Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

Consensus Guidance for Monitoring Individuals With Islet Autoantibody-Positive Pre-Stage 3 Type 1 Diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programs are being increasingly emphasized. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk for (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in nonspecialized settings. To inform this monitoring, JDRF, in conjunction with international experts and societies, developed consensus guidance. Broad advice from this guidance includes the following: 1) partnerships should be fostered between endocrinologists and primary care providers to care for people who are IAb+; 2) when people who are IAb+ are initially identified, there is a need for confirmation using a second sample; 3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; 4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; 5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and 6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasizes significant unmet needs for further research on early-stage type 1 diabetes to increase the rigor of future recommendations and inform clinical care.

The effect of diabetes management on the workload of district and community nursing teams in the UK.

AIMS: The number of older people with diabetes requiring care from district nursing teams is increasing. The role of district nursing teams in diabetes management has expanded to involve diagnosis, treatment and medication administration. As the complexity of caseloads increases, the current model is likely unsustainable. This study aims to understand the current diabetes workload of district nursing teams. METHODS: An online survey was distributed via social media and key stakeholder networks to district nursing teams. Survey items were designed by the researchers prior to pilot testing with potential participants. Descriptive statistical and qualitative analyses were conducted. Data are median ± IQR. RESULTS: 159 district nursing teams completed the survey. The median caseload per team was 300 (IQR 176-407) patients including 21 with diabetes (IQR 14-40; 8.7% (4-20%)). 1.09 home visits per day per person with diabetes lasting 13.8 minutes (excluding travel time) were needed, with most requiring insulin administration. 96% of nursing teams undertake multiple daily visits for some patients. 91% reported workloads relating to diabetes management had increased over the last 2 years; 76% stated current diabetes workloads were unsustainable. More insulin usage, more referrals and a lack of ability or willingness to self-administer insulin has increased the diabetes workload. Possible solutions include better collaboration between healthcare professionals, simplification of insulin administration and glucose monitoring, better training and upskilling of healthcare assistants and promotion of self-efficacy. CONCLUSIONS: Diabetes management forms an increasing component of district nursing workload and is likely to be unsustainable unless new models are found.

Towards the standardisation of adult person-reported outcome domains in diabetes research: A Consensus Statement development panel.

Diabetes is unique among chronic diseases because clinical outcomes are intimately tied to how the person living with diabetes reacts to and implements treatment recommendations. It is further characterised by widespread social stigma, judgement and paternalism. This physical, social and psychological burden collectively influences self-management behaviours. It is widely recognised that the individual's perspective about the impact of trying to manage the disease and the burden that self-management confers must be addressed to achieve optimal health outcomes. Standardised, rigorous assessment of mental and behavioural health status, in interaction with physical health outcomes is crucial to aid understanding of person-reported outcomes (PROs). Whilst tempting to conceptualise PROs as an issue of perceived quality of life (QoL), in fact health-related QoL is multi-dimensional and covers indicators of physical or functional health status, psychological and social well-being. This complexity is illuminated by the large number of person reported outcome measures (PROMs) that have been developed across multiple psychosocial domains. Often measures are used inappropriately or because they have been used in the scientific literature rather than based on methodological or outcome assessment rigour. Given the broad nature of psychosocial functioning/mental health, it is important to broadly define PROs that are evaluated in the context of therapeutic interventions, real-life and observational studies. This report summarises the central themes and lessons derived in the assessment and use of PROMs amongst adults with diabetes. Effective assessment of PROMs routinely in clinical research is crucial to understanding the true impact of any intervention. Selecting appropriate measures, relevant to the specific factors of PROs important in the research study will provide valuable data alongside physical health data.

Regional differences in mortality risk and in attenuating or aggravating factors in schizophrenia: A systematic review and meta-analysis.

