The impact of machine learning on the prediction of diabetic foot ulcers - A systematic review.

INTRODUCTION: Globally, diabetes mellitus poses a significant health challenge as well as the associated complications of diabetes, such as diabetic foot ulcers (DFUs). The early detection of DFUs is important in the healing process and machine learning may be able to help inform clinical staff during the treatment process. METHODS: A PRISMA-informed search of the literature was completed via the Cochrane Library and MEDLINE (OVID), EMBASE, CINAHL Plus and Scopus databases for reports published in English and in the last ten years. The primary outcome of interest was the impact of machine learning on the prediction of DFUs. The secondary outcome was the statistical performance measures reported. Data were extracted using a predesigned data extraction tool. Quality appraisal was undertaken using the evidence-based librarianship critical appraisal tool. RESULTS: A total of 18 reports met the inclusion criteria. Nine reports proposed models to identify two classes, either healthy skin or a DFU. Nine reports proposed models to predict the progress of DFUs, for example, classing infection versus non-infection, or using wound characteristics to predict healing. A variety of machine learning techniques were proposed. Where reported, sensitivity = 74.53-98 %, accuracy = 64.6-99.32 %, precision = 62.9-99 %, and the F-measure = 52.05-99.0 %. CONCLUSIONS: A variety of machine learning models were suggested to successfully classify DFUs from healthy skin, or to inform the prediction of DFUs. The proposed machine learning models may have the potential to inform the clinical practice of managing DFUs and may help to improve outcomes for individuals with DFUs. Future research may benefit from the development of a standard device and algorithm that detects, diagnoses and predicts the progress of DFUs.

The impact of a student-led anti-racism programme on medical students' perceptions and awareness of racial bias in medicine and confidence to advocate against racism.

INTRODUCTION: Systemic racism impacts personal and community health; however, education regarding its role in perpetuating healthcare inequity remains limited in medical curricula. This study implemented and evaluated the impact of a student-led anti-racism programme on medical students' perceptions of racial bias in medicine, awareness of, and confidence to advocate against racism in medicine. METHOD: A total of 543 early stage medical students were invited to participate in the programme. Participants were assigned readings and videos exploring racial injustice in medicine and attended a virtual small-group discussion facilitated by faculty and students. Online surveys were used to collect pre- and post-programme data using Likert scales for response items. Open-ended questions were independently reviewed by three authors using reflexive thematic analysis. RESULTS: Sixty-three early-stage medical students enrolled in the programme, of which 42 completed the pre-programme survey. There was a 76% (n = 32) response rate for the post-programme survey. The majority of students (60%, n = 25) had no previous education about racism in medicine. From pre- to post-programme, there was a significant change in students' perceived definition of race from genetic, biological, geographical, and cultural factors to socio-political factors (P < 0.0001). Significant increases in almost all factors assessing student awareness of racism and confidence to advocate against racism were observed. Student-identified barriers to discussing racism included lack of education and lived experience, fear of starting conflict and offending others. All survey respondents would recommend this programme to peers and 69% (n = 32) engaged in further topical self-directed education. CONCLUSION: This simple and reproducible programme improved awareness and confidence to advocate against racism in medicine and resulted in a change in opinion regarding race-based medical practice. These findings are in line with best practice towards addressing racial bias in medicine, decolonizing medical curricula and strengthening anti-racism teaching of future physicians.

Impact of haemoglobin variants on the use of haemoglobin A1c for the diagnosis and monitoring of diabetes: a contextualised review.

HbA1c is the established test for monitoring glycaemic control in diabetes, and intervention trials studying the impact of treatment on glycaemic control and risk of complications focus predominantly on this parameter in terms of evaluating the glycaemic outcomes. It is also the main parameter used when targets for control are being individualised, and more recently, it has been used for the diagnosis of type 2 diabetes. For laboratories performing this test and clinicians utilising it in their decision-making process, a thorough understanding of factors that can impact on the accuracy, and appropriate interpretation of the test is essential. The changing demographic in the Irish population over the last two decades has brought this issue sharply into focus. It is therefore timely to review the utility, performance and interpretation of the HbA1c test to highlight factors impacting on the results, specifically the impact of haemoglobin variants, and the impact of these factors on its utilisation in clinical practice.

