to old age. The impact of age on cognitive function is heterogeneous and the identification of risk factors associated with adverse cognitive ageing profiles would allow well-targeted interventions, behavioural or pharmacological, to delay and reduce the population burden of dementia. A shift away from binary outcomes such as dementia assessed at one point in time in elderly populations to research on cognitive ageing using repeated measures of cognitive function and starting earlier in the life course would allow the sources of variability in ageing to be better understood.
doi:10.1007/s11357-010-9147-7
PMCID: PMC2980594  PMID: 20454932
Alzheimer’s disease; Dementia; Cognitive ageing
8.  The importance of cognitive aging for understanding dementia 
Age  2010;32(4):509-512.
A third of those over 80 years of age are likely to have dementia, the lack of a cure requires efforts directed at prevention and delaying the age of onset. We argue here for the importance of understanding the cognitive ageing process, seen as the decline in various cognitive functions from adulthood to old age. The impact of age on cognitive function is heterogeneous and the identification of risk factors associated with adverse cognitive ageing profiles would allow well targeted interventions, behavioural or pharmacological, to delay and reduce the population burden of dementia. A shift away from binary outcomes such as dementia assessed at one point in time in elderly populations to research on cognitive ageing using repeated measures of cognitive function and staring earlier in the lifecourse would allow the sources of variability in ageing to be better understood.
doi:10.1007/s11357-010-9147-7
PMCID: PMC2980594  PMID: 20454932
Aging; Alzheimer Disease; epidemiology; physiopathology; Cognition; Dementia; diagnosis; epidemiology; physiopathology; prevention & control; therapy; France; epidemiology; Humans; Prevalence; Risk Factors; World Health Organization
9.  Dehydroepiandrosterone and age-related cognitive decline 
Age  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
10.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
11.  Long non-coding RNA produced by RNA polymerase V determines boundaries of heterochromatin 
eLife  null;5:e19092.
RNA-mediated transcriptional gene silencing is a conserved process where small RNAs target transposons and other sequences for repression by establishing chromatin modifications. A central element of this process are long non-coding RNAs (lncRNA), which in Arabidopsis thaliana are produced by a specialized RNA polymerase known as Pol V. Here we show that non-coding transcription by Pol V is controlled by preexisting chromatin modifications located within the transcribed regions. Most Pol V transcripts are associated with AGO4 but are not sliced by AGO4. Pol V-dependent DNA methylation is established on both strands of DNA and is tightly restricted to Pol V-transcribed regions. This indicates that chromatin modifications are established in close proximity to Pol V. Finally, Pol V transcription is preferentially enriched on edges of silenced transposable elements, where Pol V transcribes into TEs. We propose that Pol V may play an important role in the determination of heterochromatin boundaries.
DOI: http://dx.doi.org/10.7554/eLife.19092.001
doi:10.7554/eLife.19092
PMCID: PMC5079748  PMID: 27779094
lncRNA; RdDM; transposons; A. thaliana
12.  Gastrointestinal Dopamine as an Anti-Incretin and Its Possible Role in Bypass Surgery as Therapy for Type 2 Diabetes with Associated Obesity 
Minerva endocrinologica  2015;41(1):43-56.
The objective of this review is to summarize and integrate specific clinical observations from the field of gastric bypass surgery and recent findings in beta cell biology. When considered together, these data sets suggest a previously unrecognized physiological mechanism which may explain how Roux-en-Y gastric bypass (RYGB) surgery mediates the early rapid reversal of hyperglycemia, observed before weight loss, in certain Type 2 Diabetes Mellitus (T2DM) patients. The novel mechanism is based on a recently recognized inhibitory circuit of glucose stimulated insulin secretion driven by dopamine (DA) stored in β-cell vesicles and the gut. We propose that dopamine (DA) and Glucagon like peptide 1 (GLP-1) represent two opposing arms of a glucose stimulated insulin secretion (GSIS) regulatory system and hypothesize that DA represents the “anti incretin” hypothesized to explain the beneficial effects of bariatric surgery on T2DM. These new hypotheses and the research driven by them may directly impact our understanding of: 1) the mechanisms underlying improved glucose homeostasis seen before weight loss following bariatric surgery, and 2) the regulation of glucose stimulated insulin secretion within islets. On a practical level, these studies may result in the development of novels drugs to modulate insulin secretion and/or methods to quantitatively asses in real time beta cell function and mass.