People with schizophrenia die prematurely, yet regional differences are unclear. PRISMA 2020-compliant systematic review/random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) versus any control group, and moderators, in people with ICD/DSM-defined schizophrenia, comparing countries and continents. We conducted subgroup, meta-regression analyses, and quality assessment. The primary outcome was all-cause mortality. Secondary outcomes were suicide-, /natural-cause- and other-cause-related mortality. We included 135 studies from Europe (n = 70), North-America (n = 29), Asia (n = 33), Oceania (n = 2), Africa (n = 1). In incident plus prevalent schizophrenia, differences across continents emerged for all-cause mortality (highest in Africa, RR=5.98, 95 %C.I.=4.09-8.74, k = 1, lowest in North-America, RR=2.14, 95 %C.I.=1.92-2.38, k = 16), suicide (highest in Oceania, RR=13.5, 95 %C.I.=10.08-18.07, k = 1, lowest in North-America, RR=4.4, 95 %C.I.=4.07-4.76, k = 6), but not for natural-cause mortality. Europe had the largest association between antipsychotics and lower all-cause mortality/suicide (Asia had the smallest or no significant association, respectively), without differences for natural-cause mortality. Higher country socio-demographic index significantly moderated larger suicide-related and smaller natural-cause-related mortality risk in incident schizophrenia, with reversed associations in prevalent schizophrenia. Antipsychotics had a larger/smaller protective association in incident/prevalent schizophrenia regarding all-cause mortality, and smaller protective association for suicide-related mortality in prevalent schizophrenia. Additional regional differences emerged in incident schizophrenia, across countries, and secondary outcomes. Significant regional differences emerged for all-cause, cause-specific and suicide-related mortality. Natural-cause death was homogeneously increased globally. Moderators differed across countries. Global initiatives are needed to improve physical health in people with schizophrenia, local studies to identify actionable moderators.

Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment.

An association between diabetes and infection has been recognised for many years, with infection being an important cause of death and morbidity in people with diabetes. The COVID-19 pandemic has re-kindled an interest in the complex relationship between diabetes and infection. Some infections occur almost exclusively in people with diabetes, often with high mortality rates without early diagnosis and treatment. However, more commonly, diabetes is a complicating factor in many infections. A reciprocal relationship occurs whereby certain infections and their treatments may also increase the risk of diabetes. People with diabetes have a 1.5- to 4-fold increased risk of infection. The risks are the most pronounced for kidney infection, osteomyelitis and foot infection, but are also increased for pneumonia, influenza, tuberculosis, skin infection and general sepsis. Outcomes from infection are worse in people with diabetes, with the most notable example being a twofold higher rate of death from COVID-19. Hyperglycaemia has deleterious effects on the immune response. Vascular insufficiency and neuropathy, together with altered skin, mucosal and gut microbial colonisation, contribute to the increased risk of infection. Vaccination is important in people with diabetes although the efficacy of certain immunisations may be compromised, particularly in the presence of hyperglycaemia. The principles of treatment largely follow those of the general population with certain notable exceptions.

A core outcome set for trials evaluating self-management interventions in people with severe mental illness and coexisting type 2 diabetes.

BACKGROUND: People with severe mental illness (SMI), such as schizophrenia, have higher rates of type 2 diabetes and worse outcomes, compared to those without SMI and it is not known whether diabetes self-management interventions are effective for people who have both conditions. Research in this area has been impeded by a lack of consensus on which outcomes to prioritise in people with co-existing SMI and diabetes. AIMS: To develop a core outcome set (COS) for use in effectiveness trials of diabetes self-management interventions in adults with both type 2 diabetes and SMI. METHODS: The COS was developed in three stages: (i) identification of outcomes from systematic literature review of intervention studies, followed by multi-stakeholder and service user workshops; (ii) rating of outcomes in a two-round online Delphi survey; (iii) agreement of final 'core' outcomes through a stakeholder consensus workshop. RESULTS: Seven outcomes were selected: glucose control, blood pressure, body composition (body weight, BMI, body fat), health-related quality of life, diabetes self-management, diabetes-related distress and medication adherence. CONCLUSIONS: This COS is recommended for future trials of effectiveness of diabetes self-management interventions for people with SMI and type 2 diabetes. Its use will ensure trials capture important outcomes and reduce heterogeneity so findings can be readily synthesised to inform practice and policy.

