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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.

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.

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.

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.

Hypoglycemia requiring paramedic assistance places a large burden on the health care system (HCS), and negatively impacts quality of life and long-term outcomes in patients with diabetes. Prior studies have shown that only a small proportion of patients with paramedic-assist requiring hypoglycemia are subsequently brought to the Emergency Room; thus severe hypoglycemia (SHG) is often “invisible” to the HCS and is not adequately followed up on. We created an innovative, two-step hypoglycemia education program in London, Canada which consists of a direct electronic referral system by paramedics at the time they assess patients with SHG to the local Diabetes Education Center (DEC) for a standardized hypoglycemia education. There were a total of 446 SHG calls to the Middlesex-London Paramedic Service from September 2017- June 2018. Of those, 322 (72%) were eligible for our study, of whom 135 (42%) were referred to the DEC and only 79 patients agreed to attend. Of the 79 patients who were enrolled over 21 months, 49 (62%) were male; the mean age was 61±16 (range 18-88 yrs); and 40 (51%) had type 2, 32 (41%) type 1, and 7 (9%) were unknown diabetes type. Of those 48 (61%) were taking insulin, 8 (10%) oral hypoglycemic agents of which the most common was glyburide (5/8, 63%), and 19 (24%) were on both oral agents and insulin. Three (4%) patients were on an insulin pump. Mean HbA1c was 63±9 mmol/mol (7.9±1.3, range 4.8-10.6%) and the majority did not have an Endocrinologist (49, 62%). Only 50 (63%) completed the education program. There were no statistically significant differences between the characteristics of the patients who attended and did not attend DEC program. Patients experiencing SHG remain ’hidden’ from the HCS. Hence, the impact of SHG is underestimated and understudied. Despite an accessible referral system to a focused intervention, our program was not successful in engaging many patients with SHG requiring paramedic assistance in a program to decrease their risk for SHG. Further study to explore barriers is needed. Disclosure T. Spaic: Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Dexcom, Inc., Sanofi. S.L. Liu: Consultant; Self; Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Novo Nordisk Inc., Sanofi. D.R. Carter: None. M. Peddle: None. J. Mahon: None. Funding Academic Medical Organization of Southwestern Ontario

Hypoglycemia requiring paramedic assistance negatively impacts outcomes in people with diabetes. Prior studies have shown only a small proportion of those with paramedic assist-requiring HG are brought to hospital. These episodes are thus “invisible” to the health care system. An innovative direct electronic referral program in which paramedics sent a referral for focused HG education to the Diabetes Education Centre (DEC) at the time of paramedic assessment was implemented for 18 months. Program uptake was lower than expected (133 referrals, 79 scheduled, and 50 attended). This qualitative study examines barriers and facilitators of DEC attendance for HG education after paramedic assist-requiring HG. We conducted semi-structured interviews of patients with paramedic-assisted HG and surveyed paramedics about their experiences. Of 34 paramedics, 30 (88%) attended at least 1 HG call in the study period and 26 (76%) used the referral program. Fourteen patients (18% response rate) participated: 8 men (57%); 13 (93%) age ≥ 50 yrs. Eight patients (57%) recalled the paramedic referral, 6 (43%) did not, and 4 (29%) thought they were referred by their family doctor. One patient thought attendance was mandatory to keep their drivers’ license. Themes identified from patient responses included: positive impact of diabetes education especially if delivered early after diagnosis, importance of spousal support and in-person education. Barriers to attendance were prior DEC attendance especially in those with long diabetes duration and embarrassment (failure to self-manage, memory loss around the HG event). While patients felt that focused HG education is an excellent strategy to reduce recurrent episodes, many had already attended similar sessions and felt further education was not needed. Hence, an important gap in providing HG education to patients with severe HG may be both system-based and disease-related. Disclosure S.L. Liu: Consultant; Self; Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Novo Nordisk Inc., Sanofi. A. Rosa: None. S.L. Sibbald: None. J. Mahon: None. D.R. Carter: None. M. Peddle: None. T. Spaic: Research Support; Self; Novo Nordisk Inc. Speaker’s Bureau; Self; Dexcom, Inc., Sanofi. Funding Academic Medical Association of Southwestern Ontario (INN16-004)

