Alanna Weisman

Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes.

OBJECTIVE In vivo corneal confocal microscopy (IVCCM) has been proposed as a noninvasive technique to assess small nerve fiber structural morphology. We investigated the structure-function relationship of small fibers in diabetic sensorimotor polyneuropathy (DSP). RESEARCH DESIGN AND METHODS Ninety-six type 1 diabetic subjects with a spectrum of clinical DSP and 64 healthy volunteers underwent IVCCM examinations to determine corneal nerve structure, including corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and fiber tortuosity (CNFT). Small nerve fiber function was assessed by cooling detection thresholds (CDTs), axon reflex–mediated neurogenic vasodilatation in response to cutaneous heating by laser Doppler imaging flare technique (LDIFLARE), and heart rate variability (HRV). Linear associations between structural and functional measures in type 1 diabetic subjects were determined using Spearman correlation coefficients and linear regression analysis. RESULTS Of the type 1 diabetic subjects, with a mean age of 38.2 ± 15.5 years and a mean HbA1c of 7.9 ± 1.4%, 33 (34%) had DSP according to the consensus definition. Modest correlations were observed between CNFL, CNFD, and CNBD and all functional small-fiber tests (rs = 0.25 to 0.41; P ≤ 0.01 for all comparisons). For example, quantitatively every 1 mm/mm2 lower CNFL was associated with a 0.61°C lower CDT, a 0.07 cm2 lower LDIFLARE area, and a 1.78% lower HRV. No significant associations were observed for CNFT and the functional small-fiber measures. CONCLUSIONS Small nerve fiber structural morphology assessed by IVCCM correlated well with functional measures of small nerve fiber injury. In particular, CNFL, CNFD, and CNBD demonstrated clear structure-function relationships.

Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials

BACKGROUND Closed-loop artificial pancreas systems have been in development for several years, including assessment in numerous varied outpatient clinical trials. We aimed to summarise the efficacy and safety of artificial pancreas systems in outpatient settings and explore the clinical and technical factors that can affect their performance. METHODS We did a systematic review and meta-analysis of randomised controlled trials comparing artificial pancreas systems (insulin only or insulin plus glucagon) with conventional pump therapy (continuous subcutaneous insulin infusion [CSII] with blinded continuous glucose monitoring [CGM] or unblinded sensor-augmented pump [SAP] therapy) in adults and children with type 1 diabetes. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies published from 1946, to Jan 1, 2017. We excluded studies not published in English, those involving pregnant women or participants who were in hospital, and those testing adjunct medications other than glucagon. The primary outcome was the mean difference in percentage of time blood glucose concentration remained in target range (3·9-10 mmol/L or 3·9-8 mmol/L, depending on the study), assessed by random-effects meta-analysis. This study is registered with PROSPERO, number 2015:CRD42015026854. FINDINGS We identified 984 reports; after exclusions, 27 comparisons from 24 studies (23 crossover and one parallel design) including a total of 585 participants (219 in adult studies, 265 in paediatric studies, and 101 in combined studies) were eligible for analysis. Five comparisons assessed dual-hormone (insulin and glucagon), two comparisons assessed both dual-hormone and single-hormone (insulin only), and 20 comparisons assessed single-hormone artificial pancreas systems. Time in target was 12·59% higher with artificial pancreas systems (95% CI 9·02-16·16; p<0·0001), from a weighted mean of 58·21% for conventional pump therapy (I2=84%). Dual-hormone artificial pancreas systems were associated with a greater improvement in time in target range compared with single-hormone systems (19·52% [95% CI 15·12-23·91] vs 11·06% [6·94 to 15·18]; p=0·006), although six of seven comparisons compared dual-hormone systems to CSII with blinded CGM, whereas 21 of 22 single-hormone comparisons had SAP as the comparator. Single-hormone studies had higher heterogeneity than dual-hormone studies (I2 79% vs 66%). Bias assessment characteristics were incompletely reported in 12 of 24 studies, no studies masked participants to the intervention assignment, and masking of outcome assessment was not done in 12 studies and was unclear in 12 studies. INTERPRETATION Artificial pancreas systems uniformly improved glucose control in outpatient settings, despite heterogeneous clinical and technical factors. FUNDING None.

