Exposure to corticosteroids in the first trimester is associated with an increased risk of urogenital congenital anomalies.

STUDY QUESTION: Does maternal exposure to first trimester corticosteroids in IVF/ICSI treatment result in an increased risk of congenital anomalies? SUMMARY ANSWER: Children born with the aid of IVF/ICSI whose mothers were treated with adjuvant corticosteroids during the first trimester had an increased risk of cryptorchidism, hypospadias and talipes. WHAT IS KNOWN ALREADY: Maternal exposure to corticosteroids may increase the risk of congenital anomalies such as cleft palate and neural tube defects. However, the existing studies have conflicting outcomes, are underpowered, and do not study a population undergoing IVF/ICSI, a group known to be at increased risk of abnormalities. STUDY DESIGN, SIZE, DURATION: This retrospective cohort analysis covering Monash IVF fertility clinics in Melbourne, Australia assessed the outcomes of 12 426 live births from both fresh and frozen embryo transfers between 2010 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 618 live births included in our study group of mothers exposed to corticosteroids (oral prednisolone or dexamethasone) during their IVF/ICSI treatment, with the remainder of births not exposed to steroids (control, n = 11 808). The primary outcome measured was the presence of congenital anomalies and secondary outcomes were birth weight and gestation length. Multivariate binary logistic regression was used to assess the independent effects of corticosteroid exposure and the freezing of embryos, with adjustment for maternal age at oocyte retrieval, smoking status, number of cycles taken, BMI, etiology of the infertility and the use of ICSI. Results are presented as incidence rate ratios (IRRs) with 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE: Amongst 12 426 live births, and 597 birth defects, multivariate logistic regression demonstrated there was an increased incidence in talipes equinovarus (1.33% vs 0.32%, adjusted IRR = 4.30, 95% CI = 1.93, 9.58; P < 0.001), hypospadias (0.66% vs 0.18%, adjusted IRR = 5.90, 95% CI = 2.09, 16.69; P = 0.001) and cryptorchidism (0.83% vs 0.19%, adjusted IRR = 5.53, 95% CI = 1.91, 15.42; P = 0.001) in the offspring of mothers exposed to corticosteroids compared to those who were unexposed. The incidence of neither neural tube defects nor cleft palate were significantly increased in babies exposed to corticosteroids. The sex ratio of infants exposed to corticosteroids during a fresh embryo transfer cycle significantly favored males but reverted to the normal sex ratio in infants conceived in frozen embryo transfer cycles. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective observational cohort study using administrative datasets with the potential for measurement error and unobserved confounding. Missing outcome data were obtained from patients using self-report leading to possible ascertainment bias. Given the rare incidence of some of the anomalies assessed, the study was underpowered to identify differences in abnormality rates for some specific anomalies. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study, the largest of its kind, suggest that caution should be heeded when prescribing corticosteroids to women undergoing IVF/ICSI, given that this study has now identified three previously unassociated serious neonatal complications (talipes, hypospadias and cryptorchidism), plus a potential alteration in sex ratio. Physicians should be careful in using corticosteroids in the critical first trimester and should counsel patients regarding the potential risks of this treatment. STUDY FUNDING/COMPETING INTEREST(S): There was no funding sought or obtained for this study. K.T., V.T., B.V. and D.Z.-F. are employees or contractors to Monash IVF and hold a minority stock position in Monash IVF. R.J.W. reports no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Utility of four sarcopenia criteria for the prediction of falls-related hospitalization in older Australian women.

