The where, who and how of adrenal vein sampling in Australia and New Zealand.

INTRODUCTION: Primary aldosteronism (PA) causes 10-15% of cases of hypertension, and it is increasingly recognised as being under-diagnosed. An interventional radiology procedure, adrenal vein sampling (AVS), is a necessary and important diagnostic procedure for complete workup of PA. There is an anticipated increase in demand for AVS as detection of PA improves. This study aims to describe the current landscape of AVS in Australia and New Zealand (NZ). METHODS: Two surveys exploring AVS methodology and performance were conducted of (i) Endocrinology Unit Heads and (ii) interventional radiologists who perform AVS, at public hospitals with Endocrinology Units across Australia and NZ. RESULTS: Responses were received from 48/53 Endocrinology Unit Heads (91%) and 35 radiologists from 26 sites (87% of AVS sites). AVS was provided at 28/48 Endocrinology sites (58%) across Australia and NZ. In Australia, sites were concentrated in Victoria, New South Wales and Queensland with none in the Northern Territory; in NZ, sites were more evenly distributed across the North and South Islands. AVS was performed by 1-2 dedicated radiologists at 24 sites, 2-3 radiologists at two sites and a rotating roster of radiologists at two sites. Responses to both surveys revealed significant variation in AVS methodology and interpretation of AVS results. CONCLUSION: There is significant heterogeneity in the availability of AVS, the procedural details and the interpretation of results across Australia and NZ, which potentially impacts the quality of patient care and ability to scale up AVS capacity to meet increasing demand.

The value of plasma metanephrine measurements during adrenal vein sampling.

Objective: The assessment of primary aldosteronism incorporates adrenal vein sampling (AVS) to lateralize aldosterone excess. Current adrenal vein sampling protocols rely on concurrent cortisol measurements to assess successful cannulation and lateralization and may be inaccurate in the setting of autonomous cortisol secretion. We aimed to compare the measurement of plasma cortisol and metanephrine concentrations to assess cannulation and lateralization during AVS. Design: This is a diagnostic accuracy study in a tertiary referral endocrinology department. Methods: Forty-one consecutive patients with confirmed primary aldosteronism undergoing AVS (49 procedures) were included. None had cortisol autonomy. The use of plasma metanephrine-based ratios were compared with standard cortisol-based ratios to assess cannulation and lateralization during ACTH-stimulated AVS. Results: There was strong agreement between a cortisol selectivity index (SI) ≥5.0 and an adrenal vein (AV) to peripheral vein (PV) plasma metanephrine ratio (AVmet-PVmet) of ≥12.0 to indicate successful cannulation of the AV (n = 117, sensitivity 98%, specificity 89%, positive predictive value (PPV) 95%, negative predictive value (NPV) 94%). There was strong agreement between the standard cortisol-based SI and an AV plasma metanephrine-to-normetanephrine ratio (AVmet-AVnormet) of ≥2.0 to indicate successful cannulation (n = 117, sensitivity 93%, specificity 86%, PPV 94%, NPV 84%). There was strong agreement between the cortisol- or metanephrine-derived lateralization index (LI) > 4.0 for determining lateralization (n = 26, sensitivity 100%, specificity 94.1%, PPV 91.6%, NPV 100%). Conclusions: Ratios incorporating plasma metanephrines provide comparable outcomes to standard cortisol-based measurements for interpretation of AVS. Further studies are required to assess the use of metanephrine-derived ratios in the context of confirmed cortisol autonomy. Significance statement: Primary aldosteronism is a common cause of secondary hypertension, and adrenal vein sampling remains the gold standard test to assess lateralization. Cortisol-derived ratios to assess cannulation and lateralization may be affected by concurrent cortisol dysfunction, which is not uncommon in the context of primary aldosteronism. Our study showed comparable outcomes when using accepted cortisol-derived or metanephrine-derived ratios to determine cannulation and lateralization during adrenal vein sampling. Further research is required to validate these findings and to assess the use of metanephrine-derived ratios in the context of confirmed concurrent cortisol dysfunction.

Increasing rates of referrals for investigation of primary aldosteronism at a tertiary centre.

