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Venous leg ulcers (VLUs) pose a significant burden on patients, health care systems, and national economies. Nutritional health is an important determinant of wound healing. Vitamin C and D levels and additional biochemical markers, C-reactive protein, and albumin in a group of patients with VLUs, were compared with a control group without VLUs. No significant difference in either nutrient marker was found with the presence, size, or duration of VLUs. Obesity was significantly more common in the VLU group, as noted in other studies. Additional controlled studies should be performed with measures of VLU size and duration to assess long-term outcomes with nutritional therapy., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Context: The gonadotropin-releasing hormone receptor variant GNRHR p.Q106R (rs104893836) in homozygosity, compound heterozygosity, or single heterozygosity is often reported as the causative variant in idiopathic hypogonadotropic hypogonadism (IHH) patients with GnRH deficiency. Genotyping of a Maltese newborn cord-blood collection yielded a minor allele frequency (MAF) 10 times higher (MAF = 0.029; n = 493) than that of the global population (MAF = 0.003)., Objective: To determine whether GNRHR p.Q106R in heterozygosity influences profiles of endogenous hormones belonging to the hypothalamic-pituitary axis and the onset of puberty and fertility in adult men (n = 739) and women (n = 239)., Design Setting and Participants: Analysis of questionnaire data relating to puberty and fertility, genotyping of the GNRHR p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study., Main Outcome and Results: Out of 978 adults, 43 GNRHR p.Q106R heterozygotes (26 men and 17 women) were identified. Hormone levels and fertility for all heterozygotes are within normal parameters except for TSH, which was lower in men 50 years or older., Conclusion: Hormone data and baseline fertility characteristics of GNRHR p.Q106R heterozygotes are comparable to those of homozygous wild-type individuals who have no reproductive problems. The heterozygous genotype alone does not impair the levels of investigated gonadotropins and sex steroid hormones or affect fertility. GNRHR p.Q106R heterozygotes who exhibit IHH characteristics must have at least another variant, probably in a different IHH gene, that drives pathogenicity. We also conclude that GNRHR p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Thiazide diuretics exert a natriuretic and diuretic effect by inhibiting sodium reabsorption in the distal convoluted tubule. Furthermore, thiazide diuretics affect renal calcium handling by increasing calcium reabsorption, leading to hypocalciuria. The effect that thiazide diuretics exert on parathyroid hormone secretion is controversial. Some studies found parathyroid hormone levels were suppressed with the use of thiazide diuretics, while others found that thiazides were associated with initial parathyroid hormone suppression followed by raised parathyroid hormone levels. This makes the relationship between thiazide diuretics and primary hyperparathyroidism interesting. If a patient is taking thiazide diuretics, this may make it harder to establish the aetiology of hypercalcaemia and may unmask normocalcaemic or mild primary hyperparathyroidism. Thiazide diuretics may have a beneficial role in the diagnosis of patients with concomitant hyperparathyroidism and hypercalciuria by distinguishing secondary hyperparathyroidism caused by hypercalciuria from normocalcaemic primary hyperparathyroidism. In addition, thiazide diuretics may have a role in managing patients with primary hyperparathyroidism who have an indication for parathyroidectomy in view of significant hypercalciuria, but are unfit for surgery.

We report a rare case of a functional bladder paraganglioma diagnosed in a young man who presented with acute compressive thoracic myelopathy secondary to vertebral metastasis. A histological diagnosis of a metastatic paraganglioma was made following biopsy of a rib lesion. CT revealed a lesion in the inferior wall of the bladder, which demonstrated avid uptake on 68Ga-DOTATATE PET/CT. Serum metanephrine levels were more than 40 times the upper limit of normal. The patient was hypertensive and treatment with doxazosin was initiated. In view of neurological deterioration, he required urgent spinal decompression to preserve neurological function and prevent permanent paraplegia. Despite inadequate alpha-blockade, surgery was successful, and the perioperative course was uneventful. Alpha-blockade was subsequently optimised. Treatment with cyclophosphamide, vincristine and dacarbazine was started but, in view of disease progression, treatment was subsequently changed to sunitinib., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Endocrine-disrupting chemicals (EDCs) have gained more importance in the past decade, mostly due to their role in the pathogenesis of disease, especially in carcinogenesis. However, there is limited literature on the environmental burden on some of the less common endocrine neoplasia., Areas Covered: This review focuses on both observational and experimental studies linking exposure to EDCs and endocrine neoplasia specifically pituitary, thyroid, adrenal and neuroendocrine tumors. Following PRISMA guidelines, a search of English peer-reviewed literature was performed using Medline and Google Scholar, giving preference to recent publications., Expert Opinion: Exposure to EDC occurs not only in the household but also at work, whether it is in the office, factory, or farm and during transport from one location to another. Many studies have evaluated the effect of single environmental agents; however, humans are rarely exposed to only one EDC. Different EDCs and different levels of exposure may interact together to provide either a synergistic and/or an antagonistic disruption on human health, and hence a complex mechanism to elucidate. The ultimate adverse effect is difficult to predict, as it is not only influenced by the degree of exposure, but also by genetics, lifestyle, comorbidities, and other stressors.

Introduction: MR imaging is an essential and fundamental tool in the diagnosis, management, and follow-up of patients with pituitary adenomas (PAs). Recent advances have continued to enhance the usefulness of this imaging modality., Areas Covered: This article focuses on signal intensity patterns of PAs and associated clinical characteristics, vertical extension patterns, and cavernous sinus invasion with a special focus on the clinical implications that arise. A search using Medline and Google Scholar was conducted using different combinations of relevant keywords, giving preference to recent publications., Expert Opinion: A higher proportion of GH-secreting PAs are hypointense on T2 weighted images compared to other tumor subtypes. Hypointense tumors are generally smaller compared to hyperintense ones, and among the GH-secreting subgroup, a better response to somatostatin analogue treatment was noted together with an association for a densely granulated pattern. Nonfunctional PAs show a predilection to extend upwards while GH-secreting PAs and prolactinomas show a predominantly inferior extension growth pattern. Further studies to better understand the mechanisms responsible for this behavior are anticipated. Further development, refining and validation of predictive scoring systems for tumor behavior might be useful adjuncts in the management of patients with PAs.

