Effectiveness of Nonmydriatic Ultra-Widefield Retinal Imaging to Screen for Diabetic Eye Disease: A Randomized Controlled Trial (Clearsight).

OBJECTIVE: Suboptimal diabetic eye disease screening is a major cause of preventable vision loss. Screening barriers include mydriasis and the need for dedicated screening appointments. The Clearsight trial assessed whether nonmydriatic ultra-widefield (NM UWF) screening on the day of a diabetes clinic visit improved detection of clinically important eye disease versus usual screening. RESEARCH DESIGN AND METHODS: This single-center, randomized, parallel-group controlled trial was conducted at St. Joseph's Health Care, London, Ontario, Canada. Adults with diabetes due for screening were randomized to same-day, on-site screening (NM UWF imaging) on the day of a scheduled diabetes clinic visit or usual screening (encouraged to arrange optometrist screening). The primary outcome was detection of actionable eye disease (AED), defined as the need for an ophthalmology referral or increased ocular surveillance. The primary analysis (modified intention-to-screen) compared the proportions of AED between groups within 1 year of enrollment. RESULTS: Of 740 participants randomized between 7 March 2016 and 17 April 2019, 335 on-site screening and 323 usual screening participants met criteria for the primary analysis. More AED was detected in the on-site screening group than in the usual screening group (50 of 335 [14.9%] vs. 22 of 323 [6.8%]; adjusted odds ratio 2.51; 95% CI 1.49-4.36). The number needed to screen by on-site screening in order to detect 1 additional patient with AED was 13 (95% CI 8-29). CONCLUSIONS: Same-day, on-site screening by NM UWF imaging increased the detection of clinically important diabetic eye disease versus usual screening. Integration of NM UWF imaging into routine diabetes clinic visits improved screening adherence and has the potential to prevent vision loss.

Hypoglycemia requiring paramedic assistance among adults in southwestern Ontario, Canada: a population-based retrospective cohort study.

BACKGROUND: People with diabetes mellitus commonly experience hypoglycemia, but they may not necessarily present to hospital after severe hypoglycemia requiring paramedic assistance. We sought to describe the incidence and characteristics of calls for hypoglycemia requiring paramedic assistance among adults in southwestern Ontario, Canada, and to determine predictors of hospital transport. METHODS: This population-based retrospective cohort study used data extracted from ambulance call reports (ACRs) of 8 paramedic services of the Southwest Ontario Regional Base Hospital Program from January 2008 to June 2014. We described calls in which treatment for hypoglycemia was administered, summarized the incidence of hypoglycemia calls and performed logistic regression to determine predictors of hospital transport. RESULTS: Out of 470 467 ACRs during the study period, 9185 paramedic calls occurred in which hypoglycemia treatment was administered to an adult (mean age 60.2 yr, 56.8% male, 81.1% with documented diabetes). Refusal of hospital transport occurred in 2243 (24.4%) of calls. Documented diabetes diagnosis (adjusted odds ratio [OR] 0.82, 95% confidence interval [CI] 0.69-0.96), higher capillary blood glucose (adjusted OR 0.31, 95% CI 0.22-0.44) and overnight calls (adjusted OR 0.80, 95% CI 0.72-0.91) were associated with lower odds of hospital transport. Higher-acuity calls (adjusted OR 2.05, 95% CI 1.58-2.66) were associated with higher odds of transport. The estimated annual incidence rate of hypoglycemia requiring paramedic assistance was 108 per 10 000 people with diabetes per year. INTERPRETATION: Hypoglycemia requiring paramedic assistance in southwestern Ontario is common, and close to 25% of calls do not result in hospital transport. Physicians managing diabetes care may be unaware of patients' hypoglycemia requiring paramedic care, suggesting a potential gap in follow-up care; we suggest that paramedics play an important role in identifying those at high recurrence risk and communicating with their care providers.

Patient and paramedic experiences with a direct electronic referral programme for focused hypoglycaemia education following paramedic service assist-requiring hypoglycaemia in London and Middlesex County, Ontario, Canada.

AIMS: Hypoglycaemia is a common treatment consequence in diabetes mellitus. Prior studies have shown that a large proportion of people with paramedic assist-requiring hypoglycaemia prefer not to be transported to hospital. Thus, these episodes are "invisible" to their usual diabetes care providers. A direct electronic referral programme where paramedics sent referrals focused hypoglycaemia education at the time of paramedic assessment was implemented in our region for 18 months; however, referral programme uptake was low. In this study, we examined patient and paramedic experiences with a direct electronic referral programme for hypoglycaemia education postparamedic assist-requiring hypoglycaemia, including barriers to programme referral and education attendance. METHODS: We surveyed paramedics and conducted semistructured telephone interviews of patients with paramedic-assisted hypoglycaemia who consented to the referral programme and were scheduled for an education session in London and Middlesex County, Canada. RESULTS: Paramedics and patient participants felt that the direct referral programme was beneficial. A third of paramedics who responded to our survey used the referral programme for each encounter where they treated patients for hypoglycaemia. Patients felt very positive about the referral programme and their paramedic encounter; however, they described embarrassment, guilt and prior negative experience as key barriers to attending education. CONCLUSIONS: Paramedics and patients felt that direct referral for focused hypoglycaemia education postparamedic assist-requiring hypoglycaemia was an excellent strategy. Despite this, referral programme participation was low and thus there remain ongoing barriers to implementation and attendance. Future iterations should consider how best to meet patient needs through innovative delivery methods.

