GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

MC3R links nutritional state to childhood growth and the timing of puberty.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation.

Dispersion compensation of high-speed data using an integrated silicon nitride ring resonator.

Dispersion impairments are a well-known limitation in data center communications, limiting both the usable data rates and reaches. Several companies today adopt silicon photonics as a core technology in their transceiver products. This presents an opportunity for silicon photonics-based dispersion management technologies to be integrated with the transceiver transmitter or receiver. In this manuscript, we present a ring-resonator based, tunable dispersion compensation device, providing dispersion ranging as wide from + 12.9 × 103ps/nm to -12.3 × 103ps/nm. Thermo-optic tuning from 20°C to 70°C is demonstrated to allow continuous wavelength tuning across 200 GHz. High-speed experiments using 25 Gb/s non-return-to-zero data propagating through 20 km of single mode fiber show that a significant improvement in the eye diagram is achieved after compensation with the ring-resonator device. We demonstrate a significant improvement in the BER from 10-3 to 10-11 for data rates of 25 and 25.78125 Gb/s.

Changes over time in latent patterns of childhood-to-adulthood BMI development in Great Britain: evidence from three cohorts born in 1946, 1958, and 1970.

BACKGROUND: Most studies on secular trends in body mass index (BMI) are cross-sectional and the few longitudinal studies have typically only investigated changes over time in mean BMI trajectories. We aimed to describe how the evolution of the obesity epidemic in Great Britain reflects shifts in the proportion of the population demonstrating different latent patterns of childhood-to-adulthood BMI development. METHODS: We used pooled serial BMI data from 25,655 participants in three British cohorts: the 1946 National Survey of Health and Development (NSHD), 1958 National Child Development Study (NCDS), and 1970 British Cohort Study (BCS). Sex-specific growth mixture models captured latent patterns of BMI development between 11 and 42 years. The classes were characterised in terms of their birth cohort composition. RESULTS: The best models had four classes, broadly similar for both sexes. The 'lowest' class (57% of males; 47% of females) represents the normal weight sub-population, the 'middle' class (16%; 15%) represents the sub-population who likely develop overweight in early/mid-adulthood, and the 'highest' class (6%; 9%) represents those who likely develop obesity in early/mid-adulthood. The remaining class (21%; 29%) reflects a sub-population with rapidly 'increasing' BMI between 11 and 42 years. Both sexes in the 1958 NCDS had greater odds of being in the 'highest' class compared to their peers in the 1946 NSHD but did not have greater odds of being in the 'increasing' class. Conversely, males and females in the 1970 BCS had 2.78 (2.15, 3.60) and 1.87 (1.53, 2.28), respectively, times higher odds of being in the 'increasing' class. CONCLUSIONS: Our results suggest that the obesity epidemic in Great Britain reflects not only an upward shift in BMI trajectories but also a more recent increase in the number of individuals demonstrating more rapid weight gain, from normal weight to overweight, across the second, third, and fourth decades of life.

Changing paradigm of sacral neuromodulation and external anal sphincter repair for faecal incontinence in specialist centres.

AIM: The aim of this study was to determine whether the paradigm of surgical intervention for faecal incontinence (FI) has changed between 2000 and 2013. METHOD: This was a multi-centre retrospective study of patients who had undergone either sacral neuromodulation (SNM) or delayed sphincter repair or sphincteroplasty (SR) as a primary surgical intervention for FI in five centres in Europe and one in the United States. The flow of patients according to the intervention, sustainability of the treatment at a minimum follow-up of 5 years, complications and requirement for further interventions were recorded. RESULTS: A total of 461 patients (median age 56 years, range 24-90 years, 41 men) had either SNM or SR as an index operation during the study period [SNM 284 (61.6%), SR 177 (38.4%)]. Among SNM patients, there were 169 revisional operations (change of battery and/or lead, re-siting or removal). At the time of last follow-up 203 patients (71.4%) continued to use SNM. Among SR patients, 30 (16.9%) had complications, most notably wound infection (22, 12.4%). During follow-up 32 patients (18.1%) crossed over to SNM. Comparing two 4-year periods (2000-2003 and 2007-2010), the proportion of patients operated on who had a circumferential sphincter defect of less than 90° was 48 (68%) and 45 (46%), respectively (P = 0.03), while those who had SNM as the primary intervention increased from 29% to 89% (P < 0.05). CONCLUSION: The paradigm of surgical intervention for FI has changed with increasing use of SNM.

