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The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the “single disease” approach appears untenable, as does the notion of individualizing each single patient’s care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.

The worldwide outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an unprecedented pandemic. Early on, even as the signs and symptoms of coronavirus disease 2019 (COVID-19) were first characterized, significant concerns were articulated regarding its potential impact on people with chronic disease, including type 1 diabetes. Information about the basic and clinical interrelationships between COVID-19 and diabetes has rapidly emerged. Initial rapid reports were useful to provide alerts and guide health care responses and initial policies. Some of these have proven subsequently to have durable findings, whereas others lacked scientific rigor/reproducibility. Many publications that report on COVID-19 and “diabetes” also have not distinguished between type 1 and type 2 (1). Available evidence now demonstrates that people with type 1 diabetes have been acutely affected by COVID-19 in multiple ways. This includes effects from limited access to health care, particularly during lockdown periods, and increased morbidity/mortality in infected adults with type 1 diabetes compared with peers without diabetes.

OBJECTIVE Women are broadly underrepresented in scientific leadership positions and their accomplishments are not provided equal recognition compared with those of men, but the imbalance in the field of diabetes is unknown. Hence, we analyzed multiple aspects of historical and present-day female representation in the diabetes field. RESEARCH DESIGN AND METHODS We quantified gender representation at annual American Diabetes Association (ADA) meetings; editorial board service positions for ADA and the European Association for the Study of Diabetes (EASD) journals; principal investigators for ADA, JDRF, and National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases P30 grant funding; and ADA, JDRF, and EASD award recipients. RESULTS There are many women in the field of diabetes: registration for the ADA Scientific Sessions has been 43% female since 2016, and for over five decades, women comprised 83% of ADA Presidents of Health Care and Education. Yet, only 9% of ADA Presidents of Medicine and Science have been women. Women were well represented on editorial boards for journals focused on diabetes education (Diabetes Spectrum, 89% female) and primary care (Clinical Diabetes, 49% female) but not for the more academically targeted Diabetes Care (34% female), Diabetes (21% female), and Diabetologia (30% female). Only one-third of ADA Pathway to Stop Diabetes and JDRF grants have been awarded to women, and females only lead 2 of 18 (11%) of the P30-supported Diabetes Research Centers. Finally, only 2–12% of major ADA, JDRF, and EASD awards were given to women, without significant change over time. CONCLUSIONS Despite increasing recognition of gender imbalance in research and medicine, many disparities in the field of diabetes persist. We call for decreasing barriers for advancement of female investigators and creating environments that promote their retention and equitable recognition for their contributions to the field.

The American Diabetes Association 2020 Standards of Medical Care in Diabetes (Standards of Care) recommends a hemoglobin A1c (A1C) of

We developed an outpatient salvage chemotherapy regimen using bendamustine, ofatumumab, carboplatin and etoposide (BOCE) to treat relapsed/refractory non-Hodgkin lymphoma (RR NHL) in a single-center phase I/II study. Primary objectives were safety, tolerability and overall response rate (ORR). Thirty-five RR NHL patients (57% de novo large cell [DLBCL] or grade 3B follicular [FL], 26% transformed DLBCL, 9% grade 3A FL, 3% mantle cell; median age = 62, median prior therapies = 1) were treated. Median follow-up was 24.1 months. ORR was 69% (CR = 49%, PR = 20% [ORR = 70%, CR = 50%, PR = 20% in the de novo DLBCL/grade 3B FL subgroup]). Median progression-free survival was 5.1 months and overall-survival 26.2 months. Twelve patients subsequently underwent stem cell transplantation. The most common non-hematologic grade 3-4 toxicities were neutropenic fever and hypophosphatemia. There were no treatment-related deaths. In conclusion, BOCE is a safe and effective outpatient salvage regimen for patients with RR NHL and serves as an effective bridge to stem cell transplantation.

Ustekinumab is an effective treatment for psoriasis, but response varies between patients. The formation of anti-drug antibodies (ADAs) may explain part of this variation by reducing the free ustekinumab level. Currently, published analyses of the clinical impact of ADAs are incomplete. In this observational cross-sectional multicenter study of 340 patients, we evaluated the impact of ADAs on ustekinumab level and clinical response as assessed by the PASI. Circulating ADA levels were measured using two assays: a drug-sensitive radioimmunoassay and a drug-tolerant ELISA. Circulating ustekinumab levels were measured using an ELISA. ADAs were detected in 3.8% (95% confidence interval [CI] = 3.2–4.2) and in 10.6% (95% CI = 7.9–13.9) of patients using the radioimmunoassay and drug-tolerant ELISA, respectively. At least 85% of the ADAs were neutralizing. Compared with patients negative for ADAs, ADA positivity in the radioimmunoassay and drug-tolerant ELISA were associated with lower median ustekinumab levels (−0.62 μg/ml [95% CI = −1.190 to −0.30] and −0.74 μg/ml [95% CI = −1.09 to −0.47], respectively) and higher absolute PASI (6.6 [95% CI = 3.0–9.9] and 1.9 [95% CI = 0.4–4.0], respectively). Absence of detectable ustekinumab regardless of ADA status correlated with poor clinical outcome (median sample PASI 10.1, 6.5 [95% CI = 3.9–8.8] compared with patients positive for ustekinumab). In conclusion, substantially reduced drug exposure resulting from ADAs formation is associated with impaired clinical response.

