An Improved Chromosome-scale Genome Assembly and Population Genetics resource for Populus tremula.

Aspen (Populus tremula L.) is a keystone species and a model system for forest tree genomics. We present an updated resource comprising a chromosome-scale assembly, population genetics and genomics data. Using the resource, we explore the genetic basis of natural variation in leaf size and shape, traits with complex genetic architecture. We generated the genome assembly using long-read sequencing, optical and high-density genetic maps. We conducted whole-genome resequencing of the Umeå Aspen (UmAsp) collection. Using the assembly and re-sequencing data from the UmAsp, Swedish Aspen (SwAsp) and Scottish Aspen (ScotAsp) collections we performed genome-wide association analyses (GWAS) using Single Nucleotide Polymorphisms (SNPs) for 26 leaf physiognomy phenotypes. We conducted Assay of Transposase Accessible Chromatin sequencing (ATAC-Seq), identified genomic regions of accessible chromatin, and subset SNPs to these regions, improving the GWAS detection rate. We identified candidate long non-coding RNAs in leaf samples, quantified their expression in an updated co-expression network, and used this to explore the functions of candidate genes identified from the GWAS. A GWAS found SNP associations for seven traits. The associated SNPs were in or near genes annotated with developmental functions, which represent candidates for further study. Of particular interest was a ~177-kbp region harbouring associations with several leaf phenotypes in ScotAsp. We have incorporated the assembly, population genetics, genomics, and GWAS data into the PlantGenIE.org web resource, including updating existing genomics data to the new genome version, to enable easy exploration and visualisation. We provide all raw and processed data to facilitate reuse in future studies.

External Validation of Prognostic Models in Critical Care: A Cautionary Tale From COVID-19 Pneumonitis.

OBJECTIVES BACKGROUND: To externally validate clinical prediction models that aim to predict progression to invasive ventilation or death on the ICU in patients admitted with confirmed COVID-19 pneumonitis. DESIGN: Single-center retrospective external validation study. DATA SOURCES: Routinely collected healthcare data in the ICU electronic patient record. Curated data recorded for each ICU admission for the purposes of the U.K. Intensive Care National Audit and Research Centre (ICNARC). SETTING: The ICU at Manchester Royal Infirmary, Manchester, United Kingdom. PATIENTS: Three hundred forty-nine patients admitted to ICU with confirmed COVID-19 Pneumonitis, older than 18 years, from March 1, 2020, to February 28, 2022. Three hundred two met the inclusion criteria for at least one model. Fifty-five of the 349 patients were admitted before the widespread adoption of dexamethasone for the treatment of severe COVID-19 (pre-dexamethasone patients). OUTCOMES: Ability to be externally validated, discriminate, and calibrate. METHODS: Articles meeting the inclusion criteria were identified, and those that gave sufficient details on predictors used and methods to generate predictions were tested in our cohort of patients, which matched the original publications' inclusion/exclusion criteria and endpoint. RESULTS: Thirteen clinical prediction articles were identified. There was insufficient information available to validate models in five of the articles; a further three contained predictors that were not routinely measured in our ICU cohort and were not validated; three had performance that was substantially lower than previously published (range C-statistic = 0.483-0.605 in pre-dexamethasone patients and C = 0.494-0.564 among all patients). One model retained its discriminative ability in our cohort compared with previously published results (C = 0.672 and 0.686), and one retained performance among pre-dexamethasone patients but was poor in all patients (C = 0.793 and 0.596). One model could be calibrated but with poor performance. CONCLUSIONS: Our findings, albeit from a single center, suggest that the published performance of COVID-19 prediction models may not be replicated when translated to other institutions. In light of this, we would encourage bedside intensivists to reflect on the role of clinical prediction models in their own clinical decision-making.

Diagnostic utility of 11 C-methionine PET/CT in primary hyperparathyroidism in a UK cohort: A single-centre experience and literature review.