Utility of screening for silent myocardial ischaemia in diabetes with an annual electrocardiogram.

BACKGROUND AND METHODS: Asymptomatic coronary artery disease (CAD) is common in people with diabetes mellitus, but there is a lack of consensus regarding appropriate screening for the condition. We performed a 12-lead electrocardiogram (ECG) on 312 consecutive participants with diabetes mellitus attending for routine annual outpatient review in order to determine the effectiveness of a yearly ECG in screening people with diabetes for asymptomatic CAD. RESULTS: Three of 312 participants (0.96%, 95% CI 0.2%-2.78%) had a newly identified ECG abnormality. One person had newly discovered atrial fibrillation. Two people had abnormalities which prompted further investigation for asymptomatic CAD. One of these participants underwent percutaneous coronary intervention. Seventeen further participants had abnormalities on ECG which had been previously documented, the majority having been present since their diagnosis of diabetes. CONCLUSION: A low positive yield of routine annual ECG in our study does not support its use as a screening tool for asymptomatic CAD in diabetes. Our findings support advice to perform an ECG at diagnosis of diabetes and to repeat only if a person develops relevant symptoms.

Screening for Hereditary Hemochromatosis in Newly Referred Diabetes Mellitus.

Aims: Hereditary hemochromatosis (HH) is the most common inherited disease in European populations. It is particularly common in people of Irish heritage, approximately 2% of whom will be at risk of iron overload as a result of human homoeostatic iron regulator protein (HFE) gene mutations. We aimed to evaluate the utility of screening for HH in newly referred patients with DM of Irish heritage in a prospective study. Methods: Of 575 patients newly referred between March 2018 and March 2021, 556 attended for blood testing, to include fasting transferrin saturations, prior to their first clinic visit. Patients with elevated transferrin saturations were further screened for hereditary hemochromatosis (HH) with HFE gene analysis. Results: Transferrin saturations were elevated in 13 of 556 patients (2.3%), 3 of whom had a preexisting diagnosis of HH. Of the remaining 10 patients, 7 had HFE gene mutations suggestive of HH (2 C282Y homozygous, 3 C282Y/H63D compound heterozygous, and 2 H63D homozygous), 1 was a HH carrier (C282Y heterozygous), and 2 had normal genetics. Conclusions: The prevalence of HH of 1.8% in this screened DM population is lower than the reported incidence of HH in the Irish population, suggesting a limited utility of routine screening for HH in newly referred patients with DM.

An exploratory study of associations between sleep timing variability and cardiometabolic health in middle-aged adults with type 2 diabetes mellitus.

Sleep is increasingly recognised as an important risk factor for metabolic disease, and as an important influence on severity in established metabolic disease. Recent evidence suggests that sleep timing variability (the day-to-day fluctuations of sleep timing) may be an important factor in metabolic diseases such as type 2 diabetes mellitus. In the current study, we explore the associations between measures of sleep timing variability and cardiometabolic measures in a group of healthy middle-aged adults with and without type 2 diabetes mellitus. Healthy controls (N = 27) and adults with well-controlled uncomplicated type 2 diabetes mellitus (N = 30) wore actiwatches for an average of 9 days for objective assessment of sleep timing parameters, and also underwent a detailed clinical assessment. We found greater self-reported social jetlag in the diabetes group, but no groupwise differences in measures of sleep timing variability. In the diabetes patients, HbA1c levels were inversely correlated with variability in the time of sleep onset and midsleep, and with sleep duration. HOMA-IR did not correlate with any sleep timing variability measure, nor were there associations between sleep timing variability and other metabolic biomarkers (cholesterol, LDL, HDL, triglycerides and uric acid). Systolic blood pressure was inversely correlated with actigraphically defined social jetlag in both the control and diabetes groups. The results of this study indicate associations between sleep timing variability and HbA1c, but the direction of these relationships is at variance with some other recent reports. Our results indicate a need for future hypothesis-testing studies to further explore the impact of sleep timing variance on metabolic health.

