Modifiable factors to prevent severe hypoglycaemic and diabetic ketoacidosis presentations in people with type 1 diabetes.

AIMS: In tackling rising diabetes-related emergencies, the need to understand and address emergency service usage by people with type 1 diabetes is vital. This review aimed to quantify current trends in presentations for type 1 diabetes-related emergencies and identify public health strategies that reduce the frequency of diabetes-related emergencies and improve glycaemic management. METHODS: Medline (OVID), Cochrane and CINAHL were searched for studies published between 2000 and 2023, focusing on people with type 1 diabetes, severe hypoglycaemia and/or diabetic ketoacidosis, and ambulance and/or emergency department usage. There were 1313 papers identified, with 37 publications meeting review criteria. RESULTS: The incidence of type 1 diabetes-related emergencies varied from 2.4 to 14.6% over one year for hypoglycaemic episodes, and between 0.07 and 11.8 events per 100 person-years for hyperglycaemic episodes. Notably, our findings revealed that ongoing diabetes education and the integration of diabetes technology, such as continuous glucose monitoring and insulin pump therapy, significantly reduced the incidence of these emergencies. However, socio-economic disparities posed barriers to accessing these technologies, subsequently shifting the cost to emergency healthcare and highlighting the need for governments to consider subsidising these technologies as part of preventative measures. CONCLUSIONS: Improving access to continuous glucose monitoring and insulin pump therapy, in combination with ongoing diabetes education focusing on symptom recognition and early management, will reduce the incidence of diabetes-related emergencies. Concurrent research assessing emergency healthcare usage patterns during the implementation of such measures is essential to ensure these are cost-effective.

Continuous glucose monitoring: A review of the evidence in type 1 and 2 diabetes mellitus.

CONTEXT AND AIM: Continuous glucose monitoring (CGM) is becoming widely accepted as an adjunct to diabetes management. Compared to standard care, CGM can provide detailed information about glycaemic variability in an internationally standardised ambulatory glucose profile, enabling more informed user and clinician decision making. We aimed to review the evidence, user experience and cost-effectiveness of CGM. METHODS: A literature search was conducted by combining subject headings 'CGM' and 'flash glucose monitoring', with key words 'type 1 diabetes' and 'type 2 diabetes', limited to '1999 to current'. Further evidence was obtained from relevant references of retrieved articles. RESULTS: There is a strong evidence for CGM use in people with type 1 diabetes, with benefits of reduced glycated haemoglobin and hypoglycaemia, and increased time in range. While the evidence for CGM use in type 2 diabetes is less robust, similar benefits have been demonstrated. CGM can improve diabetes-related satisfaction in people with diabetes (PWD) and parents of children with diabetes, as well as the clinician experience. However, CGM does have limitations including cost, accuracy and perceived inconvenience. Cost-effectiveness analyses have indicated that CGM is a cost-effective adjunct to type 1 diabetes management that is associated with reduced diabetes-related complications and hospitalisation. CONCLUSIONS: Continuous glucose monitoring is revolutionising diabetes management. It is a cost-effective adjunct to diabetes management that has the potential to improve glycaemic outcomes and quality of life in PWD, especially type 1 diabetes.

Model-informed drug repurposing: A pharmacometric approach to novel pathogen preparedness, response and retrospection.

During a pandemic caused by a novel pathogen (NP), drug repurposing offers the potential of a rapid treatment response via a repurposed drug (RD) while more targeted treatments are developed. Five steps of model-informed drug repurposing (MIDR) are discussed: (i) utilize RD product label and in vitro NP data to determine initial proof of potential, (ii) optimize potential posology using clinical pharmacokinetics (PK) considering both efficacy and safety, (iii) link events in the viral life cycle to RD PK, (iv) link RD PK to clinical and virologic outcomes, and optimize clinical trial design, and (v) assess RD treatment effects from trials using model-based meta-analysis. Activities which fall under these five steps are categorized into three stages: what can be accomplished prior to an NP emergence (preparatory stage), during the NP pandemic (responsive stage) and once the crisis has subsided (retrospective stage). MIDR allows for extraction of a greater amount of information from emerging data and integration of disparate data into actionable insight.

