TCR+/BCR+ dual-expressing cells and their associated public BCR clonotype are not enriched in type 1 diabetes.

Ahmed and colleagues recently described a novel hybrid lymphocyte expressing both a B and T cell receptor, termed double expresser (DE) cells. DE cells in blood of type 1 diabetes (T1D) subjects were present at increased numbers and enriched for a public B cell clonotype. Here, we attempted to reproduce these findings. While we could identify DE cells by flow cytometry, we found no association between DE cell frequency and T1D status. We were unable to identify the reported public B cell clone, or any similar clone, in bulk B cells or sorted DE cells from T1D subjects or controls. We also did not observe increased usage of the public clone VH or DH genes in B cells or in sorted DE cells. Taken together, our findings suggest that DE cells and their alleged public clonotype are not enriched in T1D. This Matters Arising paper is in response to Ahmed et al. (2019), published in Cell. See also the response by Ahmed et al. (2021), published in this issue.

Induction of bronchus-associated lymphoid tissue is an early life adaptation for promoting human B cell immunity.

Infants and young children are more susceptible to common respiratory pathogens than adults but can fare better against novel pathogens like severe acute respiratory syndrome coronavirus 2. The mechanisms by which infants and young children mount effective immune responses to respiratory pathogens are unknown. Through investigation of lungs and lung-associated lymph nodes from infant and pediatric organ donors aged 0-13 years, we show that bronchus-associated lymphoid tissue (BALT), containing B cell follicles, CD4+ T cells and functionally active germinal centers, develop during infancy. BALT structures are prevalent around lung airways during the first 3 years of life, and their numbers decline through childhood coincident with the accumulation of memory T cells. Single-cell profiling and repertoire analysis reveals that early life lung B cells undergo differentiation, somatic hypermutation and immunoglobulin class switching and exhibit a more activated profile than lymph node B cells. Moreover, B cells in the lung and lung-associated lymph nodes generate biased antibody responses to multiple respiratory pathogens compared to circulating antibodies, which are mostly specific for vaccine antigens in the early years of life. Together, our findings provide evidence for BALT as an early life adaptation for mobilizing localized immune protection to the diverse respiratory challenges during this formative life stage.

Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood.

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated T cells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory T cells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory T cells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased T cell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory T cells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.

A gut microbial peptide and molecular mimicry in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic ß-cells. One of the earliest aspects of this process is the development of autoantibodies and T cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to the insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these 17 peptides, the hprt4-18 peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T cell hybridomas from nonobese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells, and destructive CD8+ T cells, while decreasing FoxP3+ regulatory T cells. Western blot analysis identified P. distasonis-reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis-treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human children gut microbiome data from a longitudinal DIABIMMUNE study revealed that seroconversion rates (i.e., the proportion of individuals developing two or more autoantibodies) were consistently higher in children whose microbiome harbored sequences capable of producing the hprt4-18 peptide compared to individuals who did not harbor it. Taken together, these data demonstrate the potential role of a gut microbiota-derived insB:9-23-mimic peptide as a molecular trigger of T1D pathogenesis.

Diabetes Study of Children of Diverse Ethnicity and Race: Study design.

AIMS: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)-supported multicenter, prospective, observational study that enrols children and adolescents with non-secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. MATERIALS AND METHODS: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non-fasting serum C-peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3-10 years) for a cross-sectional evaluation or with recent onset diabetes (duration 3 weeks-15 months) for the longitudinal observation with annual visits for 3 years. Cross-sectional data will be used to develop models. Longitudinal data will be used to externally validate the best-fitting model. RESULTS: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. CONCLUSIONS: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease.

Human islet T cells are highly reactive to preproinsulin in type 1 diabetes.

Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.

Social identification and risk dynamics: How perceptions of (inter)personal and collective risk impact the adoption of COVID-19 preventative behaviors.

