OBJECTIVES:To examine associations between osteoarthritis (OA)-related biochemical markers and knee symptoms in middle-aged adults over 10-13 year follow-up. METHODS:Blood samples were collected during the Childhood Determinants of Adult Health (CDAH)-1 study (2004-06) and follow-up at CDAH-3. Serum samples from baseline (n=156) and follow-up (n=167) were analyzed for cartilage oligomeric matrix protein (COMP), matrix metalloproteinase (MMP)-3, and hyaluronan (HA) using enzyme-linked immunosorbent assays. Knee symptoms were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale at follow-up. Zero-inflated Poisson regression models adjusted for age, sex, and body mass index were used for analysis. RESULTS:Significant associations were observed between COMP, MMP-3, and HA with knee pain and WOMAC-total score at follow-up. Baseline MMP-3 [ratio of means (RoM): 1.013; 95% CI: 1.006, 1.020], cumulative COMP (baseline + follow-up) [RoM: 1.022; 95% CI: 1.011, 1.033], and increased HA levels over time [RoM: 1.014; 95% CI: 1.007, 1.020] were positively associated with knee pain after 10-13 years. CONCLUSION:Cumulative COMP, baseline MMP-3, and changes in HA were associated with knee pain over a a 10-13 year follow-up. These markers may help predict future knee symptoms in middle-aged adults.

OBJECTIVE:Multiple Endocrine Neoplasia Type 1 (MEN 1) is an autosomal dominant disease predisposing to hyperplasia and neoplasia in diverse endocrine tissues. Patients typically present with endocrine abnormalities before the age of 30 years and have reduced life expectancy. Our objective was to determine predictors of premature mortality in MEN 1. DESIGN:Tertiary hospital based retrospective cohort study. PATIENTS:One hundred and thirty patients with a common MEN1 genotype. MEASUREMENTS:Kaplan-Meier survival analysis of median life expectancy (MLE). RESULTS:The overall cohort MLE was 70.8 years. Sex and year of birth were not predictive of survival. A diagnosis before age 45 years of adrenal nodularity (MLE 51.8 years), hypergastrinaemia (MLE 66.2 years), or liver lesions (MLE 38.6) were associated with a significant reduction in survival (26.2 years, p < 0.01, 6.4 years, p = 0.03, and 30.3 years, p < 0.01 respectively) compared to being diagnosed with these conditions later in life. In contrast, diagnosis before age 45 years of pancreatic nodularity (MLE 68.9 years) and primary hyperparathyroidism (MLE 68.9 years) were not predictive of survival. CONCLUSION:Patients with MEN 1 diagnosed before age 45 with adrenal nodularity, hypergastrinaemia or liver lesions had significantly reduced survival. The explanation for non-secretory and benign adrenal macronodular hyperplasia being associated with diminished life expectancy is unclear.

Aim: To determine the reliability of hospital discharge codes for heart failure (HF), acute myocardial infarction (AMI) and stroke compared with adjudicated diagnosis, and to pilot a scalable approach to adjudicate records on a population-based sample. Methods: A population-based sample of 685 people with diabetes admitted (1274 admissions) to one of three Australian hospitals during 2018-2020 were randomly selected for this study. All medical records were reviewed and adjudicated. Results: Cardiovascular diseases were the most common primary reason for hospitalisation in people with diabetes, accounting for similar to 17% (215/1274) of all hospitalisations, with HF as the leading cause. ICD-10 codes substantially underestimated HF prevalence and had the lowest agreement with the adjudicated diagnosis of HF (Kappa = 0.81), compared with AMI and stroke (Kappa >= 0.91). While ICD-10 codes provided suboptimal sensitivity (72%) for HF, the performance was better for AMI (sensitivity 84%; specificity 100%) and stroke (sensitivity 85%; specificity 100%). A novel approach to screen possible HF cases only required adjudicating 8% (105/1274) of records, correctly identified 78/81 of HF admissions and yielded 96% sensitivity and 98% specificity. Conclusions: While ICD-10 codes appear reliable for AMI or stroke, a more complex diagnosis such as HF benefits from a two-stage process to screen for suspected HF cases that need adjudicating. The next step is to validate this novel approach on large multi-centre studies in diabetes.

