Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Renal Hemodynamic Function and RAAS Activation Over the Natural History of Type 1 Diabetes.

RATIONALE & OBJECTIVE: The renin-angiotensin-aldosterone system (RAAS) is associated with renal and cardiovascular disease in diabetes. Unfortunately, early RAAS blockade in patients with type 1 diabetes mellitus (T1DM) does not prevent the development of complications. We sought to examine the role of hyperfiltration and RAAS activation across a wide range of T1DM duration to better understand renal hemodynamic status in patients with T1DM. STUDY DESIGN: Post hoc analysis of blood samples. SETTING & PARTICIPANTS: 148 Canadian patients with T1DM: 28 adolescents (aged 16.2±2.0 years), 54 young adults (25.4±5.6 years), and 66 older adults (65.7±7.5 years) studied in a clinical investigation unit. EXPOSURE: Angiotensin II infusion (1ng/kg/min; a measure of RAAS activation) during a euglycemic clamp. OUTCOMES: Glomerular filtration rate measured using inulin clearance, effective renal plasma flow measured using para-aminohippurate, afferent (RA) and efferent (RE) arteriolar resistances, and glomerular hydrostatic pressure estimated using the Gomez equations. RESULTS: In a stepwise fashion, glomerular filtration rate, effective renal plasma flow, and glomerular hydrostatic pressure were higher, while renal vascular resistance and RA were lower in adolescents versus young adults versus older adults. RE was similar in adolescents versus young adults but was higher in older adults. Angiotensin II resulted in blunted renal hemodynamic responses in older adults (renal vascular resistance increase of 3.3% ± 1.6% vs 4.9% ± 1.9% in adolescents; P<0.001), suggesting a state of enhanced RAAS activation. LIMITATIONS: Homogeneous study participants limit the generalizability of findings to other populations. Studying older adult participants with T1DM may be associated with a survivorship bias. CONCLUSIONS: A state of relatively low RAAS activity and predominant afferent dilation rather than efferent constriction characterize early adolescents and young adults with T1DM. This state of endogenous RAAS inactivity in early T1DM may explain why pharmacologic blockade of this neurohormonal system is often ineffective in reducing kidney disease progression in this setting. Older adults with long-standing T1DM who have predominant afferent constriction and RAAS activation may experience renoprotection from therapies that target the afferent arteriole. Further work is required to understand the potential role of non-RAAS pharmacologic agents that target RA in patients with early and long-standing T1DM.

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.

Growth patterns for untreated individuals with MPS I: Report from the international MPS I registry.

Mucopolysaccharidosis Type I (MPS I), caused by deficiency of α-L-iduronidase results in progressive, multisystemic disease with a broad phenotypic spectrum including patients with severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) disease. Disordered growth is common with either phenotype. The study objectives were to construct sex- and age-specific estimated length/height and head circumference growth curves for untreated individuals with severe and attenuated disease and compare them with clinical reference standards. Untreated individuals in the MPS I Registry with at least one observation for length/height and/or head circumference and assigned phenotype as of May 2017 were included. Median growth for 463 untreated individuals with severe disease deviated from reference growth curves by ~6 months of age and fell below the third percentile by 4 years of age. Median head circumference was above reference curves from 3 to 4 months through 3 years of age. Among 207 individuals with untreated attenuated disease, median height fell below the third percentile by 9 years of age with divergence from reference curves by 2 years of age. MPS I-specific growth curves will be useful in evaluation of long-term outcomes of therapeutics interventions and will provide a foundation for understanding the pathogenesis of skeletal disease in MPS I.

Association between uric acid, renal haemodynamics and arterial stiffness over the natural history of type 1 diabetes.

AIMS: To examine the relationship between normal plasma uric acid (PUA) levels, renal haemodynamic function, arterial stiffness and plasma renin and aldosterone over a wide range of type 1 diabetes (T1D) durations in adolescents, young adults and older adults. MATERIALS AND METHODS: PUA, glomerular filtration rate (GFR), effective renal plasma flow (ERPF), vascular stiffness parameters (aortic augmentation index [AIx], carotid AIx, carotid femoral pulse wave velocity [cfPWV]), and plasma renin and aldosterone were measured during a euglycaemic clamp in people with T1D: 27 adolescents (mean ± SD age 16.8 ± 1.9 years), 52 young adults (mean ± SD age 25.6 ± 5.5 years) and 66 older adults (mean ± SD age 65.7 ± 7.5 years). RESULTS: PUA was highest in patients with the longest T1D duration: 197 ± 44 µmol/L in adolescents versus 264 ± 82 µmol/L in older adults (P < 0.001). Higher PUA correlated with lower GFR only in older adults, even after correcting for age, glycated haemoglobin and sex (ß = -2.12 ± 0.56; P = 0.0003), but not in adolescents or young adults. Higher PUA correlated with lower carotid AIx (ß = -1.90, P = 0.02) in adolescents. In contrast, PUA correlated with higher cfPWV (P = 0.02) and higher plasma renin (P = 0.01) in older adults with T1D. CONCLUSIONS: The relationship between higher PUA with lower GFR, increased arterial stiffness and renin angiotensin aldosterone system (RAAS) activation was observed only in older adults with longstanding T1D. T1D duration may modify the association between PUA, renal haemodynamic function and RAAS activation, leading to renal vasoconstriction and ischaemia. Further work must determine whether pharmacological PUA-lowering prevents or reverses injurious haemodynamic and neurohormonal sequelae of longstanding T1D, thereby improving clinical outcomes.