Public adoption of preventative behaviors to reduce the transmission of COVID-19 is crucial to managing the pandemic, and so it is vital to determine what factors influence the uptake of those behaviors. Previous studies have identified COVID-19 risk perceptions as a key factor, but this work has typically been limited both in assuming that risk means risk to the personal self, and in being reliant on self-reported data. Drawing on the social identity approach, we conducted two online studies in which we investigated the effects of two different types of risk on preventative measure taking: risk to the personal self and risk to the collective self (i.e., members of a group with which one identifies). Both studies involved behavioral measures using innovative interactive tasks. In Study 1 (n = 199; data collected 27 May 2021), we investigated the effects of (inter)personal and collective risk on physical distancing. In Study 2 (n = 553; data collected 20 September 2021), we investigated the effects of (inter)personal and collective risk on the speed at which tests are booked as COVID-19 symptoms develop. In both studies, we find that perceptions of collective risk, but not perceptions of (inter)personal risk, influence the extent to which preventative measures are adopted. We discuss the implications both conceptually (as they relate to both the conceptualization of risk and social identity processes) and also practically (in terms of the implications for public health communications).

Milder loss of insulin-containing islets in individuals with type 1 diabetes and type 2 diabetes-associated TCF7L2 genetic variants.

AIMS/HYPOTHESIS: TCF7L2 variants are the strongest genetic risk factor for type 2 diabetes. In individuals with type 1 diabetes, these variants are associated with a higher C-peptide AUC, a lower glucose AUC during an OGTT, single autoantibody positivity near diagnosis, particularly in individuals older than 12 years of age, and a lower frequency of type 1 diabetes-associated HLA genotypes. Based on initial observations from clinical cohorts, we tested the hypothesis that type 2 diabetes-predisposing TCF7L2 genetic variants are associated with a higher percentage of residual insulin-containing cells (ICI%) in pancreases of donors with type 1 diabetes, by examining genomic data and pancreatic tissue samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) programme. METHODS: We analysed nPOD donors with type 1 diabetes (n=110; mean±SD age at type 1 diabetes onset 12.2±7.9 years, mean±SD diabetes duration 15.3±13.7 years, 53% male, 80% non-Hispanic White, 12.7% African American, 7.3% Hispanic) using data pertaining to residual beta cell number; quantified islets containing insulin-positive beta cells in pancreatic tissue sections; and expressed these values as a percentage of the total number of islets from each donor (mean ± SD ICI% 9.8±21.5, range 0-92.2). RESULTS: Donors with a high ICI% (≥5) (n=30; 27%) vs a low ICI% (<5) (n=80; 73%) were older at onset (15.3±6.9 vs 11.1±8 years, p=0.013), had a shorter diabetes duration at donor tissue procurement (7.0±7.4 vs 18.5±14.3 years, p<0.001), a higher African ancestry score (0.2±0.3 vs 0.1±0.2, p=0.043) and a lower European ancestry score (0.7±0.3 vs 0.9±0.3, p=0.023). After adjustment for age of onset (p=0.105), diabetes duration (p<0.001), BMI z score (p=0.145), sex (p=0.351) and African American race (p=0.053), donors with the TCF7L2 rs7903146 T allele (TC or TT, 45.5%) were 2.93 times (95% CI 1.02, 8.47) more likely to have a high ICI% than those without it (CC) (p=0.047). CONCLUSIONS/INTERPRETATION: Overall, these data support the presence of a type 1 diabetes endotype associated with a genetic factor that predisposes to type 2 diabetes, with donors in this category exhibiting less severe beta cell loss. It is possible that in these individuals the disease pathogenesis may include mechanisms associated with type 2 diabetes and thus this may provide an explanation for the poor response to immunotherapies to prevent type 1 diabetes or its progression in a subset of individuals. If so, strategies that target both type 1 diabetes and type 2 diabetes-associated factors when they are present may increase the success of prevention and treatment in these individuals.

Chronic Airways Assessment Test: psychometric properties in patients with asthma and/or COPD.