Fractures of the distal femur metaphysis (DFM) are rare. The main objective of this study was to retrospectively evaluate the clinical and radiographic outcomes of displaced DFM fractures in children treated by elastic stable intramedullary nailing (ESIN). We retrospectively reviewed 24 DFM fractures, including five pathological fractures secondary to non-ossifying fibroma (mean age, 10.9 years; range, 6-16) who underwent surgical treatment by ESIN. The patients were followed radiographically and clinically on a regular basis. Sixteen boys and eight girls were included in the study. Radiographically, all fractures healed, but five healed with complications. Most of the DFM fractures were transverse (n = 18, 75%), and all patients but two (91.7%) underwent closed reduction and stabilization of the fracture. All the patients were pain-free at their last follow-up. All regained full normal activities, although five patients developed a postoperative complication (20.8%). At the last follow-up visit, all fractures achieved union including the two cases of nonunion; moreover, none of the patients showed any signs of growth arrest or disturbances in radiological and clinical assessment. On the ESIN outcome measure scale, 12/24 patients (50%) had excellent results, 11/24 (45.8%) had good-satisfactory results and 1/24 (4.2%) had poor results. Fracture of the DFM can be challenging due to the relatively short length of the distal fragment, the proximity of the growth plate and the tendency of the distal fragment to displace. Following the surgical principles and understanding the anatomical constraints of the distal femur help to obtain satisfactory clinical and radiological results.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide pandemic has been devastating particularly for older adults and those from vulnerable groups, including racial and ethnic minority populations. Additionally, people with certain underlying medical conditions, including diabetes, are also at increased risk of severe illness from coronavirus disease 2019 (COVID-19) (1,2). Some children experience significant disease (3), and pediatric deaths have been reported (4). Because “diabetes” (generally grouping together type 1 diabetes and type 2 diabetes) and chronically elevated hyperglycemia have been associated with worse outcomes in adults with COVID-19 (5), the pediatric community has voiced great concerns about risk and outcomes for children with diabetes. A foundation of pediatrics is caution about the extrapolation of adult practice to children. Many publications report poor outcomes from COVID-19 and diabetes without emphasizing that data reported are from adults, frequently older adults with additional comorbidities. Moreover, there have been warnings related to COVID-19 and immunosuppression leading to confusion, predominately outside the medical community, about the difference between immunocompromised and autoimmune. In sum, these worries have led to increases in frequency and severity of diabetic ketoacidosis (DKA), due in part to families being reluctant to enter health care settings, especially in areas where COVID-19 cases cluster (6,7). Data scarcity regarding many aspects of how COVID-19 is affecting children with both new-onset and established diabetes has magnified these concerns. In this issue of Diabetes Care , Rabbone et al. (8) describe cross-sectional data from Italy, an early pandemic epicenter. This team examined diabetes diagnoses as well as reports of DKA and SARS-CoV-2 infection in children with new-onset and established type 1 diabetes from 20 February to 14 April 2020. They compare data on new presentations and DKA rates to data from the same period in 2019. They report …

The use of an orthopedic traction table (OTT) during elastic stable intramedullary nailing (ESIN) in the management of displaced diaphyseal tibia fractures (DTFs) is controversial. The aim of this study was to evaluate the clinical and radiological outcome of children with displaced DTF managed by ESIN with and without the use of an OTT. Medical records were retrospectively reviewed for all pediatric patients sustaining DTF managed by ESIN from 2011 to 2019 at two different institutions. In all, 160 consecutive children with displaced DTF were recorded, of whom 80 underwent operative treatment by ESIN without OTT (group A), and 80 by ESIN with the use of an OTT and skeletal traction (group B). ESIN outcome measure scale, Beaty radiologic criteria and Radiographic Union Scale for Tibia fractures (RUST) score were used to evaluate the results. Average patient age at time of injury was 10.8 years (range 7-15). The mean follow-up was 55.8 months (range 12-96). All complications (2.5%) and poorer results according to ESIN outcome measure scale and Beaty radiological criteria were recorded among children managed with OTT. No complications related to pin insertion for skeletal traction were observed. Mean RUST score, length of surgery and cumulative time of radiation exposure were comparable between the two groups. Children with a displaced DTF treated by ESIN without the use of OTT showed superior results as there are no additional procedures (traction wire insertion and removal) decreased theater time and no complications with similar radiation dose.

Physical activity is an important element of type 1 diabetes management, and hypoglycemia is a known risk. There are few data on strategies adolescents use to mitigate this risk. We surveyed 66 adolescents with type 1 diabetes who were 12–18 years of age about blood glucose monitoring, carbohydrate intake, and insulin management before, during, and after exercise. The adolescents completed the International Physical Activity Questionnaire–Short Form and the Children’s Hypoglycemia Fear Survey. We found that adolescents with type 1 diabetes do not generally follow guidelines about glucose monitoring or about food and insulin adjustment around exercise. More targeted education and interventions are needed to improve adolescents’ uptake of recommended behaviors and improve outcomes.

PurposeThe use of mobile health (mHealth) technologies to augment patient care, enables providers to communicate remotely with patients enhancing the quality of care and patient engagement. Few studies addressed barriers to its implementation, especially in medically underserved populations.MethodsA cross-sectional study of 151 cancer patients was conducted at an academic medical center in the United States. A trained interviewer performed structured interviews regarding the barriers and facilitators of patients’ current and desired utilization of technology for healthcare services.ResultsOf the 151 participants, 35.8% were male and ages ranged from 21-104 years. Only 73.5% of participants currently have daily access to internet, and 68.2% currently own a smartphone capable of displaying mobile applications. Among all participants, utilization of a daily mHealth application was significantly higher in patients with a college-level degree (OR; 2.78, ppp<0.01).ConclusionThe study suggests the access to mobile technology is the predominant determinant of utilization. Healthcare organizations should consider these factors when launching patient engagement platforms.

For two decades, many scores, questionnaires, and rating systems have been used to evaluate the functional outcome of children with an upper extremity fracture (UEF). However, only a few of these were created specifically for children, and many assess only elbow function. In the absence of any published review on this topic, we set out to identify and categorize different scores used to evaluate the clinical and functional outcomes of surgically treated pediatric UEFs. A literature search was performed, and 38 studies were identified. The scores used more often were the shortened version of the Disability of the Arm, Shoulder and Hand questionnaire and the Mayo Elbow Performance Score/Index. In a lower number of studies, authors used other scoring systems, including the Mayo Wrist Score, the Patient-Rated Wrist Evaluation, the Patient-Rated Elbow Evaluation, the Metaizeau functional scoring system, the Oxford Elbow Score, the Price and Flynn criteria, the Hardacre Functional Score, the Neer Shoulder Score, the Constant-Murley Shoulder Score, the Modified Orthopedic Trauma Association Score, the Medical Outcomes Study Short Form-36, and the Pediatric Outcomes Data Collection Instrument. Some specific pediatric scoring systems to evaluate the functional outcome of children with a UEF have been suggested, but a single tool that is valid and reliable for skeletally immature patients of all ages is not yet available. Further studies are needed to identify specific pediatric measurements to increase validity, responsiveness, sensitivity, and interpretability of upper limb functional outcome scores in common clinical practice.

Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients. Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years). Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated. Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes. Trial Registration ClinicalTrials.gov NCT02293837. Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

International audience; The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease COVID-19 has killed over 2 million people as of 22 January 2021. We have used a modified susceptible, infected, recovered epidemiological model to predict how the spread of the virus in France will vary depending on the public health strategies adopted, including anti-COVID-19 vaccination. Our prediction model indicates that the French authorities' adoption of a gradual release from lockdown could lead in March 2021 to a virus prevalence similar to that before lockdown. However, a massive vaccination campaign initiated in January 2021 and the continuation of public health measures over several months could curb the spread of virus and thus relieve the load on hospitals.

