Multivariate analysis of a missense variant in CREBRF reveals associations with measures of adiposity in people of Polynesian ancestries.

The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log10 Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log10 BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log10 BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.

A Polynesian-specific copy number variant encompassing the MICA gene associates with gout.

Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.

Mitochondrial disease in New Zealand: a nationwide prevalence study.

BACKGROUND: The complexities of mitochondrial disease make epidemiological studies challenging, yet this information is important in understanding the healthcare burden and addressing service and educational needs. Existing studies are limited to quaternary centres or focus on a single genotype or phenotype and estimate disease prevalence at 12.5 per 100 000. New Zealand's (NZ) size and partially integrated national healthcare system make it amenable to a nationwide prevalence study. AIM: To estimate the prevalence of molecularly confirmed and suspected mitochondrial disease on 31 December 2015 in NZ. METHODS: Cases were identified from subspecialists and laboratory databases and through interrogation of the Ministry of Health National Minimum Dataset with a focus on presentations between 2000 and 2015. Patient records were reviewed, and those with a diagnosis of 'mitochondrial disease' who were alive and residing in NZ on the prevalence date were included. These were divided into molecularly confirmed and clinically suspected cases. Official NZ estimated resident population data were used to calculate prevalence. RESULTS: Seven hundred twenty-three unique national health index numbers were identified. Five hundred five were excluded. The minimum combined prevalence for mitochondrial disease was 4.7 per 100 000 (95% confidence interval (CI): 4.1-5.4). The minimum prevalence for molecularly confirmed and suspected disease was 2.9 (95% CI 2.4-3.4) and 1.8 (95% CI 1.4-2.2) cases per 100 000 respectively. CONCLUSIONS: Within the limitations of this study, comparison to similar prevalence studies performed by specialist referral centres suggests mitochondrial disease is underdiagnosed in NZ. This highlights a need for improved education and referral pathways for mitochondrial disease in NZ.

Association of rs9939609 in FTO with BMI among Polynesian peoples living in Aotearoa New Zealand and other Pacific nations.

The fat mass and obesity associated (FTO) locus consistently associates with higher body mass index (BMI) across diverse ancestral groups. However, previous small studies of people of Polynesian ancestries have failed to replicate the association. In this study, we used Bayesian meta-analysis to test rs9939609, the most replicated FTO variant, for association with BMI with a large sample (n = 6095) of Aotearoa New Zealanders of Polynesian (Maori and Pacific) ancestry and of Samoan people living in the Independent State of Samoa and in American Samoa. We did not observe statistically significant association within each separate Polynesian subgroup. Bayesian meta-analysis of the Aotearoa New Zealand Polynesian and Samoan samples resulted in a posterior mean effect size estimate of +0.21 kg/m2, with a 95% credible interval [+0.03 kg/m2, +0.39 kg/m2]. While the Bayes Factor (BF) of 0.77 weakly favors the null, the BF = 1.4 Bayesian support interval is [+0.04, +0.20]. These results suggest that rs9939609 in FTO may have a similar effect on mean BMI in people of Polynesian ancestries as previously observed in other ancestral groups.

Tuberculosis and diabetes: increased hospitalisations and mortality associated with renal impairment.

BACKGROUND: Diabetes mellitus (DM) triples a person's risk of active tuberculosis (TB) and is associated with increased mortality. It is unclear whether diabetes status and/or the associated renal dysfunction is associated with poor TB outcomes in New Zealand, which has high diabetes screening. AIM: To characterise the population of TB-DM and TB-alone to assess the effect of diabetes status and renal function on hospitalisation and mortality. METHODS: Clinical records from all adult patients diagnosed with TB in Auckland over a 6-year period (2010-2015) were reviewed. Baseline demographics, clinical presentation and microbiological data were assessed to compare the rates of hospitalisation and mortality between those with TB-DM and TB-alone. Statistical significance was defined as P < 0.05. RESULTS: A total of 701 patients was identified with TB; 120 (17%) had an unknown diabetes status and were excluded, and 135 had co-existing diabetes. The TB-DM and TB-alone groups had similar distribution of TB site and proportions of Mycobacterium tuberculosis culture positivity. Univariate analysis showed TB-DM patients had statistically significantly higher proportions of acute hospitalisation and mortality. Multivariate logistic regression showed only a reduced estimated glomerular filtration rate (eGFR) accounted for the higher rates of hospitalisation, with the odds of hospitalisation increasing by 2% for every unit decrease in eGFR. The odds of mortality increased by 6% for every year increase in age, and the odds of mortality increased by 3% for every unit reduction in eGFR. CONCLUSIONS: Diabetes is associated with higher TB hospitalisation and mortality; however, this is likely mediated by increased age and chronic kidney disease.