The relationships between markers of tubular injury and intrarenal haemodynamic function in adults with and without type 1 diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Our aim was to define the relationships between plasma biomarkers of kidney injury and intrarenal haemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], renal vascular resistance [RVR]) in adults with type 1 diabetes (T1D). METHODS: The study sample comprised patients with longstanding T1D (duration ≥50 years), among whom 44 were diabetic kidney disease (DKD) resistors (eGFR >60 mL/min/1.73 m2 and <30 mg/d urine albumin excretion) and 22 had DKD, in addition to 73 control participants. GFRINULIN and ERPFPAH were measured, RVR was calculated, and afferent (RA )/efferent (RE ) areteriolar resistances were derived from Gomez equations. Plasma neutrophil gelatinase-associated lipocalin (NGAL), ß2 microglobulin (B2M), osteopontin (OPN) and uromodulin (UMOD) were measured using immunoassay kits from Meso Scale Discovery. RESULTS: Plasma NGAL, B2M and OPN were higher and UMOD was lower in DKD patients vs DKD resistors and non-diabetic controls. In participants with T1D, plasma NGAL inversely correlated with GFR (r = -0.33; P = 0.006) and ERPF (r = -0.34; P = 0.006), and correlated positively with RA (r = 0.26; P = 0.03) and RVR (r = 0.31; P = 0.01). In participants without T1D, NGAL and B2M inversely correlated with GFR (NGAL r = -0.18; P = 0.13 and B2M r = -0.49; P < 0.0001) and with ERPF (NGAL r = -0.19; P = 0.1 and B2M r = -0.42; P = 0.0003), and correlated positively with RA (NGAL r = 0.19; P = 0.10 and B2M r = 0.3; P = 0.01) and with RVR (NGAL r = 0.20; P = 0.09 and B2M r = 0.34; P = 0.003). Differences were significant after adjusting for age, sex, HbA1c, SBP and LDL. There were statistical interactions between T1D status, B2M and intrarenal haemodynamic function (P < 0.05). CONCLUSIONS: Elevated NGAL relates to intrarenal haemodynamic dysfunction in T1D, whereas elevated NGAL and B2M relate to intrarenal haemodynamic dysfunction in adults without T1D. These data may define a diabetes-specific interplay between tubular injury and intrarenal haemodynamic dysfunction.

Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function.

OBJECTIVE: The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis. APPROACH AND RESULTS: Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE-/-) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE-/- mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE-/- mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-α, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (P<0.05) comparing insulin-implanted versus sham HFD ApoE-/- mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE-/- mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor. CONCLUSIONS: Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE-/- mice.

Risk factors for diabetic kidney disease in adults with longstanding type 1 diabetes: results from the Canadian Study of Longevity in Diabetes.

Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.

Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS). METHODS: We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n = 1303), fasting (n = 2019) and random (n = 1497) C-peptide levels. RESULTS: In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p = 4.13 × 10-8), meeting the genome-wide significance threshold (p < 5 × 10-8). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p = 8.43 × 10-8). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (ß [SE] = - 0.39 [0.07], p = 9.72 × 10-8). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n = 258) with annual repeated measures for up to 6 years (p = 0.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p = 3.49 × 10-8). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. CONCLUSIONS/INTERPRETATION: We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.

High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M). METHODS: CD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro. RESULTS: Subjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = -0.424, p = 0.02), large (r = -0.413, p = 0.02) and intermediate (r = -0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05). CONCLUSIONS: Low OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation.

Cardiovascular disease guideline adherence and self-reported statin use in longstanding type 1 diabetes: results from the Canadian study of longevity in diabetes cohort.