Numerous sarcopenia definitions are not associated with increased falls-related hospitalization risk over 5 years to 9.5 years in older community-dwelling Australian women. Measures of muscle strength and physical function, but not appendicular lean mass (measured by dual-energy X-ray absorptiometry) may help discriminate the risk of falls-related hospitalization. INTRODUCTION: The aim of this prospective, population-based cohort study of 903 Caucasian-Australian women (mean age 79.9 ± 2.6 years) was to compare the clinical utility of four sarcopenia definitions for the prediction of falls-related hospitalization over 9.5 years. METHODS: The four definitions were the United States Foundation for the National Institutes of Health (FNIH), the European Working Group on Sarcopenia in Older People (EWGSOP), and modified FNIH (AUS-POPF) and EWGSOP (AUS-POPE) definitions using Australian population-specific cut points (< 2 SD below the mean of young healthy Australian women). Components of sarcopenia including muscle strength, physical function, and appendicular lean mass (ALM) were quantified using hand grip strength, timed-up-and-go (TUG), and dual-energy X-ray absorptiometry (DXA), respectively. Incident 9.5-year falls-related hospitalization were captured by linked data. RESULTS: Baseline prevalence of sarcopenia according to FNIH (9.4%), EWGSOP (24.1%), AUS-POPF (12.0%), and AUS-POPE (10.7%) differed substantially. Sarcopenia did not increase the relative hazard ratio (HR) for falls-related hospitalization before or after adjustment for age (aHR): FNIH aHR 1.00 95%CI (0.69-1.47), EWGSOP aHR 1.20 95%CI (0.93-1.54), AUS-POPF aHR 0.96 95%CI (0.68-1.35), and AUS-POPE aHR 1.33 95%CI (0.94-1.88). When examining individual components of sarcopenia, only muscle strength and physical function but not ALM (adjusted for height2 or BMI) were associated with falls-related hospitalization. CONCLUSION: Current definitions of sarcopenia were not associated with falls-related hospitalization risk in this cohort of community-dwelling older Australian women. Finally, measures of muscle strength and physical function, but not ALM (measured by DXA) may help discriminate the risk of falls-related hospitalization.

Seasonality of birth patterns in an Australian cohort of patients with biopsy-confirmed idiopathic inflammatory myopathy.

Environmental exposures in the foetal period may predispose to autoimmunity. Aim of this study is to investigate whether seasonality in birth patterns exists in idiopathic inflammatory myopathies (IIM). We used Stata (StataCorp USA, version 13.0) and the user-written routine command 'circsummarise' to assess birth seasonality among South Australian patients with histologically confirmed IIM subsequent to 1980 using their date of birth. There was no evidence for a seasonal birth pattern among IIM patients overall (n = 568), however there were some ethnic variances in birth patterns among non-Caucasian patients. There was evidence for birth seasonality among both Aboriginal (mean = 7 July, Rayleigh P = 0.04) and Asian patients (mean = 12 August, Rayleigh P-value = 0.038). Non-Caucasians born in the third quarter of the calendar year may have an increased risk of developing IIM. Large international studies of IIM patients of diverse ethnicity are required to clarify the role of perinatal exposures in disease susceptibility.

Rising incidence of hepatitis B-related hepatocellular carcinoma in South Australia: 1996-2010.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is likely to be an important driver of increasing hepatocellular carcinoma (HCC) incidence in Australia. However, there is paucity of Australian data on HBV-related HCC incidence or outcomes. AIMS: To determine the incidence rates and survival trends of HBV-related HCC in South Australia (SA) over 15 years. METHODS: A population-based cohort study was performed in HBV patients notified to the SA Communicable Disease Control Branch between 1996 and 2010. The dataset was probabilistically linked with the SA Cancer Registry and death registry. Incidence rate trends and survival were determined for three 5-year time periods (1996-2000, 2001-2006 and 2006-2010). RESULTS: Forty-seven of 3881 notifications with HBV were linked to a HCC record (median (interquartile range) age at diagnosis: 58.9 (13.4) years, 83% males, 8.5% born in Australia, 62% diagnosed between 51-69 years). The overall crude HCC incidence was 111.3/100 000 person-years with an age-standardised HCC incidence of 189.1/100 000 person-years, the rate for men was higher than for women: 241.7 versus 88.6/100 000 person-years. The age-standardised HCC incidence increased over time with an annual percentage increase of 20.8% (95% CI: 10.06-32.54, P = 0.001). Median survival following HCC diagnosis was 12.5 months (95% CI: 3.6-21.4), with a trend towards longer survival during the 2006-2010 time period (21.8 months) compared to the previous two time periods (9.2 and 10.2 months, P = 0.056). CONCLUSION: Both crude and age-standardised incidences of HBV-related HCC increased between 1996 and 2010 in SA. There was a trend to longer survival in the latter time-period.