The New Zealand eating behavior questionnaire - Validation study for a novel assessment tool to describe actionable eating behavior traits.

Individualised management of obesity remains challenging and, to date, most treatment is based on clinical judgement. This study aimed to develop and validate a novel questionnaire-based tool to identify three pre-defined eating behavior (EB) traits, emotional eating, reduced satiety (constant hunger) and reduced satiation (feasters) that may predict selective medication response given their targeted actions. We recruited 977 individuals from a tertiary academic diabetes clinic to participate in this two-phase validation study. Participants self-reported weight management activities and were asked to self-assess their EB characteristics. The initial questionnaire included 42 visual analogue scale questions. In Phase I, 729 participants completed the questionnaire, including Maori (11.8%) and Pacific peoples (19.3%). After random division of the study sample, Exploratory Factor Analysis (EFA) confirmed a three-factor model as the best fit. Stepwise removal of items with inadequate factor loading retained 27 of 42 items, which accounted for 96% of the variance. Confirmatory Factor Analysis (CFA), performed on the second half of the sample, demonstrated good model fit with the final 27-item questionnaire. Internal consistency was high for factor (α = 0.82-0.95) and demographic subgroups, and similar to those obtained in the EFA. Test-retest reliability in a subset of 399 participants who repeated the questionnaire after a four-week interval (Phase II) showed moderate to good reliability. Participants classified into one of three EB types based on the highest median score among the factors. Test-retest reliability was robust for emotional eaters (71.25%) and constant hunger (68.9%). The correlation between aggregate EB score (sum of three EB scores) and BMI was significant (Spearman rho = 0.314, P = .0005). The questionnaire reliably identified three distinct EB traits, which may be informative for precision medicine applications for obesity management.

Twelve tips for improving the quality of assessor judgements in senior medical student clinical assessments.

Assessment of senior medical students is usually calibrated at the level of achieving expected learning outcomes for graduation. Recent research reveals that clinical assessors often balance two slightly different perspectives on this benchmark. The first is the formal learning outcomes at graduation, ideally as part of a systematic, program-wide assessment approach that measures learning achievement, while the second is consideration of the candidate's contribution to safe care and readiness for practice as a junior doctor. The second is more intuitive to the workplace, based on experience working with junior doctors. This perspective may enhance authenticity in assessment decisions made in OSCEs and work-based assessments to better align judgements and feedback with professional expectations that will guide senior medical students and junior doctors' future career development. Modern assessment practices should include consideration of qualitative as well as quantitative information, overtly including perspectives of patients, employers, and regulators. This article presents 12 tips for how medical education faculty might support clinical assessors by capturing workplace expectations of first year medical graduates and develop graduate assessments based on a shared heuristic of 'work-readiness'. Peer-to-peer assessor interaction should be facilitated to achieve correct calibration that 'merges' the differing perspectives to produce a shared construct of an acceptable candidate.

Cardiovascular risk prediction in type 2 diabetes before and after widespread screening: a derivation and validation study.