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Background: The numbers of women attending Diabetes and Pregnancy Clinics (DPC) are increasing. Some of the increase may reflect obesity effects on GDM prevalence, but changes in numbers and characteristics of women with type 1 diabetes (T1DM) are unknown. The DPC in London Ontario sees all pregnant women with diabetes within the catchment area with stable clinic structures and procedures. Longitudinal characteristics of women with T1DM were documented for demographic insights. Methods: DPC pregnancy charts were assessed for 2000-2002, 2010-2012 and 2014-2016. Data were abstracted for: age; weight, A1C and medication use. Continuous results were analyzed by one-way analysis of variance (ANOVA); non-parametric results by Chi-square testing; p≤ 0.05 signifying significance. Conclusions: Clinic numbers of pregnant women with T1DM increased non-significantly over the study timeline while pump usage rose concurrent with access to government funding. A1C values fell 0.5% from first to last visit in all time periods. A1C values at first visit rose over the time periods suggesting women with less optimal glucose control were conceiving pregnancies. Disclosure P. Khanna: None. K. Anukam: None. L. Chow: None. E. Brydges: None. S.L. Liu: Consultant; Self; Novo Nordisk Inc., Sanofi. Research Support; Self; Physicians' Services Inc. Foundation. J. Mahon: None. T.R. Joy: Speaker's Bureau; Self; Amgen Inc., Novo Nordisk Inc., Sanofi. Other Relationship; Self; Amgen Inc., AstraZeneca, Novo Nordisk Inc. R.M. McManus: None.

Pregnancies complicated by diabetes are increasingly frequent. The Endocrine and Pregnancy Clinic [EPC] at St Joseph’s Health Care London is the stable, local provider of all outpatient pregnancy diabetes care, thereby providing an opportunity to document patient characteristics with time. Methods EPC charts were reviewed for: 2000-2002; 2010-2012; 2014-2016 documenting DM type (T1DM, T2DM, GDM); age; weight; year/week of DM diagnosis; medication/pump use; A1C. Continuous results were analyzed by one-way analysis of variance (ANOVA); non-parametric results were analyzed by Chi-square testing; p Results Total EPC DM women were: 2000-2002: 408; 2010-2012: 571; 2014-2016: 813. GDM women represented 72.8% of EPC patients in 2001-2002 and 88.4% in 2014-2016. Weights and oral medication use increased with time for women with GDM, while insulin use decreased. Pump use in women with T1DM increased by 2010-2012 and 2014-2016 while A1C decreased significantly comparing first to last visits within each time interval. Numbers of women with T2DM increased significantly but weight at first clinic visit was lower over time, while A1C decreased significantly when comparing first to last visits within each time interval. Discussion/Conclusions EPC volumes doubled from 2000 to 2016 with no increase in background deliveries, predominantly due to increased numbers of women GDM, along with a small increase in women with T2DM. These findings may help inform decisions around health care planning and resource allocation.

Autoantibody positive (Ab+) relatives of T1D patients have an increased risk for dysglycemia and progression to T1D. However, the occurrence of dysglycemia in Ab- relatives is not known. Thus, we compared the frequency and pattern of dysglycemia from oral glucose tolerance tests (OGTTs) between Ab- (n=101; mean age: 11.7± 3.6 years) and single Ab+ (n=977; mean age 10.4± 3.9 years) relatives in the TrialNet Pathway to Prevention study. Single Abs were ICA, GADA, IA-2A, mIAA, or ZnT8A. The glucose criteria for dysglycemia were: fasting 110-125 mg/dl; 30, 60, and/or 90-minutes glucose ≥ 200 mg/dl; and/or 120-minutes glucose 140-199 mg/dl. Of the Ab-’s, 29/101 (28.7%) had at least one dysglycemic OGTT at baseline or during follow-up, whereas 192/977 (19.7%) Ab+’s had a dysglycemic OGTT. At baseline, there were no significant differences in the proportions of dysglycemia [Ab-’s: 13/101 (12.9%) vs. Ab+’s: 114/977 (11.7%)]. Of those with normal OGTTs at baseline, the proportion progressing to dysglycemia was actually higher (p=0.007) in the Ab-’s (dysglycemia/total: [16/87 (18.4%) vs. 78/846 (9.2%)], but the hazard ratio for dysglycemia risk from a Cox regression analysis was not significant after adjustments for age, BMI%tile, relation to proband, and number of OGTTs performed. OGTT glucose and C-peptide at the first dysglycemic OGTT did not differ significantly between Ab-’s and Ab+’s after adjustments, except for a higher 90-minutes glucose in the Ab-’s (p=0.004). The early C-peptide response values (30-0 minutes C-peptide) did not differ significantly between the groups and were not indicative of overt insulin deficiency (Ab-’s: 5.6± 3.2 ng/ml vs. Ab+’s: 5.2± 3.3 ng/ml). In summary, dysglycemia was as common in Ab- relatives as in single Ab+ relatives with similar dysglycemic OGTT patterns. These findings suggest that dysglycemia can precede Ab’s during the progression to T1D and/or an appreciable proportion of single Ab+ dysglycemic individuals do not develop T1D. Disclosure E.K. Sims: None. P. Xu: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Abvance. Consultant; Self; AstraZeneca, Becton, Dickinson and Company, Boehringer Ingelheim GmbH. Advisory Panel; Self; Dance Biopharm. Consultant; Self; Diavacs, Inc., Elcelyx Therapeutics, Inc., Eli Lilly and Company, Ideal Life Inc., ImmunoMolecular Therapeutics, Intrexon, Merck & Co., Inc.. Advisory Panel; Self; Orgenesis Inc.. Consultant; Self; Sanofi, Servier, VTV Therapeutics, Valeritas, Inc., Viacyte, Inc.. Board Member; Self; Dexcom, Inc.. Stock/Shareholder; Self; Dexcom, Inc.. Board Member; Self; Intarcia Therapeutics, Inc.. Stock/Shareholder; Self; Intarcia Therapeutics, Inc.. Board Member; Self; Moerae Matrix. Stock/Shareholder; Self; Moerae Matrix, Dance Biopharm, Ideal Life Inc., Intrexon, VasoPrep Surgical. A. Pugliese: None. J. Krischer: None. C. Greenbaum: Research Support; Self; Janssen Research & Development. Consultant; Self; Bristol-Myers Squibb Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. J. Mahon: None. K.C. Herold: None. J.P. Palmer: None. J. Sosenko: None.