Purpose: To provide complete epidemiological data on Cushing's syndrome (CS) with analysis and differentiation of biochemical parameters, including blood count indices and serum inflammation-based scores., Methods: Clinical records of 35 patients diagnosed with CS between 2008 and 2020 at Malta's only central National Health Service hospital were retrospectively analyzed. Detailed clinical and biochemical data were obtained for each patient. Correlation and receiver operator characteristics (ROC) curve analyses were used to establish a threshold value for different variables to predict malignant CS., Results: Standardized incidence rate (SIR) (/million/year) of CS was 4.5, and SIR of Cushing's disease (CD) was 2.3, 0.5 for ectopic CS, 1.5 for cortisol secreting adrenal adenoma, and 0.3 cases for cortisol-producing ACC. Malignant cause of CS had statistically significantly higher cortisol levels and size of tumor and lower potassium at diagnosis (P < 0.001). Additionally, malignant causes had a higher neutrophil-to-lymphocyte ratio (NLR) (P = 0.001) and systemic immune inflammation index (P = 0.005) and a lower lymphocyte-to-monocyte ratio (P < 0.001). Using ROC curve analysis to predict malignant cause of CS, a potassium level of < 3.05 was 75% sensitive and 100% specific (ROC-AUC 0.907, P = 0.001), a post-ODST cortisol level of > 841 nmol/L was 100% sensitive and 91% specific (ROC-AUC 0.981, P < 0.001), while a NLR ratio > 3.9 was 100% sensitive and 57.7% specific (ROC-AUC 0.885, P = 0.001)., Conclusion: Biochemical and blood count indices and serum inflammatory-based scores differ remarkably between benign and malignant causes of endogenous CS. Such indices can help predict the severity of disease and prognosis., (© 2022. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Introduction: Hyperglycaemia is related to poorer outcomes among hospital inpatients. We investigated the impact of hyperglycaemia at admission on length of hospital stay, readmission rate and mortality rate., Method: We retrospectively analysed the records of 1,132 patients admitted to hospital in January 2019, April 2019, August 2019 and April 2020., Results: Hyperglycaemia was present in 14.1% of patients. New-onset hyperglycaemia on admission (in 3.9% of patients) was related to a higher mortality rate than in patients known to have diabetes admitted with hyperglycaemia (43.3% vs 17.9%; p=0.006). Mortality at 90 days and 1 year increased with higher admission glucose levels (p=0.03 and p=0.005, respectively), severe hyperglycaemia (>20 mmol/L) having a 1-year mortality of 34.3%. After accounting for confounding variables, admission glucose and length of stay remained significant predictors of 1-year mortality (p=0.034 and p=0.003, respectively)., Conclusion: Hyperglycaemia is an important prognostic marker and may indicate a more severe illness. These patients should be highlighted for a greater level of care., (© Royal College of Physicians 2022. All rights reserved.)

Hypercalcaemia is a common metabolic abnormality and its differential diagnosis is vast. Immobility is an uncommon cause of hypercalcaemia. Immobilisation hypercalcaemia is independent of parathyroid hormone and is associated with low levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. In addition, it is characterised by elevated levels of markers of bone resorption and low levels of bone-specific alkaline phosphatase, highlighting an imbalance of bone remodelling favouring osteoclastic bone resorption. Although immobilisation hypercalcaemia is a diagnosis of exclusion, physicians need to be aware of this condition to avoid excessive and invasive investigations when all other causes of parathyroid hormone-independent hypercalcaemia have been excluded. Management of immobilisation hypercalcaemia revolves around early mobilisation and rehabilitation together with pharmacotherapeutic agents such as intravenous isotonic saline, calcitonin and bisphosphonates. Denosumab may be a potential alternative yet off-label treatment for immobility hypercalcaemia in patients with renal insufficiency.

Introduction: Adrenal insufficiency (AI) is one of the most common potentially life-threatening endocrine complications in people living with human immunodeficiency virus (PLHIV) infection and acquired immunodeficiency syndrome (AIDS)., Areas Covered: In this review, the authors explore the definitions of relative AI, primary AI, secondary AI and peripheral glucocorticoid resistance in PLHIV. It also focuses on the pathophysiology, etiology, diagnosis and management of this endocrinopathy in PLHIV. A literature review was conducted through Medline and Google Scholar search on the subject., Expert Opinion: Physicians need to be aware of the endocrinological implications of HIV infection and its treatment, especially CYP3A4 enzyme inhibitors. A high index of clinical suspicion is needed in the detection of AI, especially in PLHIV, as it may present insidiously with nonspecific signs and symptoms and may be potentially life threatening if left untreated. Patients with overt primary and secondary AI require glucocorticoid replacement therapy. Overt primary AI also necessitates mineralocorticoid replacement. On the other hand, the management of relative AI remains controversial. In order to reduce the risk of adrenal crisis during periods of stress, the short-term use of glucocorticoids may be necessary in relative AI.

A 55-year-old woman presented with a 4-month history of right-sided non-specific loin pain and 6 kg weight loss. A CT scan of the abdomen and pelvis showed an incidental 4.5 cm right-sided adrenal lesion which was not typical of an adrenal adenoma. This was further confirmed on MRI of the adrenals. Biochemical investigations to investigate for a functional adrenal lesion included serum catecholamines and metanephrines, an aldosterone to renin ratio and an overnight dexamethasone suppression test. These were all negative. A laparoscopic adrenalectomy was performed in view of the large size of the lesion. Histology was consistent with a phaeochromocytoma, which confirmed the diagnosis of a non-secreting phaeochromocytoma. Non-secreting phaeochromocytomas are rare and usually found in patients with known genetic mutations. Adrenal lesions not related to any mutations similar to our case are even rarer and reported even less in the literature., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

A 37-year-old woman presented with a few days' history of lower abdominal pain and an incidental finding of hypercalcaemia. A thorough workup ensued, and the cause was found to be an exceptionally rare ovarian tumour-ovarian small cell carcinoma of the hypercalcaemic type. Acute treatment of hypercalcaemia consisted of aggressive intravenous fluids and bisphosphonates. She underwent surgery to remove the tumour and is currently receiving systemic platinum/etoposide chemotherapy combination to be followed by pelvic radiotherapy. This case highlights the wide range of differential diagnosis for hypercalcaemia and the importance of a stepwise and thorough approach during investigations. We discuss the pathophysiology of malignancy-related hypercalcaemia, focusing especially on parathyroid hormone-related peptide-associated hypercalcaemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite being benign tumours, craniopharyngiomas are challenging to manage and can cause significant morbidity and mortality in both the paediatric and adult population. The aim of the study was to analyse the epidemiology of craniopharyngiomas, patient and tumour characteristics through a population-based study in Malta, enabling a better quantification of the disease burden., Methods: Thorough research was carried out to identify the number of patients who were diagnosed with craniopharyngiomas. Epidemiological data, including both standardised incidence rates (SIR) and prevalence rates, were established in a well-defined population. For incidence estimates, patients who were diagnosed between 2008 and 2019 were included. The background population formed 4.8 million patient-years at risk., Result: Twenty-nine subjects were identified and included in our study. The overall SIR was 0.3/100,000/year, with a higher SIR for males compared to females (0.4/100,000/year and 0.2/100,000/year, respectively). The highest SIR was recorded in the 10-19 year age group. The estimated prevalence rate amounted to 5.27/100,000 people, with a lower prevalence rate for childhood-onset when compared to the adult-onset category (2.03/100,000 vs 3.24/100,000 people). The median longest tumour diameter was 31.0 mm (IQR 21-41), with a statistically significant difference between childhood- and adult-onset disease; 43.0 mm (IQR 42.5-47.25) vs 27.0 mm (IQR 20.55-31.55) ( P  = 0.011)., Conclusion: Through this population-based study, accurate and up-to-date prevalence and incidence rates for craniopharyngiomas are reported. These provide a clearer reflection of the true health burden of the disease., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© The authors.)