BACKGROUND: Older patients with longstanding type 1 diabetes have high cardiovascular disease (CVD) risk such that statin therapy is recommended independent of prior CVD events. We aimed to determine self-reported CVD prevention guideline adherence in patients with longstanding diabetes. RESEARCH DESIGN AND METHODS: 309 Canadians with over 50 years of type 1 diabetes completed a medical questionnaire for presence of lifestyle and pharmacological interventions, stratified into primary or secondary CVD prevention subgroups based on absence or presence of self-reported CVD events, respectively. Associations with statin use were analyzed using multivariable logistic regression. RESULTS: The 309 participants had mean ± SD age 65.7 ± 8.5 years, median diabetes duration 54.0 [IQR 51.0, 59.0] years, and HbA1c of 7.5 ± 1.1 % (58 mmol/mol). 159 (52.7 %) participants reported diet adherence, 296 (95.8 %) smoking avoidance, 217 (70.5 %) physical activity, 218 (71.5 %) renin-angiotensin-system inhibitor use, and 220 (72.1 %) statin use. Physical activity was reported as less common in the secondary prevention subgroup, and current statin use was significantly lower in the primary prevention subgroup (65.5 % vs. 84.8 %, p = 0.0004). In multivariable logistic regression, the odds of statin use was 0.38 [95 % CI 0.15-0.95] in members of the primary compared to the secondary prevention subgroup, adjusting for age, sex, hypertension history, body mass, HbA1c, cholesterol, microvascular complications, acetylsalicylic acid use, and renin-angiotensin system inhibitor use. CONCLUSION: Despite good self-reported adherence to general CVD prevention guidelines, against the principles of these guidelines we found that statin use was substantially lower in those without CVD history. Interventions are needed to improve statin use in older type 1 diabetes patients without a history of CVD.

Bone Microarchitecture in Type 1 Diabetes: It Is Complicated.

Patients with type 1 diabetes (T1DM) experience a disproportionate number of fractures for their bone mineral density (BMD). Differences in bone microarchitecture from those without the disease are thought to be responsible. However, the literature is inconclusive. New studies of the microarchitecture using three-dimensional imaging have the advantage of providing in vivo estimates of "bone quality," rather than examining areal BMD alone. There are drawbacks in that most studies have been done on those with less than a 30-year duration of T1DM, and the techniques used to measure vary as do the sites assessed. In addition to the rise in these imaging techniques, very recent literature presents evidence of an intimate relationship between skeletal health and vascular complications in T1DM. The following review provides an overview of the available studies of the bone microarchitecture in T1DM with a discussion of the burgeoning field of complications and skeletal health.

Bridging the gap--planning Lifestyle Medicine fellowship curricula: A cross sectional study.

BACKGROUND: The emerging field, Lifestyle Medicine (LM), is the evidence-based practice of assisting individuals and families to adopt and sustain behaviors that can improve health. While competencies for LM education have been defined, and undergraduate curricula have been published, there are no published reports that address graduate level fellowship in LM. This paper describes the process of planning a LM fellowship curriculum at a major, academic teaching institution. METHODS: In September 2012 Harvard Medical School Department of Physical Medicine and Rehabilitation approved a "Research Fellowship in Lifestyle Medicine". A Likert scale questionnaire was created and disseminated to forty LM stakeholders worldwide, which measured perceived relative importance of six domains and eight educational experiences to include in a one-year LM fellowship. Statistical procedures included analysis of variance and the Wilcoxon signed-rank test. RESULTS: Thirty-five stakeholders (87.5%) completed the survey. All domains except smoking cessation were graded at 4 or 5 by at least 85% of the respondents. After excluding smoking cessation, nutrition, physical activity, behavioral change techniques, stress resiliency, and personal health behaviors were rated as equally important components of a LM fellowship curriculum (average M = 4.69, SD = 0.15, p = 0.12). All educational experiences, with the exception of completing certification programs, research experience and fund raising, were graded at 4 or 5 by at least 82% of the responders. The remaining educational experiences, i.e. clinical practice, teaching physicians and medical students, teaching other health care providers, developing lifestyle interventions and developing health promotion programs were ranked as equally important in a LM fellowship program (average M = 4.23, SD = 0.11, p = 0.07). CONCLUSIONS: Lifestyle fellowship curricula components were defined based on LM stakeholders' input. These domains and educational experiences represent the range of competencies previously noted as important in the practice of LM. As the foundation of an inaugural physician fellowship, they inform the educational objectives and future evaluation of this fellowship.

The association between physical activity time and neuropathy in longstanding type 1 diabetes: A cross-sectional analysis of the Canadian study of longevity in type 1 diabetes.

