Insulin-dependent Diabetes Research Articles

Middle segment preserving pancreatectomy versus total pancreatectomy: a comparative analysis of short- and long-term outcomes.

Middle-segment preserving pancreatectomy (MSPP) serves as an alternative to total pancreatectomy (TP) for preserving the pancreatic body in multifocal pancreatic neoplasms. Despite the potential benefits of TP, the detailed short- and long-term prognoses remain unclear. We evaluated the feasibility of MSPP by comparing the perioperative outcomes and postoperative endocrine and exocrine functions with those of TP. The study included 10 TP and 7 MSPP patients. Patients with pancreatic ductal adenocarcinoma and invasive intraductal papillary mucinous carcinoma were excluded. MSPP was associated with a high incidence (57.1%) of postoperative pancreatic fistula (POPF); however, there were no cases of post-pancreatectomy hemorrhage or postoperative mortality in any group. The postoperative hospital stay and readmission rates were comparable between the groups. At 1year postoperatively, MSPP reduced the risk of new-onset insulin-dependent diabetes mellitus, maintained good glycemic control with minimal hypoglycemic events, and preserved skeletal muscle, subcutaneous fat, and visceral fat. One patient in the MSPP group with a neuroendocrine tumor had postoperative recurrence in the para-aortic lymph node. Despite the high POPF rate and oncologic limitations, MSPP showed superior long-term outcomes in glycemic control and preservation of body composition. MSPP may be an acceptable treatment option for selected patients.

Same Day Discharge after Metabolic and Bariatric Surgery in Adults 65 Years and Older: An Analysis of the 2015 to 2022 MBSAQIP.

There is increasing interest in same day discharge (SDD) after metabolic and bariatric surgery (MBS). Among older adults, the safety of SDD is unclear and, as a result, this age group is often excluded from SDD protocols. We aimed to characterize the safety profile of SDD in adults ≥ 65years. The 2015-2022 MBSAQIP was queried for patients ≥ 65years undergoing primary sleeve gastrectomy or RYGB. Patients were stratified based on postoperative day (POD) of discharge: SDD, POD1, POD2, POD3, and ≥ POD4. Logistic regression was used to examine associations between SDD and 30-day Clavien-Dindo complications and readmissions. We identified 63,486 patients ≥ 65years; the median (IQR) age was 68 (4) years. Overall, 2.12% of patients underwent SDD while the majority (52.8%) were discharged on POD1. From 2015 to 2022, the proportion with SDD increased from 1.15% to 4.33%. Compared to those discharged on later days, patients undergoing SDD had proportionally fewer obesity-associated diseases, including insulin-dependent diabetes (SDD 14.2%, POD1 15.5%, POD2 20.4%, POD3 23.2%, POD4 + 26.1%) and COPD (SDD 3.2%, POD1 4.7%, POD2 5.7%, POD3 7.2%, POD4 + 9.6%) (all p < 0.001). Compared to POD1 discharge, SDD was not significantly associated with any class of Clavien-Dindo complications or 30-day readmissions (all p > 0.05). Though use of SDD after MBS in adults ≥ 65years has increased from 2015 to 2022, it remains an uncommon practice. Those undergoing SDD have fewer obesity-associated diseases and, in this select cohort of older adults, SDD is not associated with worse postoperative morbidity and mortality. Careful patient selection is critical for safe SDD in adults ≥ 65years.

Caregiver satisfaction with the use of continuous glucose monitoring and flash glucose monitoring in very young children with type 1 diabetes