An elderly gentleman was admitted to hospital with severe hypokalaemia of 1.75mmol/L. A background of a recently diagnosed metastatic gastric carcinoma with a neuroendocrine component pointed towards the diagnosis of ectopic ACTH secretion causing this dangerous electrolyte imbalance. He was treated with aggressive potassium supplementation and the adrenal steroid synthesis blocker metyrapone to acutely control his Cushing's syndrome. Chemotherapy consisting of carboplatin/etoposide combination was initiated but unfortunately the patients' health deteriorated, and he died three months after his initial diagnosis. This case highlights the accelerated presentation of hypercortisolism due to ectopic ACTH secretion. It discusses the classification of neuroendocrine tumours and their varied prognosis depending on the underlying tumour grade. It emphasises the importance of having a multidisciplinary team to be able to care for two underlying pathologies simultaneously: both the severe hypercortisolism and his metastatic gastric tumour., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

A70-year-old man, with established hypoadrenalism due to a previous bilateral adrenalectomy, was admitted with recurrent episodes of postural dizziness and presyncope. He had been discharged from hospital 3 weeks earlier on a 1-month course of cotrimoxazole following a diagnosis of prostatitis. His electrolytes on admission showed new onset hyponatraemia and hyperkalaemia.His usual glucocorticoid replacement dose was doubled in view of a presumed diagnosis of hypocortisolaemia. However, the hyperkalaemia persisted. On rereviewing his treatment, we suspected a possible diagnosis of cotrimoxazole-induced hyperkalaemia. Cotrimoxazole was stopped and ciprofloxacin started instead. His fludrocortisone replacement was doubled for 3 days after stopping treatment to decrease his postural symptoms. His postural symptoms improved, his serum potassium decreased to normal levels and he was safely discharged.It is essential to remember that cotrimoxazole, a commonly used antibiotic, can induce a potentially fatal hyperkalaemia especially in patients with known hypoadrenalism., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Behavioural counselling is an effective method to improve smoking cessation during pregnancy. Audio recordings of consultations have been used previously to assess fidelity in specialized smoking cessation services, but not in primary care., Aims: The study is aimed at assessing the feasibility of audio-recording smoking cessation counselling as part of an intervention in primary care settings and exploring the number and type of behaviour change techniques (BCTs) delivered., Methods: This study was a nested feasibility study within a larger trial. Health providers (HPs) and pregnant women were asked to agree or decline audio recording their smoking-related consultations. Data collected included percentage providing consent, number of recordings performed, HP type, and date (pre/post intervention). Interviews were conducted to assess the trial procedures' acceptability., Results: Two services provided seven recordings, all pre-intervention. Of the 22 recruited women, 14 consented to being audio recorded (64%) and five provided recordings; of the 23 recruited HPs, 16 agreed (69%), and two provided recordings. Qualitative data suggest that HPs found audio recording difficult to remember. HPs spent on average two minutes discussing smoking and used few BCTs., Conclusions: Audio recordings of smoking-related counselling were not feasible as planned. Future research will need to explore acceptable methods to assess BCT use in primary care., Competing Interests: YBZ has received fees for lectures from Pfizer Ltd. Israel (2012-2015, 2017-2019) and GSK Consumer Health Israel (2019) (both distributing smoking cessation pharmacotherapies in Israel). She has not received any fees from pharmaceutical companies in Australia. No other coauthors have conflicts of interest., (Copyright © 2021 Yael Bar-Zeev et al.)

Lithium is a mood stabiliser widely used in the treatment and prophylaxis of mania, bipolar disorders and recurrent depression. Treatment with lithium can give rise to various endocrine and metabolic abnormalities, including thyroid dysfunction, nephrogenic diabetes insipidus and hypercalcaemia. Lithium may induce hypercalcaemia through both acute and chronic effects. The initial acute effects are potentially reversible and occur as a result of lithium's action on the calcium-sensing receptor pathway and glycogen synthase kinase 3, giving rise to a biochemical picture similar to that seen in familial hypocalciuric hypercalcaemia. In the long term, chronic lithium therapy leads to permanent changes within the parathyroid glands by either unmasking hyperparathyroidism in patients with a subclinical parathyroid adenoma or possibly by initiating multiglandular hyperparathyroidism. The latter biochemical picture is identical to that of primary hyperparathyroidism. Lithium-associated hyperparathyroidism, especially in patients on chronic lithium therapy, is associated with increased morbidity. Hence, regular monitoring of calcium levels in patients on lithium therapy is of paramount importance as early recognition of lithium-associated hyperparathyroidism can improve outcomes. This review focuses on the definition, pathophysiology, presentation, investigations and management of lithium-associated hyperparathyroidism.

Introduction: Hormone replacement in females with hypogonadism is advocated to address the various clinical aspects of estrogen deficiency., Areas Covered: This article focuses on hormone replacement in young females with hypogonadism, including a rationale as to why hormone replacement in such patients differs from treatment in postmenopausal females, a summary of symptoms encountered by females with hypogonadism and a comprehensive discussion of the various treatment options available, specifically focusing on the latest advances in the subject. A Medline search was conducted using different combinations of relevant keywords, giving preference to recent publications., Expert Opinion: Whilst traditionally oral contraceptive pills (containing ethynyl estradiol) were commonly used as a form of hormone replacement, it is now increasingly recognized that this is not the optimal treatment option. Physiological hormone replacement with transdermal estradiol is found to be superior. Evidence suggests that micronized progesterone may be associated with fewer side effects, although its effect on endometrial protection is not yet proven. Synthetic progestins confer varying degrees of androgenic and thromboembolic properties which should be kept in mind when prescribing individualized treatment. Further studies in different sub-cohorts of female patients with hypogonadism might help address the specific needs of individual patients.

