Androgen activity and markers of inflammation among men in NHANES III

ObjectivesInflammation contributes to chronic diseases. Lower serum testosterone among men is associated with less inflammation, yet immune defense is thought to trade-off against reproduction with androgens adversely affecting immune function. Anti-androgens are effective at castrate levels of serum testosterone, suggesting serum testosterone may not capture all androgen activity. The association of two androgen biomarkers with key markers of inflammation was examined. Methods The adjusted association of serum testosterone and androstanediol glucuronide with Creactive protein, white blood cell, granulocyte and lymphocyte count, fibrinogen and hemoglobin, as a control outcome because testosterone administration raises hemoglobin, were examined in a nationally representative sample of 1490 US men from NHANES III phase 1 (1988-91) using multivariable linear regression. Results Serum testosterone and androstanediol glucuronide were weakly correlated (0.13). Serum testosterone was associated with lower white blood cell count (−0.26*10−9 per standard deviation, 95% confidence interval (CI) −0.37 to −0.14) and granulocyte count (−0.21*10−9, 95% CI −0.29 to −0.13) but not with hemoglobin (0.02 g/L, 95% CI −0.89 to 0.92), adjusted for age, education, race/ethnicity, smoking and alcohol. Similarly adjusted, androstanediol glucuronide was not associated with white blood cell count (0.10*10−9, 95% CI −0.05 to −0.25), granulocyte count (0.12*10−9, 95% CI −0.02 to 0.25) or fibrinogen (0.05g/L, 95% CI −0.004 to 0.11), but was with hemoglobin (0.70g/L, 95% CI 0.07 to 1.32). Conclusions Different androgen biomarkers had different associations with inflammatory markers, highlighting the need to consider several androgen biomarkers. The possibility remains that androgens may generate inflammatory processes with implications for chronic disease

Informal Child Care and Adolescent Psychological Well-Being: Hong Kong’s “Children of 1997” Birth Cohort

Background Informal child care (child care by untrained family members, relatives or employees in the home) in Western populations is often associated with poorer psychological well-being, which may be confounded by socioeconomic position. We examined the association of informal child care, common in non-Western settings, with adolescent psychological wellbeing, using Hong Kong’s Chinese “Children of 1997” birth cohort. Methods Multivariable linear regression was used to examine the adjusted associations of informal child care (at 0.5, 3, 5 and 11 years) with parent-reported Rutter score for child behavior at 11 years, self-reported Culture-Free Self-Esteem Inventories score at 11 years and selfreported Patient Health Questionnaire-9 depressive symptom score at 13 years. Model comparisons were used to identify the best representation of child care, in terms of a critical period of exposure to informal child care (independent variable) at a specific age, combination of exposures to informal child care at several ages or an accumulation of exposures to informal child care. Results Child care was not associated with behavioral problems. A model considering child care at 3 years best represented the association of child care with self-esteem while a model considering child care at 5 years best represented the association of child care with depressive symptoms. Informal child care at 3 years was associated with lower self-esteem (-0.70, 95% confidence interval (CI) -1.26 to -0.14). Informal child care at 5 years was associated with more depressive symptoms (0.45, 95% CI 0.17 to 0.73)

Re-thinking Alzheimer\u27s disease therapeutic targets using gene-based tests

Background: Alzheimer\u27s disease (AD) is a devastating condition with no known effective drug treatments. Existing drugs only alleviate symptoms. Given repeated expensive drug failures, we assessed systematically whether approved and investigational AD drugs are targeting products of genes strongly associated with AD and whether these genes are targeted by existing drugs for other indications which could be re-purposed. Methods: We identified genes strongly associated with late-onset AD fromthe loci of genetic variants associated with AD at genome-wide-significance and from a gene-based test applied to the most extensively genotyped late-onset AD case (n=17,008)-control (n=37,154) study, the International Genomics of Alzheimer\u27s Project. We used three gene-to-drug cross-references, Kyoto Encyclopedia of Genes and Genomes, Drugbank and Drug Repurposing Hub, to identify genetically validated targets of AD drugs and any existing drugs or nutraceuticals targeting products of the genes strongly associated with late-onset AD. Findings: A total of 67 autosomal genes (forming 9 gene clusters) were identified as strongly associated with lateonset AD, 28 from the loci of single genetic variants, 51 from the gene-based test and 12 by both methods. Existing approved or investigational AD drugs did not target products of any of these 67 genes. Drugs for other indications targeted 11 of these genes, including immunosuppressive disease-modifying anti-rheumatic drugs targeting PTK2B gene products. Interpretation: Approved and investigational AD drugs are not targeting products of genes strongly associated with late-onset AD. However, other drugs targeting products of these genes exist and could perhaps be repurposing to combat late-onset AD after further scrutiny

Mode of delivery and child and adolescent psychological well-being: Evidence from Hong Kong’s “Children of 1997” birth cohort