Maternal serum concentrations of bisphenol A and propyl paraben in early pregnancy are associated with male infant genital development.

STUDY QUESTION: Are maternal serum phthalate metabolite, phenol and paraben concentrations measured at 10-17 weeks of gestation associated with male infant genital developmental outcomes, specifically cryptorchidism, anogenital distance (AGD), penile length and testicular descent distance, at birth and postnatally? SUMMARY ANSWER: Maternal serum bisphenol A (BPA) concentration at 10-17 weeks of gestation was positively associated with congenital or postnatally acquired cryptorchidism, and n-propyl paraben (n-PrP) concentration was associated with shorter AGD from birth to 24 months of age. WHAT IS KNOWN ALREADY: Male reproductive disorders are increasing in prevalence, which may reflect environmental influences on foetal testicular development. Animal studies have implicated phthalates, BPA and parabens, to which humans are ubiquitously exposed. However, epidemiological studies have generated conflicting results and have often been limited by small sample size and/or measurement of chemical exposures outside the most relevant developmental window. STUDY DESIGN, SIZE, DURATION: Case-control study of cryptorchidism nested within a prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at 10-17 postmenstrual weeks of gestation from a single UK maternity unit between 2001 and 2009 and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 330 mothers of 334 male infants (30 with congenital cryptorchidism, 25 with postnatally acquired cryptorchidism and 279 unmatched controls) were included in the present analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Maternal blood was collected at enrolment, and serum levels of 16 phthalate metabolites, 9 phenols (including BPA) and 6 parabens were measured using liquid chromatography/tandem mass spectrometry. Logistic regression was used to model the association of cryptorchidism with serum chemical concentrations, adjusting for putative confounders. Additionally, offspring AGD, penile length and testicular descent distance were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between serum chemical levels and these outcomes were tested using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal serum BPA concentration was associated with offspring all-type cryptorchidism both when considered as a continuous exposure (adjusted odds ratio per log10 µg/l: 2.90, 95% CI 1.31-6.43, P = 0.009) and as quartiles (phet = 0.002). Detection of n-PrP in maternal serum was associated with shorter AGD (by 0.242 standard deviations, 95% CI 0.051-0.433, P = 0.01) from birth to 24 months of age; this reduction was independent of body size and other putative confounders. We did not find any consistent associations with offspring outcomes for the other phenols, parabens, and phthalate metabolites measured. LIMITATIONS, REASONS FOR CAUTION: We cannot discount confounding by other demographic factors or endocrine-disrupting chemicals. There may have been misclassification of chemical exposure due to use of single serum measurements. The cohort was not fully representative of pregnant women in the UK, particularly in terms of smoking prevalence and maternal ethnicity. WIDER IMPLICATIONS OF THE FINDINGS: Our observational findings support experimental evidence that intrauterine exposure to BPA and n-PrP during early gestation may adversely affect male reproductive development. More evidence is required before specific public health recommendations can be made. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), Newlife the Charity for Disabled Children, the Mothercare Group Foundation, Mead Johnson Nutrition and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Visiting Fellowship (J.M.): Regional Programme 'Jiménez de la Espada' for Research Mobility, Cooperation and Internationalization, Seneca Foundation-Science and Technology Agency for the Region of Murcia (No. 20136/EE/17). K.O. is supported by the Medical Research Council (UK) (Unit Programme number: MC_UU_12015/2). The authors declare no conflict of interest.

A review on colorimetric methods for determination of organophosphate pesticides using gold and silver nanoparticles.