Prevalence of hepatic osteodystrophy and vitamin D deficiency in cirrhosis.

BACKGROUND: Hepatic osteodystrophy (HO) is a major complication of cirrhosis. However, the prevalence of HO in a general cirrhotic patient population is not well defined as previous studies were in single aetiology or pre-liver transplant patients. AIMS: The aims of this study were to investigate the prevalence of HO and vitamin D deficiency in patients with cirrhosis of mixed aetiology and disease severity and to determine the risk factors for HO. METHODS: This is a single-centre cross-sectional study of all patients newly diagnosed with cirrhosis between September 2009 and December 2012. All patients underwent bone mineral density assessment using dual energy X-ray absorptiometry within 3 months of diagnosis. Demographic and biochemical factors, severity of underlying liver disease, previous fragility fractures, smoking status and alcohol use were collected on diagnosis. Logistic regression analysis was used to assess risk factors for HO. RESULTS: Among the 406 patients (67% males), the median (range) age was 56 years (21-85) and most (84%) were Childs-Pugh A or B with a median (range) model for end-stage liver disease score of 11 (5-40). Alcohol (41%) was the most common underlying aetiology. The prevalence of HO and vitamin D deficiency (≤50 nmol/L) was 56% and 54%, respectively, and previous fragility fractures had occurred in 3%. Increasing age (odds ratio (95% confidence interval): 1.49 per 10 years (1.02-2.18), P = 0.04), excessive alcohol intake (2.34 (1.03-5.32), P = 0.04) and lower body mass index (0.92 per kg/m2 (0.87-0.98), P = 0.009) were independent risk factors for HO. CONCLUSION: There is a high prevalence of HO and vitamin D deficiency in patients with cirrhosis at presentation irrespective of disease severity or underlying aetiology.

The effect of ondansetron on the efficacy of postoperative tramadol: a systematic review and meta-analysis of a drug interaction.

Several studies have investigated the presence of a drug interaction between tramadol and ondansetron that reduced the efficacy of tramadol postoperatively. Most of these studies were small and the results inconsistent, so we performed a systematic review and meta-analysis of randomised controlled trials comparing the cumulative dose of tramadol administered by patient-controlled analgesia within the first 24 h after surgery between subjects receiving tramadol alone and those who received tramadol with ondansetron. Six studies, with a total of 340 participants, met the selection criteria and were included in the meta-analysis. There was an increased tramadol requirement in patients receiving ondansetron. The standardised mean difference in tramadol requirements, expressed in terms of standard deviations (95% CI), was 1.03 (0.54-1.53) (p < 0.001) at 4 h, 0.66 (0.06-1.25) (p = 0.03) at 8 h, 0.86 (0.41-1.31) (p < 0.001) at 12 h and 0.45 (0.01-0.90) (p = 0.046) at 24 h postoperatively, where the mean pooled standard deviations were 79.5, 157.7, 238.1 and 289.4 mg at 4, 8, 12 and 24 h, respectively. There was a significant linear time effect over the 24 h, indicating that the effect of ondansetron on tramadol consumption diminished with time. The results support the presence of a drug interaction between tramadol and ondansetron in the early postoperative period that potentially decreases the effectiveness of tramadol.

BK virus encoded microRNAs are present in blood of renal transplant recipients with BK viral nephropathy.

BK viral infection is an important cause of renal transplant dysfunction and failure. Current strategies utilize surveillance for infection with DNA polymerase chain reaction assays and modulation of immunosuppression. Many viruses including polyomaviruses encode microRNAs (miRNAs). We have detected BK virus (BKV) encoded miRNAs in the blood of infected renal transplant recipients, and see a strong correlation between BKV encoded miRNA and BKV DNA in blood and a relationship between levels of bkv-miR-B1-5p and the presence of biopsy-proven BK viral nephropathy. Further research is needed to determine whether the detection of this and other virally encoded miRNAs may be useful in the diagnosis of active viral replication.