PMCID: PMC5079753  PMID: 26505694
Anti-incretin; Bariatric surgery; Dopamine; Glucose stimulated insulin secretion
13.  Homology modeling, molecular dynamics, and virtual screening of NorA efflux pump inhibitors of Staphylococcus aureus 
Emerging drug resistance in clinical isolates of Staphylococcus aureus might be implicated to the overexpression of NorA efflux pump which is capable of extruding numerous structurally diverse compounds. However, NorA efflux pump is considered as a potential drug target for the development of efflux pump inhibitors. In the present study, NorA model was constructed based on the crystal structure of glycerol-3-phosphate transporter (PDBID: 1PW4). Molecular dynamics (MD) simulation was performed using NAMD2.7 for NorA which is embedded in the hydrated lipid bilayer. Structural design of NorA unveils amino (N)- and carboxyl (C)-terminal domains which are connected by long cytoplasmic loop. N and C domains are composed of six transmembrane α-helices (TM) which exhibits pseudo-twofold symmetry and possess voluminous substrate binding cavity between TM helices. Molecular docking of reserpine, totarol, ferruginol, salvin, thioxanthene, phenothiazine, omeprazole, verapamil, nalidixic acid, ciprofloxacin, levofloxacin, and acridine to NorA found that all the molecules were bound at the large hydrophobic cleft and indicated significant interactions with the key residues. In addition, structure-based virtual screening was employed which indicates that 14 potent novel lead molecules such as CID58685302, CID58685367, CID5799283, CID5578487, CID60028372, ZINC12196383, ZINC72140751, ZINC72137843, ZINC39227983, ZINC43742707, ZINC12196375, ZINC66166948, ZINC39228014, and ZINC14616160 have highest binding affinity for NorA. These lead molecules displayed considerable pharmacological properties as evidenced by Lipinski rule of five and prophecy of toxicity risk assessment. Thus, the present study will be helpful in designing and synthesis of a novel class of NorA efflux pump inhibitors that restore the susceptibilities of drug compounds.
doi:10.2147/DDDT.S113556
PMCID: PMC5055111  PMID: 27757014
Staphylococcus aureus; NorA efflux pump; molecular dynamics; virtual screening; docking
14.  Plasma tenofovir trough concentrations are associated with renal dysfunction in Japanese patients with HIV infection: a retrospective cohort study 
Background
Plasma tenofovir (TFV) trough concentrations may be relevant for tenofovir disoproxil fumarate (TDF)-induced renal dysfunction. The purpose of this study was to determine the association between plasma TFV trough concentrations and TDF-induced renal dysfunction in Japanese patients with human immunodeficiency virus (HIV) infection.
Methods
A 48-week, retrospective cohort study was performed with Japanese patients with HIV infection who started a TDF-containing combination antiretroviral therapy regimen. Plasma TFV trough concentrations were obtained at steady state. The following variables were included in the analysis: sex, age, body weight, body mass index (BMI), serum creatinine, CD4+ cell count, HIV-RNA, concomitant medications, comorbidities, plasma TFV trough concentrations, and estimated glomerular filtration rate (eGFR). For comparisons of variables, we used Mann-Whitney U tests or Fisher’s exact tests. Then, variables associated with renal dysfunction in the univariate analysis were entered into correlation analysis.
Results
The analysis included 11 patients. The rate of decrease in eGFR was significantly correlated with body weight (Spearman correlation = −0.645, p = 0.041), BMI (Spearman correlation = −0.682, p = 0.031), and plasma TFV trough concentrations (Spearman correlation = 0.709, p = 0.025).
Conclusions
Despite the small sample size, our findings suggest that higher plasma TFV trough concentrations may cause TDF-induced renal dysfunction. To prevent TDF-induced renal dysfunction, we propose that individual monitoring of plasma TFV trough concentrations should be performed in Japanese patients with HIV infection.