This review (with 99 refs.) summarizes the progress that has been made in colorimetric (i.e. spectrophotometric) determination of organophosphate pesticides (OPPs) using gold and silver nanoparticles (NPs). Following an introduction into the field, a first large section covers the types and functions of organophosphate pesticides. Methods for colorimetric (spectrophotometric) measurements including RGB techniques are discussed next. A further section covers the characteristic features of gold and silver-based NPs. Syntheses and modifications of metal NPs are covered in section 5. This is followed by overviews on enzyme inhibition-based assays, aptamer-based assays and chemical (non-enzymatic) assays, and a discussion of specific features of colorimetric assays. Several Tables are presented that give an overview on the wealth of methods and materials. A concluding section addresses current challenges and discusses potential future trends and opportunities. Graphical abstractSchematic representation of organophosphate pesticide determinations based on aggregation of nanoparticles (particular silver or gold nanoparticles). This leads to a color change which can be determined visually and monitored by a red shift in the absorption spectrum.

Diabetic foot infection and surgical treatment in a secondary health care centre in Malaysia.

INTRODUCTION: Diabetic foot infection is often associated with high morbidity, disability and poor quality of life. This study focuses on the demography, the number of repetitive surgery and length of stay in hospital of patients with diabetic foot infection. METHOD: This is a retrospective observational study. Patients who were admitted to the Orthopaedic ward of Hospital Segamat (HS), Johor, Malaysia from January 2016 to December 2018 and required surgical intervention were included in the study. Data was collected from the computer system of HS and medical notes of patients. RESULTS: 35.6% of the total orthopaedic emergency surgeries performed were for patients with diabetic foot infection, 25% of the surgical procedures performed were major amputations of lower limb and 40% of the patients with diabetic foot infection required more than one surgical operation. DISCUSSION: The demographics of the patients is consistent with the demographics of Malaysia where majority of them are Malays followed by Chinese, Indians and others. Despite being only 10% of total admission to the department, this group of patients contributed to 35.6% of the total emergency surgeries performed. The amputation rate in the centre is comparable to the other local studies. The average length of stay in hospital was found to be shorter compared to overseas due to different rehabilitation protocols.

HIV care cost in England: a cross-sectional analysis of antiretroviral treatment and the impact of generic introduction.

OBJECTIVES: Reliable and timely HIV care cost estimates are important for policy option appraisals of HIV treatment and prevention strategies. As HIV clinical management and outcomes have changed, we aimed to update profiles of antiretroviral (ARV) usage pattern, patent/market exclusivity details and management costs in adults (≥ 18 years old) accessing HIV specialist care in England. METHODS: The data reported quarterly to the HIV and AIDS Reporting System in England was used to identify ARV usage pattern, and were combined with British National Formulary (BNF) prices, non-ARV care costs and patent/market exclusivity information to generate average survival-adjusted lifetime care costs. The cumulative budget impact from 2018 to the year in which all current ARVs were expected to lose market exclusivity was calculated for a hypothetical 85 000 (± 5000) person cohort, which provided an illustration of potential financial savings afforded by bioequivalent generic switches. Price scenarios explored BNF70 (September 2015) prices and generics at 10/20/30/50% of proprietary prices. The analyses took National Health Service (NHS) England's perspective (as the payer), and results are presented in 2016/2017 British pounds. RESULTS: By 2033, most currently available ARVs would lose market exclusivity; that is, generics could be available. Average per person lifetime HIV cost was ~£200 000 (3.5% annual discount) or ~£400 000 (undiscounted), reducing to ~£70 000 (3.5% annual discount; ~£120 000 undiscounted) with the use of generics (assuming that generics cost 10% of proprietary prices). The cumulative budget to cover 85 000 (± 5000) persons for 16 years (2018-2033) was £10.5 (± 0.6) billion, reducing to £3.6 (± 0.2) billion with the use of generics. CONCLUSIONS: HIV management costs are high but financial efficiency could be improved by optimizing generic use for treatment and prevention to mitigate the high cost of lifelong HIV treatment. Earlier implementation of generics as they become available offers the potential to maximize the scale of the financial savings.

Voice break in boys-temporal relations with other pubertal milestones and likely causal effects of BMI.

