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Observational studies suggest that 25-hydroxy vitamin D (25(OH)D) concentration is inversely associated with pain. However, findings from intervention trials are inconsistent. We assessed the effect of vitamin D supplementation on pain using data from a large, double-blind, population-based, placebo-controlled trial (the D-Health Trial). 21 315 participants (aged 60–84 years) were randomly assigned to a monthly dose of 60 000 IU vitamin D3 or matching placebo. Pain was measured using the six-item Pain Impact Questionnaire (PIQ-6), administered 1, 2 and 5 years after enrolment. We used regression models (linear for continuous PIQ-6 score and log-binomial for binary categorisations of the score, namely ‘some or more pain impact’ and ‘presence of any bodily pain’) to estimate the effect of vitamin D on pain. We included 20 423 participants who completed ≥1 PIQ-6. In blood samples collected from 3943 randomly selected participants (∼800 per year), the mean (sd) 25(OH)D concentrations were 77 (sd 25) and 115 (sd 30) nmol/l in the placebo and vitamin D groups, respectively. Most (76 %) participants were predicted to have 25(OH)D concentration >50 nmol/l at baseline. The mean PIQ-6 was similar in all surveys (∼50·4). The adjusted mean difference in PIQ-6 score (vitamin D cf placebo) was 0·02 (95 % CI (−0·20, 0·25)). The proportion of participants with some or more pain impact and with the presence of bodily pain was also similar between groups (both prevalence ratios 1·01, 95 % CI (0·99, 1·03)). In conclusion, supplementation with 60 000 IU of vitamin D3/month had negligible effect on bodily pain.

Background Falls cause considerable morbidity and mortality in older people. It is unclear how vitamin D supplementation affects falls risk, particularly when taken at high doses. We sought to determine whether monthly high‐dose vitamin D supplementation reduces risk and incidence of falls. Methods We used data from the randomized, double‐blind, placebo‐controlled D‐Health Trial conducted in Australia. Between February 2014 and May 2015, 21 315 participants aged 60–84 years were randomized (1:1) to monthly doses of either 60 000 IU of colecalciferol or placebo for a maximum of 5 years. People who reported a history of osteomalacia, sarcoidosis, hyperparathyroidism, hypercalcaemia or kidney stones or who were taking >500 IU/day supplementary vitamin D were ineligible. Each year, we collected blood samples from ~450 randomly sampled participants from each trial arm and measured 25‐hydroxyvitamin D [25(OH)D]. Falls, a prespecified tertiary outcome, were ascertained using annual surveys and, for a subset of participants, 3‐month falls diaries. The primary outcome for this analysis was any fall in the month before completing an annual survey. As part of our process to maintain blinding, we used random samples of participants (surveys, n = 16 000; diaries, n = 2400), with equal numbers per group. Participants with no outcome data were excluded. Following an intention‐to‐treat approach, we analysed outcomes using logistic, ordinal and negative binomial regression. Registration: Australian New Zealand Clinical Trials Registry (ACTRN12613000743763); registered 4 July 2013. Results Mean treatment duration was 4.3 years (standard deviation [SD] = 1.4 years). Mean serum 25(OH)D concentrations during the trial were 114.8 (SD 30.3) nmol/L and 77.5 (SD 25.2) nmol/L in the vitamin D and placebo groups, respectively. Survey and diary analytic sets included 15 416 and 2200 participants, respectively; approximately half were randomized to vitamin D (surveys: 50.1%; diaries: 50.4%). Vitamin D had no effect on falling in the past month (odds ratio [OR] 1.02, 95% confidence interval [CI] 0.95–1.10). There was an interaction with body mass index (BMI) (P‐interaction = 0.001); vitamin D increased risk in participants with BMI

OBJECTIVE: Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer. DESIGN AND PATIENTS: We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex. METHODS: Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias. RESULTS: We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99). CONCLUSION: We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers.

Ectopic pituitary adenomas are a rare clinical entity and are frequently mistaken for other base of skull lesions on imaging. We report the clinical presentation and management of a woman presenting with an ectopic prolactinoma located in the clivus. A 66-year-old female presented with a 6-month history of headaches and light-headedness. Anatomical imaging demonstrated a clival lesion most suspicious for chordoma. Endocrinological assessment revealed modestly increased prolactin level with lower-than-expected gonadotrophins levels for her age. Surgical resection confirmed an ectopic prolactinoma. A skull base lesion in a patient with hormonal derangement should lend to a high clinical suspicion of an EPA as they may be treated with medications before surgery. Guidelines could assist clinicians investigating skull-based lesions to identify the rare, but important diagnosis of ectopic pituitary adenomas.

To investigate whether vitamin D supplementation reduces depressive symptoms and incidence of antidepressant use.We used data from the D-Health Trial (N = 21,315), a randomized double-blind placebo-controlled trial of monthly vitamin DAnalyses of PHQ-9 scores included 20,487 participants (mean age 69·3 years, 46% women); the mean difference (MD) in PHQ-9 score (vitamin D vs. placebo) was 0·02 (95% CI -0·06, 0·11). There was negligible difference in the prevalence of clinically relevant depression (PHQ-9 score ≥10) (odds ratio 0·99; 95% CI 0·90, 1·08). We included 16,670 participants in the analyses of incident antidepressant use (mean age 69·4 years, 43% women). Incidence of antidepressant use was similar between the groups (hazard ratio [HR] 1·04; 95% CI 0·96, 1·12). In subgroup analyses, vitamin D improved PHQ-9 scores in those taking antidepressants at baseline (MD -0·25; 95% CI -0·49, -0·01; p-interaction = 0·02). It decreased risk of antidepressant use in participants with predicted 25(OH)D concentration50 nmol/L (HR 0·88; 95% CI 0·75, 1·02; p-interaction = 0·01) and increased risk in those with predicted 25(OH)D ≥ 50 nmol/L (HR 1·10; 95% CI 1·01, 1·20).Monthly supplementation with high-dose vitamin DThe trial is registered on the Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/.