Do metastatic colorectal cancer patients who present with late relapse after curative surgery have a better survival?

BACKGROUND: Patients who relapse after potentially curative surgery for colorectal cancer tend to relapse within 5 years. There is, however, a group of patients who relapse beyond 5 years after resection and this late relapsing group may have a different behaviour and prognosis. METHODS: We analysed data from a prospective population-based registry to compare the characteristics and survival of relapsed patients with metachronous mCRC. Patients were categorised into relapse at <2, 2-5 and >5 years following their initial surgery. Univariate log-rank tests and multivariate Cox regression was performed to determine whether time to relapse (TTR) and other factors were associated with overall survival (OS). RESULTS: A total of 750 metachronous mCRC patients were identified. In all, 56% relapsed ≤2 years, 32.4% at 2-5 years and 11.6% >5 years. Median survival time from the time of diagnosis of mCRC for the three groups was 17.6, 26.1 and 27.5 months, respectively. Short TTR (<2 years) was significantly associated with survival (HR=0.75, 95% confidence interval (CI)=0.60-0.93 and HR=0.73, 95% CI=0.53-1.01, respectively, for 2-5 and >5 years vs <2 years, P<0.05). However, there was no significant difference in survival between patients who relapsed at 5 years or later compared with those who relapsed between 2 and 5 years (HR=0.98, 95% CI=0.69-1.38, P=0.90). CONCLUSION: TTR within 2 years is an independent predictor of shorter survival time for mCRC patients who experience a relapse. These data do not support the hypothesis that patients who have late relapse late (>5 years) have a 'better' biology or survival compared with patients with a TTR of 2-5 years.

Mortality and its predominant causes in a large cohort of patients with biopsy-determined inflammatory myositis.

BACKGROUND: There is a paucity of literature on the patterns and predictors of mortality in idiopathic inflammatory myopathies (IIM). AIMS: To determine the patterns and predictors of mortality in a South Australian cohort of patients with biopsy-proven IIM. METHODS: The living/deceased status (and for deceased patients the causes of death) of patients with histologically determined IIM was determined from the Births, Deaths and Marriages Registry. Standardised mortality ratios (SMR) were generated compared with the age/gender matched South Australian population. The effect of presence/absence of the components of the Bohan and Peter criteria on risk ratios (RR) for mortality was determined. The effect of comorbidities and autoantibodies on mortality was investigated. RESULTS: The SMR for mortality in IIM was 1.75 and was significantly increased in all disease subgroups, being highest in patients with dermatomyositis (2.40). Dominant causes of death were cardiovascular disease (31%), infections (22%) and malignancy (11%). Risk factors for death were age at time of biopsy (hazard ratio 1.05), ischaemic heart disease (RR 2.97, P < 0.0001), proximal weakness at diagnosis (RR 1.8, P= 0.03), definite diagnosis of IIM per the Bohan and Peter criteria (RR 2.14, P < 0.0001), and the absence of autoantibodies (RR 1.9, P < 0.001). CONCLUSIONS: Patients with IIM are at 75% increased risk for mortality, and cardiovascular diseases account for the commonest causes of death. This study suggests a thorough cardiovascular evaluation of these patients is indicated, and raises the possibility that targeted interventions such as the use of aspirin or statins may improve outcomes in IIM.

Effects of lupin-enriched foods on body composition and cardiovascular disease risk factors: a 12-month randomized controlled weight loss trial.

