The Growth Hormone Deficiency (GHD) Reversal Trial: effect on final height of discontinuation versus continuation of growth hormone treatment in pubertal children with isolated GHD—a non-inferiority Randomised Controlled Trial (RCT)

Background: Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. // Methods/design: Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH < 6.7 mcg/L) whose deficiency has reversed on early re-testing. Children will be randomised to either continue or discontinue GH therapy. This phase III, international, multicentre, open-label, randomised controlled, non-inferiority trial (including an internal pilot study) will assess whether children with early I-GHD reversal who stop GH therapy achieve non-inferior near FH SDS (primary outcome; inferiority margin 0.55 SD), target height (TH) minus near FH, HRQoL, bone health index and lipid profiles (secondary outcomes) than those continuing GH. In addition, the study will assess cost-effectiveness of GH discontinuation in the early retesting scenario. // Discussion: If this study shows that a significant proportion of children with presumed I-GHD reversal generate enough GH naturally in puberty to achieve a near FH within the target range, then this new care pathway would rapidly improve national/international practice. An assumed 50% reversal rate would provide potential UK health service cost savings of £1.8–4.6 million (€2.05–5.24 million)/year in drug costs alone. This new care pathway would also prevent children from having unnecessary daily GH injections and consequent exposure to potential adverse effects. // Trial registration: EudraCT number: 2020-001006-3

Assessing the efficacy, safety and utility of closed-loop insulin delivery compared with sensor-augmented pump therapy in very young children with type 1 diabetes (KidsAP02 study): an open-label, multicentre, multinational, randomised cross-over study protocol

Introduction: Diabetes management in very young children remains challenging. Glycaemic targets are achieved at the expense of high parental diabetes management burden and frequent hypoglycaemia, impacting quality of life for the whole family. Our objective is to assess whether automated insulin delivery can improve glycaemic control and alleviate the burden of diabetes management in this particular age group. Methods and analysis: The study adopts an open-label, multinational, multicentre, randomised, crossover design and aims to randomise 72 children aged 1-7 years with type 1 diabetes on insulin pump therapy. Following screening, participants will receive training on study insulin pump and study continuous glucose monitoring devices. Participants will be randomised to 16-week use of the hybrid closed-loop system (intervention period) or to 16-week use of sensor-augmented pump therapy (control period) with 1-4 weeks washout period before crossing over to the other arm. The order of the two study periods will be random. The primary endpoint is the between-group difference in time spent in the target glucose range from 3.9 to 10.0 mmol/L based on sensor glucose readings during the 16-week study periods. Analyses will be conducted on an intention-to-treat basis. Key secondary endpoints are between group differences in time spent above and below target glucose range, glycated haemoglobin and average sensor glucose. Participants' and caregivers' experiences will be evaluated using questionnaires and qualitative interviews, and sleep quality will be assessed. A health economic analysis will be performed. Ethics and dissemination: Ethics approval has been obtained from Cambridge East Research Ethics Committee (UK), Ethics Committees of the University of Innsbruck, the University of Vienna and the University of Graz (Austria), Ethics Committee of the Medical Faculty of the University of Leipzig (Germany) and Comité National d'Ethique de Recherche (Luxembourg). The results will be disseminated by peer-reviewed publications and conference presentations