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 (

BACKGROUND. Neutrophils and their inflammatory mediators are key pathogenic components in multiple autoimmune diseases, while their role in human type 1 diabetes (T1D), a disease that progresses sequentially through identifiable stages prior to the clinical onset, is not well understood. We previously reported that the number of circulating neutrophils is reduced in patients with T1D and in presymptomatic at-risk subjects. The aim of the present work was to identify possible changes in circulating and pancreas-residing neutrophils throughout the disease course to better elucidate neutrophil involvement in human T1D. METHODS. Data collected from 389 subjects at risk of developing T1D, and enrolled in 4 distinct studies performed by TrialNet, were analyzed with comprehensive statistical approaches to determine whether the number of circulating neutrophils correlates with pancreas function. To obtain a broad analysis of pancreas-infiltrating neutrophils throughout all disease stages, pancreas sections collected worldwide from 4 different cohorts (i.e., nPOD, DiViD, Siena, and Exeter) were analyzed by immunohistochemistry and immunofluorescence. Finally, circulating neutrophils were purified from unrelated nondiabetic subjects and donors at various T1D stages and their transcriptomic signature was determined by RNA sequencing. RESULTS. Here, we show that the decline in β cell function is greatest in individuals with the lowest peripheral neutrophil numbers. Neutrophils infiltrate the pancreas prior to the onset of symptoms and they continue to do so as the disease progresses. Of interest, a fraction of these pancreas-infiltrating neutrophils also extrudes neutrophil extracellular traps (NETs), suggesting a tissue-specific pathogenic role. Whole-transcriptome analysis of purified blood neutrophils revealed a unique molecular signature that is distinguished by an overabundance of IFN-associated genes; despite being healthy, said signature is already present in T1D-autoantibody-negative at-risk subjects. CONCLUSIONS. These results reveal an unexpected abnormality in neutrophil disposition both in the circulation and in the pancreas of presymptomatic and symptomatic T1D subjects, implying that targeting neutrophils might represent a previously unrecognized therapeutic modality. FUNDING. Juvenile Diabetes Research Foundation (JDRF), NIH, Diabetes UK.

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 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.

Statin-related myalgia compared with myalgia due to other causes is difficult to distinguish and may often lead to statin discontinuation. This proof-of-concept study involved patients who previous...

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 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.

