A surge in serum mucosal cytokines associated with seroconversion in children at risk for type 1 diabetes.

AIMS/INTRODUCTION: Autoantibodies to pancreatic islet antigens identify young children at high risk of type 1 diabetes. On a background of genetic susceptibility, islet autoimmunity is thought to be driven by environmental factors, of which enteric viruses are prime candidates. We sought evidence for enteric pathology in children genetically at-risk for type 1 diabetes followed from birth who had developed islet autoantibodies ("seroconverted"), by measuring mucosa-associated cytokines in their sera. MATERIALS AND METHODS: Sera were collected 3 monthly from birth from children with a first-degree type 1 diabetes relative, in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. Children who seroconverted were matched for sex, age, and sample availability with seronegative children. Luminex xMap technology was used to measure serum cytokines. RESULTS: Of eight children who seroconverted, for whom serum samples were available at least 6 months before and after seroconversion, the serum concentrations of mucosa-associated cytokines IL-21, IL-22, IL-25, and IL-10, the Th17-related cytokines IL-17F and IL-23, as well as IL-33, IFN-γ, and IL-4, peaked from a low baseline in seven around the time of seroconversion and in one preceding seroconversion. These changes were not detected in eight sex- and age-matched seronegative controls, or in a separate cohort of 11 unmatched seronegative children. CONCLUSIONS: In a cohort of children at risk for type 1 diabetes followed from birth, a transient, systemic increase in mucosa-associated cytokines around the time of seroconversion lends support to the view that mucosal infection, e.g., by an enteric virus, may drive the development of islet autoimmunity.

Experiences of Caregivers and At-Risk Children Enrolled in a Prospective Pregnancy-Birth Cohort Study into the Causes of Type 1 Diabetes: The ENDIA Study.

BACKGROUND: We sought research experiences of caregivers and their children were enrolled in the Environmental Determinants of Islet Autoimmunity (ENDIA) study. METHODS: ENDIA is a pregnancy-birth cohort investigating early-life causes of type 1 diabetes (T1D). Surveys were sent to 1090 families between June 2021 and March 2022 with a median participation of >5 years. Caregivers completed a 12-item survey. Children ≥ 3 years completed a four-item survey. RESULTS: The surveys were completed by 550/1090 families (50.5%) and 324/847 children (38.3%). The research experience was rated as either "excellent" or "good" by 95% of caregivers, and 81% of children were either "ok", "happy" or "very happy". The caregivers were motivated by contributing to research and monitoring their children for T1D. Relationships with the research staff influenced the experience. The children most liked virtual reality headsets, toys, and "helping". Blood tests were least liked by the children and were the foremost reason that 23.4% of the caregivers considered withdrawing. The children valued gifts more than their caregivers. Only 5.9% of responses indicated dissatisfaction with some aspects of the protocol. The self-collection of samples in regional areas, or during the COVID-19 pandemic restrictions, were accepted. CONCLUSIONS: This evaluation identified modifiable protocol elements and was conducted to further improve satisfaction. What was important to the children was distinct from their caregivers.

A Long-Term Evaluation of Facebook for Recruitment and Retention in the ENDIA Type 1 Diabetes Pregnancy-Birth Cohort Study.

BACKGROUND: The Environmental Determinants of Islet Autoimmunity (ENDIA) study is an Australia-wide pregnancy-birth cohort study following children who have a first-degree relative with type 1 diabetes (ACTRN1261300794707). A dedicated ENDIA Facebook page was established in 2013 with the aim of enhancing recruitment and supporting participant retention through dissemination of study information. To measure the impact of Facebook, we evaluated the sources of referral to the study, cohort demographics, and withdrawal rates. We also investigated whether engagement with Facebook content was associated with specific post themes. METHODS: Characteristics of Facebook versus conventional recruits were compared using linear, logistic, and multinomial logistic regression models. Logistic regression was used to determine the risk of study withdrawal. Data pertaining to 794 Facebook posts over 7.5 years were included in the analysis. RESULTS: Facebook was the third largest source of referral (300/1511; 19.9%). Facebook recruits were more frequently Australian-born (P < .001) enrolling postnatally (P = .01) and withdrew from the study at a significantly lower rate compared with conventional recruits (4.7% vs 12.3%; P < .001) after a median of follow-up of 3.3 years. Facebook content featuring stories and images of participants received the highest engagement even though <20% of the 2337 Facebook followers were enrolled in the study. CONCLUSIONS: Facebook was a valuable recruitment tool for ENDIA. Compared with conventional recruits, Facebook recruits were three times less likely to withdraw during long-term follow-up and had different sociodemographic characteristics. Facebook content featuring participants was the most engaging. These findings inform social media strategies for future cohort and type 1 diabetes studies. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN1261300794707.