AIM: To describe the frequency and characteristics of patients referred for specialist investigation of primary aldosteronism (PA) in the lower North Island over a 5-year period, and the outcomes of those who received treatment. METHODS: Patients who underwent confirmatory testing or treatment for PA at Wellington Regional Hospital were retrospectively identified and data were collected from electronic clinical records. RESULTS: There has been a five-fold increase in both referrals and confirmatory testing for PA in 2021 compared to 2015. Compared to patients without PA, those eventually diagnosed with PA had a higher ARR, serum sodium, antihypertensive requirement and cardiovascular disease prevalence, as well as lower serum renin, potassium and GFR (all p <0.05), but similar blood pressure. Complete or partial clinical success was achieved in 96% of surgically treated patients compared with 70% of medically treated patients. Thirty-nine percent of patients experienced minor adverse effects with spironolactone and only one significant adverse event was experienced perioperatively. CONCLUSIONS: The rate of referrals and confirmatory testing for PA are increasing in our region. Adrenalectomy and mineralocorticoid antagonist therapy are both safe and effective treatments, although minor adverse effects were common with spironolactone.

Randomised controlled trial of the Community Navigator programme to reduce loneliness and depression for adults with treatment-resistant depression in secondary community mental health services: trial protocol.

BACKGROUND: New treatments are needed for people with treatment-resistant depression (TRD), who do not benefit from anti-depressants and many of whom do not recover fully with psychological treatments. The Community Navigator programme was co-produced with service users and practitioners. It is a novel social intervention which aims to reduce loneliness and thus improve health outcomes for people with TRD. Participants receive up to 10 individual meetings with a Community Navigator, who helps them to map their social world and set and enact goals to enhance their social connections and reduce loneliness. Participants may also access group meet-ups with others in the programme every 2 months, and may be offered modest financial support to enable activities to support social connections. METHODS: A researcher-blind, multi-site, 1:1 randomised controlled trial with N = 306 participants will test the effectiveness of the Community Navigator programme for people with TRD in secondary community mental health teams (CMHTs). Our primary hypothesis is that people who are offered the Community Navigator programme as an addition to usual CMHT care will be less depressed, assessed using the PHQ-9 self-report measure, at 8-month, end-of-treatment follow-up, compared to a control group receiving usual CMHT care and a booklet with information about local social groups and activities. We will follow participants up at end-of-treatment and at 14 months, 6 months after end-of-treatment follow-up. Secondary outcomes include the following: loneliness, anxiety, personal recovery, self-efficacy, social network, social identities. We will collect data about health-related quality of life and service use to investigate the cost-effectiveness of the Community Navigator programme. DISCUSSION: This trial will provide definitive evidence about the effectiveness and cost-effectiveness of the Community Navigator programme and whether it can be recommended for use in practice. The trial is due to finish in August 2025. TRIAL REGISTRATION: Prospectively registered on 8th July 2022 at: ISRCTN13205972.

Characteristics and gender affirming healthcare needs of transgender and non-binary students starting hormone therapy in a student health service in Aotearoa New Zealand.

Introduction Traditionally, gender-affirming hormonal therapy (GAHT) is initiated in secondary care, but a primary care based approach has been developed to reduce access barriers. Aim We aim to describe the demographics, hormone choices, and additional referrals made for young people initiating GAHT in a primary care setting in Aotearoa New Zealand. Methods Clinical notes were reviewed for all patients who commenced GAHT between 1 July 2020 to the end of 2022 at a tertiary education health service. Data were collected on age, ethnicity, gender, type of hormones prescribed, and any additional referrals. Results Eighty five patients commenced GAHT during the review period (64% assigned male at birth and starting oestrogen-based GAHT, 36% assigned female at birth and commencing testosterone-based GAHT). Fourty seven percent of patients identified as transgender female, 38% as non-binary, and 15% as transgender male. Spironolactone was the most common choice of testosterone blocker (81%). The choice of oestrogen formulation was fairly equal between patches (54%) and tablets (46%). Eighty percent of those assigned male at birth chose to preserve fertility, 54% requested voice therapy, and 87% of those assigned female at birth requested top surgery. Discussion There is a need for improved understanding of non-binary gender-affirmation needs, in particular those of Maori and Pasifika youth. An informed consent approach in primary care can reduce barriers and distress for transgender youth seeking GAHT. The high unmet need for top surgery for transgender people assigned female at birth requires attention.

Circadian disruption in lung fibroblasts enhances NF-κB activity to exacerbate neutrophil recruitment.