BackgroundNew technologies for the management of children with type 1 diabete (T1D) are constantly and rapidly evolving. However, few real-life studies have been conducted, and rarely in the youngest patients (<6 years). AimTo study parental satisfaction with continuous and flash glucose monitoring devices in young children with T1D. MethodsA questionnaire was completed by the parents of 114 children under the age of 6 years with T1D treated with an insulin pump followed-up in one of the hospitals of the French ADIM network between January and July 2020. ResultsOne hundred and nine patients (96 %) were equipped with a glucose monitor and 95 % (104/109) of parents stated that they were satisfied or very satisfied with their child's monitoring device, with no significant difference in satisfaction rates between flash and continuous glucose monitoring. The parameter most strongly associated with satisfaction was confidence in the reliability of the device (p = 0.008). Parents who struggled to apply the device were significantly less satisfied (p = 0.024). In real-life use, 83 % of parents (90/109) used additional adhesives, 28 % reported mild skin reactions (30/108) and 39 % severe skin reactions (42/108), 50 % stated that applying the device was not painful, and 95 % found the device easy to apply. The most commonly reported unexpected difficulties were device malfunction (by 16 respondents), the device being too large and causing scarring (6 respondents), and lengthy calibration (6 respondents). ConclusionThe vast majority of parents in this group of young children with T1D were satisfied with continuous or flash glucose monitoring. Satisfaction was strongly associated with confidence in the reliability of the device. Reported adverse effects such as skin reaction and difficulties attaching the device highlight the importance of data on real-life use.

Decreased prevalence and altered clinical phenotype of systemic sclerosis and other autoimmune connective tissue diseases in type 1 and type 2 diabetes: A cross-sectional observational study.

Evidence has demonstrated that autoimmune diseases tend to coexist at a higher rate than expected, reflecting a common pathogenic pathway. In this study, we investigate the co-occurrence of systemic sclerosis, systemic lupus erythematosus, and Sjogren syndrome in patients with type 1 and type 2 diabetes mellitus. Our data were obtained using the 2019 Healthcare Cost and Utilization Project, and International Classification of Diseases, 10th Revision diagnosis codes were used to identify patients with systemic sclerosis, systemic lupus erythematosus, lupus nephritis, and Sjogren syndrome, as well as patients with type 1 and type 2 diabetes. We utilized Statistical Analysis System 9.4 for all analyses and included designated weight values to produce nationally representative estimates. The prevalence of systemic sclerosis among patients with type 1 diabetes mellitus and type 2 diabetes mellitus was significantly lower than that for the non-diabetes mellitus control group (0.0007% vs 0.09%, p-value = 0.0064 and 0.01% vs 0.07%, p-value < 0.0001), respectively. Similarly, there was a significant decrease in the prevalence of systemic sclerosis with lung involvement in patients with type 1 and type 2 diabetes mellitus, with a statically significant difference in type 2 diabetes mellitus versus nondiabetic group (0.001% vs 0.006%, p-value < 0.0001). We noted a similar pattern regarding the prevalence of systemic lupus erythematosus and lupus nephritis in patients with type 1 and 2 diabetes. Similarly, there was a significant decrease in the prevalence of Sjogren syndrome in patients with type 1 diabetes and type 2 diabetes. The collected data demonstrates an inverse relation between some autoimmune connective tissue diseases and diabetes. This suggests that these diseases and diabetes mellitus may have different immune pathogenesis. There was also a significantly lower incidence of organ complications such as lupus nephritis and systemic sclerosis lung disease among patients with diabetes, suggesting that diabetes and treatment of diabetes may alter the clinical expression of these disorders.

Updated Insights on Childhood Diabetes Epidemiology 2019-2021 and Projections to 2045

This cross-sectional study examines global childhood diabetes trends to guide health care policies, resource allocation, and targeted interventions.

Protocol for a feasibility and acceptability study for UK general population paediatric type 1 diabetes screening-the EarLy Surveillance for Autoimmune diabetes (ELSA) study.

The EarLy Surveillance for Autoimmune (ELSA) study aims to explore the feasibility and acceptability of UK paediatric general population screening for type 1 diabetes. We aim to screen 20,000 children aged 3-13 years for islet-specific autoantibodies through dried blood spot sample collection at home, hospital or community settings. Children with two or more autoantibodies are offered metabolic staging via oral glucose challenge testing. Feasibility assessments will compare recruitment modalities and uptake according to demographic factors (age, gender, ethnicity, level of deprivation and family history of diabetes) to determine optimal approaches for general population screening. The study is powered to identify 60 children (0.3%) with type 1 diabetes (stage 1-3). Parents are invited to qualitative interviews following ELSA completion (child screened negative or positive, single autoantibody or multiple, stage 1-3) to share their screening experience, strengths of the programme and any areas for improvement (acceptability assessments). Parents who decline screening or withdraw from participation are invited to interview to explore any concerns. Finally, we will interview professional stakeholders delivering the ELSA study to explore barriers and facilitators to implementation. Early detection of type 1 diabetes allows insulin treatment to be started sooner, avoids diagnosis as an emergency, gives families time to prepare and the opportunity to benefit from future prevention trials and treatments. ELSA will provide essential feasibility and acceptability assessments for UK general population screening to inform a future national screening programme for paediatric type 1 diabetes.

