The prevalence and incidence of diabetes in pediatrics have dramatically increased over the last three decades. Comparatively, pediatric diabetes has faster pancreatic β-cells decline and early progression to complications compared with adult diabetes. Therefore, diabetic complications are a major concern in children and adolescents with diabetes. Diabetes has detrimental effects on the macro- and microvascular systems, resulting in cardiovascular diseases, leading causes of morbidity and mortality in youth with diabetes. Oxidative stress plays a critical role in developing cardiovascular complications in the context of pediatric diabetes. In pediatric patients with diabetes, several factors can contribute to the development of excess reactive oxygen species and oxidative stress, including nutritional deficiencies, puberty, environmental exposures, and metabolic disorders such as obesity and high blood pressure. The present study aims to raise awareness of diabetic cardiovascular complications in children and adolescents with diabetes and the role of oxidative stress and their molecular mechanisms in the pathogenesis of cardiovascular complications. In addition, some novel therapeutic strategies for the treatment and prevention of diabetic cardiovascular complications in the pediatric populations are highlighted. In summary, children and adolescents with diabetes no matter type 1 diabetes (T1D) or type 1 diabetes (T2D), have many features similar to those in adults with same kinds of diabetes, but also have many their own features distinct from adults. By developing targeted therapies and preventive measures, healthcare providers can better address the rising incidence of diabetes-related complications in children and adolescents.

This study assessed trends in age-standardized incidence (ASIR), prevalence (ASPR), and mortality rates (ASMR) per 100,000 population for asthma, Type 1 Diabetes Mellitus (T1DM), Inflammatory Bowel Disease (IBD), Multiple Sclerosis (MS), Psoriasis, and Rheumatoid Arthritis (RA) in China from 1990 to 2021 and projected ASIR trends through 2046. Data were obtained from the Global Burden of Disease (GBD) 2021 study. Trends in ASIR, ASPR, and ASMR were analyzed using Joinpoint regression to calculate annual percentage change (APC) and average APC (AAPC). Bayesian age-period-cohort (BAPC) modeling was applied to project future ASIR trends. In 2021, asthma had the highest ASIR (364.17/100,000), followed by psoriasis (59.70/100,000) and RA (13.70/100,000), while MS (0.16/100,000) and IBD (1.40/100,000) were the least common. Asthma exhibited significant declines in ASIR (-1.23% AAPC), ASPR (-1.49%), and ASMR (-4.4%). Conversely, T1DM showed rising ASIR (+ 1.16%) and ASPR (+ 1.15%) alongside declining ASMR (-2.62%). Psoriasis (+ 0.74%) and IBD (+ 2.09%) also showed rising ASIR. Gender differences were notable, with greater T1DM ASIR increases in males and more significant asthma improvements in females. By 2046, the ASIR of T1DM, psoriasis, and RA is projected to reach 5.8, 80.9, and 15.54 per 100,000, respectively, while asthma is expected to decline to 330.98 per 100,000. The rising ASIR and ASPR for most autoimmune diseases in China contrast with declining ASMR, highlighting the dual challenge of managing increasing disease burdens while sustaining reductions in mortality. Targeted prevention and management strategies are essential to address these evolving public health needs.

Background: Young-onset diabetes (YOD) is characterised by unique diagnostic and management challenges more pronounced in resource-limited settings like Sri Lanka. Aims: We aimed to ascertain the prevalence, patterns and characteristics of YOD in Sri Lanka and describe the state of care. Methods: Retrospective review of baseline data of all patients enrolled in the prospective multicentre Database for Young-Onset Diabetes, Sri Lanka (DYOD-SL), was performed, from April 2021 to April 2023. Results: A total of 2531 patient data were included from 28 centres island-wide. Females were 57.6%. The median age was 20 years (interquartile range (IQR) 17, 23), and the age at diagnosis was 15 years (IQR 12, 18). Type 1 diabetes (T1D) was the commonest (57.6%), followed by Type 2 diabetes (T2D) at 34.3%. Younger age at disease onset (p < 0.001), lower BMI (p < 0.001), and diabetic ketoacidosis (DKA) at presentation (p < 0.001) favoured T1D. In the total cohort, the median HbA1c was 9.8% (IQR 7.8, 12.1) with younger patients having poorer control (p = 0.001). Prevalence of nephropathy was 8.1%, retinopathy was 6.6%, neuropathy was 4.1%, moderate-high-risk diabetic foot disease was 1.9%, and macrovascular complications were 0.5%. Hypertension and dyslipidaemia occurred in 2.7% and 14%, respectively. Among patients > 18 years, overweight and obese were 22.2% and 10.4%. Corresponding prevalence in the 5-18-year age group was 20% and 14.7%. Among the insulin users (76%) in the total cohort, the majority (64.7%) were on premixed-based insulin regimens delivered by syringes. Self-monitoring of blood glucose (BG) was reported in 71.3% of the total population. None were on continuous/flash glucose monitoring or insulin pumps. Conclusion: T1D was the commonest subtype of YOD in this hospital-based population. However, T2D was notably higher and is of significant concern. Overall, suboptimal glycaemic control and high rate of complications were noted along with substandard insulin regimens and BG monitoring.

Type 1 diabetes is one of the fastest-growing chronic health conditions. Estimating the incidence rate of childhood type 1 diabetes will allow to aid in adequate planning of health care resources. The study's aim was to assess the incidence rate of type 1 diabetes in children below 15 years of age from Greater Poland (Poland) between 2006 and 2018, and then to compare obtained data to records collected between 1998 and 2003 in pediatric population aged 0-14 years from the same area.

In this cohort study covering the period from January 1998 to December 2018, data were collected for children and adolescents below 14 years of age with newly diagnosed type 1 diabetes living in Greater Poland. The overall population size was taken from the Statistical Office of Poland. Total, sex-, and age-specific incidence rates per 100,000 person-years were calculated for each calendar year.