Fibroblasts are stromal cells abundant throughout tissues, including the lungs. Fibroblasts are integral coordinators of immune cell recruitment through chemokine secretion. Circadian rhythms direct the recruitment of immune cells to the lung, which in turn impacts response to infection and survival. Although fibroblasts display robust circadian rhythms, the contribution of the fibroblast molecular clock to lung-specific migration of immune cells and recruitment remains to be established. Mice challenged intranasally with lipopolysaccharide (LPS) at dusk showed increased expression of the pro-inflammatory cytokine IL-1ß and chemokine CXCL5 in the lung, which was accompanied by increased neutrophil recruitment. Primary lung fibroblasts with knockdown of the core clock gene Bmal1 and immortalized Bmal1-/- lung fibroblasts also displayed increased Cxcl5 expression under IL-1ß stimulation. Conditioned media obtained from IL-1ß-stimulated Bmal1-/- immortalized fibroblasts-induced greater neutrophil migration compared with Bmal1+/+ lung fibroblast controls. Phosphorylation of the NF-κB subunit, p65, was enhanced in IL-1ß-stimulated Bmal1-/- lung fibroblasts, and pharmacological inhibition of NF-κB attenuated the enhanced CXCL5 production and neutrophil recruitment observed in these cells. Collectively, these results demonstrate that Bmal1 represses NF-κB activity in lung fibroblasts to control chemokine expression and immune cell recruitment during an inflammatory response.

The circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing.

Dendritic cells play a key role in processing and presenting antigens to naïve T cells to prime adaptive immunity. Circadian rhythms are known to regulate many aspects of immunity; however, the role of circadian rhythms in dendritic cell function is still unclear. Here, we show greater T cell responses when mice are immunised in the middle of their rest versus their active phase. We find a circadian rhythm in antigen processing that correlates with rhythms in both mitochondrial morphology and metabolism, dependent on the molecular clock gene, Bmal1. Using Mdivi-1, a compound that promotes mitochondrial fusion, we are able to rescue the circadian deficit in antigen processing and mechanistically link mitochondrial morphology and antigen processing. Furthermore, we find that circadian changes in mitochondrial Ca2+ are central to the circadian regulation of antigen processing. Our results indicate that rhythmic changes in mitochondrial calcium, which are associated with changes in mitochondrial morphology, regulate antigen processing.

Intertwining roles of circadian and metabolic regulation of the innate immune response.

It has emerged that an interconnected relationship exists between metabolism, circadian rhythms, and the immune system. The relationship between metabolism and circadian rhythms is not that surprising given the necessity to align rhythms of feeding/fasting with activity/rest. Recently, our understanding of the importance of metabolic pathways in terms of immune function, termed immunometabolism, has grown exponentially. It is now appreciated that the time of day during which the innate immune system is challenged strongly conditions the subsequent response. Recent observations have found that many individual components that make up the circadian clock also control aspects of metabolism in innate immune cells to modulate inflammation. This circadian/metabolic axis may be a key factor driving rhythmicity of immune function and circadian disruption is associated with a range of chronic inflammatory diseases such as atherosclerosis, obesity, and diabetes. The field of "circadian immunometabolism" seeks to reveal undiscovered circadian controlled metabolic pathways that in turn regulate immune responses. The innate immune system has been intricately linked to chronic inflammatory diseases, and within the immune system, individual cell types carry out unique roles in inflammation. Therefore, circadian immunometabolism effects are unique to each innate immune cell.

A contemporary clinical approach to genetic testing for heritable hyperparathyroidism syndromes.

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

The Circadian Clock Protein BMAL1 Acts as a Metabolic Sensor In Macrophages to Control the Production of Pro IL-1ß.

The transcription factor BMAL1 is a clock protein that generates daily or circadian rhythms in physiological functions including the inflammatory response of macrophages. Intracellular metabolic pathways direct the macrophage inflammatory response, however whether the clock is impacting intracellular metabolism to direct this response is unclear. Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1ß. We now describe that the macrophage molecular clock, through Bmal1, regulates the uptake of glucose, its flux through glycolysis and the Krebs cycle, including the production of the metabolite succinate to drive Il-1ß production. We further demonstrate that BMAL1 modulates the level and localisation of the glycolytic enzyme PKM2, which in turn activates STAT3 to further drive Il-1ß mRNA expression. Overall, this work demonstrates that BMAL1 is a key metabolic sensor in macrophages, and its deficiency leads to a metabolic shift of enhanced glycolysis and mitochondrial respiration, leading to a heightened pro-inflammatory state. These data provide insight into the control of macrophage driven inflammation by the molecular clock, and the potential for time-based therapeutics against a range of chronic inflammatory diseases.

