Onset Of Type Research Articles

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy

Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P=.001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P=.006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P=.38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P=.0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P=.0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P=.0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

Urban and rural differences in new onset type 2 diabetes: Comparisons across national and regional samples in the diabetes LEAD network

IntroductionGeographic disparities in diabetes burden exist throughout the United States (US), with many risk factors for diabetes clustering at a community or neighborhood level. We hypothesized that the likelihood of new onset type 2 diabetes (T2D) would differ by community type in three large study samples covering the US. Research design and methodsWe evaluated the likelihood of new onset T2D by a census tract-level measure of community type, a modification of RUCA designations (higher density urban, lower density urban, suburban/small town, and rural) in three longitudinal US study samples (REGARDS [REasons for Geographic and Racial Differences in Stroke] cohort, VADR [Veterans Affairs Diabetes Risk] cohort, Geisinger electronic health records) representing the CDC Diabetes LEAD (Location, Environmental Attributes, and Disparities) Network. ResultsIn the REGARDS sample, residing in higher density urban community types was associated with the lowest odds of new onset T2D (OR [95% CI]: 0.80 [0.66, 0.97]) compared to rural community types; in the Geisinger sample, residing in higher density urban community types was associated with the highest odds of new onset T2D (OR [95% CI]: 1.20 [1.06, 1.35]) compared to rural community types. In the VADR sample, suburban/small town community types had the lowest hazard ratios of new onset T2D (HR [95% CI]: 0.99 [0.98, 1.00]). However, in a regional stratified analysis of the VADR sample, the likelihood of new onset T2D was consistent with findings in the REGARDS and Geisinger samples, with highest likelihood of T2D in the rural South and in the higher density urban communities of the Northeast and West regions; likelihood of T2D did not differ by community type in the Midwest. ConclusionsThe likelihood of new onset T2D by community type varied by region of the US. In the South, the likelihood of new onset T2D was higher among those residing in rural communities.

The description of neuromyelitis optica spectrum disorder: Patient registry in Yangtze River Delta area of China

ObjectiveTo describe the clinical features of neuromyelitis optica spectrum disorder (NMOSD) through patient registry in Yangtze River Delta area of China. MethodsA total of 502 consecutive patients diagnosed with aquaporin-4 antibody (AQP4-ab)-positive NMOSD were registered between December 2018 to January 2021 in multiple tertiary referral centers within the framework of Yangtze River Delta of China. Their baseline data were reviewed, and follow-up clinical information were collected prospectively. ResultsThe mean age at onset was 37.3 (range 3–80 years) years and the female-to-male ratio was 8.1:1. The median disease duration was 47 months (interquartile range [IQR] 25–84 months). A total of 1372 attacks of the 502 patients were recorded till the last follow-up, with a median annualized relapse rate of 0.4 (IQR 0.3–0.6). Nearly one-fourth (24.5%, 336/1372) of the attacks had prodromic events, including upper respiratory tract infection (36.3%, 122/336), fever (20.2%, 68/336) and pregnancy-related issues (17.9%, 60/336), etc. Myelitis was the most common attack type throughout the disease course (51.4%, 705/1372), followed by optic neuritis (ON, 43.1%, 592/1372). As for onset phenotype, ON (37.3%, 187/502) prevailed over myelitis (28.3%, 142/502). The median time to first relapse was 12 months (IQR 5–25 months). Patients with brainstem encephalitis at onset were more likely to have other anatomical region involved in subsequent attacks (p < 0.001), compared to other onset type. The median serum AQP4-ab titer measured by cell-based assays was 1:100 (IQR 1:32–1:320, range 1:10–1:10,000). The baseline AQP4-ab titer in cerebrospinal fluid (r = 0.542, p <0.001), overall ARR (r = 0.232, p< 0.001) and the EDSS scores at last follow-up (r = 0.119, p = 0.022) significantly correlated with baseline serum AQP4-ab titer. Antinuclear antibodies (48.4%), thyroid peroxidase antibodies (30.7%), and anti-SSA antibodies (26.2%) represented the most frequent concomitant antibodies, while autoimmune thyroid disorders (13.1%, 66/502) and Sjogren's syndrome (10.8%, 54/502) were the most common accompanying autoimmune diseases. Till the last follow-up, 403 patients received preventive treatments. Azathioprine represented the most common initial treatment, mycophenolate mofetil and rituximab was the most common second and third-line treatment, respectively. The EDSS score at the last follow-up ranged from 0 to 8.5 with a median of 2 (IQR 1–3). ConclusionsA comprehensive clinical picture of patients with AQP4-ab-positive NMOSD in Yangtze River Delta area of China was presented. More information on disease tragedy and predictive prognostic factors could be generated through long-term observations.