Over a 20-year period, the incidence rate of type 1 diabetes in children aged 0-14 years rose around 3.6-fold, from 8.4/100,000 in 1998 to 30.8/100,000 in 2018, with the peak incidence recorded in last year of the study. A clear male predominance of type 1 diabetes was seen in all ages. The rate of type 1 diabetes incidence growth was comparable between all age groups, while the highest incidence rate was mostly observed in children aged 5-9 and 10-14 years.

The incidence of type 1 diabetes in children aged 0-14 years is rapidly increasing in Greater Poland.

Type II Diabetes mellitus (T2DM) patients often do not achieve glycemic control with oral hypoglycemic agents (OHAs). There are two main approaches to address this challenge: transitioning to a triple OHA regimen, or adding Insulin to the existing dual OHA regimen.

This study aimed to compare the efficacy of adding Insulin to dual OHAs (Sitagliptin + Metformin) against adding a third OHA to Sitagliptin + Metformin in achieving glycemic control among patients with uncontrolled T2DM.

A pre-post study was conducted between 21 September 2023 and 21 December 2023 at Services Hospital Peshawar, Pakistan. Patients with uncontrolled T2DM with >7% HbA1c were divided into group 1 (Sitagliptin + Metformin plus a third OHA), and group 2 (Sitagliptin + Metformin plus pre-mixed Insulin 70/30). Glycemic control based on HbA1c values, fasting and random blood sugar levels, lipid profile, and body weight were evaluated after 3 months of therapy. The pre- and post- effect was compared by using a paired t-test.

The study included n = 80 patients with T2DM. Between groups 1 and 2, no significant difference was found in HbA1c values (9.1 vs. 9, with p = 0.724). However, BMI, cholesterol, and LDL significantly decreased in group 1 compared to group 2 (p<0.001 vs. p = 0.131, p = 0.023 vs. p = 0.896, and p = 0.003 vs. p = 0.395, respectively). Additionally, the incidence of hypoglycemic episodes was significantly lower in group 1 (7.5%) than in group 2 (47.5%, p = 0.004). No significant difference was observed between the triple OHA and dual OHA plus Insulin regimens in achieving glycemic control.

The triple OHA regimen improved BMI, cholesterol, and LDL levels, and reduced hypoglycemic episodes more effectively than dual OHA plus Insulin, despite similar HbA1c outcomes, suggesting it may be preferable for uncontrolled T2DM.

Diabetic ketoacidosis (DKA) is a common presentation to an emergency department (ED), with the majority presenting to community EDs. Adherence to clinical guidelines in these EDs can reduce morbidity and mortality. Few methods to describe practice gaps for DKA management have been reported.

We hypothesized that high-fidelity in situ simulation can be used to measure and compare the quality of the care provided to pediatric patients with DKA presenting to community EDs in the state of Indiana.

This observational study examined multiprofessional teams caring for a simulated pediatric patient who presented with DKA to community EDs. The primary outcome was overall adherence to pediatric DKA guidelines as measured by a validated performance checklist. A composite adherence score (CAS) was calculated using the sum of 9 checklist performance parameters. Multivariable logistic regression was used to examine the impact of ED volume and characteristics on the scores.

A 49 multiprofessional teams from 13 sites were enrolled. Of the 252 participants, 26 (10.3%) were physicians, 143 (56.7%) registered nurses, 25 (9.9%) respiratory therapists, and 58 (23.0%) were other. The overall CAS for all sites was 55.6% (25th, 75th interquartile range, 44.4%, 66.7%). Excessive intravenous fluid boluses were given by 53.1%, whereas 30.6% and 26.5% incorrectly administered insulin and sodium bicarbonate boluses, respectively. Only 10.2% used an appropriate intravenous fluid rate, and 57.1% performed an hourly glucose. No significant difference in the CAS was found due to pediatric ED volume or presence of an inpatient pediatric service.

Using validated in situ simulation; we revealed high variability in adherence to the pediatric DKA management guidelines at a wide range of community EDs. A statewide education initiative focused on decreasing variation and improving adherence to pediatric DKA guidelines is necessary for patient safety.

The worldwide geographical and temporal variation in the prevalence of diabetes represents a challenge, but also an opportunity for gaining etiological insights. Encompassing the bulk of East Asians, a large and distinct proportion of the world population, China can be a source of valuable epidemiological insights for diabetes, especially in early life, when pathophysiology begins. We carried out a nationwide, epidemiological survey of Prevalence and Risk of Obesity and Diabetes in Youth (PRODY) in China, from 2017 to 2019, to estimate the population-based prevalence of diagnosed pediatric diabetes and screen for undiagnosed pediatric type 2 diabetes (T2D).

PRODY was a nation-wide, school population-based, cross-sectional, multicenter survey by questionnaire, fasting urine glucose test and simple oral glucose tolerance test (s-OGTT), among a total number of 193,801 general-population children and adolescents (covered a pediatric population of more than 96.8 million), aged 3-18, from twelve provinces across China. The prevalence of the self-reported pediatric diabetes, the proportion of subtypes, the crude prevalence of undiagnosed T2D and prediabetes in general juvenile population and the main risk factors of type 1 (T1D) and type 2 (T2D) diabetes had been analyzed in the study.

The prevalence of all self-reported pediatric diabetes was estimated at 0.62/1000 (95% CI: 0.51-0.74), with T1D at 0.44/1000 (95% CI: 0.35-0.54) and T2D at 0.18/1000 (95% CI: 0.13-0.25). For undiagnosed T2D, the crude prevalence was almost ten-fold higher, at 1.59/1000, with an estimated extra 28.45/1000 of undiagnosed impaired glucose tolerance (IGT) and 53.74/1000 of undiagnosed impaired fasting glucose (IFG) by s-OGTT screening. Maternal diabetes history is the major risk factors for all subtypes of pediatric diabetes in China.

The PRODY study provides the first population-based estimate of the prevalence of pediatric diabetes China and reveals a magnitude of the problem of undiagnosed pediatric T2D. We propose a practical screening strategy by s-OGTT to address this serious gap.

The National Key Research and Development Programme of China, Key R&D Program of Zhejiang, the National Natural Science Foundation of China and the Zhejiang Provincial Key Disciplines of Medicine, Key R&D Program Projects in Zhejiang Province.