Primary hyperparathyroidism in adults-(Part I) assessment and medical management: Position statement of the endocrine society of Australia, the Australian & New Zealand endocrine surgeons, and the Australian & New Zealand bone and mineral society.

OBJECTIVE: To formulate clinical consensus recommendations on the presentation, assessment, and management of primary hyperparathyroidism (PHPT) in adults. METHODS: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing nine key questions. RESULTS: PHPT is a biochemical diagnosis. Serum calcium should be measured in patients with suggestive symptoms, reduced bone mineral density or minimal trauma fractures, and in those with renal stones. Other indications are detailed in the manuscript. In patients with hypercalcaemia, intact parathyroid hormone, 25-hydroxy vitamin D, phosphate, and renal function should be measured. In established PHPT, assessment of bone mineral density, vertebral fractures, urinary tract calculi/nephrocalcinosis and quantification of urinary calcium excretion is warranted. Parathyroidectomy is the only definitive treatment and is warranted for all symptomatic patients and should be considered for asymptomatic patients without contraindications to surgery and with >10 years life expectancy. In patients who do not undergo surgery, we recommend annual evaluation for disease progression. Where the diagnosis is not clear or the risk-benefit ratio is not obvious, multidisciplinary discussion and formulation of a consensus management plan is appropriate. Genetic testing for familial hyperparathyroidism is recommended in selected patients. CONCLUSIONS: These clinical consensus recommendations were developed to provide clinicians with contemporary guidance on the assessment and management of PHPT in adults. It is anticipated that improved health outcomes for individuals and the population will be achieved at a decreased cost to the community.

Primary hyperparathyroidism in adults-(Part II) surgical management and postoperative follow-up: Position statement of the Endocrine Society of Australia, The Australian & New Zealand Endocrine Surgeons, and The Australian & New Zealand Bone and Mineral Society.

OBJECTIVE: To develop evidence-based recommendations to guide the surgical management and postoperative follow-up of adults with primary hyperparathyroidism. METHODS: Representatives from relevant Australian and New Zealand Societies used a systematic approach for adaptation of guidelines (ADAPTE) to derive an evidence-informed position statement addressing eight key questions. RESULTS: Diagnostic imaging does not determine suitability for surgery but can guide the planning of surgery in suitable candidates. First-line imaging includes ultrasound and either parathyroid 4DCT or scintigraphy, depending on local availability and expertise. Minimally invasive parathyroidectomy is appropriate in most patients with concordant imaging. Bilateral neck exploration should be considered in those with discordant/negative imaging findings, multi-gland disease and genetic/familial risk factors. Parathyroid surgery, especially re-operative surgery, has better outcomes in the hands of higher volume surgeons. Neuromonitoring is generally not required for initial surgery but should be considered for re-operative surgery. Following parathyroidectomy, calcium and parathyroid hormone levels should be re-checked in the first 24 h and repeated early if there are risk factors for hypocalcaemia. Eucalcaemia at 6 months is consistent with surgical cure; parathyroid hormone levels do not need to be re-checked in the absence of other clinical indications. Longer-term surveillance of skeletal health is recommended. CONCLUSIONS: This position statement provides up-to-date guidance on evidence-based best practice surgical and postoperative management of adults with primary hyperparathyroidism.

Pituitary function following peptide receptor radionuclide therapy for neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is an increasingly used treatment for unresectable neuroendocrine tumours (NETs) that express somatostatin receptors. Normal pituitary tissue expresses somatostatin receptors so patients receiving PRRT may be at risk of developing hypopituitarism. The aim was to assess the prevalence of clinically significant hypopituitarism a minimum of 2 years following radioisotope therapy for metastatic NET. This was a multicentre study (Australia and New Zealand). Sixty-six patients with unresectable NETs were included-34 had received PRRT and 32 comparison patients. Median follow-up after PRRT was 68 months. Male hypogonadism was the most common hormonal abnormality (16 of 38 men [42%]) from the total cohort. Of these, seven men had primary hypogonadism (five from PRRT group) and nine had secondary hypogonadism (six in PRRT group). There was no difference in either male hypogonadism or other hormonal dysfunction between patients who had received PRRT and those that had not. Patients who have received PRRT out to 68 months following treatment do not show concerning hypopituitarism although there may be the suggestion of growth hormone deficiency developing. However, hypogonadism is common in men with NETs so the gonadal axis should be assessed in men with suggestive symptoms as the treatment of testosterone deficiency may improve the quality of life.