BACKGROUND: Until recently, most patients with diabetes worldwide have been diagnosed when symptomatic and have high cardiovascular risk, meaning most should be prescribed cardiovascular preventive medications. However, in New Zealand, a world-first national programme led to approximately 90% of eligible adults being screened for diabetes by 2016, up from 50% in 2012, identifying many asymptomatic patients with recent-onset diabetes. We hypothesised that cardiovascular risk prediction equations derived before widespread screening would now significantly overestimate risk in screen-detected patients. METHODS: New Zealanders aged 30-74 years with type 2 diabetes and without known cardiovascular disease, heart failure, or substantial renal impairment were identified from the 400 000-person PREDICT primary care cohort study between Oct 27, 2004, and Dec 30, 2016, covering the period before and after widespread screening. Sex-specific equations estimating 5-year risk of cardiovascular disease were developed using Cox regression models, with 18 prespecified predictors, including diabetes-related and renal function measures. Equation performance was compared with an equivalent equation derived in the New Zealand Diabetes Cohort Study (NZDCS), which recruited between 2000 and 2006, before widespread screening. FINDINGS: 46 652 participants were included in the PREDICT-1° Diabetes subcohort, of whom 4114 experienced first cardiovascular events during follow-up (median 5·2 years, IQR 3·3-7·4). 14 829 (31·8%) were not taking oral hypoglycaemic medications or insulin at baseline. Median 5-year cardiovascular risk estimated by the new equations was 4·0% (IQR 2·3-6·8) in women and 7·1% (4·5-11·2) in men. The older NZDCS equation overestimated median cardiovascular risk by three times in women (median 14·2% [9·7-20·0]) and two times in men (17·1% [4·5-20·0]). Model and discrimination performance measures for PREDICT-1° Diabetse equations were also significantly better than for the NZDCS equation (eg, for women: R2=32% [95% CI 29-34], Harrell's C=0·73 [0·72-0·74], Royston's D=1·410 [1·330-1·490] vs R2=24% [21-26], C=0·69 [0·67-0·70], and D=1·147 [1·107-1·187]). INTERPRETATION: International treatment guidelines still consider most people with diabetes to be at high cardiovascular risk; however, we show that recent widespread diabetes screening has radically changed the cardiovascular risk profile of people with diabetes in New Zealand. Many of these patients have normal renal function, are not dispensed glucose-lowering medications, and have low cardiovascular risk. These findings have clear international implications as increased diabetes screening is inevitable due to increasing obesity, simpler screening tests, and the introduction of new-generation glucose-lowering medications that prevent cardiovascular events. Cardiovascular risk prediction equations derived from contemporary diabetes populations, with multiple diabetes-related and renal function predictors, will be required to better differentiate between low-risk and high-risk patients in this increasingly heterogeneous population and to inform appropriate non-pharmacological management and cost-effective targeting of expensive new medications. FUNDING: Health Research Council of New Zealand, Heart Foundation of New Zealand, and Healthier Lives National Science Challenge.

Correlation between the progression of diabetic retinopathy and inflammasome biomarkers in vitreous and serum - a systematic review.

Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway has been implicated in Diabetic retinopathy (DR) pathogenesis, but its impact on DR development and progression remains unclear. Therefore, the primary aim of this systematic literature review was to determine the role of the inflammasome in DR development. Furthermore, the secondary aim was to determine whether systemic inflammasome activity can be used to predict DR progression. Studies measuring vitreous and/or serum inflammasome biomarkers in DR patients with Type 2 Diabetes Mellitus (T2DM) were searched systematically using online databases EMBASE, PubMed and Web of Science with the last search conducted on 29th of September 2021. The risk of bias was assessed using the Newcastle Ottawa Scale and 20 studies were eligible for narrative analysis. Limitations included the heterogeneity in detection assays used, the small and uneven sample size, a lack of vitreous data in earlier disease stages, and not accounting for patients with other systemic co-morbidities. Analysis showed that inflammasome biomarkers IL-1ß and IL-18 increased significantly from non-proliferative DR to proliferative DR in both vitreous and serum, suggesting the inflammasome pathway is activated as DR progresses and that serum inflammasome levels could be explored as potential biomarkers for DR progression.

Characterization of NLRP3 Inflammasome Activation in the Onset of Diabetic Retinopathy.

The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus alone (DM), and with DR. Retinal expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the key markers of retinal inflammation, connexin43 (Cx43) which is involved in upstream inflammasome regulation, as well as NLRP3 and cleaved caspase-1, the main markers of inflammasome activation, were evaluated using immunohistochemistry and Western blotting. Vitreous interleukin (IL)-1ß and IL-18, biomarkers of the activated inflammasome, were measured using a Luminex multiplex assay. Results showed a significant increase in the number and size of Iba-1+ cells and NLRP3 expression in DM, while a significant increase in GFAP, Cx43, cleaved caspase-1 and vitreous IL-18, as well as a further increase in Iba-1 and NLRP3 was found in DR. This suggests that the inflammasome is already primed in DM before its activation in DR. Furthermore, IL-18 may act as the major effector of inflammasome activation in DR while nuclear translocation of cleaved caspase-1 may play a role in gene transcription contributing to DR onset.

The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Maori and Pacific ancestry.

AIMS/HYPOTHESIS: The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased BMI, but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Maori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes. METHODS: A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Maori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled IVGTT and hyperinsulinaemic-euglycaemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation. RESULTS: The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins glucagon-like polypeptide-1 or gastric inhibitory polypeptide. Consistent with this point, following an i.v. infusion of a glucose bolus, participants with an A allele had higher early (p < 0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p > 0.05) in insulin sensitivity index or glucose disposal during hyperinsulinaemic-euglycaemic clamp. CONCLUSIONS/INTERPRETATION: rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase insulin release to reduce the risk of type 2 diabetes.