Background Notwithstanding improving rates of hypertension control in North America, management of patients with both hypertension and dyslipidemia remains problematic. Based on evidence of improved control utilizing a simplified algorithm for management of hypertension (STITCH), we questioned whether a simplified comprehensive treatment algorithm featuring initial use of single-pill combinations (SPCs) would improve management of participants with both hypertension and dyslipidemia. Method We randomized 35 primary care practices in Ontario to either Guidelines-care (following current Canadian guidelines) or STITCH2-care (following a treatment algorithm featuring SPCs). Practices each enrolled up to 50 participants with at least one risk factor above target at entry based on Canadian guidelines for BP and LDL-cholesterol control. The primary endpoint was achieving targets for both hypertension and dyslipidemia control after 6 months, assessed at the practice level. Results The primary endpoint was achieved in 31.3% of participants in STITCH2-care practices, compared with 28.1% in Guidelines-care practices, yielding a difference of 3.2% (P = 0.63). Notably, STITCH2-care practices had a significantly greater reduction in SBP while LDL-cholesterol reduction was only marginally greater in STITCH2 practices. Conclusion The STITCH2 algorithm resulted in significantly greater use of any SPC compared with Guidelines-care and greater use of the SPC of calcium channel blocker/statin. Unwillingness of the prescribing physician to advance treatment beyond a monotherapy threshold was found to be an important determinant for failing to achieve blood pressure control. In contrast, the more important determinant for failing to achieve LDL control appeared to be the unwillingness of the prescribing physician to initiate therapy with a statin.

OBJECTIVE We assessed the utility of the Diabetes Prevention Trial–Type 1 Risk Score (DPTRS) for identifying individuals who are highly likely to progress to type 1 diabetes (T1D) within 2 years. RESEARCH DESIGN AND METHODS The DPTRS was previously developed from Diabetes Prevention Trial–Type 1 (DPT-1) data and was subsequently validated in the TrialNet Natural History Study (TNNHS). DPTRS components included C-peptide and glucose indexes from oral glucose tolerance testing, along with age and BMI. The cumulative incidence of T1D was determined after DPTRS thresholds were first exceeded and after the first occurrences of glucose abnormalities. RESULTS The 2-year risks after the 9.00 DPTRS threshold was exceeded were 0.88 and 0.77 in DPT-1 (n = 90) and the TNNHS (n = 69), respectively. In DPT-1, the 2-year risks were much lower after dysglycemia first occurred (0.37; n = 306) and after a 2-h glucose value between 190 and 199 mg/dL was first reached (0.64; n = 59). Among those who developed T1D in DPT-1, the 9.00 threshold was exceeded 0.81 ± 0.53 years prior to the conventional diagnosis. Postchallenge C-peptide levels were substantially higher (P = 0.001 for 30 min; P < 0.001 for other time points) when the 9.00 threshold was first exceeded compared with the levels at diagnosis. CONCLUSIONS A DPTRS threshold of 9.00 identifies individuals who are very highly likely to progress to the conventional diagnosis of T1D within 2 years and, thus, are essentially in a preclinical diabetic state. The 9.00 threshold is exceeded well before diagnosis, when stimulated C-peptide levels are substantially higher.

Despite improvements in blood pressure (BP) control, a substantial percentage of patients do not achieve target. The relative importance of determinants of poor BP control is unclear. Therefore, the authors conducted a post hoc exploratory analysis to assess determinants of BP control. Data were collected in 45 general practices, which enrolled patients with uncontrolled hypertension. Antihypertensive medication changes throughout the 6‐month follow‐up period were documented. Baseline and 6‐month BPs were recorded. Of the 2030 patients analyzed, 320 had diabetes. Overall, 42% of patients did not achieve BP control. In multivariate analysis, failure to intensify therapy was identified as a significant independent predictor of lesser BP reduction. Of patients unable to reach target after 6 months, only 25% were prescribed ≥3 drugs. Patients with diabetes were significantly less likely to reach target than those without (26% vs 64%, P

OBJECTIVE We characterized fluctuations between states of glycemia in progressors to type 1 diabetes and studied whether those fluctuations are related to the early C-peptide response to oral glucose. RESEARCH DESIGN AND METHODS Oral glucose tolerance tests (OGTTs) from differing states of glycemia were compared within individuals for glucose and C-peptide. Dysglycemic OGTTs (DYSOGTTs) were compared with normal OGTTs (NLOGTT), while transient diabetic OGTTs (TDOGTTs) were compared with subsequent nondiabetic OGTTs and with OGTTs performed at diagnosis. RESULTS Of 135 progressors with four or more OGTTs, 30 (22%) went from NLOGTTs to DYSOGTTs at least twice. Area under the curve (AUC) glucose values from the second NLOGTT were higher (P < 0.001) than values from the first NLOGTT. Among 98 progressors whose DYSOGTTs and NLOGTTs were synchronized for the time before diagnosis, despite higher glucose levels (P < 0.01 at all time points) in the DYSOGTTs, 30- to 0-min C-peptide difference values changed little. Likewise, 30- to 0-min C-peptide difference values did not differ between TDOGTTs and subsequent (within 3 months) nondiabetic OGTTs in 55 progressors. In contrast, as glucose levels increased overall from the first to last OGTTs before diagnosis (P < 0.001 at every time point, n = 207), 30- to 0-min C-peptide difference values decreased (P < 0.001). CONCLUSIONS Glucose levels fluctuate widely as they gradually increase overall with progression to type 1 diabetes. As glucose levels increase, the early C-peptide response declines. In contrast, glucose fluctuations are not related to the early C-peptide response. This suggests that changes in insulin sensitivity underlie the glucose fluctuations.