Treatment implications of a delayed diagnosis of maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a rare form of monogeneic diabetes that classically presents as non-insulin requiring diabetes with evidence of autosomal dominant inheritance in individuals who are typically young and lean. However, these criteria do not capture all cases and can also overlap with other types of diabetes. The hepatocyte nuclear factor-1 alpha (HNF1A) mutation is a common cause of MODY and is highly sensitive to sulphonylureas, which should be first-line therapy. Our case represents the diagnostic challenges of HNF1A MODY and the implications of a delayed diagnosis, which can lead to reduced success of sulphonylurea treatment.

Inter-observer agreement of canine and feline paroxysmal event semiology and classification by veterinary neurology specialists and non-specialists.

BACKGROUND: Advances in mobile technology mean vets are now commonly presented with videos of paroxysmal events by clients, but the consistency of the interpretation of these videos has not been investigated. The objective of this study was to investigate the level of agreement between vets (both neurology specialists and non-specialists) on the description and classification of videos depicting paroxysmal events, without knowing any results of diagnostic workup. An online questionnaire study was conducted, where participants watched 100 videos of dogs and cats exhibiting paroxysmal events and answered questions regarding: epileptic seizure presence (yes/no), seizure type, consciousness status, and the presence of motor, autonomic and neurobehavioural signs. Agreement statistics (percentage agreement and kappa) calculated for each variable, with prevalence indices calculated to aid their interpretation. RESULTS: Only a fair level of agreement (κ = 0.40) was found for epileptic seizure presence. Overall agreement of seizure type was moderate (κ = 0.44), with primary generalised seizures showing the highest level of agreement (κ = 0.60), and focal the lowest (κ =0.31). Fair agreement was found for consciousness status and the presence of autonomic signs (κ = 0.21-0.40), but poor agreement for neurobehavioral signs (κ = 0.16). Agreement for motor signs ranged from poor (κ = ≤ 0.20) to moderate (κ = 0.41-0.60). Differences between specialists and non-specialists were identified. CONCLUSIONS: The relatively low levels of agreement described here highlight the need for further discussions between neurology experts regarding classifying and describing epileptic seizures, and additional training of non-specialists to facilitate accurate diagnosis. There is a need for diagnostic tools (e.g. electroencephalogram) able to differentiate between epileptic and non-epileptic paroxysms.

Exposure-response analyses of efzofitimod in patients with pulmonary sarcoidosis.

Background: Preliminary evidence for efficacy in pulmonary sarcoidosis has been shown for efzofitimod. Here we present supportive evidence of efficacy based on an exposure-response analysis. Methods: Data from two studies (Phase 1, N = 24, single dose in healthy volunteers, and Phase 1b/2a, N = 25, multiple doses over 24 weeks in participants with pulmonary sarcoidosis) were used to build a population pharmacokinetic model. Using this model, the relationship between efzofitimod exposure and three prespecified efficacy parameters [mean daily oral corticosteroid (OCS) dose, percent-predicted forced vital capacity (ppFVC) and King's Sarcoidosis Questionnaire-Lung (KSQ-Lung) score] was explored. Linear regression described the relationship of efzofitimod exposure and OCS reduction, ppFVC and KSQ-Lung score. Logistic regression related efzofitimod exposure to the probability of achieving a minimal clinically important difference for ppFVC and KSQ-Lung score. Due to the small study size, trends (not statistical significance) in relationships are reported. Results: In patients with pulmonary sarcoidosis, as efzofitimod exposure increased, the mean daily OCS dose decreased, and ppFVC and KSQ-Lung score improved over baseline. The slope for all the endpoints by both linear and logistic regression showed an improving trend with increased exposure. Conclusion: These preliminary findings of a positive exposure-response across multiple efficacy endpoints support the claim that proof of concept has been established for the use of efzofitimod in pulmonary sarcoidosis. Clinical Trial Registration: clinicaltrials.gov, identifier NCT03824392.