BACKGROUND: No short patient-reported outcome (PRO) instruments assess overall health status across different obstructive lung diseases. Thus, the wording of the introduction to the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) was modified to permit use in asthma and/or COPD. This tool is called the Chronic Airways Assessment Test (CAAT). METHODS: The psychometric properties of the CAAT were evaluated using baseline data from the NOVELTY study (NCT02760329) in patients with physician-assigned asthma, asthma + COPD or COPD. Analyses included exploratory/confirmatory factor analyses, differential item functioning and analysis of construct validity. Responses to the CAAT and CAT were compared in patients with asthma + COPD and those with COPD. RESULTS: CAAT items were internally consistent (Cronbach's alpha: > 0.7) within each diagnostic group (n = 510). Models for structural and measurement invariance were strong. Tests of differential item functioning showed small differences between asthma and COPD in individual items, but these were not consistent in direction and had minimal overall impact on the total score. The CAAT and CAT were highly consistent when assessed in all NOVELTY patients who completed both (N = 277, Pearson's correlation coefficient: 0.90). Like the CAT itself, CAAT scores correlated moderately (0.4-0.7) to strongly (> 0.7) with other PRO measures and weakly (< 0.4) with spirometry measures. CONCLUSIONS: CAAT scores appear to reflect the same health impairment across asthma and COPD, making the CAAT an appropriate PRO instrument for patients with asthma and/or COPD. Its brevity makes it suitable for use in clinical studies and routine clinical practice. TRIAL REGISTRATION: NCT02760329.

Capuchin monkeys learn to use information equally well from individual exploration and social demonstration.

The limited evidence of complex culture in non-human primates contrasts strikingly with human behaviour. This may be because non-human primates fail to use information acquired socially as effectively as they use information acquired individually. Here, monkeys were trained on a stimulus discrimination task with a win-stay, lose-shift (WSLS) reward structure. In a social learning condition, the experimenter performed an information trial by choosing between the available stimuli; in an individual condition, monkeys made this choice themselves. The monkeys' subsequent test trials displayed the same stimulus array. They were rewarded for repetition of rewarded ('win-stay') and avoidance of unrewarded ('lose-shift') information trial selections. Nine monkeys reached our pre-determined performance criterion on the initial two-stimulus stage. Their ability to generalise the WSLS strategy was then evaluated by transfer to a three-stimulus stage. Minimal differences were found in information use between the social and individual conditions on two-stimuli. However, a bias was found towards repetition of the information trial, regardless of information source condition or whether the information trial selection was rewarded. Proficient subjects were found to generalise the strategy to three-stimuli following rewarded information trials, but performed at chance on unrewarded. Again, this was not found to vary by source condition. Overall, results suggest no fundamental barrier to non-human primates' use of information from a social source. However, the apparent struggle to learn from the absence of rewards hints at a difficulty with using information acquired from unsuccessful attempts; this could be linked to the limited evidence for cumulative culture in non-human primates.

Overexpression of the PTPN22 Autoimmune Risk Variant LYP-620W Fails to Restrain Human CD4+ T Cell Activation.

A missense mutation (R620W) of protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes lymphoid-tyrosine phosphatase (LYP), confers genetic risk for multiple autoimmune diseases including type 1 diabetes. LYP has been putatively demonstrated to attenuate proximal T and BCR signaling. However, limited data exist regarding PTPN22 expression within primary T cell subsets and the impact of the type 1 diabetes risk variant on human T cell activity. In this study, we demonstrate endogenous PTPN22 is differentially expressed and dynamically controlled following activation. From control subjects homozygous for the nonrisk allele, we observed 2.1- (p < 0.05) and 3.6-fold (p < 0.001) more PTPN22 transcripts in resting CD4+ memory and regulatory T cells (Tregs), respectively, over naive CD4+ T cells, with expression peaking 24 h postactivation. When LYP was overexpressed in conventional CD4+ T cells, TCR signaling and activation were blunted by LYP-620R (p < 0.001) but only modestly affected by the LYP-620W risk variant versus mock-transfected control, with similar results observed in Tregs. LYP overexpression only impacted proliferation following activation by APCs but not anti-CD3- and anti-CD28-coated microbeads, suggesting LYP modulation of pathways other than TCR. Notably, proliferation was significantly lower with LYP-620R than with LYP-620W overexpression in conventional CD4+ T cells but was similar in Treg. These data indicate that the LYP-620W variant is hypomorphic in the context of human CD4+ T cell activation and may have important implications for therapies seeking to restore immunological tolerance in autoimmune disorders.

