Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of Vitamin D supplementation

Context: Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. Objective and methods: Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30–60 ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. Results: Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. Conclusion: Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23

Gold-catalysed Heck reaction: Fact or fiction? Correspondence on “Unlocking the Chain Walking Process in Gold Catalysis”

Two recent high-profile publications reported the formation of Heck-type arylated alkenes catalysed by MeDalPhosAuCl / AgOTf (J. Am. Chem. Soc. 2023, 145, 8810) and their cyclisation to tetralines (Angew. Chem. Int. Ed. 2023, e202312786). It was claimed that these were the first demonstrations in gold catalysis of alkene insertion into Au-aryl bonds, β-H elimination and chain-walking by Au-H dications. We show here that in fact this chemistry is a two-stage process. Only the first step, the production of an alkyl triflate ester as the primary organic product by the well-known alkene heteroarylation sequence, involves gold. The subsequent formation of Heck-type olefins and their cyclisation to tetralines represent classical H+-triggered carbocationic chemistry. These steps proceed in the absence of gold with identical results. Literature claims of new gold reactivity such as chain walking by the putative [LAuH]2+ dication have no basis in fact

Automated closed-loop insulin delivery for the management of type 1 diabetes during pregnancy: the AiDAPT RCT

Background: There are over 2000 pregnancies annually in women with type 1 diabetes in the UK. Despite recent improvements in diabetes technology, most women cannot achieve and maintain the recommended pregnancy glucose targets. Thus, one in two babies experience complications requiring neonatal care unit admission. Recent studies demonstrate that hybrid closed-loop therapy, in which algorithms adjust insulin delivery according to continuous glucose measurements, is effective for managing type 1 diabetes outside of pregnancy, but efficacy during pregnancy is unclear.   Objective: To examine the clinical efficacy of hybrid closed-loop compared to standard insulin therapy in pregnant women with type 1 diabetes.   Design: A multicentre, parallel-group, open-label, randomised, controlled trial in pregnant women with type 1 diabetes.   Setting: Nine antenatal diabetes clinics in England, Scotland and Northern Ireland.   Participants: Pregnant women with type 1 diabetes and above-target glucose levels, defined as glycated haemoglobin A1c of ≥ 48 mmol/mol (6.5%) in early pregnancy.   Interventions: A hybrid closed-loop system compared to standard insulin delivery (via insulin pump or multiple daily injections) with continuous glucose monitoring.   Outcome measures: The primary outcome is the difference between the intervention and control groups in percentage time spent in the pregnancy glucose target range (3.5–7.8 mmol/l) as measured by continuous glucose monitoring from 16 weeks’ gestation until delivery. Secondary outcomes include overnight time in range, time above range (> 7.8 mmol/l), glycated haemoglobin A1c, safety outcomes (diabetic ketoacidosis, severe hypoglycaemia, adverse device events), psychosocial functioning obstetric and neonatal outcomes.   Results: The percentage of time that maternal glucose levels were within target range was higher with closed-loop than standard insulin therapy: 68.2 ± 10.5 in closed-loop and 55.6 ± 12.5 in the control group (mean‑adjusted difference 10.5 percentage points, 95% confidence interval 7.0 to 14.0; p < 0.001). Results were consistent in secondary outcomes, with less time above range (−10.2%, 95% confidence interval −13.8 to −6.6%; p < 0.001), higher overnight time in range (12.3%, 95% confidence interval 8.3 to 16.2%; p < 0.001) and lower glycated haemoglobin A1c (−0.31%, 95% confidence interval −0.50 to −0.12%; p < 0.002) all favouring closed-loop. The treatment effect was apparent from early pregnancy and consistent across clinical sites, maternal glycated haemoglobin A1c categories and previous insulin regimen. Maternal glucose improvements were achieved with 3.7 kg less gestational weight gain and without additional hypoglycaemia or total daily insulin dose. There were no unanticipated safety problems (six vs. five severe hypoglycaemia cases, one diabetic ketoacidosis per group) and seven device-related adverse events associated with closed-loop. There were no between-group differences in patient-reported outcomes. There was one shoulder dystocia in the closed-loop group and four serious birth injuries, including one neonatal death in the standard care group.   Limitations: Our results cannot be extrapolated to closed-loop systems with higher glucose targets, and our sample size did not provide definitive data on maternal and neonatal outcomes.   Conclusions: Hybrid closed-loop therapy significantly improved maternal glycaemia during type 1 diabetes pregnancy. Our results support National Institute for Health and Care Excellence guideline recommendations that hybrid closed-loop therapy should be offered to all pregnant women with type 1 diabetes.   Future work: Future trials should examine the effectiveness of hybrid closed-loop started before pregnancy, or as soon as possible after pregnancy confirmation

An exact solution to the inverse problem of steady free-surface flow over topography

A simple exact solution is presented to the inverse problem in steady, two-dimensional idealised flow over topography that seeks the bottom profile given knowledge of the free-surface data. Attention is focused on the case when a uniform stream flows over a localised obstacle, although the solution is not restricted to this case. The inverse problem is formulated as a Stieltjes integral equation which is solved exactly using a Fourier transform. The solution requires the analytic continuation of two real functions representing the surface speed and the angle between the surface velocity vector and the horizontal. Some example surface profiles and their corresponding bottom topographies are discussed. Although the solution requires the prescription of the surface as a function of the velocity potential, it is shown to closely resemble the corresponding profile in physical space, even for quite large surface displacements, while significant discrepancy occurs at the bottom. Inference of the bottom profile from discrete surface data is accomplished by way of polynomial interpolation and rational approximation in the complex plane for the sample case of a hydraulic fall