The identification in primary care of patients who have been repeatedly referred to hospital for medically unexplained symptoms: a pilot study.

OBJECTIVES: The study aimed (a) to test a method of identifying patients who have been repeatedly referred (RR) from primary care to medical outpatient clinics where they have received multiple diagnoses of medically unexplained symptoms (MUS) and (b) to describe the prevalence and characteristics of these patients. METHODS: RR patients with MUS (RRMUS) were arbitrarily defined as those with (a) five or more referrals in a 5-year period and (b) a specialist final diagnosis of MUS for at least three of these referrals. A two-stage method of identifying these patients was piloted in one primary care practice: Stage 1 used computerized health service data to identify RR; Stage 2 used manual case note review to identify referrals that ended with specialist diagnoses of MUS. The RRMUS patients identified were asked to complete a questionnaire, a psychiatric diagnostic interview, and their GPs were asked to rate how "difficult to manage" they were. RESULTS: The process was feasible and reasonably accurate. From 6770 registered patients aged 18 to 65 years, 23 (0.3%) were identified as RRMUS. They accounted for 157 referrals over the 5-year period. Sixteen agreed to further assessment, and 8 (50%) had a current anxiety or depressive disorder. GPs rated only 8 (50%) as "difficult to manage." CONCLUSION: This two-stage procedure offers a practical method of identifying RRMUS patients in primary care as a first step in achieving more cost-effective care. These patients have substantial psychiatric morbidity.

Reliability of the knee examination in osteoarthritis: effect of standardization.

OBJECTIVE: To assess the reliability of physical examination of the osteoarthritic (OA) knee by rheumatologists, and to evaluate the benefits of standardization. METHODS: Forty-two physical signs and techniques were evaluated using a 6 x 6 Latin square design. Patients with mild to severe knee OA, based on physical and radiographic signs, were examined in random order prior to and following standardization of techniques. For those signs with dichotomous scales, agreement among the rheumatologists was calculated as the prevalence-adjusted bias-adjusted kappa (PABAK), while for the signs with continuous and ordinal scales, a reliability coefficient (R(c)) was calculated using analysis of variance. A PABAK of >0.60 and an R(c) of >0.80 were considered to indicate adequate reliability. RESULTS: Adequate poststandardization reliability was achieved for 30 of 42 physical signs/techniques (71%). The most highly reliable signs identified by physical examination of the OA knee included alignment by goniometer (R(c) = 0.99), bony swelling (R(c) = 0.97), general passive crepitus (R(c) = 0.96), gait by inspection (PABAK = 0.78), effusion bulge sign (R(c) = 0.97), quadriceps atrophy (R(c) = 0.97), medial tibiofemoral tenderness (R(c) = 0.94), lateral tibiofemoral tenderness (R(c) = 0.85), patellofemoral tenderness by grind test (R(c) = 0.94), and flexion contracture (R(c) = 0.95). The standardization process resulted in substantial improvements in reliability for evaluation of a number of physical signs, although for some signs, minimal or no effect of standardization was noted. After standardization, warmth (PABAK = 0.14), medial instability at 30 degrees flexion (PABAK = 0.02), and lateral instability at 30 degrees flexion (PABAK = 0.34) were the only 3 signs that were highly unreliable. CONCLUSION: With the exception of physical examinations for instability, a comprehensive knee examination can be performed with adequate reliability. Standardization further improves the reliability for some physical signs and techniques. The application of these findings to future OA studies will contribute to improved outcome assessments in OA.