STUDY QUESTION: How is timing of voice break related to other male pubertal milestones as well as to BMI? SUMMARY ANSWER: We provide a comprehensive temporal analysis of male pubertal milestones, including reproductive hormone dynamics, confirm voice break as a late milestone of male puberty and report a likely causal relationship between higher BMI and earlier age at voice break in men. WHAT IS KNOWN ALREADY: Voice break represents a late pubertal milestone and recalled age at voice break is frequently used in epidemiological studies as a measure of puberty. In contrast, clinical studies use mainly testicular enlargement and/or genital tanner stage as the marker of pubertal onset. However, neither correlation of pubertal milestones nor reproductive hormone dynamics have been assessed in detail previously. Further, although BMI and puberty timing are known to be closely linked, cause and effect between these traits are not known. STUDY DESIGN, SIZE, DURATION: The study included a population-based mixed cross-sectional and longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) of 730 healthy Danish boys. Data for 55 871 male research participants from the 23andMe study were obtained, including genome-wide single nucleotide polymorphism data and age at voice break. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a detailed evaluation of pubertal milestones and reproductive hormone levels (study population 1). A Mendelian randomization (MR) approach was used to determine the likely causal link between BMI and timing of voice break (study population 2). MAIN RESULTS AND THE ROLE OF CHANCE: Voice break occurred at mean age 13.6 (95% CI: 13.5-13.8) years. At voice break, mean (95% CI) testosterone levels, LH levels and bi-testicular volume were 10.9 (10.0-11.7) nmol/L, 2.4 (2.2-2.5) IU/L and 24 (23-25) mL, respectively. Voice break correlated moderately strongly with timing of male pubertal milestones, including testicular enlargement, gonadarche, pubarche, sweat odor, axillary hair growth and testosterone above limit of detection (r2 range: 0.43-0.61). Timing of all milestones was negatively associated with age-specific BMI (all P ≤ 0.001). MR analyses inferred likely causal effects of higher BMI on earlier voice break in males (-0.35 years/approximate SD, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Participation rate of the population-based cohort was 25%. Further, boys that were followed longitudinally were examined approximately every 6 months limiting the time resolution of pubertal milestones. Using adult BMI as exposure instead of prepubertal BMI in the MR analysis and the known inaccuracies of the testosterone immunoassay at low testosterone levels may be further limitations. WIDER IMPLICATIONS OF THE FINDINGS: We provide valuable normative data on the temporal relation of male pubertal milestones. Further, the likely causal relationship between BMI and puberty timing highlights the importance of preventing obesity in childhood. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Danish Agency for Science, Technology and Innovation (09-067 180); Danish Ministry of the Environment, CeHoS (MST-621-00 065); Capital Region of Denmark (R129-A3966); Ministry of Higher Education and Science (DFF-1331-00 113); Innovation Fund Denmark (InnovationsFonden, 14-2013-4); The International Center for Research and Research Training in Endocrine Disrupting Effects of Male Reproduction and Child Health. B.H., F.R.D., J.R.B.P. and K.K.O. are supported by the Medical Research Council (MC_UU_12015/2). The 23andMe study is supported by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981). Members of the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe. TRIAL REGISTRATION NUMBER: NCT01411527.

Correction to: Were VCF patients at higher risk of mortality following the 2009 publication of the vertebroplasty "sham" trials?

The article Were VCF patients at higher risk of mortality following the 2009 publication of the vertebroplasty "sham" trials?, written by K. L. Ong, D. P. Beall, M. Frohbergh, E. Lau, and J. A. Hirsch was originally published electronically on the publisher's internet portal.

Adolescent parenthood associated with adverse socio-economic outcomes at age 30 years in women and men of the Pelotas, Brazil: 1982 Birth Cohort Study.