Objectives: To visualise the geographic variations of diabetes burden and identify areas where targeted interventions are needed. Methods: Using diagnostic criteria supported by hospital codes, 51,324 people with diabetes were identi fied from a population-based dataset during 2004 -2017 in Tasmania, Australia. An interactive map visualising geographic distribution of diabetes prevalence, mortality rates, and healthcare costs in people with diabetes was generated. The cluster and outlier analysis was performed based on statistical area level 2 (SA2) identify areas with high (hot spot) and low (cold spot) diabetes burden. Results: There were geographic variations in diabetes burden across Tasmania, with highest age-adjusted prevalence (6.1%), excess cost ($2627), and annual costs per person ($5982) in the West and Northwest. Among 98 SA2 areas, 16 hot spots and 25 cold spots for annual costs, and 10 hot spots and 10 cold spots for diabetes prevalence were identi fied (p <0.05). 15/16 (94%) and 6/10 (60%) hot spots identi fied were the West and Northwest. Conclusions: We have developed a method to graphically display important diabetes outcomes for different geographical areas. Implications for Public Health: The method presented in our study could be applied to any other diseases, regions, and countries where appropriate data are available to identify areas where interventions are needed to improve diabetes outcomes.

Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs’s cycle enzymes, including succinate dehydrogenase ( SDH ). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew’s Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 ( P = 0.005) in the discovery cohort, 0.67 ( P < 0.001) in the validation cohort, and 0.63 ( P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 ( P < 0.001) excluding families with incomplete family size data; 0.58 ( P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

Objective To estimate the risk of an emergency department (ED)/inpatient visit due to complications in people with diabetes and compare them to their non-diabetes counterparts. Methods This matched retrospective cohort study used a linked dataset in Tasmania, Australia for the 2004-17 period. People with diabetes (n = 45 378) were matched on age, sex and geographical regions with people without diabetes (n = 90 756) based on propensity score matching. The risk of an ED/inpatient visit related to each complication was estimated using negative binomial regression. Results In people with diabetes, the combined ED and admission rates per 10 000 person-years were considerable, especially for macrovascular complications (ranging from 31.8 (lower extremity amputation) to 205.2 (heart failure)). The adjusted incidence rate ratios of ED/inpatient visits were: retinopathy 59.1 (confidence interval 25.8, 135.7), lower extremity amputation 11.1 (8.8, 14.1), foot ulcer/gangrene 9.5 (8.1, 11.2), nephropathy 7.4 (5.4, 10.1), dialysis 6.5 (3.8, 10.9), transplant 6.3 (2.2, 17.8), vitreous haemorrhage 6.0 (3.7, 9.8), fatal myocardial infarction 3.4 (2.3, 5.1), kidney failure 3.3 (2.3, 4.5), heart failure 2.9 (2.7, 3.1), angina pectoris 2.1 (2.0, 2.3), ischaemic heart disease 2.1 (1.9, 2.3), neuropathy 1.9 (1.7, 2.0), non-fatal myocardial infarction 1.7 (1.6, 1.8), blindness/low vision 1.4 (0.8, 2.5), non-fatal stroke 1.4 (1.3, 1.6), fatal stroke 1.3 (0.9, 2.1) and transient ischaemic attack 1.1 (1.0, 1.2). Conclusions Our results demonstrated the high demand on hospital services due to diabetes complications (especially macrovascular complications) and highlighted the importance of preventing and properly managing microvascular complications. These findings will support future resource allocation to reduce the increasing burden of diabetes in Australia.