Dead in bed - A systematic review of overnight deaths in type 1 diabetes.

BACKGROUND: Type 1 diabetes is a significant, life-long condition which affects many people worldwide. One of the most feared causes of type 1 diabetes mortality, overnight mortality, often caused by the dead in bed syndrome, is largely underreported. A systematic literature search was undertaken to understand the frequency, risk factors, causes and impact that diabetes-related technologies have on overnight mortality, in this population. METHODS: MEDLINE (Ovid), Embase (Ovid) and Cochrane were searched to June 2021, using defined inclusion and exclusion criteria. Quality appraisal was undertaken. RESULTS: Overall, 26 records met the inclusion criteria. Large-scale cohort studies examined data up to 2013, and there were no studies published after 2018. The proportion of deaths attributable to the dead in bed syndrome was between 2 and 5% of deaths in children, adolescents, and young adults, with a slight decrease in proportion of dead in bed syndrome since 1991. CONCLUSION: Overnight mortality is occurring for people with type 1 diabetes, reported as recently as in 2018. Living alone, alcohol and illicit substances consistently appear as risk factors, and the impact of technology on overnight mortality is not fully understood, with more recent data, from larger cohort studies being required.

Time to Step Up: A Call to Action For the Clinical and Quantitative Pharmacology Community to Accelerate Therapeutics for COVID-19.

The global response to finding therapeutics for coronavirus disease 2019 (COVID-19) is chaotic even if well intentioned. There is an opportunity, but more importantly, an obligation for the global clinical and quantitative pharmacology community to come together and use our state-of-the-art tools and expertise to help society accelerate therapeutics to fight COVID-19. This brief commentary is a call to action and highlights how the global pharmacology community should contribute to the COVID-19 pandemic and prepare for future pandemics.

Accelerating Clinical Evaluation of Repurposed Combination Therapies for COVID-19.

As the global COVID-19 pandemic continues, unabated and clinical trials demonstrate limited effective pharmaceutical interventions, there is a pressing need to accelerate treatment evaluations. Among options for accelerated development is the evaluation of drug combinations in the absence of prior monotherapy data. This approach is appealing for a number of reasons. First, combining two or more drugs with related or complementary therapeutic effects permits a multipronged approach addressing the variable pathways of the disease. Second, if an individual component of a combination offers a therapeutic effect, then in the absence of antagonism, a trial of combination therapy should still detect individual efficacy. Third, this strategy is time saving. Rather than taking a stepwise approach to evaluating monotherapies, this strategy begins with testing all relevant therapeutic options. Finally, given the severity of the current pandemic and the absence of treatment options, the likelihood of detecting a treatment effect with combination therapy maintains scientific enthusiasm for evaluating repurposed treatments. Antiviral combination selection can be facilitated by insights regarding SARS-CoV-2 pathophysiology and cell cycle dynamics, supported by infectious disease and clinical pharmacology expert advice. We describe a clinical evaluation strategy using adaptive combination platform trials to rapidly test combination therapies to treat COVID-19.

Recent advances in management of type 1 diabetes

BACKGROUND: Management options for people with type 1 diabetes mellitus (T1DM) are evolving rapidly. Individuals with T1DM are able to obtain information regarding new therapeutic options online. It is important for all members of the multidisciplinary diabetes care team to keep up with the latest therapies for optimal clinical care of people with T1DM. OBJECTIVE: The aim of this article is to provide an overview of new and changing therapeutic options for management of T1DM. DISCUSSION: Insulin pumps, continuous and flash glucose monitoring and new insulins are changing the treatment landscape for people with T1DM. As well as access to evidence-based medicine, financial and personal factors play a significant role in influencing management choices.