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Role of Magnetic Resonance Imaging Findings in Adults Presenting with New-Onset Seizures

Background: New-onset seizure can be potential life threatening condition. It raises the suspicion of intracranial abnormality or a primary epilepsy .These are mostly diagnosed and differentiated clinically, however diagnostic imaging has important role in evaluating the cause of seizure . Previously studies done on neuroimaging in seizures have mostly focused on assessment of seizures in children or adults in acute emergency however this study focused on new onset seizures in adults .Magnetic Resonance Imaging (MRI) is readily available in tertiary care hospitals these days and is important diagnostic modality for evaluating the causes of new-onset seizure in adults. Aims and Objectives: The purpose of this study was to discuss the magnetic resonance imaging finding in adult patients presenting with new-onset seizure and if the MRI established the cause for the patient's new onset seizure Methods: This was prospective cross sectional study done in 330 adult patients above age of 18 year who presented with new-onset seizures from May 2020 to April 2021. These patients were referred to Radiology department Hayatabad Medical Complex to evaluate intracranial abnormality and to find out the cause of seizure. MRI brain was performed on 1.5T machine and images were independently reviewed by two consultant Radiologists. The findings were summarized and categorized into a study database. Results: In our study 330 adults presenting with new onset seizures underwent MRI within 48 hours of seizure . The mean age was 47 yrs . MRI determined the cause of new-onset seizure in 139 (42.1%) patients while 191(57.9%) studies were normal.. The most common findings were encephalomalacia with gliosis related to previous trauma ,chronic infarcts and surgery ( 38.1%),primary/metastatic brain tumour (24.4%), infectious encephalitis and meningitis(15.8 %), venous sinus thrombosis (8.6%), while and PRESS(7.2%) and vascular malformation(5.7%) were less common findings, . Patients with focal seizures had a higher proportion of potentially epileptogenic lesions (64.7%) compared with those with seizures of generalized onset (10.8%) or uncertain type (24.6%) Conclusion: This study emphasizes the importance of magnetic resonanace imaging in adults presenting with acute seizures and its usefulness in determining the epileptogenic lesions and helps in planning the treatment strategy. Keywords: Seizures, Magnetic resonance imaging, Intracranial abnormality.

The Impact of Visual Impairment on Completion of Cognitive Screening Assessments: A Post-Hoc Analysis from the IVIS Study.

Aim:The aim of this study was to evaluate completed cognitive screens in stroke survivors with and without visual impairment to explore whether the presence of visual impairment impacts on completion of cognitive screening.Materials and methods:Cognitive screening assessment was undertaken using the Oxford Cognitive Screen (OCS). Data from visual function assessments (inclusive of visual acuity, visual fields, eye movements and visual perception evaluation) were analysed to determine whether presence and/or type of visual impairment impacted on cognitive screening scores achieved. Covariates, including glasses use, gender, age at stroke onset and stroke type, were used to assess confounding impacts on scores attained during cognitive screening.Results:1500 stroke admissions were recruited. One hundred ninety-seven who completed the OCS, were identified from the IVIS study database. Those who reported visual symptoms performed worse statistically on all cognitive tasks except the recall recognition (p = 0.232) and executive tasks (p = 0.967). Visual symptoms did not prevent participants from completing every section of the OCS (p = 0.095). In certain tasks, those not wearing their required glasses performed worse, including the executive function (p = 0.012), broken hearts and sentence reading tasks.Conclusions:Many tasks within cognitive screening assessment are impacted by presence of visual deficits, and adjustments, where possible (e.g. good lighting, large print) should be used to facilitate completion of cognitive screening. It is important to ensure required reading correction is worn during screening.