Electronic supplementary material
The online version of this article (doi:10.1186/s40780-016-0056-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s40780-016-0056-5
PMCID: PMC5034427  PMID: 27688900
Combination antiretroviral therapy; HIV; Plasma tenofovir trough concentration; Renal dysfunction; Tenofovir disoproxil fumarate; Therapeutic drug monitoring
15.  A prospective comparison of ER, PR, Ki67 and gene expression in paired sequential core biopsies of primary, untreated breast cancer 
BMC Cancer  2016;16:745.
Background
Sequential biopsy of breast cancer is used to assess biomarker effects and drug efficacy. The preoperative “window of opportunity” setting is advantageous to test biomarker changes in response to therapeutic agents in previously untreated primary cancers. This study tested the consistency over time of paired, sequential biomarker measurements on primary, operable breast cancer in the absence of drug therapy.
Methods
Immunohistochemistry was performed for ER, PR and Ki67 on paired preoperative/operative tumor samples taken from untreated patients within 2 weeks of each other. Microarray analysis on mRNA extracted from formalin fixed paraffin embedded cores was performed using Affymetrix based arrays on paired core biopsies analysed using Ingenuity Pathway Analysis (IPA) and Gene Set Analysis (GSA).
Results
In 41 core/resection pairs, the recognised trend to lower ER, PR and Ki67 score on resected material was confirmed. Concordance for ER, PR and Ki67 without changing biomarker status (e.g. ER+ to ER-) was 90, 74 and 80 % respectively. However, in 23 paired core samples (diagnostic core v on table core), Ki67 using a cut off of 13.25 % was concordant in 22/23 (96 %) and differences in ER and PR immunohistochemistry by Allred or Quickscore between the pairs did not impact hormone receptor status. IPA and GSA demonstrated substantial gene expression changes between paired cores at the mRNA level, including reduced expression of ER pathway analysis on the second core, despite the absence of drug intervention.
Conclusions
Sequential core biopsies of primary breast cancer (but not core versus resection) was consistent and is appropriate to assess the effects of drug therapy in vivo on ER, PR and Ki67 using immunohistochemistry. Conversely, studies utilising mRNA expression may require non-treatment controls to distinguish therapeutic from biopsy differences.
doi:10.1186/s12885-016-2788-x
PMCID: PMC5034430  PMID: 27658825
Breast cancer; Biomarkers; Expression arrays
16.  The relation between angioarchitectural factors of developmental venous anomaly and concomitant sporadic cavernous malformation 
BMC Neurology  2016;16:183.
Background
Past studies found that cerebral developmental venous anomaly (DVA) is often concurrent with cavernous malformation (CM). But the reason of the concurrency remains unknown. The purpose of this study was to confirm whether angioarchitectural factors relate to the concurrence and which angioarchitectural factors can induce the concurrency.
Methods
DVA cases were selected from the records of the same 3.0 T MR. The DVA cases was divided into two group which are DVA group and DVA concurrent with CM group. 8 angioarchitectural factors of the DVAs were selected and measured. Statistical analysis was performed by the Pearson chi-square statistic,analysis of variance (ANOVA) and multi-factor logistic regression analysis.
Results
Five hundred three DVA lesions were found and 76 CM lesions coexisting with DVA. In the single factor analysis, all the 8 angioarchitectural factors of DVA were related to the concurrency. In the multivariate analysis, 6 angioarchitectural factors. Result of multi-factor logistic regression analysis is Logit(P) = -4.858-0.932(Location) + 1.616(Direction) + 1.757(Torsion) + 0.237(Number) + 2.119(Stenosis rate of medullary vein)-0.015(Angle), goodness of fit is 90.1 %.
Conclusions
The angioarchitectural factors of DVA are related to the concurrency of DVA and CM. 6 angioarchitectural factors may induce the concurrency.
doi:10.1186/s12883-016-0691-3
PMCID: PMC5034432  PMID: 27660100
Developmental venous anomaly (DVA); Cavernous malformation (CM); Angioarchitectural factors; Contrast-enhanced magnetic resonance imaging
17.  Prevalence of PTSD and other mental disorders in UK service personnel by time since end of deployment: a meta-analysis 
BMC Psychiatry  2016;16:333.