Introduction The use of the orthopaedic traction table (OTT) during elastic stable intramedullary nailing (ESIN) in the management of displaced diaphyseal femur fractures (DFFs) is still debated. In most centers, children with displaced DFF are treated using an OTT. In some other institutions, however, fracture reduction and stabilization by ESIN are performed on a radiolucent table without an OTT. The aim of this study was to evaluate the clinical and radiologic outcome of children with displaced DFF managed by ESIN with and without the use of an OTT. Methods Charts and radiographs were retrospectively reviewed for all pediatric patients sustaining DFF managed by ESIN from 2011 to 2017 at 2 different institutions. In all, 69 consecutive children with displaced DFF were recorded, of whom 35 underwent operative treatment by ESIN with the use of an OTT with skeletal traction (Group A), and 34 by ESIN without OTT (Group B). The titanium elastic nails outcome measure scale score and Beaty radiologic criteria were used to evaluate the results. Results Average patient age at time of injury was 9 years (range, 5 to 13) and 10 years (range, 4 to 15) in Groups A and B, respectively. The mean follow-up was 54 months (range, 24 to 96). Overall, complications were observed in 6 patients (8.6%). Complication rate was higher among children managed without OTT (11.8%) than among children treated with OTT (2.5%); no complication related to pin insertion for skeletal traction was recorded. However, the number of patients with a poor outcome according to the titanium elastic nails outcome score was higher in Group A (20%) than in Group B (5.8%). Beaty radiologic criteria were comparable between the 2 groups. Mean length of surgery and mean cumulative time of radiation exposure during surgery were similar between the 2 groups. Conclusions Overall, both techniques work equally well although patients treated by ESIN with the use of an OTT and skeletal traction tended to have a lower rate of complications and radiologic outcome was worse than for patients treated without using an OTT; however, no statistically significant difference was found.Despite their limitations, the results of this study suggest that displaced DFF can be safely managed by ESIN with or without the use of intraoperative OTT and skeletal traction, according to the surgeon's preference. Further studies are now needed to consolidate these conclusions and clarify the role of the OTT. Level of evidence Level III.

Context Cardiovascular disease (CVD) is a major cause of mortality in adults with type 1 diabetes. Objective We prospectively evaluated CVD risk factors in a large, contemporary cohort of adults with type 1 diabetes living in the United States. Design Observational study of CVD and CVD risk factors over a median of 5.3 years. Setting The T1D Exchange clinic network. Patients Adults (age ≥ 18 years) with type 1 diabetes and without known CVD diagnosed before or at enrollment. Main Outcome Measure Associations between CVD risk factors and incident CVD were assessed by multivariable logistic regression. Results The study included 8,727 participants (53% female, 88% non-Hispanic white, median age 33 years [interquartile ratio {IQR} = 21, 48], type 1 diabetes duration 16 years [IQR = 9, 26]). At enrollment, median HbA1c was 7.6% (66 mmol/mol) (IQR = 6.9 [52], 8.6 [70]), 33% used a statin, and 37% used blood pressure medication. Over a mean follow-up of 4.6 years, 325 (3.7%) participants developed incident CVD. Ischemic heart disease was the most common CVD event. Increasing age, body mass index, HbA1c, presence of hypertension and dyslipidemia, increasing duration of diabetes, and diabetic nephropathy were associated with increased risk for CVD. There were no significant gender differences in CVD risk. Conclusion HbA1c, hypertension, dyslipidemia and diabetic nephropathy are important risk factors for CVD in adults with type 1 diabetes. A longer follow-up is likely required to assess the impact of other traditional CVD risk factors on incident CVD in the current era.

BACKGROUND: Across all age groups, management of type 1 diabetes (T1D) places substantial responsibility and emotional burden upon families. This study explored parent perceptions of the burdens of caring for very young children with T1D. METHODS: Semi-structured qualitative interviews were conducted with parents (85% mothers) of 79 children with T1D, aged 1 to

OBJECTIVE To better understand potential facilitators of individual engagement in type 1 diabetes natural history and prevention studies through analysis of enrollment data in the TrialNet Pathway to Prevention (PTP) study. RESEARCH DESIGN AND METHODS We used multivariable logistic regression models to examine continued engagement of eligible participants at two time points: 1) the return visit after screening to confirm an initial autoantibody-positive (Ab+) test result and 2) the initial oral glucose tolerance test (OGTT) for enrollment into the monitoring protocol. RESULTS Of 5,387 subjects who screened positive for a single autoantibody (Ab), 4,204 (78%) returned for confirmatory Ab testing. Younger age was associated with increased odds of returning for Ab confirmation (age 18 years: odds ratio [OR] 2.12, P < 0.0001). Racial and ethnic minorities were less likely to return for confirmation, particularly nonwhite non-Hispanic (OR 0.50, P < 0.0001) and Hispanic (OR 0.69, P = 0.0001) relative to non-Hispanic white subjects. Of 8,234 subjects, 5,442 (66%) were identified as eligible to be enrolled in PTP OGTT monitoring. Here, younger age and identification as multiple Ab+ were associated with increased odds of returning for OGTT monitoring (age 18 years: OR 1.43, P < 0.0001; multiple Ab+: OR 1.36, P < 0.0001). Parents were less likely to enroll into monitoring than other relatives (OR 0.78, P = 0.004). Site-specific factors, including site volume and U.S. site versus international site, were also associated with differences in rates of return for Ab+ confirmation and enrollment into monitoring. CONCLUSIONS These data confirm clear differences between successfully enrolled populations and those lost to follow-up, which can serve to identify strategies to increase ongoing participation.

Parents of young children with type 1 diabetes (T1D) experience unique, developmental challenges in managing their child's T1D, resulting in psychosocial distress. Only a small portion of young children reach glucose goals and adherence to diabetes devices that help improve T1D management have historically been low in this population. The purpose of this study is to test four interventions that couple developmentally tailored behavioral supports with education to optimize use of diabetes devices, improve glucose control, and reduce psychosocial distress for parents of young children with T1D. The study team designed four behavioral interventions, two aimed at improving glucose control and two aimed at optimizing use of diabetes devices. The goal of this paper is to describe the behavioral interventions developed for this study, including the results of a pilot test, and describe the methods and analysis plan to test this intervention strategy with ninety participants in a large-scale, randomized trial using a sequential multiple assignment randomization trial (SMART) design. A SMART design will permit a clinically relevant evaluation of the intervention strategy, as it allows multiple randomizations based on individualized assessments throughout the study instead of a fixed intervention dose seen in most traditional randomized controlled trials.