Insulin Receptor-Expressing T Cells Appear in Individuals at Risk for Type 1 Diabetes and Can Move into the Pancreas in C57BL/6 Transgenic Mice.

Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic ß cells occurs. In previous work, when purified IR+ and IR- T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis.

Image-Based Machine Learning Algorithms for Disease Characterization in the Human Type 1 Diabetes Pancreas.

Emerging data suggest that type 1 diabetes affects not only the ß-cell-containing islets of Langerhans, but also the surrounding exocrine compartment. Using digital pathology, machine learning algorithms were applied to high-resolution, whole-slide images of human pancreata to determine whether the tissue composition in individuals with or at risk for type 1 diabetes differs from those without diabetes. Transplant-grade pancreata from organ donors were evaluated from 16 nondiabetic autoantibody-negative controls, 8 nondiabetic autoantibody-positive subjects with increased type 1 diabetes risk, and 19 persons with type 1 diabetes (0 to 12 years' duration). HALO image analysis algorithms were implemented to compare architecture of the main pancreatic duct as well as cell size, density, and area of acinar, endocrine, ductal, and other nonendocrine, nonexocrine tissues. Type 1 diabetes was found to affect exocrine area, acinar cell density, and size, whereas the type of difference correlated with the presence or absence of insulin-positive cells remaining in the pancreas. These changes were not observed before disease onset, as indicated by modeling cross-sectional data from pancreata of autoantibody-positive subjects and those diagnosed with type 1 diabetes. These data provide novel insights into anatomic differences in type 1 diabetes pancreata and demonstrate that machine learning can be adapted for the evaluation of disease processes from cross-sectional data sets.

Shielding reduced incidence of COVID-19 in patients with inflammatory arthritis but vulnerability is associated with increased mortality.

OBJECTIVES: Investigate whether individuals with inflammatory arthritis (IA), their treatments and shielding status affect the risk of adverse outcomes from COVID-19 for the entire population of Wales, UK. METHODS: Retrospective, population-based cohort study using linked, anonymized electronic health data from SAIL Databank, including primary/secondary care, rheumatology, Office for National Statistics Mortality and COVID-19 laboratory data. Individuals aged 18 years and over testing positive for COVID-19 between March 2020 and May 2021 with READ Codes present for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis formed the study cases. RESULTS: A total of 1966 people with IA and 166 602 without tested positive for COVID-19. The incidence rate was 3.5% (1966/56 914) in IA, vs 6% in the general population (166 602/2 760 442), (difference: 2.5%, 95% CI: 2.4%, 2.7%, P ≤0.001). In an adjusted Cox proportional hazard model, IA was not associated with higher mortality (HR: 0.56, 95% CI: 0.18, 1.64, P=0.286). Significant risk factors included shielding (HR: 1.52, 95% CI: 1.40, 1.64, P ≤0.001), hospitalization for previous infections (HR: 1.20, 95% CI: 1.12, 1.28, P ≤0.001), hospitalizations one year pre-pandemic (HR: 1.34, 95% CI: 1.25, 1.44, P ≤0.001) and glucocorticoid use (HR: 1.17, 95% CI: 1.09, 1.25, P ≤0.001). CONCLUSIONS: Individuals with IA had a lower incidence of COVID-19, probably due to shielding. IA was not associated with increased mortality following COVID-19 infection; being vulnerable (shielded), comorbidities and other factors were associated with increased risk. These key risk factors can identify individuals with IA at greater risk from COVID-19 and advised to shield during high community prevalence.

Validity and reliability of global ratings of satisfaction with epilepsy surgery.