Background
US studies have shown an increase of posttraumatic stress disorder (PTSD) and depression, but not alcohol misuse related to time of assessment since returning from deployment. We assessed if similar trends occur in the UK Armed Forces.
Methods
We selected UK studies based on our data base of King’s Centre for Military Health Research publications from 2006 until January 2016 with at least one of the following measures: PTSD checklist-civilian version (PCL-C), the General Health Questionnaire (GHQ-12) and the Alcohol Use Disorders Identification Test (AUDIT). The studies included personnel assessed for these outcomes after their most recent deployment. A search in Medline, Psycho-Info and Embase confirmed that no relevant publication was missed.
Results
Twenty one thousand, seven hundred and forty-six deployed personnel from nine studies contributed to the meta-analyses by time since end of deployment in the PTSD analysis. The number of studies for period of time varied from two to four studies. The trend by time-category of questionnaire completion since returning from deployment were for PTSD β = 0.0021 (95 % CI −0.00046 to 0.0049, p = 0.12), for psychological distress β = 0.0123 (95 % CI 0.005 to 0.019, p = 0.002) and for alcohol misuse β = 0.0013 (−0.0079 to 0.0105, p = 0.77).
Conclusions
There was no evidence that the prevalence of PTSD and alcohol misuse changed according to time since the end of deployment over a three-year period, but there was evidence for an association with increasing psychological distress.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-016-1038-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-016-1038-8
PMCID: PMC5034433  PMID: 27659728
Alcohol misuse; Impact of deployment over time; Posttraumatic stress disorder (PTSD); Psychological distress; Prevalence trends
18.  A cross-sectional study on the concordance between vaginal HPV DNA detection and type-specific antibodies in a multi-ethnic cohort of women from Amsterdam, the Netherlands – the HELIUS study 
BMC Infectious Diseases  2016;16:502.
Background
Acquisition of genital human papillomavirus (HPV) infection is common among the young, sexually active population. Genital HPV infections do not always lead to seroconversion. We aimed to assess the association between cervico-vaginal high risk (hr) HPV DNA and type-specific antibodies in an ethnically diverse cohort of young women.
Methods
Women of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Moroccan and Turkish origin participating in a large-scale multi-ethnic population-based cohort (the HELIUS study) provided vaginal self-samples and blood samples, and completed a questionnaire regarding demographics, lifestyle and sexual health. Vaginal swabs were tested for HPV using the highly sensitive SPF10-PCR DEIA/LiPA25 system (version1). Serum samples were tested for type-specific L1 antibodies against 7 hrHPV types (16,18,31,33,45,52,58) with multiplex serology. We assessed the association between vaginal HPV DNA and type-specific seropositivity with logistic and linear regression, using generalized estimating equations (GEE). We determined whether this association varies by ethnicity by adding an interaction term.
Results
We selected 532 women who completed the questionnaire, provided a vaginal swab and a blood sample. Their median age was 27 years (interquartile range 24–31 years). Prevalence of DNA of any of the 7 hrHPV was 22 %; HPV-52 was most common. Prevalence of antibodies against one or more hrHPV types was 24 %; HPV-16 seropositivity was most common. In multivariable logistic regression analysis using GEE, adjusting for other determinants, vaginal HPV DNA detection was associated with type-specific HPV seropositivity (OR 1.53, 95 % CI 1.06-2.20). In multivariable linear regression analysis using GEE, the geometric mean of type-specific antibody reactivity was 1.15 (95 % CI 1.04-1.27) times higher in women positive for HPV DNA compared to HPV DNA-negative women. There was little evidence that ethnicity modified the association between HPV DNA, and type-specific seropositivity, or with antibody reactivities (p = 0.47 and p = 0.57, respectively).