BACKGROUND: Regular consumption of diets with increased protein or fibre intakes may benefit body weight and composition and cardiovascular disease risk factors. Lupin flour is a novel food ingredient high in protein and fibre. OBJECTIVE: To investigate the effects of a lupin-enriched diet, during and following energy restriction, on body weight and composition and cardiovascular disease risk factors in overweight individuals. DESIGN: Participants (n = 131) were recruited to a 12-month parallel-design trial. They were randomly assigned to consume lupin-enriched foods or matching high-carbohydrate control foods. All participants underwent 3 months of weight loss, 1 month of weight stabilization and 8 months of weight maintenance. Body weight and composition and cardiovascular disease risk factors were assessed at baseline, 4 and 12 months. RESULTS: Lupin, relative to control, did not significantly influence (mean difference (95% CI)) weight loss at 4 months (0.1 kg (-1.2, 1.4)) and 12 months (-0.6 kg (-2.0, 0.8)), maintenance of weight loss from 4 to 12 months (-0.7 kg (-1.83, 0.48)) or measures of body fat and fat-free mass. Relative to control, 24-h ambulatory systolic (-1.3 mm Hg (-2.4, -0.3), P = 0.016) and diastolic (-1.0 mm Hg (-1.9, -0.2), P = 0.021) blood pressures were lower at 12 months but not at 4 months; fasting insulin concentrations and homeostasis model assessment (HOMA) scores were significantly lower at 4 months (-1.2 mU l(-1) (-1.3, -1.1), P = 0.004 and -0.6 units (-1.0, -0.19), P = 0.004) and 12 months (-1.3 mU l(-1) (-1.4, -1.1), P < 0.001 and -0.7 units (-1.1, -0.24), P = 0.002). CONCLUSIONS: A diet higher in protein and fibre derived from lupin-enriched foods does not enhance weight loss or improve the maintenance of weight loss. However, such a diet may provide cardiovascular health benefits in terms of insulin sensitivity and blood pressure.

Survival in scleroderma: results from the population-based South Australian Register.

AIM: To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR). METHODS: The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786). RESULTS: Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period. CONCLUSIONS: Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

The functional paradox of CD43 in leukocyte recruitment: a study using CD43-deficient mice.

Although there is considerable evidence implicating a role for CD43 (leukosialin) in leukocyte cell-cell interactions, its precise function remains uncertain. Using CD43-deficient mice (CD43(-/-)) and intravital microscopy to directly visualize leukocyte interactions in vivo, we investigated the role of CD43 in leukocyte-endothelial cell interactions within the cremasteric microcirculation under flow conditions. Our studies demonstrated significantly enhanced leukocyte rolling and adhesion after chemotactic stimuli in CD43(-/-) mice compared with wild type mice. Using an in vitro flow chamber, we established that the enhanced rolling interactions of CD43(-/-) leukocytes, primarily neutrophils, were also observed using immobilized E-selectin as a substrate, suggesting that passive processes related to steric hindrance or charge repulsion were likely mechanisms. Despite increased adhesion and rolling interactions by CD43(-/-) leukocytes, we uncovered a previously unrecognized impairment of CD43(-/-) leukocytes to infiltrate tissues. Oyster glycogen-induced neutrophil and monocyte infiltration into the peritoneum was significantly reduced in CD43(-/-) mice. In response to platelet activating factor, CD43(-/-) leukocytes were impaired in their ability to emigrate out of the vasculature. These results suggest that leukocyte CD43 has a dual function in leukocyte-endothelial interactions. In addition to its role as a passive nonspecific functional barrier, CD43 also facilitates emigration of leukocytes into tissues.

Development of an international spinal injury prevention module: application of the international classification of external cause of injury to spinal cord injury.

STUDY DESIGN: An end-user response survey and assessments of inter-rater reliability before and after training. OBJECTIVES: Evaluate the spinal cord injury (SCI) application of the international classification of external cause of injury (ICECI) in a mixed group of untrained and trained coders to assess agreement, refine coding and training methodology. SETTING: An interactive coding workshop for an international group of coders with varying previous training. METHODS: Evaluate content validity (qualitative survey) and inter-rater reliability (kappa estimate of agreement) of the ICECI in a variety of injury scenarios presented within a computerized data-entry and training module. The results of this evaluation are compared with an earlier published gold standard. RESULTS: The ICECI is a flexible data coding system that appears to work with reasonable content validity in the regions assessed with English-language coders. Training appeared to narrow the difference between the inexperienced and trained coders. This is reflected in a borderline tendency for lower kappa scores pre-training compared with an earlier examined group of expert coders (P=0.073) but no difference in kappa scores after training (P=0.67). Computer-based training on a face-to-face level with computerized data entry appears an effective tool for training coders to use the ICECI. CONCLUSIONS: This report shows that using electronic data-entry and training assistance, inexperienced coders using the SCI-ICECI computerized system quickly approach the levels of agreement of trained coders in related data systems. The content validity of the training data set is adequate but needs to include more cases representative for use in SCI.