OBJECTIVE: Primary hyperparathyroidism is a common endocrine disorder, with 80% of all cases usually caused by one single hyperfunctioning parathyroid adenoma. Conventional imaging modalities for the diagnostic work-up of primary hyperparathyroidism (PHPT) include ultrasound of the neck, 99mTc-sestamibi scintigraphy, and four-dimensional computed tomography (4D-CT). However, the role of other imaging modalities, such as 11C-methionine PET/CT, in the care pathway for PHPT is currently unclear. Here, we report our experience of the diagnostic utility of 11C-methionine PET/CT in a single-center patient cohort (n = 45). DESIGN: Retrospective single-center cohort study. PATIENTS AND MEASUREMENTS: The data of eligible patients that underwent 11C-methionine PET/CT between 2014 and 2022 at Addenbrooke's Hospital (Cambridge, UK) were collected and analyzed. The clinical utility of imaging modalities was determined by comparing the imaging result with histopathological and biochemical outcomes following surgery. RESULTS: In patients with persistent primary hyperparathyroidism following previous surgery, 11C-methionine PET/CT identified a candidate lesion in 6 of 10 patients (60.0%), and histologically confirmed in 5 (50.0%). 11C-methionine PET/CT also correctly identified a parathyroid adenoma in 9 out of 12 patients (75.0%) that failed to be localized on other imaging modalities. 11C-methionine PET/CT had a sensitivity of 70.0% (95% CI 55.8 - 84.2%) for the detection of parathyroid adenomas. CONCLUSIONS: This study highlights a diagnostic role for 11C-methionine PET/CT in patients that have undergone unsuccessful prior surgery or have equivocal or negative prior imaging results, aiding localization and a targeted surgical approach.

miR-3156-5p is downregulated in serum of MEN1 patients and regulates expression of MORF4L2.

Multiple endocrine neoplasia type 1 (MEN1), caused by mutations in the MEN1 gene encoding menin, is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic neuroendocrine tumours (NETs). Development of these tumours is associated with wide variations in their severity, order and ages (from <5 to >80 years), requiring life-long screening. To improve tumour surveillance and quality of life, better circulating biomarkers, particularly for pancreatic NETs that are associated with higher mortality, are required. We, therefore, examined the expression of circulating miRNA in the serum of MEN1 patients. Initial profiling analysis followed by qRT-PCR validation studies identified miR-3156-5p to be significantly downregulated (-1.3 to 5.8-fold, P < 0.05-0.0005) in nine MEN1 patients, compared to matched unaffected relatives. MEN1 knock-down experiments in BON-1 human pancreatic NET cells resulted in reduced MEN1 (49%, P < 0.05), menin (54%, P < 0.05) and miR-3156-5p expression (20%, P < 0.005), compared to control-treated cells, suggesting that miR-3156-5p downregulation is a consequence of loss of MEN1 expression. In silico analysis identified mortality factor 4-like 2 (MOR4FL2) as a potential target of miR-3156-5p, and in vitro functional studies in BON-1 cells transfected with either miR-3156-5p mimic or inhibitors showed that the miR-3156-5p mimic significantly reduced MORF4L2 protein expression (46%, P < 0.005), while miR-3156-5p inhibitor significantly increased MORF4L2 expression (1.5-fold, P < 0.05), compared to control-treated cells, thereby confirming that miR-3156-5p regulates MORF4L2 expression. Thus, the inverse relationship between miR-3156-5p and MORF4L2 expression represents a potential serum biomarker that could facilitate the detection of NET occurrence in MEN1 patients.

Transfusion-associated necrotizing enterocolitis (NEC) in extremely preterm infants: experience of a tertiary neonatal center in UK.

OBJECTIVE: To compare the characteristics and short-term outcomes in extremely preterm infants, who developed necrotizing enterocolitis (NEC) following a packed red blood cell transfusion (pRBC) within 48 h (TANEC), with those who developed NEC beyond 48 h (non-TANEC). SETTING: A single-center retrospective cohort study in a Tertiary neonatal intensive care unit in the UK over a 5-year period. PATIENTS AND METHODS: Extremely premature infants (23-27 weeks gestation) were selected. TANEC and non-TANEC incidence were calculated from the confirmed NEC group (defined as modified Bell's stage II and beyond). The characteristics and short-term outcomes of infants with TANEC in the first 8 weeks of life were compared to infants with non-TANEC. RESULTS AND INTERPRETATION: Incidence of confirmed NEC was 14% (28/207). On further subgroup analysis of the confirmed NEC cases, 46% (13/28) of infants were identified with TANEC and 54% (15/28) with non-TANEC. The incidence of TANEC did not correlate with the number of antecedent pRBC transfusions or the pre-transfusion median hemoglobin (Hb) levels. There were no significant differences in characteristics between the TANEC and non-TANEC groups. Infants within the TANEC group required more intensive neonatal care support, greater surgical intervention (p-value 0.043) with loss of gut integrity and an increase in number of TPN dependency days (p-value 0.014). CONCLUSIONS: A significantly worse clinical course and short-term outcome was observed in the TANEC group when compared with the non-TANEC group.