Mode of delivery (vaginal or cesarean section) is thought to affect gut microbiota, which in turn may affect psychological well-being. As such, mode of delivery is potentially a modifiable factor for psychological well-being. Here we examined the association of mode of delivery with child and adolescent psychological well-being. We used multivariable linear regression in a populationrepresentative Hong Kong Chinese birth cohort, “Children of 1997,” to examine the adjusted associations of mode of delivery with behavioral problems assessed from parent-reported Rutter score at ~7 (n = 6294) and ~11 years (n = 5598), self-esteem assessed from self-reported Culture-Free Self- Esteem Inventory score at ~11 years (n = 6937) and depressive symptoms assessed from self-reported Patient Health Questionnaire-9 score at ~13 years (n = 5797). Cesarean Section (CS) was associated with children born in private hospitals, boys, and firstborns, higher maternal body mass index, higher maternal age, preeclampsia, higher socioeconomic position (SEP) and maternal birth in Hong Kong. CS was unrelated to behavior, self-esteem and depressive symptoms adjusted for infant characteristics (sex, gestational age, birthweight, parity and breast feeding), maternal characteristics (mother’s age and place of birth) and SEP. In a developed non-Western setting, mode of delivery was not clearly associated with childhood or early adolescent psychological well-being

Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials

Background Testosterone therapy is increasingly promoted. No randomized placebo-controlled trial has been implemented to assess the effect of testosterone therapy on cardiovascular events, although very high levels of androgens are thought to promote cardiovascular disease. Methods A systematic review and meta-analysis was conducted of placebo-controlled randomized trials of testosterone therapy among men lasting 12+ weeks reporting cardiovascular-related events. We searched PubMed through the end of 2012 using “(“testosterone” or “androgen”) and trial and (“random*”)” with the selection limited to studies of men in English, supplemented by a bibliographic search of the World Health Organization trial registry. Two reviewers independently searched, selected and assessed study quality with differences resolved by consensus. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting. Results Of 1,882 studies identified 27 trials were eligible including 2,994, mainly older, men who experienced 180 cardiovascular-related events. Testosterone therapy increased the risk of a cardiovascular-related event (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.09 to 2.18). The effect of testosterone therapy varied with source of funding (P-value for interaction 0.03), but not with baseline testosterone level (P-value for interaction 0.70). In trials not funded by the pharmaceutical industry the risk of a cardiovascular-related event on testosterone therapy was greater (OR 2.06, 95% CI 1.34 to 3.17) than in pharmaceutical industry funded trials (OR 0.89, 95% CI 0.50 to 1.60). Conclusions The effects of testosterone on cardiovascular-related events varied with source of funding. Nevertheless, overall and particularly in trials not funded by the pharmaceutical industry, exogenous testosterone increased the risk of cardiovascular-related events, with corresponding implications for the use of testosterone therapy

Trends in Mortality from Septicaemia and Pneumonia with Economic Development: An Age-Period-Cohort Analysis

BackgroundHong Kong population has experienced drastic changes in its economic development in the 1940s. Taking advantage of Hong Kong’s unique demographic and socioeconomic history, characterized by massive, punctuated migration waves from Southern China, and recent, rapid transition from a pre-industrialized society to the first ethnic Chinese community reaching ‘‘first world’’ status over the last 60 years (i.e., in two or three generations), we examined the longitudinal trends in infection related mortality including septicemia compared to trends in non-bacterial pneumonia to generate hypotheses for further testing in other recently transitioned economies and to provide generalized aetiological insights on how economic transition affects infection-related mortality. Methods We used deaths from septicemia and pneumonia not specified as bacterial, and population figures in Hong Kong from 1976–2005. We fitted age-period-cohort models to decompose septicemia and non-bacterial pneumonia mortality rates into age, period and cohort effects. Results Septicaemia-related deaths increased exponentially with age, with a downturn by period. The birth cohort curves had downward inflections in both sexes in the 1940s, with a steeper deceleration for women. Non-bacterial pneumoniarelated deaths also increased exponentially with age, but the birth cohort patterns showed no downturns for those born in the 1940s. Conclusion The observed changes appeared to suggest that better early life conditions may enable better development of adaptive immunity, thus enhancing immunity against bacterial infections, with greater benefits for women than men. Given the interaction between the immune system and the gonadotropic axis, these observations are compatible with the hypothesis that upregulation of the gonadotropic axis underlies some of the changes in disease patterns with economic development

Breast cancer incidence and mortality in a transitioning Chinese population: current and future trends

Background Projections of future trends in cancer incidence and mortality are important for public health planning. Methods By using 1976–2010 data in Hong Kong, we fitted Poisson age-period-cohort models and made projections for future breast cancer incidence and mortality to 2025. Results Age-standardised breast cancer incidence (/mortality) is projected to increase (/decline) from 56.7 (/9.3) in 2011–2015 to 62.5 (/8.6) per 100 000 women in 2021–2025. Conclusions The incidence pattern may relate to Hong Kong’s socio-economic developmental history, while falling mortality trends are, most likely, due to improvements in survival from treatment advancement and improved health service delivery

Inflammation and bone mineral density: A Mendelian randomization study

Osteoporosis is a common age-related disorder leading to an increase in osteoporotic fractures and resulting in significant suffering and disability. Inflammation may contribute to osteoporosis, as it does to many other chronic diseases. We examined whether inflammation is etiologically relevant to osteoporosis, assessed from bone mineral density (BMD), as a new potential target of intervention, or whether it is a symptom/biomarker of osteoporosis. We obtained genetic predictors of inflammatory markers from genome-wide association studies and applied them to a large genome wide association study of BMD. Using two-sample Mendelian randomization, we obtained unconfounded estimates of the effect of high-sensitivity C-reactive protein (hsCRP) on BMD at the forearm, femoral neck, and lumbar spine. After removing potentially pleiotropic single nucleotide polymorphisms (SNPs) possibly acting via obesity-related traits, hsCRP, based on 16 SNPs from genes including CRP, was not associated with BMD. A causal relation of hsCRP with lower BMD was not evident in this study