Mid-pass whole genome sequencing enables biomedical genetic studies of diverse populations.

BACKGROUND: Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at "mid-pass" 1-7x coverage. RESULTS: Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). CONCLUSION: Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

Untargeted metabolomics reveals plasma metabolites predictive of ectopic fat in pancreas and liver as assessed by magnetic resonance imaging: the TOFI_Asia study.

BACKGROUND: Excess visceral obesity and ectopic organ fat is associated with increased risk of cardiometabolic disease. However, circulating markers for early detection of ectopic fat, particularly pancreas and liver, are lacking. METHODS: Lipid storage in pancreas, liver, abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) from 68 healthy or pre-diabetic Caucasian and Chinese women enroled in the TOFI_Asia study was assessed by magnetic resonance imaging/spectroscopy (MRI/S). Plasma metabolites were measured with untargeted liquid chromatography-mass spectroscopy (LC-MS). Multivariate partial least squares (PLS) regression identified metabolites predictive of VAT/SAT and ectopic fat; univariate linear regression adjusting for potential covariates identified individual metabolites associated with VAT/SAT and ectopic fat; linear regression adjusted for ethnicity identified clinical and anthropometric correlates for each fat depot. RESULTS: PLS identified 56, 64 and 31 metabolites which jointly predicted pancreatic fat (R2Y = 0.81, Q2 = 0.69), liver fat (RY2 = 0.8, Q2 = 0.66) and VAT/SAT ((R2Y = 0.7, Q2 = 0.62)) respectively. Among the PLS-identified metabolites, none of them remained significantly associated with pancreatic fat after adjusting for all covariates. Dihydrosphingomyelin (dhSM(d36:0)), 3 phosphatidylethanolamines, 5 diacylglycerols (DG) and 40 triacylglycerols (TG) were associated with liver fat independent of covariates. Three DGs and 12 TGs were associated with VAT/SAT independent of covariates. Notably, comparison with clinical correlates showed better predictivity of ectopic fat by these PLS-identified plasma metabolite markers. CONCLUSIONS: Untargeted metabolomics identified candidate markers of visceral and ectopic fat that improved fat level prediction over clinical markers. Several plasma metabolites were associated with level of liver fat and VAT/SAT ratio independent of age, total and visceral adiposity, whereas pancreatic fat deposition was only associated with increased sulfolithocholic acid independent of adiposity-related parameters, but not age.

The Pacific-specific CREBRF rs373863828 allele protects against gestational diabetes mellitus in Maori and Pacific women with obesity.

AIMS/HYPOTHESIS: The CREBRF rs373863828 minor (A) allele is associated with increased BMI but reduced prevalence of type 2 diabetes in Maori and Pacific people. Given the shared aetiology of type 2 diabetes and gestational diabetes mellitus (GDM), we tested for an association between the CREBRF rs373863828 variant and GDM. METHODS: We conducted a prospective cohort study of Maori and Pacific women nested within a nutritional intervention study for pregnant women with obesity. Women were enrolled at 12-17 weeks' gestation and underwent anthropometry and collection of buffy coats for later genetic testing. GDM was diagnosed by 75 g OGTT at 24-28 weeks' gestation using the International Association of Diabetes and Pregnancy Study Groups criteria. Genotyping was performed by real-time PCR with a custom CREBRF rs373863828 probe-set. The association between CREBRF rs373863828 and GDM was analysed separately by ethnic group using logistic regression, with effect estimates combined in a meta-analysis. RESULTS: Of 112 Maori and Pacific pregnant women with obesity, 31 (28%) carried the CREBRF rs373863828 A allele (A/G or A/A) and 35 (31%) developed GDM. Women who carried the CREBRF rs373863828 A allele did not differ in BMI when compared with non-carriers (G/G). There was a fivefold reduction in the likelihood of GDM per CREBRF rs373863828 A allele (OR 0.19 [95% CI 0.05, 0.69], p = 0.01), independent of age, BMI and family history of diabetes (adjusted OR 0.13 [95% CI 0.03, 0.53], p = 0.004). GDM was diagnosed in 10% and 40% of women with and without the CREBRF rs373863828 A allele, respectively (no woman with the A/A genotype developed GDM). CONCLUSIONS/INTERPRETATION: The CREBRF rs373863828 (A) allele is associated with reduced likelihood of GDM in Maori and Pacific women with obesity and may improve GDM risk prediction. Graphical abstract.

The Maori and Pacific specific CREBRF variant and adult height.