OBJECTIVE: To investigate the potential long-term effects of adolescent parenthood on completed education and income. DESIGN: Population-based birth cohort study. SETTING: All live births in 1982, whose mothers lived in the urban area of Pelotas, southern Brazil. SAMPLE: A total of 3701 participants: 1914 women and 1787 men at age 30 years. METHODS: Questionnaires were completed by the mothers in the early phases of this study, and by the cohort members in adolescence and adulthood. Linear regression models and G-computation were used in the analyses. MAIN OUTCOME MEASURES: Educational attainment and income at age 30 years. RESULTS: In women, adolescent parenthood was associated with lower attained education compared with women without adolescent maternity: by -2.8 years [95% confidence interval (CI) -3.2 to -2.3] if their first birth was at age 16-19, and by -4.4 years (-5.5 to -3.3) at age 11-15. These effects were greater among women who had three or more children. Women with adolescent parenthood also had 49 or 33% lower income at age 30 if their first child was born when aged 16-19 or 11-15, respectively. In men, the adverse effect of adolescent parenthood on education appeared to be mediated by a higher number of children and there was no effect of adolescent paternity on income at age 30 years. CONCLUSION: These findings suggest lasting socio-economic disadvantages of adolescent parenthood, with larger effects being apparent in women than in men. TWEETABLE ABSTRACT: Adolescent parenthood has an adverse effect on educational attainment later in life, and on household income among women.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Bactericidal and cytotoxic activity of a diarylheptanoid (etlingerin) isolated from a ginger (Etlingera pubescens) endemic to Borneo.

AIMS: The aim of this study was to investigate the antimicrobial activities of Etlingera pubescens, and to isolate and identify the antimicrobial compound. METHODS AND RESULTS: The crude extracts of E. pubescens were obtained through methanol extraction, and evaluated for antimicrobial activities. From this extract, 1,7-bis(3,4-dihydroxyphenyl)heptan-3-yl acetate (etlingerin) was isolated. When compared to curcumin (a compound with a similar chemical structure), etlingerin showed twofold lower minimum inhibitory concentration values while also being bactericidal. Through time kill assay, etlingerin showed rapid killing effects (as fast as 60 min) against the Gram-positive bacteria (Staphylococcus aureus ATCC 43300 and Bacillus subtilis ATCC 8188). Further assessment revealed that etlingerin caused leakage of intracellular materials, therefore suggesting alteration in membrane permeability as its antimicrobial mechanism. Cytotoxicity study demonstrated that etlingerin exhibited approximately 5- to 12-fold higher IC50 values against several cell lines, as compared to curcumin. CONCLUSIONS: Etlingerin isolated from E. pubescens showed better antibacterial and cytotoxic activities when compared to curcumin. Etlingerin could be safe for human use, though further cytotoxicity study using animal models is needed. SIGNIFICANCE AND IMPACT OF THE STUDY: Etlingerin has a potential to be used in treating bacterial infections due to its good antimicrobial activity, while having potentially low cytotoxicity.

Necrotising fasciitis caused by aeromonas sobria: Not just a simple catfish sting.

Necrotising fasciitis is a life-threatening infection of the soft tissue which can be caused by different microorganisms, but infection caused by Aeromonas spp. or Vibrio spp. is frequently associated with higher mortality rate. Necrotising fasciitis progresses rapidly and often need aggressive surgical intervention. We present a rare case of necrotising fasciitis cause by Aeromonas sobria which mortality was successfully prevented by swift diagnosis and aggressive surgery.

Polymorphisms in the androgen receptor CAG repeat sequence are related to tumour stage but not to ERG or androgen receptor expression in Malaysian men with prostate cancer.