Summary Background Observational studies have linked vitamin D deficiency with acute respiratory tract infection, but results from randomised controlled trials are heterogeneous. We analysed data from the D-Health Trial to determine whether supplementing older Australian adults, recruited from the general population, with monthly doses of vitamin D reduced the risk, duration, and severity of acute respiratory tract infections. Methods We used data from the D-Health Trial, a randomised, double-blind, placebo-controlled trial of monthly vitamin D supplementation, for which acute respiratory infection was a pre-specified trial outcome. Participants were supplemented and followed for up to 5 years. The trial was set within the Australian general population, using the Commonwealth Electoral Roll as the sampling frame, but also allowing some volunteers to participate. Participants were men and women aged 60 to 79 years (with volunteers up to age 84 years). Participants were randomly assigned to receive either vitamin D or placebo (1:1) using computer-generated permuted block randomisation, which was stratified by age, sex, and state. This was an automated process and the assignment list was not visible to study staff or investigators. Active and placebo gel capsules, identical in appearance to ensure masking, were labelled A and B and the code was not available to study staff or investigators. Participants were asked to report occurrence of acute respiratory symptoms over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. As part of our process to maintain blinding, a random sample of participants was selected for analysis of survey data and a separate sample selected for analysis of diary data. Blood samples were obtained from a random sample of participants (about 450 per group per year) and serum 25-hydroxy vitamin D (25[OH]D) concentrations were measured to monitor adherence. We used regression models to estimate odds ratios (OR), rate ratios, and rate differences. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000743763. Findings Between Jan 13, 2014, and May 26, 2015, 421 207 invitations were sent, 40 824 people were interested in participating, and 21 315 participants were recruited and randomised. Of the 16 000 participants selected for potential analysis of survey data, 15 373 were included in the analysis; 295 in the vitamin D group and 332 in the placebo group who were missing data for all five annual surveys were excluded from the analysis. Of the 3800 selected for potential analysis of diary data, 3070 were invited to complete the diaries because 730 had already withdrawn. 2598 people were included in the analysis; 218 people in the vitamin D group and 254 in the placebo group were missing data and were therefore excluded from the analysis. In blood samples collected from randomly sampled participants throughout the trial, the mean serum 25(OH)D concentration was 114·8 (SD 30·3) nmol/L in the vitamin D group and 77·5 (25·2) nmol/L in the placebo group. Vitamin D supplementation did not reduce the risk of acute respiratory tract infection (survey OR 0·98, 95% CI 0·93 to 1·02; diary OR 0·98, 0·83 to 1·15). Analyses of diary data showed reductions in the overall duration of symptoms and of severe symptoms, but these were small and unlikely to be clinically significant. Interpretation Monthly bolus doses of 60 000 IU of vitamin D did not reduce the overall risk of acute respiratory tract infection, but could slightly reduce the duration of symptoms in the general population. These findings suggest that routine vitamin D supplementation of a population that is largely vitamin D replete is unlikely to have a clinically relevant effect on acute respiratory tract infection. Funding National Health and Medical Research Council.

Background Vitamin D supplementation may reduce the risk or severity of infection, but this has been investigated in few large population-based trials. We analyzed data from the D-Health Trial, using prescription of antibiotics as a surrogate for infection. Methods The D-Health Trial is a randomized, double-blind, placebo-controlled trial in which 21 315 Australians aged 60–84 years were randomized to 60 000 IU of supplementary vitamin D3 or placebo monthly for 5 years. For this analysis, the primary outcome was the number of antibiotic prescription episodes; secondary outcomes were total number of prescriptions, repeat prescription episodes, and antibiotics for urinary tract infection. We estimated incidence rate ratios (IRRs) using negative binomial regression, and odds ratios using logistic regression. Results Vitamin D supplementation slightly reduced the number of prescription episodes (IRR, 0.98; 95% confidence interval [CI], .95–1.01), total prescriptions (IRR, 0.97; 95% CI, .93–1.00), and repeat prescription episodes (IRR, 0.96; 95% CI, .93–1.00). There was stronger evidence of benefit in people predicted to have insufficient vitamin D at baseline (prescription episodes IRR, 0.93; 95% CI, .87–.99). Conclusions Vitamin D may reduce the number of antibiotic prescriptions, particularly in people with low vitamin D status. This supports the hypothesis that vitamin D has a clinically relevant effect on the immune system. Clinical Trials Registration Australian New Zealand Clinical Trials Registry: ACTRN12613000743763. https://www.anzctr.org.au/.

Background: Thyroid cancer incidence has increased in many parts of the world since the 1980s, as has the prevalence of obesity. Evidence suggests that people with greater body size have higher thy...

Background Hysterectomy (surgical removal of the uterus) has been consistently associated with increased thyroid cancer risk. While there may be a biologic explanation, increased ascertainment (over-diagnosis) because of greater healthcare use by women having this procedure might also contribute to the observed increased risk. We explored this association considering indications for hysterectomy, age at hysterectomy, and the potential for the association to be mediated by increased contact with health professionals or increased thyroid function testing. Methods We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. We estimated odds ratios (OR) using logistic regression to assess the associations and used causal mediation analysis to investigate potential mediation. Results Prior hysterectomy was associated with an increased thyroid cancer risk (OR = 1.55, 95% CI: 1.14-2.12). When stratified by indication for hysterectomy, the increased risk was apparent only among those who had undergone hysterectomy for bleeding disorders (OR = 1.79, 95% CI: 1.26-2.56). Additionally, the association varied by age at hysterectomy ( Conclusions Hysterectomy for bleeding disorders was associated with an increased risk of thyroid cancer among women and a moderate proportion of this appeared due to frequent medical contact. Key messages The way in which women use health services probably explains at least some of the association between hysterectomy and risk of thyroid cancer.