Physical activity, suicidal ideation, suicide attempt and death among individuals with mental or other medical disorders: A systematic review of observational studies.

A growing body of research has demonstrated the potential role for physical activity as an intervention across mental and other medical disorders. However, the association between physical activity and suicidal ideation, attempts, and deaths has not been systematically appraised in clinical samples. We conducted a PRISMA 2020-compliant systematic review searching MEDLINE, EMBASE, and PsycINFO for observational studies investigating the influence of physical activity on suicidal behavior up to December 6, 2023. Of 116 eligible full-text studies, seven (n = 141691) were included. Depression was the most frequently studied mental condition (43%, k = 3), followed by chronic pain as the most common other medical condition (29%, k = 2). Two case-control studies examined suicide attempts and found an association between physical activity and a reduced frequency of such attempts. However, in studies examining suicidal ideation (k = 3) or suicide deaths (k = 2), no consistent associations with physical activity were observed. Overall, our systematic review found that physical activity may be linked to a lower frequency of suicide attempts in non-prospective studies involving individuals with mental disorders.

The Fusion Clinic: Integrating the care of people with severe mental illness and diabetes.

AIM: People with coexisting severe mental illness (SMI) and type 2 diabetes have a shorter life expectancy and poorer diabetes outcomes than those without SMI. This is partly explained by the separate treatment of diabetes and SMI, which occurs in parallel silos in many healthcare systems. The Steno Diabetes Center Sjaelland and Region Zealand established the Fusion Clinic to offer combined psychiatric and diabetes care delivered by both diabetes and mental healthcare professionals. This study describes how the clinic was established and the initial diabetes outcomes. METHODS: The Fusion Clinic was co-designed by people with diabetes and SMI and healthcare professionals to improve the care of adults with diabetes and SMI. The clinic approach utilised the F-ACT model. The 63 people referred to the Fusion Clinic between 01.02.2020 and 01.01.2022 who attended the clinic for more than 6 months were included in this study. Diabetes outcomes were recorded in the electronic medical records (Sundhedsplatformen EPIC). RESULTS: There was a high prevalence of diabetes complications at baseline. Furthermore, 70% had one or more additional concomitant diseases, as well as SMI and diabetes. Assessment of diabetes complications and measurements of HbA1c and lipid profile improved after referral to the clinic. HbA1c declined during the first 6 months of attendance at the clinic. CONCLUSIONS: This model of service delivery has the potential to improve the quality of care for people with SMI and type 2 diabetes.

The psychosocial burdens of living with diabetes.

AIM: To better understand the prevalence of self-reported psychosocial burdens and the unmet needs identified by people with diabetes in relation to routine diabetes visits. METHODS: An English language, online survey was distributed via social media, key stakeholder networks, charity and advocacy groups to adults with type 1 diabetes or type 2 diabetes. Survey items were designed by members of the FDA RESCUE Collaborative Community Governing Committee prior to pilot testing with potential participants. Descriptive statistical analyses were conducted, as well as thematic analyses on free-text responses using NVivo v14. RESULTS: Four hundred and seventy-eight participants completed the survey: 373 (78%) had type 1 diabetes, 346 (73%) identified as a woman and 433 (91%) were white. Most participants had experienced self-reported (rather than diagnosed) anxiety and depression (n = 323 and n = 313, respectively), as well as fear of low blood sugars (n = 294), low mood (n = 290) and diabetes-related distress (n = 257). Sixty-eight percent reported that diabetes had negatively affected self-esteem, 62% reported the feelings of loneliness, but 93% reported that friends/family/work colleagues were supportive when needed. Two hundred and seventy-two percent (57%) reported that their diabetes team had never raised the topic of mental health. The overwhelming majority stated that the best thing their diabetes team could do to help was to simply ask about mental well-being, listen with empathy and without judgement, and practice skills to understand psychosocial issues in diabetes. CONCLUSION: Integrating psychosocial discussions and support within routine healthcare visits is crucial to improve outcomes for people with diabetes. Such a biopsychosocial model of healthcare has long been advocated by regulatory bodies.