The number of patients with type 2 diabetes (T2D) and type 1 diabetes (T1D) is on the rise, partly due to a global increase in new T1D cases among children. Beyond the well-documented microvascular and macrovascular complications, there is now substantial evidence indicating that diabetes also impacts the brain, leading to neuropsychological impairments. The risk of developing neuropsychiatric symptoms is notably higher in childhood due to the ongoing maturation of the brain, which makes it more susceptible to damage. Despite this awareness, the specific effects of diabetes on cognitive function remain poorly understood.

This review synthesizes literature on the impact of diabetes on cognition and its relationship with brain structural changes. It presents data and hypotheses to explain how T1D contributes to cognitive dysfunction, with a particular focus on children and adolescents. The emphasis on the pediatric population is intentional, as young diabetic patients typically have fewer comorbidities, reducing confounding factors and simplifying the investigation of cognitive alterations.

We examine the roles of hypo- and hyperglycemia, as well as the emerging role of glucocorticoids in the development of neuropsychological disorders. When specific mechanisms related to T1D are available, they are highlighted; otherwise, data and hypotheses applicable to both T1D and T2D are discussed.

Is the mode of conception (natural, subfertility and non-IVF, and IVF) associated with the risk of Type 1 diabetes mellitus among offspring?

The risk of Type 1 diabetes in offspring does not differ among natural, subfertility and non-IVF, and IVF conceptions.

Evidence has shown that children born through IVF have an increased risk of impaired metabolic function.

A population-based, nested case-control study was carried out, including 769 children with and 3110 children without Type 1 diabetes mellitus within the prospective cohort of 2 228 073 eligible parent-child triads between 1 January 2004 and 31 December 2017.

Using registry data from Taiwan, the mode of conception was divided into three categories: natural conception, subfertility, and non-IVF (indicating infertility diagnosis but no IVF-facilitated conception), and IVF conception. The diagnosis of Type 1 diabetes mellitus was determined according to the International Classification of Diseases, 9th or 10th Revision, Clinical Modification. Each case was matched to four controls randomly selected after matching for child age and sex, residential township, and calendar date of Type 1 diabetes mellitus occurrence.

Based on 14.3 million person-years of follow-up (median, 10 years), the incidence rates of Type 1 diabetes were 5.33, 5.61, and 4.74 per 100 000 person-years for natural, subfertility and non-IVF, and IVF conceptions, respectively. Compared with natural conception, no significant differences in the risk of Type 1 diabetes were observed for subfertility and non-IVF conception (adjusted odds ratio, 1.04 [95% CI, 0.85-1.27]) and IVF conception (adjusted odds ratio, 1.00 [95% CI, 0.50-2.03]). In addition, there were no significant differences in the risk of Type 1 diabetes according to infertility source (male/female/both) and embryo type (fresh/frozen).

Although the population-level data from Taiwanese registries was used, a limited number of exposed cases was included. We showed risk of Type 1 diabetes was not associated with infertility source or embryo type; however, caution with interpretation is required owing to the limited number of exposed events after the stratification. The exclusion criterion regarding parents' history of diabetes mellitus was only applicable after 1997, and this might have caused residual confounding.

It has been reported that children born to parents who conceived through IVF had worse metabolic profiles than those who conceived naturally. Considering the findings of the present and previous studies, poor metabolic profiles may not be sufficient to develop Type 1 diabetes mellitus during childhood.

This study was supported by grants from Shin Kong Wu Ho-Su Memorial Hospital (No. 109GB006-1). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The authors have no competing interests to disclose.

N/A.

Type 1 diabetes (T1D) results from a complex interplay of genetic predisposition, immunological dysregulation, and environmental triggers, that culminate in the destruction of insulin-secreting pancreatic β cells. This review provides a comprehensive examination of the multiple factors underpinning T1D pathogenesis, to elucidate key mechanisms and potential therapeutic targets. Beginning with an exploration of genetic risk factors, we dissect the roles of human leukocyte antigen (HLA) haplotypes and non-HLA gene variants associated with T1D susceptibility. Mechanistic insights gleaned from the NOD mouse model provide valuable parallels to the human disease, particularly immunological intricacies underlying β cell-directed autoimmunity. Immunological drivers of T1D pathogenesis are examined, highlighting the pivotal contributions of both effector and regulatory T cells and the multiple functions of B cells and autoantibodies in β-cell destruction. Furthermore, the impact of environmental risk factors, notably modulation of host immune development by the intestinal microbiome, is examined. Lastly, the review probes human longitudinal studies, unveiling the dynamic interplay between mucosal immunity, systemic antimicrobial antibody responses, and the trajectories of T1D development. Insights garnered from these interconnected factors pave the way for targeted interventions and the identification of biomarkers to enhance T1D management and prevention strategies.

This study aims to systematically review the illness experience of adolescent patients with type 1 diabetes mellitus (T1DM). The JBI qualitative systematic review method was used and meta-aggregate analysis of 14 qualitative studies was performed. Qualitative studies on the disease experience of adolescent patients with T1DM were obtained from Cochrane, PubMed, Web of Science, CINAHL, Embase, Wanfang, CNKI, and VIP, and the search period was from 1995 to 2024. The qualitative research quality evaluation tool of JBI the Evidence-based Health Care Center in Australia was used to evaluate the analysis results. Thirty-one results were distilled and categorized into 7 themes and then synthesized into 3 overarching findings: (1) experiencing psychological distress and developing coping mechanisms following adjustment; (2) acknowledging self-management shortcomings and actively seeking support; and (3) overcoming challenges and growing through experiences. The findings illuminate that adolescents with T1DM often experience negative physical and emotional challenges during their illness. Transitioning from dependency to independence poses numerous obstacles that can be overcome by improving both internal and external support, cultivating self-management skills, strengthening coping mechanisms, and achieving control over the disease while fostering personal growth.