Background Observational studies link vitamin D deficiency with acute respiratory tract infection (ARTI) but results from randomised controlled trials are heterogeneous. Methods We used data from The D-Health Trial (N = 21,315); ARTI was a pre-specified trial outcome. Participants were men and women aged 60 to 79 years (with volunteers aged up to 84 years), supplemented with monthly doses of 60,000 international units of vitamin D and followed for up to 5 years. Participants were asked to report occurrence of ARTI over the previous month via annual surveys, and a subset of participants completed 8-week respiratory symptom diaries in winter. We used regression models to estimate odds ratios, rate ratios and rate differences. Results Vitamin D supplementation did not reduce the risk of ARTI (survey OR 0.98, 95% CI 0.93 to 1.02; diary OR 0.98, 95% CI 0.83 to 1.15). Analyses of diary data showed that vitamin D reduced the average duration by 0.5 days (95% CI 0.2 to 0.7 days) and the average number of days with severe symptoms by 0.4 days (95% CI 0.3 to 0.6 days). Conclusions Monthly bolus doses of 60,000 IU of vitamin D did not reduce the overall risk of ARTI but slightly reduce the duration of symptoms in the general population. Key messages The reduction in the duration of symptoms suggests a potential impact of vitamin D on the immune response to infection.

Smoking has been associated with a reduced risk of thyroid cancer, but whether the association varies between higher- and lower-risk cancers remains unclear. We aimed to assess the association between smoking and risk of thyroid cancer overall as well as by tumour BRAF mutational status as a marker of potentially higher-risk cancer.We recruited 1013 people diagnosed with thyroid cancer and 1057 population controls frequency-matched on age and sex.Multivariable logistic regression was used to assess the association overall and in analyses stratified by tumour characteristics. We used sensitivity analysis to assess the potential for selection bias.We found little evidence of an association with current smoking (odds ratio [OR] = 0.93; 95% confidence interval [CI]: 0.69-1.26; current vs. never smoking), but a higher number of pack-years of smoking was associated with a lower risk of thyroid cancer (OR = 0.75; 95% CI: 0.57-0.99; ≥20 pack-years vs. never). However, after correcting for potential selection bias, we observed a statistically significant inverse association between current smoking and risk of thyroid cancer (bias-corrected OR = 0.65; 95% CI: 0.51-0.83). Those with BRAF-positive cancers were less likely to be current smokers than those with BRAF-negative cancers (prevalence ratio: 0.79; 95% CI: 0.62-0.99).We found smoking was inversely related to thyroid cancer risk and, in particular, current smoking was associated with a reduced risk of potentially more aggressive BRAF-positive than the likely more indolent BRAF-negative papillary thyroid cancers.

Microscopic extra-thyroidal extension occurs when thyroid cancer advances beyond the thyroid capsule into the surrounding peri-thyroidal soft tissues of fat and/or skeletal muscle, without visual evidence of this invasion (which is often called macroscopic or gross invasion). It is common, with a reported prevalence of between 11% and 44%. It must also be distinguished from major extra-thyroidal extension, which implies more advanced disease and worse prognosis. Tumors with microscopic extra-thyroidal extension may be slightly more aggressive than tumors with none, although in the absence of other important prognostic findings, prognosis can be excellent. This case discussion details possible risks for patients with microscopic extra-thyroidal extension and explores treatment options, their rationale, and available evidence to make informed treatment decisions.

Background: The majority of small papillary thyroid cancers (sPTCs) are treated surgically, rather than by active surveillance. Patient and clinician preference for surgery may be partially driven by the use of cancer terminology. Some experts propose that changing terminology would better communicate the indolent nature of sPTCs and improve uptake of active surveillance. Others argue that terminology that includes "cancer" correctly reflects the biological nature of these tumors. The views of informed lay publics can provide value-based perspectives on complex issues and guide policy discussions. Methods: We recruited 40 people for three community juries, held in Sydney, Wodonga, and Cairns, Australia. Participants were of diverse backgrounds and ages, recruited through random digit dialing and a topic-blinded social media strategy. Juries were informed about thyroid cancer, overdiagnosis, and overtreatment, and heard arguments for and against terminology change before deliberation. The deliberative process in Jury 1 led to a refinement of jury charge, the updated version that was then used in Juries 2 and 3. Results: Jury 1 favored no terminology change, and Juries 2 and 3 were divided on the topic. Key reasons for opposing terminology change included a strong desire to retain terminology that aligns with the pathological definition of cancer, and to avoid even a minimal risk of harm that could arise if patients became complacent in follow-up. Key reasons to support terminology change included a desire to reduce psychological distress, stigma, and discrimination associated with a cancer diagnosis, and an argument that terminology change may be a more effective trigger for health system reform compared with other options. The juries unanimously recommended community education and health system reforms to reduce harms of overtreatment, and expressed an expectation that clinicians and researchers reach agreement on clinical guidelines to promote better uptake of active surveillance. Conclusions: The conceptual tension between a pathological and an outcome-based understanding of cancer was apparent in deliberation. This highlights an ongoing challenge for those advocating changing disease terminology. Regardless of action on terminology, jurors shared a strong expectation that practical changes would be made to respond to the harms of overtreatment.

