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CONTEXT: Trends in incidence of Polycystic Ovary Syndrome (PCOS) and effects on health resource utilization are unclear. OBJECTIVES: To describe trends in prevalence and incidence of PCOS in the United Kingdom. To establish healthcare resource use and associated costs. DESIGN: Data were extracted from the Clinical Practice Research Datalink Aurum and Hospital Episode Statistics databases. Point prevalence and incidence were calculated (2004-2020). Patients with PCOS were matched to controls (1:1) by age, body mass index and primary care practice. Primary care contacts were assigned an average cost and prescription items assigned a net ingredient cost. Inpatient admissions and outpatient consultations were processed into Healthcare Resource Groups and costed to the National Tariff. RESULTS: PCOS incidence increased from 1.22 per 1000 person years in 2004 to 1.77 (2012) and 2.20 (2019). Point prevalence increased from 1.02% (2004) to 2.2% (2012) and 3.5% (2020), and was highest in Asians. Mean contacts per person year (ppy) for patients with PCOS versus controls were 0.48 vs 0.29 for inpatients (p<0.001), 3.81 vs 2.15 for outpatients (p<0.001) and 6.43 vs 4.68 (p<0.001) for primary care. Mean healthcare costs (ppy) were £837 vs £493 (p<0.001) for inpatients, £444 vs £253 (p<0.001) for outpatients, £157 vs £112 for primary care and £109 vs £83 (p<0.001) for primary care prescriptions. Total health care contacts ppy were 10.72 vs 7.11 (p<0.001) and total associated costs £1,546 vs £940 (p<0.001). CONCLUSION: The incidence of PCOS has risen significantly. Health resource utilization and costs of PCOS are significantly greater than controls.

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Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how Protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.

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Computational free energy-based methods have the potential to significantly improve throughput and decrease costs of protein design efforts. Such methods must reach a high level of reliability, accuracy, and automation to be effectively deployed in practical industrial settings in a way that impacts protein design projects. Here, we present a benchmark study for the calculation of relative changes in protein-protein binding affinity for single point mutations across a variety of systems from the literature, using free energy perturbation (FEP+) calculations. We describe a method for robust treatment of alternate protonation states for titratable amino acids, which yields improved correlation with and reduced error compared to experimental binding free energies. Following careful analysis of the largest outlier cases in our dataset, we assess limitations of the default FEP+ protocols and introduce an automated script which identifies probable outlier cases that may require additional scrutiny and calculates an empirical correction for a subset of charge-related outliers. Through a series of three additional case study systems, we discuss how protein FEP+ can be applied to real-world protein design projects, and suggest areas of further study.

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CONTEXT: Children born to mothers with gestational hypo- or hyperthyroidism may have increased risk of adverse neurodevelopmental outcomes. However, the effects of maternal thyroid status on offspring brain development are unclear. OBJECTIVE: To establish whether adolescent brain morphology is affected by suboptimal gestational thyroid function (SGTF). DESIGN AND SETTING: The Controlled Antenatal Thyroid Screening (CATS) study randomized mothers with SGTF to levothyroxine or no supplementation from ∼12 weeks' gestation. At age 9, children born to mothers who were over-treated with levothyroxine had a higher risk of conduct and hyperactivity traits. For the current CATS III study, children underwent neuroimaging studies, including T1-weighted structural magnetic resonance imaging (MRI). PARTICIPANTS: A total of 85 children aged 11-16 years had usable T1-weighted MRI data (exposed to untreated SGTF (n=21), normal GTF (n=24), or treated SGTF (optimally-treated (n=21), over-treated (n=20)). MAIN OUTCOME MEASURES: Primary outcome: to examine the association of SGTF and its treatment with global brain volumes. Secondary and exploratory outcomes: to investigate the association of maternal TSH and free T4 levels with global and subregional brain volumes. Results were adjusted for age, sex and pubertal scores. RESULTS: There were no significant differences in global brain volumetric measures between groups, including total gray matter volume (p=0.373). Weak positive correlations were found between maternal TSH, but not FT4, levels and several brain volumes, but these did not survive testing for multiple comparisons. CONCLUSIONS: We found no evidence that SGTF was associated with differences in adolescent brain morphology, and no impact of levothyroxine supplementation.

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We describe a helium source cell for use in cryogenic experiments that is hermetically sealed in situ on the cold plate of a cryostat. The source cell is filled with helium gas at room temperature and, subsequently, sealed using a cold weld crimping tool before the cryostat is closed and cooled down. At low temperatures, the helium condenses and collects in a connected experimental volume, as monitored via the frequency response of a planar superconducting resonator device sensitive to small amounts of liquid helium. This on-cryostat helium source negates the use of a filling tube between the cryogenic volumes and room temperature, thereby preventing unwanted effects such as temperature instabilities that arise from the thermomechanical motion of helium within the system. This helium source can be used in experiments investigating the properties of quantum fluids or to better thermalize quantum devices.