Identification and Prediction of Diabetic Sensorimotor Polyneuropathy Using Individual and Simple Combinations of Nerve Conduction Study Parameters

Objective Evaluation of diabetic sensorimotor polyneuropathy (DSP) is hindered by the need for complex nerve conduction study (NCS) protocols and lack of predictive biomarkers. We aimed to determine the performance of single and simple combinations of NCS parameters for identification and future prediction of DSP. Materials and Methods 406 participants (61 with type 1 diabetes and 345 with type 2 diabetes) with a broad spectrum of neuropathy, from none to severe, underwent NCS to determine presence or absence of DSP for cross-sectional (concurrent validity) analysis. The 109 participants without baseline DSP were re-evaluated for its future onset (predictive validity). Performance of NCS parameters was compared by area under the receiver operating characteristic curve (AROC). Results At baseline there were 246 (60%) Prevalent Cases. After 3.9 years mean follow-up, 25 (23%) of the 109 Prevalent Controls that were followed became Incident DSP Cases. Threshold values for peroneal conduction velocity and sural amplitude potential best identified Prevalent Cases (AROC 0.90 and 0.83, sensitivity 80 and 83%, specificity 89 and 72%, respectively). Baseline tibial F-wave latency, peroneal conduction velocity and the sum of three lower limb nerve conduction velocities (sural, peroneal, and tibial) best predicted 4-year incidence (AROC 0.79, 0.79, and 0.85; sensitivity 79, 70, and 81%; specificity 63, 74 and 77%, respectively). Discussion Individual NCS parameters or their simple combinations are valid measures for identification and future prediction of DSP. Further research into the predictive roles of tibial F-wave latencies, peroneal conduction velocity, and sum of conduction velocities as markers of incipient nerve injury is needed to risk-stratify individuals for clinical and research protocols.

Commonly Measured Clinical Variables Are Not Associated With Burden of Complications in Long-standing Type 1 Diabetes: Results From the Canadian Study of Longevity in Diabetes

Twenty-five percent of individuals with long-standing type 1 diabetes (T1D) are resistant to complications, and this is not entirely explained by superior glycemic control (1–4). Although associations between clinical variables and individual complications have been comprehensively examined (1–4), analysis of total complication burden may detect previously unrecognized associations. The Canadian Study of Longevity in Diabetes actively recruited 325 individuals who had T1D for 50 or more years (5). Subjects completed a questionnaire, and recent laboratory tests and eye reports were provided by primary care physicians and eye specialists, respectively. Nephropathy was defined by an albumin-to-creatinine ratio of >2 mg/mmol for participants on an ACE inhibitor or angiotensin receptor blocker (ARB) or >3.4 mg/mmol for participants not on an ACE inhibitor or ARB. Symptomatic neuropathy was defined by a score ≥3 on the Michigan Neuropathy Screening Instrument (MNSI) questionnaire component. Retinopathy was defined by documentation of nonproliferative or proliferative retinopathy in the eye specialist report. Coronary artery disease was defined by self-reported …

Diabetes Care Disparities in Long-standing Type 1 Diabetes in Canada and the U.S.: A Cross-sectional Comparison

OBJECTIVE To assess national differences in diabetes care and quality of life (QOL) between individuals with long-standing type 1 diabetes (≥50 years) in Canada and the U.S. RESEARCH DESIGN AND METHODS Cross-sectional data from identical surveys administered in the Canadian Study of Longevity in Diabetes and the Joslin Medalist Study, collected in 2013–2016 and 2005–2011, respectively, were compared. Laboratory values and ophthalmic examination were completed by clinical care physicians for Canadians and the Joslin Clinic for Americans. Univariate comparisons and multivariable regression for HbA1c, QOL, insulin pump use, and coronary artery disease (CAD) were performed. Nephropathy, CAD, and peripheral arterial disease (PAD) were self-reported; neuropathy was defined by a Michigan Neuropathy Screening Instrument (Questionnaire component) score ≥3, and proliferative retinopathy was documented from ophthalmic examination. QOL was self-reported on an ordinal scale. RESULTS Three hundred sixty-one Canadians and 668 Americans had similar ages (mean 65.78 years [SD 8.67] vs. 66.38 years [7.66], P = 0.27) and durations of diabetes (median 53.00 years [interquartile range 51.00, 58.00] vs. 53.00 years [51.00, 57.00], P = 0.51). Canadians had higher HbA1c (mean 7.53% [SD 1.03] [59 mmol/mol] vs. 7.22% [0.98] [55 mmol/mol], P < 0.0001), lower QOL (36.9% vs. 48.7% with “excellent” QOL, P = 0.0002), and less CAD (29.7% vs. 41.2%, P = 0.0003) and insulin pump use (43.3% vs. 55.6%, P = 0.0002). Other complication rates were similar. Residual differences for Canadians compared with Americans remained after adjustment for age, sex, CAD, PAD, education, and relevant a priori selected variables: 0.28% higher HbA1c (P = 0.0004); and odds ratios of 0.68 (95% CI 0.51, 0.90), 0.46 (0.31, 0.68), and 0.71 (0.52, 0.96) for higher QOL, CAD, and insulin pump use, respectively. CONCLUSIONS Although Canadians and Americans have similar rates of complications other than CAD, further research is required to understand why Canadians have higher HbA1c levels, lower QOL, and less insulin pump use.