NOD alleles at Idd1 and Idd2 loci drive exocrine pancreatic inflammation.

Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes and have enabled the identification of several loci associated with diabetes susceptibility, termed insulin-dependent diabetes (Idd). The generation of congenic mice has allowed the characterization of the impact of several loci on disease susceptibility. For instance, NOD.B6-Idd1 and B6.NOD-Idd1 congenic mice were instrumental in demonstrating that susceptibility alleles at the MHC locus (known as Idd1) are necessary but not sufficient for autoimmune diabetes progression. We previously showed that diabetes resistance alleles at the Idd2 locus provide significant protection from autoimmune diabetes onset, second to Idd1. In search of the minimal genetic factors required for T1D onset, we generated B6.Idd1.Idd2 double-congenic mice. Although the combination of Idd1 and Idd2 is not sufficient to induce diabetes onset, we observed immune infiltration in the exocrine pancreas of B6.Idd2 mice, as well as an increase in neutrophils and pancreatic tissue fibrosis. In addition, we observed phenotypic differences in T-cell subsets from B6.Idd1.Idd2 mice relative to single-congenic mice, suggesting epistatic interaction between Idd1 and Idd2 in modulating T-cell function. Altogether, these data show that Idd1 and Idd2 susceptibility alleles are not sufficient for autoimmune diabetes but contribute to inflammation and immune infiltration in the pancreas.

Yonder: Obesity care, maternal body mass index and childhood infections, frozen shoulder and diabetes, and locums.

Yonder: Obesity care, maternal body mass index and childhood infections, frozen shoulder and diabetes, and locums.

Latent Autoimmune Diabetes of Adults Presenting as Recurrent Diabetic Ketoacidosis

Diabetes mellitus encompasses a spectrum of metabolic disorders characterized by hyperglycaemia, resulting from genetic and environmental interactions that impair insulin secretion, glucose utilization, and production. The World Health Organization revised its diabetes classification in 2019 to include six categories: Type 1 -insulin-dependent, Type 2 -insulin-resistant, hybrid forms e.g., Latent Autoimmune Diabetes in Adults -LADA and ketosis-prone diabetes, other specific types, unclassified diabetes, and hyperglycaemia first detected during pregnancy. LADA is a hybrid form of diabetes characterized by gradual autoimmune beta-cell destruction, commonly misdiagnosed as Type 2 diabetes. Diagnostic criteria include onset after 30 years, islet autoantibodies e.g., GAD, and delayed insulin dependence. LADA risk factors include low BMI, autoimmune history, and progressive hyperglycaemia despite oral antidiabetic therapy. High-risk patients undergo GAD antibody testing for confirmation. Accurate identification of LADA is essential for appropriate management, as it bridges features of Type 1 and Type 2 diabetes. Article Details

Treatment regimens and glycaemic outcomes in more than 100 000 children with type 1 diabetes (2013-22): a longitudinal analysis of data from paediatric diabetes registries.

