Management aspects of congenital adrenal hyperplasia during adolescence and transition to adult care

The adolescent period is characterised by fundamental hormonal changes, which affect sex steroid production, cortisol metabolism and insulin sensitivity. These physiological changes have a significant impact on patients with congenital adrenal hyperplasia (CAH). An essential treatment aim across the lifespan in patients with CAH is to replace glucocorticoids sufficiently to avoid excess adrenal androgen production but equally to avoid cardiometabolic risks associated with excess glucocorticoid intake. The changes to the hormonal milieu at puberty, combined with poor adherence to medical therapy, often result in unsatisfactory control exacerbating androgen excess and increasing the risk of metabolic complications due to steroid over‐replacement. With the physical and cognitive maturation of the adolescent with CAH, fertility issues and sexual function become a new focus of patient care in the paediatric clinic. This requires close surveillance for gonadal dysfunction, such as irregular periods/hirsutism or genital surgery‐associated symptoms in girls and central hypogonadism or testicular adrenal rest tumours in boys. To ensure good health outcomes across the lifespan, the transition process from paediatric to adult care of patients with CAH must be planned carefully and early from the beginning of adolescence, spanning over many years into young adulthood. Its key aims are to empower the young person through education with full disclosure of their medical history, to ensure appropriate follow‐up with experienced physicians and facilitate access to multispecialist teams addressing the complex needs of patients with CAH

Induction of the nicotinamide riboside kinase NAD⁺ salvage pathway in a model of sarcoplasmic reticulum dysfunction

Background Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11 beta-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. Methods We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD(+) precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. Results H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD(+) biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD(+) biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD(+) levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD(+)/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD(+) availability. Conclusions These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD(+) salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved

Causes, patterns and severity of androgen excess in 487 consecutively recruited pre- and post-pubertal children

Objective Androgen excess in childhood is a common presentation and may signify sinister underlying pathology. Data describing its patterns and severity are scarce, limiting the information available for clinical decision processes. Here, we examined the differential diagnostic value of serum DHEAS, androstenedione (A4) and testosterone in childhood androgen excess. Design Retrospective review of all children undergoing serum androgen measurement at a single center over 5 years. Methods Serum A4 and testosterone were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased androgen underwent phenotyping by clinical notes review. Results In 487 children with simultaneous DHEAS, A4 and testosterone measurements, we identified 199 with androgen excess (140 pre- and 59 post-pubertal). Premature adrenarche (PA) was the most common pre-pubertal diagnosis (61%), characterized by DHEAS excess in 85%, while A4 and testosterone were only increased in 26 and 9% respectively. PCOS was diagnosed in 40% of post-pubertal subjects, presenting equally frequent with isolated excess of DHEAS (29%) or testosterone (25%) or increases in both A4 and testosterone (25%). CAH patients (6%) predominantly had A4 excess (86%); testosterone and DHEAS were increased in 50 and 33% respectively. Concentrations increased above the two-fold upper limit of normal were mostly observed in PA for serum DHEAS (&gt;20-fold in the single case of adrenocortical carcinoma) and in CAH for serum androstenedione. Conclusions Patterns and severity of childhood androgen excess provide pointers to the underlying diagnosis and can be used to guide further investigations.</p

Service evaluation suggests variation in clinical care provision in adults with congenital adrenal hyperplasia in the UK and Ireland

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

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Selection and Application of Beam Pumping Unit for Heavy Oil Production

Beam pumping units were among the first and are still among the most widely used artificial lift systems. This study investigates the components of beam pumping units and the manufacturing mechanism and design procedure recommended by Recommended Practice and the QRod simulator. The API provides API RP 11L Recommended Practice to obtain the values and operating characteristics for each component in dimensionless form. A trial-and-error method is used during the design procedures to determine the best surface and subsurface equipment for a given well's data. When completing a well, the artificial lift method must be considered to ensure that the well is able to be produced at a satisfactory rate. Besides, the procedures created nine cases to compare the requirements of different production rates and depths for a heavy oil well with 14 APIs. A depth of 5,000 ft with a rate of 300 bbl/day and a depth of 7,000 ft with a rate of 500 bbl/day is the specific production rate and depths at which the well will produce. For 300 BBL/Day the tubing size selected was 2-7/8” OD, for this size the suitable plunger size is 2”, and the suitable stroke length was 74in. In cases 6, 8, and 9, all the simulated rod strings were unable to handle the stress imposed by the combination of high depth and high production rate. As a result, all designed systems will fail during production

The effects of somatostatin analogues on glycaemia in the treatment of neuroendocrine tumours.

