ISPAD ANNUAL CONFERENCE HIGHLIGHTS 2023.

The 49th Annual Conference of the International Society of Pediatric and Adolescent Diabetes (ISPAD), held from October 18 to 21, 2023, in Rotterdam, Netherlands, showcased significant advancements and diversity in paediatric and adolescent diabetes research and clinical innovations. The conference, renowned for its global impact, brought together experts to discuss cutting-edge developments in the field. Highlights from the plenary sessions included ground-breaking research on immunotherapies and diabetes technologies and offering new insights into personalised treatment approaches. Keynote speakers emphasised the importance of early diagnosis, prevention and the potential of novel biomarkers in predicting disease progression. The symposia covered a broad spectrum of topics, from advancements in continuous glucose monitoring technologies to the latest in hybrid closed loop systems which promise to revolutionise diabetes management for young patients.

Corrigendum to "Blend to Limit OxygEN in ECMO: A RanDomised ControllEd Registry (BLENDER) trial: Study protocol and statistical analysis plan" [Crit Care Resuscit 25 (2023) 118-125].

[This corrects the article DOI: 10.1016/j.ccrj.2023.06.001.].

Impact of Sarcoidosis on In-hospital Outcomes Among Patients with Atrial Fibrillation: A Nationwide Readmissions Database Analysis.

Sarcoidosis is a disease that involves multiple organs, including the cardiovascular system. While cardiac sarcoidosis has been increasingly recognized, the impact of sarcoidosis on atrial fibrillation (AF) is not well established. This study aimed to analyze the impact of sarcoidosis on in-hospital outcomes among patients who were admitted for a primary diagnosis of AF. Using the all-payer, nationally representative Nationwide Readmissions Database, our study included patients aged ≥18 years who were admitted for AF between 2017-2020. We stratified the cohort into two groups depending on the presence of sarcoidosis diagnosis. The in-hospital outcomes were assessed between the two groups via propensity score analysis. A total of 1031 (0.27%) AF patients with sarcoidosis and 387,380 (99.73%) AF patients without sarcoidosis were identified in our analysis. Our propensity score analysis of 1031 (50%) patients with AF and sarcoidosis and 1031 (50%) patients with AF but without sarcoidosis revealed comparable outcomes in early mortality (1.55% vs. 1.55%, P = 1.000), prolonged hospital stay (9.51% vs. 9.70%, P = .874), non-home discharge (7.95% vs. 9.89%, P = .108), and 30-day readmission (13.29% vs. 13.69%, P = .797) between the two groups. The cumulative cost of hospitalization was also similar in both groups ($12,632.25 vs. $12,532.63, P = .839). The in-hospital adverse event rates were comparable in both groups. Sarcoidosis is not a risk factor for poorer in-hospital outcomes following AF admission. These findings provide valuable insights into the effectiveness of the current guideline for AF management in patients with concomitant sarcoidosis and AF.

Long-term assessment of the NHS hybrid closed-loop real-world study on glycaemic outcomes, time-in-range, and quality of life in children and young people with type 1 diabetes.

Hybrid closed-loop (HCL) systems seamlessly interface continuous glucose monitoring (CGM) with insulin pumps, employing specialised algorithms and user-initiated automated insulin delivery. This study aimed to assess the efficacy of HCLs at 12 months post-initiation on glycated haemoglobin (HbA1c), time-in-range (TIR), hypoglycaemia frequency, and quality of life measures among children and young people (CYP) with type 1 diabetes mellitus (T1DM) and their caregivers in a real-world setting. Conducted between August 1, 2021, and December 10, 2022, the prospective recruitment took place in eight paediatric diabetes centres across England under the National Health Service England's (NHSE) HCL pilot real-world study. A cohort of 251 CYP (58% males, mean age 12.3 years) with T1DM participated (89% white, 3% Asian, 4% black, 3% mixed ethnicity, and 1% other). The study utilised three HCL systems: (1) Tandem Control-IQ AP system, which uses the Tandem t:slim X2 insulin pump (Tandem Diabetes Care, San Diego, CA, USA) with the Dexcom G6® CGM (Dexcom, San Diego, CA, USA) sensor; (2) Medtronic MiniMed™ 780G with the Guardian 4 sensor (Medtronic, Northridge, CA, USA); and (3) the CamAPS FX (CamDiab, Cambridge, UK) with the Ypsomed insulin pump (Ypsomed Ltd, Escrick, UK) and Dexcom G6® CGM.All systems were fully funded by the NHS. Results demonstrated significant improvements in HbA1c (average reduction at 12 months 7 mmol/mol; P < 0.001), time-in-range (TIR) (average increase 13.4%; P < 0.001), hypoglycaemia frequency (50% reduction), hypoglycaemia fear, and quality of sleep (P < 0.001) among CYP over a 12-month period of HCL usage. Additionally, parents and carers experienced improvements in hypoglycaemia fear and quality of sleep after 6 and 12 months of use. In addition to the improvements in glycaemic management, these findings underscore the positive impact of HCL systems on both the well-being of CYP with T1DM and the individuals caring for them.