Citrus bioflavonoids are polyphenolic plant-derived pigments found in high levels in oranges, lemons, grapefruits and other citrus fruits. The three most abundant types of citrus bioflavonoids are hesperidin, naringenin and eriocitrin. Citrus bioflavonoids have long been known to possess powerful free radical-scavenging properties and cardioprotective effects. The study involved the analysis of 10 commercially available citrus bioflavonoid supplements from three different countries: Australia, the United States and Canada. The supplements were tested for their citrus bioflavonoid content which varied from 0.8 to 33.3% w/w. The daily bioflavonoid dose varied from 19 mg to 560 mg. Hesperidin was the major citrus bioflavonoid in nine out of ten supplements. One supplement was found to contain less than 10% of the quantity of rutin claimed to have been added. The DPP-4 inhibitory potential, compared through an estimation of rutin equivalence, ranged from 1.9 mg to 400 mg per day. This data highlights the variability between the supplements in their potential to inhibit DPP-4 for subsequent health benefits.

BACKGROUND:Current guidelines recommend thyroid-stimulating hormone (TSH) for initial biochemical evaluation of thyroid function, with borderline TSH abnormalities a common finding. The likelihood of a borderline TSH progressing to overt abnormality is not well characterised at the population level.AIMS:To determine risk factors and likelihood for progression of borderline TSH to overt abnormality.METHODS:Population-based retrospective longitudinal data-linkage study for TSH tests performed in Tasmania (1996-2013). Kaplan-Meier methodology was used to summarise conversion time for overt TSH elevation (≥10 mU/L) and overt suppression (≤0.1 mU/L) in patients whose initial TSH was borderline elevated (BeTSH; 4.0-9.99 mU/L) and borderline suppressed (BsTSH; 0.10-0.39 mU/L) respectively. Main outcome measures are the progression from borderline to overt TSH abnormality.RESULTS:A total of 1 296 060 TSH tests was performed on 367 917 patients. Of these, 14 507 (3.9%) patients had BeTSH on initial assessment; mean age 51.4 ± 21.8 years and median TSH of 5.0 mU/L (interquartile range (IQR) 4.4, 5.2). Patients aged ≥80 years were most likely to progress (hazard ratio (HR) = 2.09 compared with age <20 years reference group (95% confidence interval (CI): 1.64, 2.68)). Patients aged 20-39 years had the second-highest rate of progression (HR = 1.49 (95% CI: 1.18, 1.88)). Seven thousand, eight hundred and eighty-three (2.14%) patients had BsTSH; mean age 50.7 ± 22.1 years and median TSH 0.30 mU/L (IQR 0.22, 0.35). Patients aged 60-79 years had the highest rate of progression to overt TSH suppression (HR = 2.47 compared with age <20 years reference group (95% CI: 1.88, 3.22)).CONCLUSIONS:Follow-up intervals for patients with borderline TSH abnormalities should take into account patient age as a progression risk factor.

Objective. We set out to estimate healthcare costs of diabetes complications in the year of first occurrence and the second year, and to quantify the incremental costs of diabetes versus non-diabetes related to each complication. Methods. In this cohort study, people with diabetes (n = 45 378) and their age/sex propensity score matched controls (n = 90 756) were identified from a linked dataset in Tasmania, Australia between 2004 and 2017. Direct costs (including hospital, emergency room visits and pathology costs) were calculated from the healthcare system perspective and expressed in 2020 Australian dollars. The average-per-patient costs and the incremental costs in people with diabetes were calculated for each complication. Results. First-year costs when the complications occurred were: dialysis $78 152 (95% CI 71 095, 85 858), lower extremity amputations $63 575 (58 290, 68 688), kidney transplant $48 487 (33 862, 68 283), non-fatal myocardial infarction $30 827 (29 558, 32 197), foot ulcer/gangrene $29 803 (27 183, 32 675), ischaemic heart disease $29 160 (26 962, 31 457), non-fatal stroke $27 782 (26 285, 29 354), heart failure $27 379 (25 968, 28 966), kidney failure $24 904 (19 799, 32 557), angina pectoris $18 430 (17 147, 19 791), neuropathy $15 637 (14 265, 17 108), nephropathy $15 133 (12 285, 18 595), retinopathy $14 775 (11 798, 19 199), transient ischaemic attack $13 905 (12 529, 15 536), vitreous hemorrhage $13 405 (10 241, 17 321), and blindness/low vision $12 941 (8164, 19 080). The second-year costs ranged from 16% (ischaemic heart disease) to 74% (dialysis) of first-year costs. Complication costs were 109-275% higher than in people without diabetes. Conclusions. Diabetes complications are costly, and the costs are higher in people with diabetes than without diabetes. Our results can be used to populate diabetes simulation models and will support policy analyses to reduce the burden of diabetes.