Conclusions
In this multi-ethnic group of young women in Amsterdam, cervico-vaginal hrHPV DNA detection was an independent determinant of type-specific HPV seropositivity.
doi:10.1186/s12879-016-1832-4
PMCID: PMC5034434  PMID: 27659061
Human papillomavirus; Vaginal; Antibodies; Serology; Concordance; HELIUS study
19.  Whether G-CSF administration has beneficial effect on the outcome after assisted reproductive technology? A systematic review and meta-analysis 
Background
Previous studies have explored the effect of granulocyte colony stimulating factor (G-CSF) administration on the outcome of assisted reproductive technology (ART), and came into controversial conclusions. The present meta-analysis aims to assess whether G-CSF administration has beneficial effect on the outcome after ART.
Method
The electronic databases Pubmed, Embase and Google Scholar were searched up to May 2016. Articles that studied the effect of G-CSF administration on the outcome after ART were included in the present meta-analysis. Odds ratio (OR) with 95 % confidence interval (95 % CI) were calculated to assess the effect of G-CSF administration on the outcome after ART. The outcomes of interest were implantation rate (IR) and pregnancy rate (PR).
Results
Four cohort studies with 1101 embryos transplantation assessed the effect of G-CSF administration on IR and 6 studies with 621 cycles assessed the role of G-CSF administration in PR. Meta-analysis did not found an increased embryo IR in G-CSF administration cycles [OR 1.59 (95 % CI 0.74–3.41). whereas the PR with G-CSF administration was significantly higher compared with cases without G-CSF administration [OR 2.03 (95 % CI 1.19–3.46)]. Additionally, we found that G-CSF administrated subcutaneously resulted in significantly higher PR [OR 3.12 (95 % CI 1.67–5.81)] and IR [OR 2.82 (95 % CI 1.29–6.15)] compared with control group, whereas G-CSF administrated via local uterine infusion had no beneficial effect on the PR [OR 1.42 (95 % CI 0.91–2.24)] and IR [OR 1.10 (95 % CI 0.76–1.60)] after ART.
Conclusions
G-CSF administration may have beneficial effect on clinical pregnancy outcome after ART. Subcutaneous injection may be an optimal route of G-CSF administration. Further cohort studies are required to explore the mechanisms undergone the effect and investigate the best route and dose of G-CSF administration.
Electronic supplementary material
The online version of this article (doi:10.1186/s12958-016-0197-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12958-016-0197-2
PMCID: PMC5034435  PMID: 27659067
Granulocyte colony-stimulating factor (G-CSF); Implantation rate; Pregnancy rate; Assisted reproductive technology (ART)
20.  Antibacterial in vitro effects of preparations from Anthroposophical Medicine 
Background
Medications from Anthroposophical Medicine (AM) are clinically used for the treatment of infections within a whole medical system but have not yet been evaluated regarding antibacterial effects. The aims of this study was to investigate antibacterial activity of AM medications in cell culture.
Methods
Screening of AM drug registers for preparations used to treat any kind of infection and being available in dilutions ≤ D2 and without alcoholic content. Selected medications were screened for antimicrobial activity against Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa using the agar diffusion method. For antimicrobial active preparations growth kinetics (drop plate method) and minimal inhibitory concentrations (MIC, macrodilution method) were determined.
Results
Thirty-three preparations matched the selection criteria and were chosen for own experiments. One of them (Berberis Decoctum D2) exhibited bactericidal activities against Bacillus subtilis and Staphylococcus aureus, including methicillin resistant strains. The MIC could be determined as 5 mg/ml. The effects could be related to the content of berberine in the extract. No activity towards gram-negative bacteria was found. The other tested extracts had no antibacterial effects.
Conclusion
Berberis Decoctum D2 which is used in AM to treat infections exhibits bactericidal effects on Staphylococcus aureus, including methicillin resistant strains.
doi:10.1186/s12906-016-1350-3
PMCID: PMC5034436  PMID: 27660088
Staphylococcus; MRSA; Berberis radix; Berberine; Parenteral use
21.  The central role of national programme management for the achievement of malaria elimination: a cross case-study analysis of nine malaria programmes 
Malaria Journal  2016;15:488.
Background
A malaria eradication goal has been proposed, at the same time as a new global strategy and implementation framework. Countries are considering the strategies and tools that will enable progress towards malaria goals. The eliminating malaria case-study series reports were reviewed to identify successful programme management components using a cross-case study analytic approach.