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

Clinical examination of the newborn's foot is a complex exercise that requires a lot of sensitivity, practice and deep understanding of normal and pathological anatomy, and the clinical assessment of a child with congenital talipes equinovarus, or congenital clubfoot, must be complete and it should not be limited to a simple orthopedic evaluation of the foot; the search for a cause is a pressing concern. This narrative review article aims to provide the key information about clinical examination of children with congenital clubfoot; classification systems are also described. Clinical examination of children with congenital clubfoot is essential. In particular, it is important to evaluate the mental age of the child (developmental milestones), to rule out the presence of a spinal dysraphism, to eliminate a mild form of neurological disease (congenital myopathy or arthrogryposis), as well as to carefully examine the face and hands of the patient. The examination of the foot and the classification of the clubfoot deformity complete the clinical evaluation. In the end, the pediatric orthopedic surgeon must not underestimate any clinical signs, and must act as a pediatrician. This narrative review summarizes the key points in taking a history and performing a comprehensive clinical examination for patients with congenital clubfoot; the review also briefly describes the normal foot anatomy and growth as to give the reader the opportunity to better understand the morphological and functional modifications secondary to congenital clubfoot.

The role and performance of chest CT in the diagnosis of the coronavirus disease 2019 pandemic remains under active investigation. A recent case report in this journal found that a COVID-19 diagnosis has been made from the serological results despite first CT scan and RT-PCR negative results. We have included 311 consecutive patients with COVID-19-like symptoms who underwent a RT-PCR test on nasopharyngeal swab samples and a chest CT scan. Patients with a positive chest scan and a negative RT-PCR were screened for serum total anti-SARS-CoV-2 antibodies 2 months after the onset of symptoms using the Wantai test in order to arbitrate between RT-PCR and CT scans discordant results. Most of the RT-PCR and chest CT results agreed but the serological tests indicate that most CT positive/NAT negative patients are not infected by SARS-CoV-2 and alternative diagnoses should be seriously considered. This article is protected by copyright. All rights reserved.

The SARS-CoV-2 virus has spread world-wide since December 2019, killing more than 2.9 million of people. We have adapted a statistical model from the SIR epidemiological models to predict the spread of SARS-CoV-2 in France. Our model is based on several parameters and assumed a 4.2% seroprevalence in Occitania after the first lockdown. The recent use of serological tests to measure the effective seroprevalence of SARS-CoV-2 in the population of Occitania has led to a seroprevalence around 2.4%. This implies to review the parameters of our model to conclude at a lower than expected virus transmission rate, which may be due to infectivity varying with the patient’s symptoms or to a constraint due to an uneven population geographical distribution.

The efficacy of dasiglucagon 0.6 mg, a glucagon analog stable in aqueous formulation, has been established versus placebo in previously reported trials in adults with type 1 diabetes mellitus. An integrated analysis was conducted to investigate efficacy in demographic and other subgroups. To allow as many individuals as possible in the evaluation, the analysis comprised data from 4 trials in adults, including 2 pivotal trials, an additional phase 3 trial, and a phase 2 trial. The trials were conducted under similar conditions with respect to design characteristics, such as target population, background therapy and treatment duration. All trials included efficacy assessments following insulin-induced hypoglycemia and showed consistent efficacy results across trials. The primary endpoint was time to plasma glucose (PG) recovery, defined as first PG increase ≥ 20 mg/dL after treatment initiation without need for rescue intravenous glucose. A total of 220 participants were exposed to dasiglucagon 0.6 mg across trials. Results of the integrated analysis are shown as a Forest plot of median time to PG recovery for dasiglucagon, including 95% confidence intervals by subgroup. In conclusion, the results showed that the efficacy of dasiglucagon was highly consistent across subgroups, with a median time to recovery from insulin-induced hypoglycemia of 10 minutes in most groups. Disclosure T. Battelino: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Sanofi, Research Support; Self; European Union, National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Slovenian Research Agency, Zealand Pharma A/S, Speaker’s Bureau; Self; Abbott Diabetes, AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Pfizer Inc., Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Danne: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Tandem Diabetes Care, Zealand Pharma A/S, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. R. Tehranchi: Employee; Self; Zealand Pharma A/S. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. U. Hovelmann: None. L. Plum-moerschel: None. A. E. Melgaard: Employee; Self; Zealand Pharma A/S. R. Aronson: None.

The efficacy of dasiglucagon 0.6 mg has been investigated in multiple trials in individuals with T1DM. The primary endpoint was time to plasma glucose (PG) recovery from insulin-induced hypoglycemia, defined as first PG increase ≥20 mg/dL after treatment initiation without the need for IV glucose. Different PG sampling schemes were used in phase 2 (5-min intervals) versus phase 3 trials (more frequent sampling). Estimating the true but unmeasured time to recovery for each individual enables for a better comparison between trials when compared to use of observed time only. The true time was calculated using linear interpolation between the 2 time points before and after recovery occurred, assuming a linear PG increase in this limited time interval. The difference between the observed and the estimated true recovery for an individual is illustrated in the figure. The PG sample taken at 10 min is the first sample showing an increase of at least 20 mg/dL from the predose level, leading to an observed time to recovery of 10 min. Linear interpolation estimates the increase of 20 mg/dL to occur at 9 min for this individual. Using interpolated PG values, the median estimated true time to recovery for dasiglucagon was 8.7 min in the phase 2 trial and 9.0 to 9.3 min in phase 3 trials. These data provide further insight into the probable “true time to recovery” and confirm the consistent efficacy of dasiglucagon in the treatment of hypoglycemia. Disclosure T. Battelino: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Sanofi, Research Support; Self; European Union, National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Slovenian Research Agency, Zealand Pharma A/S, Speaker’s Bureau; Self; Abbott Diabetes, AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Pfizer Inc., Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Danne: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Tandem Diabetes Care, Zealand Pharma A/S, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. A. L. Peters: Advisory Panel; Self; Abbott Diabetes, Eli Lilly and Company, MannKind Corporation, Medscape, Merck & Co., Inc., Novo Nordisk Inc., Zealand Pharma A/S, Other Relationship; Self; Livongo, Research Support; Self; Abbott Diabetes, Dexcom, Inc. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. R. Tehranchi: Employee; Self; Zealand Pharma A/S. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. U. Hovelmann: None. L. Plum-moerschel: None. A. E. Melgaard: Employee; Self; Zealand Pharma A/S. R. Aronson: None.