Hypoglycemic effects of dracorhodin and dragon blood crude extract from Daemonorops draco.

BACKGROUND: Dragon blood is a red fruit resin from the palm tree Daemonorops draco and is a herbal ingredient used in the traditional Chinese medicine, "Jinchuang Ointment," which is used to treat non-healing diabetic wounds. According to the Taiwan Herbal Pharmacopeia, the dracorhodin content in dragon blood should exceed 1.0%. RESULTS: Our findings indicate that dracorhodin and dragon blood crude extracts can stimulate glucose uptake in mouse muscle cells (C2C12) and primary rat aortic smooth muscle cells (RSMC). Dracorhodin is not the only active compound in dragon blood crude extracts from D. draco. Next, we orally administered crude dragon blood extracts to male B6 mice. The experimental group displayed a decreasing trend in fasting blood glucose levels from the second to tenth week. In summary, crude extracts of dragon blood from D. draco demonstrated in vivo hypoglycemic effects in B6 male mice. CONCLUSIONS: We provide a scientific basis "Jinchuang ointment" in treating non-healing wounds in patients with diabetes.

Anxiety and its risk factors among non-Japanese residents living in Japan undergoing COVID-19 situation: A cross-sectional survey.

INTRODUCTION: In the context of collective efforts taken in Japan to control the spread of COVID-19, the state of emergency and social distancing have caused a negative impact on the mental health of all residents, including foreign communities in Japan. This study aimed to evaluate the level of anxiety and its associated factors among non-Japanese residents residing in Japan during the COVID-19 pandemic. METHODS: A web-based survey in 13 languages was conducted among non-Japanese residents living in Japan during the COVID-19 situation. The State-Trait Anxiety Inventory assessed the level of anxiety-State (STAI-S) scores prorated from its six-item version. The multivariable logistic regression using the Akaike Information Criterion (AIC) method was performed to identify the associated factors of anxiety among participants. RESULTS: From January to March 2021, we collected 392 responses. A total of 357 valid responses were analyzed. 54.6% of participants suffered from clinically significant anxiety (CSA). In multivariable logistic model analysis, the CSA status or the high level of anxiety was associated with three factors, including having troubles/difficulties in learning or working, decreased sleep duration, and decreased overall physical health (p<0.05). CONCLUSION: Our study suggests several possible risk factors of anxiety among non-Japanese residents living in Japan undergoing the COVID-19 pandemic, including the troubles or difficulties in learning or working, the decrease in sleep duration, and the decrease in overall physical health.

A new model of axon degeneration in the mouse optic nerve using repeat intraocular pressure challenge.

We characterize a new experimental model for inducing retinal ganglion cell (RGC) dysfunction and degeneration in mice. C57BL/6J mice were subjected to two acute periods of intraocular pressure (IOP) elevation (50 mmHg for 30 min) by cannulation of the anterior chamber. We used full-field electroretinography and visual evoked potentials (VEPs) to measure subsequent changes in retina and optic nerve function, and histochemical techniques to assess RGC survival and optic nerve structure. In 12 month old mice, a single IOP challenge caused loss and subsequent recovery of RGC function over the following 28 days with minimal cell death and no observed axonal damage. A second identical IOP challenge resulted in persistent RGC dysfunction and significant (36%) loss of RGC somas. This was accompanied by a 16.7% delay in the latency and a 27.6% decrease in the amplitude of the VEP. Severe axonal damage was seen histologically with enlargement of axons, myelin disruption, reduced axon density, and the presence of glial scarring. In contrast, younger 3 month old mice when exposed to a single or repeat IOP challenge showed quicker RGC functional recovery after a single challenge and full functional recovery after a repeat challenge with no detectable optic nerve dysfunction. These data demonstrate a highly reproducible and minimally invasive method for inducing RGC degeneration and axonal damage in mice. Resilience of the optic nerve to damage is highly dependent on animal age. The time-defined nature of functional versus structural loss seen in this model stands to facilitate investigation of neuroglial responses in the retina after IOP injury and the associated evaluation of neuroprotective treatment strategies. Further, the model may be used to investigate the impact of aging and the cellular switch between neurorecovery and neurodegeneration.