Increased Severe Cases and New-Onset Type 1 Diabetes Among Children Presenting With Diabetic Ketoacidosis During First Year of COVID-19 Pandemic in Turkey

IntroductionThere have been some significant changes regarding healthcare utilization during the COVID-19 pandemic. Majority of the reports about the impact of the COVID-19 pandemic on diabetes care are from the first wave of the pandemic. We aim to evaluate the potential effects of the COVID-19 pandemic on the severity of diabetic ketoacidosis (DKA) and new onset Type 1 diabetes presenting with DKA, and also evaluate children with DKA and acute COVID-19 infection.MethodsThis is a retrospective multi-center study among 997 children and adolescents with type 1 diabetes who were admitted with DKA to 27 pediatric intensive care units in Turkey between the first year of pandemic and pre-pandemic year.ResultsThe percentage of children with new-onset Type 1 diabetes presenting with DKA was higher during the COVID-19 pandemic (p < 0.0001). The incidence of severe DKA was also higher during the COVID-19 pandemic (p < 0.0001) and also higher among children with new onset Type 1 diabetes (p < 0.0001). HbA1c levels, duration of insulin infusion, and length of PICU stay were significantly higher/longer during the pandemic period. Eleven patients tested positive for SARS-CoV-2, eight were positive for new onset Type 1 diabetes, and nine tested positive for severe DKA at admission.DiscussionThe frequency of new onset of Type 1 diabetes and severe cases among children with DKA during the first year of the COVID-19 pandemic. Furthermore, the cause of the increased severe presentation might be related to restrictions related to the pandemic; however, need to evaluate the potential effects of SARS-CoV-2 on the increased percentage of new onset Type 1 diabetes.

Development and validation of machine learning models for prediction of seizure outcome after pediatric epilepsy surgery.

There is substantial variability in reported seizure outcome following pediatric epilepsy surgery, and lack of individualized predictive tools that could evaluate the probability of seizure freedom postsurgery. The aim of this study was to develop and validate a supervised machine learning (ML) model for predicting seizure freedom after pediatric epilepsy surgery. This is a multicenter retrospective study of children who underwent epilepsy surgery at five pediatric epilepsy centers in North America. Clinical information, diagnostic investigations, and surgical characteristics were collected, and used as features to predict seizure-free outcome 1 year after surgery. The dataset was split randomly into 80% training and 20% testing data. Thirty-five combinations of five feature sets with seven ML classifiers were assessed on the training cohort using 10-fold cross-validation for model development. The performance of the optimal combination of ML classifier and feature set was evaluated in the testing cohort, and compared with logistic regression, a classical statistical approach. Of the 801 patients included, 61.3% were seizure-free 1 year postsurgery. During model development, the best combination was XGBoost ML algorithm with five features from the univariate feature set, including number of antiseizure medications, magnetic resonance imaging lesion, age at seizure onset, video-electroencephalography concordance, and surgery type, with a mean area under the curve (AUC) of .73 (95% confidence interval [CI] = .69-.77). The combination of XGBoost and univariate feature set was then evaluated on the testing cohort and achieved an AUC of .74 (95% CI = .66-.82; sensitivity=.87, 95% CI = .81-.94; specificity=.58, 95% CI = .47-.71). The XGBoost model outperformed the logistic regression model (AUC=.72, 95% CI = .63-.80; sensitivity=.72, 95% CI = .63-.82; specificity=.66, 95% CI = .53-.77) in the testing cohort (p= .005). This study identified important features and validated an ML algorithm, XGBoost, for predicting the probability of seizure freedom after pediatric epilepsy surgery. Improved prognostication of epilepsy surgery is critical for presurgical counseling and will inform treatment decisions.