Exploring medical students' perceptions of the challenges and benefits of volunteering in the intensive care unit during the COVID-19 pandemic: a qualitative study.

OBJECTIVES: In March 2020, the WHO declared SARS-CoV-2 a pandemic. Hospitals across the world faced staff, bed and supply shortages, with some European hospitals calling on medical students to fill the staffing gaps. This study aimed to document the impact of volunteering during the COVID-19 pandemic on students' professional development, resilience and future perceived career choices. DESIGN: This is a retrospective, qualitative study of student reflections, using purposive sampling.The Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences recruited 26 medical student volunteers to assist in pronation and supination of ventilated patients affected by SARS-CoV-2. These students were invited to complete an anonymous survey based on their experiences as volunteers. Thematic analysis was performed on these written reflections. RESULTS: The results showed that volunteering during the COVID-19 pandemic developed key skills from RCSI's medical curriculum, significantly fostered medical students' resilience and guided their career choices. Major areas of development included communication, teamwork, compassion and altruism, which are not easily developed through the formal curriculum. A further area that was highlighted was the importance of evidence-based health in a pandemic. Finally, our respondents were early stage medical students with limited clinical exposure. Some found the experience difficult to cope with and therefore supports should be established for students volunteering in such a crisis. CONCLUSION: These results suggest that clinical exposure is an important driver in developing students' resilience and that volunteering during a pandemic has multiple benefits to students' professional development and professional identity formation.

Testicular swelling leading to a diagnosis of adrenocortical carcinoma - co-incidence or causation?

SUMMARY: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 0.7-2.0 cases/million/year. A majority of patients present with steroid hormone excess or abdominal mass effects, and in 15% of patients ACC is discovered incidentally. We present a case of 30-year-old otherwise asymptomatic Caucasian male who presented with a testicular swelling. Subsequent imaging and investigations revealed disseminated sarcoidosis and an 11 cm adrenal lesion. An adrenalectomy was performed. Histological examination of the resected specimen confirmed an ACC and also demonstrated a thin rim of adrenal tissue containing non-caseating granulomas, consistent with adrenal sarcoid. LEARNING POINTS: This case highlights an unusual presentation of two uncommon diseases. This case also highlights how separate and potentially unrelated disease processes may occur concomitantly and the importance, therefore, of keeping an open mind when dealing with unusual diagnostic findings. We also hypothesize a potential link between the ACC and sarcoidosis in our patient.

Barriers and facilitators to accessing insulin pump therapy by adults with type 1 diabetes mellitus: a qualitative study.

AIMS: Uptake of continuous subcutaneous insulin infusion (CSII) by people with diabetes (PwD) in Ireland is low and exhibits regional variation. This study explores barriers and facilitators to accessing CSII by adults with Type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS: A qualitative study employing focus groups with adults with Type 1 diabetes mellitus (n = 26) and semi-structured interviews with health care professionals (HCP) and other key stakeholders (n = 21) was conducted. Reflexive thematic analysis was used to analyze data, using NVivo. RESULTS: Four main themes comprising barriers to or facilitators of CSII uptake were identified. These included: (1) awareness of CSII and its benefits, (2) the structure of diabetes services, (3) the capacity of the diabetes service to deliver the CSII service, and (4) the impact of individuals' attitudes and personal characteristics-both PwD, and HCP. Each of these themes was associated with a number of categories, of which 18 were identified and explored. If the structure of the health-service is insufficient and capacity is poor (e.g., under-resourced clinics), CSII uptake appears to be impacted by individuals': interest, attitude, willingness and motivation, which may intensify the regional inequality in accessing CSII. CONCLUSIONS: This study identified factors that contribute to gaps in the delivery of diabetes care that policy-makers may use to improve access to CSII for adult PwD.

Sociodemographic variables as predictors of adverse outcome in SARS-CoV-2 infection: an Irish hospital experience.