Closing the Gap: Results of the Multicenter Canadian Randomized Controlled Trial of Structured Transition in Young Adults With Type 1 Diabetes.

OBJECTIVE: To determine if a structured transition program for young adults with type 1 diabetes improves clinic attendance, glycemic control, diabetes-related distress, quality of life, and satisfaction with care. RESEARCH DESIGN AND METHODS: In this multicenter randomized controlled trial, young adults (17-20 years) with type 1 diabetes were randomly assigned to a transition program with a transition coordinator or to standard care. The intervention lasted 18 months (6 in pediatric and 12 in adult care). The primary outcome was the proportion of participants who failed to attend at least one adult diabetes clinic visit during the 12-month follow-up after completion of the intervention. RESULTS: We randomized 205 participants, 104 to the transition program and 101 to standard care. Clinic attendance was improved in the transition program (mean [SD] number of visits 4.1 [1.1] vs. 3.6 [1.2], P = 0.002), and there was greater satisfaction with care (mean [SD] score 29.0 [2.7] vs. 27.9 [3.4], P = 0.032) and less diabetes-related distress (mean [SD] score 1.9 [0.8] vs. 2.1 [0.8], P = 0.049) reported than in standard care. There was a trend toward improvement in mean HbA1c (8.33% [68 mmol/mol] vs. 8.80% [73 mmol/mol], P = 0.057). During the 12-month follow-up, there was no difference in those failing to attend at least one clinic visit (P = 0.846), and the mean change in HbA1c did not differ between the groups (P = 0.073). At completion of follow-up, the groups did not differ with respect to satisfaction with care or diabetes-related distress and quality of life. CONCLUSIONS: Transition support during this 18-month intervention was associated with increased clinic attendance, improved satisfaction with care, and decreased diabetes-related distress, but these benefits were not sustained 12 months after completion of the intervention.

Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.

Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.

A randomised trial of non-mydriatic ultra-wide field retinal imaging versus usual care to screen for diabetic eye disease: rationale and protocol for the Clearsight trial.

INTRODUCTION: Suboptimal screening for diabetic eye disease is a major cause of preventable vision loss. Screening barriers include mydriasis and the extra time patients need to attend dedicated eye screening appointments. In the Clearsight trial, we are testing whether screening by non-mydriatic ultra-wide field (NM UWF) imaging on the day patients attend their diabetes outpatient clinic visit improves detection of clinically important eye disease compared with usual screening. METHODS AND ANALYSIS: Patients with diabetes due for a screening eye exam by the 2013 Canadian Diabetes Association (CDA) practice guidelines are being randomised to on-site screening by NM UWF imaging on the day of their clinic visit or to usual screening where, per CDA guidelines, they are encouraged to arrange an exam by an optometrist. The primary outcome is actionable eye disease (AED) based on a need for referral to ophthalmology and/or increased ocular surveillance. The primary analysis will use an intention-to-screen approach that compares the proportions of detected AED between on-site and usual screening groups under a superiority hypothesis in favour of on-site screening. With 740 randomised participants, the study will have 80% power to detect ≥5% absolute increase in the AED rate among on-site screening versus usual screening participants. This difference translates into a number-needed-to-screen by on-site screening of 20 to detect 1 additional person with AED. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board of Western University. The findings of the trial will be disseminated directly to participants and through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov NCT02579837 (registered 16 October 2015). PROTOCOL ISSUE DATE: 18 November 2015.

Use of n-of-1 (single patient) trials to assess the effect of age of transfused blood on health-related quality of life in transfusion-dependent patients.