Childhood and adolescent onset type 2 diabetes mellitus (CAT2DM): The yoke of the young diabetics

AimsTo study the prevalence, clinical characteristics, complications, and treatment pattern of childhood – and adolescent-onset type 2 diabetes among young diabetes patients (<25 years at diagnosis). MethodsWe conducted an observational retro-prospective study among young diabetics at a tertiary care hospital between January 2012 and December 2020. A detailed medical assessment, laboratory evaluation, and screening for complications were done in all patients. ResultsWe analyzed a total of 130 patients, with a mean age of 23 years. Forty-seven (36.2%) had a family history. Osmotic symptoms and weight loss were the predominant features, 4 had ketosis, but 34.65% were detected incidentally. Seventy-two (55.2%) were overweight and obese. Most of the patients were uncontrolled, with a mean HbA1c of 9.4 ± 2.8%. There were 1.5%, 1.5%, and 2.3% of retinopathy, nephropathy, and neuropathy cases detected at evaluation. Seventy-nine (60.8%) patients were controlled on oral hypoglycemic agents (OHAs) alone, and 45 (34.5%) needed insulin at onset for control. ConclusionThis study on CAT2DM emphasizes the fact that diabetes has emerged over the past decade among young adults. Screening may be needed in high-risk groups, and prompt, effective treatment may change prognosis significantly.

Glucose-independent racial disparity in HbA1c is evident at onset of type 1 diabetes

ObjectiveHigher levels of HbA1c, independent of blood glucose levels, have been described in Blacks compared to Whites patients with established diabetes. The goal of this study was to determine if glucose-independent racial disparity in HbA1C is evident at diabetes onset. Research design and methodsWe conducted a retrospective single-center chart review of 189 youth with new onset Type 1 diabetes (T1D) 60 % Whites and 40 % Blacks. HbA1c, glucose and other biochemistry measures were obtained at presentation in the Emergency Department before initiation of any therapy. HbA1c levels were adjusted for presenting glucose, self-identified race, age, gender, hematocrit, and RDW-CV. ResultsBlacks with T1D had statistically significant higher unadjusted HbA1c (11.9 ± 1.9 vs 11.04 ± 2.0 %, p = 0.004), initial glucose (530.6 ± 230.4 vs 442 ± 211.3 mg/dL, p = 0.0075) and lower pHs (7.28 ± 0.15 vs 7.33 ± 0.12, p = 0.02) compared to white patients. Least squares means of HbA1c remained higher in Black patients even after statistical adjustment for presenting glucose, age, gender, RDW-CV, and pH. In a multiple variable model (R2 = 0.38, p < 0.0001) c-peptide was influenced by HCO3 (p = 0.0035), gender (p = 0.0092), BMI (p < 0.0001), but not race or glucose. ConclusionsHbA1c at initial presentation of T1D is higher in young Black patients compared to Whites even after adjustment for glucose, age, gender, and RDW-CV. This racial disparity is consistent with other studies in individuals without diabetes and patients with long-standing diabetes under treatment.

Immune checkpoint inhibitor–induced diabetes mellitus across NCI trials.

2668 Background: Immune checkpoint inhibitors (CPI) are known to rarely cause new onset diabetes (CPI DM). While rare, this adverse event is quite challenging for patients and clinicians to manage. Therefore, it is important to identify risk factors and clinical characteristics. This is the first comprehensive, multi-institutional study of CPI-DM across multiple agents and cancer types. Methods: The NCI Cancer Therapy Program (CTEP) database of adverse events (AEs) was queried for AEs related to diabetes (Grade 3 or 4 hyperglycemia, Acidosis including Diabetic Ketoacidosis (DKA), glucose intolerance and diabetes mellitus) among 6,925 patients who had been treated with a PD-(L)1 inhibitor alone or in combination from 6/2015 to 12/2019. Each AE report was reviewed and classified as due to CPI DM, new onset type 2 diabetes mellitus (T2DM), T2DM exacerbation without medication non-compliance, existing DM with medication non-compliance, or association with steroids (SDM). CPI DM was diagnosed based on: evidence of insulin deficiency either through presentation in DKA or low c-peptide with need for long term basal bolus insulin to maintain euglycemia and/or positive islet autoantibodies. Results: In total, there were 82 cases with at least one of these AEs; 41 had CPI-DM, 22 had SDM, 1 had new T2DM, 4 had T2DM exacerbation, 3 had medication noncompliance and 11 had acidosis not attributable to diabetes or had insufficient data. After excluding non-hyperglycemic acidosis, 57.8% had CPI-DM. Furthermore, if not on steroids and in good compliance with diabetes medications, 89.1% had CPI-DM. The incidence of CPI-DM was 0.59%; it was most common on combination PD-1/CTLA-4 inhibitor therapy (0.85%, 15/1767), followed by PD-(L)1 inhibitor monotherapy (0.54%, 18/3354), followed by CPIs combined with additional agents including chemotherapy and targeted agents (0.44%, 8/1804)(p = 0.25). Hospitalization was required for 87.5% of CPI-DM cases with 74.3% of those requiring an inpatient endocrine consult. All but one CPI-DM case had an endocrine consult at as either an inpatient or outpatient. Conclusions: While rare, this cohort shows the large health care burden of CPI-DM and that any hyperglycemia, and especially marked hyperglycemia, should be treated as CPI-DM until proven otherwise. [Table: see text]