Advances in paediatric type 1 diabetes management and increased use of diabetes technology have led to improvements in glycaemia, reduced risk of severe hypoglycaemia, and improved quality of life. Since 1993, progressively lower HbA1c targets have been set. The aim of this study was to perform a longitudinal analysis of HbA1c, treatment regimens, and acute complications between 2013 and 2022 using data from eight national and one international paediatric diabetes registries. In this longitudinal analysis, we obtained data from the Australasian Diabetes Data Network, Czech National Childhood Diabetes Register, Danish Registry of Childhood and Adolescent Diabetes, Diabetes Prospective Follow-up Registry, Norwegian Childhood Diabetes Registry, England and Wales' National Paediatric Diabetes Audit, Swedish Childhood Diabetes Registry, T1D Exchange Quality Improvement Collaborative, and the SWEET initiative. All children (aged ≤18 years) with type 1 diabetes with a duration of longer than 3 months were included. Investigators compared data from 2013 to 2022; analyses performed on data were pre-defined and conducted separately by each respective registry. Data on demographics, HbA1c, treatment regimen, and event rates of diabetic ketoacidosis and severe hypoglycaemia were collected. ANOVA was performed to compare means between registries and years. Joinpoint regression analysis was used to study significant breakpoints in temporal trends. In 2022, data were available for 109 494 children from the national registries and 35 590 from SWEET. Between 2013 and 2022, the aggregated mean HbA1c decreased from 8·2% (95% CI 8·1-8·3%; 66·5 mmol/mol [65·2-67·7]) to 7·6% (7·5-7·7; 59·4mmol/mol [58·2-60·5]), and the proportion of participants who had achieved HbA1c targets of less than 7% (<53 mmol/mol) increased from 19·0% to 38·8% (p<0·0001). In 2013, the aggregate event rate of severe hypoglycaemia rate was 3·0 events per 100 person-years (95% CI 2·0-4·9) compared with 1·7 events per 100 person-years (1·0-2·7) in 2022. In 2013, the aggregate event rate of diabetic ketoacidosis was 3·1 events per 100 person-years (95% CI 2·0-4·8) compared with 2·2 events per 100 person-years (1·4-3·4) in 2022. The proportion of participants with insulin pump use increased from 42·9% (95% CI 40·4-45·5) in 2013 to 60·2% (95% CI 57·9-62·6) in 2022 (mean difference 17·3% [13·8-20·7]; p<0·0001), and the proportion of participants using continuous glucose monitoring (CGM) increased from 18·7% (95% CI 9·5-28·0) in 2016 to 81·7% (73·0-90·4) in 2022 (mean difference 63·0% [50·3-75·7]; p<0·0001). Between 2013 and 2022, glycaemic outcomes have improved, parallel to increased use of diabetes technology. Many children had HbA1c higher than the International Society for Pediatric and Adolescent Diabetes (ISPAD) 2022 target. Reassuringly, despite targeting lower HbA1c, severe hypoglycaemia event rates are decreasing. Even for children with type 1 diabetes who have access to specialised diabetes care and diabetes technology, further advances in diabetes management are required to assist with achieving ISPAD glycaemic targets. None. For the Norwegian, German, Czech, Danish and Swedish translations of the abstract see Supplementary Materials section.

Vitamin D Supplementation as a Therapeutic Strategy in Autoimmune Diabetes: Insights and Implications for LADA Management.

Latent autoimmune diabetes of adults (LADA) is the most prevalent form of autoimmune diabetes (AI-D) in adulthood; however, its accurate diagnosis and optimal treatment remain challenging. Vitamin D deficiency (VDD) is commonly observed in LADA patients, while increased vitamin D exposure through supplementation and dietary intake is associated with a reduced incidence of LADA. Although limited, case reports, case-control studies, and randomized clinical trials have examined the effects of vitamin D supplementation-alone or combined with dipeptidyl peptidase-4 inhibitors (DPP4-is)-on glucose regulation, residual β-cell function, and glutamic acid decarboxylase antibody (GADA65) levels. Findings, while preliminary, indicate that vitamin D supplementation may enhance glycemic control, preserve β-cell function, and reduce autoimmune activity. Given its accessibility, affordability, and relative safety, vitamin D supplementation presents an attractive adjunct treatment option for LADA patients. This narrative review discusses current evidence on the potential therapeutic benefits of vitamin D supplementation in patients with AI-D, including LADA, who are also vitamin D deficient. Beginning with an exploration of the epidemiological patterns, clinical presentation, and diagnostic framework essential for understanding and identifying LADA, this review then examines the proposed mechanisms through which vitamin D may influence autoimmune modulation of pancreatic β-cells, integrating recent data pertinent to LADA pathology. By distilling and consolidating existing research, we aim to provide a platform for advancing targeted investigations within this distinct patient population.