Long-acting somatostatin analogues (SSAs) are the most commonly used drugs in the management of neuroendocrine tumours (NETs) because of their ability to control symptoms and prolong survival. SSA use is associated with changes in glucose metabolism. However, the impacts on glycaemic control and body mass index (BMI) caused by SSAs in NETs are largely unknown. In the present study, we evaluated the effects of SSA treatment on BMI and glycated haemoglobin (HbA1c) in our cohort of patients with NETs. We also assessed changes in glycaemic control and BMI before and after SSA treatment. In addition, we assessed the incidence of new diabetes or whether there was worsening of glycaemic control for patients with pre-existing diabetes. The study comprised a retrospective study of 279 patients with NETs who were treated with SSAs between January 2014 and January 2019. Glycaemic control was assessed by measuring changes in Hba1c. A number needed to harm analysis was used to look at new cases of diabetes within the study population. Treatment with SSAs was associated with a mean increase in HbA1c of 3.35 ± 6.30 mmol mol despite a mean decrease in BMI of -1.04 ± 2.79 kg m . There were 19 new cases of type 2 diabetes mellitus (T2DM) in the population of 209 with a number needed to harm of 12.5. Of the 34 patients with pre-existing T2DM, five had worsening of their mean HbA1c. Treatment with SSAs for NETs is associated with an increase in HbA1c, despite a reduction in BMI and, importantly, a risk of developing T2DM with a number needed to harm of 12.5. This project was registered with the National Health Service Clinical Audit and Registries. It has a CARMS number - 17666

The effect of short-term exercise prehabilitation on skeletal muscle protein synthesis and atrophy during bed rest in older men.

BACKGROUND Poor recovery from periods of disuse accelerates age-related muscle loss, predisposing individuals to the development of secondary adverse health outcomes. Exercise prior to disuse (prehabilitation) may prevent muscle deterioration during subsequent unloading. The present study aimed to investigate the effect of short-term resistance exercise training (RET) prehabilitation on muscle morphology and regulatory mechanisms during 5 days of bed rest in older men. METHODS Ten healthy older men aged 65-80 years underwent four bouts of high-volume unilateral leg RET over 7 days prior to 5 days of inpatient bed rest. Physical activity and step-count were monitored over the course of RET prehabilitation and bed rest, whilst dietary intake was recorded throughout. Prior to and following bed rest, quadriceps cross-sectional area (CSA), and hormone/lipid profiles were determined. Serial muscle biopsies and dual-stable isotope tracers were used to determine integrated myofibrillar protein synthesis (iMyoPS) over RET prehabilitation and bed rest phases, and acute postabsorptive and postprandial myofibrillar protein synthesis (aMyoPS) rates at the end of bed rest. RESULTS During bed rest, daily step-count and light and moderate physical activity time decreased, whilst sedentary time increased when compared with habitual levels (P < 0.001 for all). Dietary protein and fibre intake during bed rest were lower than habitual values (P < 0.01 for both). iMyoPS rates were significantly greater in the exercised leg (EX) compared with the non-exercised control leg (CTL) over prehabilitation (1.76 ± 0.37%/day vs. 1.36 ± 0.18%/day, respectively; P = 0.007). iMyoPS rates decreased similarly in EX and CTL during bed rest (CTL, 1.07 ± 0.22%/day; EX, 1.30 ± 0.38%/day; P = 0.037 and 0.002, respectively). Postprandial aMyoPS rates increased above postabsorptive values in EX only (P = 0.018), with no difference in delta postprandial aMyoPS stimulation between legs. Quadriceps CSA at 40%, 60%, and 80% of muscle length decreased significantly in EX and CTL over bed rest (0.69%, 3.5%, and 2.8%, respectively; P < 0.01 for all), with no differences between legs. No differences in fibre-type CSA were observed between legs or with bed rest. Plasma insulin and serum lipids did not change with bed rest. CONCLUSIONS Short-term resistance exercise prehabilitation augmented iMyoPS rates in older men but did not offset the relative decline in iMyoPS and muscle mass during bed rest