288-OR: Effect of 24 Months of Optimised Glucose Control on Residual C-Peptide Secretion in Youth with New Onset Type 1 Diabetes (T1D)

Background: We assessed whether improved glucose control with hybrid closed loop can preserve C-peptide secretion compared to standard insulin therapy in youth with T1D. Methods: In a multicentre, randomised, parallel trial, youth aged to &amp;lt;17 yrs were randomised within 21 days of T1D diagnosis to hybrid closed loop using Cambridge algorithm (CL) or standard insulin therapy (control) for 24 months. Analysis was by intention to treat. Results: We randomised 97 participants (mean±SD age 12±2 yrs) , 51 to CL and 46 to control. There was no difference in C-peptide AUC at 12 months (primary endpoint) or 24 months between groups (geometric mean [95% CI] 12 months CL: 0.35 pmol/mL [0.27, 0.43] vs. control: 0.46 pmol/mL [0.33, 0.61]; mean adjusted difference -0.[-0.14 to 0.03]; p=0. and 24 months CL: 0.17 pmol/mL [0.12, 0.23] vs. control: 0.25 pmol/mL [0.12, 0.39]; mean adjusted difference -0.[-0.14 to 0.05]; p=0.25) . Glycated haemoglobin was lower in the CL group by 4 mmol/mol [0.4%] (95% CI 0 to 8 mmol/mol [0.0 to 0.7%]) at 12 months, and mmol/mol [0.9%], (95% CI 7 to 15 mmol/mol [0.4 to 1.5%]; p&amp;lt;0.001) at 24 months. Five severe hypoglycaemic events occurred in CL group (3 participants) , and two in control group (2 participants) ; one DKA occurred in the CL group. Conclusions: In new onset T1D, optimising glucose control for 24 months does not appear to prevent the decline in residual C-peptide secretion. Disclosure C.K. Boughton: Consultant; CamDiab Ltd. J. Ware: None. J.M. Allen: None. M.E. Wilinska: Consultant; CamDiab Ltd. S. Hartnell: Advisory Panel; Medtronic. Speaker's Bureau; Dexcom, Inc., Sanofi. Other Relationship; Ask Diabetes Ltd. A. Thankamony: None. T. Randell: Consultant; Abbott Diabetes. Speaker's Bureau; Novo Nordisk. A. Ghatak: None. D. Elleri: None. R. Bailey: None. G.J. Dunseath: None. R. Hovorka: Advisory Panel; Eli Lilly and Company. Research Support; Abbott Diabetes, Dexcom, Inc., Medtronic. Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. Other Relationship; CamDiab Ltd. Funding National Institute for Health Research EME Grant (14/23/09) Leona M &amp; Harry B Helmsley Charitable Trust Grant (#2016PG-T1D046) Additional support for the artificial pancreas work is from National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z) . Medtronic and Dexcom supplied discounted CGM devices, sensors and details of communication protocol to facilitate real-time connectivity. Abbott Diabetes Care provided Libre Pro sensors.