Hypoglycaemia in older people with dementia and diabetes

Objective To explore the effect of hypoglycaemia on adverse events in older people with diabetes and dementia and determine the feasibility of using continuous glucose monitoring in this patient group. Methods Systematic review on continuous glucose monitoring in older people with diabetes: Hypothesis-generating systematic review to inform my feasibility study and to identify gaps in the evidence. Feasibility study: I conducted a feasibility study of continuous blood glucose monitoring to explore continuous glucose monitoring in older people with diabetes and memory problems. Pharmacoepidemiological study: Retrospective cohort study using the Clinical Research Practice Datalink database to test the effect of exposure to hypoglycaemia in older patients with dementia. Systematic review and meta-analysis on the associations between hypoglycaemia and adverse events in older people treated with glucose-lowering agents: Updated systematic review and meta-analysis of serious adverse events associated with hypoglycaemia in older patients treated with glucose-lowering agents. Findings Systematic review on continuous glucose monitoring in older people with diabetes: 9 studies were included with a total of nearly 1000 patients. Hypoglycaemic episodes occurred in a sizeable proportion and most of these episodes were asymptomatic. Some patients spent nearly 2 hours per day in the hypoglycaemic range. CGM is acceptable to patients and improved health-related well-being. Feasibility study: 12 participants completed the study and found using CGM device acceptable. Data capture with this device varied considerably (3%-92%). The device captured hypoglycaemic episodes in 6 participants, two of which lasted for over 300 minutes. Pharmacoepidemiological study: Older people with dementia and diabetes who have had a hypoglycaemic event are at substantially higher risk of death, cardiovascular events, falls, fractures and emergency department attendances, than those who have not had a hypoglycaemic event. Systematic review and meta-analysis on the associations between hypoglycaemia and adverse events in older people treated with glucose-lowering agents: 42 included studies with over 2 million patients. Hypoglycaemia is associated with an 80% increased risk in vascular complications, a doubling in risk of all-cause mortality, a 55% increased risk in dementia, and a 78% and 68% increased risk in falls and fractures respectively. Conclusions My research has highlighted the complications associated with hypoglycaemia in older people with diabetes and dementia and set the ground work for future studies using continuous glucose monitoring in this patient group

Evaluating Risks from Antibacterial Medication Therapy

ABSTRACT EVALUATING RISKS FROM ANTIBACTERIAL MEDICATION THERAPY USING AN OBSERVATIONAL PRIMARY CARE DATABASE Sharon B. Meropol Joshua P. Metlay Virtually everyone in the U.S. is exposed to antibacterial drugs at some point in their lives. It is important to understand the benefits and risks related to these medications with nearly universal public exposure. Most information on antibacterial drug-associated adverse events comes from spontaneous reports. Without an unexposed control group, it is impossible to know the real risks for treated vs. untreated patients. We used an electronic medical record database to select a cohort of office visits for non-bacterial acute respiratory tract infections (excluding patients with pneumonia, sinusitis, or acute exacerbations of chronic bronchitis), and compared outcomes of antibacterial drug-exposed vs. -unexposed patients. By limiting our assessment to visits with acute nonspecific respiratory infections, we promoted comparability between exposed and unexposed patients. To further control for confounding by indication and practice, we explored methods to promote further comparability between exposure groups. Our rare outcome presented an additional analytic challenge. Antibacterial drug prescribing for acute nonspecific respiratory infections decreased over the study period, but, in contrast to the U.S., broad spectrum antibacterial prescribing remained low. Conditional fixed effects linear regression provided stable estimates of exposure effects on rare outcomes; results were similar to those using more traditional methods for binary outcomes. Patients with acute nonspecific respiratory infections treated with antibacterial drugs were not at increased risk of severe adverse events compared to untreated patients. Patients with acute nonspecific respiratory infections exposed to antibacterials had a small decreased risk of pneumonia hospitalizations vs. unexposed patients. This very small measurable benefit of antibacterial drug therapy for acute nonspecific respiratory infections at the patient level must be weighed against the public health risk of emerging antibacterial resistance. Our data provide valuable point estimates of risks and benefits that can be used to inform future decision analysis and guideline recommendations for patients with acute nonspecific respiratory infections. Ultimately, improved point-of-care diagnostic testing may help direct antibacterial drugs to the subset of patients most likely to derive benefit

Sex Differences in Cardiovascular Outcomes of Older Adults After Myocardial Infarction

Background Evidence on the impact of sex on prognoses after myocardial infarction (MI) among older adults is limited. We evaluated sex differences in long-term cardiovascular outcomes after MI in older adults. Methods and Results All patients with MI >= 70 years admitted to 20 Finnish hospitals during a 10-year period and discharged alive were studied retrospectively using a combination of national registries (n=31 578, 51% men, mean age 79). The primary outcome was combined major adverse cardiovascular event within 10-year follow-up. Sex differences in baseline features were equalized using inverse probability weighting adjustment. Women were older, with different comorbidity profiles and rarer ST-segment-elevation MI and revascularization, compared with men. Adenosine diphosphate inhibitors, anticoagulation, statins, and high-dose statins were more frequently used by men, and renin-angiotensin-aldosterone inhibitors and beta blockers by women. After balancing these differences by inverse probability weighting, the cumulative 10-year incidence of major adverse cardiovascular events was 67.7% in men, 62.0% in women (hazard ratio [HR], 1.17; CI, 1.13-1.21; P= 80 years. Conclusions Older men had higher long-term risk of major adverse cardiovascular events after MI, compared with older women with similar baseline features and evidence-based medications. Our results highlight the importance of accounting for confounding factors when studying sex differences in cardiovascular outcomes.Peer reviewe