INTRODUCTION: Polymorphic expression of a CAG repeat sequence in the androgen receptor (AR) gene may influence the activity of the AR and the occurrence of prostate cancer and the TMPRSS2-ERG fusion event. Furthermore, this polymorphism may be responsible for the ethnic variation observed in prostate cancer occurrence and expression of the ERG oncogene. We investigate the expression of AR and ERG in the biopsies of Malaysian men with prostate cancer and in the same patients relate this to the length of the CAG repeat sequence in their AR gene. MATERIALS AND METHODS: From a PSA screening initiative, 161 men were shown to have elevated PSA levels in their blood and underwent prostatic tissue biopsy. DNA was extracted from the blood, and exon 1 of the AR gene amplified by PCR and sequenced. The number of CAG repeat sequences were counted and compared to the immunohistochemical expression of ERG and AR in the matched tumour biopsies. RESULTS: Of men with elevated PSA, 89 were diagnosed with prostate cancer, and 72 with benign prostatic hyperplasia (BPH). There was no significant difference in the length of the CAG repeat in men with prostate cancer and BPH. The CAG repeat length was not associated with; age, PSA or tumour grade, though a longer CAG repeat was associated with tumour stage. ERG and AR were expressed in 36% and 86% of the cancers, respectively. There was no significant association between CAG repeat length and ERG or AR expression. However, there was a significant inverse relationship between ERG and AR expression. In addition, a significantly great proportion of Indian men had ERG positive tumours, compared to men of Malay or Chinese descent. CONCLUSIONS: CAG repeat length is not associated with prostate cancer or expression of ERG or AR. However, ERG appears to be more common in the prostate cancers of Malaysian Indian men than in the prostate cancers of other Malaysian ethnicities and its expression in this study was inversely related to AR expression.

Were VCF patients at higher risk of mortality following the 2009 publication of the vertebroplasty "sham" trials?

The 5-year period following 2009 saw a steep reduction in vertebral augmentation volume and was associated with elevated mortality risk in vertebral compression fracture (VCF) patients. The risk of mortality following a VCF diagnosis was 85.1% at 10 years and was found to be lower for balloon kyphoplasty (BKP) and vertebroplasty (VP) patients. INTRODUCTION: BKP and VP are associated with lower mortality risks than non-surgical management (NSM) of VCF. VP versus sham trials published in 2009 sparked controversy over its effectiveness, leading to diminished referral volumes. We hypothesized that lower BKP/VP utilization would lead to a greater mortality risk for VCF patients. METHODS: BKP/VP utilization was evaluated for VCF patients in the 100% US Medicare data set (2005-2014). Survival and morbidity were analyzed by the Kaplan-Meier method and compared between NSM, BKP, and VP using Cox regression with adjustment by propensity score and various factors. RESULTS: The cohort included 261,756 BKP (12.6%) and 117,232 VP (5.6%) patients, comprising 20% of the VCF patient population in 2005, peaking at 24% in 2007-2008, and declining to 14% in 2014. The propensity-adjusted mortality risk for VCF patients was 4% (95% CI, 3-4%; p < 0.001) greater in 2010-2014 versus 2005-2009. The 10-year risk of mortality for the overall cohort was 85.1%. BKP and VP cohorts had a 19% (95% CI, 19-19%; p < 0.001) and 7% (95% CI, 7-8%; p < 0.001) lower propensity-adjusted 10-year mortality risk than the NSM cohort, respectively. The BKP cohort had a 13% (95% CI, 12-13%; p < 0.001) lower propensity-adjusted 10-year mortality risk than the VP cohort. CONCLUSIONS: Changes in treatment patterns following the 2009 VP publications led to fewer augmentation procedures. In turn, the 5-year period following 2009 was associated with elevated mortality risk in VCF patients. This provides insight into the implications of treatment pattern changes and associated mortality risks.

Heterogenous expression of ERG oncoprotein in Malaysian men with adenocarcinoma of the prostate.

INTRODUCTION: Prostate cancer is a heterogenous disease and the mechanisms that drive it to behave differently are not well understood. Tumour expression of the ERG oncogene occurs in the majority of patients with prostate cancer in Western studies. This is considered to be oncogenic as ERG acts as a transcription factor to regulate genes involved in tumour proliferation and invasion. In this study we investigated expression of ERG in Malaysian men with prostate cancer. METHODS: Tissues were collected from 80 patients with clinically detected prostate cancer and treated with radical prostatectomy. Cases were tested for ERG by immunohistochemistry using the mouse monoclonal antibody EP111. All blocks on 48 cases were tested in order to determine the extent of heterogeneity of ERG expression within individual cases. ERG expression was analysed in relation to patient age, ethnicity and tumour stage and grade. RESULTS: Forty-six percent of cases were ERG positive. There was no significant association between ERG and tumour grade or stage. Sixty-nine percent of Indian patients had ERG positive tumours; this was significantly higher (p=0.031) than for Chinese (40%) and Malay (44%) patients. Heterogeneity of ERG expression, in which both positive and negative clones were present, was seen in 35% of evaluated cases. Evaluation by tumour foci showed younger patients had more ERG positive tumour foci than older patients (p=0.01). Indian patients were more likely to have the majority of tumour foci with ERG staining positively, compared to either Chinese or Malay patients (P <0.01). CONCLUSION: In this study, tumour expression of ERG was more likely to occur in patients of Indian ethnicity.