The incidence of type 1 diabetes (T1D) in children and adolescents has been increased over decades worldwide. Recent studies showed that the trend of T1D incidences were different between developed and underdeveloped countries. This review aimed to summarize the changes of childhood T1D incidences in underdeveloped countries over the past decade.

Majority of the underdeveloped countries lacked of nationwide population-based studies on childhood T1D. We reviewed the trend of childhood T1D in important underdeveloped countries with available data in recent years. The incidences of childhood T1D in underdeveloped countries were low decades ago, but it increased significantly recently, particularly in the sub-Saharan African, Middle East and North African regions.

The incidences of childhood T1D increased significantly in underdeveloped countries, especially in the sub-Saharan African, Middle East and North African regions. T1D registry and population-based studies are helpful to understand the situation and characteristic of childhood T1D in underdeveloped countries.

The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is an ongoing Australian prospective cohort study investigating how modifiable prenatal and early-life exposures drive the development of islet autoimmunity and type 1 diabetes (T1D) in children. In this profile, we describe the cohort's parental demographics, maternal and neonatal outcomes and human leukocyte antigen (HLA) genotypes.

Inclusion criteria were an unborn child, or infant aged less than 6 months, with a first-degree relative (FDR) with T1D. The primary outcome was persistent islet autoimmunity, with children followed until a T1D diagnosis or 10 years of age. Demographic data were collected at enrollment. Lifestyle, clinical and anthropometric data were collected at each visit during pregnancy and clinical pregnancy and birth data were verified against medical case notes. Data were compared between mothers with and without T1D. HLA genotyping was performed on the ENDIA child and all available FDRs.

The final cohort comprised 1473 infants born to 1214 gestational mothers across 1453 pregnancies, with 80% enrolled during pregnancy. The distribution of familial T1D probands was 62% maternal, 28% paternal and 11% sibling. The frequency of high-risk HLA genotypes was highest in T1D probands, followed by ENDIA infants, and lowest among unaffected family members. Mothers with T1D had higher rates of pregnancy complications and perinatal intervention, and larger babies of shorter gestation. Parent demographics were comparable to the Australian population for age, parity and obesity. A greater percentage of ENDIA parents were Australian born, lived in a major city and had higher socioeconomic advantage and education.

This comprehensive profile provides the context for understanding ENDIA's scope, methodology, unique strengths and limitations. Now fully recruited, ENDIA will provide unique insights into the roles of early-life factors in the development of islet autoimmunity and T1D in the Australian environment.

ACTRN12613000794707.

Do children born after ART have a higher risk of developing Type 1 diabetes (DM1) than children conceived without ART?

The risk of DM1 was similar for children conceived with and without ART, and there were no clear differences in risk according to method of fertility treatment.

ART is associated with a higher risk of adverse perinatal outcomes, and the risk depends on the method of ART. The Developmental Origins of Health and Disease theory proposes that prenatal stress can provoke changes in endocrine processes which impact health later in life.

A Nordic register-based cohort study was carried out, including all children born in Denmark (birth years 1994-2014), Finland (1990-2014), and Norway (1984-2015). The study included 76 184 liveborn singletons born after ART and 4 403 419 born without ART. Median follow-up was 8.3 and 13.7 years in the ART and non-ART group, respectively.

The cohort, initiated by the Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS), was established by linking national registry data from the medical birth registries and national patient registries available in the Nordic countries. We performed multivariable logistic regression analyses for the birth year intervals 1984-1990, 1991-1995, 1996-2000, 2001-2005, 2006-2010, and 2011-2015, while adjusting for year of birth within each interval, sex of the child, parity, maternal age, maternal diabetes, and maternal smoking during pregnancy as potential confounders.

During follow-up, 259 (3.4‰) children born after ART were diagnosed with DM1, while this was the case for 22 209 (5.0‰) born without ART, corresponding to an adjusted odds ratio of 0.98 (95% CI: 0.861.11). Within the different birth year intervals, no significant difference in risk of DM1 between the two groups was found, except for the youngest cohort of children born 2011-2015 where ART was associated with a higher risk of DM1. We found no significant differences in risk of DM1 when comparing children born after IVF versus ICSI or fresh versus frozen embryo transfer, but with only few cases in each group.

The main limitation of the study is the relatively short follow-up time. The incidence rate of DM1 peaks during ages 10-14 years, hence a longer follow-up would benefit all analyses and, in particular, the subgroup analyses.

Overall, our findings are reassuring especially considering the concomitantly increasing number of children born from ART and the increasing incidence of DM1 globally.

This Nordic registry study has been supported by the Nordic Trial Alliance/NORDFORSK and Rigshospitalets Research Foundation. The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. None of the authors has any conflicts of interest to declare regarding this study.

ISRCTN11780826.

The objective of this study is to explore the information needs related to insulin therapy in children and adolescents with type 1 diabetes mellitus (T1DM) from the children's perspectives as well as their caregivers.

Qualitative study; semistructured interviews. To identify emerging themes relating to information needs, open coding and thematic analysis were employed.

Participants were recruited from a tertiary care children's hospital in Kuala Lumpur, Malaysia and a specialist hospital in Riyadh, Saudi Arabia.

Thirty one children with a mean age of 11.5 years (SD=1.9) and their caregivers were interviewed. Seventeen participants were from Malaysia and 14 were from Saudi Arabia.

Four themes of information emerged from the interviews, including information related to (1) hypoglycaemia and hyperglycaemia, (2) insulin therapy, (3) injection technique and (4) other information needs pertaining to continuous glucose monitoring, access to peer groups and future advances in insulin therapy.

This study provided valuable insights into the information needs related to T1DM and insulin therapy among children and adolescents with T1DM that should be considered by stakeholders in the development of age-appropriate education materials. Such materials will assist children and adolescents to better manage their life-long T1DM condition from adolescence until adulthood.

Periodontitis is a chronic inflammatory disease caused by plaque biofilm which shares risk factors with systemic chronic diseases such as diabetes, cardiovascular disease, and osteoporosis. Many studies have found increased prevalence and rate of progression of periodontal disease in children with common metabolic disorders. Although the causal relationship and specific mechanism between them has not been determined yet. The aim of this paper is to progress on the impact of metabolic disorders on periodontal health in children and the underlying mechanisms, which provides new evidences for the prevention and intervention of metabolic disorders and periodontitis in children.

Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences, which result in the specific destruction of insulin-producing pancreatic β-cells. Currently, there are over 1.6 million cases of T1D in the United States with a worldwide incidence rate that has been increasing since 1990. Here, we examined the effect of Cornus officinalis (CO), a well-known ethnopharmacological agent, on a T1D model of the non-obese diabetic (NOD) mouse. A measured dose of CO extract was delivered into 10-week-old NOD mice by oral gavage for 15 weeks. T1D incidence and hyperglycemia were significantly lower in the CO-treated group as compared to the water gavage (WT) and a no handling or treatment control group (NHT) following treatment. T1D onset per group was 30%, 60% and 86% for the CO, WT and NHT groups, respectively. Circulating C-peptide was higher, and pancreatic insulitis was decreased in non-T1D CO-treated mice. Our findings suggest that CO may have therapeutic potential as both a safe and effective interventional agent to slow early stage T1D progression.

The simultaneous presence of celiac disease and type 1 diabetes (T1DM) is coupled with more hazards of comorbidities and complications. This current study aimed to screen for celiac disease in Egyptian children with type 1 diabetes and evaluate its impact on glycemic control.

A cross-sectional study was verified with 200 Egyptian children diagnosed with T1DM and having a diabetic duration of less than five years. Testing for anti-tissue transglutaminase IgA (tTG-IgA), anti-tissue transglutaminase IgG (tTG-IgG), anti-Endomysial IgA (EMA), and Hb A1c levels were done.

The serological screening revealed that 11 cases (5.5%) tested positive; 8 children with T1DM (4.0%) showed tTG-IgA antibodies ≥ 10 times the upper limit of normal (ULN) with at least one symptom; and 3 cases (1.5%) had levels between 20 and 50 IU/ml (considering a cut-off point of 10 U/ML for positive results). Intestinal biopsy was performed for these three cases, with one case detected to have subtotal villous atrophy, resulting in an overall prevalence of celiac disease in T1DM as 4.5%. Children with positive screening exhibited a higher insulin dose, a higher HbA1c, an increased frequency of hypoglycemic attacks, and recurrent DKA compared to negative cases. A negative correlation was detected between tTG-IgA antibodies with height Z score and hemoglobin level, while a positive correlation was found between tTG-IgA antibodies and HbA1c level.

Undiagnosed celiac disease in children with T1DM negatively impacted metabolic control and affected their general health.

Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control.

We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants in DRB1, DQA1 and DQB1 genes in children with EOT1D (diagnosed at ≤5 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population.

Allelic association analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed that the rare DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0x10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4x10-2). In corroboration, HLA class II haplotype analysis showed that the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4x10-5) and represents the major HLA class II genetic driver and discriminative factor in the development of early onset disease.

This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibility loci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings encompassing other ethnicities and may impact target screening strategies and follow-up of young children with high T1D genetic risk as well as personalized therapeutic approaches.

To analyse spatial and temporal changes in the global burden of diabetes mellitus (DM) attributable to dietary factors from 1990 to 2019.

The burden of DM was analysed in terms of age-standardized disability-adjusted life-year (DALY) rates and age-standardized death rates (ASDRs), which were obtained from the Global Burden of Disease Study 2019, and their corresponding estimated annual percentage changes (EAPCs).

The ASDR exhibited a decreasing trend (EAPC = -0.02), while the age-standardized DALY rate exhibited an increasing trend (EAPC = 0.65). Forty-four percent of the burden of DM was attributable to dietary factors, with the three largest contributors being high intake of red meat, high intake of processed meat, and low intake of fruit. Residence in a region with a high sociodemographic index (SDI) was associated with a diet low in whole grains and high in red meat and processed meat, while residence in a low-SDI region was associated with a diet low in whole grains and fruits, and high in red meat.

The age-standardized DALYs of DM attributable to dietary factors increased between 1990 and 2019 but differed among areas. The three largest dietary contributors to the burden of DM were high intake of red meat, high intake of processed meat, and low intake of fruit.

Between 1985 and 1996, Sweden experienced an "epidemic" of celiac disease with a fourfold increase in incidence in young children. Timing and amount of gluten introduced during infancy have been thought to explain this "epidemic". We aimed to study whether the cumulative incidence of type 1 diabetes differs between children born during the "epidemic" compared to children born after.

This is a national register study in Sweden comparing the cumulative incidence of type 1 diabetes in two birth cohorts of 240 844 children 0-17 years old born 1992-1993, during the "epidemic", and 179 530 children born 1997-1998, after the "epidemic". Children diagnosed with type 1 diabetes were identified using three national registers.

The cumulative incidence of type 1 diabetes by the age of 17 was statistically significantly higher in those born after the "epidemic" 0.77% than in those born during the "epidemic" 0.68% (p < 0.001).

The incidence of type 1 diabetes is higher in those born after the epidemic compared to those born during the epidemic, which does not support the hypothesis that gluten introduction increases the incidence of T1D. Changes in gluten introduction did not halt the increased incidence of type 1 diabetes in Sweden.

There are no data on type 1 diabetes (T1D) incidence and prevalence in Burkina Faso. We aimed to determine these in persons aged <25 years (y) since the implementation of Life for a Child (LFAC) program in 2013.

Data were collected from the prospective program register. Diagnosis of T1D was clinical, based on presentation, abrupt onset of symptomatic hyperglycemia, need for insulin replacement therapy from diagnosis, and no suggestion of other diabetes types.