Dasiglucagon was developed to provide a fast and effective treatment for severe hypoglycemia (SH) in people with diabetes. An integrated cross-program analysis was performed to assess the safety of dasiglucagon in a representative population of T1DM. Three randomized, placebo-controlled phase 3 trials (2 in adults and 1 in pediatric subjects) were included in the analysis (212 adults and 41 children/adolescents with T1DM). No severe or adverse events (AEs) leading to withdrawal were reported. Most AEs were mild or moderate in severity. Nausea and vomiting were the most-frequent AEs reported with active treatment both in adults and children. No differences in the frequency of nausea and vomiting were observed between adults receiving dasiglucagon versus glucagon. A higher percentage of adolescents experienced these events with dasiglucagon than with glucagon, while no treatment-related imbalance was observed in the 6- to 11-year-old age group. In the pediatric trial, no relationship between exposure (AUC0-5 hr or Cmax) to dasiglucagon, and nausea and vomiting was found. The majority of nausea and vomiting occurred within 1-3 hr and 2-3 hr of dosing, respectively. In conclusion, dasiglucagon 0.6 mg for treatment of SH was found to be generally safe, and the safety profile of dasiglucagon was consistent with that observed across the class of glucagon products. Disclosure S. R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Zealand Pharma A/S, Consultant; Self; Zealand Pharma A/S, Other Relationship; Self; Dexcom, Inc., Eli Lilly and Company, MannKind Corporation, Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. R. Aronson: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Danne: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Tandem Diabetes Care, Zealand Pharma A/S, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. T. Battelino: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Sanofi, Research Support; Self; European Union, National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Slovenian Research Agency, Zealand Pharma A/S, Speaker’s Bureau; Self; Abbott Diabetes, AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Pfizer Inc., Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. R. Tehranchi: Employee; Self; Zealand Pharma A/S. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. U. Hovelmann: None. L. Plum-moerschel: None. A. E. Melgaard: Employee; Self; Zealand Pharma A/S.

Aims: We assessed safety and efficacy of Cambridge hybrid closed-loop (HCL) compared with usual care over 6 months in children and young people with T1D. Methods: In an open-label multicentre multinational parallel randomised controlled trial, we randomly assigned participants on insulin pump therapy aged 6 to 18 years to receive either HCL therapy (CL) or continue usual care (control) for 6 months. We used the same Cambridge model predictive control algorithm in two consecutive hardware iterations, FlorenceM then CamAPS FX. Primary endpoint was central laboratory HbA1c at 6 months. Results: We randomised 133 participants: 65 to CL and 68 to control (baseline HbA1c 8.2±0.7% vs. 8.3±0.8%). At 6 months mean HbA1c was 0.32% lower in CL compared to control (95% CI -0.59 to -0.04; p=0.02). Closed-loop usage was low (40% [26, 53]; median [IQR]) with FlorenceM due to hardware issues, and high (93% [88, 96]) with CamAPS FX. In the CamAPS FX CL group (n=21) HbA1c was 1.05% lower (95% CI -1.43 to -0.67; p Conclusion: Cambridge HCL is safe and significantly improves glycaemic control in children and young people with T1D. Efficacy relies on consistent usage of closed-loop, as demonstrated by CamAPS FX. Disclosure J. Fuchs: None. B. A. Buckingham: Advisory Panel; Self; Medtronic, Tolerion, Inc., Research Support; Self; Beta Bionics, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. N. Davis: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. N. Mauras: Advisory Panel; Self; Novo Nordisk, Research Support; Self; LifeScan, Medtronic, Novo Nordisk. R. Besser: None. A. Ghatak: None. S. A. Weinzimer: Advisory Panel; Self; Dompe, Zealand Pharma A/S, Speaker’s Bureau; Self; Medtronic. K. K. Hood: Consultant; Self; Cecelia Health, Cercacor, LifeScan Diabetes Institute. D. Fox: None. L. Kanapka: None. C. K. Boughton: None. C. Kollman: Consultant; Self; Diasome Pharmaceuticals, Inc., Research Support; Self; Dexcom, Inc., Tandem Diabetes Care. J. Sibayan: None. R. Beck: Consultant; Self; Bigfoot Biomedical, Inc., Diasome Pharmaceuticals, Inc., Insulet Corporation, Lilly Diabetes, vTv Therapeutics, Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Medtronic, Novo Nordisk, Tandem Diabetes Care. R. Hovorka: Research Support; Self; Abbott Laboratories, Dexcom, Inc., Medtronic, Speaker’s Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Stock/Shareholder; Self; CamDiab Ltd. Dan05 consortium: n/a. J. M. Allen: None. M. E. Wilinska: Consultant; Self; CamDiab Ltd. M. Tauschmann: None. L. Denvir: None. A. Thankamony: None. F. Campbell: n/a. R. Wadwa: Consultant; Self; Tandem Diabetes Care, Research Support; Self; Dexcom, Inc., Eli Lilly and Company, Tandem Diabetes Care. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UC4DK108520)

The TrialNet OI prevention trial (TN07) with T1D as an endpoint showed no effect. However, in a smaller trial run in parallel with TN07 (termed secondary stratum 1), in which all participants had low first-phase insulin release, a statistically significant delay in T1D onset was found. Since trials with T1D as an endpoint take years to complete, we aimed to determine if combination C-peptide and glucose markers could identify a therapeutic benefit after 12 months of OI in this high-risk population. All participants were at-risk relatives with multiple autoantibodies including mIAA and normal glucose tolerance (n=40 with full data). The Figure shows changes in glucose and C-peptide response curves and their centroids (central points). Glucose rose and C-peptide declined in the placebo group compared to a minimal glucose rise with an increase of C-peptide in the OI group. Change from baseline to 1 year in the centroid ratio (C-peptide/glucose) differed significantly between groups (p=0.037 after adjustments for age, BMI, and baseline C-peptide and glucose). The AUC C-peptide/AUC glucose ratio and Index60 did not differ (both p=0.108). In conclusion, the findings support a positive effect of OI on combined glucose and C-peptide endpoints in high-risk individuals. These measures appear to detect differences in a shorter time than the standard T1D endpoint. Disclosure L. M. Jacobsen: None. M. A. Atkinson: None. J. Krischer: None. D. Schatz: Advisory Panel; Self; Abbott, Medtronic. J. Sosenko: None. D. D. Cuthbertson: None. E. K. Sims: None. H. M. Ismail: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. M. Triolo: None. M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. M. Lundgren: None. P. Gottlieb: Advisory Panel; Self; Janssen Research & Development, LLC, Tolerion, Inc., Viacyte, Inc., Other Relationship; Self; ImmunoMolecular Therapeutics, Inc., Research Support; Self; Caladrius Biosciences, Inc., Immune Tolerance Network, Mercia Pharma Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Precigen, Inc., Tolerion, Inc.