INTRODUCTION: Our hospital found itself at the epicentre of the Irish COVID-19 pandemic. We describe the organisational challenges faced in managing the surge and identified risk factors for mortality and ICU admission among hospitalised SARS-CoV-2-infected patients. METHODS: All hospitalised SARS-CoV-2 patients diagnosed between March 13 and May 1, 2020, were included. Demographic, referral, deprivation, ethnicity and clinical data were recorded. Multivariable regression, including age-adjusted hazard ratios (HR (95% CI), was used to explore risk factors associated with adverse outcomes. RESULTS: Of 257 inpatients, 174 were discharged (68%) and 39 died (15%) in hospital. Two hundred three (79%) patients presented from the community, 34 (13%) from care homes and 20 (8%) were existing inpatients. Forty-five percent of community patients were of a non-Irish White or Black, Asian or minority ethnic (BAME) population, including 34 Roma (13%) compared to 3% of care home and 5% of existing inpatients, (p < 0.001). Twenty-two patients were healthcare workers (9%). Of 31 patients (12%) requiring ICU admission, 18 were discharged (58%) and 7 died (23%). Being overweight/obese HR (95% CI) 3.09 (1.32, 7.23), p = 0.009; a care home resident 2.68 (1.24, 5.6), p = 0.012; socioeconomically deprived 1.05 (1.01, 1.09), p = 0.012; and older 1.04 (1.01, 1.06), p = 0.002 were significantly associated with death. Non-Irish White or BAME were not significantly associated with death 1.31 (0.28, 6.22), p = 0.63 but were significantly associated with ICU admission 4.38 (1.38, 14.2), p = 0.014 as was being overweight/obese 2.37 (1.37, 6.83), p = 0.01. CONCLUSION: The COVID-19 pandemic posed unprecedented organisational issues for our hospital resulting in the greatest surge in ICU capacity above baseline of any Irish hospital. Being overweight/obese, a care home resident, socioeconomically deprived and older were significantly associated with death, while ethnicity and being overweight/obese were significantly associated with ICU admission.

Low uptake of continuous subcutaneous insulin infusion therapy in people with type 1 diabetes in Ireland: a retrospective cross-sectional study.

BACKGROUND: The uptake of continuous subcutaneous insulin infusion (CSII) therapy in those with type 1 diabetes varies internationally and is mainly determined by the national healthcare reimbursement systems. The aim of this study is to estimate national and regional uptake of CSII therapy in children, adolescents and adults with type 1 diabetes in Ireland. METHODS: A retrospective cross-sectional study was conducted utilizing the national pharmacy claims database in 2016. Individuals using CSII were identified by dispensing of infusion sets. The uptake of CSII was calculated as the percentage of people with type 1 diabetes claiming CSII sets in 2016, both in children and adolescent (age < 18 years) and adult populations (≥ 18 years). Descriptive statistics including percentages with 95% confidence intervals (CIs) are presented, stratified by age-groups and geographical regions, and chi-square tests used for comparisons. RESULTS: Of 20,081 people with type 1 diabetes, 2111 (10.5, 95% CI: 10.1-10.9%) were using CSII in 2016. Uptake was five-fold higher in children and adolescents at 34.7% (95% CI: 32.9-36.5%) than in adults at 6.8% (95% CI: 6.4-7.2%). Significant geographical heterogeneity in CSII uptake was found, from 12.6 to 53.7% in children and adolescents (p < 0.001), and 2 to 9.6% in adults (p < 0.001). CONCLUSIONS: Uptake of CSII in people with type 1 diabetes is low in Ireland, particularly in those ≥18 years. Identification of barriers to uptake, particularly in this group, is required.

Prevalence and incidence of type 1 diabetes in Ireland: a retrospective cross-sectional study using a national pharmacy claims data from 2016.