OBJECTIVE: We aimed to assess the reliability and validity of single-item global ratings (GR) of satisfaction with epilepsy surgery. METHODS: We recruited 240 patients from four centers in Canada and Sweden who underwent epilepsy surgery ≥1 year earlier. Participants completed a validated questionnaire on satisfaction with epilepsy surgery (the ESSQ-19), plus a single-item GR of satisfaction with epilepsy surgery twice, 4-6 weeks apart. They also completed validated questionnaires on quality of life, depression, health state utilities, epilepsy severity and disability, medical treatment satisfaction and social desirability. Test-retest reliability of the GR was assessed with the intra-class correlation coefficient (ICC). Construct and criterion validity were examined with polyserial correlations between the GR measure of satisfaction and validated questionnaires and with the ESSQ-19 summary score. Non-parametric rank tests evaluated levels of satisfaction, and ROC analysis assessed the ability of GRs to distinguish among clinically different patient groups. RESULTS: Median age and time since surgery were 42 years (IQR 32-54) and 5 years (IQR 2-8), respectively. The GR demonstrated good to excellent test-retest reliability (ICC = 0.76; 95% CI 0.67-0.84) and criterion validity (0.85; 95% CI 0.81-0.89), and moderate correlations in the expected direction with instruments assessing quality of life (0.59; 95% CI 0.51-0.63), health utilities (0.55; 95% CI 0.45-0.65), disability (-0.51; 95% CI -0.41, -0.61), depression (-0.48; 95% CI -0.38, -0.58), and epilepsy severity (-0.48; 95% CI -0.38, -0.58). As expected, correlations were lower for social desirability (0.40; 95% CI 0.28-0.52) and medical treatment satisfaction (0.33; 95% CI 0.21-0.45). The GR distinguished participants who were seizure-free (AUC 0.75; 95% CI 0.67-0.82), depressed (AUC 0.75; 95% CI 0.67-0.83), and self-rated as having more severe epilepsy (AUC 0.78; 95% CI 0.71-0.85) and being more disabled (AUC 0.82; 95% CI 0.74-0.90). SIGNIFICANCE: The GR of epilepsy surgery satisfaction showed good measurement properties, distinguished among clinically different patient groups, and appears well-suited for use in clinical practice and research.

Clinical features, biochemistry, and HLA-DRB1 status in youth-onset type 1 diabetes in Mali.

OBJECTIVE: Limited information is available regarding youth-onset diabetes in Mali. We investigated demographic, clinical, biochemical, and genetic features in new diabetes cases in children and adolescents. RESEARCH DESIGN AND METHODS: The study was conducted at Hôpital du Mali in Bamako. A total of 132 recently-diagnosed cases <21 years were enrolled. Demographic characteristics, clinical information, biochemical parameters (blood glucose, HbA1c, C-peptide, glutamic acid decarboxylase-65 (GAD-65) and islet antigen-2 (IA2) autoantibodies) were assessed. DNA was genotyped for HLA-DRB1 using high-resolution genotyping technology. RESULTS: A total of 130 cases were clinically diagnosed as type 1 diabetes (T1D), one with type 2 diabetes (T2D), and one with secondary diabetes. A total of 66 (50.8%) T1D cases were males and 64 (49.2%) females, with a mean age at diagnosis of 13.8 ± 4.4 years (range 0.8-20.7 years) peak onset of 15 years. 58 (44.6%) presented in diabetic ketoacidosis; with 28 (21.5%) IA2 positive, 76 (58.5%) GAD-65 positive, and 15 (11.5%) positive for both autoantibodies. HLA was also genotyped in 195 controls without diabetes. HLA-DRB1 genotyping of controls and 98 T1D cases revealed that DRB1*03:01, DRB1*04:05, and DRB1*09:01 alleles were predisposing for T1D (odds ratios [ORs]: 2.82, 14.76, and 3.48, p-values: 9.68E-5, 2.26E-10, and 8.36E-4, respectively), while DRB1*15:03 was protective (OR = 0.27; p-value = 1.73E-3). No significant differences were observed between T1D cases with and without GAD-65 and IA2 autoantibodies. Interestingly, mean C-peptide was 3.6 ± 2.7 ng/ml (1.2 ± 0.9 nmol/L) in T1D cases at diagnosis. CONCLUSIONS: C-peptide values were higher than expected in those diagnosed as T1D and autoantibody rates lower than in European populations. It is quite possible that some cases have an atypical form of T1D, ketosis-prone T2D, or youth-onset T2D. This study will help guide assessment and individual management of Malian diabetes cases, potentially enabling healthier outcomes.