Naive damselfish, Dascyllus albisella, were tested for their initial response to the Hawaiian cleaning wrasse, Labroides phthirophagus. Contrary to some current theory, some individuals, including both lab-reared and wild-caught fish, showed a full ‘pose’ response to visual stimuli from the cleaner without prior tactile stimulation, while others failed to show this response even after 4 d of exposure to visual and tactile stimuli. These individual differences could have resulted from innate differences or uncontrolled variables in their experience.

BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (HUS) may be complicated by acute and long-term insulin deficiency. However, the glycemic consequences of acute bacterial gastroenteritis in the absence of HUS have never been considered. We studied the long-term risk of dysglycemia after an outbreak of acute gastroenteritis due to contamination of a regional drinking water supply with Escherichia coli O157:H7 and Campylobacter species. METHODS: Previously healthy residents aged 10 years or older participated in a longitudinal study Of the 3259 participants, 1139 had no bacterial gastroenteritis at the time of the outbreak, while 1492 and 628 had possible and confirmed gastroenteritis, respectively. The primary outcome of dysglycemia was defined as the composite of diabetes, impaired fasting glucose or impaired glucose tolerance. Participants were followed for a mean of 4.5 years (range 1.9-5.6 years) after the outbreak. RESULTS: We found no association between acute symptomatic gastroenteritis and subsequent rates of dysglycemia (asymptomatic: 11.0% [95% CI 8.8-13.2]; possible gastroenteritis: 11.6% [95% CI 9.0-14.4]; confirmed gastroenteritis: 10.9% [95% CI 9.4-12.5]; p for trend=0.9). There were also no differences in mean fasting glucose levels between the groups. CONCLUSION: In this study, there was no association between bacterial gastroenteritis and the risk of dysglycemia in later years.

OBJECTIVE—The accurate prediction of type 1 diabetes is essential for appropriately identifying prevention trial participants. Thus, we have developed a risk score for the prediction of type 1 diabetes. RESEARCH DESIGN AND METHODS—Diabetes Prevention Trial–Type 1 (DPT-1) participants, islet cell autoantibody (ICA)-positive relatives of type 1 diabetic patients (n = 670), were randomly divided into development and validation samples. Risk score values were calculated for the validation sample from development sample model coefficients obtained through forward stepwise proportional hazards regression. RESULTS—A risk score based on a model including log-BMI, age, log-fasting C-peptide, and postchallenge glucose and C-peptide sums from 2-h oral glucose tolerance tests (OGTTs) was derived from the development sample. The baseline risk score strongly predicted type 1 diabetes in the validation sample (χ2 = 82.3, P < 0.001). Its strength of prediction was almost the same (χ2 = 83.3) as a risk score additionally dependent on a decreased first-phase insulin response variable from intravenous glucose tolerance tests (IVGTTs). Biochemical autoantibodies did not contribute significantly to the risk score model. A final type 1 diabetes risk score was then derived from all participants with the same variables as those in the development sample model. The change in the type 1 diabetes risk score from baseline to 1 year was in itself also highly predictive of type 1 diabetes (P < 0.001). CONCLUSIONS—A risk score based on age, BMI, and OGTT indexes, without dependence on IVGTTs or additional autoantibodies, appears to accurately predict type 1 diabetes in ICA-positive relatives.

OBJECTIVE—Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers. RESEARCH DESIGN AND METHODS—The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged RESULTS—The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0–62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3). CONCLUSIONS—These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.