Fever of Unknown Origin in a Patient With Human Immunodeficiency Virus.

Fever of unknown origin (FUO) presents a diagnostic challenge, particularly in patients with human immunodeficiency virus (HIV) due to their immunocompromised state. We report a case of a 21-year-old male with HIV who presented with persistent fever and was found to have a positive proteinase-3 antibody, raising suspicion of granulomatosis with polyangiitis (GPA). The patient's symptoms, negative infectious workup, and elevated proteinase-3 levels prompted consideration of non-infectious etiologies. Despite the absence of renal involvement, corticosteroid therapy was initiated, leading to the resolution of fever. However, the false positive association of proteinase-3 in HIV patients introduces uncertainty regarding the definitive diagnosis of GPA. A tissue biopsy would have provided further clarity, but it was not performed in this case. Our workup aligns more closely with a diagnosis of GPA, considering the patient's response to treatment and the absence of clinical deterioration. This case highlights the complexity of diagnosing non-infectious causes of FUO in HIV-infected individuals. It emphasizes the need for a multidisciplinary approach involving infectious disease specialists and rheumatologists to ensure accurate diagnosis and appropriate management.

Internet analytics of an innovative digital educational resource of type 1 diabetes HelloType1 in local languages for people living with diabetes families and healthcare professionals in Southeast Asia.

BACKGROUND: There is minimal data of health outcomes for Type 1 Diabetes (T1D) in Southeast Asia (SEA) where government funding of insulin and blood glucose monitoring either do not exist or is limited. The full impact of Covid-19 pandemic on the national economies of SEA remain unknown. In the midst of the pandemic, in 2021, HelloType1 was developed by Action4Diabetes (A4D), a non-government organisation charity in collaboration with Southeast Asia local healthcare professionals as an innovative digital educational resource platform of T1D in local languages. HelloType1 was launched in Cambodia, Vietnam, Thailand and Malaysia in 2021 to 2022 with Memorandums of Understandings (MOUs) signed between A4D and each country. Internet data analytics were undertaken between the 1st of January 2022 to 31st of December 2022. AIMS: The aims of this study were to explore the usability and internet data analytics of the HelloType1 online educational platform within each country. METHODS: The data analytics were extracted Google analytics that tracks data from the website hellotype1.com and Facebook analytics associated with the website. RESULTS: There was a 147% increase in the number of HelloType1 users between the first 6 months versus the latter 6 months in 2022 and a 15% increase in the number of pages visited were noted. The majority of traffic source were coming from organic searches with a significant increase of 80% growth in 2022. CONCLUSIONS: The results of the analytics provide important insights on how an innovative diabetes digital educational resource in local languages may be optimally delivered in low-middle income countries with limited resources.

Beyond the formation: unveiling the atmospheric transformation of organosulfates via heterogeneous OH oxidation.

Organosulfates (OSs), characterized with a sulfate ester group (R-OSO3-), are abundant constituents in secondary organic aerosols. Recent laboratory-based investigations have revealed that OSs can undergo efficient chemical transformation through heterogeneous oxidation by hydroxyl radicals (˙OH, interchangeably termed as OH in this article), which freshly derives functionalized and fragmented OSs. The reaction not only contributes to the presence of structurally transformed OSs in the atmosphere of which sources were unidentified, but it also leads to the formation of inorganic sulfates (e.g., SO42-) with profound implication on the form of aerosol sulfur. In this article, we review the current state of knowledge regarding the heterogeneous OH oxidation of OSs based on state-of-the-art designs of experiments, computational approaches, and chemical analytical techniques. Here, we discuss the formation potential of new OSs and SO42-, in light of the influence of diverse OS structures on the relative importance of different reaction pathways. We propose future research directions to advance our mechanistic understanding of these reactions, taking into account aerosol matrix effects, interactions with other atmospheric pollutants, and the incorporation of experimental findings into atmospheric chemical transport models.

