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Abstract Context Standard glucocorticoid therapy in congenital adrenal hyperplasia (CAH) regularly fails to control androgen excess, causing glucocorticoid overexposure and poor health outcomes. Objective We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control. Methods A 6-month, randomized, phase 3 study was conducted of MR-HC vs standard glucocorticoid, followed by a single-arm MR-HC extension study. Primary outcomes were change in 24-hour SD score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase 3, and efficacy, safety and tolerability of MR-HC for the extension study. Results The phase 3 study recruited 122 adult CAH patients. Although the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P = .007) and 12 (P = .019) weeks, and between 07:00h to 15:00h (P = .044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (< 1200 ng/dL) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P = .002), and 80% for MR-HC at 18 months’ extension. The median daily hydrocortisone dose was 25 mg at baseline, at 6 months 31 mg for standard therapy, and 30 mg for MR-HC, and after 18 months 20 mg MR-HC. Three adrenal crises occurred in phase 3, none on MR-HC and 4 in the extension study. MR-HC resulted in patient-reported benefit including menses restoration in 8 patients (1 on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy). Conclusion MR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

BackgroundGermline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers.MethodsA retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.ResultsTumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).ConclusionsOverall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

Catecholamines (epinephrine and norepinephrine) are synthesised and produced by the adrenal medulla and postganglionic nerve fibres of the sympathetic nervous system. It is known that essential hypertension has a significant neurogenic component, with the rise in blood pressure mediated at least in part by overactivity of the sympathetic nervous system. Moreover, novel therapeutic strategies aimed at reducing sympathetic activity show promise in the treatment of hypertension. This article reviews recent advances within this rapidly changing field, particularly focusing on the role of genetic polymorphisms within key catecholamine biosynthetic enzymes, cofactors, and storage molecules. In addition, mechanisms linking the sympathetic nervous system and other adverse cardiovascular states (obesity, insulin resistance, dyslipidaemia) are discussed, along with speculation as to how recent scientific advances may lead to the emergence of novel antihypertensive treatments.

Aims/hypothesis The euglycaemic–hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC. Methods We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained ( R 2 ). Results A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R 2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R 2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R 2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R 2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R 2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R 2 0.444 [0.391, 0.497]; ULSAM to RISC R 2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2. Conclusions/interpretation A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences. Graphical Abstract

BackgroundStandard glucocorticoid therapy in congenital adrenal hyperplasia regularly fails to control androgen excess, causing glucocorticoid over-exposure and poor health outcomes. We investigated whether modified-release hydrocortisone (MR-HC), which mimics physiologic cortisol secretion, could improve disease control.Methods6-month randomized phase III study, MR-HC versus standard glucocorticoid, followed by single-arm MR-HC extension study. Primary outcomes were change in 24-hour standard deviation score (SDS) of androgen precursor 17-hydroxyprogesterone (17OHP) for phase III, and efficacy, safety and tolerability of MR-HC for the extension study.ResultsThe phase III study recruited 122 adult CAH patients. While the study failed its primary outcome at 6 months, there was evidence of better biochemical control on MR-HC, with lower 17OHP SDS at 4 (P=0.007) and 12 (P=0.019) weeks, and between 07:00h to 15:00h (P=0.044) at 6 months. The percentage of patients with controlled 09:00h serum 17OHP (<1200 ng/dl) was 52% at baseline, at 6 months 91% for MR-HC and 71% for standard therapy (P=0.002), and 80% for MR-HC at 18 months extension. The median daily hydrocortisone dose was 25mg at baseline, at 6 months 31mg for standard therapy and 30mg for MR-HC, and after 18 months 20mg MR-HC. Three adrenal crises occurred in phase III, none on MR-HC and 4 in extension study. MR-HC resulted in patient-reported benefit including menses restoration in eight patients (one on standard therapy), and 3 patient and 4 partner pregnancies (none on standard therapy).ConclusionMR-HC improved biochemical disease control in adults with reduction in steroid dose over time and patient-reported benefit.