BACKGROUND: The CREBRF missense variant (p.Arg457Gln) is paradoxically associated with lower risk of type 2 diabetes, yet higher body mass index (BMI). Here we sought to determine whether this CREBRF variant might be associated with adult height. METHODS: Linear regression was used to analyse the association of the CREBRF minor (A) allele with height in 2286 Maori and Pacific adults living in Aotearoa/New Zealand. A potential type 2 diabetes index event was corrected to account for a bias that may be the cause of paradoxical association between the CREBRF diabetes-protective allele and higher BMI and height. RESULTS: The CREBRF protective allele was associated with increased adult height (ß = 1.25 cm, P = 3.9 × 10-6), with the effect being more pronounced in males. The lower odds of diabetes remained similar when analyses were adjusted for height (OR = 0.67-0.65). We found no evidence of a diabetes index event bias to explain the paradoxical effect of CREBRF with either BMI or height and diabetes. The orthologous CREBRF p.Arg457Gln variant was created in knock-in mice to independently assess the effect of the variant, and length was found to be greater in male mice at 8 weeks of age. CONCLUSION: These data taken together indicate that CREBRF p.Arg457Gln is associated with taller stature in Maori and Pacific adults.

Early adolescent physical activity, sleep and symptoms of depression at 16 years of age.

AIM: To examine early adolescent physical activity and risk of later depressive symptoms at age 16 years in a prospective cohort study. METHODS: Participants were children and parents enrolled at birth of the child. Approximately half the children enrolled in the Auckland Birthweight Collaborative Study were small for gestational age at birth (SGA ≤10th percentile for sex and gestation) and half were appropriate for gestational age (AGA >10th percentile). Maternal demographic data were collected at birth, and children were followed through to age 16 years. Depression at 16 was assessed using the Center for Epidemiological Studies Depression Scale for Children. Accelerometer measures of physical activity and sleep were measured at 11 years of age. RESULTS: Moderate to severe depression was present in 15.6% of the 467 16-year-olds. Objectively measured physical activity and sleep at 11 years were not significantly associated with depressive symptoms at 16 years of age. CONCLUSION: Prospectively collected objective measures of physical activity levels and sleep were not predictive of depressive symptoms later in adolescence in a healthy community cohort. While interventions to promote increased physical activity and sleep in adolescents who are depressed may be effective, physical activity and sleep in the general population of adolescents does not protect against future depression.

Fibroblast growth factor 23 levels decline following sleeve gastrectomy.

OBJECTIVE: Levels of fibroblast growth factor 23 (FGF23) have been positively associated with measures of adiposity, cardiovascular disease and mortality. It is unclear whether the relationship of FGF23 with cardiovascular disease and mortality is confounded by obesity. We aimed to determine whether FGF23 concentrations decline following a reduction in adiposity after sleeve gastrectomy (SG). DESIGN: The effect of SG on FGF23 was evaluated in 22 obese adults (59% male) with type 2 diabetes. Fat mass, weight, BMI, plasma intact FGF23, parathyroid hormone (PTH) and leptin were determined at baseline and at 12 months following SG. RESULTS: At baseline, median (IQR) age was 51 (43-54) years, fat mass 47.8 (41.0-59.4) kg, BMI 40.9 (36.9-46.9) kg/m2 and FGF23 66.2 (55.3-82.9) pg/mL. Significant changes in median BMI (-10.8 kg/m2 , 95% CI: -12.9 to -7.2, P < 0.0001), fat mass (-20.0 kg, 95% CI: -26.7 to -12.4, P < 0.0001) and weight (-34.7 kg, 95% CI -40.0 to -23.1, P < 0.0001) were observed after SG. FGF23 (-12.4 pg/mL, 95% CI: -19.5 to 2.0, P = 0.005), PTH (-1.1 pmol/L, 95% CI: -1.7 to 0.2, P = 0.009) and leptin (-1687 pg/mL, 95% CI -4524 to -563, P = 0.01) declined following SG. Change in FGF23 was not significantly associated with change in measures of adiposity, PTH or leptin. CONCLUSIONS: FGF23 concentrations decline in the setting of significant weight loss following SG, implying that increased FGF23 concentrations are a downstream consequence of obesity, which may confound its association with cardiometabolic dysfunction. Mediators of the relationship between adiposity and FGF23 require further elucidation.

Prevalence of diabetes in liver cirrhosis: A systematic review and meta-analysis.