Comprehensive geriatric assessment for people with both COPD and frailty starting pulmonary rehabilitation: a mixed-methods feasibility trial

Introduction Many people with COPD experience frailty. Frailty increases risk of poor health outcomes, including non-completion of pulmonary rehabilitation. Integrated approaches to support people with COPD and frailty throughout and following rehabilitation are indicated. The aim of the present study was to determine the feasibility of conducting a randomised controlled trial of integrating comprehensive geriatric assessment (CGA) for people with COPD and frailty starting pulmonary rehabilitation. Methods A multicentre mixed-methods randomised controlled feasibility trial (“Breathe Plus”; ISRCTN13051922) was carried out. People with COPD, aged ⩾50 years, Clinical Frailty Scale ⩾5 and referred for pulmonary rehabilitation were randomised 1:1 to usual pulmonary rehabilitation, or pulmonary rehabilitation plus CGA. Remote intervention delivery was used during COVID-19 restrictions. Outcomes (physical, psychosocial, service use) were measured at baseline, 90 and 180 days, alongside process data and qualitative interviews. Results Recruitment stopped at 31 participants (mean±SD age 72.4±10.1 years, 68% Medical Research Council Dyspnoea Scale 4–5), due to COVID-19-related disruptions. Recruitment (46% eligible recruited) and retention (87% at 90-and 180-day follow-up) were acceptable. CGAs occurred on average 60.5 days post-randomisation (range 8–129) and prompted 46 individual care recommendations (median 3 per participant, range 0–12), 65% of which were implemented during follow-up. The most common domains addressed during CGA were nutrition and cardiovascular health. Participants valued the holistic approach of CGA but questioned the optimal time to introduce it. Conclusion Integrating CGA alongside pulmonary rehabilitation is feasible and identifies unmet multidimensional need in people with COPD and frailty. Given challenges around timing and inclusivity, the integration of geriatric and respiratory care should not be limited to rehabilitation services

The effectiveness of psychological interventions for adults who set fires: A systematic review

Firesetting is an international public health concern with significant consequences for individuals and society. However, the adult firesetting literature is limited, especially for treatment provision. PsycINFO, EMBASE, MEDLINE Complete, PsycArticles, Web of Science, Scopus, ProQuest Central, and CINAHL were searched for peer-reviewed quantitative studies considering psychological interventions targeting deliberate firesetting in adults and subject to a narrative synthesis. Of the 4542 identified studies, 14 (n = 343 firesetters) met the broad inclusion criteria. Most studies comprised single-case or small-scale evaluations with highly selected samples, heterogeneous needs, and methodological limitations (e.g., lacking experimental control or reliable evaluation methods). Cognitive behaviour therapy (CBT) in a group format is currently the most evaluated intervention in UK secure living environments. High-quality studies showed that CBT group-based interventions improved firesetting-specific outcomes (i.e., problematic interest and associations with fire) and psychological vulnerabilities associated with firesetting (e.g., anger expression or offence-supporting attitudes) among prisoners and mental health inpatients. The paucity of high-quality evaluation studies and the considerable heterogeneity of the available study designs make it difficult to compare the existing interventions and draw reliable conclusions about what works for whom. Larger prospective longitudinal studies are needed internationally with multi-site designs, follow-up recidivism data in the community, and control groups to determine whether these interventions can effectively reduce firesetting risk

Doing research in non-specialist mental health services for children and young people: lessons learnt from a process evaluation of the ICALM (Interpersonal Counselling for Adolescent Low Mood) feasibility randomised controlled trial

Background: The rising prevalence of adolescent mild depression in the UK and the paucity of evidence-based interventions in non-specialist sectors where most cases present, creates an urgent need for early psychological interventions. Randomised controlled trials (RCTs) are considered the gold standard for obtaining unbiased estimates of intervention effectiveness. However, the complexity of mental health settings poses great challenges for effectiveness evaluations. This paper reports learning from an embedded process evaluation of the ICALM RCT which tested the feasibility of delivering Interpersonal Counselling for Adolescents (IPC-A) plus Treatment as Usual (TAU) versus TAU only for adolescent (age 12–18) mild depression by non-qualified mental health professionals in non-specialist sectors. Methods: A qualitative mixed methods process evaluation, drawing on Bronfenbrenner’s socioecological model to investigate key influences on trial delivery across macro-(e.g. policy), meso-(e.g. service characteristics) and micro-(e.g. on-site trial processes) contextual levels. Data collection methods included 9 site questionnaires, 4 observations of team meetings, policy documents, and 18 interviews with stakeholders including therapists, heads of service and managers. Thematic analysis focused on understanding how contextual features shaped trial implementation. Results: The ICALM trial concluded in 2022 having only randomised 14 out of the target 60 young people. At a macro-level, trial delivery was impacted by the COVID-19 pandemic, with services reporting a sharp increase in cases of (social) anxiety over low mood, and backlogs at central referral points which prolonged waiting times for mild cases (e.g. low mood). An interaction between high demand and lack of capacity at a meso-service level led to low prioritisation of trial activities at a micro-level. Unfamiliarity with research processes (e.g. randomisation) and variation in TAU support also accentuated the complexities of conducting an RCT in this setting. Conclusions: Conducting a RCT of IPC-A in non-specialist services is not feasible in the current context. Failure to conduct effectiveness trials in this setting has clinical implications, potentially resulting in escalation of mild mental health problems. Research done in this setting should adopt pragmatic and innovative recruitment and engagement approaches (e.g. creating new referral pathways) and consider alternative trial designs, e.g. cluster, stepped-wedge or non-controlled studies using complex systems approaches to embrace contextual complexity