Background Prednisolone and prednisone have a longer plasma elimination half-life after oral administration than hydrocortisone: 2.1 to 3.5 vs ∼1.5hrs1,2. For this reason, prednis(ol)one has been used in Congenital Adrenal Hyperplasia (CAH) by giving a dose in the evening to try to prevent the overnight rise in adrenal androgens. Modified-release hydrocortisone (MRHC) capsules, (Efmody, Diurnal Ltd, Cardiff UK), replicate the cortisol diurnal rhythm and improve the control of CAH compared to standard glucocorticoid therapy3. This post-hoc sub-analysis examines CAH control in MRHC treated patients switched from prednis(ol)one. Methods We reviewed the data of all patients taking prednis(ol)one in the randomised study of standard treatment versus MRHC3: 39 classic CAH patients on prednis(ol)one (alone or combined with hydrocortisone) (36 prednisolone; 3 prednisone) were randomised either to continue prednis(ol)one or switched to MRHC at the same hydrocortisone dose equivalent (HDE=prednisolone dose x5). Patients were assessed after 4 weeks following which blinded dose titration according to 17OHP and A4 control was performed to bring 17OHP into the optimal range (<36 nmol/l) and A4 into the reference range. After 24 weeks, 31 patients from the prednis(ol)one prior therapy group participated in an ongoing MHRC single arm extension study with 28 patients completing 18 months follow up. Control of CAH was defined as a 0900h 17OHP <36 nmol/l. Results Median baseline dose (HDE) was 30mg (n=39), androgen control was 56%. In patients randomised to MRHC (n=18), 39% were controlled at baseline and 94% at 4 weeks without dose adjustment. At 24 weeks, after androgen-control guided titration, the HDE dose in the prednis(ol)one group was 34mg, and in the MRHC group 27.5mg, with control being 71% and 94%, respectively. Percentage inhibition of 9am 17OHP from the levels at baseline to that at 24 weeks in the prednis(ol)one group was 32% and in the MRHC group 91%. In this study period there were no adrenal crises in the MRHC group and one in the prednis(ol)one group. MRHC-treated patients in the extension study were further titrated according to clinician assessment, at interim analysis the median MRHC dose was 20mg (median reduction 10mg) and 82% of patients were controlled at 18 months (n=28). In the ongoing extension study of all patients on MRHC (221 patient years), there were 12 adrenal crises in 5 patients (5.4/100 patient years). Conclusions Control of CAH is better on MRHC than prednisolone: 94% vs 39%; and the dose of MRHC can be down titrated to an adrenal replacement dose whilst maintaining control in the majority (82%) of patients. References 1. Pickup ME. Clin Pharmacokinet 1979 4 111-128; 2. Toothaker RD. J Pharm Sci 1982 71 573-576; 3. Merke DP. JCEM 2021 106 e2063-e2077. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

With composite materials becoming increasingly desirable across a wide range of industries due to their high strength to weight ratios and ability to be designed to accommodate specific applications, the need to understand their complex behavior is paramount. These plates often exhibit highly nonlinear and coupled behavior, especially for cases of large deflections, necessitating nonlinear analysis to properly predict the response of the structure. Numerical solutions such as the finite element and finite difference methods are commonly employed to model nonlinear analysis, however these methods have several drawbacks. Numerical solutions estimate solutions at discrete points, resulting in discontinuities between elements depending on the interpolation functions assumed. Moreover, numerical methods cannot provide relationships between the various parameters used in analysis without extensive effort. Purely symbolic analytical solutions are preferred, but expressions for nonlinear analysis only exist for limited situations. It is possible to obtain purely symbolic analytical expressions with the aid of a mathematical method known as Groebner bases. The primary objective of this thesis is to obtain purely symbolic analytical expressions for rectangular composite plates subjected to a uniformly distributed load that are resting on a Pasternak model soil foundation. A limited amount of literature is available for the Pasternak model, especially for problems involving geometrically nonlinear analysis. This thesis also explores the application of Groebner bases as an aid to solve structural mechanics problems with the hope that it will be applied in other fields of engineering. In the present study, the governing integro-(partial) differential equation was derived using the principle of minimum potential energy. Approximate solutions were assumed based on the Ritz method of approximation for both fully clamped and simply supported boundary conditions. The variational principle was then applied to produce a system of coupled nonlinear multivariate polynomial equations with unknown constant coefficients. Maple 2016 was used to compute the reduced Groebner basis for the system of polynomial equations and then used to symbolically solve for the unknown coefficients. Expressions for deflection were generated for symmetric cross-ply, angle-ply, and quasi-isotropic composite plates. These results were then compared to numerical solutions obtained from the commercial finite element analysis software ANSYS and showed very good agreement. As a result, the deflection expressions can be used to find continuous functions for internal stresses, shear forces, and moments in the plate as well. The results of the current study have shown that the application of Groebner bases provides a valuable alternative to numerical methods, thereby providing incentive for its implementation in other fields of engineering application.

One such new therapy is recombinant parathyroid hormone (PTH). Early studies of daily subcutaneous administration of PTH demonstrated an anabolic effect on bone, with particular improvements in vertebral bone mineral density (BMD). In a comparison of the effect of PTH in combination with hormone replacement therapy (HRT) versus HRT alone over a three-year period, improvements in BMD and reductions in vertebral fracture were observed, even one year after discontinuation of PTH.6

The layered-ruthenate family of materials possess an intricate interplay of structural, electronic and magnetic degrees of freedom that yields a plethora of delicately balanced ground states. This is exemplified by Ca 3 Ru 2 O 7 , which hosts a coupled transition in which the lattice parameters jump, the Fermi surface partially gaps and the spins undergo a 90 ∘ in-plane reorientation. Here, we show how the transition is driven by a lattice strain that tunes the electronic bandwidth. We apply uniaxial stress to single crystals of Ca 3 Ru 2 O 7 , using neutron and resonant x-ray scattering to simultaneously probe the structural and magnetic responses. These measurements demonstrate that the transition can be driven by externally induced strain, stimulating the development of a theoretical model in which an internal strain is generated self-consistently to lower the electronic energy. We understand the strain to act by modifying tilts and rotations of the RuO 6 octahedra, which directly influences the nearest-neighbour hopping. Our results offer a blueprint for uncovering the driving force behind coupled phase transitions, as well as a route to controlling them. Ca 3 Ru 2 O 7 is a layered ruthenate, which undergoes a spin-reorientation transition where the spins rotate 90 degrees between two anti-ferromagnetic states. Despite extensive study, the driver of this transition has proved elusive. Here, using neutron and resonant x-ray scattering, Dashwood et al. show that this transition is driven by lattice strain.