This study explored Aboriginal and Torres Strait Islander women's use of supports for their general health, for smoking cessation, and the health of babies or children, and analyzed the women's predictors for seeking types of support. Aboriginal and Torres Strait Islander women were recruited for a cross-sectional survey in two regions of NSW N = 132. The 19-item survey questioned the likelihood that the participant would use the various supports for their health, to quit smoking, and for a baby or child's health. Logistic regression analyses were performed on N = 98 with complete data. Older participants were less likely to use Facebook or the internet for their health, or the health of a child, but were more likely to consult with health professionals. Women who had quit smoking were less likely to use an app for their health compared to smokers. Women who had a child living in their household were less likely to use the internet for a child's health. This community-based study revealed age-related differences for access to health services and differences according to smoking status. Patterns of internet and app use warrant further consideration when planning strategies to improve Aboriginal and Torres Strait Islander women and children's health.

Clinical reasoning is an extensive and intricate field, dealing with the process of thinking and decision making in practice. Its study can be quite challenging because it is context and task dependent. Educational frameworks such as the conscious competence model and the dual process reasoning model have been developed to help its understanding. To enhance the learning of clinical reasoning, there are significant areas that can be targeted through learning processes. These include knowledge adequacy; ability to gather appropriate patient data; use of proper reasoning strategies to address specific clinical questions; and the ability to reflect and evaluate on decisions taken, together with the role of the wider practice community and the activity of professional socialisation. This article explores the characteristics of clinical reasoning and delves deeper into the various strategies that prove useful for learning.

A 57-year-old woman presented with severe lethargy, dizziness and nausea 1 week after transsphenoidal resection of a growth hormone secreting pituitary adenoma. She was found to have severe hyponatremia of 115 mmol/L. Importantly, she was neurologically intact and clinically euvolaemic. Her fluid intake was restricted and her sodium levels increased to 131 mmol/L over 4 days. She made a full recovery.She was diagnosed with isolated second-phase diabetes insipidus, a state of symptomatic hypoosmolar hyponatremia that usually occurs 7-10 days after transsphenoidal surgery. The sodium levels improve with fluid restriction., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Addressing smoking cessation during pregnancy among Aboriginal women is a national priority under the Closing the Gap campaign. There is a need to measure and report interventions to support Aboriginal women during pregnancy., Aim: To quantitatively assess women's smoking experiences over a 12 week ICAN QUIT in Pregnancy program., Methods: Aboriginal women and/or women expecting an Aboriginal baby reported their smoking experiences through repeated cross-sectional survey at baseline, four weeks, and 12 weeks. Self-reported nicotine dependence measures (heaviness of smoking index, strength of urges and frequency of urges to smoke), intentions to quit smoking, quit attempts, use of nicotine replacement therapy were gathered as well as a carbon-monoxide measure at each time point., Results: Expectant mothers (n=22) of Aboriginal babies participated from six Aboriginal Community Controlled Health Services between November 2016 and July 2017. At 12 weeks women reported (n=17) low heaviness of smoking index 1.21 with high strength of urges 2.64 and frequency of urges 3.00; 12/13 (92%) reported likely/very likely to quit smoking, made a mean 1.67 number of quit attempts, three women (13.6%) quit smoking (validated); 5/16 (31%) reported using nicotine replacement therapy., Discussion: Participating women made multiple quit attempts demonstrating motivation to quit smoking. Smoking cessation interventions should be tailored to address high strength and frequency of nicotine dependence despite low consumption., Conclusion: Prolonged smoking cessation support is recommended to address physical, behavioural and psychological aspect of smoking. Cessation support should address previous quitting experiences to assess smoking dependence and tailoring of support., Trial Registration: Australian and New Zealand Clinicial Trials Registry (Ref #ACTRN12616001603404)., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Smoking during pregnancy is a national priority to improve Aboriginal health. Empowerment approaches underpin the priorities set by the government to improve Aboriginal health and wellbeing; however, empowerment is seldom evaluated within interventions for Aboriginal people. Literature was searched to April 2018 and data was extracted using an assessment tool with domains of individual and community empowerment in smoking cessation during pregnancy studies with Aboriginal women. Three interventions were found in published and grey literature. Elements of individual empowerment were embedded in all interventions. Interventions considered barriers for Aboriginal women to quit smoking and areas for capacity building. Interventions used health education resources. There was limited reporting of community empowerment domains. Aboriginal ethics and capacity building was the only criterium addressed by all studies. Interventions are incorporating individual empowerment, but seldom report community empowerment. The development of reporting guidelines or extensions of current guidelines would be beneficial to set a consistently high standard reporting across Aboriginal health interventions, similar to the work conducted to develop the extension of Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Equity (PRISMA-E) for health equity in systematic review reporting. Reporting empowerment domains would reflect the government priority of empowerment to improve Aboriginal health, as well as enhancing knowledge translation into practice.