Neuropathy and presence of emotional distress and depression in longstanding diabetes: Results from the Canadian study of longevity in type 1 diabetes

AIM To determine the association of neuropathy and other complications with emotional distress and depression among patients with longstanding type 1 diabetes (T1DM). METHODS Canadians with ≥50years of T1DM completed a questionnaire including assessment of distress and depression by the Problem Areas in Diabetes Scale (PAID) and Geriatric Depression Scale (GDS), respectively. Complications were determined using the Michigan Neuropathy Screening Instrument (Questionnaire Component), fundoscopy reports, renal function tests, and self-reported peripheral-(PVD) and cardiovascular (CVD) disease. Associations were analyzed by Poisson regression. RESULTS Among 323 participants, 137 (42.4%) had neuropathy, 113 (36.5%) nephropathy, 207 (69.5%) retinopathy, 95 (29.4%) CVD, and 31 (9.8%) PVD. The neuropathy subgroup had higher prevalence of distress (13 (9.5%) vs. 6 (3.3%), p=0.029) and depression (34 (24.9%) vs. 12 (6.5%), p<0.001). Adjusting for diabetes complications, neuropathy was associated with higher PAID (adjusted RR 1.44 (95% CI 1.14-1.82), p=0.003) and GDS scores (adjusted RR1.57 (1.18-2.11), p=0.002). Independent of potential confounders, neuropathy remained associated with higher PAID (adjusted RR 1.39 (1.10-1.76), p=0.006) and GDS scores (adjusted RR 1.37 (1.03-1.83), p=0.032). Associations with neuropathy were not fully explained by neuropathic pain. CONCLUSION Compared to other complications, neuropathy had the greatest association with distress and depression in longstanding T1DM, independent of pain. Strategies beyond pain management are needed to improve quality of life in diabetic neuropathy.

Adiposity Impacts Intrarenal Hemodynamic Function in Adults With Long-standing Type 1 Diabetes With and Without Diabetic Nephropathy: Results From the Canadian Study of Longevity in Type 1 Diabetes

OBJECTIVE Central adiposity is considered to be an important cardiorenal risk factor in the general population and in type 1 diabetes. We sought to determine the relationship between central adiposity and intrarenal hemodynamic function in adults with long-standing type 1 diabetes with and without diabetic nephropathy (DN). RESEARCH DESIGN AND METHODS Patients with type 1 diabetes (n = 66, duration ≥50 years) and age-/sex-matched control subjects (n = 73) were studied. The cohort was stratified into 44 DN Resistors (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2 and <30 mg/day urine albumin) and 22 patients with DN (eGFR ≤60 mL/min/1.73 m2 or ≥30 mg/day urine albumin). Intrarenal hemodynamic function (glomerular filtration rate for inulin [GFRINULIN], effective renal plasma flow for p-aminohippuric acid [ERPFPAH]) was measured. Afferent arteriolar resistance, efferent arteriolar resistance, renal blood flow, renal vascular resistance [RVR], filtration fraction, and glomerular pressure were derived from the Gomez equations. Fat and lean mass were quantified by DXA. RESULTS Whereas measures of adiposity did not associate with GFRINULIN or ERPFPAH in healthy control subjects, trunk fat mass inversely correlated with GFRINULIN (r = −0.46, P < 0.0001) and ERPFPAH (r = −0.31, P = 0.01) and positively correlated with RVR (r = 0.53, P = 0.0003) in type 1 diabetes. In analyses stratified by DN status, greater central adiposity related to lower GFRINULIN values in DN and DN Resistors, but the relationships between central adiposity and ERPFPAH and RVR were attenuated and/or reversed in patients with DN compared with DN Resistors. CONCLUSIONS The adiposity-intrarenal hemodynamic function relationship may be modified by the presence of type 1 diabetes and DN, requiring further study of the mechanisms by which adiposity influences renal hemodynamic function.