BACKGROUND: The impact of age of red blood cells on health-related quality of life (HRQL) in patients who require chronic transfusions is not known. We assessed this using n-of-1 trials in patient populations where large randomized trials have not been done to date. STUDY DESIGN AND METHODS: Chronically transfusion-dependent adult patients were randomly assigned over time to four fresh (<7 days of storage) and four standard-issue (up to 42 days of storage) blood transfusions in prospective double-blinded multicrossover studies (n-of-1 trials). HRQL questionnaires were completed before and at 24 hours after each transfusion. Hemoglobin (Hb) levels were measured before each subsequent transfusion. RESULTS: Twenty transfusion-dependent patients were enrolled, of whom nine (five myelodysplastic syndromes, two myelofibrosis, one ß-thalassemia major, one Diamond-Blackfan anemia) completed at least six transfusions. Mean ages of fresh and standard-issue blood transfused were 4.0 and 23.2 days, respectively. There were no significant differences in the effect of standard and fresh blood on follow-up Hb levels or the eight HRQL dimensions assessed in all analyses. CONCLUSIONS: In chronically transfused patients, there were no significant differences in HRQL or Hb levels between fresh versus standard blood. While larger trials are needed, these results support current practices in hospital blood transfusion laboratories using a first-in, first-out model of blood utilization for these transfusion-dependent patients. Use of n-of-1 trials to determine the benefits of transfusions in single patients appears to be feasible.

Trends in Antihyperglycemic Medication Prescriptions and Hypoglycemia in Older Adults: 2002-2013.

BACKGROUND: Over the last decade, several new antihyperglycemic medications have been introduced including those associated with a lower hypoglycemia risk. We aimed to investigate how these medications are being prescribed to older adults in our region. METHODS: We conducted population-based cross-sectional analyses of older adults (mean age 75 years) with treated diabetes in Ontario, Canada from 2002 until 2013, to examine the percentage prescribed insulin, sulphonylureas, alpha-glucosidase inhibitors, metformin, thiazolidinediones, meglitinides, and dipeptidyl peptidase-4 inhibitors. Over the study period, we also examined their hospital encounters for hypoglycemia (emergency room or inpatient encounter). RESULTS: The mean age of treated patients increased slightly over the study quarters and the proportion that were women declined. With the exception of chronic kidney disease, cancer, dementia, and neuropathy, the percentage with a comorbidity appeared to decline. The percentage of treated patients prescribed metformin, gliclazide and dipeptidyl peptidase-4 inhibitors increased as did combination therapy. Glyburide and thiazolidinedione prescriptions declined, and insulin use remained stable. In those with newly treated diabetes, the majority were prescribed metformin, with smaller percentages prescribed insulin and other oral agents. Although the absolute number of treated patients with a hypoglycemia encounter increased until mid-2006 and then decreased, the overall percentage with an encounter declined over the study period (0.8% with an event in the first quarter, 0.4% with an event in the last quarter). CONCLUSIONS: Antihyperglycemic medications with safer profiles are being increasingly prescribed to older adults. In this setting there has been a decrease in the percentage of treated patients with a hospital encounter for hypoglycemia.

Posterior Reversible Encephalopathy Syndrome due to High Dose Corticosteroids for an MS Relapse.

Increased blood pressure is a known adverse effect associated with corticosteroids but little is published regarding the risk with the high doses used in multiple sclerosis (MS). A 53-year-old female with known relapsing remitting MS presented with a new brainstem relapse. Standard of care treatment for an acute MS relapse, 1250 mg of oral prednisone for 5 days, was initiated. She developed an occipital headache and dizziness and felt generally unwell. These symptoms persisted after treatment was complete. On presentation to medical attention, her blood pressure was 199/110 mmHg, although she had no history of hypertension. MRI changes were consistent with posterior reversible encephalopathy syndrome (PRES), demonstrating abnormal T2 signal in both thalami, the posterior occipital and posterior parietal white matter with mild sulcal effacement. As her pressure normalized with medication, her symptoms resolved and the MRI changes improved. No secondary cause of hypertension was found. This is the first reported case of PRES secondary to high dose corticosteroid use for an MS relapse without a history of hypertension and with no other secondary cause of hypertension identified. This rare complication should be considered in MS patients presenting with a headache or other neurological symptoms during treatment for a relapse.

The development and utility of a novel scale that quantifies the glycemic progression toward type 1 diabetes over 6 months.

OBJECTIVE: We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. RESEARCH DESIGN AND METHODS: The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. RESULTS: The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). CONCLUSIONS: The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers.

A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history.

OBJECTIVE: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. RESEARCH DESIGN AND METHODS: Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. RESULTS: Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. CONCLUSIONS: An approach based on prediction and natural history appears to have utility for diagnosing T1D.

N-of-1 (single-patient) trials for statin-related myalgia.