Caregivers, mostly parents, of youth with T1D are integral to management; yet little is known about their care time burden. We assessed time spent providing care to youth with T1D (aged 2- Disclosure A. Glynn: None. L. Kanapka: None. K. Miller: Other Relationship; Self; Dexcom, Inc., Tandem Diabetes Care, Research Support; Self; JDRF, Leona M. and Harry B. Helmsley Charitable Trust. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Songer: Employee; Spouse/Partner; Boehringer Ingelheim Pharmaceuticals, Inc. Funding The Leona M. and Harry B. Helmsley Charitable Trust

The specificity of subject selection is crucial for T1D prevention trials. GCRCs are glucose and C-peptide values at 30 to 120-minute OGTT timepoints plotted on a glucose (y-axis) and C-peptide (x-axis) grid. Since GCRCs change characteristically on the grid during T1D progression, the identification of GCRC phenotypes among screening OGTTs would refine selection for T1D prevention trials. We aimed to determine if AUC glucose (AUCglu) and AUC C-peptide (AUCpep) identify GCRCs at screening that match GCRCs specific to times pre-diagnosis. We analyzed OGTT data from DPT-1 and TrialNet (TN) participants, both antibody positive (Ab+) populations. AUCglu and AUCpep of 52 TN participants at screening were matched to AUCglu and AUCpep 1.5 yrs pre-diagnosis in 162 DPT-1 participants (AUCglu means: 152.7 vs. 152.3 mg/dl; AUCpep means: 3.7 vs. 3.7 ng/dl, respectively). By matching the AUC values at TN screening to the DPT-1 AUC values 1.5 yrs pre-diagnosis, we were able to match GCRCs at TN screening to the DPT-1 GCRCs 1.5 yrs pre-diagnosis. Figure 1 shows the matched GCRCs obtained by matching AUC values. In conclusion, AUCglu and AUCpep can identify GCRCs at screening that match GCRCs specific to a time before diagnosis, even across Ab+ populations. This novel finding should considerably enhance the metabolic specificity of subject selection for T1D prevention trials. Disclosure H. M. Ismail: None. B. M. Nathan: None. M. A. Atkinson: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. J. Sosenko: None. D. D. Cuthbertson: None. M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. A. Steck: None. H. Rodriguez: Advisory Panel; Self; Provention Bio, Inc., Other Relationship; Self; Merck & Co., Inc., Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Medtronic, Precigen, Inc., Provention Bio, Inc., Takeda Pharmaceutical Co., Tolerion, Inc. S. E. Gitelman: Advisory Panel; Self; Provention Bio, Inc., Tolerion, Inc., Consultant; Self; Avotres Inc., Biolojic, Research Support; Self; Intrexon, Janssen Research & Development, LLC, Provention Bio, Inc., Tolerion, Inc. K. C. Herold: Consultant; Self; Provention Bio, Inc., Viela Bio, Consultant; Spouse/Partner; Provention Bio, Inc. J. S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Oramed Pharmaceuticals, Inc., Orgenesis Inc., Tolerion, Inc., Viacyte, Inc., Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics, Inc., Consultant; Self; AstraZeneca, Avotres Inc., Bayer AG, IM Therapeutics, Novo Nordisk, Precigen, Inc., Provention Bio, Inc., Sanofi, Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc.

International audience; The spread of SARS-CoV-2 and the resulting disease COVID-19 has killed over 2.6 million people as of 18 March 2021. We have used a modified susceptible, infected, recovered (SIR) epidemiological model to predict how the spread of the virus in regions of France will vary depending on the proportions of variants and on the public health strategies adopted, including anti-COVID-19 vaccination. The proportion of SARS-CoV-2 variant B.1.1.7, which was not detected in early January, increased to become 60% of the forms of SARS-CoV-2 circulating in the Toulouse urban area at the beginning of February 2021, but there was no increase in positive nucleic acid tests. Our prediction model indicates that maintaining public health measures and accelerating vaccination are efficient strategies for the sustained control of SARS-CoV-2.

Hepatitis E virus (HEV) genotypes 3 and 4 are the major causes of acute hepatitis in industrialized countries. Genotype 3 is mainly found in Europe and America, while genotype 4 is predominant in Asia. Several Japanese studies have suggested that genotype 4 is more virulent than genotype 3. We investigated this aspect by analyzing the clinical and biological data for 27 French and Belgian immunocompetent patients infected with HEV genotype 4. Their infections were probably acquired locally, since none of these patients reported traveling outside France or Belgium during the 2–8 weeks before symptoms onset. Each patient was matched for age (±5 years) and gender with two patients infected with HEV genotype 3. Bivariate analysis indicated that the HEV genotype 4-infected patients had significantly higher alanine aminotransferase (ALT) (2067 IU/L) and aspartate aminotransferase (AST) (1581 IU/L) activities and total bilirubin concentrations (92.4 μmol/L) than did those infected with HEV genotype 3 (1566 IU/L, p = 0.016; 657 IU/L, p = 0.003 and 47 μmol/L, p = 0.046) at diagnosis. In contrast, more patients infected with HEV genotype 3 reported dark urine (71% vs. 39%, p = 0.02) and experienced asthenia (89% vs. 58%, p < 0.01) than did those infected with HEV genotype 4. Two HEV genotype 4-infected patients died of multi-organ failure, while none of the genotype 3-infected patients died (p = 0.035). Finally, stepwise regression analysis retained only a greater increase in ALT (odds-ratio: 1.0005, 95% confidence interval: 1.00012–1.00084) and less frequent fever (odds-ratio = 0.1244; 95% confidence interval: 0.01887–0.82020) for patients infected with HEV genotype 4. We conclude that HEV-4 infections are likely to be associated with higher ALT activity than HEV-3 infections. Additional immunological and virological studies are required to confirm these findings and better understand the influence, if any, of genotype on HEV pathophysiology.

Each January, the editors of Diabetes Care look back at the last year and forward to the next. In January 2021 we have much to be thankful and happy about. The journal continues to publish outstanding scientific reports together with illuminating and provocative Commentary, Perspective, and Review articles. We are indebted to the authors who submit their manuscripts, the reviewers who evaluate them, and the editorial and production group that manages the process. They make it all possible. In 2020, Diabetes Care ’s impact factor increased once again, from 15.27 to 16.02. Accumulating scientific evidence presented by our journal and others continues to improve understanding of the pathophysiology of diabetes and add to the array of treatments. And yet . . . it’s been a hell of a year in other ways. The coronavirus disease 2019 (COVID-19) pandemic started a year ago and still has the world in its grip. It has tested all of us and brought many activities nearly to a halt. Countless people have fallen ill, sadly many have died, and the daily routines of most families are disturbed. The lockdown to prevent spread of the virus keeps people at home, limits travel, harms businesses, closes schools, and interferes with diagnosis and treatment of other ailments. Acute medical facilities have been overwhelmed in some regions. Fierce debates about controlling the spread of COVID-19 and mitigating its human and economic costs have ensued. Yet, in this crisis we see much heroism. Medical personnel and those who support …