Abstract Context Carriers of succinate dehydrogenase type B (SDHB) pathogenic variants (PVs) are at risk of pheochromocytoma and paraganglioma (PPGL) from a young age. It is widely recommended carriers enter a surveillance program to detect tumors, but there are limited studies addressing outcomes of surveillance protocols for SDHB PV carriers. Objective The purpose of this study was to describe surveillance-detected (s-d) tumors in SDHB PV carriers enrolled in a surveillance program and to compare their outcomes to probands. Methods This was a multicenter study of SDHB PV carriers with at least 1 surveillance episode (clinical, biochemical, imaging) in Australian genetics clinics. Data were collected by both retrospective and ongoing prospective follow-up. Median duration of follow-up was 6.0 years. Results 181 SDHB PV carriers (33 probands and 148 nonprobands) were assessed. Tumors were detected in 20% of nonprobands undergoing surveillance (age range 9-76 years). Estimated 10-year metastasis-free survival was 66% for probands and 84% for nonprobands with s-d tumors (P = .027). S-d tumors were smaller than those in probands (median 27 mm vs 45 mm respectively, P = .001). Tumor size ≥40 mm was associated with progression to metastatic disease (OR 16.9, 95% CI 2.3-187.9, P = .001). Patients with s-d tumors had lower mortality compared to probands: 10-year overall survival was 79% for probands and 100% for nonprobands (P = .029). Conclusion SDHB carriers with s-d tumors had smaller tumors, reduced risk of metastatic disease, and lower mortality than probands. Our results suggest that SDHB PV carriers should undertake surveillance to improve clinical outcomes.

Tropomyosins from the red and white portions of rat semitendinosus muscle were isolated in the presence of a proteolytic inhibitor and separated electrophoretically into their constituent α- and β-chain subunits. Densitometric analyses of fast green-stained gels indicated approximate α:β ratios of 1.5:1 and 3:1 for purified red and white tropomyosins, respectively. Identical peptide maps were obtained when the α-subunits from the two portions of the muscle were compared. Peptide maps of the β-subunits from the two preparations were identical to each other but differed significantly from those of α-subunits. These results provide evidence for the presence in skeletal muscle of non-identical tropomyosin chains.

PURPOSE:The improved access and affordability of next generation sequencing has facilitated the clinical use of gene panel testing to test concurrently patients for multiple heritable hyperparathyroidism syndromes. However, there is little guidance as to which patients should be selected for gene panel testing and which genes should be included in such panels. In this review, we provide a practical approach to considering, interpreting and managing genetic testing for familial primary hyperparathyroidism (PHPT) syndromes and familial hypocalciuric hypercalcaemia (FHH) in patients with PTH-dependent hypercalcaemia. We discuss known genes implicated in PHPT and FHH, testing criteria and yields, pre-test counselling, laboratory considerations, and post-test management.METHODS:In addition to reviewing the literature, we conducted audits of local genetic testing data to examine the real-world yield of genetic testing in patients with PTH-dependent hypercalcaemia.RESULTS:Our local audits revealed a positive genetic testing rate of 15-26% in patients with suspected hyperparathyroidism syndromes.CONCLUSION:Based on the particular testing criteria met, affected patients should be tested for variants in the genes currently implicated in PHPT (MEN1, CDC73, RET, CDKN1B, GCM2, CASR) and/or FHH (CASR, GNA11, AP2S1). Patients should be provided with pre- and post-test counselling, including consideration of potential implications for family members.