OBJECTIVES: The aim of this study is to estimate the prevalence and incidence of type 1 diabetes in the Irish population using a national pharmacy claims database in the absence of a national diabetes register. DESIGN: National, population-based, retrospective, cross-sectional study. SETTING: Community care with data available through the Health Service Executive Pharmacy Claims Reimbursement Scheme from 2011 to 2016. PARTICIPANTS: Individuals with type 1 diabetes were identified by coprescription of insulin and glucometer test strips without any prolonged course (>12 months) of oral hypoglycaemic agents prior to commencing insulin. Those claiming prescriptions for long-acting insulin only, without any prandial insulin, were excluded from the analysis. Incidence was estimated based on the first claim for insulin in 2016, with no insulin use in the preceding 12 months. MAIN OUTCOME MEASURES: Prevalence of type 1 diabetes in children (<18 years) and adults (≥18 years); incidence of type 1 diabetes in children (≤14 years) and adolescents and adults (>14 years). RESULTS: There were 20 081 prevalent cases of type 1 diabetes in 2016. The crude prevalence was 0.42% (95% CI 0.42% to 0.43%). Most prevalent cases (n=17 053, 85%) were in adults with a prevalence of 0.48% (95% CI 0.47% to 0.48%). There were 1527 new cases of type 1 diabetes in 2016, giving an incidence rate of 32 per 100 000 population/year (95% CI 30.5 to 33.7). There was a significant positive linear trend for age, for prevalence (p<0.0001) and incidence (p=0.014). The prevalence and incidence were 1.2-fold and 1.3-fold higher in men than women, respectively. Significant variations in prevalence (p<0.0001) and incidence (p<0.001) between the different geographical regions were observed. CONCLUSIONS: This study provides epidemiological estimates of type 1 diabetes across age groups in Ireland, with the majority of prevalent cases in adults. Establishing a national diabetes register is essential to enable updated epidemiological estimates of diabetes and for planning of services in Ireland.

Availability of and access to continuous subcutaneous insulin infusion therapy for adults with type 1 diabetes in Ireland.

AIMS: The uptake of continuous subcutaneous insulin infusion (CSII) is low in adults with type 1 diabetes mellitus (T1DM) in Ireland, compared to other countries where CSII is reimbursed. To explore the reasons for the low uptake, this study aims to investigate the availability of CSII in adult diabetes clinics in Ireland. METHODS: A national survey of all adult diabetes clinics (public and private) in Ireland was conducted and completed anonymously by the lead physician/diabetes nurse specialist in each clinic. Descriptive statistics and comparisons between clinics offering different levels of care for CSII are presented. RESULTS: Of 50 diabetes clinics invited, 47 (94%) participated in the study. Fifteen clinics (32%) offered no support for CSII, while 21 (45%) reported offering both training to commence CSII and ongoing support. Based on the survey findings, access to CSII was unavailable for 2426 (11%) of those with T1DM. The majority (n = 15,831, 71% of 22,321 T1DM population) received diabetes care from clinics offering CSII training, but only 2165 were using CSII (10% of T1DM population). Uptake of CSII was higher in clinics offering training than in those offering follow-up care for CSII only (12% vs. 5%, p < 0.001). Clinics offering all CSII services had more specialists (p = 0.005 for endocrinologists and p < 0.001 for dietitians). Reasons for not offering CSII services included staff shortages and heavy workload. CONCLUSIONS: This study highlights the low uptake of CSII in Ireland and demonstrates that, even when reimbursed, other barriers to uptake of CSII can limit its use.

Greater social jetlag associates with higher HbA1c in adults with type 2 diabetes: a cross sectional study.