Copenhagen Diabetes Consensus (CODIAC) 2021: User involvement in diabetes care, prevention and research.

AIMS: User involvement is pivotal for health development, but there are significant gaps in our understanding of the concept. The Copenhagen Diabetes Consensus on User Involvement in Diabetes Care, Prevention and Research (CODIAC) was established to address these gaps, share knowledge and develop best practices. METHODS: A literature review of user involvement was undertaken in diabetes care, prevention and research. Moreover, a Group Concept Mapping (GCM) survey synthesized the knowledge and opinions of researchers, healthcare professionals and people with diabetes and their carers to identify gaps between what is important for user involvement and what is being done in practice. Finally, a consensus conference discussed the main gaps in knowledge and practice while developing plans to address the shortcomings. RESULTS: The literature review demonstrated that user involvement is an effective strategy for diabetes care, prevention and research, given the right support and conditions, but gaps and key challenges regarding the value and impact of user involvement approaches were found. The GCM process identified 11 major gaps, where important issues were not being sufficiently practised. The conference considered these gaps and opportunities to develop new collaborative initiatives under eight overall themes. CONCLUSIONS: User involvement is effective and adds value to diabetes care, prevention and research when used under the right circumstances. CODIAC developed new learning about the way in which academic and research knowledge can be transferred to more practice-oriented knowledge and concrete collaborative initiatives. This approach may be a potential new framework for initiatives in which coherence of process can lead to coherent outputs.

Bringing an end to diabetes stigma and discrimination: an international consensus statement on evidence and recommendations.

People with diabetes often encounter stigma (ie, negative social judgments, stereotypes, prejudice), which can adversely affect emotional, mental, and physical health; self-care, access to optimal health care; and social and professional opportunities. To accelerate an end to diabetes stigma and discrimination, an international multidisciplinary expert panel (n=51 members, from 18 countries) conducted rapid reviews and participated in a three-round Delphi survey process. We achieved consensus on 25 statements of evidence and 24 statements of recommendations. The consensus is that diabetes stigma is driven primarily by blame, perceptions of burden or sickness, invisibility, and fear or disgust. On average, four in five adults with diabetes experience diabetes stigma and one in five experience discrimination (ie, unfair and prejudicial treatment) due to diabetes, such as in health care, education, and employment. Diabetes stigma and discrimination are harmful, unacceptable, unethical, and counterproductive. Collective leadership is needed to proactively challenge, and bring an end to, diabetes stigma and discrimination. Consequently, we achieved unanimous consensus on a pledge to end diabetes stigma and discrimination.

Risk factors associated with overweight and obesity in people with severe mental illness in South Asia: cross-sectional study in Bangladesh, India, and Pakistan.

Obesity is one of the major contributors to the excess mortality seen in people with severe mental illness (SMI) and in low- and middle-income countries people with SMI may be at an even greater risk. In this study, we aimed to determine the prevalence of obesity and overweight in people with SMI and investigate the association of obesity and overweight with sociodemographic variables, other physical comorbidities, and health-risk behaviours. This was a multi-country cross-sectional survey study where data were collected from 3989 adults with SMI from three specialist mental health institutions in Bangladesh, India, and Pakistan. The prevalence of overweight and obesity was estimated using Asian BMI thresholds. Multinomial regression models were then used to explore associations between overweight and obesity with various potential determinants. There was a high prevalence of overweight (17·3 %) and obesity (46·2 %). The relative risk of having obesity (compared to normal weight) was double in women (RRR = 2·04) compared with men. Participants who met the WHO recommendations for fruit and vegetable intake had 2·53 (95 % CI: 1·65-3·88) times greater risk of having obesity compared to those not meeting them. Also, the relative risk of having obesity in people with hypertension is 69 % higher than in people without hypertension (RRR = 1·69). In conclusion, obesity is highly prevalent in SMI and associated with chronic disease. The complex relationship between diet and risk of obesity was also highlighted. People with SMI and obesity could benefit from screening for non-communicable diseases, better nutritional education, and context-appropriate lifestyle interventions.