Supplemental table for Surveillance improves outcomes for carriers of SDHB pathogenic variants: a multi-center study

CONTEXT Helicobacter pylori (H. pylori) and Multiple Endocrine Neoplasia Type 1 (MEN 1) are risk factors for hypergastrinaemia. Gastrin-secreting neoplasms of the foregut mucosa are both a source of, and potentially stimulated by, hypergastrinaemia. OBJECTIVE To determine the relationship between H. pylori exposure and the prevalence and severity of hypergastrinaemia in patients with MEN 1. DESIGN setting & patients Cross-sectional analysis of patients with a common MEN1 gene mutation managed at a tertiary referral hospital that underwent fasting serum gastrin and H. pylori serum IgG measurement. INTERVENTION H. pylori IgG and serum gastrin concentration, determined via immunoassay. MAIN OUTCOME MEASURES The prevalence and severity of hypergastrinaemia, and its relationship to past H. pylori exposure. RESULTS Thirty four of 95 (36%) patients were H. pylori IgG seropositive. H. pylori seropositive patients were significantly more likely to exhibit hypergastrinaemia compared to seronegative patients (RR 1.72, p=0.023). H. pylori exposure also predicted severe hypergastrinaemia (RR 3.52, p=0.026 and RR 9.37, p=0.031 for patients with gastrin ≥x4 and ≥x8 the upper limit of normal [ULN], respectively). Gastrin concentrations ≥x10 ULN occurred exclusively in H. pylori seropositive patients (0/61 vs 6/34, p=0.001). Serum gastrin and alpha subunit were positively associated in H. pylori-exposed (β=0.69, p=0.001), but not in H. pylori-unexposed patients. CONCLUSION Past H. pylori exposure was associated with increased prevalence and severity of hypergastrinaemia in MEN 1 patients. Past H. pylori-related hypergastrinaemia may contribute to the pathogenesis of ongoing gastrin hypersecretion by susceptible foregut neuroendocrine tissues.

The use of high-concentration formulations of insulin is becoming more prevalent in the management of patients with diabetes mellitus. Situations of intentional overdose utilizing these agents pose particular challenges because of the altered pharmacology at large doses and the potential complications arising thereof. A patient with type 1 diabetes mellitus self-administered 4050 units of high-concentration (300 units/mL) insulin glargine, in addition to coingestants. The patient subsequently required 7 days of high-dose dextrose infusion in order to avoid hypoglycemia, with no further insulin needed during this period. The patient also developed reversible hepatic steatosis secondary to the prolonged use of high-dose dextrose. Owing to the altered pharmacology of high-concentration insulin glargine when administered at large doses in cases of intentional overdose, patients are likely to require a much longer period of supplemental dextrose support than may otherwise be expected when these agents are used at therapeutic doses. The complication of hepatic injury in the form of steatosis also needs to be considered in these patients, and should prompt the use of adaptive prescriptions of intravenous dextrose where possible.