Taking account of others' goals in social information use: Developmental changes in 3- to 7-year-old children.

The ability to take mental states such as goals into account when interpreting others' behavior has been proposed to be what sets human use of social information apart from that of other animals. If so, children's social information use would be expected to change as their understanding of others' mental states develops. We explored age-related changes in 3- to 7-year-old children's ability to strategically use social information by taking into account another's goal when it was, or was not, aligned with their own. Children observed as a puppet demonstrator selected a capsule, peeked inside, and chose to accept or reject it, following which children made their own selection. Children were able to account for others' conflicting motivations from around 4 years of age and reliably inferred the outcome of others' behavior from 6 years. However, using social information based on such inferences appeared to be challenging regardless of whether the demonstrator's goal was, or was not. aligned to that of the participant. We found that social information use improved with age; however, this improvement was restricted to cases in which the appropriate response was to avoid copying the demonstrator's selection. In contrast to previous research, appropriate copying responses remained at chance. Possible explanations for this unexpected pattern of results are discussed. The cognitive challenge associated with the ability to account for others' goals could offer humans a significant advantage over that of other animals in their ability to use social information.

Restricted Access to Working Memory Does Not Prevent Cumulative Score Improvement in a Cultural Evolution Task.

Some theories propose that human cumulative culture is dependent on explicit, system-2, metacognitive processes. To test this, we investigated whether access to working memory is required for cumulative cultural evolution. We restricted access to adults' working-memory (WM) via a dual-task paradigm, to assess whether this reduced performance in a cultural evolution task, and a metacognitive monitoring task. In total, 247 participants completed either a grid search task or a metacognitive monitoring task in conjunction with a WM task and a matched control. Participants' behaviour in the grid search task was then used to simulate the outcome of iterating the task over multiple generations. Participants in the grid search task scored higher after observing higher-scoring examples, but could only beat the scores of low-scoring example trials. Scores did not differ significantly between the control and WM distractor blocks, although more errors were made when under WM load. The simulation showed similar levels of cumulative score improvement across conditions. However, scores plateaued without reaching the maximum. Metacognitive efficiency was low in both blocks, with no indication of dual-task interference. Overall, we found that taxing working-memory resources did not prevent cumulative score improvement on this task, but impeded it slightly relative to a control distractor task. However, we found no evidence that the dual-task manipulation impacted participants' ability to use explicit metacognition. Although we found minimal evidence in support of the explicit metacognition theory of cumulative culture, our results provide valuable insights into empirical approaches that could be used to further test predictions arising from this account.