Hypoalbuminaemia and impaired renal function are associated with increased anticholinergic drug prescribing.

BACKGROUND: A higher anticholinergic risk score (ARS) is associated with an increased risk of anticholinergic adverse effects in elderly patients. It is unknown whether factors other than the use of anticholinergic drugs determine the ARS. METHODS: A comprehensive medical record review was conducted in 155 consecutive hospitalised patients (median age 79.0 years, interquartile range 66.0-86.0). Information was collected on: demographics; clinical characteristics (including medications and their doses); history of anticholinergic-induced adverse effects; and biochemical markers of hepatic and renal function (serum albumin concentrations and estimated glomerular filtration rate, eGFR). The ARS was calculated for each patient using a standard scoring approach and Poisson regression was used for identifying variables associated with the ARS. RESULTS: Patients with an ARS >or= 3 had a lower eGFR (p = 0.012) and were receiving more non-anticholinergic drugs (p < 0.001) than patients with an ARS < 3. In addition to being prescribed more anticholinergic drugs, patients with ARS >or= 3 were prescribed high doses of these drugs more often than patients with ARS < 3 (41.3% vs. 26.9%, p = 0.034). A higher number of non-anticholinergic drugs (p < 0.001), a lower serum albumin concentration (p = 0.014), and a lower eGFR (p = 0.012) were independently associated with a higher ARS. CONCLUSIONS: Polypharmacy, hypoalbuminaemia and low eGFR are independently associated with the ARS. Patients with a higher ARS are also prescribed higher doses of anticholinergic medications than those with lower ARS.

Erratum: The rate of euploid miscarriage is increased in the setting of adenomyosis.

[This corrects the article DOI: 10.1093/hropen/hoy011.].

The rate of euploid miscarriage is increased in the setting of adenomyosis.

STUDY QUESTION: Does the rate of miscarriage increase in the setting of adenomyosis independent of other known risk factors for miscarriage such as maternal age, BMI, embryo genetic status? SUMMARY ANSWER: Adenomyosis and high BMI both significantly increase miscarriage risk independent of each other, maternal age and embryo health. This study is the first to suggest that ultra-long down regulation GnRH agonist treatment may reduce the rate of early pregnancy loss in adenomyosis patients. WHAT IS KNOWN ALREADY: The presence of adenomyosis is known to be associated with lower rates of successful implantation and increased risk of early pregnancy loss. However, it is presently unclear whether this reproductive impairment is directly mediated by adenomyosis itself, or indirectly caused by adenomyosis association with known risk factors for miscarriage such as obesity and advancing maternal age/foetal aneuploidy. STUDY DESIGN SIZE DURATION: A retrospective cohort study was undertaken in a private infertility (IVF) clinic examining the outcome for women (n = 345) undergoing the transfer of a genetically screened frozen-thawed embryo between 2012 and 2015. PARTICIPANTS/MATERIALS SETTING AND METHOD: A total of 171 women who successfully conceived (positive serum ßhCG) following the transfer of a single euploid good morphology frozen-thawed embryo were included in analysis after meeting the inclusion criteria. Only the first conception cycle for each patient was included in the study. Patients with known pre-existing medical risk factors for miscarriage (e.g. thrombophilia, poorly controlled diabetes, coeliac disease, SLE, uterine septum, chromosomal abnormalities) and those women undergoing treatment using donated oocytes and surrogacy were excluded. Patients were then classified as having adenomyosis or not based on a high-quality pelvic ultrasound or MRI. The direct and indirect effects of adenomyosis and BMI on overall miscarriage rate by 12 weeks gestation was then assessed using multivariate logistic regression and mediation analysis. Furthermore, the data were also analysed to elucidate the influence of GnRH ultra-long down-regulation therapy on miscarriage rates. MAIN RESULTS AND ROLE OF CHANCE: Overall, the adjusted rate of miscarriage was higher in those patients with adenomyosis compared to those without (44.1 vs 15.3%, P < 0.0001), with most of these miscarriages occurring at the early biochemical stage. The rate of miscarriage was especially high in adenomyosis patients not receiving GnRH agonist pre-treatment (82.4%), compared to those patients who did receive GnRH pre-treatment (35.7%, P = 0.0089). LIMITATIONS REASONS FOR CAUTION: The study is mainly limited by its small sample size and retrospective design which carries inherent potential for bias (i.e. misclassification and errors due to inadequate clinical notes). The small sample size precluded analysis to distinguish how the extent of adenomyosis disease may modify miscarriage risk (i.e. focal or diffuse disease). Furthermore, the relatively low number of adenomyosis patients not receiving GnRH agonist treatment, plus the non-randomized nature of the decision not to offer such treatment, precludes definitive conclusions on the benefit of GnRH agonist therapy to reduce miscarriage risk. WIDER IMPLICATIONS OF THE FINDINGS: Considering the significant emotional and financial impact of miscarriage, we suggest screening of all women undergoing IVF treatment for the presence of adenomyosis, with consideration given to ultra-long down regulation GnRH agonist treatment in any woman identified as having adenomyosis. Furthermore, given the persistent and often progressive nature of the disease, adenomyosis should also be considered as a potential uterine cause of recurrent miscarriage. Finally, we hope our study highlights the need for high-quality prospective RCT to be undertaken to provide superior evidence for the potential benefit of GnRH agonist pre-treatment. STUDY FUNDING/COMPETING INTERESTS: K.T. is a practicing IVF gynaecologist and holds a minority stake in the publicly listed company Monash IVF. The other authors declare that they have no conflict of interest. This study was financially supported by Flinders University Medical School.