Blend to Limit OxygEN in ECMO: A RanDomised ControllEd Registry (BLENDER) Trial: Study Protocol and Statistical Analysis Plan.

Introduction: Critically ill patients supported with venoarterial extracorporeal membrane oxygenation (VA ECMO) are at risk of developing severe arterial hyperoxia, which has been associated with increased mortality. Lower saturation targets in this population may lead to deleterious episodes of severe hypoxia. This manuscript describes the protocol and statistical analysis plan for the Blend to Limit OxygEN in ECMO: A RanDomised ControllEd Registry (BLENDER) Trial. Design: The BLENDER trial is a pragmatic, multicentre, registry-embedded, randomised clinical trial., registered at ClinicalTrials.gov (NCT03841084) and approved by The Alfred Hospital Ethics Committee project ID HREC/50486/Alfred-2019. Participants and setting: Patients supported by VA ECMO for cardiogenic shock or cardiac arrest who are enrolled in the Australian national ECMO registry. Intervention: The study compares a conservative oxygenation strategy (target arterial saturations 92-96%) with a liberal oxygenation strategy (target 97-100%). Main Outcome Measures: The primary outcome is the number of intensive care unit (ICU)-free days for patients alive at day 60. Secondary outcomes include duration of mechanical ventilation, ICU and hospital mortality, the number of hypoxic episodes, neurocognitive outcomes, and health economic analyses. The 300-patient sample size enables us to detect a 3-day difference in ICU-free days at day 60, assuming a mean ICU-free days of 11 days, with a risk of type 1 error of 5% and power of 80%. Data will be analysed according to a predefined analysis plan. Findings will be disseminated in peer-reviewed publications. Conclusions: This paper details the protocol and statistical analysis plan for the BLENDER trial, a registry-embedded, multicentre interventional trial comparing liberal and conservative oxygenation strategies in VA ECMO.

Ten-year review of trends in children with type 1 diabetes in England and Wales.

This review describes the prevalence, incidence, and demographics of children and young people (CYP) with type 1 diabetes in England and Wales using data from the United Kingdom National Paediatric Diabetes Audit (NPDA) and has almost 100% submission from all paediatric diabetes centres annually. It is a powerful benchmarking tool and is an essential part of a long-term quality improvement programme for CYP with diabetes. Clinical characteristics of this population by age, insulin regimen, complication rates, health inequalities, access to diabetes technology, socioeconomic deprivation and glycaemic outcomes over the past decade is described in the review. The NPDA for England and Wales is commissioned by the United Kingdom Healthcare Quality Improvement Partnership as part of the National Clinical Audit for the United Kingdom National Service Framework for Diabetes. The rising incidence of Type 1 diabetes is evidenced in the past decade. Reduction in national median glycated hemoglobin for CYP with diabetes is observed over the last 10 years and the improvement sustained by various initiatives and quality improvement pro-grammes implemented with universal health coverage.

Targeting STING oligomerization with small-molecule inhibitors.

Stimulator of interferon genes (STING) is an essential adaptor protein required for the inflammatory response to cytosolic DNA. dsDNA activates cGAS to generate cGAMP, which binds and activates STING triggering a conformational change, oligomerization, and the IRF3- and NFκB-dependent transcription of type I Interferons (IFNs) and inflammatory cytokines, as well as the activation of autophagy. Aberrant activation of STING is now linked to a growing number of both rare as well as common chronic inflammatory diseases. Here, we identify and characterize a potent small-molecule inhibitor of STING. This compound, BB-Cl-amidine inhibits STING signaling and production of type I IFNs, IFN-stimulated genes (ISGs) and NFκB-dependent cytokines, but not other pattern recognition receptors. In vivo, BB-Cl-amidine alleviated pathology resulting from accrual of cytosolic DNA in Trex-1 mutant mice. Mechanistically BB-Cl-amidine inhibited STING oligomerization through modification of Cys148. Collectively, our work uncovers an approach to inhibit STING activation and highlights the potential of this strategy for the treatment of STING-driven inflammatory diseases.