Red, green, and blue model assessment and AQbD approach to HPTLC method for concomitant analysis of metformin, pioglitazone, and teneligliptin

BackgroundThe CDSCO of India has authorized a combination of metformin hydrochloride, teneligliptin hydrochloride, and pioglitazone hydrochloride for the treatment of insulin-independent diabetes. For the purpose of estimating metformin, teneligliptin, and pioglitazone combinations as well as individual commercial formulations, there are a plethora of publicly accessible chromatographic techniques. More importantly, the development of these chromatographic procedures has included the use of chemical solvents that are dangerous to both animals and the environment.ObjectivesHowever, to date, there has been no documented chromatographic technique that can concomitantly estimate various commercial formulations of drugs under study employing a uniform chromatographic condition and environmentally friendly solvents. In order to concomitantly estimate drugs under study utilizing unified chromatographic conditions, a green HPTLC method was developed.MethodThe AQbD approach was used to carry out the method development. To determine the most important method parameters and response variables, the analytical risk assessment was conducted using the risk priority number ranking and screening approach. Critical method parameters and response variables were modeled using the response surface modeling approach, which relies on the central composite design. Optimal ranges for the intended method operable design region were determined, and control strategy was framed. The chromatographic separation was carried out on preparative TLC plate precoated with silica gel G-60 F254 using 1.0%W/V ammonium acetate in ethanol: water: triethylamine (6.5:0.4:0.6, V/V) as mobile phase. The detection of the anti-diabetic drugs under study was carried out at 267 nm wavelength.ResultsThe linearity of metformin, teneligliptin, and pioglitazone was found to be 5000–25000 ng/band, 200–1000 ng/band, and 150–750 ng/band, respectively. The %RSD for robustness and precision study was found to be less than 2.0%. The %recovery of method was found to be 98–102%. The assay results were shown to be in compliance with respective labeled claims of anti-diabetic medications when the suggested method was used for concurrent analysis of several formulations and combinations of drugs under study.ConclusionThe suggested technique was evaluated utilizing red–green–blue model scoring tools. The suggested technique was determined to be precise, accurate, rapid, cost-effective, and easy to apply for the estimation of drugs under study.

The Anti-Inflammatory Roles of Vitamin D for Improving Human Health

Vitamin D receptors (VDRs) are present in almost all cells of the immune system, including B cells, T cells, NK (Natural Killer) cells, dendritic cells, and monocytes, as well as the epithelial cells of many organs such as the intestine, pancreas, prostate, lungs, and cardiomyocytes. In addition, some immune cells, including dendritic cells, macrophages, and B and T cells, can synthesize calcitriol by expressing 1α-hydroxylase. Upon binding to VDRs, vitamin D (Vit D) regulates the expression of genes involved in immune responses, including those encoding for cytokines. It modulates the production of pro-inflammatory cytokines while promoting the synthesis of anti-inflammatory cytokines. Vit D also affects the differentiation and maturation of cells of the immune system. By inhibiting the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, Vit D reduces the expression of pro-inflammatory genes. These effects highlight the potential of Vit D as a therapeutic agent in the management of inflammatory diseases, including autoimmune disorders, cardiovascular diseases, diabetes, metabolic syndrome, cancer, neurological diseases, depression, and inflammatory bowel disease.

Chronic corticosteroid use does not increase short-term complications following carpometacarpal arthroplasty.