Type 1 diabetes results from autoimmune-mediated destruction of β cells. The tyrosine kinase inhibitor imatinib might affect relevant immunological and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our aim was to evaluate the safety and efficacy of imatinib in preserving β-cell function in patients with recent-onset type 1 diabetes.We did a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients with recent-onset type 1 diabetes (100 days from diagnosis), aged 18-45 years, positive for at least one type of diabetes-associated autoantibody, and with a peak stimulated C-peptide of greater than 0·2 nmol LPatients were screened and enrolled between Feb 12, 2014, and May 19, 2016. 45 patients were assigned to receive imatinib and 22 to receive placebo. After withdrawals, 43 participants in the imatinib group and 21 in the placebo group were included in the primary ITT analysis at 12 months. The study met its primary endpoint: the adjusted mean difference in 2-h C-peptide AUC at 12 months for imatinib versus placebo treatment was 0·095 (90% CI -0·003 to 0·191; p=0·048, one-tailed test). This effect was not sustained out to 24 months. During the 24-month follow-up, 32 (71%) of 45 participants who received imatinib had a grade 2 severity or worse adverse event, compared with 13 (59%) of 22 participants who received placebo. The most common adverse events (grade 2 severity or worse) that differed between the groups were gastrointestinal issues (six [13%] participants in the imatinib group, primarily nausea, and none in the placebo group) and additional laboratory investigations (ten [22%] participants in the imatinib group and two [9%] in the placebo group). Per the trial protocol, 17 (38%) participants in the imatinib group required a temporary modification in drug dosing and six (13%) permanently discontinued imatinib due to adverse events; five (23%) participants in the placebo group had temporary modifications in dosing and none had a permanent discontinuation due to adverse events.A 26-week course of imatinib preserved β-cell function at 12 months in adults with recent-onset type 1 diabetes. Imatinib might offer a novel means to alter the course of type 1 diabetes. Future considerations are defining ideal dose and duration of therapy, safety and efficacy in children, combination use with a complimentary drug, and ability of imatinib to delay or prevent progression to diabetes in an at-risk population; however, careful monitoring for possible toxicities is required.Juvenile Research Diabetes Foundation.

Aims/hypothesis Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. Methods Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial–Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. Results Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. Conclusions/interpretation Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification. Graphical abstract

Background: Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. Methods: We conducted a phase 2, randomised, placebo-controlled, blinded clinical trial. Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 sites in the USA and Australia. Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by study site. The primary endpoint was the change in 2-hour area under the curve (AUC) C-peptide response to MMTT from baseline to 12 months, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975. Findings: Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016. 45 patients were assigned to imatinib, 22 to placebo. The study met its primary endpoint: the 12-mo C-peptide AUC mean was 0·583 (95% CI: 0·519, 0·650) nmoles/L in the imatinib group versus 0·489 (95% CI: 0·403, 0·579) nmoles/L for the placebo group, adjusted for baseline C-peptide, age, and gender (p = 0·048, 1-tail test). In secondary analyses, compared to the placebo group, imatinib-treated subjects required less exogenous insulin and trended towards lower HbA 1c , with higher beta cell glucose sensitivity, lower proinsulin/C-peptide ratios, improved insulin sensitivity, and higher serum adiponectin levels. No significant changes were noted in autoantibody titers and immune cell phenotyping. Interpretation: A 26-wk course of imatinib preserves beta cell function at 12 months in adults with recent onset type 1 diabetes. Although no overt effects on immune responses were detected, imatinib may have novel metabolic effects on both beta cell function and insulin sensitivity. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT01781975. Funding: Juvenile Research Diabetes Foundation Declaration of Interests: SG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Intrexon, Janssen, Provention Bio, and Tolerion. JB has consulted for Vertex Pharmaceuticals, Inc, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk and Pfizer, and is co-founder and chief medica officer for ImmunoMolecular Therapeutics, Inc. RM has a patent application for DNA methylation in inflammatory disease. SW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals, Inc. and Medtronic, and a DSMB for the National Institutes of Health. All other authors report no potential conflicts of interest. Ethics Approval Statement: This phase 2, randomised, placebo-controlled, double-blinded clinical trial was conducted according to the Declaration of Helsinki and in accordance with good clinical practice guidelines, performed under an investigational new drug application (IND 117644) and was approved by independent institutional review boards at each participating center.

OBJECTIVE This study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to RESEARCH DESIGN AND METHODS This was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to RESULTS Approximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level CONCLUSIONS CGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.

To assess risk factors and incidence of diabetes complications in women with type 1 diabetes (T1D) based on parity.Data were collected from women (16-40 years old) in the T1D Exchange completing pregnancy/childbirth questionnaires during 2011-2013 and 2016-2018. Incidence of risk factors and diabetes complications were compared between women with a first pregnancy at/within 1-year of enrollment (There was a trend for lower HbA1c (adjustedFour-5 years after delivery, parous women with T1D tended to have lower HbA1c levels despite higher body mass indices and more frequent adverse lipid profiles and hypertension compared with nulliparous women. Further studies based on these trends are warranted.

Objectives: To examine changes in device use and glycemic outcomes for pregnant women from the T1D Exchange Clinic Registry between the years 2010-2013 and 2016-2018. Methods: Participant-reported device use and glycemic outcomes were compared for women aged 16-40 years who were pregnant at the time of survey completion, comparing 2010-2013 (cohort 1) and 2016-2018 (cohort 2). Hemoglobin A1c results within 30 days prior to survey completion were obtained from medical records. Results: There were 208 pregnant women out of 5,236 eligible participants completing the questionnaire in cohort 1 and 47 pregnant women out of 2,818 eligible participants completing the questionaire in cohort 2. Continuous glucose monitor (CGM) use while pregnant trended upward among cohort 2 (70% vs 37%, P = .02), while reported continuous subcutaneous insulin infusion (CSII) use while pregnant declined (76% vs 64%, P = .04). HbA1c levels trended downward (6.8% cohort 1 vs 6.5% cohort 2, P = .07). Conclusions: Self-reported CGM use while pregnant increased over the studied intervals whereas CSII use decreased. Additional evaluation of device use and the potential benefits for T1D pregnancies is needed.

International audience; The new virus, SARS-CoV-2, has probably affected millions of people world-wide since December 2019 and killed thousand. We have designed a model and used it to quantify the effect of local protective measures on the SARS-CoV-2 epidemic, assess their effectiveness and adapt health service strategies in Toulouse, France.