Objectives: This study aimed to examine the impact of the 'ICAN QUIT in Pregnancy' intervention on individual health providers (HPs) smoking cessation care (SCC) knowledge, attitudes and practices in general, and specifically regarding nicotine replacement therapy (NRT) prescription., Design: Step-wedge clustered randomised controlled study. HPs answered a preintervention and 1-6 months postintervention survey., Setting: Six Aboriginal Medical Services (AMSs) in three states of Australia., Participants: All HPs were invited to participate. Of 93 eligible, 50 consented (54%), 45 completed the presurvey (90%) and 20 the post (40%)., Intervention: Included three 1-hour webinar sessions, educational resource package and free oral NRT., Outcomes: HPs knowledge was measured using two composite scores-one from all 24 true/false statements, and one from 12 NRT-specific statements. Self-assessment of 22 attitudes to providing SCC were measured using a five-point Likert scale (Strongly disagree to Strongly agree). Two composite mean scores were calculated-one for 15 general SCC attitudes, and one for 7 NRT-specific attitudes. Self-reported provision of SCC components was measured on a five-point Likert scale (Never to Always). Feasibility outcomes, and data collected on the service and patient level are reported elsewhere., Results: Mean knowledge composite scores improved from pre to post (78% vs 84% correct, difference 5.95, 95% CI 1.57 to 10.32). Mean NRT-specific knowledge composite score also improved (68% vs 79% correct, difference 9.9, 95% CI 3.66 to 16.14). Mean attitude composite score improved (3.65 (SD 0.4) to 3.87 (SD 0.4), difference 0.23, 95% CI 0.05 to 0.41). Mean NRT-specific attitudes composite score also improved (3.37 (SD 0.6) to 3.64 (SD 0.7), difference 0.36, 95% CI 0.13 to 0.6). Self-reported practices were unchanged, including prescribing NRT., Conclusions: A multicomponent culturally sensitive intervention in AMSs was feasible, and might improve HPs provision of SCC to pregnant Aboriginal women. Changes in NRT prescription rates may require additional intensive measures., Trial Registration Number: ACTRN 12616001603404; Results., Competing Interests: Competing interests: YBZ has received funds in the past (2012–2015) from the Novartis NCH, who used to distribute NRT in Israel. She has not received any funding from pharmaceutical companies in Australia., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Health providers are lacking in their provision of smoking cessation care during pregnancy. The aim of this study was to systematically review all available global studies on the effectiveness of interventions in improving health providers' provision of smoking cessation care during pregnancy., Methods: Five databases were searched, Inclusion criteria included all intervention study types. Two reviewers screened abstracts and full texts independently. Interventions were characterized according to the Effective Practice Of Care taxonomy. Random-effects meta-analyses examined intervention effects on smoking cessation care components based on the 5As. Estimates were number of participants reporting each outcome, or mean score, transformed into Cohen's d. Crude meta-regressions, and meta-analysis subgrouping, were performed to examine whether intervention effects for 'Ask', 'Advise' and 'Assist' differed by intervention components., Results: Of 3165 manuscripts, 16 fulfilled inclusion criteria. Pooled analysis showed significant small to large intervention effects on the different care components (Cohen's d ranging from 0.47 for 'Ask' (95%CI 0.13-0.81) to 1.12 (95%CI 0.45-1.79) for 'Setting a quit date'). Crude meta-regression suggested that for 'Ask', having a theoretical basis may improve effectiveness (Cohen's d difference 0.62, 95% CI 0.12-1.1). Subgrouping the meta-analysis suggested that audit and feedback possibly increases intervention effectiveness for 'Advise' and 'Assist'., Conclusion: Interventions designed to improve provision of smoking cessation care during pregnancy show a small increase in care components. Studies vary substantially in design, intervention components, and outcome measurement, impacting ability to synthesize available data. Audit and feedback and enhancing intervention design by using behaviour change theories may improve effectiveness., Registration: PROSPERO CRD42016030143., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Many health providers (HPs) lack knowledge, confidence, optimism and skills in addressing smoking with pregnant women. This study aimed to explore the feasibility and acceptability of a) a co-designed multi-component intervention for HPs at Aboriginal Medical Services (AMSs) in culturally-targeted pregnancy-specific smoking cessation care and b) the study design., Methods: Using a randomised step-wedge cluster design, the Indigenous Counselling And Nicotine (ICAN) QUIT in Pregnancy Trial was evaluated across six AMSs in three Australian states. HPs were provided educational resource packages including live interactive webinars, treatment manuals, patient resources, carbon monoxide (CO) meters, and oral Nicotine Replacement Therapy (NRT). Feasibility was assessed through recruitment and retention rates of both pregnant women (12-weeks) and HPs (end of study) as well as the potential to improve women's quit rates. Qualitative interviews with staff post-trial explored acceptability of the intervention and study, based on capability, opportunity and motivation from the Behaviour Change Wheel., Results: Pregnant women (n = 22; 47% (95% CI: 32%, 63%) eligible) and HPs (n = 50; 54% (95% CI: 44%, 64%) eligible) were recruited over 6 months with retention rates of 77% (95% CI: 57%, 90%) and 40% (95% CI: 28%, 54%) respectively. Self-reported 12-week 7-day point-prevalence abstinence was 13.6% (n = 3) and validated abstinent with CO readings ≤6 ppm. Staff interviewed regarding intervention implementation highlighted the importance of provision and use of resources, including training materials, patient resources, CO meters and oral NRT. Resources helped increase capability and opportunity, restructure the environment, and provided social comparison and modelling. Staff were motivated by greater engagement with pregnant women and seeing the women's reductions in CO readings. Having the intervention at the AMSs improved organisational capacity to engage with pregnant women. Staff reported changes to their routine practice that were potentially sustainable. Recommendations for improvement to the implementation of the intervention and research included reducing training length and the tasks related to conducting the study., Conclusion: ICAN QUIT in Pregnancy was a pilot study with the ability to enrol Indigenous women. It was feasible to implement and acceptable to most staff of the AMSs in three states, with modifications recommended. Smoking in pregnancy is a key challenge for Indigenous health. The intervention needs to be evaluated through a methodologically rigorous fully-powered study to determine the efficacy of outcomes for women., Trial Registration: Australian and New Zealand Clinical Trials Registry, ACTRN12616001603404. Registered 21 November 2016 - retrospectively registered, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371778., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The diagnosis of maturity onset diabetes of the young (MODY) is a challenging process in view of the extensive clinical and genetic heterogeneity of the disease. Mutations in the gene encoding hepatocyte nuclear factor 1α ( HNF1A ) are responsible for most forms of monogenic diabetes in Northern European populations. Genetic analysis through a combination of whole exome sequencing and Sanger sequencing in three Maltese siblings and their father identified a rare duplication/frameshift mutation in exon 4 of HNF1A that lies within a known mutational hotspot in this gene. In this report, we provide the first description of an HNF1A -MODY3 phenotype in a Maltese family. The findings reported are relevant and new to a regional population, where the epidemiology of atypical diabetes has never been studied before. This report is of clinical interest as it highlights how monogenic diabetes can be misdiagnosed as either type 1, type 2, or gestational diabetes. It also reinforces the need for a better characterisation of monogenic diabetes in Mediterranean countries, particularly in island populations such as Malta with a high prevalence of diabetes., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: General practitioners can play an important role in addressing smoking among pregnant women but studies suggest they rarely do so. The aim of this study was to explore general practitioners perceptions about the management of smoking in pregnancy, and what would enable them to provide better care., Methods: Qualitative semi-structured interviews were conducted (Feb-July 2017), with 19 Australian general practitioners recruited from a sample that participated in a national survey on managing smoking during pregnancy; and through a national conference. The interview guide was structured using the theoretical domains framework, exploring previously reported barriers and two specific components of smoking cessation care - nicotine replacement therapy prescription and Quitline referral., Results: Participants reported high confidence and knowledge to provide pregnant patients adequate support for quitting. Nonetheless, participants reported lacking communication skills, focusing on providing information on smoking harm, accepting cutting down cigarettes as adequate, while following the 'Stages of Change' model and only providing treatment options to motivated patients. Lack of time, nicotine replacement therapy cost and safety concerns, and being unfamiliar with the Quitline (particularly for Aboriginal and Torres Strait Islander pregnant smokers) were perceived as challenges. Participants reported needing better communication skills, clear detailed nicotine replacement therapy guidelines for special populations, and visual resources they could use to discuss treatment options with patients., Conclusions: Difficulty communicating with pregnant patients about smoking, using the 'Stages of Change' model to guide support provision and concerns regarding nicotine replacement therapy safety are barriers to providing cessation support to pregnant patients for general practitioners. Training on specific effective behaviour change techniques, clear guidance for nicotine replacement therapy use, and practical visual patient education tools may facilitate smoking cessation care provision to pregnant women.