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BACKGROUND: Congenital adrenal hyperplasia (CAH) encompasses a rare group of autosomal recessive disorders, characterised by enzymatic defects in steroidogenesis. Heterogeneity in management practices has been observed internationally. The International Congenital Adrenal Hyperplasia registry (I-CAH, https://sdmregistries.org/) was established to enable insights into CAH management and outcomes, yet its global adoption by endocrine centres remains unclear. DESIGN: We sought (1) to assess current practices amongst clinicians managing patients with CAH in the United Kingdom and Ireland, with a focus on choice of glucocorticoid, monitoring practices and screening for associated co-morbidities, and (2) to assess use of the I-CAH registry. MEASUREMENTS: We designed and distributed an anonymised online survey disseminated to members of the Society for Endocrinology and Irish Endocrine Society to capture management practices in the care of patients with CAH. RESULTS: Marked variability was found in CAH management, with differences between general endocrinology and subspecialist settings, particularly in glucocorticoid use, biochemical monitoring and comorbidity screening, with significant disparities in reproductive health monitoring, notably in testicular adrenal rest tumours (TARTs) screening (p = .002), sperm banking (p = .0004) and partner testing for CAH (p < .0001). Adoption of the I-CAH registry was universally low. CONCLUSIONS: Differences in current management of CAH continue to exist. It appears crucial to objectify if different approaches result in different long-term outcomes. New studies such as CaHASE2, incorporating standardised minimum datasets including replacement therapies and monitoring strategies as well as longitudinal data collection, are now needed to define best-practice and standardise care.

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A 35-year-old woman with a progressive, bilateral upper limb tremor, personality change, behavioral disturbance, and primary ovarian insufficiency was found to have AARS2-related leukodystrophy. She had congenital nystagmus which evolved to head titubation by age 8 years and then developed an upper limb tremor in her mid-teens. These symptoms stabilized during her 20s, but soon after this presentation at age 35 years, neurologic and behavioral disturbances progressed rapidly over a 12-month period requiring transition to an assisted living facility with care support (4 visits/day) and assistance for all activities of daily living. MRI of the brain demonstrated confluent white matter changes predominantly involving the frontal lobes consistent with a leukodystrophy. All other investigations were unremarkable. Nongenetic causes of a leukodystrophy including sexually transmitted diseases and recreational drug use were excluded. Family history was negative for similar symptoms. Gene panel testing identified compound heterozygous pathogenic AARS2 mutations. This case highlights the importance of MRI brain imaging in progressive tremor syndromes, the utility of gene panels in simultaneous testing of multiple disorders with overlapping phenotypes, and the need for awareness of comorbid endocrinological disorders in many of the genetic leukodystrophies, whose identification may aid in clinical diagnosis.

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CONTEXT: The serum total cortisol response to the ACTH stimulation test is widely used to assess adrenocortical function but is affected by changes in cortisol-binding globulin (CBG) concentration. Salivary cortisol reflects free cortisol concentrations and may offer a reliable alternative. OBJECTIVES: (1) To establish the salivary cortisol response to ACTH stimulation in healthy volunteers and patients with altered CBG concentrations; (2) to evaluate the performance of a lower reference limit (LRL) determined in healthy volunteers in patients with suspected hypoadrenalism (SH-patients). DESIGN: A 250 µg ACTH stimulation test was undertaken in 139 healthy volunteers, 24 women taking an estradiol-containing oral contraceptive pill (OCP-females), 10 patients with low serum protein concentration (LP-patients), and 30 SH-patients. Salivary cortisol was measured by liquid chromatography-tandem mass spectrometry. Mean and LRL of the 30-minute salivary cortisol response (mean-1.96 standard deviation) were derived from log-transformed concentrations. The LRL was applied as a diagnostic cut-off in SH-patients, with comparison to the serum response. RESULTS: Mean CBG concentrations (range) were 58 (42-81) mg/L, 64 (43-95) mg/L, 41 (28-60) mg/L, and 116 (84-159) mg/L in males, females, LP-patients, and OCP-females, respectively. The mean 30-minute salivary cortisol concentration was 19.3 (2.5th-97.5th percentile 10.3-36.2) nmol/L in healthy volunteers. Corresponding values were not different in OCP-females [19.7 (9.5-41.2) nmol/L; P = .59] or LP-patients [19.0 (7.7-46.9) nmol/L; P = .97]. Overall diagnostic agreement between salivary and serum responses in SH-patients was 79%. CONCLUSION: Salivary cortisol response to ACTH stimulation offers a reliable alternative to serum and may be especially useful in conditions of altered CBG concentration.