1137-P: Continuous Glucose Monitoring (CGM) Use and Its Impact on Glycemic Control and Acute Complications among Older-Onset Type 1 Diabetes Patients within the Veterans Health Administration (VHA)

There is increasing recognition that older onset type 1 diabetes (T1D) is not uncommon. Although CGM use is rising dramatically among those with T1D, little is known regarding its use and benefits within this older T1D population. To address these questions, we identified new CGM users (new CGM sensor prescriptions for T1D developing after military enrollment) and non-users (T1D receiving care and glucose strips from the VHA) during the years 2015-2020 and used national VHA healthcare data and ICD-9/ICD-diagnostic codes from visit encounters to compare baseline characteristics, change in glucose control and new emergency (ER) or hospital admissions. Linear mixed models and Cox proportional models (with propensity score overlap weighting) , were used to compare pre/post changes in HbA1c, and time to acute admissions, respectively. Compared with 4732 nonCGM users, CGM users (n=5,143) had similar HbA1c levels but differed in many ways at initiation of CGM, including: being significantly younger (59 vs. 65 years) , higher proportion White (83 vs. 75%) , and more frequently using glucagon (36 vs. 12 %) , short-acting insulin (99 vs. 86%) and insulin pumps (54 vs.7%) . After propensity overlap weighting, all characteristics were nearly identical between groups. Initiation of CGM was associated with reduced HbA1c levels (- 0.2 and -0.26% at 6 and 12 months (p’s&amp;lt; 0.001) compared with nonCGM users. Similarly, CGM users also had greater declines in risk for total hospitalizations (HR = .88; CI 0.79-0.98) and hypoglycemic (HR = .69; CI 0.53-0.90) and hyperglycemic (HR = .77; CI 0.64-0.94) related ER visits/hospitalizations (all p’s &amp;lt; 0.02) . In this large national study of CGM initiation in older T1D patients, CGM use was linked with improved glucose control as well as reduced ER and/or hospital admissions for hypoglycemia, hyperglycemia or any cause. Disclosure J.Zhou: Research Support; Dexcom, Inc. M.Newell: Research Support; Dexcom, Inc. S.Rivas: None. X.Zhou: None. G.J.Norman: Employee; Dexcom, Inc. P.Reaven: Research Support; AstraZeneca, Dexcom, Inc. Funding DexCom, Inc

1144-P: Risk of Diabetic Retinopathy in Early-Onset Type 2 Diabetes in Mexico

Early onset type 2 diabetes (EOD) seems to have an aggressive disease progression with a higher risk for diabetes complications at an early age. Screening for Diabetic Retinopathy (DR) is poorly executed in primary care of low-and-middle income countries. Thus, we aimed to analyze the characteristics of EOD in comparison with later-onset group. Data were obtained from the largest cohort of patients evaluated for DR within the primary care in Mexico (DIABEMPIC program) . Early and later-onset groups were defined as age of diagnosis &amp;lt;40 and ≥40 years, respectively. DR assessment by an ophthalmologist included fundoscopy with a mydriatic camera. Proliferative DR and severe non-proliferative DR were considered as severe DR. A total of 3063 patients with T2D were included of which 9had EOD. Prevalence of DR and severe DR was significantly higher in the EOD group than in the later-onset group (p&amp;lt;0.0001) ; however, an increase in the prevalence of DR and severe DR was observed after years of diagnosis (p&amp;lt;0.0001) . Burden of DR at different diabetes durations are shown in Table 1. EOD was associated with increased risk of DR compared with late onset T2D (OR 2.18, 95%CI 1.85-2.57) . In conclusion, EOD patients with regular primary care presented a higher risk of DR and of severe DR not only explained for longer disease duration. Our study enhances the need for the management of DR risk factors and proper screening of DR in patients with T2D, especially in EOD. Disclosure R.Silva-tinoco: n/a. E.León-garcía: None. J.Ochoa-moreno: n/a. O.Lopez-arellano: None. T.Cuatecontzi-xochitiotzi: None. D.Cabrera-gerardo: n/a. V.Delatorre-saldaña: None. L.Castillo-martinez: None. F.Bernal-ceballos: None. E.B.Guzman: None. S.Bouchan-delino: None. A.Ramirez: None.