Issue Addressed: Tobacco is a major risk factor contributing to Indigenous health disparities. Art may be a powerful and transformative tool to enable health providers to develop targeted messages for tobacco control., Methods: Indigenous and non-Indigenous staff, working in Indigenous tobacco control, attended a 2-hour workshop, and were led through a process to create individual artworks. Participants completed surveys before and after the workshop. Scales compared understandings of how art can be used in tobacco control, and the likelihood of utilising arts in future programs. Three pairs of Indigenous and non-Indigenous researchers analysed the artworks, using the Four Frames (New South Wales Board of Studies), explored themes, and developed a model., Results: Nineteen participants completed both surveys; 17 artworks were analysed. Pre- to post-workshop increases in "understanding" about the use of arts (P < 0.00001) for tobacco control, and "likelihood" of use of arts in the next 6 months (P < 0.006) were significant. Participants expressed personal and professional benefits from the workshop. Artworks demonstrated themes of optimism, the strength of family and culture, smoking as a barrier, resilience, recovery and urgency., Conclusions: The workshop increased the understanding and likelihood of using the arts for tobacco control. Artworks revealed contemporary challenges impacting on equity; health staff expressed optimism for being engaged in their work. SO WHAT?: The Framework Convention for Tobacco Control supports novel techniques to increase the reach and relevance of health messages for diverse populations. This study successfully demonstrated how a novel, positively framed art-based technique proved to be advantageous for health professionals, working in an area of Indigenous tobacco control, where behavioural change can be complex., (© 2018 Australian Health Promotion Association.)

Stress-induced hyperglycaemia is an important clinical entity. It is an adaptive immune-neurohormonal response to physiological stress in an attempt to increase metabolic substrates to struggling organs during a time of crisis. However, this acute hyperglycaemia is also responsible for a number of detrimental effects implying that treatment is necessary. Hence, admission hyperglycaemia is not necessarily equivalent to a diagnosis of diabetes mellitus but the blood glucose level needs to be interpreted in context of the patient's presenting complaint and previous glycaemic status. Stress-induced hyperglycaemia is associated with increased morbidity and short-term mortality. Thus prompt recognition of stress-induced hyperglycaemia and high risk hyperglycaemic patients with the stress hyperglycaemia ratio can help improve inpatient management. Patients with stress-induced hyperglycaemia who have recovered from their acute illness should be followed up as they remain at risk for incident diabetes. This review focuses on the definition, pathophysiology, targets, management and significance of stress-induced hyperglycaemia.

The use of nicotine replacement therapy in pregnancy has been debated but evidence suggests that it is safer than smoking. A cross-sectional survey was conducted with: (i) general practitioners and obstetricians from a college database; and (ii) general practitioners with a special interest in Indigenous health. General practitioners had higher odds of prescribing compared to obstetricians. Reading guidelines, confidence, viewing nicotine replacement therapy as safe, effective and with good adherence, also significantly increased the odds of prescription. Clear guidance regarding safety and efficacy, with practical clinical protocols, are required in order to reduce variation in prescribing rates across these clinicians., (© 2017 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

The authors report a case of a 68-year-old man who was diagnosed with an irreversible second-degree atrioventricular (AV) Mobitz II 2:1 block temporally associated with profound hyponatraemia. The cause of the hyponatraemia was beer potomania. The co-occurrence of reversible first, second and third-degree heart blocks and hyponatraemia has been described in a few published case reports. However, this case is noteworthy as the AV block persisted, despite correction of serum sodium concentration as opposed to other published cases, which meant that the patient required a permanent pacemaker., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Nicotine replacement therapy (NRT) is recommended in current Australian clinical guidelines for pregnant women who are unable to quit smoking unassisted. Clinicians report low levels of prescribing NRT during pregnancy, due to safety concerns and low levels of confidence in their ability to prescribe NRT. Animal models show that nicotine is harmful to the fetus, especially for brain and lung development, but human studies have not found any harmful effects on fetal and pregnancy outcomes. Studies of efficacy and effectiveness in the real world suggest that NRT use during pregnancy increases smoking cessation rates. These rates may be hampered by the fact that studies so far have used an NRT dose that does not adequately account for the higher nicotine metabolism during pregnancy and, therefore, does not adequately treat withdrawal symptoms. Further research is needed to assess the safety and efficacy of higher dosages of NRT in pregnancy, specifically of combination treatment using dual forms of NRT. As NRT is safer than smoking, clinicians need to offer this option to all pregnant women who smoke. A practical guide for initiating and tailoring the dose of NRT in pregnancy is suggested.

Tobacco smoking leads to one in five deaths of Aboriginal Australians and accounts for 17% of the reversible health gap. One in two Aboriginal women are reported to smoke during pregnancy, with no effective strategies currently available for health practitioners to utilise for supporting Aboriginal women. Aboriginal community participation in primary health research is crucial to implementing ethical research, with a clear benefit to the people and communities involved. However, currently there is little evidence on how Aboriginal programs and interventions are being developed in partnership with Aboriginal people and communities. 'Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy' aims to address the prevalence of smoking during pregnancy by enhancing health providers' training in offering evidence-based smoking cessation care to Aboriginal mothers during pregnancy. This paper outlines the participatory research approach adopted for the developmental phase of the 'ICAN QUIT in Pregnancy' project developed in partnership with two Aboriginal Community-Controlled Health Services in NSW, and negotiation processes undertaken to implement a pilot intervention across NSW, SA and Qld.

Australian Aboriginal pregnant women have a high smoking prevalence (45%). Health professionals lack adequate educational resources to manage smoking. Resources need to be tailored to ensure saliency, cultural-sensitivity and account for diversity of Indigenous populations. As part of an intervention to improve health professionals' smoking cessation care in Aboriginal pregnant women, a resource package was developed collaboratively with two Aboriginal Medical Services. The purpose of this study was to assess and validate this resource package. A multi-centred community-based participatory 4-step process (with three Aboriginal Medical Services from three Australian states), included: (1) Scientific review by an expert panel (2) 'Suitability of Materials' scoring by two Aboriginal Health Workers (3) Readability scores (4) Focus groups with health professionals. Content was analysed using six pre-determined themes (attraction, comprehension, self-efficacy, graphics and layout, cultural acceptability, and persuasion), with further inductive analysis for emerging themes. Suitability of Material scoring was adequate or superior. Average readability was grade 6.4 for patient resources (range 5.1-7.2), and 9.8 for health provider resources (range 8.5-10.6). Emergent themes included 'Getting the message right'; 'Engaging with family'; 'Needing visual aids'; and 'Requiring practicality under a tight timeframe'. Results were presented back to a Stakeholder and Consumer Aboriginal Advisory Panel and resources were adjusted accordingly. This process ensured materials used for the intervention were culturally responsive, evidence-based and useful. This novel formative evaluation protocol could be adapted for other Indigenous and culturally diverse interventions. The added value of this time-consuming and costly process is yet to be justified in research, and might impact the potential adaption by other projects., Competing Interests: The authors declare no conflict of interest.