BackgroundThe D-Health Trial aims to determine whether monthly high-dose vitamin D supplementation can reduce the mortality rate and prevent cancer. We did not have adequate statistical power for subgroup analyses, so could not justify the high cost of collecting blood samples at baseline. To enable future exploratory analyses stratified by baseline vitamin D status, we developed a model to predict baseline serum 25 hydroxy vitamin D [25(OH)D] concentration.MethodsWe used data and serum 25(OH)D concentrations from participants who gave a blood sample during the trial for compliance monitoring and were randomised to placebo. Data were partitioned into training (80%) and validation (20%) datasets. Deseasonalised serum 25(OH)D concentrations were dichotomised using cut-points of 50 nmol/L, 60 nmol/L and 75 nmol/L. We fitted boosted regression tree models, based on 13 predictors, and evaluated model performance using the validation data.ResultsThe training and validation datasets had 1788 (10.5% ConclusionsWe exploited compliance monitoring data to develop models to predict serum 25(OH)D concentration for D-Health participants at baseline. This approach may prove useful in other trial settings where there is an obstacle to exhaustive data collection.

In their recent publication, Baron and colleagues ([1][1]) reviewed the epidemiologic and biological evidence for the protective association between tobacco smoking and four “estrogen-related” malignancies (endometrial cancer, endometrioid and clear-cell ovarian cancers, and thyroid cancer).

Background Hysterectomy has been associated with increased thyroid cancer risk but whether this reflects a biological link or increased diagnosis of indolent cancers due to greater medical contact remains unclear. Methods We recruited 730 women diagnosed with thyroid cancer and 785 age-matched population controls. Multivariable logistic regression was used to assess the association overall, and by tumour BRAF mutational status as a marker of potentially higher-risk cancers. We used causal mediation analysis to investigate potential mediation of the association by healthcare service use. Results Having had a hysterectomy was associated with an increased risk of thyroid cancer (odds ratio [OR] = 1.45, 95 % confidence interval [CI] 1.07–1.96). When stratified by indication for hysterectomy, the risk appeared stronger for those who had a hysterectomy for menstrual disorders (OR = 1.67, 95 % CI 1.17–2.37) but did not differ by tumour BRAF status. Approximately 20 % of the association between hysterectomy and thyroid cancer may be mediated by more frequent use of healthcare services. Conclusions The observed increased risk of thyroid cancer among those with hysterectomy may be driven, at least partly, by an altered sex steroid hormone milieu. More frequent healthcare service use by women with hysterectomy accounts for only a small proportion of the association.

Objective Little data is in existence about the most cost-effective primary treatment for Graves’ disease. We performed a cost–utility analysis comparing radioactive iodine (RAI), anti-thyroid drugs (ATD) and total thyroidectomy (TT) as first-line therapy for Graves’ disease in England and Australia. Methods We used a Markov model to compare lifetime costs and benefits (quality-adjusted life-years (QALYs)). The model included efficacy, rates of relapse and major complications associated with each treatment, and alternative second-line therapies. Model parameters were obtained from published literature. One-way sensitivity analyses were conducted. Costs were presented in 2015£ or Australian Dollars (AUD). Results RAI was the least expensive therapy in both England (£5425; QALYs 34.73) and Australia (AUD5601; 30.97 QALYs). In base case results, in both countries, ATD was a cost-effective alternative to RAI (£16 866; 35.17 QALYs; incremental cost-effectiveness ratio (ICER) £26 279 per QALY gained England; AUD8924; 31.37 QALYs; ICER AUD9687 per QALY gained Australia), while RAI dominated TT (£7115; QALYs 33.93 England; AUD15 668; 30.25 QALYs Australia). In sensitivity analysis, base case results were stable to changes in most cost, transition probabilities and health-relative quality-of-life (HRQoL) weights; however, in England, the results were sensitive to changes in the HRQoL weights of hypothyroidism and euthyroidism on ATD. Conclusions In this analysis, RAI is the least expensive choice for first-line treatment strategy for Graves’ disease. In England and Australia, ATD is likely to be a cost-effective alternative, while TT is unlikely to be cost-effective. Further research into HRQoL in Graves’ disease could improve the quality of future studies.

There are no data on the epidemiology of amyloidosis in Australia. Most international epidemiological studies are based on death certificate data [1–4]. This study aims to describe the incidence an...

The incidence of thyroid cancer has rapidly increased, and ecological evidence suggests this is due in some part to over-diagnosis. Understanding pathways to diagnosis could help determine whether unnecessary diagnosis can be avoided.A population-based sample (n = 1007) of thyroid cancer patients diagnosed between July 2013 and August 2016 was recruited from Queensland, Australia (response rate 67%). Information from structured telephone interviews was used to describe diagnostic pathways for thyroid cancer, to investigate factors associated with diagnostic pathways, and to assess the most prevalent modes of diagnoses by which the lowest-risk, potentially over-diagnosed thyroid cancers (intrathyroidal microcarcinomas) are detected.Only 38% of participants presented with symptoms potentially related to thyroid cancer. Older age at diagnosis was associated with a lower prevalence of symptomatic diagnosis (prevalence ratio [PR] = 0.46 [confidence interval (CI) 0.31-0.68] for 70-79 vs.30 years), as was frequent medical contact, while living in rural/regional areas was associated with a higher prevalence of symptomatic diagnosis (PR = 1.17 [CI 1.00-1.37] for rural/regional areas vs. major cities). Symptomatic diagnosis also occurred more for those whose tumors had adverse histopathological features (larger size, lymph node involvement, lymphovascular invasion). The likelihood of diagnosis of intrathyroidal microcarcinomas was greatest for those having surgical resection or monitoring for benign thyroid disease (PR = 3.87 [CI 2.81-5.32] and PR = 2.21 [CI 1.53-3.18], respectively).A minority of newly detected thyroid cancer cases were diagnosed because of symptoms. Access to medical care and factors related to cancer aggressiveness were associated with how diagnoses occurred. The likelihood of diagnosing the lowest-risk thyroid cancers was higher in situations related to management of other thyroid conditions. Adherence to thyroid management guidelines could reduce some thyroid cancer over-diagnosis, but ultimately better diagnostic tools are needed to differentiate between indolent cancers and those of clinical significance.