Background and aims: Several commercially available phytosterol supplements are promoted for their cholesterol-lowering effects. However, limited information is available about their potential anti-hyperglycaemic effects. This study aimed to evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitory effects of phytosterol supplements in silico and in vitro to determine their potential for anti-diabetic activity. Methods: Docking studies were carried out in silico to evaluate the potential for interactions between three major phytosterol compounds (stigmasterol, beta-sitosterol, campesterol) and the DPP-4 enzyme, the enzyme that is inhibited by the anti-diabetic gliptins. Gas chromatography-tandem mass spectrometry (GC-MS/MS) was used to analyse three different supplements for phytosterol content. DPP-4 inhibitory activity was tested in vitro for these phytosterol supplements and two major phytosterol standards. Results: In silico calculations predicted free binding energies for DPP-4 with the phytosterols to be: stigmasterol -8.78 kcal/mol; beta-sitosterol -8.70 kcal/mol; campesterol -8.40 kcal/mol. These binding energies indicated a potential for significant DPP-4 inhibition. However, these results were not supported by the in vitro studies. Stigmasterol and beta-sitosterol had an IC50 > 50 mg/ml (maximum tested concentration) and the Thompson's Cholesterol Manager (R) and Mega Strength Beta Sitosterol (R) supplements gave an IC50 > 100 mg/ml (maximum tested concentration). Blackmores Cholesterol Health (R) gave an IC50 value of 40 mg/ml which was attributed to beta-carotene content. Conclusions: Phytosterol supplements do not appear to offer any anti-diabetic activity potential via pathways that involve the inhibition of DPP-4. (c) 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

CONTEXT:Multiple endocrine neoplasia type 1 (MEN 1) is characterized by multisystem neoplasia including primary hyperparathyroidism and pituitary adenoma. Despite the adolescent onset of endocrinopathies, information regarding the impact of maternal MEN 1 on pregnancy is limited to case reports.OBJECTIVE:To explore pregnancy outcomes in MEN 1 positive women.METHODS:Retrospective case series of maternofoetal outcomes MEN 1 positive mothers managed at the Royal Hobart Hospital between 1967 and 2018. Data were retrieved from medical records and Australian averages calculated based on the Australian Institute of Health and Welfare data.RESULTS:Twenty-six women with MEN 1 were identified accounting for 96 pregnancies and 76 live born infants. Hyperparathyroidism was evident in 16 pregnancies. A significant increase in serum calcium in the second trimester (β = 0.14, P < .001) occurred that was not mediated by parathyroid hormone. Hypercalcaemia was mild-moderate with parathyroidectomy or medical management required in one and four pregnancies, respectively. Compared to the Australian average, women with MEN 1 were more likely to develop gestational diabetes (56% vs 8.9%, P = .001), hypertensive disorders (25.9% vs 7.6, P = .018), have shorter gestations (38.1 vs 38.7 weeks, P = .015) and have low birthweight infants (30.1% vs 6.5%, P = .001). However, emergency caesarean deliveries (63.2% vs 52.3%) and miscarriage rate (20.8% vs 20%) were not significantly different.CONCLUSION:Maternal MEN 1 is associated with an increased risk of gestational diabetes, hypertensive disorders and low neonatal birthweight, but not with an increased miscarriage rate. Whilst hypercalcaemia worsens during the second trimester, most pregnancies progressed without overt complications or requirement for intervention.

Introduction: Various pressures exist for curricular change, including economic forces, burgeoning knowledge, broadening learning outcomes, and improving quality and outcomes of learning experiences. In an Australian 5-year undergraduate medical course, staff were asked to reduce teaching hours by 20% to alleviate perceived overcrowded preclinical curriculum, achieve operating efficiencies and liberate time for students' self-directed learning. Methods: A case study design with mixed methods was used to evaluate outcomes. Results: Teaching hours were reduced by 198 hours (14%) overall, lectures by 153 hours (19%) and other learning activities by 45 hours (7%). Summative assessment scores did not change significantly after the reductions: 0.4% increase, 1.5% decrease and 1.7% increase in Years 1, 2 and 3, respectively. The percentage of students successfully completing their academic year did not change significantly: 94.4% before and 93.3% after the reductions. Student evaluations from eVALUate surveys changed little, except workload was perceived to be more reasonable. Conclusions: Teaching hours, particularly lectures, can be moderately reduced with little impact on student learning outcomes or satisfaction with an undergraduate medical course.