We diagnosed 312 cases of T1D <25y in 2013-2022. Male-to-female ratio was 1:1. T1D incidence <25y per 100,000 population/year increased from 0.08 (CI 95% 0.07-0.60) in 2013 to 0.34 (CI 95% 0.26-0.45) in 2022 (p=0.002). Incidence <15y/y rose from 0.04 (CI 95% 0.01-0.10) to 0.27 (CI 95% 0.18-0.38) per 100,000/year in 2013 and 2022, respectively (p < 0.002). Prevalence per 100,000 population <25y was 0.27 (CI 95% 0.19-0.37) in 2013 and rose to 1.76 (CI 95% 1.546-1.99) in 2022 (p<0.0001). Mortality rate was 20 (CI 95% 13-29.6) per 1,000-person y.

There is a low but sharply rising T1D incidence and prevalence rates in children and youth in Burkina Faso since LFAC program implementation. It is very likely this is partly due to improved case detection. Mortality remains substantial.

To undertake a systematic review of publications describing Type 1 diabetes (T1DM) incidence, trends over time and associated factors in the Western Pacific Region (WPR).

As per the PROSPERO-registered (CRD42019122646) protocol English (MEDLINE, Embase, Global Health) and Chinese data-bases (China National Knowledge Infrastructure, VIP, Wanfang) from onset to 31/12/2019 were searched for T1DM incidence in the WPR. Country level data extracted included annual crude incidence rates by sex, number of new cases per annum (p.a.) and cumulatively, and the population at-risk. A meta-analysis for T1DM incidence was performed (by region and narrow age-bands, where possible) with subgroup analyses by time and by region.

Forty-five population-based studies (21 from China), published 1973-2017, estimated T1DM incidence, mostly in youth, in 11 WPR countries. After 2000, mean annual T1DM incidence/100,000 person years aged 0-14 years ranged from 0.9 (95 % confidence intervals (CI), 0.6-1.3) in Fiji to 23.2 (95 % CI, 21.3-25.2) in Australia. The mean annual increase over time ranged from 2.8 % in Australia (1990-2002) to 14.2 % in Shanghai (1997-2011). T1DM incidence increased most in China (2.7-fold over 30-years) then Thailand (2-fold over 15-years). Most studies documented increasing incidence with age, though only two studies included people aged ≥ 20 years. Many, but not all studies reported significantly higher T1DM incidence in females vs. males.

T1DM incidence in the WPR is generally increasing, varying by age, sex, time and country. Results increase understanding of regional T1DM incidence and inform research and healthcare strategies.

Early-onset diabetes is poorly diagnosed partly due to its heterogeneity and variable presentations. Although several genes have been associated with the disease, these genes are not well studied in Africa. We sought to identify the major neonatal, early childhood, juvenile, or early-onset diabetes genes in Africa; and evaluate the available molecular methods used for investigating these gene variants. A literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. The retrieved records were screened and analyzed to identify genetic variants associated with early-onset diabetes. Although 319 records were retrieved, 32 were considered for the current review. Most of these records (22/32) were from North Africa. The disease condition was genetically heterogenous with most cases possessing unique gene variants. We identified 22 genes associated with early-onset diabetes, 9 of which had variants (n = 19) classified as pathogenic or likely pathogenic (PLP). Among the PLP variants, IER3IP1: p.(Leu78Pro) was the variant with the highest number of cases. There was limited data from West Africa, hence the contribution of genetic variability to early-onset diabetes in Africa could not be comprehensively evaluated. It is worth mentioning that most studies were focused on natural products as antidiabetics and only a few studies reported on the genetics of the disease. ABCC8 and KCNJ11 were implicated as major contributors to early-onset diabetes gene networks. Gene ontology analysis of the network associated ion channels, impaired glucose tolerance, and decreased insulin secretions to the disease. Our review highlights 9 genes from which PLP variants have been identified and can be considered for the development of an African diagnostic panel. There is a gap in early-onset diabetes genetic research from sub-Saharan Africa which is much needed to develop a comprehensive, efficient, and cost-effective genetic panel that will be useful in clinical practice on the continent and among the African diasporas.

Nerve conduction velocity (NCV) abnormalities are the forerunners of diabetic peripheral neuropathy (DPN). Therefore, this study aimed to analyze the effect of glucose profile quality on NCV in children and young adults with type 1 diabetes. Fifty-three children age 5 to 23 years with type 1 diabetes were recruited to participate in the study, which was conducted prospectively at the Children's Hospital of Eastern Switzerland from 2016 to 2022. Glycemic targets were recorded, and a cross-sectional nerve conduction study analyzing the peroneal, tibial, median motor, and median sensory nerves was performed. Data were compared with those of a control group of 50 healthy children. In the age- and height-matched diabetes subgroup aged 10-16 years, all four nerves showed significantly slower NCV, most pronounced for the peroneal nerve. Because height has a retarding effect on peroneal NCV, NCV was adjusted for height (dNCV). Peroneal dNCV correlated negatively with long-term glycated hemoglobin and highly significantly with glucose variability. Because high glucose variability clearly increases the risk of neuropathy, together with but also independently of the mean glucose level, this aspect of glycemic control should be given more attention in the care of individuals with diabetes.

There is a strong need for the better identification of early subclinical manifestations of microvascular complications, such as diabetic peripheral neuropathy, in young individuals with diabetes. To identify peripheral neuropathy and contributing factors at an asymptomatic disease stage, and to exclude height as a known modifying factor, we performed association studies of height-adjusted nerve conduction velocity. We identified high glucose variability, especially the SD of mean glucose, as an unexpectedly strong predictor of slowed nerve conduction velocity. More attention should be paid to the goal of low glucose variability in the care of individuals with diabetes.