An association between diabetes mellitus (DM) and liver cirrhosis is well-known, but estimates of the prevalence of DM in patients with liver cirrhosis vary widely. A systematic review was undertaken to determine the prevalence of DM in adult patients with liver cirrhosis. The Medline, EMBASE, and Cochrane Library databases were searched for peer-reviewed studies published in English (1979-2017) that investigated the prevalence of diabetes in adult patients with cirrhosis. Pooled estimates of prevalence of DM were determined for all eligible patients and according to aetiology and severity of liver disease. Fifty-eight studies satisfied criteria for inclusion, with 9705 patients included in the pooled prevalence analysis. The overall prevalence of DM was 31%. The prevalence of DM was highest in patients with nonalcoholic fatty liver disease (56%), cryptogenic (51%), hepatitis C (32%), or alcoholic (27%) cirrhosis. For assessing prevalence of DM as a function of severity of liver disease, evaluable data were available only for hepatitis C and hepatitis B cirrhosis. DM may be more prevalent in cirrhosis than previously thought. This has implications for prognosis and treatment in these patients.

Effect of antenatal dietary interventions in maternal obesity on pregnancy weight-gain and birthweight: Healthy Mums and Babies (HUMBA) randomized trial.

BACKGROUND: Pregnancy interventions that improve maternal and infant outcomes are urgently needed in populations with high rates of obesity. We undertook the Healthy Mums and Babies (HUMBA) randomized controlled trial to assess the effect of dietary interventions and or probiotics in a multiethnic population of pregnant women with obesity, living in an area of high deprivation. OBJECTIVES: To determine whether a culturally tailored dietary intervention and or daily probiotic capsules in pregnant women with obesity reduces the co-primary outcomes of (1) excessive gestational weight gain (mean >0.27 kg/week) and (2) birthweight. STUDY DESIGN: We conducted a 2 × 2 factorial, randomized controlled trial in women without diabetes at pregnancy booking, body mass index ≥30 kg/m2, and a singleton pregnancy. At 12+0 to 17+6 weeks' gestation, eligible women were randomized to a dietary intervention (4 tailored educational sessions at ≤28 weeks' gestation by a community health worker trained in key aspects of pregnancy nutrition plus text messaging until birth) or to routine dietary advice; and to daily capsules containing either (Lactobacillus rhamnosus GG and Bifidobacterium lactis BB12, minimum 6.5 × 109 colony forming units), or placebo, until birth. Analysis was by intention to treat with adjustment for maternal baseline body mass index. Infant outcomes were additionally adjusted for ethnicity, sex, and gestational age at birth. RESULTS: In total, 230 women were recruited between April 2015 and June 2017 (dietary intervention N = 116 vs routine dietary advice N = 114; probiotics N = 115 vs placebo N = 115). Baseline characteristics and demographic variables were similar across all groups. There was no significant difference between intervention groups, for the co-primary outcomes of (1) proportion of women with excessive gestational weight gain (dietary intervention vs routine advice: 79/107 [73.8%] vs 90/110 [81.8%], adjusted relative risk [relative risk, 0.92; 95% confidence interval, 0.80-1.05]; probiotics versus placebo: 89/108 [82.4%] and 80/109 [73.4%], relative risk, 1.14, 95% confidence interval, 0.99-1.31) or (2) birthweight (dietary intervention vs routine advice: 3575 vs 3612 g, adjusted mean difference, -24 g, 95% confidence interval, -146 to 97; probiotics vs placebo: 3685 vs 3504 g, adjusted mean difference, 107 g, 95% confidence interval, -14 to 228). Total maternal weight gain, a secondary outcome, was lower with dietary intervention compared with routine dietary advice (9.7 vs 11.4 kg, adjusted mean difference, -1.76, 95% confidence interval, -3.55 to 0.03). There were no significant differences between intervention groups in other secondary maternal or neonatal outcomes. CONCLUSION: Although dietary education and or probiotics did not alter rates of excessive gestational weight gain or birthweight in this multiethnic, high-deprivation population of pregnant women with obesity, dietary education was associated with a modest reduction in total weight gain with potential future benefit for the health of mothers and their offspring if sustained.

Variation in public-funded bariatric surgery intervention rate by New Zealand region.

Inequitable access to bariatric surgery by geographical region has been reported internationally, but comparable data on provision of bariatric surgery have not previously been reported in New Zealand. We examined allocated funding and provision of bariatric surgery amongst different regions in New Zealand in the 2013/14 year, and found that there was large variation in both. This highlights that public funded bariatric surgery needs to take into account population prevalence of morbid obesity to reduce inequities by geographical region.