Chronic steroid use has been found to be significantly associated with postoperative complications following total joint arthroplasty. The purpose of this study was to investigate the relationship between chronic steroid and immunosuppressant use and postoperative complications following carpometacarpal (CMC) arthroplasty. The American College of Surgeons National Surgical Quality Improvement Program database was queried for all records of patients who underwent carpometacarpal (CMC) arthroplasty between 2015 and 2020. The initial pool of records was divided into two cohorts: chronic steroid and no chronic steroid use. Patient demographics and comorbidities were compared between cohorts using bivariate logistic regression. A total of 6624 records of CMC arthroplasty were identified in NSQIP from 2015 to 2020. Of the 6432 records remaining after exclusion criteria, 223 (3.5%) were chronic steroid use and 6209 (96.5%) were without chronic steroid use. The patient demographics and comorbidities significantly associated with chronic steroid use were ASA classification ≥ 3 (p < 0.001), insulin-dependent diabetes mellitus (p = 0.032), and COPD (p < 0.001). Compared to no chronic steroid use, chronic steroid use had higher rates of any complication (2.24% vs. 2.01%), superficial incisional SSI (1.35% vs. 0.63%), urinary tract infection (0.45% vs. 0.31%), sepsis (0.45% vs. 0.05%), and mortality (0.45% vs. 0.05%). However, these differences in complication rates were not statistically significant. Chronic preoperative steroid use was not significantly associated with any increased postoperative complication within 30days following CMC arthroplasty. Level III; Retrospective Cohort Comparison; Prognosis Study.

A Review on Diabetes: Current and Future Perspectives

Diabetes Mellitus (DM) is a metabolic syndrome that gradually leads to chronic microvascular or macrovascular complications. There are 2 types of DM: Insulin-dependent diabetes, commonly called type I DM, is an organ-specific autoimmune disorder that destroys the body’s pancreatic β cells, causing insulin deficiency, and can be treated through insulin replacement therapy. Non-insulin-dependent diabetes mellitus, or type II DM, is caused by pancreatic cell dysfunction that affects a person’s ability to use insulin and can be treated with oral hypoglycaemics. Recent investigation confirms that combination therapy of metformin (biguanides), sodium-glucose co-transporter-2 (SGLT2) inhibitors, and Dipeptidyl Peptidase-4 (DPP-4) inhibitors not only reduces HbA1c glucose dependently but also provides better sustained glycaemic stability with good tolerability in comparison to monotherapy. Multi-particulate drug delivery provides targeted drug administration with high bioavailability and compressed dosage administration. In this review analysis, an effort has been made to explore the pathophysiology of type II DM and the importance of combination therapy using microspheres for the delivery of drugs for the management of type II DM.

Current Treatment Options for Diabetes: A Review

Diabetes mellitus, a chronic condition characterized by insufficient insulin production or utilization, has a rich historical context and has evolved significantly since its early identification in ancient civilizations. This article explores the multifaceted nature of diabetes, including its types—Type 1 diabetes (T1D), Type 2 diabetes (T2D), and Latent Autoimmune Diabetes in Adults (LADA)—alongside the pathogenic mechanisms that contribute to its development. The prevalence of diabetes has escalated globally, posing a substantial healthcare burden and leading to serious complications, including cardiovascular diseases and kidney failure. Management strategies have advanced, highlighting the importance of lifestyle modifications, continuous glucose monitoring, and emerging treatments such as artificial pancreas systems, smart insulin, and gene therapy. Furthermore, the potential of stem cell therapy and nanotechnology in the management of diabetes is discussed, indicating a shift towards innovative therapeutic approaches. This comprehensive overview underscores the necessity of tailored treatment strategies and the ongoing research efforts aimed at improving the quality of life for individuals affected by diabetes while addressing the global diabetes epidemic.

Continuous glucose monitoring (CGM) for effective glucose control in a pregnant woman living with type IIIa glycogenosis. A case report

Glycogenosis type III is a rare autosomal recessive disease caused by a mutation in the AGL gene that results in a deficiency of the glycogen debranching enzyme. This deficiency impairs fasting tolerance and leads to hypoglycemia. While the symptomatology tends to improve with age, pregnancy can trigger a recurrence of hypoglycemia due to increased carbohydrate requirements. Since the late 1990s, continuous glucose monitoring (CGM) has been used in insulin-dependent diabetes to aid in the prevention of hypoglycemia. It has also been employed in type I glycogenosis for the same purpose. However, it has never been evaluated for the prevention of hypoglycemia in pregnant women with type III glycogenosis. report: We present the case of a 32-year-old pregnant woman with type IIIa glycogenosis diagnosed at the age of 2 years old. The resurgence of nocturnal hypoglycemia initially led to the reinstatement of continuous nocturnal nutrition. We established remote glucose monitoring via CGM, facilitating medical and dietary teleconsultations until delivery. These teleconsultations enabled dietary adjustment according to the patient's needs, based on the CGM data. This subsequently led to a reduction in the frequency and duration of nocturnal hypoglycemia, even after discontinuing continuous nutrition. No severe hypoglycemia was observed. Our results suggest that CGM combined with telemonitoring can provide effective support for individuals living with glycogenosis during pregnancy and may eliminate the need for resuming continuous nocturnal enteral nutrition. However, these results need to be confirmed with additional patient cases. CGM is a safe tool to limit the risk of hypoglycemia and to improve the quality of life of pregnant patients with type III glycogenosis.