The political economy of co-ordination challenges in the National Health Service: a postpositivist evaluation of diabetes policy and governance

The present PhD thesis develops and applies an evaluative methodology suited to the evaluation of policy and governance in complex policy areas. While extensive literatures exist on the topic of policy evaluation, governance evaluation has received less attention. At the level of governance, policymakers confront choices between different policy tools and governance arrangements in their attempts to solve policy problems, including variants of hierarchy, networks and markets. There is a need for theoretically-informed empirical research to inform decision-making at this level. To that end, the PhD develops an approach to evaluation by combining postpositivist policy analysis with heterodox political economy. Postpositivist policy analysis recognises that policy problems are often contested, that choices between policy options can involve significant trade-offs and that knowledge of policy options is itself dispersed and fragmented. Similarly, heterodox economics combines a concept of incommensurable values with an appreciation of the strengths and weaknesses of different institutional arrangements to realise them. A central concept of the field is coordination, which orientates policy analysis to the interactions of stakeholders in policy processes. The challenge of governance is to select the appropriate policy tools and arrangements which facilitate coordination. Via a postpositivist exploration of stakeholder ‘frames’, it is possible to ascertain whether coordination is occurring and to identify problems if it is not. Evaluative claims of governance can be made where arrangements can be shown to frustrate the realisation of shared values and objectives. The research makes a contribution to knowledge in a number of ways a) a distinctive evaluative approach that could be applied to other areas of health and public policy b) greater appreciation of the strengths and weaknesses of different forms of evidence in public policy and in particular health policy and c) concrete policy proposals for the governance and organisation of diabetes services, with implications for the NHS more broadly

The association between cardiac drug therapy and anxiety among cardiac patients:results from the national DenHeart survey

BACKGROUND: Neuropsychiatric side effects of cardiac drugs such as nervousness, mood swings and agitation may be misinterpreted as symptoms of anxiety. Anxiety in cardiac patients is highly prevalent and associated with poor outcomes, thus an accurate identification is essential. The objectives were to: (I) describe the possible neuropsychiatric side effects of common cardiac drug therapies, (II) describe the use of cardiac drug therapy in cardiac patients with self-reported symptoms of anxiety compared to those with no symptoms of anxiety, and (III) investigate the association between the use of cardiac drug therapy and self-reported symptoms of anxiety. METHODS: DenHeart is a large national cross-sectional survey combined with national register data. Symptoms of anxiety were measured by the Hospital Anxiety and Depression Scale (HADS-A) on patients with ischemic heart disease, arrhythmia, heart failure and heart valve disease. Side effects were obtained from ‘product summaries’, and data on redeemed prescriptions obtained from the Danish National Prescription Registry. Multivariate logistic regression analyses explored the association between cardiac drug therapies and symptoms of anxiety (HADS-A ≥ 8). RESULTS: Among 8998 respondents 2891 (32%) reported symptoms of anxiety (HADS-A ≥ 8). Neuropsychiatric side effects were reported from digoxin, antiarrhythmics, beta-blockers, ACE-inhibitors and angiotensin receptor antagonists. Statistically significant higher odds of reporting HADS ≥ 8 was found in users of diuretics, lipid-lowering agents, nitrates, antiarrhythmics and beta-blockers compared to patients with no prescription. CONCLUSION: Some cardiac drugs were associated with self-reported symptoms of anxiety among patients with cardiac disease. Of these drugs neuropsychiatric side effects were only reported for antiarrhythmics and beta-blockers. Increased awareness about the possible adverse effects from these drugs are important. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12872-022-02724-4