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Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, CID modules have been used primarily in engineering cells for in vitro applications. To broaden their utility to the clinical setting, including the potential to control cell and gene therapies, the identification of novel CID modules should consider factors such as the safety and pharmacokinetic profile of the small molecule inducer, and the orthogonality and immunogenicity of the protein components. Here we describe a CID module based on the orally available, approved, small molecule simeprevir and its target, the NS3/4A protease from hepatitis C virus. We demonstrate the utility of this CID module as a molecular switch to control biological processes such as gene expression and apoptosis in vitro, and show that the CID system can be used to rapidly induce apoptosis in tumor cells in a xenograft mouse model, leading to complete tumor regression.

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Polycystic ovary syndrome is characterised by excessive levels of androgens and ovulatory dysfunction, and is a common endocrine disorder in women of reproductive age. Polycystic ovary syndrome arises as a result of polygenic susceptibility in combination with environmental influences that might include epigenetic alterations and in utero programming. In addition to the well recognised clinical manifestations of hyperandrogenism and ovulatory dysfunction, women with polycystic ovary syndrome have an increased risk of adverse mental health outcomes, pregnancy complications, and cardiometabolic disease. Unlicensed treatments have limited efficacy, mostly because drug development has been hampered by an incomplete understanding of the underlying pathophysiological processes. Advances in genetics, metabolomics, and adipocyte biology have improved our understanding of key changes in neuroendocrine, enteroendocrine, and steroidogenic pathways, including increased gonadotrophin releasing hormone pulsatility, androgen excess, insulin resistance, and changes in the gut microbiome. Many patients with polycystic ovary syndrome have high levels of 11-oxygenated androgens, with high androgenic potency, that might mediate metabolic risk. These advances have prompted the development of new treatments, including those that target the neurokinin-kisspeptin axis upstream of gonadotrophin releasing hormone, with the potential to lessen adverse clinical sequelae and improve patient outcomes.

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BACKGROUND: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33ox) is thought to limit its activity. We investigated whether IL-33ox has functional activities that are independent of ST2 in the airway epithelium. METHODS: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. RESULTS: We demonstrate that IL-33ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro. IL-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox were enriched in airway epithelia from patients with severe COPD. CONCLUSIONS: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD.

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OBJECTIVE: Functioning gonadotroph adenomas (FGAs) are rare pituitary tumours stimulating ovarian function with potential life-threatening consequences in women. However, a lack of aggregated clinical experience of FGAs impairs management in affected women. The aim of this study is to present the clinical course of FGA-induced ovarian hyperstimulation syndrome (OHSS) cases as identified by some of the largest UK pituitary endocrine tertiary centres with a view to increasing awareness and improving diagnosis and management of women with FGA. DESIGN: A retrospective observational study; audit of eight UK regional pituitary centres for cases of FGAs. SETTING: Specialist neuroendocrine centres in the United Kingdom. PATIENTS AND MEASUREMENTS: Women diagnosed with FGA-induced OHSS. Description of their clinical course. RESULTS: Seven cases of FGA were identified in women, all causing OHSS. Mean age was 33.4 years at diagnosis. Abdominal pain, irregular periods, headache, and visual disturbances were reported at presentation by 100%, 71%, 57% and 43% of women, respectively. Three of seven women underwent ovarian surgery before FGA diagnosis. Six women underwent transsphenoidal surgery (TSS) with incomplete tumour resection in five of those, but all showed improvement or resolution in symptoms and biochemistry postoperatively. CONCLUSION: FGA is a rare cause of spontaneous OHSS. TSS improves clinical and biochemical features of ovarian hyperstimulation in FGAs. Improved awareness of FGA will prevent inappropriate emergency ovarian surgery.

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PURPOSE: Individuals who experience social and emotional difficulties struggle to maintain successful social relationships and incur an increased risk of developing mood disorders. These, in turn, have a significant impact on psychological and physical wellbeing. A small number of medical studies suggest that patients with adult-onset craniopharyngioma (AoC) report poorer quality of life, however, no in-depth psychological research has been carried out. The present study aimed to capture a rich understanding of whether patients with AoC experience a psychological impact from their diagnosis and whether psychological factors may contribute to a poorer quality of life. METHOD: Both patients with AoC and clinicians with experience of working with patients with AoC were invited to take part in a semi-structured interview. Participants were recruited from three geographically disperse National Health Service (NHS) units across the United Kingdom (UK). Eight patients and 10 clinicians took part in the study. Interviews were recorded and transcribed verbatim and analysed using inductive thematic analysis. RESULTS: Two key themes, with multiple subthemes, were identified: 1) Patients experience psychological impacts of AoC; and 2) Patients also experience common physical symptoms. CONCLUSIONS: Patients and clinicians recognised significant psychological impact as a result of AoC, and these impacts contributed to overall poorer quality of life. Crucially, both parties also felt that further research into psychological impact of AoC was both interesting and useful.