Paediatric rhombencephalitis presenting with bradycardia: a good recovery despite cardiac involvement.

Rhombencephalitis is a rare condition, often caused by infection, commonly presenting with myoclonic jerks, ataxia and cranial nerve palsy. Typically, it has a high morbidity and mortality, with worse prognosis associated with cardiopulmonary involvement. Herein, we present the case of a 10-year-old boy, presenting with headache, vomiting, symptomatic bradycardia and rapidly progressing ophthalmoplegia from a sixth nerve palsy, without additional brainstem symptoms. Previously, pericarditis, myocarditis and heart failure have been associated with rhombencephalitis, but not bradycardia. The cause of his rhombencephalitis was presumed viral, but despite extensive screening, the virus responsible was never isolated. Following treatment with intravenous antibiotics and antivirals in a high dependency unit, he recovered well with no neurological deficit on discharge and marked radiological improvement on MRI 4 weeks later. Although rare, rhombencephalitis should be considered in a child presenting with neurological symptoms, particularly alongside a cranial nerve palsy, developing over a rapid time course.

Videolaryngoscopy: a help or a hindrance?

Airway management is fundamental to anaesthesia, and technology may help with the safety of this procedure. Videolaryngoscopy is a developing area, which is becoming commonplace in anaesthesia practice.

Ap2s1 mutation causes hypercalcaemia in mice and impairs interaction between calcium-sensing receptor and adaptor protein-2.

Adaptor protein 2 (AP2), a heterotetrameric complex comprising AP2α, AP2ß2, AP2µ2 and AP2σ2 subunits, is ubiquitously expressed and involved in endocytosis and trafficking of membrane proteins, such as the calcium-sensing receptor (CaSR), a G-protein coupled receptor that signals via Gα11. Mutations of CaSR, Gα11 and AP2σ2, encoded by AP2S1, cause familial hypocalciuric hypercalcaemia types 1-3 (FHH1-3), respectively. FHH3 patients have heterozygous AP2S1 missense Arg15 mutations (p.Arg15Cys, p.Arg15His or p.Arg15Leu) with hypercalcaemia, which may be marked and symptomatic, and occasional hypophosphataemia and osteomalacia. To further characterize the phenotypic spectrum and calcitropic pathophysiology of FHH3, we used CRISPR/Cas9 genome editing to generate mice harboring the AP2S1 p.Arg15Leu mutation, which causes the most severe FHH3 phenotype. Heterozygous (Ap2s1+/L15) mice were viable, and had marked hypercalcaemia, hypermagnesaemia, hypophosphataemia, and increases in alkaline phosphatase activity and fibroblast growth factor-23. Plasma 1,25-dihydroxyvitamin D was normal, and no alterations in bone mineral density or bone turnover were noted. Homozygous (Ap2s1L15/L15) mice invariably died perinatally. Co-immunoprecipitation studies showed that the AP2S1 p.Arg15Leu mutation impaired protein-protein interactions between AP2σ2 and the other AP2 subunits, and also with the CaSR. Cinacalcet, a CaSR positive allosteric modulator, decreased plasma calcium and parathyroid hormone concentrations in Ap2s1+/L15 mice, but had no effect on the diminished AP2σ2-CaSR interaction in vitro. Thus, our studies have established a mouse model that is representative for FHH3 in humans, and demonstrated that the AP2S1 p.Arg15Leu mutation causes a predominantly calcitropic phenotype, which can be ameliorated by treatment with cinacalcet.

Climate affects neighbour-induced changes in leaf chemical defences and tree diversity-herbivory relationships.