OBJECTIVE—We assessed the extent to which both standard and alternative indexes from 2-h oral glucose tolerance testing predict type 1 diabetes and whether oral glucose tolerance tests (OGTTs) predict type 1 diabetes in individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS—The prediction of type 1 diabetes from baseline OGTTs was studied in 704 Diabetes Prevention Trial-Type 1 participants (islet-cell autoantibody [ICA]-positive relatives of type 1 diabetic patients). The maximum follow-up was 7.4 years. Analyses utilized receiver-operator curves (ROCs), proportional hazards models, and survival curves. RESULTS—ROC areas under the curve (ROCAUCs) for both the AUC glucose (0.73 ± 0.02) and an OGTT prediction index (0.78 ± 0.02) were higher (P < 0.001) than those for the fasting (0.53 ± 0.02) and 2-h glucose (0.66 ± 0.02). ROCAUCs for the 60- and 90-min glucose (0.71 ± 0.02 and 0.72 ± 0.02, respectively) were also higher (P < 0.01) than those for the fasting and 2-h glucose. Among individuals with normal glucose tolerance, OGTTs were highly predictive, with 4th versus 1st quartile hazard ratios for the 2-h glucose, AUC glucose, and OGTT prediction index ranging from 3.77 to 5.30 (P < 0.001 for all). CONCLUSIONS—Certain alternative OGTT indexes appear to better predict type 1 diabetes than standard OGTT indexes in ICA-positive relatives of type 1 diabetic patients. Moreover, even among those with normal glucose tolerance, OGTTs are strongly predictive. This suggests that subtle metabolic abnormalities are present several years before the diagnosis of type 1 diabetes.

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.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.Twenty transfusion-dependent patients were enrolled, of whom nine (five myelodysplastic syndromes, two myelofibrosis, one β-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.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.

OBJECTIVE—To quantify the incidence of diabetes during the acute phase of diarrhea-associated hemolytic uremic syndrome (D+HUS) and to identify features associated with its development. RESEARCH DESIGN AND METHODS—A systematic review and meta-analysis of articles assessing diabetes during D+HUS was conducted. Relevant citations were identified from Medline, Embase, and Institute for Scientific Information Citation Index databases. Bibliographies of relevant articles were hand searched. All articles were independently reviewed for inclusion and data abstraction by two authors. RESULTS—Twenty-one studies from six countries were included. Only 2 studies reported a standard definition of diabetes; 14 defined diabetes as hyperglycemia requiring insulin. The incidence of diabetes during the acute phase of D+HUS could be quantified in a subset of 1,139 children from 13 studies (1966–1998, age 0.2–16 years) and ranged from 0 to 15%, with a pooled incidence of 3.2% (95% CI 1.3–5.1, random-effects model, significant heterogeneity among studies, P = 0.007). Children who developed diabetes were more likely to have severe disease (e.g., presence of coma or seizures, need for dialysis) and had higher mortality than those without diabetes. Twenty-three percent of those who developed diabetes acutely died, and 38% of survivors required long-term insulin (median follow-up 12 months). Recurrence of diabetes was possible up to 60 months after initial recovery. CONCLUSIONS—Children with D+HUS should be observed for diabetes during their acute illness. Consideration should be given to long-term screening of D+HUS survivors for diabetes.

Purposes: Are utility scores for hypothetical health states stable over time even when the health of the patient changes dramatically? Can investigators who use scores for hypothetical states be confident about the stability of those scores? The first purpose is to assess the stability of standard gamble utility scores for three hypothetical health states describing mild, moderate, and severe osteoarthritis (OA) (test–retest reliability). How should investigators interpret utility scores? The second purpose is to provide evidence on the marker-state approach to assist in interpreting utility scores. Background: SG scores for three hypothetical marker states and the patient's current state were obtained at multiple times in a longitudinal study of elective total hip arthroplasty (THA). SG scores for current health increased from a mean of 0.59 pre-surgery to 0.76 post-surgery. Methods: Test–retest reliability was assessed using the intra-class correlation coefficient (ICC). The effects of time on scores were analysed using an analysis of covariance. Results: At the group level the marker-state scores were stable. Mean scores for mild, moderate, and severe OA were 0.69, 0.61, and 0.41. With respect to test–retest reliability, ICCs varied from 0.49 to 0.62. In general, time did not affect the scores for the three marker states. Conclusions: Group-level standard gamble scores are stable. At the individual level scores for hypothetical health states are somewhat stable over time. The marker states assist in interpretation indicating that, on average, THA converted moderate OA to better than mild.