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations.

BACKGROUND: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in retinol-binding protein 4 (RBP4), encoding a serum retinol-specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC). METHODS: We report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, of whom we performed biochemical analyses. RESULTS: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes, depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypical expression in dominant forms, suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that retinol-binding protein blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum. CONCLUSION: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.

Health Care Professional Experiences and Opinions on Depression and Suicide in People With Diabetes.

OBJECTIVE: People with diabetes have an increased risk of depression, intentional self-injury and self-harm (ISI), and suicide compared with the general population. This study aimed to explore experiences and awareness of health care professionals (HCPs) regarding depression, ISI, and suicide, and understand resource use and needs among HCPs who care for persons with diabetes (PWD). METHODS: Health care professionals who see children and/or adults with type 1 diabetes or type 2 diabetes anonymously completed an online survey about their experiences, opinions, barriers, and needs surrounding identification and care of PWD with depression, ISI, and suicide. RESULTS: One hundred twenty-nine HCPs participated. The majority were medical doctors (MDs) or advanced practice providers (APPs). Only a quarter of MDs and APPs felt very comfortable asking about ISI or suicidal ideation (SI), whereas 20% felt they had received appropriate training to support those with ISI or SI. The primary needs reported include more training on how to ask, respond, and support those expressing ISI and SI. Health care professionals reported wanting better access to resources for PWD. DISCUSSION: The HCPs tend to underestimate SI in the diabetes population and rates of training were low. Areas to address include providing education and training to HCPs to improve identification and management of ISI and suicide risk. These data can inform the development of mechanisms to improve discussions of depression and suicide and of resources to help HCPs support PWD.

Development of a Supported Self-management Intervention for People With Severe Mental Illness and Type 2 Diabetes: Theory and Evidence-Based Co-design Approach.

BACKGROUND: Type 2 diabetes is 2 to 3 times more common among people with severe mental illness (SMI). Self-management is crucial, with additional challenges faced by people with SMI. Therefore, it is essential that any diabetes self-management program for people with SMI addresses the unique needs of people living with both conditions and the inequalities they experience within health care services. OBJECTIVE: We combined theory, empirical evidence, and co-design approaches to develop a type 2 diabetes self-management intervention for people with SMI. METHODS: The development process encompassed 4 steps: step 1 involved prioritizing the mechanisms of action (MoAs) and behavior change techniques (BCTs) for the intervention. Using findings from primary qualitative research and systematic reviews, we selected candidate MoAs to target in the intervention and candidate BCTs to use. Expert stakeholders then ranked these MoAs and BCTs using a 2-phase survey. The average scores were used to generate a prioritized list of MoAs and BCTs. During step 2, we presented the survey results to an expert consensus workshop to seek expert agreement with the definitive list of MoAs and BCTs for the intervention and identify potential modes of delivery. Step 3 involved the development of trigger films using the evidence from steps 1 and 2. We used animations to present the experiences of people with SMI managing diabetes. These films were used in step 4, where we used a stakeholder co-design approach. This involved a series of structured workshops, where the co-design activities were informed by theory and evidence. RESULTS: Upon the completion of the 4-step process, we developed the DIAMONDS (diabetes and mental illness, improving outcomes and self-management) intervention. It is a tailored self-management intervention based on the synthesis of the outputs from the co-design process. The intervention incorporates a digital app, a paper-based workbook, and one-to-one coaching designed to meet the needs of people with SMI and coexisting type 2 diabetes. CONCLUSIONS: The intervention development work was underpinned by the MoA theoretical framework and incorporated systematic reviews, primary qualitative research, expert stakeholder surveys, and evidence generated during co-design workshops. The intervention will now be tested for feasibility before undergoing a definitive evaluation in a pragmatic randomized controlled trial.

Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta.

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.

Combined statistical decision limits based on two GH-2000 scores for the detection of growth hormone misuse.

The growth hormone-2000 biomarker method, based on the measurements of insulin-like growth factor-I and the amino-terminal pro-peptide of type III collagen, has been developed as a powerful technique for the detection of growth hormone misuse by athletes. Insulin-like growth factor-I and amino-terminal pro-peptide of type III collagen are combined in gender-specific formulas to create the growth hormone-2000 score, which is used to determine whether growth hormone has been administered. To comply with World Anti-Doping Agency regulations, each analyte must be measured by two methods. Insulin-like growth factor-I and amino-terminal pro-peptide of type III collagen can be measured by a number of approved methods, each leading to its own growth hormone-2000 score. Single decision limits for each growth hormone-2000 score have been introduced and developed by Bassett, Erotokritou-Mulligan, Holt, Böhning and their co-authors in a series of papers. These have been incorporated into the guidelines of the World Anti-Doping Agency. A joint decision limit was constructed based on the sample correlation between the two growth hormone-2000 scores generated from an available sample to increase the sensitivity of the biomarker method. This paper takes this idea further into a fully developed statistical approach. It constructs combined decision limits when two growth hormone-2000 scores from different assay combinations are used to decide whether an athlete has been misusing growth hormone. The combined decision limits are directly related to tolerance regions and constructed using a Bayesian approach. It is also shown to have highly satisfactory frequentist properties. The new approach meets the required false-positive rate with a pre-specified level of certainty.

5-ASA induced interstitial nephritis in patients with inflammatory bowel disease: a systematic review.

BACKGROUND: Acute interstitial nephritis (AIN) is an important cause of kidney injury accounting for up to 27% of unexplained renal impairment. In up to 70% of cases, drugs, including aminosalicylates, are reported as the underlying cause. Following two recent paediatric cases of suspected mesalazine induced AIN within our own department, we performed a systematic review of the literature to address the following question: In patients with inflammatory bowel disease (IBD), is interstitial nephritis associated with 5-aminosalicylate (5-ASA) treatment? Our primary objective was to identify the number of cases reported in the literature of biopsy-proven 5-ASA induced interstitial nephritis, in children and adults with IBD. We also aimed to identify which variables influence the onset, severity and recovery of 5-ASA interstitial nephritis. METHODS: Embase and PubMed databases were searched from inception to 07/10/20. Search terms had three main themes: "inflammatory bowel disease", "interstitial nephritis" and "aminosalicylates". Studies were included if they reported an outcome of AIN, confirmed on biopsy, suspected to be secondary to a 5-ASA drug in those with IBD. A narrative synthesis was performed. RESULTS: Forty-one case reports were identified. Mesalazine was the most frequently reported aminosalicylate associated with AIN (95%). The median duration of treatment before AIN was diagnosed was 2.3 years (Interquartile Range (IQR) 12-48 months). The median rise in creatinine was 3.3 times the baseline measurement (IQR 2.5-5.5). Aminosalicylate withdrawal and steroids were the most frequently used treatments. Despite treatment, 15% of patients developed end-stage renal failure. CONCLUSIONS: AIN is a serious adverse drug reaction associated with aminosalicylates, with mesalazine accounting for most reports. The current guidance of annual monitoring of renal function may not be sufficient to identify cases early. Given the severity of AIN and reports in the literature that early treatment with steroids may be beneficial, we would recommend at least 6 monthly monitoring of renal function. PROSPERO registration number CRD42020205387.