Associational resistance theory predicts that insect herbivory decreases with increasing tree diversity in forest ecosystems. However, the generality of this effect and its underlying mechanisms are still debated, particularly since evidence has accumulated that climate may influence the direction and strength of the relationship between diversity and herbivory.We quantified insect leaf herbivory and leaf chemical defences (phenolic compounds) of silver birch Betula pendula in pure and mixed plots with different tree species composition across 12 tree diversity experiments in different climates. We investigated whether the effects of neighbouring tree species diversity on insect herbivory in birch, that is, associational effects, were dependent on the climatic context, and whether neighbour-induced changes in birch chemical defences were involved in associational resistance to insect herbivory.We showed that herbivory on birch decreased with tree species richness (i.e. associational resistance) in colder environments but that this relationship faded as mean annual temperature increased.Birch leaf chemical defences increased with tree species richness but decreased with the phylogenetic distinctiveness of birch from its neighbours, particularly in warmer and more humid environments.Herbivory was negatively correlated with leaf chemical defences, particularly when birch was associated with closely related species. The interactive effect of tree diversity and climate on herbivory was partially mediated by changes in leaf chemical defences.Our findings confirm that tree species diversity can modify the leaf chemistry of a focal species, hence its quality for herbivores. They further stress that such neighbour-induced changes are dependent on climate and that tree diversity effects on insect herbivory are partially mediated by these neighbour-induced changes in chemical defences.

Control of PTH secretion by the TRPC1 ion channel.

Familial hypocalciuric hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia, and, in some cases, inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in the gene encoding the Ca2+-sensing receptor (CaSR), a GPCR, and GNA11 encoding G protein subunit α 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels, mimicking human FHH. Ex vivo and in vitro studies revealed that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTGs) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacted with both the N- and C-termini of TRPC1 and enhanced CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR.

Activating Mutations of the G-protein Subunit α 11 Interdomain Interface Cause Autosomal Dominant Hypocalcemia Type 2.

CONTEXT: Autosomal dominant hypocalcemia types 1 and 2 (ADH1 and ADH2) are caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and its signaling partner, the G-protein subunit α 11 (Gα 11), respectively. More than 70 different gain-of-function CaSR mutations, but only 6 different gain-of-function Gα 11 mutations are reported to date. METHODS: We ascertained 2 additional ADH families and investigated them for CaSR and Gα 11 mutations. The effects of identified variants on CaSR signaling were evaluated by transiently transfecting wild-type (WT) and variant expression constructs into HEK293 cells stably expressing CaSR (HEK-CaSR), and measuring intracellular calcium (Ca2+i) and MAPK responses following stimulation with extracellular calcium (Ca2+e). RESULTS: CaSR variants were not found, but 2 novel heterozygous germline Gα 11 variants, p.Gly66Ser and p.Arg149His, were identified. Homology modeling of these revealed that the Gly66 and Arg149 residues are located at the interface between the Gα 11 helical and GTPase domains, which is involved in guanine nucleotide binding, and this is the site of 3 other reported ADH2 mutations. The Ca2+i and MAPK responses of cells expressing the variant Ser66 or His149 Gα 11 proteins were similar to WT cells at low Ca2+e, but significantly increased in a dose-dependent manner following Ca2+e stimulation, thereby indicating that the p.Gly66Ser and p.Arg149His variants represent pathogenic gain-of-function Gα 11 mutations. Treatment of Ser66- and His149-Gα 11 expressing cells with the CaSR negative allosteric modulator NPS 2143 normalized Ca2+i and MAPK responses. CONCLUSION: Two novel ADH2-causing mutations that highlight the Gα 11 interdomain interface as a hotspot for gain-of-function Gα 11 mutations have been identified.

Association of prolactin receptor (PRLR) variants with prolactinomas.

Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.

Large-scale exome datasets reveal a new class of adaptor-related protein complex 2 sigma subunit (AP2σ) mutations, located at the interface with the AP2 alpha subunit, that impair calcium-sensing receptor signalling.