Background: Indigenous smoking rates are up to 80% among pregnant women: prevalence among pregnant Australian Indigenous women was 45% in 2014, contributing significantly to the health gap for Indigenous Australians. We aimed to develop an implementation intervention to improve smoking cessation care (SCC) for pregnant Indigenous smokers, an outcome to be achieved by training health providers at Aboriginal Medical Services (AMS) in a culturally competent approach, developed collaboratively with AMS., Method: The Behaviour Change Wheel (BCW), incorporating the COM-B model (capability, opportunity and motivation for behavioural interventions), provided a framework for the development of the Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy implementation intervention at provider and patient levels. We identified evidence-practice gaps through (i) systematic literature reviews, (ii) a national survey of clinicians and (iii) a qualitative study of smoking and quitting with Aboriginal mothers. We followed the three stages recommended in Michie et al.'s "Behaviour Change Wheel" guide., Results: Targets identified for health provider behaviour change included the following: capability (psychological capability, knowledge and skills) by training clinicians in pharmacotherapy to assist women to quit; motivation (optimism) by presenting evidence of effectiveness, and positive testimonials from patients and clinicians; and opportunity (environmental context and resources) by promoting a whole-of-service approach and structuring consultations using a flipchart and prompts. Education and training were selected as the main intervention functions. For health providers, the delivery mode was webinar, to accommodate time and location constraints, bringing the training to the services; for patients, face-to-face consultations were supported by a booklet embedded with videos to improve patients' capability, opportunity and motivation., Conclusions: The ICAN QUIT in Pregnancy was an intervention to train health providers at Aboriginal Medical Services in how to implement culturally competent evidence-based practice including counselling and nicotine replacement therapy for pregnant patients who smoke. The BCW aided in scientifically and systematically informing this targeted implementation intervention based on the identified gaps in SCC by health providers. Multiple factors impact at systemic, provider, community and individual levels. This process was therefore important for defining the design and intervention components, prior to a conducting a pilot feasibility trial, then leading on to a full clinical trial.

Objective: One in two Indigenous Australian pregnant women smoke, yet little is known about their trajectory of smoking. This study aimed to explore Aboriginal women's narratives from starting smoking through to pregnancy., Methods: A female Aboriginal Researcher conducted individual face-to-face interviews with 20 Aboriginal women from New South Wales, Australia. Recruitment, through Aboriginal services and community networks, continued until saturation was reached. Audio-recorded transcripts were independently open coded by two researchers, inductively analysed and reported using a three-dimensional structure of looking backwards, forwards, inwards, outwards and a sense of place, to elucidate the chronology of events, life stages, characters, environments, and turning points of the stories., Results: A chronology emerged from smoking initiation in childhood, coming of age, becoming pregnant, through to attempts at quitting, and relapse post-partum. Several new themes emerged: the role mothers play in women's smoking and quitting; the contribution of nausea to spontaneous quitting; depression as a barrier to quitting; and the hopes of women for their own and their children's future. The epiphany of pregnancy was a key turning point for many - including the interplay of successive pregnancies; and the intensity of expressed regret., Conclusions: Aboriginal women report multiple influences in the progression of early smoking to pregnancy and beyond. Potential opportunities to intervene include: a) childhood, coming of age, pregnancy, post-natal, in-between births; b) key influencers; c) environments, and d) targeting concurrent substance use. Morning sickness appears to be a natural deterrent to continued smoking. Depression, and its relationship to smoking and quitting in Australian Indigenous pregnant women, requires further research., (Copyright © 2017. Published by Elsevier Ltd.)

Introduction: Indigenous women have the highest smoking prevalence during pregnancy (47%) in Australia. Health professionals report lack of knowledge, skills and confidence to effectively manage smoking among pregnant women in general. We developed a behaviour change intervention aimed to improve health professionals' management of smoking in Indigenous pregnant women-the Indigenous Counselling And Nicotine (ICAN) QUIT in Pregnancy. This intervention includes webinar training for health professionals, an educational resources package for health professionals and pregnant women, free oral nicotine replacement therapy (NRT) for pregnant women, and audit and feedback on health professionals' performance.The aim of this study is to test the feasibility and acceptability of the ICAN QUIT in Pregnancy intervention to improve health professionals' provision of evidence-based culturally responsive smoking cessation care to Australian Indigenous pregnant smokers., Methods and Analysis: This protocol describes the design of a step-wedge cluster randomised pilot study. Six Aboriginal Medical Services (AMSs) are randomised into three clusters. Clusters receive the intervention staggered by 1 month. Health professionals report on their knowledge and skills pretraining and post-training and at the end of the study. Pregnant women are recruited and followed up for 3 months. The primary outcome is the recruitment rate of pregnant women. Secondary outcomes include feasibility of recruitment and follow-up of participating women, and webinar training of health professionals, measured using a designated log; and measures of effectiveness outcomes, including quit rates and NRT prescription rates., Ethics and Dissemination: In accordance with the Aboriginal Health and Medical Research Council guidelines, this study has been developed in collaboration with a Stakeholder and Consumer Aboriginal Advisory Panel (SCAAP). The SCAAP provides cultural consultation, advice and direction to ensure that implementation is acceptable and respectful to the Aboriginal communities involved. Results will be disseminated to AMSs, Aboriginal communities and national Aboriginal bodies., Registration Details: This protocol (version 4, 14 October 2016) is registered with the Australian and New Zealand Clinical Trials Registry (Ref #: ACTRN12616001603404)., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: The pathogenesis of pituitary adenomas (PA) is complex. Ki-67, pituitary tumour transforming gene (PTTG), vascular endothelial growth factor (VEGF), cyclin D1, c-MYC and pituitary adenylate cyclase-activating peptide (PACAP) protein expression were analysed and correlated with tumour and patient characteristics., Methods: 74 pituitary tumour samples (48 non-functional PA, 26 functional PAs); Immunohistochemical analysis of protein expression, retrospective analysis of MR images and in vitro analysis of octreotide treatment was carried out on GH3 cells., Results: PTTG expression was negatively associated with age and positively with PA size, regrowth and Ki-67 index. Cyclin D1 correlated with Ki-67 and tumour size. c-MYC negatively correlated with size of tumour and age; and correlated with PTTG expression. Somatostatin analogue treatment was associated with lower Ki-67, PTTG and Cyclin D1 expression while T2 hypointense PAs were associated with lower PTTG, cyclin D1, c-MYC and Ki-67. In vitro analyses confirmed the effect of somatostatin analogue treatment on Pttg and Cyclin D1 expression., Conclusions: Interesting and novel observations on the differences in expression of tumour markers studied are reported. Correlation between Ki-67 expression, PTTG nuclear expression and recurrence/regrowth of PAs, emphasizes the role that Ki-67 and PTTG expression have as markers of increased proliferation. c-MYC and PTTG nuclear expression levels were correlated providing evidence that PTTG induces c-MYC expression in PAs and we propose that c-MYC might principally have a role in early pituitary tumorigenesis. Evidence is shown that the anti-proliferative effect of somatostatin analogue treatment in vivo occurs through regulation of the cell cycle.