The 90-kDa chaperon family includes heat shock protein (hsp) 90 and glucose-regulated protein (grp) 94. These proteins play an important role in normal cellular architecture, in the etiology of some autoimmune and infectious diseases and in antigen presentation to T cells. Owing to its role in autoimmunity, we explored anti-hsp90 autoantibody (hsp90AA) response in the sera of persons with type 1 diabetes, first-degree relatives (FDR) and in normal subjects. Significant high level of hsp90AA was found in FDR, but there was no significant difference between the normal and diabetic persons. The IgG1 and IgG3 isotypes of hsp90AA were higher in persons with type 1 diabetes and FDR than in normal subjects. We found a good correlation between hsp90AA measured by ELISA and RIA. A positive correlation between serum hsp90AA and glutamic acid decarboxylase (GAD65) autoantibody (GAA) was also observed. Hsp90AA positive sera from diabetic persons immunoblotted recombinant hsp90, GAD65 and corresponding proteins in islet lysates. Our study suggests that hsp90AA are present in normal, FDR and diabetic persons. However, there is a higher level of IgG1 and IgG3 isotypes of hsp90AA in FDR and type 1 diabetic subjects. Thus, autoimmunity leading to type 1 diabetes significantly alters the autoantibody isotype to autoantigens, such as hsp90.

In the article cited above, the last paragraph of the RESULTS section was corrected to read: The application of the DPTRS is presented in the following hypothetical example. An 8-year-old with a BMI of 18.0 kg/m2 (log …

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

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.

IntroductionSuboptimal 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 analysisPatients 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 disseminationThe 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 numberClinicalTrials.GovNCT02579837(registered 16 October 2015).Protocol issue date18 November 2015.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

This multicenter, randomized, double-blind, placebo- and captopril-controlled, parallel-group trial evaluated the efficacy and safety of valsartan 80 and 160 mg in patients with incipient diabetic nephropathy. Patients were randomized to receive either valsartan 80 mg or 160 mg once daily, captopril 25 mg 3 times daily, or placebo. The study comprised 122 normotensive and treated hypertensive patients with type 2 diabetes mellitus and microalbuminuria (mean age, 56 years; 90% white). Treatment lasted 52 weeks. Efficacy variables included albumin excretion rate (AER), progression to clinical proteinuria, and glomerular filtration rate. In both the valsartan 80-mg (n = 31) and 160-mg (n = 31) groups and in the captopril group ( n = 29), a decrease in AER from baseline was observed at end point, compared with an increase in the placebo group (n = 31). The positive effect of valsartan 80 mg versus placebo on AER was statistically significant (95% confidence interval [CI] for end point/baseline ratio: 0.365 to 0.966); the 95% CI for valsartan 160 mg versus placebo was 0.407 to 1.043. No significant differences in AER occurred in the comparisons of valsartan 80 mg and valsartan 160 mg versus captopril. The percentage of patients with trial drug—related adverse experiences was highest in the captopril group (34.5%). The corresponding values for the groups receiving valsartan 80 mg, valsartan 160 mg, and placebo were 9.7%, 22.6%, and 13.8%, respectively. Results of this study suggest that treatment with valsartan slows the progressive rise of AER in normotensive and treated hypertensive patients with type 2 diabetes mellitus with comparable efficacy and superior tolerability to captropril.

The minimal important difference (MID) is the smallest benefit of treatment that would result in clinicians recommending it to their patients. The MID is necessary to calculate sample size for randomized clinical trials, but its chosen value is often arbitrary. This study set out to determine the practicability of surveying physicians to elicit the MID for clinical trial sample-size calculation. Using a mail survey, we elicited the MID of different physician specialties (family medicine, internal medicine, vascular surgery) for using propranolol to slow abdominal aortic aneurysm (AAA) growth assuming that propranolol was efficacious in this condition. We used different outcome measures (growth rate or proportion of patients requiring surgery) and different methods of data presentation for the proportion of patients requiring surgery (absolute risk reduction or number needed to treat). The MID varied significantly by physician specialty, experience with AAA and propranolol, and the method used to elicit the MID. Consequently, sample-size calculations using these various MIDs varied from 116 to 3015. Future attempts to elicit the MID need to consider carefully who is surveyed, how data are presented, and how opinions are elicited.

Study objective: To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline (Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice. Design: Randomized study of n of 1 trials vs standard practice. Setting: Outpatient departments in two tertiary care centers. Patients: Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N 5 34) or standard practice. Interventions: The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization. Measurements and results: The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, ‐2.8; 95% confidence limits [CLs], ‐ 8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, ‐ 4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, ‐26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment. Conclusions: Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usage, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice. (CHEST 1999; 115:38‐48)

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 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). 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 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.