Prehospital Tranexamic Acid for Severe Trauma.

BACKGROUND: Whether prehospital administration of tranexamic acid increases the likelihood of survival with a favorable functional outcome among patients with major trauma and suspected trauma-induced coagulopathy who are being treated in advanced trauma systems is uncertain. METHODS: We randomly assigned adults with major trauma who were at risk for trauma-induced coagulopathy to receive tranexamic acid (administered intravenously as a bolus dose of 1 g before hospital admission, followed by a 1-g infusion over a period of 8 hours after arrival at the hospital) or matched placebo. The primary outcome was survival with a favorable functional outcome at 6 months after injury, as assessed with the use of the Glasgow Outcome Scale-Extended (GOS-E). Levels on the GOS-E range from 1 (death) to 8 ("upper good recovery" [no injury-related problems]). We defined survival with a favorable functional outcome as a GOS-E level of 5 ("lower moderate disability") or higher. Secondary outcomes included death from any cause within 28 days and within 6 months after injury. RESULTS: A total of 1310 patients were recruited by 15 emergency medical services in Australia, New Zealand, and Germany. Of these patients, 661 were assigned to receive tranexamic acid, and 646 were assigned to receive placebo; the trial-group assignment was unknown for 3 patients. Survival with a favorable functional outcome at 6 months occurred in 307 of 572 patients (53.7%) in the tranexamic acid group and in 299 of 559 (53.5%) in the placebo group (risk ratio, 1.00; 95% confidence interval [CI], 0.90 to 1.12; P = 0.95). At 28 days after injury, 113 of 653 patients (17.3%) in the tranexamic acid group and 139 of 637 (21.8%) in the placebo group had died (risk ratio, 0.79; 95% CI, 0.63 to 0.99). By 6 months, 123 of 648 patients (19.0%) in the tranexamic acid group and 144 of 629 (22.9%) in the placebo group had died (risk ratio, 0.83; 95% CI, 0.67 to 1.03). The number of serious adverse events, including vascular occlusive events, did not differ meaningfully between the groups. CONCLUSIONS: Among adults with major trauma and suspected trauma-induced coagulopathy who were being treated in advanced trauma systems, prehospital administration of tranexamic acid followed by an infusion over 8 hours did not result in a greater number of patients surviving with a favorable functional outcome at 6 months than placebo. (Funded by the Australian National Health and Medical Research Council and others; PATCH-Trauma ClinicalTrials.gov number, NCT02187120.).

G-CSF drives autoinflammation in APLAID.

Missense mutations in PLCG2 can cause autoinflammation with phospholipase C gamma 2-associated antibody deficiency and immune dysregulation (APLAID). Here, we generated a mouse model carrying an APLAID mutation (p.Ser707Tyr) and found that inflammatory infiltrates in the skin and lungs were only partially ameliorated by removing inflammasome function via the deletion of caspase-1. Also, deleting interleukin-6 or tumor necrosis factor did not fully prevent APLAID mutant mice from autoinflammation. Overall, these findings are in accordance with the poor response individuals with APLAID have to treatments that block interleukin-1, JAK1/2 or tumor necrosis factor. Cytokine analysis revealed increased granulocyte colony-stimulating factor (G-CSF) levels as the most distinct feature in mice and individuals with APLAID. Remarkably, treatment with a G-CSF antibody completely reversed established disease in APLAID mice. Furthermore, excessive myelopoiesis was normalized and lymphocyte numbers rebounded. APLAID mice were also fully rescued by bone marrow transplantation from healthy donors, associated with reduced G-CSF production, predominantly from non-hematopoietic cells. In summary, we identify APLAID as a G-CSF-driven autoinflammatory disease, for which targeted therapy is feasible.

Paediatric Society and Hyperinsulinism Charity National Surveys on CGM Access for Patients With Recurrent Hypoglycaemia.