BACKGROUND/OBJECTIVES: Later chronotype has been associated with poorer glycemic control in type 2 diabetes. It is unclear whether this is a direct relationship, or if personality factors or social jetlag ([SJL], ie, chronic circadian misalignment reflecting the discrepancy between the entrained phase of the circadian clock and socially-determined behavioural cycles) play a role. This study aimed to determine the relationships among chronotype, SJL, personality factors and glycemic control in type 2 diabetes, independently of sleep disturbances and daily caloric distribution. METHODS: In sum, 252 type 2 diabetes patients attending an annual review outpatients' clinic completed questionnaires, including the Munich Chronotype Questionnaire to assess chronotype and SJL, the Pittsburgh Sleep Quality index (PSQI), the Big Five Personality Inventory and the Center for Epidemiologic Studies Depression Scale. Chart review provided information on diabetes duration, Hemoglobin A1c (HbA1c), body mass index (BMI) and other clinical variables. Caloric intake was assessed via 24-h dietary recall. RESULTS: Hierarchical linear regression revealed that SJL, but not chronotype or personality factors, was a significant predictor of HbA1c levels (ß = 0.16, p < 0.05). There was a significant relationship between later chronotype and HbA1c levels, but only in patients who had more than 90 min SJL (r = 0.51, p = 0.002). Younger age was associated with a higher HbA1c (r = -0.23, p < 0.001), and this effect was partially mediated through SJL (Pm = 0.22). CONCLUSIONS: We identify SJL as a novel factor that may impact on glycemic control in type 2 diabetes. Further study is needed to determine whether interventions aimed at reducing SJL may lead to improvements in glycemic control.

Spurious HbA1c results in patients with diabetes treated with dapsone.

SUMMARY: Measurement of glycated haemoglobin (HbA1c) has been utilised in assessing long-term control of blood glucose in patients with diabetes, as well as diagnosing diabetes and identifying patients at increased risk of developing diabetes in the future. HbA1c reflects the level of blood glucose to which the erythrocyte has been exposed during its lifespan, and there are a number of clinical situations affecting the erythrocyte life span in which HbA1c values may be spuriously high or low and therefore not reflective of the true level of glucose control. In the present case series, we describe the particulars of three patients with diabetes who had spuriously low HbA1c levels as a result of dapsone usage. Furthermore, we discuss the limitations of HbA1c testing and the mechanisms by which it may be affected by dapsone in particular. LEARNING POINTS: Various conditions and medications can result in falsely low HbA1c. Dapsone can lead to falsely low HbA1c by inducing haemolysis and by forming methaemoglobin. Capillary glucose measurement, urine glucose measurements and fructosamine levels should be used as alternatives to HbA1c for monitoring glycaemic control if it was falsely low or high.

Closing the gap: a transatlantic collaboration to foster quality improvement training in graduate entry medical students using applications of QI methodologies to medical education.

The alarming prevalence of medical error and adverse events in the health system raises a call to action to ensure that doctors in training receive adequate training in quality improvement (QI). Training medical students in QI remains a challenge given time constraints, lack of clinical exposure, and already saturated curricula. In some instances, QI training may be delivered during clerkship through didactic, and in some instances, and experiential learning. Preclinical years of medical school remain focused on introducing students to scientific and clinical concepts, rarely do they learn about QI. The Program for Innovation in Scholarship and Medicine (PRISM) is a programme that introduces first-year medical students to the fundamentals of QI using their experience as a medical student as the context. PRISM is a condensed QI curriculum that is delivered through an international partnership, based on a previously piloted programme at a Canadian medical school. Following an introductory workshop, medical students work in teams to develop QI proposals (project charters) which detail how QI principles and tools can generate small-scale improvements within their educational programme. Project charters are assessed by a team of faculty and upper year students, who have previously participated. On completion of the programme, students demonstrated increased knowledge, skills, and attitudes towards QI. Programme participants were satisfied with the structure and expectations of PRISM and expressed a newfound interest in QI. Nearly all participants would recommend PRISM to another medical student. In conclusion, PRISM serves as a resourceful, efficient educational approach for preclerkship students that provides an introduction to the concepts of QI in order for early trainees to build on baseline knowledge and skills throughout their training.

A review of the propriety of thyroid ultrasound referrals and their follow-up burden.