Methods
Nine out of ten case-study reports were included in the analysis (Bhutan, Cape Verde, Malaysia, Mauritius, Namibia, Philippines, Sri Lanka, Turkey, Turkmenistan). A conceptual framework for malaria elimination programme management was developed and data were extracted and synthesized. Findings were reviewed at a consultative workshop, which led to a revision of the framework and further data extraction and synthesis. Success factors of implementation, programme choices and changes, and enabling factors were distilled.
Results
Decentralized programmes enhanced engagement in malaria elimination by sub-national units and communities. Integration of the malaria programme into other health services was also common. Decentralization and integration were often challenging due to the skill and experience levels of newly tasked staff. Accountability for programme impact was not clarified for most programmes. Motivation of work force was a key factor in maintaining programme quality but there were few clear, detailed strategies provided. Different incentive schemes targeted various stakeholders. Training and supervision, although not well described, were prioritized by most programmes. Multi-sectoral collaboration helped some programmes share information, build strategies and interventions and achieve a higher quality of implementation. In most cases programme action was spurred by malaria outbreaks or a new elimination goal with strong leadership. Some programmes showed high capacity for flexibility through introduction of new strategies and tools. Several case-studies described methods for monitoring implementation quality and coverage; however analysis and feedback to those implementing malaria elimination in the periphery was not well described. Political commitment and sustained financing contributed to malaria programme success. Consistency of malaria programmes depends on political commitment, human and financial resources, and leadership. Operational capacity of the programme and the overall health system structure and strength are also important aspects.
Conclusions
Malaria eradication will require adaptive, well-managed malaria programmes that are able to tailor implementation of evidence-based strategies, founded upon strong sub-national surveillance and response, with adequate funding and human resources.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-016-1518-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s12936-016-1518-9
PMCID: PMC5034437  PMID: 27659770
Malaria elimination; Program management; Case-study
22.  To gate or not to gate - dosimetric evaluation comparing Gated vs. ITV-based methodologies in stereotactic ablative body radiotherapy (SABR) treatment of lung cancer 
Background
To compare retrospectively generated gated plans to conventional internal target volume (ITV)-based plans and to evaluate whether gated radiotherapy provides clinically relevant dosimetric improvements to organs-at-risk (OARs).
Methods
Evaluation was performed of 150 stereotactic ablative radiotherapy treatment plans delivered to 128 early-stage (T1-T3 (<5 cm)) NSCLC patients. To generate gated plans, original ITV-based plans were re-optimized and re-calculated on the end-exhale phase and using gated planning target volumes (PTV). Gated and ITV-based plans were produced for 3 × 18 Gy and 4 × 12 Gy fractionation regimens. Dose differences between gated and ITV-based plans were analyzed as a function of both three-dimensional motion and tumor volume. OARs were analyzed using RTOG and AAPM dose constraints.
Results
Differences between gated and ITV-based plans for all OAR indices were largest for the 3 × 18 Gy regimen. For this regimen, MLD differences calculated by subtracting the gated values from the ITV-based values (ITV vs. Gated) were 0.10 ± 0.56 Gy for peripheral island (N = 57), 0.16 ± 0.64 Gy for peripheral lung-wall seated (N = 57), and 0.10 ± 0.64 Gy for central tumors (N = 36). Variations in V20 were similarly low, with the greatest differences occurring in peripheral tumors (0.20 ± 1.17 %). Additionally, average differences (in 2Gy-equivalence) between ITV and gated lung indices fell well below clinical tolerance values for all fractionation regimens, with no clinically meaningful differences observed from the 4 × 12 Gy regimen and rarely for the 3 × 18 Gy regimen (<2 % of cases). Dosimetric differences between gated and ITV-based methods did generally increase with increasing tumor motion and decreasing tumor volume. Dose to ribs and bronchial tree were slightly higher in gated plans compared to ITV-based plans and slightly lower for esophagus, heart, spinal cord, and trachea.