Context: Recurrent hypoglycemia can result in significant neurological impairments in children and continuous glucose monitoring (CGM) technology has been shown to reduce recurrent hypoglycemia in conditions such as type 1 diabetes. In the United Kingdom, CGM devices are currently only recommended by the National Institute of Clinical Excellence (NICE) for patients with diabetes and not for other diagnoses. Objective: To examine access to CGM technology for children and young people with recurrent hypoglycemia in the United Kingdom. Methods: In 2021, the British Society of Paediatric Endocrinology and Diabetes (BSPED) conducted a national health professional survey in England, Wales, Scotland, and Northern Ireland looking at CGM access to funding for children and young people with recurrent hypoglycemia, without the diagnosis of diabetes. The UK Children's Hyperinsulinism Charity (UK CHC) also conducted a national patient survey. Results: Responses from BSPED were received from 55 units while the UK CHC received 69 responses from individual families, the largest response to a survey carried out by the charity. The results of the BSPED and UK CHC surveys found that funding streams for CGM were highly variable. Only 29% were able to access CGM for recurrent hypoglycemia and from these, 65% were self-funding CGM. Quality of life benefits were evident from the UK CHC survey on the utility of CGM in reducing worry, improving sleep, lessening the burden of frequently finger-pricking and reducing out-of-hours appointments as a result of hypoglycemia. Patient-reported utilization rates of blood glucose test strips per week were significantly reduced. Conclusion: BSPED and UK CHC national surveys support a call and a consideration for CGM access to be widened to patients who suffer from recurrent hypoglycemia such as those with hyperinsulinism or metabolic conditions. The prevention of recurrent hypoglycemia and improving quality of life for patients and carers remain a cornerstone management for people who suffer from frequent hypoglycemia. CGM education is critical to support its use and understand its limitations. Further research is warranted to determine the safety and efficacy of CGM in detection and reduction of hypoglycemic events, impact of hospital stay, and long-term neurological outcomes in those who suffer from recurrent hypoglceamia.

Artificial cilia for soft and stable surface covalent immobilization of bone morphogenetic protein-2.

Preservation of growth factor sensitivity and bioactivity (e.g., bone morphogenetic protein-2 (BMP-2)) post-immobilization to tissue engineering scaffolds remains a great challenge. Here, we develop a stable and soft surface modification strategy to address this issue. BMP-2 (a model growth factor) is covalently immobilized onto homogeneous poly (glycidyl methacrylate) (PGMA) polymer brushes which are grafted onto substrate surfaces (Au, quartz glass, silica wafer, or common biomaterials) via surface-initiated atom transfer radical polymerization. This surface modification method multiplies the functionalized interfacial area; it is simple, fast, gentle, and has little effect on the loaded protein owing to the cilia motility. The immobilized BMP-2 (i-BMP-2) on the surface of homogeneous PGMA polymer brushes exhibits excellent bioactivity (⁓87% bioactivity of free BMP-2 in vitro and 20%-50% higher than scaffolds with free BMP-2 in vivo), with conformation and secondary structure well-preserved after covalent immobilization and ethanol sterilization. Moreover, the osteogenic activity of i-BMP-2 on the nanoline pattern (PGMA-poly (N-isopropylacrylamide)) shows ⁓110% bioactivity of free BMP-2. This is superior compared to conventional protein covalent immobilization strategies in terms of both bioactivity preservation and therapeutic efficacy. PGMA polymer brushes can be used to modify surfaces of different tissue-engineered scaffolds, which facilitates in situ immobilization of growth factors, and accelerates repair of a wide range of tissue types.

Emerging PET Tracers in Cardiac Molecular Imaging.

18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) represent emerging PET tracers used to assess atherosclerosis-related inflammation and molecular calcification, respectively. By localizing to sites with high glucose utilization, FDG has been used to assess myocardial viability for decades, and its role in evaluating cardiac sarcoidosis has come to represent a major application. In addition to determining late-stage changes such as loss of perfusion or viability, by targeting mechanisms present in atherosclerosis, PET-based techniques have the ability to characterize atherogenesis in the early stages to guide intervention. Although it was once thought that FDG would be a reliable indicator of ongoing plaque formation, micro-calcification as portrayed by NaF-PET/CT appears to be a superior method of monitoring disease progression. PET imaging with NaF has the additional advantage of being able to determine abnormal uptake due to coronary artery disease, which is obscured by physiologic myocardial activity on FDG-PET/CT. In this review, we discuss the evolving roles of FDG, NaF, and other PET tracers in cardiac molecular imaging.