Index60 as an additional diagnostic criterion for type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to compare characteristics of individuals identified in the peri-diagnostic range by Index60 (composite glucose and C-peptide measure) ≥2.00, 2 h OGTT glucose ≥11.1 mmol/l, or both. METHODS: We studied autoantibody-positive participants in the Type 1 Diabetes TrialNet Pathway to Prevention study who, at their baseline OGTT, had 2 h blood glucose ≥11.1 mmol/l and/or Index60 ≥2.00 (n = 354, median age = 11.2 years, age range = 1.7-46.6; 49% male, 83% non-Hispanic White). Type 1 diabetes-relevant characteristics (e.g., age, C-peptide, autoantibodies, BMI) were compared among three mutually exclusive groups: 2 h glucose ≥11.1 mmol/l and Index60 <2.00 [Glu(+), n = 76], 2 h glucose <11.1 mmol/l and Index60 ≥2.00 [Ind(+), n = 113], or both 2 h glucose ≥11.1 mmol/l and Index60 ≥2.00 [Glu(+)/Ind(+), n = 165]. RESULTS: Participants in Glu(+), vs those in Ind(+) or Glu(+)/Ind(+), were older (mean ages = 22.9, 11.8 and 14.7 years, respectively), had higher early (30-0 min) C-peptide response (1.0, 0.50 and 0.43 nmol/l), higher AUC C-peptide (2.33, 1.13 and 1.10 nmol/l), higher percentage of overweight/obesity (58%, 16% and 30%) (all comparisons, p < 0.0001), and a lower percentage of multiple autoantibody positivity (72%, 92% and 93%) (p < 0.001). OGTT-stimulated C-peptide and glucose patterns of Glu(+) differed appreciably from Ind(+) and Glu(+)/Ind(+). Progression to diabetes occurred in 61% (46/76) of Glu(+) and 63% (71/113) of Ind(+). Even though Index60 ≥2.00 was not a Pathway to Prevention diagnostic criterion, Ind(+) had a 4 year cumulative diabetes incidence of 95% (95% CI 86%, 98%). CONCLUSIONS/INTERPRETATION: Participants in the Ind(+) group had more typical characteristics of type 1 diabetes than participants in the Glu(+) did and were as likely to be diagnosed. However, unlike Glu(+) participants, Ind(+) participants were not identified at the baseline OGTT.

Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes.

AIMS/HYPOTHESIS: Normal cellular prion protein (PrPC) is a conserved mammalian glycoprotein found on the outer plasma membrane leaflet through a glycophosphatidylinositol anchor. Although PrPC is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. The misfolded pathogenic isoform PrPSc (the scrapie form of PrP) is a causative agent of neurodegenerative prion diseases. The aim of this study is to evaluate PrPC localisation, expression and trafficking in pancreases from organ donors with and without type 1 diabetes and to infer PrPC function through studies on interacting protein partners. METHODS: In order to evaluate localisation and trafficking of PrPC in the human pancreas, 12 non-diabetic, 12 type 1 diabetic and 12 autoantibody-positive organ donor tissue samples were analysed using immunofluorescence analysis. Furthermore, total RNA was isolated from 29 non-diabetic, 29 type 1 diabetic and 24 autoantibody-positive donors to estimate PrPC expression in the human pancreas. Additionally, we performed PrPC-specific immunoblot analysis on total pancreatic protein from non-diabetic and type 1 diabetic organ donors to test whether changes in PrPC mRNA levels leads to a concomitant increase in PrPC protein levels in human pancreases. RESULTS: In non-diabetic and type 1 diabetic pancreases (the latter displaying both insulin-positive [INS(+)] and -negative [INS(-)] islets), we found PrPC in islets co-registering with beta cells in all INS(+) islets and, strikingly, unexpected activation of PrPC in alpha cells within diabetic INS(-) islets. We found PrPC localised to the plasma membrane and endoplasmic reticulum (ER) but not the Golgi, defining two cellular pools and an unconventional protein trafficking mechanism bypassing the Golgi. We demonstrate PrPC co-registration with established protein partners, neural cell adhesion molecule 1 (NCAM1) and stress-inducible phosphoprotein 1 (STI1; encoded by STIP1) on the plasma membrane and ER, respectively, linking PrPC function with cyto-protection, signalling, differentiation and morphogenesis. We demonstrate that both PRNP (encoding PrPC) and STIP1 gene expression are dramatically altered in type 1 diabetic and autoantibody-positive pancreases. CONCLUSIONS/INTERPRETATION: As the first study to address PrPC expression in non-diabetic and type 1 diabetic human pancreas, we provide new insights for PrPC in the pathogenesis of type 1 diabetes. We evaluated the cell-type specific expression of PrPC in the human pancreas and discovered possible connections with potential interacting proteins that we speculate might address mechanisms relevant to the role of PrPC in the human pancreas.