Mutations of the sigma subunit of the heterotetrameric adaptor-related protein complex 2 (AP2σ) impair signalling of the calcium-sensing receptor (CaSR), and cause familial hypocalciuric hypercalcaemia type 3 (FHH3). To date, FHH3-associated AP2σ mutations have only been identified at one residue, Arg15. We hypothesized that additional rare AP2σ variants may also be associated with altered CaSR function and hypercalcaemia, and sought for these by analysing >111 995 exomes (>60 706 from ExAc and dbSNP, and 51 289 from the Geisinger Health System-Regeneron DiscovEHR dataset, which also contains clinical data). This identified 11 individuals to have 9 non-synonymous AP2σ variants (Arg3His, Arg15His (x3), Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu122Gly and Glu142Lys) with 3 of the 4 individuals who had Arg15His and Met117Ile AP2σ variants having mild hypercalcaemia, thereby indicating a prevalence of FHH3-associated AP2σ mutations of ∼7.8 per 100 000 individuals. Structural modelling of the novel eight AP2σ variants (Arg3His, Ala44Thr, Phe52Tyr, Arg61His, Thr112Met, Met117Ile, Glu122Gly and Glu142Lys) predicted that the Arg3His, Thr112Met, Glu122Gly and Glu142Lys AP2σ variants would disrupt polar contacts within the AP2σ subunit or affect the interface between the AP2σ and AP2α subunits. Functional analyses of all eight AP2σ variants in CaSR-expressing cells demonstrated that the Thr112Met, Met117Ile and Glu142Lys variants, located in the AP2σ α4-α5 helical region that forms an interface with AP2α, impaired CaSR-mediated intracellular calcium (Cai2+) signalling, consistent with a loss of function, and this was rectified by treatment with the CaSR positive allosteric modulator cinacalcet. Thus, our studies demonstrate another potential class of FHH3-causing AP2σ mutations located at the AP2σ-AP2α interface.

Hypercalcemic Disorders in Children.

Hypercalcemia is defined as a serum calcium concentration that is greater than two standard deviations above the normal mean, which in children may vary with age and sex, reflecting changes in the normal physiology at each developmental stage. Hypercalcemic disorders in children may present with hypotonia, poor feeding, vomiting, constipation, abdominal pain, lethargy, polyuria, dehydration, failure to thrive, and seizures. In severe cases renal failure, pancreatitis and reduced consciousness may also occur and older children and adolescents may present with psychiatric symptoms. The causes of hypercalcemia in children can be classified as parathyroid hormone (PTH)-dependent or PTH-independent, and may be congenital or acquired. PTH-independent hypercalcemia, ie, hypercalcemia associated with a suppressed PTH, is commoner in children than PTH-dependent hypercalcemia. Acquired causes of PTH-independent hypercalcemia in children include hypervitaminosis; granulomatous disorders, and endocrinopathies. Congenital syndromes associated with PTH-independent hypercalcemia include idiopathic infantile hypercalcemia (IIH), William's syndrome, and inborn errors of metabolism. PTH-dependent hypercalcemia is usually caused by parathyroid tumors, which may give rise to primary hyperparathyroidism (PHPT) or tertiary hyperparathyroidism, which usually arises in association with chronic renal failure and in the treatment of hypophosphatemic rickets. Acquired causes of PTH-dependent hypercalcemia in neonates include maternal hypocalcemia and extracorporeal membrane oxygenation. PHPT usually occurs as an isolated nonsyndromic and nonhereditary endocrinopathy, but may also occur as a hereditary hypercalcemic disorder such as familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated primary hyperparathyroidism, and less commonly, as part of inherited complex syndromic disorders such as multiple endocrine neoplasia (MEN). Advances in identifying the genetic causes have resulted in increased understanding of the underlying biological pathways and improvements in diagnosis. The management of symptomatic hypercalcemia includes interventions such as fluids, antiresorptive medications, and parathyroid surgery. This article presents a clinical, biochemical, and genetic approach to investigating the causes of pediatric hypercalcemia. © 2017 American Society for Bone and Mineral Research.

Treating prolactinomas with dopamine agonists: always worth the gamble?

Dopamine agonists are the treatment of choice for all patients with prolactinomas. They are generally safe, effective, and well-tolerated. However, a link between their use and the development of impulse control disorders has been well recognized in the field of neurology for some time, and evidence for a similar effect in endocrine patients is emerging. This has mainly been revealed through clinical case reports, plus a small number of comparative studies of varying robustness. We review the current available literature and discuss the implications for clinical practice, in particular emphasizing the need for clinicians to be alert to these uncommon but serious adverse effects.

Late neonatal presentation of reduced arm movement due to painful infective lymphadenopathy.