Context: Pituitary adenomas are relatively common tumours with diverse clinical features. Epidemiological data are important to help quantify health burden., Objective: To provide in-depth epidemiological data on macroadenomas and radiologically characterize macroadenomas., Design: Population-based retrospective analysis, Prevalence as at 2014; Incidence based on data from 2000 to 2014, Retrospective analysis of baseline MRI., Setting: The Maltese islands., Patients: 173/136 patients with macroadenomas for prevalence/incidence estimates respectively, 122 baseline MRI for radiological characterization., Main Outcome Measures: Prevalence rates, Standardized Incidence rates (SIR), MRI findings., Results: The prevalence for macroadenomas was 40·67/100 000 people and the SIR was 1·90/100 000/year. Giant pituitary adenomas (>40 mm) constituted 4·8% of the whole cohort of PAs and the SIR was 0·18/100 000/year. Giant prolactinomas constituted 4·7% of all the prolactinomas and the SIR was 0·07/100 000/year, while giant NFPA constituted 6·0% of all NFPA and the SIR was 0·12/100 000/year. There was a statistically significant difference in the degree of suprasellar extension (P < 0·001) and infrasellar extension (P = 0·028) between the different macroadenoma subtypes and in the vertical extension indices (median vertical extension index NFPA 3·0 mm; PRLoma -7·7 mm; GH-secreting PA -1·7 mm; P < 0·001). Pituitary macroadenomas with cavernous sinus invasion were statistically significantly larger than those without cavernous sinus invasion (P < 0·001). NFPA had predominantly a superior extension into the cavernous sinus (63·6%) compared to the functional PAs which had predominantly an inferior extension into the cavernous sinus (59·1%) (P = 0·032)., Conclusions: The various macroadenoma subtypes' epidemiological data are presented and differences between growth patterns among the various subtypes are highlighted., (© 2016 John Wiley & Sons Ltd.)

Carbimazole, an antithyroid drug, is associated with a significant number of side effects, but pleuropulmonary complications are rare. We report the case of a 42-year-old Caucasian man who developed dyspnoea secondary to bilateral exudative pleural effusions while on carbimazole therapy. Extensive investigations, including a vasculitic screen, ruled out other potential causes for this patient's clinical presentation. This patient's pleural effusions gradually resolved within a few months of stopping carbimazole therapy, suggesting a role for the latter in the aetiopathogenesis of his presentation. Clinicians should consider discontinuing treatment with carbimazole and introducing alternative antithyroid therapy in this setting, once other potential causes of a pleural effusion have been systematically ruled out., (2016 BMJ Publishing Group Ltd.)

Epidemiological data is important to correctly quantify the extent of disease and needed health care resources. The aim of the study was to establish the prevalence and incidence of pituitary adenomas (PAs) in the same well defined population, with in-depth analysis of the various subtypes. The design involved a retrospective cross-sectional analysis of PA patients diagnosed prior to 31 July 2011 for prevalence estimates and those diagnosed between July 2000 and July 2011 for incidence estimation. A thorough search for patients with PAs was carried out in central hospital registries including outpatients departments, surgical registries, radiological department and specialty clinic databases. Prevalence rates/100,000 and Standardised incidence ratios (SIR)/100,000/year were worked out. The respective prevalence rates and SIR for PAs overall were 75.7/100,000, and 4.27/100,000/year, for Prolactinomas 35.0/100,000 and 2.05/100,000/year, for nonfunctioning PA 25.9/100,000 and 1.79/100,000/year and for GH-secreting PAs 12.5/100,000 and 0.31/100,000/year. The overall prevalence for macroadenomas was 32.8/100,000 and SIR was 1.49/100,000/year. The prevalence rate in males for PAs overall was 46.3/100,000 and SIR was 2.08/100,000/year and in females 104.8/100,000 and SIR was 6.58/100,000/year. Females had a lower proportion of macroadenomas than males (29.5 vs. 75.0%; P < 0.001) and macroadenomas tended to present at a later age compared to microadenomas (48 vs. 34.5; P < 0.001). The highest SIR was reached in the 30-39 age group at 7.42/100,000/year. Our data confirm the considerable disease burden that PAs bear on health care resources. Males and females have similar prevalence and SIR rates for macroadenomas but there is a significant increase in SIR in females of child bearing age compared to males. These observations may have important implications in terms of the economic burden and need for early intervention.

Deregulation of the Wnt pathway has been implicated in oncogenesis of numerous tissues including the pituitary gland. Immunohistochemical localization and quantification of β-catenin, Cyclin D1, c-MYC and Survivin expression in 47 pituitary adenomas (35 non-functioning, seven GH-secreting, three prolactinomas, two ACTH-secreting tumour) and six normal controls was undertaken in this study and correlation of protein expression to patient and tumour characteristics analysed. β-catenin was strictly membrane-bound with no difference observed between normal and tumour tissue. In contrast, Cyclin D1 and c-MYC localization was nuclear and significantly higher in tumour versus normal tissue (p < 0.05). c-MYC expression correlated negatively with age at diagnosis (p = 0.006, R = -0.395) while Cyclin D1 expression correlated positively with age (p = 0.036, R = 0.306) and was higher in males than in females (p = 0.036). c-MYC expression was significantly lower in patients with functional tumours requiring octreotide treatment and in patients with non-functioning tumours suffering from hypopituitarism. Survivin expression was extremely low in tumours and absent in normal controls. Involvement of the canonical Wnt pathway appears to be minimal, given the segregation of β-catenin to the membrane. Our data suggest that c-MYC may have an important role in early pituitary tumorigenesis while Cyclin D1 is likely to promote tumour growth at a later stage. We also report a novel gender difference in Cyclin D1 expression, the biological significance of which merits further analysis. The reported reduction of c-MYC in functional tumours subsequently treated with octreotide further supports a role of c-MYC in early tumorigenesis and not in recurrence. The decrease in c-MYC in patients with hypopituitarism provides the first in vivo evidence for hormonal regulation of c-MYC expression.