BACKGROUND: Statin-related myalgia is difficult to distinguish from other conditions causing myalgia and may often lead to statin discontinuation. OBJECTIVE: To compare the effect of statin rechallenge with placebo in patients with prior statin-related myalgia and to determine whether patients resumed statin therapy after evaluating the results. DESIGN: N-of-1 trial with 3 double-blind, crossover comparisons separated by 3-week washout periods. (Clinicaltrials.gov: NCT01259791) SETTING: Tertiary care lipid clinic. PATIENTS: Patients with prior statin-related myalgia with or without mild elevation of creatine kinase levels. INTERVENTION: Rechallenge with the statin that was previously associated with myalgia within 3 weeks of open-label use versus matching placebo. MEASUREMENTS: Weekly visual analogue scale (VAS) scores for myalgia and specific symptoms (VAS myalgia score and symptom-specific VAS score, respectively), pain interference scores, and pain severity scores were recorded during the 3-week periods when patients were receiving placebo or statin. The primary outcome was the VAS myalgia score (range, 0 to 100 mm). RESULTS: Eight patients (mean age, 66 years [SD, 8 years]; 88% women, all with high 10-year Framingham cardiovascular risk) participated in n-of-1 trials. Seven patients completed 3 treatment pairs, and 1 completed 2 treatment pairs. For each n-of-1 trial, no statistically significant differences were seen between statin and placebo in the VAS myalgia score, symptom-specific VAS score, pain interference score, and pain severity score. Five patients resumed open-label statin treatment, with a median posttrial follow-up of 10 months. LIMITATION: Results are limited by the small sample size and cannot be extended to patients with longer onset of myalgia after statin initiation. CONCLUSION: In selected patients with a history of statin-related myalgia whose symptoms are difficult to evaluate, n-of-1 trials may be a useful method for determining statin tolerability. PRIMARY FUNDING SOURCE: Western University, London, Ontario, Canada.

Use of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of the risk classification of type 1 diabetes.

OBJECTIVE We studied the utility of the Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) for improving the accuracy of type 1 diabetes (T1D) risk classification in TrialNet Natural History Study (TNNHS) participants. RESEARCH DESIGN AND METHODS The cumulative incidence of T1D was compared between normoglycemic individuals with DPTRS values >7.00 and dysglycemic individuals in the TNNHS (n = 991). It was also compared between individuals with DPTRS values <7.00 or >7.00 among those with dysglycemia and those with multiple autoantibodies in the TNNHS. DPTRS values >7.00 were compared with dysglycemia for characterizing risk in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 670) and TNNHS participants. The reliability of DPTRS values >7.00 was compared with dysglycemia in the TNNHS. RESULTS The cumulative incidence of T1D for normoglycemic TNNHS participants with DPTRS values >7.00 was comparable to those with dysglycemia. Among those with dysglycemia, the cumulative incidence was much higher (P < 0.001) for those with DPTRS values >7.00 than for those with values <7.00 (3-year risks: 0.16 for <7.00 and 0.46 for >7.00). Dysglycemic individuals in DPT-1 were at much higher risk for T1D than those with dysglycemia in the TNNHS (P < 0.001); there was no significant difference in risk between the studies among those with DPTRS values >7.00. The proportion in the TNNHS reverting from dysglycemia to normoglycemia at the next visit was higher than the proportion reverting from DPTRS values >7.00 to values <7.00 (36 vs. 23%). CONCLUSIONS DPTRS thresholds can improve T1D risk classification accuracy by identifying high-risk normoglycemic and low-risk dysglycemic individuals. The 7.00 DPTRS threshold characterizes risk more consistently between populations and has greater reliability than dysglycemia.

The prediction of type 1 diabetes by multiple autoantibody levels and their incorporation into an autoantibody risk score in relatives of type 1 diabetic patients.

OBJECTIVE: We assessed whether a risk score that incorporates levels of multiple islet autoantibodies could enhance the prediction of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: TrialNet Natural History Study participants (n = 784) were tested for three autoantibodies (GADA, IA-2A, and mIAA) at their initial screening. Samples from those positive for at least one autoantibody were subsequently tested for ICA and ZnT8A. An autoantibody risk score (ABRS) was developed from a proportional hazards model that combined autoantibody levels from each autoantibody along with their designations of positivity and negativity. RESULTS: The ABRS was strongly predictive of T1D (hazard ratio [with 95% CI] 2.72 [2.23-3.31], P < 0.001). Receiver operating characteristic curve areas (with 95% CI) for the ABRS revealed good predictability (0.84 [0.78-0.90] at 2 years, 0.81 [0.74-0.89] at 3 years, P < 0.001 for both). The composite of levels from the five autoantibodies was predictive of T1D before and after an adjustment for the positivity or negativity of autoantibodies (P < 0.001). The findings were almost identical when ICA was excluded from the risk score model. The combination of the ABRS and the previously validated Diabetes Prevention Trial-Type 1 Risk Score (DPTRS) predicted T1D more accurately (0.93 [0.88-0.98] at 2 years, 0.91 [0.83-0.99] at 3 years) than either the DPTRS or the ABRS alone (P ≤ 0.01 for all comparisons). CONCLUSIONS: These findings show the importance of considering autoantibody levels in assessing the risk of T1D. Moreover, levels of multiple autoantibodies can be incorporated into an ABRS that accurately predicts T1D.