Fifty diabetic nephropathy (DN) children with type 1 diabetes mellitus (T1DM) and 50 healthy matched controls were included. Chromatographic assays of 14 amino acids, free carnitine and 27 carnitine esters using high-performance liquid chromatography/electrospray ionization-mass spectroscopy, and genetic testing for JAK2v617f mutation using real-time PCR were performed. Patients had significantly lower levels of tyrosine, branched-chain amino acids (BCAAs), and BCAA/AAA (aromatic chain amino acids) ratios, glycine, arginine, ornithine, free carnitine and some carnitine esters (C5, 6, 12 and 16) and higher phenylalanine, phenylalanine/tyrosine ratio and C18 compared with the controls and in the macro-albuminuria vs. the microalbuminuria group (p < 0.05 for all) except for free carnitine. Plasma carnitine was negatively correlated with eGFR (r = -0.488, p = 0.000). There were significant positive correlations between tyrosine with UACR ratio (r = 0.296, p = 0.037). The plasma BCAA/AAA ratio showed significant negative correlations with UACR (r = -0.484, p = 0.000). There was a significantly higher frequency of the JAK2V617F gene mutation in diabetic nephropathy patients compared with the control group and in macro-albuminuria than the microalbuminuria group (p = 0.000) for both. When monitoring children with T1DM, plasma free amino acids and acylcarnitine profiles should be considered, especially if they have tested positive for JAK2V617F for the early diagnosis of DN.

This observational study assesses trends in type 1 diabetes mellitus (T1DM) disease burden across the 19 countries of the European Union (EU) 15+ between 1990 and 2019.

The Global Burden of Disease Study database was used to gather T1DM age-standardised incidence (ASIR), prevalence (ASPR), mortality (ASMR), and disability-adjusted life-year (DALY) rates per 100,000 for each EU15+ country (1990 - 2019). Joinpoint regression analysis was used to describe the trends.

From 1990 to 2019, T1DM ASIRs and ASPRs increased globally except for females in Finland (-2.9% and -9.4%), the largest increase in ASPR for males and females was observed in France (+144.4% and +137.5% respectively). All had reductions in ASMRs for males and females, with the largest observed in Spain (-56.7% and -79.0% respectively). Trends in DALYs were variable across countries, with increases in DALYs noted in 14/19 for males, and 9/19 for females. Denmark, Finland, Norway, Netherlands, and Sweden had a reduction in DALYs for both males and females.

Mortality from T1DM is reducing across EU15+ countries, despite concomitant increases in incidence and prevalence rates. Trends in DALYs are variable across countries, reflecting differential trends in the disease burden across countries with similarly high health expenditure.

Current global information on incidence, prevalence, and mortality of type 1 diabetes (T1D) is limited, particularly in low- and middle-income countries. To address this gap in evidence, JDRF, Life for a Child, International Society for Pediatric and Adolescent Diabetes, and International Diabetes Federation have developed the T1D Index, which uses a Markov mathematical model, and machine learning and all available data to provide global estimates of the burden on T1D. This review assesses the methodology, limitations, current findings, and future directions of the Index.

Global prevalence was estimated at 8.4 million in 2021, with 1.5 million <20 years (y). T1D prevalence varied from 1.5 to 534 per 100,000, with T1D accounting for <0.1-17.8% of all diabetes in different countries. A total of 35,000 young people <25 y are estimated to have died at clinical onset of T1D from non-diagnosis. An estimated 435,000 people <25 y were receiving "minimal care." Health-adjusted life years (HALYs) lost for individuals diagnosed with T1D at age 10 y in 2021 ranged from 14 to 55 y. These results show that interventions to reduce deaths from non-diagnosis, and improve access to at least an intermediate care level, are needed to reduce projected life years lost. The results have significant uncertainties due to incomplete data across the required inputs. Obtaining recent incidence, prevalence, and mortality data, as well as addressing data quality issues, misdiagnoses, and the lack of adult data, is essential for maintaining and improving accuracy. The index will be updated regularly as new data become available.

Background and Objectives. Coeliac disease is an autoimmune disorder provoked by a dietary group of proteins called gluten in genetically predisposed individuals. Over the past several decades, the prevalence of coeliac disease has been steadily growing and it is now recognized to be occurring worldwide. The prevalence varies greatly between ethnic, racial groups and regionally. Such variability makes local epidemiological studies important for spreading awareness and setting a threshold for suspicion of coeliac disease. We explored the potential application of a quick point-of-care test for the purpose of detecting a presence of IgA class TG2 antibodies for coeliac disease and screening in a Lithuanian pediatric population. Previously, there were no data regarding coeliac disease prevalence in Lithuania. Materials and Methods. Overall, we included 1458 children 11-13 years of age from several Lithuanian schools selected randomly in this study. Utilizing one point-of-care test using a single blood sample taken from a fingertip, we identified the existence of IgA class TG2 antibodies. Only children whose parents gave consent were enrolled in the study. Those with positive IgA class TG2-ab were directed to a tertiary hospital for additional clinical assessment and confirmation of suspected coeliac disease. Results. A total of two (0.14%) of the 1458 enrolled children were detected with the presence of TG2 antibodies and the coeliac disease diagnosis was further confirmed with histological examination of duodenal biopsy samples. Additionally, we checked that patients had not previously reported any clinical symptoms and signs that could suggest coeliac disease or any other disease of the gastrointestinal tract. Conclusions. The detected prevalence of coeliac disease in the Lithuanian pediatric population is 1:729. The rapid finger prick test for the presence of IgA class TG2 antibodies is a reasonable and accurate method to screen for celiac disease in children.

With the continuous improvement of people's living standard, the incidence of metabolic diseases is gradually increasing in recent years. There is growing interest in finding drugs to treat metabolic diseases from natural compounds due to their good efficacy and limited side effects. Over the past few decades, many phytochemicals derived from natural plants, such as berberine, curcumin, quercetin, resveratrol, rutin, and hesperidin, have been shown to have good pharmacological activity against metabolic diseases in preclinical studies. More importantly, clinical trials using these phytochemicals to treat metabolic diseases have been increasing. This review comprehensively summarizes the clinical progress of phytochemicals derived from natural plants in the treatment of several metabolic diseases, including type 2 diabetes mellitus (T2DM), obesity and non-alcoholic fatty liver disease (NAFLD). Accumulating clinical evidence shows that a total of 18 phytochemicals have good therapeutic effects on the three metabolic diseases by lowering blood glucose and lipid levels, reducing insulin resistance, enhancing insulin sensitivity, increasing energy expenditure, improving liver function, and relieving inflammation and oxidative stress. The information will help us better understand the medicinal value of these phytochemicals and promote their clinical application in the treatment of metabolic diseases.