261-OR: Dorzagliatin, a Dual-Acting Glucokinase Activator. Improves Insulin Secretion and Glucose Sensitivity in Glucokinase-Maturity-Onset Diabetes of the Young (GCK-MODY)

Glucokinase maturity onset diabetes of the young (GCK-MODY) is caused by heterozygous inactivating mutations in GCK that is not responsive to conventional glucose lowering drugs. We investigated the effects of dorzagliatin, a novel allosteric activator of hepatic and beta-cell GCK on insulin secretion rates (ISR) and glucose sensitivity (GS) in GCK-MODY and recent onset type 2 diabetes (T2D) . In a double-blind, randomized cross-over study, 8 GCK-MODY (mean±SD age 36.1­±6.4years) and T2D subjects (mean age 50.2±6.9 years, median T2D duration 0.90 [0.60-1.42] years) underwent 2-hour 12 mmol/L hyperglycemic clamps following a single oral dose of dorzagliatin 75mg or matched placebo. Insulin and C-peptide were measured. GCK-MODY group showed significantly higher absolute (mean±SD 432±85 versus 272±91 pmol/min/m2, p=0.002) and incremental (342­±91 vs. 241±74 pmol/min/m2, p=0.004) second-phase ISR following dorzagliatin versus placebo. Dorzagliatin significantly improved GS in GCK-MODY (51±21 vs. 33­±13 pmol/min/m2 per mmol/L p=0.028) with an upward and leftward shift in ISR-glucose response. In T2D, basal ISR was significantly improved following dorzagliatin (102±57 vs. 60±42, p=0.018) with smaller increases in second phase ISR and GS. Dorzagliatin improves second phase ISR and GS, with larger effects in GCK-MODY than T2D. Disclosure E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. L.Chen: Employee; Hua Medicine. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. K.Wang: None. C.K.P.Lim: None. S.Tsoi: None. B.Fan: None. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. E.Ferrannini: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Oramed Pharmaceuticals, Consultant; Elgia Therapeutics, Research Support; Janssen Research &amp; Development, LLC, Oramed Pharmaceuticals, Sanofi-Aventis U.S., Speaker's Bureau; Boehringer Ingelheim International GmbH. A.Mari: Consultant; Lilly, Research Support; Lilly. Funding Hua Medicine Investigator Initiated Clinical Research

Children at onset of type 1 diabetes show altered N-glycosylation of plasma proteins and IgG

Aims/hypothesisIndividual variation in plasma N-glycosylation has mainly been studied in the context of diabetes complications, and its role in type 1 diabetes onset is largely unknown. Our aims were to undertake a detailed characterisation of the plasma and IgG N-glycomes in patients with recent onset type 1 diabetes, and to evaluate their discriminative potential in risk assessment.MethodsIn the first part of the study, plasma and IgG N-glycans were chromatographically analysed in a study population from the DanDiabKids registry, comprising 1917 children and adolescents (0.6–19.1 years) who were newly diagnosed with type 1 diabetes. A follow-up study compared the results for 188 of these participants with those for their 244 unaffected siblings. Correlation of N-glycan abundance with the levels and number of various autoantibodies (against IA-2, GAD, ZnT8R, ZnT8W), as well as with sex and age at diagnosis, were estimated by using general linear modelling. A disease predictive model was built using logistic mixed-model elastic net regression, and evaluated using a 10-fold cross-validation.ResultsOur study showed that onset of type 1 diabetes was associated with an increase in the proportion of plasma and IgG high-mannose and bisecting GlcNAc structures, a decrease in monogalactosylation, and an increase in IgG disialylation. ZnT8R autoantibody levels were associated with higher IgG digalactosylated glycan with bisecting GlcNAc. Finally, an increase in the number of autoantibodies (which is a better predictor of progression to overt diabetes than the level of any individual antibody) was accompanied by a decrease in the proportions of some of the highly branched plasma N-glycans. Models including age, sex and N-glycans yielded notable discriminative power between children with type 1 diabetes and their healthy siblings, with AUCs of 0.915 and 0.869 for addition of plasma and IgG N-glycans, respectively.Conclusions/interpretationWe defined N-glycan changes accompanying onset of type 1 diabetes, and developed a predictive model based on N-glycan profiles that could have valuable potential in risk assessment. Increasing the power of tests to identify individuals at risk of disease development would be a considerable asset for type 1 diabetes prevention trials.Graphical abstract