Temporal trends in the utilization, costs, and outcomes of concomitant left atrial appendage closure across a statewide collaborative

ObjectiveWith the rising incidence of atrial fibrillation, left atrial appendage closure (LAAC) at the time of cardiac surgery remains an important adjunct. The present study characterized trends, associated resource utilization, and potential disparities in the use of left atrial appendage exclusion. MethodsUsing a Society of Thoracic Surgeons regional academic collaborative database, we queried all adult patients undergoing coronary and valve procedures with concomitant LAAC between 2015 and 2021. Trends in LAAC, as well as the technique for closure, were evaluated. Multilevel hierarchical logistic modeling was applied to delineate factors associated with LAAC, accounting for patient and operative characteristics. Generalized linear models were developed to perform risk-adjusted incremental cost analysis. ResultsOf the 8699 patients who met the study criteria, 1377 underwent left atrial appendage closure. Over the study period, the annual rate of LAAC increased from 16.7% to 30.8% (P < .001). LAAC patients were older, but less commonly insulin-dependent diabetics or on dialysis. Female sex, redo, and urgent operative status had lower risk-adjusted odds of LAAC. Although LAAC was associated with longer bypass time, there was no significant association with 30-day mortality or 30-day readmission. LAAC was associated with an incremental increase in adjusted costs by $10,602 (95% confidence interval, $4078-$17,126). ConclusionsRates of LAAC are increasing but less common among female patients, as well as those requiring urgent/emergent interventions. LAAC did not significantly impact short-term mortality. Our results suggest that LAAC may be a high-value intervention among patient populations that have the greatest potential to derive its benefits.

Type 1 diabetes genetic risk contributes to phenotypic presentation in monogenic autoimmune diabetes.

Disease-causing variants in key immune homeostasis genes can lead to monogenic autoimmune diabetes. Some individuals carrying disease-causing variants do not develop autoimmune diabetes, even though they develop other autoimmune disease. We aimed to determine whether type 1 diabetes polygenic risk contributes to phenotypic presentation in monogenic autoimmune diabetes. We used a 67 SNP type 1 diabetes genetic risk score (T1D-GRS) to determine polygenic risk in 62 individuals with monogenic autoimmune diabetes and 180 non-autoimmune neonatal diabetes (NDM) controls. We used population-based controls (n=10,405) and individuals with type 1 diabetes (n=285) as a comparator. Individuals with monogenic autoimmune diabetes had higher T1D-GRSs compared to non-autoimmune NDM (mean 11.3 vs. 9.8; P=1.7×10-5) and controls (mean 10.3; P=7.5×10-6) but were markedly lower than type 1 diabetes (14.9; P= 3.3 × 10-21). These differences were explained by monogenic autoimmune diabetes cases having higher Class II HLA genetic risk, specifically from the DRB1*03:01-DQA1*05:01-DQB1*02:01 haplotype (DR3-DQ2) (P<0.01). In the presence of monogenic autoimmunity, the polygenic class II HLA susceptibility contributes to development of autoimmune diabetes. This suggests a role of class II HLA in targeting the dysregulated immune response towards the beta-cell.

12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing beta cells and involves an interplay between beta cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in beta cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our finding demonstrated that VLX-1005, a potent 12-LOX inhibitor, effectively delayed the onset of autoimmune diabetes in human gene replacement non-obese diabetic mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecule PD-L1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.