It is important to understand patterns in the epidemiology of type 1 diabetes because they may provide insight into its etiology. We examined the incidence of type 1 diabetes in children aged 0-14 years, and patient demographics and clinical parameters at presentation, over the period 2012-2020 using the North East and North Cumbria Young Persons diabetes register.

Patients up to the age of 14 years with type 1 diabetes, and their families- managed in a total of 18 young persons diabetes clinics-were approached in person at the time of clinic appointments or in the days following diagnosis and they consented to their data being included in the register. Data were submitted regionally to a central unit. Descriptive statistics including crude and age-specific incidence rates were calculated. Temporal trends were analyzed using Joinpoint regression. Comparisons in incidence rates were made between age, sex and areas of higher and lower affluence as measured by the Index of Multiple Deprivation (IMD).

A total of 943 cases were recorded between January 2012 and December 2020. Median age at diagnosis was 8.8 years (Q1: 5.3, Q3: 11.7). There were more males than females (54% male). The median HbA1c at diagnosis was 100 mmoL/L (IQR: 39) and over one third (35%) were in ketoacidosis (pH < 7.3). Crude incidence decreased from 25.5 (95% confidence interval [CI] 20.9, 29.9) in 2012 to 16.6 (95% CI: 13.0, 20.2) per 100,000 in 2020 (5.1% per annum, 95% CI 1.1, 8.8%). During the period of the study there was no evidence of any trends in median age, HbA1c, BMI or birthweight (p = 0.18, 0.80, 0.69, 0.32) at diagnosis. Higher rates were observed in males aged 10-14 years, but similar rates were found for both sexes aged 0-9 years and there was no difference between areas of higher or lower deprivation (p = 0.22).

The incidence of diabetes in the young may be falling in the North East of England and North Cumbria. The reasons are unclear as there were no associations identified between levels of deprivation or anthropometric measurements. Potential mechanisms include alterations in socioeconomic background or growth pattern. Further research is needed to understand the reasons behind this finding.

Type 1 diabetes (T1D) is an increasingly common condition. Although often more effective, treatment regimens for patients with T1D have become more variable and complex with newer insulin analogues and increasing use of diabetes technology. Both surgery and anesthesia are known to trigger a stress response that causes dramatic metabolic changes in the patient that tend to increase glucose variability. Close monitoring of glucose levels and clear algorithms for insulin administration can ameliorate these characteristic responses. As T1D treatment technology becomes more effective at maintaining glucose in target range, there should be more consideration of using this technology during hospitalization and surgery.

Endocrine care of pediatric and adult patients continues to be plagued by health and health care disparities that are perpetuated by the basic structures of our health systems and research modalities, as well as policies that impact access to care and social determinants of health. This scientific statement expands the Society's 2012 statement by focusing on endocrine disease disparities in the pediatric population and sexual and gender minority populations. These include pediatric and adult lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA) persons. The writing group focused on highly prevalent conditions-growth disorders, puberty, metabolic bone disease, type 1 (T1D) and type 2 (T2D) diabetes mellitus, prediabetes, and obesity. Several important findings emerged. Compared with females and non-White children, non-Hispanic White males are more likely to come to medical attention for short stature. Racially and ethnically diverse populations and males are underrepresented in studies of pubertal development and attainment of peak bone mass, with current norms based on European populations. Like adults, racial and ethnic minority youth suffer a higher burden of disease from obesity, T1D and T2D, and have less access to diabetes treatment technologies and bariatric surgery. LGBTQIA youth and adults also face discrimination and multiple barriers to endocrine care due to pathologizing sexual orientation and gender identity, lack of culturally competent care providers, and policies. Multilevel interventions to address these disparities are required. Inclusion of racial, ethnic, and LGBTQIA populations in longitudinal life course studies is needed to assess growth, puberty, and attainment of peak bone mass. Growth and development charts may need to be adapted to non-European populations. In addition, extension of these studies will be required to understand the clinical and physiologic consequences of interventions to address abnormal development in these populations. Health policies should be recrafted to remove barriers in care for children with obesity and/or diabetes and for LGBTQIA children and adults to facilitate comprehensive access to care, therapeutics, and technological advances. Public health interventions encompassing collection of accurate demographic and social needs data, including the intersection of social determinants of health with health outcomes, and enactment of population health level interventions will be essential tools.

Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.

The real causal relationship between human gut microbiota and T1D remains unclear and difficult to establish. Herein, we adopted a two-sample bidirectional mendelian randomization (MR) study to evaluate the causality between gut microbiota and T1D.

We leveraged publicly available genome-wide association study (GWAS) summary data to perform MR analysis. The gut microbiota-related GWAS data from 18,340 individuals from the international consortium MiBioGen were used. The summary statistic data for T1D (n = 264,137) were obtained from the latest release from the FinnGen consortium as the outcome of interest. The selection of instrumental variables conformed strictly to a series of preset inclusion and exclusion criteria. MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods were used to assess the causal association. The Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis were conducted to identify heterogeneity and pleiotropy.

At the phylum level, only Bacteroidetes was indicated to have causality on T1D (OR = 1.24, 95% CI = 1.01-1.53, P = 0.044) in the IVW analysis. When it comes to their subcategories, Bacteroidia class (OR = 1.28, 95% CI = 1.06-1.53, P = 0.009, P _FDR = 0.085), Bacteroidales order (OR = 1.28, 95% CI = 1.06-1.53, P = 0.009, P _FDR = 0.085), and Eubacterium eligens group genus (OR = 0.64, 95% CI = 0.50-0.81, P = 2.84×10^-4, P _FDR = 0.031) were observed to have a causal relationship with T1D in the IVW analysis. No heterogeneity and pleiotropy were detected.

The present study reports that Bacteroidetes phylum, Bacteroidia class, and Bacteroidales order causally increase T1D risk, whereas Eubacterium eligens group genus, which belongs to the Firmicutes phylum, causally decreases T1D risk. Nevertheless, future studies are warranted to dissect the underlying mechanisms of specific bacterial taxa's role in the pathophysiology of T1D.