COVID-19 in Japan, January–March 2020: insights from the first three months of the epidemic

BackgroundUnderstanding the characteristics and natural history of novel pathogens is crucial to inform successful control measures. Japan was one of the first affected countries in the COVID-19 pandemic reporting their first case on 14 January 2020. Interventions including airport screening, contact tracing, and cluster investigations were quickly implemented. Here we present insights from the first 3 months of the epidemic in Japan based on detailed case data.MethodsWe conducted descriptive analyses based on information systematically extracted from individual case reports from 13 January to 31 March 2020 including patient demographics, date of report and symptom onset, symptom progression, travel history, and contact type. We analysed symptom progression and estimated the time-varying reproduction number, Rt, correcting for epidemic growth using an established Bayesian framework. Key delays and the age-specific probability of transmission were estimated using data on exposures and transmission pairs.ResultsThe corrected fitted mean onset-to-reporting delay after the peak was 4 days (standard deviation: ± 2 days). Early transmission was driven primarily by returning travellers with Rt peaking at 2.4 (95% CrI: 1.6, 3.3) nationally. In the final week of the trusted period (16–23 March 2020), Rt accounting for importations diverged from overall Rt at 1.1 (95% CrI: 1.0, 1.2) compared to 1.5 (95% CrI: 1.3, 1.6), respectively. Household (39.0%) and workplace (11.6%) exposures were the most frequently reported potential source of infection. The estimated probability of transmission was assortative by age with individuals more likely to infect, and be infected by, contacts in a similar age group to them. Across all age groups, cases most frequently onset with cough, fever, and fatigue. There were no reported cases of patients < 20 years old developing pneumonia or severe respiratory symptoms.ConclusionsInformation collected in the early phases of an outbreak are important in characterising any novel pathogen. The availability of timely and detailed data and appropriate analyses is critical to estimate and understand a pathogen’s transmissibility, high-risk settings for transmission, and key symptoms. These insights can help to inform urgent response strategies.

Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)—study protocol for a phase 2, randomized, placebo controlled trial

BackgroundType 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening.The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function.MethodsThis will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10–30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses.DiscussionThis study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D.Trial registrationANZCTR ACTRN12620000239965. Registered on 26 February 2020. ClinicalTrials.gov NCT04774224. Registered on 01 March 2021

Adequate metabolic control at early stages of childhood onset type 1 diabetes prevent diabetic neuropathy: a 30 year follow up study

Adequate metabolic control at early stages of childhood onset type 1 diabetes prevent diabetic neuropathy: a 30 year follow up study

How do I diagnose Maturity Onset Diabetes of the Young in my patients?

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes diagnosed in young individuals that lack the typical features of type 1 and type 2 diabetes. The genetic subtype of MODY determines the most effective treatment and this is the driver for MODY genetic testing in diabetes populations. Despite the obvious clinical and health economic benefits, MODY is significantly underdiagnosed with the majority of patients being inappropriately managed as having type 1 or type 2 diabetes. Low detection rates result from the difficulty in identifying patients with a likely diagnosis of MODY from the high background population of young onset type 1 and type 2 diabetes, compounded by the lack of MODY awareness and education in diabetes care physicians. MODY diagnosis can be improved through (1) access to education and training, (2) the use of sensitive and specific selection criteria based on accurate prediction models and biomarkers to identify patients for testing, (3) the development and mainstream implementation of simple criteria‐based selection pathways applicable across a range of healthcare settings and ethnicities to select the most appropriate patients for genetic testing and (4) the correct use of next generation sequencing technology to provide accurate and comprehensive testing of all known MODY and monogenic diabetes genes. The creation and public sharing of educational materials, clinical and scientific best practice guidelines and genetic variants will help identify the missing patients so they can benefit from the more effective clinical care that a genetic diagnosis brings.