We report two cases of 21-day-old male infants, Baloo and Bagheera, both admitted with unilateral reduced arm movement secondary to painful lymphadenopathy, which is a presentation previously unreported in the paediatric literature. The only abnormal finding following investigations in both neonates was infective lymphadenopathy; we hypothesise that the inflamed lymph nodes were tender when the surrounding muscles, fascia or skin were moved, so that the infants learnt to reduce arm movement to minimise pain. This report explores the differential diagnoses for reduced arm movement in neonates, and highlights the importance of sepsis with painful lymphadenopathy as a differential diagnosis in neonates presenting with reduced arm movement.

Insulin dose adjustments with add-on glucagon-like peptide-1 receptor (GLP-1R) agonists in clinical practice.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining ground as therapeutic modalities in combination with insulin in patients with type 2 diabetes mellitus. Exploiting the multiple benefits of incretin-based therapies in certain patient populations, especially in those who would benefit most from potential weight loss or prevention of body weight gain, has provided a valuable add-on option in diabetes management. However, caution needs to be exercised when initiating such a double injectable therapy, as evidence indicates that, in most instances, the insulin dose needs to be re-adjusted. The majority of published studies suggest reduction of insulin dose, especially related to the 'bolus' component; however, some have also recommended that insulin dose should actually be increased, but we found no credible evidence to support the latter. An important determinant of the titration process is the insulin formulation already in use at baseline. As more potent and long-acting GLP-1RAs are introduced, optimal insulin dose scaling is a major challenge, especially in a primary setting. We provide an overview of the current knowledge in this rapidly changing field. Based on currently reported evidence, a reduction of basal insulin by 10% and a decrease of prandial insulin by 30 - 40% is recommended on addition of GLP-1RAs.

How does obesity affect fertility in men - and what are the treatment options?

Adiposity is associated with reduced fertility in men. The aetiology is multifactorial, with obese men at greater risk of suffering from impaired spermatogenesis, reduced circulating testosterone levels, erectile dysfunction and poor libido. The diagnosis and treatment of reduced fertility observed in obese men therefore requires insight into the underlying pathology, which has hormonal, mechanical and psychosocial aspects. This article summarises the current epidemiological, experimental and clinical trial evidence from the perspective of a practicing clinician. The following conclusions and recommendations can be drawn: Obesity is associated with low serum testosterone concentrations, but treatment with exogenous testosterone is likely to adversely impact on fertility. It is important to discuss this with men prior to initiation of testosterone therapy. Obesity adversely affects sperm concentration and may affect sperm quality. However, whether or not weight loss will correct these factors remain to be established. Oestrogen receptor modulators (and aromatase inhibitors) are unlicensed in the treatment for male hypogonadism and/or infertility. These treatments should hence be considered experimental approach until ongoing clinical trials report their outcomes.

Adrenal insufficiency in acute oral opiate therapy.

UNLABELLED: Opiate drugs such as morphine are in extensive use for pain relief and palliation. It is well established that these drugs can cause changes in endocrine function, but such effects are not always sufficiently appreciated in clinical practice, especially in relation to the hypothalamic-pituitary-adrenal (HPA) axis. Herein, we report on an 18-year-old man who was diagnosed with a slipped left femoral epiphysis following a long history of pain in his leg. On examination, he was thought to look relatively young for his age and therefore the orthopaedic surgeons arranged an endocrine assessment, which showed an undetectable concentration of serum cortisol and a suppressed concentration of testosterone; therefore, he was referred urgently with a diagnosis of hypopituitarism. We elicited a history that he had been treated with opiate analgesics for 3 days at the time of his original blood tests. Full endocrine assessment including a short Synacthen test revealed that he now had normal adrenal and pituitary function. We conclude that his morphine therapy had caused profound suppression of his HPA and pituitary-gonadal axes and suggest that clinicians should be aware of these significant changes in patients on even short-term opiate therapy. LEARNING POINTS: Therapy with opiates is the standard therapy for severe acute and chronic pain.Such drugs cause profound changes in endocrine function.Importantly, opiates suppress the HPA axis at a central level.Short-term therapy with morphine could be the cause of biochemical adrenocortical insufficiency.Morphine and related drugs also suppress the pituitary-gonadal axis.After discontinuation of therapy with such drugs, adrenal function improves.