Conclusions
Analysis of 150 SABR-based lung cancer treatment plans did not show a substantial benefit for the gating regimen when compared to ITV-based treatment plans. Small benefits were observed only for the largest tumor motion (exceeding 2 cm) and the high dose treatment regimen (3 × 18 Gy), though these benefits did not appear to be clinically relevant.
doi:10.1186/s13014-016-0699-2
PMCID: PMC5034438  PMID: 27659780
SABR; Gating; ITV-based planning; Treatment planning
23.  Forces influencing generic drug development in the United States: a narrative review 
Background
The United States (U.S.) Food and Drug Administration, as protectors of public health, encourages generic drug development and use so that patients can access affordable medications. The FDA, however, has limited mechanisms to encourage generic drug manufacturing.
Main results
Generic drug manufacturers make decisions regarding development of products based on expected profitability, influenced by market forces, features of the reference listed drug, and manufacturing capabilities, as well as regulatory restrictions. Barriers to the development of generic drugs include the challenge of demonstrating bioequivalence of some products, particularly those that are considered to be complex generics.
Conclusions
We present here a focused review describing the influences on generic manufacturers who are prioritizing drugs for generic development. We also review proposed strategies that regulators may use to incentivize generic drug development.
doi:10.1186/s40545-016-0079-1
PMCID: PMC5034442  PMID: 27688886
Generic drug; Incentives; U.S. Food and Drug Administration
24.  Health Information Technologies—Academic and Commercial Evaluation (HIT-ACE) methodology: description and application to clinical feedback systems 
Background
Health information technologies (HIT) have become nearly ubiquitous in the contemporary healthcare landscape, but information about HIT development, functionality, and implementation readiness is frequently siloed. Theory-driven methods of compiling, evaluating, and integrating information from the academic and commercial sectors are necessary to guide stakeholder decision-making surrounding HIT adoption and to develop pragmatic HIT research agendas. This article presents the Health Information Technologies—Academic and Commercial Evaluation (HIT-ACE) methodology, a structured, theory-driven method for compiling and evaluating information from multiple sectors. As an example demonstration of the methodology, we apply HIT-ACE to mental and behavioral health measurement feedback systems (MFS). MFS are a specific class of HIT that support the implementation of routine outcome monitoring, an evidence-based practice.
Results
HIT-ACE is guided by theories and frameworks related to user-centered design and implementation science. The methodology involves four phases: (1) coding academic and commercial materials, (2) developer/purveyor interviews, (3) linking putative implementation mechanisms to hit capabilities, and (4) experimental testing of capabilities and mechanisms. In the current demonstration, phase 1 included a systematic process to identify MFS in mental and behavioral health using academic literature and commercial websites. Using user-centered design, implementation science, and feedback frameworks, the HIT-ACE coding system was developed, piloted, and used to review each identified system for the presence of 38 capabilities and 18 additional characteristics via a consensus coding process. Bibliometic data were also collected to examine the representation of the systems in the scientific literature. As an example, results are presented for the application of HIT-ACE phase 1 to MFS wherein 49 separate MFS were identified, reflecting a diverse array of characteristics and capabilities.
Conclusions
Preliminary findings demonstrate the utility of HIT-ACE to represent the scope and diversity of a given class of HIT beyond what can be identified in the academic literature. Phase 2 data collection is expected to confirm and expand the information presented and phases 3 and 4 will provide more nuanced information about the impact of specific HIT capabilities. In all, HIT-ACE is expected to support adoption decisions and additional HIT development and implementation research.
doi:10.1186/s13012-016-0495-2
PMCID: PMC5034443  PMID: 27659426
Health information technology; Measurement feedback systems; Behavioral health; Mental health; Competitive analysis; Routine outcome monitoring
25.  Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways 
BMC Cancer  2016;16:746.
Background
Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood.
Methods
In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by “reverse phase protein array” (RPPA) and western blotting experiments conducted on selected proteins to confirm the results.
Results
We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia.
Conclusions
Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2776-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2776-1
PMCID: PMC5034444  PMID: 27658583
ALL; Chemoresistance; Hypoxia; Methotrexate; Prednisolone; RPPA

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