IntroductionData show that disturbances in the gut microbiota play a role in glucose homeostasis, type 1 diabetes (T1D) risk and progression. The prebiotic high amylose maize starch (HAMS) alters the gut microbiome profile and metabolites favorably with an increase in bacteria producing short chain fatty acids (SCFAs) that have significant anti-inflammatory effects. HAMS also improves glycemia, insulin sensitivity and secretion in healthy non-diabetic adults. Additionally, a recent study testing an acetylated and butyrylated form of HAMS (HAMS-AB) that further increases SCFA production prevented T1D in a rodent model without adverse safety effects. The overall objective of this human study will be to assess how daily HAMS-AB consumption impacts the gut microbiome profile, SCFA production, β-cell heath, function and glycemia as well as immune responses in newly-diagnosed T1D youth.Methods and AnalysisWe hypothesize that HAMS-AB intake will improve the gut microbiome profile, increase SCFA production, improve β-cell health, function and glycemia as well as modulate the immune system. We describe here a pilot, randomized crossover trial of HAMS-AB in 12 newly-diagnosed T1D youth with residual β-cell function. In Aim 1, we will determine the effect of HAMS-AB on the gut microbiome profile and SCFA production; in Aim 2, we will determine the effect of HAMS-AB on β-cell health, function and glycemia; and in Aim 3, we will determine the peripheral blood effect of HAMS-AB on frequency, phenotype and function of specific T cell markers. We anticipate beneficial effects from a simple, inexpensive, and safe dietary approach.Ethics and DisseminationThe Institutional Review Board at Indiana University approved the study protocol. The findings of this trial will be submitted to a peer-reviewed pediatric journal. Abstracts will be submitted to relevant national and international conferences.Trial registration numberNCT04114357; Pre-results.Article SummaryStrengths and limitations of this studyThe study design (randomized controlled trial, RCT) is the most robust methodology to assess the effectiveness of therapeutic interventions.The findings of this RCT, whether positive or negative, will contribute to the formulation of further recommendations on the use of high amylose maize starch that has been acetylated and butyrylated for improving beta-cell function in children with newly diagnosed type 1 diabetes (T1D).

International audience; In a recent review of laboratory tests for diagnosing SARS-CoV-2 infection, Zheng et al. concluded that the detection rate of real-time quantitative PCR was lower than that of computed tomography [1]. But the authors did not discuss the possibility of using saliva sampling. Nasopharyngeal (NP) swabs are the preferred collection vehicles in France and many other countries and several studies have indicated that this method is more sensitive than sampling other sites [2–4]. Saliva sampling is less invasive for patients, less hazardous for health care workers, requires fewer experimented staff and is less expensive for mass testing. However, little is known about any differences in the sensitivities of saliva and NP sampling or how any differences vary with presence or absence of clinical symptoms

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus ( R = 0.48, P < .05). Age at diagnosis significantly correlated with time to resolution ( R = 0.51, P = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation.

Dasiglucagon is a stable glucagon analog being developed in the HypoPal® auto-injector to address the need for easy-to-use, fast and effective treatment of severe hypoglycemia in individuals with diabetes. In this pediatric Phase 3 trial, ZP4207-17086, the clinical efficacy and safety of 0.6 mg dasiglucagon administered subcutaneously (SC) (same dose as adults) was compared to placebo and with reference to GlucaGen®. In total, 42 eligible children with T1D between 6 and 17 years (6-11 years: 16 children and 12-17 years: 25 children) were randomized (2:1:1) to dasiglucagon, placebo or GlucaGen® and dosed following induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery, defined as first PG increase ≥20 mg/dL after treatment initiation without rescue glucose. The results showed that dasiglucagon 0.6 mg SC induced a fast and effective PG increase. The median time (95% CI) to recovery based on sampling time was 10 (8, 12) min for dasiglucagon vs. 30 (20, -) min for placebo (p Disclosure T. Battelino: Advisory Panel; Self; Medtronic, Sanofi. Consultant; Self; Indigo Diabetes. Research Support; Self; Medtronic, Novo Nordisk A/S, Zealand Pharma A/S. Speaker’s Bureau; Self; Abbott, AstraZeneca, Dexcom, Inc., Lilly Diabetes, Medtronic. Stock/Shareholder; Self; DreaMed Diabetes. R. Tehranchi: Employee; Self; Zealand Pharma A/S. A.E. Melgaard: Employee; Self; Zealand Pharma A/S. D. Skydsgaard: Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S, Roche Diabetes Care. T.S. Bailey: Consultant; Self; Abbott, LifeScan, Inc., Novo Nordisk A/S, Sanofi US. Research Support; Self; Abbott, Ascensia Diabetes Care, Capillary Biomedical, Inc., Dance Biopharm Holdings, Inc., Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Kowa Pharmaceuticals America, Inc., Lexicon Pharmaceuticals, Inc., Medtronic, Medtrum, Novo Nordisk A/S, REMD Biotherapeutics, Sanofi-Aventis, Senseonics, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S. Speaker’s Bureau; Self; Medtronic, Sanofi US. L. DiMeglio: None. T. Danne: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Sanofi.

Parents of young children with T1D face daily psychosocial stressors that may be mitigated or worsened by the use of diabetes technologies. We assessed psychosocial functioning in parents before and after beginning CGM supported by a FBI in youth 2- Disclosure P.V. Commissariat: None. L. Kanapka: None. K. Miller: None. M.E. Hilliard: None. B. Anderson: None. L. DiMeglio: None. L.M. Laffel: Advisory Panel; Self; Roche Diabetes Care. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., ConvaTec Inc., Dexcom, Inc., Insulet Corporation, Insulogic LLC, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc., Sanofi US. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Emerging evidence suggests intrinsic β cell dysfunction contributes to T1D development. However, it is unclear whether defects in β cell response are evident in individuals at genetic risk for T1D without detectable islet autoimmunity. To explore this, we performed mixed meal tolerance tests (MMTTs) and hyperglycemic clamps to measure stimulated β cell response in 2 groups: Islet Ab negative 1st-degree adult relatives of persons with T1D (FDR-) and normoglycemic, age, sex, and BMI-matched controls without T1D family history. Median and IQR values for 1st phase responses, including C-peptide15min-0 (MMTT) and C-peptide incremental AUC (iAUC)0-10min (clamp), and 2nd phase responses, including C-peptide iAUC0-120min (MMTT) and average C-peptide (C-peptideavg) during the steady state (clamp), were compared using paired t-tests or Wilcoxon tests. MMTTs and clamps were performed in 15 euglycemic (A1c0.99, C-peptideavg steady state was 12 (10.8-18.9) vs. 11.5 (8.9-14.5), p=0.98. In this small cohort, no significant differences between stimulated 1st or 2nd phase responses were detected between FDR- and matched controls, suggesting that FDR- relatives may not have a defect in stimulated β cell response. Nondiabetic relatives are heterogeneous in their risk of autoimmunity; this could explain a lack of between-group differences. At-risk pediatric cohorts, which have increased risks of developing autoimmunity, could be more likely to show a difference in β cell response. Ongoing investigations will define β cell function in relatives with detectable Abs. Disclosure A. Neyman: None. K. Moors: None. C. Evans-Molina: Consultant; Self; Bristol-Myers Squibb. L. DiMeglio: None. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. K.J. Mather: Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. T.S. Hannon: None. E.K. Sims: None. Funding JDRF (2-SRA-2017-498-M-B)