Fasting and glucose induced thermogenesis in response to three ambient temperatures: a randomized crossover trial in the metabolic syndrome.

BACKGROUND/OBJECTIVES: Cold exposure increases thermogenesis and could improve insulin sensitivity. We hypothesized a blunted response in the metabolic syndrome (MetS). SUBJECTS/METHODS: Twenty older adults 59 ± 10.4 years (with MetS, MetS+, n = 9; without MetS, MetS-, n = 11) completed a randomized crossover design of 3.5 h exposures to 20, 25 and 27 °C on three visits. After an hour's rest at the desired temperature, resting metabolic rate (RMR), respiratory quotient (RQ), forearm to fingertip gradients (FFG), and in the ear temperature (IET) were measured over 30 min. An oral glucose tolerance test followed, and serial measurements were continued for 2 h. Venous blood was sampled for clinical chemistry, irisin, and fibroblast growth factor 21(FGF21). A mixed model ANCOVA adjusted data for age, gender, fat mass, fat-free mass and seasonality. RESULTS: There was a significant MetS×temperature interaction where adjusted RMR was significantly higher in MetS+ compared to MetS- by 12% at 20 °C and by 6% at 25 °C, but similar at 27 °C. FFG increased and IET decreased with decreasing temperature to the same extent in both groups. Fasting irisin and FGF21 did not vary with temperature but the former was significantly higher in MetS-. Adjusted postprandial RQ and insulin to glucose ratios were significantly higher at 20 °C relative to 25 °C. Partial correlation analysis of differences between 27 and 20 °C indicated significant positive relationships between fasting as well as postprandial RQ and the respective changes in irisin and FGF21. CONCLUSIONS: There could be an upward shift of the TNZ in MetS+, but this needs reevaluation.

Chronic inflammation upregulates chemokine receptors and induces neutrophil migration to monocyte chemoattractant protein-1.