Published studies on the epidemiology of amyloidosis have relied on death certificate data for case ascertainment. We estimated the incidence and mortality burden of amyloidosis among residents of the Australian state, Queensland, aged ≥20 years for the years 1999-2013 based on case ascertainment from histopathology reports. Information systems for participating laboratories were scrutinised to identify histopathology reports that documented a diagnosis of amyloidosis. Case mortality status was determined via linkage to the National Death Index. A total of 447 cases of amyloidosis were identified, with a median age at diagnosis of 66 years. A plasma cell dyscrasia was identified in 72% of patients who had paraprotein studies performed. The estimated incidence for Queenslanders aged ≥20 years was 12·1 cases per million person years. The median survival was 2·45 years. Age at diagnosis, presence of a paraprotein, earlier year of diagnosis, and inner regional location of residence (compared with residence in a major city) were independently associated with reduced survival. Our data confirms previously reported incidence data for amyloidosis of approximately 10 cases per million patient years and indicates that survival for Queensland patients with amyloidosis is improving, though it remains poor for the elderly and patients with AL amyloidosis.

An ever-increasing population of patients with papillary thyroid cancer is engaging with health care systems around the world. Numerous questions about optimal management have arisen that challenge conventional paradigms. This is particularly the case for patients with low-risk disease, who comprise most new patients. At the same time, new therapies for patients with advanced disease are also being introduced, which may have the potential to prolong life. This review discusses selected controversial issues in adult papillary thyroid cancer management at both ends of the disease spectrum. These topics include: (i) the role of active surveillance for small papillary cancers; (ii) the extent of surgery in low-risk disease (lobectomy vs total thyroidectomy); (iii) the role of postoperative remnant ablation with radioiodine; (iv) optimal follow-up strategies in patients, especially those who have only undergone lobectomy; and (v) new therapies for advanced disease. Although our current management is hampered by the lack of large randomized controlled trials, we are fortunate that data from ongoing trials will be available within the next few years. This information should provide additional evidence that will decrease morbidity in low-risk patients and improve outcomes in those with distant metastatic disease.

ObjectiveTo evaluate the role of fasting blood glucose (FBG) to minimise the use of the oral glucose tolerance test in pregnancy (POGTT) for the diagnosis of gestational diabetes mellitus (GDM).Research design and methodsWe analysed the POGTTs of 26,242 pregnant women in Queensland, Australia, performed between 1 January 2015 and 30 June 2015. A receiver operator characteristics (ROC) assessment was undertaken to indicate the FBG level that most effectively identified women at low risk of an abnormal result.ResultsThere were 3,946 (15.0%) patients having GDM with 2,262 (8.6%) having FBG ≥ 5.1mmol/l. The ROC identified FBG levels >4.6mmol/l having the best specificity (77%) and sensitivity (54%) for elevated 1 and/or 2hr BGLs. There were 19,321 (73.7%) women having FBG < 4.7mmol/l with a prevalence of GDM of 4.0%, less than 1/3rdthe overall rate. Only 4,638 (17.7%) women having FBGs from 4.7–5.0mmol/l would require further evaluation to confirm or exclude the diagnosis.ConclusionThis contemporary study of women across the state of Queensland, Australia suggests the FBG can be used effectively to define glucose tolerance in pregnancy, minimising their contact with pathology laboratories and potential exposure to the corona virus. This analysis, used in conjunction with outcome data from the HAPO study, provides reassurance to women and their health professionals that FBG < 4.7mmol/l has both a low rate of abnormal glucose tolerance and minimal adverse pregnancy-associated complications.

Thyroid cancer is unique for having age as a staging variable. Recently, the commonly used age cut-point of 45 years has been questioned.This study assessed alternate staging systems on the outcome of overall survival, and compared these with current National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging systems for papillary and follicular thyroid cancer.A total of 4721 patients with differentiated thyroid cancer were assessed. Five potential alternate staging systems were generated at age cut-points in five-year increments from 35 to 70 years, and tested for model discrimination (Harrell's C-statistic) and calibration (R(2)). The best five models for papillary and follicular cancer were further tested with bootstrap resampling and significance testing for discrimination.The best five alternate papillary cancer systems had age cut-points of 45-50 years, with the highest scoring model using 50 years. No significant difference in C-statistic was found between the best alternate and current NTCTCS systems (p = 0.200). The best five alternate follicular cancer systems had age cut-points of 50-55 years, with the highest scoring model using 50 years. All five best alternate staging systems performed better compared with the current system (p = 0.003-0.035). There was no significant difference in discrimination between the best alternate system (cut-point age 50 years) and the best system of cut-point age 45 years (p = 0.197).No alternate papillary cancer systems assessed were significantly better than the current system. New alternate staging systems for follicular cancer appear to be better than the current NTCTCS system, although they require external validation.

BACKGROUND: Thyroid cancer incidence has been increasing worldwide. Some suggest greater ascertainment of indolent tumours is the only driver, but others suggest there has been a true increase. Increases in Australia appear to have been among the largest in the world, so we investigated incidence trends in the Australian state of Queensland to help understand reasons for the rise. METHODS: Thyroid cancers diagnoses in Queensland 1982-2008 were ascertained from the Queensland Cancer Registry. We calculated age-standardized incidence rates (ASR) and used Poisson regression to estimate annual percentage change (APC) in thyroid cancer incidence by socio-demographic and tumour-related factors. RESULTS: Thyroid cancer ASR in Queensland increased from 2.2 to 10.6/100 000 between 1982 and 2008 equating to an APC of 5.5% [95% confidence interval (CI) 4.7-6.4] in men and 6.1% (95% CI 5.5-6.6) in women. The rise was evident, and did not significantly differ, across socio-economic and remoteness-of-residence categories. The largest increase seen was in the papillary subtype in women (APC 7.9%, 95% CI 7.3-8.5). Incidence of localized and more advanced-stage cancers rose over time although the increase was greater for early-stage cancers. CONCLUSION: There has been a marked increase in thyroid cancer incidence in Queensland. The increase is evident in men and women across all adult age groups, socio-economic strata and remoteness-of-residence categories as well as in localized and more advanced-stage cancers. Our results suggest 'overdiagnosis' may not entirely explain rising incidence. Contemporary aetiological data and individual-level information about diagnostic circumstances are required to further understand reasons for rising thyroid cancer incidence.