'A little bubble of utopia': constructions of a primary care-based pilot clinic providing gender affirming hormone therapy.

The provision of gender affirming hormone therapy for transgender and non-binary people is a rapidly developing area of gender affirming healthcare. While research indicates the benefits of providing gender affirming hormone therapy through interdisciplinary primary care-based models, less is known about how service users and providers construct their understandings of affirmative approaches. In this paper, we present findings from a discourse analysis of four service users' and four healthcare professionals' talk about a primary care-based pilot clinic providing gender affirming hormone therapy in Aotearoa New Zealand. Participants employed notions of pathologisation, time, and agency in their talk to construct the clinic as a personal setting which gave service users time to make their own health decisions, while constructing hospitals as impersonal with lengthy wait times. The assessment-driven nature of best practice guidelines that governed clinicians' decision-making was constructed as constraining users' agency. Findings highlight the ongoing importance of aligning gender affirming hormone therapy with other non-disease types of healthcare, and suggest new ways for achieving this through affirmative approaches to healthcare.

Caspase-11 promotes allergic airway inflammation.

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.

Immunometabolism around the Clock.

Almost every cell has a molecular clock, which controls gene expression on a 24-h cycle, providing circadian rhythmicity. An example of a circadian behaviour common to most organisms is the feeding/fasting cycle, which shapes whole-body metabolism. However, the exact mechanisms by which the clock controls cellular metabolism have only recently become clear. The molecular clock and related metabolic pathways are also key drivers of immunity. Thus, a natural convergence of circadian biology, metabolism, and immunology has emerged to form a new field that we term 'circadian immunometabolism'. Expanding our understanding of this field will provide insights into chronic conditions such as obesity, cancer, diabetes, cardiovascular disease, and arthritis.

Geochemical Evidence of First Forestation in the Southernmost Euramerica from Upper Devonian (Famennian) Black Shales.

The global dispersal of forests and soils has been proposed as a cause for the Late Devonian mass extinctions of marine organisms, but detailed spatiotemporal records of forests and soils at that time remain lacking. We present data from microscopic and geochemical analyses of the Upper Devonian Chattanooga Shale (Famennian Stage). Plant residues (microfossils, vitrinite and inertinite) and biomarkers derived from terrestrial plants and wildfire occur throughout the stratigraphic section, suggesting widespread forest in the southern Appalachian Basin, a region with no macro plant fossil record during the Famennian. Inorganic geochemical results, as shown by increasing values of SiO2/Al2O3, Ti/Al, Zr/Al, and the Chemical Index of Alteration (CIA) upon time sequence, suggest enhanced continental weathering that may be attributed to the invasion of barren lands by rooted land plants. Our geochemical data collectively provide the oldest evidence of the influences of land plants from the southernmost Appalachian Basin. Our synthesis of vascular plant fossil record shows a more rapid process of afforestation and pedogenesis across south-central Euramerica during the Frasnian and Famennian than previously documented. Together, these results lead us to propose a new hypothesis that global floral dispersal had progressed southward along the Acadian landmass rapidly during the Late Devonian.

Malonylation of GAPDH is an inflammatory signal in macrophages.

Macrophages undergo metabolic changes during activation that are coupled to functional responses. The gram negative bacterial product lipopolysaccharide (LPS) is especially potent at driving metabolic reprogramming, enhancing glycolysis and altering the Krebs cycle. Here we describe a role for the citrate-derived metabolite malonyl-CoA in the effect of LPS in macrophages. Malonylation of a wide variety of proteins occurs in response to LPS. We focused on one of these, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In resting macrophages, GAPDH binds to and suppresses translation of several inflammatory mRNAs, including that encoding TNFα. Upon LPS stimulation, GAPDH undergoes malonylation on lysine 213, leading to its dissociation from TNFα mRNA, promoting translation. We therefore identify for the first time malonylation as a signal, regulating GAPDH mRNA binding to promote inflammation.

Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa, New Zealand.

Internationally and within Aotearoa, New Zealand, there has been a substantial increase in the demand for gender affirming healthcare over the past decade. It is likely that this level of referrals to health services will continue in the foreseeable future. The Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa, New Zealand were developed following the recognition that the previous good practice guide required updating to be in step with current practice and international standards. This article presents a summary of the guideline focusing on puberty blockers, hormonal therapies, access to surgery and other gender affirming healthcare. We hope these guidelines will support the development and provision of services providing gender affirming healthcare around the country and provide helpful guidance to all health professionals involved in the care of trans people.