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Interleukin (IL)-33 is a broad-acting alarmin cytokine that can drive inflammatory responses following tissue damage or infection and is a promising target for treatment of inflammatory disease. Here, we describe the identification of tozorakimab (MEDI3506), a potent, human anti-IL-33 monoclonal antibody, which can inhibit reduced IL-33 (IL-33red) and oxidized IL-33 (IL-33ox) activities through distinct serum-stimulated 2 (ST2) and receptor for advanced glycation end products/epidermal growth factor receptor (RAGE/EGFR complex) signalling pathways. We hypothesized that a therapeutic antibody would require an affinity higher than that of ST2 for IL-33, with an association rate greater than 107 M-1 s-1, to effectively neutralize IL-33 following rapid release from damaged tissue. An innovative antibody generation campaign identified tozorakimab, an antibody with a femtomolar affinity for IL-33red and a fast association rate (8.5 × 107 M-1 s-1), which was comparable to soluble ST2. Tozorakimab potently inhibited ST2-dependent inflammatory responses driven by IL-33 in primary human cells and in a murine model of lung epithelial injury. Additionally, tozorakimab prevented the oxidation of IL-33 and its activity via the RAGE/EGFR signalling pathway, thus increasing in vitro epithelial cell migration and repair. Tozorakimab is a novel therapeutic agent with a dual mechanism of action that blocks IL-33red and IL-33ox signalling, offering potential to reduce inflammation and epithelial dysfunction in human disease.

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OBJECTIVE: Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. DESIGN: We investigated the renin-angiotensin-aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. METHODS: Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. RESULTS: The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L-1 (IQR 8.3) versus 10.5 nmol L-1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L-1 s-1 (IQR 1.0) to 0.48 ng L-1 s-1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L-1 s-1 (IQR 0.66) to 0.52 ng L-1 s-1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L-1 to 139.3 ± 1.8 mmol L-1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L-1 to 139.3 ± 1.9 mmol L-1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. CONCLUSION: 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP.

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OBJECTIVE: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID-19) infection and following ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID-19-related AH. DESIGN: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID-19-related AH using a standardized data collection tool. RESULTS: The literature search yielded 25 cases of COVID-19-related AH (19 bilateral; 13 infection-related, and 12 vaccine-related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK-based patients from the systematic review. Seven patients (4 males; median age 53 (range 26-70) years), had infection-related AH (four bilateral). Median time from positive COVID-19 test to AH detection was 8 (range 1-30) days. Eleven cases of vaccine-related AH (eight bilateral) were captured (3 males; median age 47 (range 23-78) years). Median time between vaccination (nine Oxford-AstraZeneca and two Pfizer-BioNTech) and AH was 9 (range 2-27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement. CONCLUSION: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID-19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency.

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Purpose: This report of a case of allergic contact hand dermatitis due to constituents of nitrile gloves is to bring to the attention of practitioners four important practice points: 1) allergic contact dermatitis may occur due to exposure to chemicals in nitrile gloves; 2) skin patch testing is used to identify the causative allergens; 3) targeted allergens may be necessary in addition to the baseline European standard series if the standard series is unhelpful; and 4) there are potential interventions to manage nitrile glove dermatitis. Findings: A laboratory analyst had occupational exposure to several allergens and had worn latex gloves. She was exposed to laboratory chemicals and powdered ore dust, containing precious metals. She developed hand dermatitis and was relocated to administrative duties not requiring glove use. Her dermatitis cleared but recurred when she returned to the laboratory and started using nitrile gloves. On history, nitrile gloves and platinum group metal ore dust were consistently associated with her hand dermatitis, but laboratory chemicals were not. Latex-specific immunoglobulin E (IgE) was negative, as were skin patch tests for 13 allergens in the metal series, including salts of platinum group metals. She had positive allergic reactions to cobalt chloride, formaldehyde, nickel sulphate, and quaternium 15 in the European standard series patch tests. She did not react to the rubber chemicals in the European standard series, including thiuram mix. The patient was then tested with the rubber additives series because of the glove-relatedness of her hand dermatitis. She had positive reactions to three thiuram compounds used as accelerators in rubber gloves. The patient went on vacation during which time her dermatitis improved. She was relocated to a position without glove use or ore contact and her dermatitis did not recur. Conclusions: An analytic laboratory worker developed hand allergic contact dermatitis due to nitrile glove constituents. The diagnosis is supported by the improvement in her dermatitis after cessation of glove use, negative metal series patch tests, and positive patch tests to accelerators found in rubber gloves. Nevertheless, a contribution to the dermatitis by metals in the platinum group metal ore dust cannot be excluded. Recommendations: Nitrile glove constituents should be considered in wearers who develop hand dermatitis. Skin patch testing is recommended to investigate putative agents. Specific patch test series for more targeted testing may be required