Transfer of thyroid hormone into cells is critical for normal physiology and transplacental transfer of maternal thyroid hormones is essential for normal fetal growth and development. Free thyroid hormone is known to enter cells through specific cell surface transport proteins, and for many years this uptake of unbound thyroid hormones was assumed to be the only relevant mechanism. Recently, evidence has emerged of alternate pathways for hormone entry into cells that are dependent on hormone binding proteins. In this study we identify the high-density lipoprotein receptor Scavenger Receptor class B member 1 (SR-B1) as important in the uptake and transport of transthyretin-bound thyroid hormone by placental trophoblast cells. High-density lipoprotein increases expression of SR-B1 in placental cells but also reduces uptake of transthyretin-thyroid hormone through the SR-B1 transporter. SR-B1 is expressed in many cells and this study suggests that SR-B1 may be universally important in thyroid hormone uptake. Further investigation of SR-B1-TTR interactions may fundamentally change our understanding of hormone biology and have important clinical consequences.

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression-free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as "redifferentiation" agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.

Importance Concerns around possible overdiagnosis and overtreatment of differentiated thyroid cancer (DTC) have been raised. Issues concerning health-related quality of life (HRQOL) after diagnosis and treatment of DTC are understudied in this patient group. Objective To better understand the range of HRQOL outcomes, including possible adverse effects of treatment, associated with diagnosis and treatment of DTC and whether these outcomes vary by type of surgery received. Design, Setting, and Participants This content analysis assessed responses to an open-ended question about outcomes and concerns after DTC diagnosis and treatment among patients ascertained from the major postsurgical thyroid cancer treatment center and the population-based Cancer Registry in Queensland, Australia. Participants were aged 18 to 79 years and recently diagnosed with throid cancer. Responses underwent analysis to identify and code emergent themes to describe HRQOL issues and adverse effects of treatment experienced. Quantitative analysis was used to explore whether surgery type was associated with HRQOL issues and/or adverse effects of treatment. Of 1416 eligible patients, 1005 (71.0%) participated. Data were collected from July 1, 2013, through August 31, 2016, and analyzed from January 11 through April 9, 2018. Main Outcomes and Measures Issues concerning HRQOL. Results The analysis included 1005 patients (72.2% female [n = 726]; mean [SD] age, 52 [14.0 years) with DTC. Most patients were diagnosed with papillary thyroid cancer (889 of 1003 [88.6%]), had tumors smaller than 2 cm in size (564 of 1000 [56.4%]), and received a total thyroidectomy (791 of 1005 [78.7%]). Overall, 775 patients (77.1%) reported HRQOL issues after diagnosis and treatment of DTC. The following 4 main themes emerged from content analysis of patient responses: physical (663 [66.0%]), psychological (187 [18.6%]), lifestyle (82 [8.2%]), and no issue or adverse effect (246 [24.5%]). Patients who had a total thyroidectomy (without neck dissection) were 1.5 times (odds ratio, 1.49; 95% CI, 1.04-2.12) more likely to report an HRQOL issue or an adverse effect of treatment compared with patients who underwent a hemithyroidectomy. Conclusions and Relevance According to results of this study, patients diagnosed with DTC report wide-ranging HRQOL issues; these are more prevalent among patients who have total thyroidectomies rather than hemithyroidectomies. For patients with small, localized DTCs, hemithyroidectomy may offer fewer adverse effects of treatment and better HRQOL outcomes than total thyroidectomy. It appears that issues with HRQOL should be considered by patients and physicians when deciding on the best treatment approach after a diagnosis of DTC.

ObjectivesTo investigate public perceptions of overdiagnosis and overtreatment in low-risk thyroid cancer and explore opinions regarding the proposed strategy to change the terminology of low-risk cancers.DesignQualitative study using focus groups that included a guided group discussion and presentation explaining thyroid cancer, overdiagnosis and overtreatment, and proposed communication strategies. Transcripts were analysed thematically.SettingSydney, Australia.ParticipantsForty-seven men and women of various ages from a range of socioeconomic backgrounds with no personal history of thyroid cancer.ResultsParticipants had low pre-existing general awareness of concepts of overdiagnosis and overtreatment and expressed concern regarding this new information in relation to thyroid cancer. Overall, participants understood why the strategy to change the terminology was being proposed and could see potential benefits including reducing the negative psychological impact and stigma associated with the term ‘cancer’; however, many still had reservations about the strategy. The majority of the concerns were around their worry about the risk of further disease progression and that changing the terminology may create confusion and cause patients not to take the diagnosis and its associated managements seriously. Despite varied views towards the proposed strategy, there was a strong overarching desire for greater patient and public education around overdiagnosis and overtreatment in both thyroid cancer and cancer generally in order to complement any revised terminology and/or other mitigation strategies.ConclusionsWe found a strong and apparently widely held desire for more information surrounding the topic of overdiagnosis and overtreatment. Careful consideration of how to inform both the public and current patients about the implications of a change in terminology, including changes to patients’ follow-up or treatments, would be needed if such a change were to go ahead.