Monocyte chemoattractant protein-1 (MCP-1) is a CC chemokine that stimulates monocyte recruitment when injected into tissues of healthy animals. However, the function of this chemokine in models with preexisting inflammation is not known. Therefore, MCP-1 was superfused over the mesentery of naive rats or rats with chronic adjuvant-induced vasculitis. MCP-1 elicited increased leukocyte transendothelial migration in adjuvant-immunized rats compared with naive animals. Surprisingly, histology revealed that neutrophils constituted the majority of leukocytes recruited in adjuvant-immunized animals. In vitro, MCP-1 was also able to induce chemotaxis of neutrophils isolated from adjuvant-immunized rats but not from naive rats. Flow cytometry revealed novel expression of the CC chemokine receptors CCR1 and CCR2 on neutrophils from adjuvant-immunized animals. In naive animals, an antibody against CD18 blocked leukocyte adhesion and emigration in response to MCP-1. In adjuvant-immunized animals, leukocyte adhesion was reduced by antibodies against the alpha4-integrin but not by antibodies against CD18. However, the CD18 antibody did block emigration. To our knowledge, this study is the first to show increased sensitivity to a CC chemokine in a model with preexisting inflammation, and altered leukocyte recruitment profiles in response to MCP-1. It also demonstrates that CD18 is required for chemokine-induced leukocyte transendothelial migration, independent of its known role in mediating firm adhesion. J. Clin. Invest. 103:1269-1276 (1999).

Respiratory burst oxidase and three of four oxidase-related polypeptides are associated with the cytoskeleton of human neutrophils.

Resting and phorbol-activated human neutrophils were separated by treatment with Triton X-100 into detergent-extractable and cytoskeleton fractions. Respiratory burst oxidase activity was restricted entirely to the cytoskeleton. The cytoskeleton also contained approximately 15% of the neutrophil cytochrome b558, an oxidase-associated heme protein, as well as most of the oxidase-related cytosolic polypeptide p67phox. In contrast, the components of the oxidase-associated phosphoprotein family p47phox were found almost exclusively in the detergent extract, suggesting that p47phox is needed for oxidase activation but not for O2- production by the activated oxidase. Activation of the oxidase had no apparent effect on the distribution of any of these species between the cytoskeleton and the detergent extract. Our results support earlier studies implying that the cytoskeleton participates in an important way in regulating the activity of the O2(-)-forming respiratory burst oxidase of neutrophils.

Regular consumption of black tea increases circulating kynurenine concentrations: A randomized controlled trial.

BACKGROUND: Circulating neopterin and the ratio of kynurenine to tryptophan (KYN/TRP) concentrations are biomarkers of immune activation that have been linked to cardiovascular and total mortality. Several in vitro studies indicated that tea flavonoids and other antioxidants can modulate tryptophan breakdown rates and neopterin production in immune cells. We aimed to assess the effects of regular black tea consumption on tryptophan and neopterin metabolisms in vivo. METHODS: Participants were healthy individuals, with no major illnesses and having normal to mildly elevated systolic blood pressure. They were randomly assigned to consume 3 cups/day of either powdered black tea solids (tea; n = 45) or a flavonoid-free caffeine-matched beverage (control; n = 49). Serum concentrations of tryptophan, kynurenine and neopterin were assessed at baseline and again at 3 and 6 months after daily ingestion of the respective beverage. RESULTS: Regular consumption of tea over 6 months, compared to control, did not significantly alter neopterin (p = 0.13) or tryptophan (p = 0.85) concentrations, but did result in significantly higher kynurenine (p = 0.016) and KYN/TRP (p = 0.012). Relative to the control group, in the tea group kynurenine and KYN/TRP increased during the treatment period by 0.28 µmol/L (95% CI: - 0.04, 0.60) and 3.2 µmol/mmol (95% CI: - 1.6, 8.0), respectively at 3 months, and by 0.48 µmol/L (95% CI: 0.16, 0.80) and 7.5 µmol/mmol (95% CI: 2.5, 12.5), respectively at 6 months. CONCLUSIONS: Increased circulation of kynurenine and KYN/TRP following regular black tea consumption may indicate enhanced tryptophan breakdown, possibly due to immune activation-induced tryptophan degrading enzyme indoleamine 2,3-dioxygenase. GENERAL SIGNIFICANCE: The influence of black tea consumption on biomarkers of immune system activation could relate to its general health benefits. Data suggests that the net effect strongly depends on the individual immune state, being stimulatory in healthy individuals, while acting more immune dampening in situations with an inflammatory background.