ObjectiveTo examine the use of vitamin D supplements during infancy among the participants in an international infant feeding trial.DesignLongitudinal study.SettingInformation about vitamin D supplementation was collected through a validated FFQ at the age of 2 weeks and monthly between the ages of 1 month and 6 months.SubjectsInfants (n 2159) with a biological family member affected by type 1 diabetes and with increased human leucocyte antigen-conferred susceptibility to type 1 diabetes from twelve European countries, the USA, Canada and Australia.ResultsDaily use of vitamin D supplements was common during the first 6 months of life in Northern and Central Europe (>80 % of the infants), with somewhat lower rates observed in Southern Europe (>60 %). In Canada, vitamin D supplementation was more common among exclusively breast-fed than other infants (e.g. 71 % v. 44 % at 6 months of age). Less than 2 % of infants in the USA and Australia received any vitamin D supplementation. Higher gestational age, older maternal age and longer maternal education were study-wide associated with greater use of vitamin D supplements.ConclusionsMost of the infants received vitamin D supplements during the first 6 months of life in the European countries, whereas in Canada only half and in the USA and Australia very few were given supplementation.

Objective: To compare outcomes between groups of patients with irreversible chronic airflow limitation given theophylline by n of 1 trials or standard practice. Design: Randomised controlled study of n of 1 trials versus standard practice. Setting: Tertiary care centre outpatient department. Subjects: 31 patients with irreversible chronic airflow limitation who were unsure that theophylline was helpful after an open trial. Interventions: n Of 1 trials (single patient randomised multiple crossover comparisons of theophylline against placebo) followed published guidelines. For standard practice patients theophylline was stopped and resumed if their dyspnoea worsened; if their dyspnoea then improved theophylline was continued. For both groups a decision to continue or stop the drug was made within three months of randomisation. Main outcome measures: Exercise capacity as measured by six minute walking distance, quality of life as measured by the chronic respiratory disease questionnaire at baseline and six months after randomisation, and proportions of patients taking theophylline at six months. Results: 26 patients completed follow up. 47% fewer n of 1 trial patients than standard practice patients were taking theophylline at six months (5/14 versus 10/12; 95% confidence interval of difference 14% to 80%) without differences in exercise capacity or quality of life. Conclusions: n Of 1 trials led to less theophylline use without adverse effects on exercise capacity or quality of life in patients with irreversible chronic airflow limitation. These data directly support the presence of a clinically important bias towards unnecessary treatment during open prescription of theophylline for irreversible chronic airflow limitation. Confirmation in a larger study and similar studies for other problems appropriate for n of 1 trials are needed before widespread use of n of 1 trials can be advocated in routine clinical practice. Key messages Several common clinical problems suit n of 1 tri- als, including prescription of theophylline for irre- versible chronic airflow limitation, yet they are rarely used Among patients with chronic airflow limitation randomised to receive theophylline by an n of 1 trial or standard practice 47% fewer n of 1 trial patients were taking theophylline after six months without difference in exercise capacity or quality of life There seems to be a clinically important bias towards unnecessary treatment in standard prac- tice in this setting; n of 1 trials may limit this bias

Introduction: Hypoglycemia is a common treatment consequence in diabetes mellitus (DM) and the second most common cause of Emergency Department (ED) visits for adverse drug events. Prior studies have examined the rates of ED visits and inpatient hospitalizations for hypoglycemia. These represent only a small proportion of severe hypoglycemic events, as many do not present to hospital. To date, there have been no Canadian population-based studies examining the rates of EMS assist-requiring hypoglycemia in DM patients in the pre-hospital setting. The objective of this study was to determine the prevalence and describe the EMS assist-requiring hypoglycemia in DM patients in Southwestern Ontario. Methods: A population-based retrospective cohort study was conducted on all EMS calls for diabetic emergency from 2008-2014 in Southwestern Ontario, Canada. Data was extracted from the electronic ambulance call records for 11 EMS services in the region. Results: There were 9,265 EMS calls for a diabetic emergency (mean age 59 ± 20 years, 57% male, 82% DM). For 223 calls (2.4%) patients were younger than 19 years of age. The mean blood glucose level on presentation was 2.49 ± 1.02 mmol/L and 2,116 (24%) call subjects had initial GCS score less than 9. Treatment (intravenous glucose or IM glucagon) was given in 7,126 (77%) calls. There were 3,884 (51 %) hypoglycemia episodes with documented insulin use and 1,436 (19 %) documented oral hypoglycemia agents use. Between 2008 and 2014, rates of calls increased by 7.4% (pConclusion: The rates of EMS assist-requiring hypoglycemia are almost double the rates of hospitalization/ED visits for acute DM complications in our region. Many life threatening episodes of hypoglycemia may go unreported and subsequently not followed by the patient's primary health care provider. Further assessment and proper education following those episodes may help decrease the rate of severe hypoglycemia.