BACKGROUND: Vitamin D, specifically serum 25(OH)D has been associated with mortality, cancer and multiple other health endpoints in observational studies, but there is a paucity of clinical trial evidence sufficient to determine the safety and effectiveness of population-wide supplementation. We have therefore launched the D-Health Trial, a randomized trial of vitamin D supplementation for prevention of mortality and cancer. Here we report the methods and describe the trial cohort. METHODS: The D-Health Trial is a randomized placebo-controlled trial, with planned intervention for 5years and a further 5years of passive follow-up through linkage with health and death registers. Participants aged 65-84years were recruited from the general population of Australia. The intervention is monthly oral doses of 60,000IU of cholecalciferol or matching placebo. The primary outcome is all-cause mortality. Secondary outcomes are total cancer incidence and colorectal cancer incidence. RESULTS: We recruited 21,315 participants to the trial between February 2014 and May 2015. The participants in the two arms of the trial were well-balanced at baseline. Comparison with Australian population statistics shows that the trial participants were less likely to report being in fair or poor health, to be current smokers or to have diabetes than the Australian population. However, the proportion overweight or with health conditions such as arthritis and angina was similar. CONCLUSIONS: Observational data cannot be considered sufficient to support interventions delivered at a population level. Large-scale randomized trials such as the D-Health Trial are needed to inform public health policy and practice.

Minimal extra-thyroidal extension occurs when thyroid cancer advances beyond the thyroid capsule into surrounding perithyroid soft tissues of fat and/or skeletal muscle. It is common, with a reported prevalence between 11 and 44 %. It must be distinguished from major extra-thyroidal extension, which implies more advanced disease and worse prognosis. Tumors with minimal extra-thyroidal extension may be slightly more aggressive than tumors without, although in the absence of other important prognostic findings, prognosis can be excellent. This case discussion details possible risks for patients with minimal extra-thyroidal extension and explores treatment options, their rationale, and available evidence to make informed treatment decisions.

Background Recombinant factor VIIa (rFVIIa) is used for many off-label indications without high quality evidence to support its efficacy. The aim of this study was to determine indications for use of off-label rFVIIa, efficacy and safety, and adherence to institutional guidelines. Methods We performed a retrospective review of off-label rFVIIa at two tertiary hospitals from 2007 to 2010. Results One hundred forty-five administrations were identified and analysed. Haemorrhage associated with cardiac surgery made up one-third of all rFVIIa usage, with trauma (20%) and other surgery (11%) the next most frequent indications. Compared with all others, cardiac surgery patients were older (60.0 years versus 47.4 years, P < 0.001) and had lower pre-rFVIIa transfusion requirements, a higher subjective response rate (88% versus 46%, P < 0.001) and lower mortality rates (6.1% versus 33%, P < 0.001), but higher rates of arterial thrombormbolic events (16.7% versus 2.1%, P = 0.002). Most patients received only one or two doses (n = 137; 95%), with no subject receiving a third or subsequent dose having an appreciable reduction in bleeding. Only a small number of patients (n = 15; 10.3%) had rFVIIa administered in accordance with our institutions' guidelines. Conclusion Patients administered rFVIIa for haemorrhage not associated with cardiac surgery were severely unwell. Despite lack of evidence, administration of rFVIIa may be justified by the high mortality rate, but more than two doses are unlikely to provide further benefit. The high rate of arterial thromboembolism in cardiac surgical patients raises riskbenefit considerations. Adherence to our institutions' guidelines was poor.

TSH is the major growth factor for thyrocytes and may have a causative role in thyroid cancer.The objective of the study was to systematically assess the association between serum TSH and thyroid cancer.The MEDLINE and EMBASE databases were searched using synonyms for TSH and thyroid cancer, supplemented with reference list searches and author contact.Prospective cohort, case-control, and cross-sectional studies were identified with TSH the exposure and thyroid cancer the outcome.Three reviewers independently extracted data. Studies reporting odds ratio (OR) for TSH levels and thyroid cancer were analyzed via meta-analysis and generalized least-squares trend estimation for dose-response relationships.Data extracted from 28 studies included a total of 42,032 subjects and 5,786 thyroid cancer cases. Dose-response spline analysis revealed a nonlinear relationship (P0.001). For TSH levels less than 1 mU/liter, the OR for thyroid cancer was 1.72 (1.42, 2.07) per milliunits per liter. However, the relationship changed for TSH levels 1 mU/liter and greater, with the OR thereafter being 1.16 (1.12, 1.21) per milliunits per liter. Studies controlling for autoimmunity reported the lowest OR [TSH below 2.5 mU/liter, OR 1.23 (1.02-1.47) per milliunits per liter; TSH 2.5 mU/liter or greater, OR 0.98 (0.89-1.09) per milliunits per liter]. Six groups assessed serum TSH in relation to markers of poor thyroid cancer prognosis, with three showing significant positive relationships.Higher serum TSH concentration is associated with an increased risk of thyroid cancer. Thyroid autoimmunity may partially explain the association, but further epidemiological assessment is required. Future clinical research should investigate the validity of including serum TSH in diagnostic nomograms, its prognostic importance, and the potential for therapeutic TSH suppression in thyroid cancer prevention.