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Identifying emotions correctly is essential for successful social interaction. There is therefore a keen interest in designing therapeutic interventions to improve emotion recognition in individuals who struggle with social interaction. The neuropeptide oxytocin has been proposed as a potential physiological intervention due to its important role in emotion recognition and other aspects of social cognition. However, there are a number of caveats to consider with the current form of intranasal oxytocin commonly used in the literature. Psychological interventions, on the other hand, do not carry the same caveats, and there is, therefore, a need to understand how intranasal oxytocin administration compares to psychological interventions designed to target the same psychological phenomena; and whether a combined intervention approach may provide additive benefits. Here we present a pilot, proof-of-concept study in healthy volunteers comparing the effect of intranasal oxytocin against a validated emotion training programme, finding that the psychological intervention, and not intranasal oxytocin, improved emotion recognition specifically for angry expressions. We discuss the theoretical implications of the research for future clinical trials. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

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BACKGROUND: Thyroid dysfunction in pregnancy is associated with adverse offspring outcomes and recent birth-cohort studies suggest that even mild degrees of thyroid dysfunction may be linked with a range of late cognitive and behavioural effects in childhood and adolescence. SOURCES OF DATA: This review summarizes recent literature of observational studies and critically appraises randomized controlled trials (RCTs) of antenatal thyroid screening and Levothyroxine intervention. AREAS OF AGREEMENT: Overt hypothyroidism and hyperthyroidism carry significant risks for unfavourable offspring outcomes and should be appropriately corrected in pregnancy. AREAS OF CONTROVERSY: The significance of subclinical hypothyroidism and hypothyroxinaemia is still unclear. Meta-analyses of birth-cohort studies show associations of maternal subclinical hypothyroidism and hypothyroxinaemia with intellectual deficits, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders, while hyperthyroidism and high-normal FT4 were linked with ADHD. RCTs have shown no benefits of screening on neurodevelopmental outcomes although Levothyroxine could have been initiated too late in pregnancy in these trials. GROWING POINTS: A small number of studies have shown inconsistent associations of maternal thyroid dysfunction with offspring cardiometabolic indices including blood pressure and body weight. Correction of maternal thyroid dysfunction was, however, associated with favourable long-term metabolic profiles in mothers, including lipid profiles, fat mass and body mass index. Antenatal thyroid screening may therefore present opportunities for optimizing a wider range of outcomes than envisaged. AREAS FOR DEVELOPING RESEARCH: Future trials with early antenatal thyroid screening and intervention are necessary to clarify the impact of screening on late offspring and maternal effects.

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Guava wilt disease is caused by the fungus Nalanthamala psidii. The wilt disease results in large-scale destruction of orchards in South Africa, Taiwan, and several Southeast Asian countries. De novo assembly, annotation, and in-depth analysis of the N. psidii genome were carried out to facilitate the identification of characteristics associated with pathogenicity and pathogen evolution. The predicted secretome revealed a range of CAZymes, proteases, lipases and peroxidases associated with plant cell wall degradation, nutrient acquisition, and disease development. Further analysis of the N. psidii carbohydrate-active enzyme profile exposed the broad-spectrum necrotrophic lifestyle of the pathogen, which was corroborated by the identification of putative effectors and secondary metabolites with the potential to induce tissue necrosis and cell surface-dependent immune responses. Putative regulatory proteins including transcription factors and kinases were identified in addition to transporters potentially involved in the secretion of secondary metabolites. Transporters identified included important ABC and MFS transporters involved in the efflux of fungicides. Analysis of the repetitive landscape and the detection of mechanisms linked to reproduction such as het and mating genes rendered insights into the biological complexity and evolutionary potential of N. psidii as guava pathogen. Hence, the assembly and annotation of the N. psidii genome provided a valuable platform to explore the pathogenic potential and necrotrophic lifestyle of the guava wilt pathogen.