Associations between body mass index-related genetic variants and adult body composition: The Fenland cohort study.

BACKGROUND/OBJECTIVE: Body mass index (BMI) is a surrogate measure of adiposity but does not distinguish fat from lean or bone mass. The genetic determinants of BMI are thought to predominantly influence adiposity but this has not been confirmed. Here we characterise the association between BMI-related genetic variants and body composition in adults. SUBJECTS/METHODS: Among 9667 adults aged 29-64 years from the Fenland study, a genetic risk score for BMI (BMI-GRS) was calculated for each individual as the weighted sum of BMI-increasing alleles across 96 reported BMI-related variants. Associations between the BMI-GRS and body composition, estimated by dual-energy X-ray absorptiometry (DXA) scans, were examined using age-adjusted linear regression models, separately by sex. RESULTS: The BMI-GRS was positively associated with all fat, lean and bone variables. Across body regions, associations of the greatest magnitude were observed for adiposity variables, for example, for each s.d. increase in BMI-GRS predicted BMI, we observed a 0.90 s.d. (95% confidence interval (CI): 0.71, 1.09) increase in total fat mass for men (P=3.75 × 10-21) and a 0.96 s.d. (95% CI: 0.77, 1.16) increase for women (P=6.12 × 10-22). Associations of intermediate magnitude were observed with lean variables, for example, total lean mass: men: 0.68 s.d. (95% CI: 0.49, 0.86; P=1.91 × 10-12); women: 0.85 s.d. (95% CI: 0.65, 1.04; P=2.66 × 10-17) and of a lower magnitude with bone variables, for example, total bone mass: men: 0.39 s.d. (95% CI: 0.20, 0.58; P=5.69 × 10-5); women: 0.45 s.d. (95% CI: 0.26, 0.65; P=3.96 × 106). Nominally significant associations with BMI were observed for 28 single-nucleotide polymorphisms. All 28 were positively associated with fat mass and 13 showed adipose-specific effects. CONCLUSIONS: In adults, genetic susceptibility to elevated BMI influences adiposity more than lean or bone mass. This mirrors the association between BMI and body composition. The BMI-GRS can be used to model the effects of measured BMI and adiposity on health and other outcomes.

Identification of α-tocopherol as a bioactive component of Dicranopteris linearis with disrupting property against preformed biofilm of Staphylococcus aureus.

AIMS: The potential of Dicranopteris linearis leaves' extract and its bioactive components were investigated for the first time for its disrupting ability against Staphylococcus aureus biofilms. METHODS AND RESULTS: The leaves of D. linearis were subjected to sonication-assisted extraction using hexane (HEX), dichloromethane, ethyl acetate and methanol (MeOH). It was found that only the MeOH fraction exhibited antimicrobial activity using broth microdilution assay; while all four fractions do not exhibit biofilm inhibition activity against S. aureusATCC 6538P, S. aureusATCC 43300, S. aureusATCC 33591 and S. aureusATCC 29213 using crystal violet assay. Among the four fractions tested, only the HEX fraction showed biofilm disrupting ability, with 60-90% disruption activity at 5 mg ml-1 against all four S. aureus strains tested. Bioassay-guided purification of the active fraction has led to the isolation of α-tocopherol. α-Tocopherol does not affect the cells within the biofilms but instead affects the biofilm matrix in order to disrupt S. aureus biofilms. CONCLUSIONS: α-Tocopherol was identified to be the bioactive component of D. linearis with disruption activity against S. aureus biofilm matrix. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of α-tocopherol as a biofilm disruptive agent might potentially be useful to treat biofilm-associated infections in the future.