Diabet. Med. 29, e199e204 (2012) Abstract Aims To assess associations between maternal serum vitamin D concentration and glucose metabolism in a cohort of pregnant women living in an Australian subtropical environment. Methods Cross-sectional assessment of 25-hydroxy vitamin D concentrations in 399 Hyperglycemia and Adverse Pregnancy Outcome ancillary study participants, treated at an obstetric teaching hospital in Brisbane, Australia. All patients underwent a blinded 75-g oral glucose tolerance test at 2432 (target 28) weeks gestation. Results The mean (+/- standard deviation) fasting plasma glucose was 4.5 +/- 0.4 mmol/l. Mean (+/- standard deviation) serum 25-hydroxy vitamin D was 132.5 +/- 44.0 nmol/l. A difference of one standard deviation in maternal 25-hydroxy vitamin D was inversely related to fasting glucose (fasting glucose lower by 0.047 mmol/l, P = 0.012) when assessed with multiple linear regression after adjusting for confounders. Maternal 25-hydroxy vitamin D correlated with beta-cell function as estimated by the log-transformed homeostasis model assessment beta-cell function equation (r = 0.131, P = 0.009), but not with the homeostasis model assessment of insulin resistance. Conclusions An association between mid-gestational 25-hydroxy vitamin D and fasting glucose was confirmed in a largely normoglycaemic and vitamin D-replete pregnant population. The correlation between 25-hydroxy vitamin D and beta-cell function suggests that vitamin D may influence glucose metabolism through this mechanism. Intervention studies are required to determine causality and the role of vitamin D replacement in deficient individuals.

We report the case of a 56-year-old man with the rare autoimmune pathologies of alternating hypothyroidism and hyperthyroidism due to thyroid-stimulating hormone receptor antibodies, and rheumatoid arthritis as manifestations of a human immunodeficiency virus-related immune reconstitution inflammatory syndrome. The patient also developed overt progression of a pre-existing skin malignancy that may also be related. This case highlights immune reconstitution syndrome as an important differential diagnosis following antiretroviral therapy commencement, and that a high index of suspicion should be maintained for this rare but important cluster of conditions. Furthermore, the patient's genetic predisposition to autoimmunity provides helpful insights into the pathogenesis of these disorders.

We describe 16 previously unreported patients with histoplasmosis from Queensland and northern New South Wales, Australia, and review all previous Australian reports, providing 63 cases in total to study (17 cases of acute pulmonary histoplasmosis, 2 cases of chronic pulmonary disease, and 44 cases of systemic disease, including 17 cases of single-organ infection and 27 instances of disseminated disease). All acute pulmonary disease was acquired in Australia, with 52% of systemic disease definitely autochthonous. Most cases of single-organ disease occurred in immunocompetent patients (76%), and were oropharyngeal (53%) in location. Forty-one percent of disseminated disease occurred in patients with human immunodeficiency virus (HIV). Patients with HIV had high rates of systemic symptoms, pancytopenia, fungemia, and hepatosplenomegaly. Oropharyngeal and adrenal involvement as well as systemic symptoms were prominent in immunocompetent patients with disseminated disease, with 6 of 7 cases of adrenal involvement leading to Addison disease. Most systemic disease was diagnosed by culture of Histoplasma capsulatum. Where serology was assessed in cases other than acute pulmonary disease, it was positive in only 32%.Prognosis for patients with single-organ disease was excellent. Disseminated disease was associated with recurrence in 30% and death in 37%. The results of this study confirm several previously known patterns of disease but also provide new insights into this rare but endemic condition in Australia.

Background: Within hospitals, bedside blood glucose measurements are widely used for investigating suspected hyper- or hypoglycemia, monitoring diabetes, and adjusting glucose-lowering medication. Numerous point-of-care glucose meters are available, but for large hospitals using the same meter in all settings has practical and economic advantages. This investigation sought to identify a meter that was accurate, precise, and free from interferences, making it suitable for use across all ages and diseases. Methods: Lithium-heparinized whole blood was analyzed, under various conditions, on the HemoCue Glucose 201 (Hemocue AB, Angelhom, Sweden), Accu-Chek® Performa (Roche Diagnostics, Basel Switzerland) (using the newly reformulated maltose-insensitive strips), and Optium (Abbott Diabetes, Alameda, CA, USA) glucose meters and compared with plasma glucose measurements on the Vitros 5,1 FS analyzer (Ortho Clinical Diagnostics, Neckargemund, Germany). Results: Biases of 3.2%, −5.8%, and −8% were found w...

Vasculogenesis and/or angiogenesis are thought to be the major mechanisms for new vessel formation during development. A third mechanism, haemo-vasculogenesis, has been described in which blood vessel and blood cells (haematopoiesis (expression of CD34(+)) and erythropoiesis (presence of epsilon chain of haemoglobin or Hb-epsilon(+))) differentiate from a common precursor, the haemangioblast. This review describes the mechanism(s) for development of human choroidal vascular from 6 until 22 weeks gestation (WG). Endothelial cell or EC (CD31, CD34, CD39, VEGFR-2) and angioblast (CD39, VEGFR-2) markers were present in choriocapillaris (CC) by 7 WG through 22 WG. From 6 to 8 WG, many erythroblasts (nucleated Hb-epsilon(+) RBCs) were observed in the CC layer. Erythroblasts (Hb-epsilon(+)) were also positive for CD34, CD31, and/or VEGFR-2. Proliferation of vascular cells (Ki67+), suggesting angiogenesis, was not observed until 12 WG. TEM analysis demonstrated that CC was structurally immature even at 11 WG: no basement membrane, absence of pericytes, and poorly formed lumens that were filled with filopodia. Contiguous fenestrations and significant PV-1 (protein in diaphragms of fenestrations) were not observed until 21-22 WG. Smooth muscle actin was prominent at 20 WG and the maturation of pericytes was confirmed by TEM. Therefore, the embryonic CC appears to form initially by haemo-vasculogenesis (Hb-epsilon(+)/CD31(+) cells), whereas angiogenesis (CD34(+)/Ki67(+)) appears to be the mode of intermediate and large choroidal vessel development later in the foetus. Contiguous fenestrations, mature pericytes, and EC basal lamina occur late in development, around 22 WG, which coincides with photoreceptors developing inner segments.