PURPOSE: The overdiagnosis of thyroid nodules and indolent thyroid cancers represents an increasing burden on health services, with thyroid ultrasound (US) imaging often representing the initial entry point into the thyroid nodule diagnostic pathway. The aim of this study was to retrospectively review thyroid US referrals to a single Irish hospital to determine if the stated indications for imaging had been appropriate, to review the results of the scans, and to assess the follow-up required in each case. METHODS: Patient demographics, scan indications, results, and outcomes were retrospectively reviewed for all patients undergoing thyroid ultrasound from 2012 to 2016. Data were analyzed using GraphPad Prism and expressed in mean ± standard deviation. RESULTS: In total, 318 patients (mean age 53 ± 15 years, 85% female) had at least one ultrasound. Most US scans were performed for appropriate indications in order to follow up known thyroid nodular disease and/or malignancy (34.3%), to assess new thyroid goiters or discrete neck lumps (33.3%), and to follow up incidental findings from other imaging modalities (12.6%). However, scans were also requested (in the absence of any palpable goiter or mass) for choking/neck pain/swallowing complaints (12.3%), hypo/hyperthyroidism (6.6%), and miscellaneous reasons (0.6%) that were deemed either potentially or likely inappropriate. Of these scans, approximately half of the identified nodule(s) were deemed unlikely to be related to the stated symptoms, but which subsequently required follow-up imaging ± biopsy. No cases of malignancy were identified. CONCLUSIONS: In our center, a significant percentage of thyroid US scans along with their subsequent follow-up were potentially avoidable.

A case of pembrolizumab-induced severe DKA and hypothyroidism in a patient with metastatic melanoma.

Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy and improved outcomes for patients with advanced disease. Pembrolizumab, a monoclonal antibody that acts as a programmed cell death 1 (PD-1(PDCD1)) inhibitor, has been approved for the treatment of advanced melanoma and other solid tumours. Immune-related adverse events (irAEs) including endocrinopathies have been well described with this and other PD-1 inhibitors. While hypothyroidism and hyperthyroidism, and less commonly hypophysitis, are the most common endocrinopathies occurring in patients treated with pembrolizumab, the incidence of type 1 diabetes mellitus (T1DM) was low in clinical trials. We report a case of pembrolizumab-induced primary hypothyroidism and T1DM presenting with severe diabetic ketoacidosis (DKA). A 52-year-old male patient was treated with pembrolizumab for metastatic melanoma. He presented to the emergency department with a 1-day history of nausea and vomiting 2 weeks after his seventh dose of pembrolizumab, having complained of polyuria and polydipsia for 2 months before presentation. He had been diagnosed with thyroid peroxidase (TPO) antibody-negative hypothyroidism, requiring thyroxine replacement, shortly after his fifth dose. Testing revealed a severe DKA (pH: 6.99, glucose: 38.6 mmol/L, capillary ketones: 4.9 and anion gap: 34.7). He was treated in the intensive care unit as per the institutional protocol, and subsequently transitioned to subcutaneous basal-bolus insulin. After his diabetes and thyroid stabilised, pembrolizumab was recommenced to treat his advanced melanoma given his excellent response. This case highlights the importance of blood glucose monitoring as an integral part of cancer treatment protocols composed of pembrolizumab and other ICIs. Learning points: The incidence of T1DM with pembrolizumab treatment is being increasingly recognised and reported, and DKA is a common initial presentation. Physicians should counsel patients about this potential irAE and educate them about the symptoms of hyperglycaemia and DKA. The ESMO guidelines recommend regular monitoring of blood glucose in patients treated with ICIs, a recommendation needs to be incorporated into cancer treatment protocols for pembrolizumab and other ICIs in order to detect hyperglycaemia early and prevent DKA.

Clocks in the clinic: circadian rhythms in health and disease.

Circadian rhythms are endogenously generated recurring patterns of around 24 hours with well-established roles in physiology and behaviour. These circadian clocks are important in both the aetiology and treatment of various psychiatric and metabolic diseases. To maintain physiological homeostasis and optimal functioning, living life synchronised to these clocks is desirable; modern society, however, promotes a '24/7' lifestyle where activity often occurs during the body's 'biological night', resulting in mistimed sleep and circadian misalignment. This circadian desynchrony can increase the risk of disease and can also influence treatment response. Clinicians should be aware of the influence that circadian desynchrony can have on health and disease, in order to potentially develop new therapeutic strategies and to incorporate chronotherapeutics into current treatment strategies to enhance their utility.