Evolving Trends in the Epidemiology, Risk Factors, and Prevention of Type 2 Diabetes: A Review

Currently, the global prevalence of diabetes is 8.8%. This figure is expected to increase worldwide, with the largest changes projected to occur in low- and middle-income countries. The aging of the worlds population and substantial increases in obesity have contributed to the rise in diabetes. Global shifts in lifestyles have led to the adoption of unhealthy behaviours such as physical inactivity and poorer-quality diets. Correspondingly, diabetes is a rapidly-increasing problem in higher- as well as lower-income countries. In Canada, the prevalence of diabetes increased approximately 70% in the past decade. Although diabetes-related mortality rates have decreased in Canada, the number of people affected by diabetes has continued to grow because of a surge in the number of new diabetes cases. Non-European ethnic groups and individuals of lower socioeconomic status have been disproportionately affected by diabetes and its risk factors. Clinical trials have proven efficacy in reducing the onset of diabetes in high-risk populations through diet and physical activity interventions. However, these findings have not been broadly implemented into the Canadian health care context. In this article we review the evolving epidemiology of type 2 diabetes, with regard to trends in occurrence rates and prevalence; the role of risk factors including those related to ethnicity, obesity, diet, physical activity, socioeconomic status, prediabetes, and pregnancy; and the identification of critical windows for lifestyle intervention. Identifying high-risk populations and addressing the upstream determinants and risk factors of diabetes might prove to be effective diabetes prevention strategies to curb the current diabetes epidemic.

Lower corneal nerve fibre length identifies diabetic neuropathy in older adults with diabetes: results from the Canadian Study of Longevity in Type 1 Diabetes

Abbreviations CNBD Corneal nerve branch density CNFD Corneal nerve fibre density CNFL Corneal nerve fibre length IVCCM In vivo corneal confocal microscopy ROC Receiver operating characteristic ROC-AUC Area under the ROC curve To the Editor: There exists an urgent need to better characterise and identify the presence of early-stage diabetic neuropathy when therapy is most likely to be effective. The lack of an objective endpoint for early neuropathy has seriously hindered the evaluation of disease-modifying therapies in clinical research and the prediction of neuropathy progression in clinical care [1, 2]. There is considerable evidence that injury to small, thinly myelinated and unmyelinated nerve fibres precedes injury to large myelinated fibres in individuals with diabetic neuropathy [3]. Morphological examination of the small nerve fibres of the cornea by in vivo corneal confocal microscopy (IVCCM) has emerged as an objective and non-invasive imaging technique for identifying diabetic neuropathy. Specifically, lower corneal nerve fibre length (CNFL) has been confirmed as a valid biomarker for neuropathy identification in younger adults with type 1 diabetes [4, 5] and may represent a surrogate endpoint for trials of disease-modifying therapies for neuropathy. However, CNFL’s diagnostic performance may be impaired with advanced age and diabetes duration owing to ageand extensive disease-related changes in corneal nerve morphology [6]. We aimed to determine whether CNFL retains its diagnostic validity in a unique cohort of older adults who have lived with type 1 diabetes for over 50 years. As part of the second phase of the Canadian Study of Longevity in Type 1 Diabetes [7], 67/75 (89%) participants with type 1 diabetes and 69/75 (92%) participants forming a non-diabetic control group from age/sex-matched subgroups underwent electrophysiology-based procedures to define neuropathy (reference standard) and evaluation of corneal morphology by IVCCM (index test) in a cross-sectional analysis of the baseline evaluation. All participants provided written informed consent and the study and its procedures were approved by the institutional ethics board at the University * Bruce A. Perkins bruce.perkins@sinaihealthsystem.ca

Whipple's endocarditis: An enigmatic cause of culture-negative bacterial endocarditis

Case Presentation An 80-year-old man living in Eastern Ontario was assessed at a local emergency department for a syncopal episode that occurred after awakening from sleep and ambulating to the bathroom. He had experienced malaise, anorexia and episodes of presyncope for four months. His medical history was significant for rheumatic fever in childhood without known cardiac sequelae, diverticulitis, hypertension and gastroesophageal reflux disease. A review of systems was notable for the absence of fever, weight loss, arthralgias, gastrointestinal (GI) and neurological complaints. The patient’s medications were hydrochlorothiazide and rabeprazole. A transthoracic echocardiogram revealed a mobile mass on the aortic valve. There was no history of antimicrobial exposure within the preceding 12 months, and the patient denied illicit drug use, travel or exposure to animals. A physical examination revealed a systolic ejection murmur at the left upper sternal border. No stigmata of infective endocarditis (IE) were present. The remainder of the general examination was normal. A transesophageal echocardiogram revealed a 1.5 cm × 0.5 cm mobile mass on the right coronary cusp of the aortic valve and moderatesevere aortic insufficiency. Laboratory investigations were significant for normocytic anemia, with a hemoglobin level of 109 g/L and a serum albumin level of 39 g/L.