AIM: Physical activity (PA) is recommended to improve glycemic control in T1D; however, the effect of PA on distal symmetric polyneuropathy (DSPN) and cardiac autonomic function in longstanding T1D is unknown. METHODS: Data from 75 participants were collected as part of the Canadian Study of Longevity in T1D. Participants completed a physical exam, medical history, extensive complications phenotyping and reported their daily PA from the preceding 12-months. Pearson and Spearman correlations were used to assess PA time and complications variables. Linear regression was used to test associations between PA time, neurological and electrophysiological measures. Univariable regression was used to indicate the change in the given independent variables associated with a 30-min increase in PA per week. RESULTS: Participants were 66 ± 8 years old with diabetes duration of 54 [52,58] years, HbA1c was 7.3 ± 0.8, 65(89%) had DSPN. Weekly PA time was 156 ± 132 min, and 35(47%) reported ≧150 min/week. Participants with DSPN reported lower PA time compared to individuals without DSPN (141 ± 124 min/week vs. 258 ± 129 min/week; p = 0.015). PA time was associated with better cooling detection threshold (r = 0.24; p = 0.043), peroneal and sural amplitude (r = 0.36; p = 0.0017, rs = 0.26; p = 0.024) and conduction velocity (rs = 0.28; p = 0.015, r = 0.23; p = 0.050). Linear regression adjusting for age and HbA1c, showed that for each 30-min of PA there was a 0.09mv higher peroneal amplitude (p = 0.032) and 0.048 ms lower peroneal F-wave latency (p = 0.022). CONCLUSION: In longstanding T1D, PA time is associated with superior large nerve fibre function in the lower limbs and some better measures of small nerve fibre function.

Renal hemodynamic dysfunction and neuropathy in longstanding type 1 diabetes: Results from the Canadian study of longevity in type 1 diabetes.

AIMS: To determine the relationship between renal hemodynamic function and neuropathy in adults with ≥50-years of type 1 diabetes (T1D) compared to nondiabetic controls. METHODS: Glomerular filtration rate (GFR, inulin), effective renal plasma flow (ERPF, p-aminohippurate), modified Toronto Clinical Neuropathy Score (mTCNS), corneal confocal microscopy, nerve conduction, and heart rate variability (autonomic function) were measured; afferent (RA) and efferent (RE) arteriolar resistances were estimated using the Gomez equations in 74 participants with T1D and in 75 controls. Diabetic kidney disease (DKD) non-resistors were defined by eGFRMDRD < 60 ml/min/1.73 m2 or 24-h urine albumin excretion >30 mg/day. Linear regression was applied to examine the relationships between renal function (dependent variable) and neuropathy measures (independent variable), adjusted for age, sex, HbA1c, systolic blood pressure, low density lipoprotein cholesterol, and 24-h urine albumin to creatinine ratio. RESULTS: Higher mTCNS associated with lower renal blood flow (ß ± SE:-9.29 ± 4.20, p = 0.03) and greater RE (ß ± SE:32.97 ± 15.43, p = 0.04) in participants with T1D, but not in controls. DKD non-resistors had a higher mTCNS and worse measures of corneal nerve morphology compared to those without DKD. Renal hemodynamic parameters did not associate with autonomic nerve function. CONCLUSIONS: Although neurological dysfunction in the presence of diabetes may contribute to impaired renal blood flow resulting in ischemic injury in patients with T1D, early autonomic dysfunction does not appear to be associated with kidney function changes.

Trends in characteristics and outcomes among US adults hospitalised with COVID-19 throughout 2020: an observational cohort study.

OBJECTIVES: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020. DESIGN: Observational cohort study. SETTING: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA. PARTICIPANTS: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident acute clinical outcomes, including in-hospital all-cause mortality. RESULTS: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort. CONCLUSION: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.

Improvement in time to treatment, but not time to diagnosis, in patients with mucopolysaccharidosis type I.

OBJECTIVE: Early diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years. STUDY DESIGN: Data from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included. RESULTS: Data were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014-2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period. CONCLUSIONS: Times to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.

Real-world treatment patterns and clinical outcomes for inpatients with COVID-19 in the US from September 2020 to February 2021.

The objective of this retrospective cohort study was to describe pre-treatment characteristics, treatment patterns, health resource use, and clinical outcomes among adults hospitalized with COVID-19 in the United States (US) who initiated common treatments for COVID-19. The Optum® COVID-19 electronic health records database was used to identify patients >18 years, diagnosed with COVID-19, who were admitted to an inpatient setting and received treatments of interest for COVID-19 between September 2020 and January 2021. Patients were stratified into cohorts based on index treatment use. Patient demographics, medical history, care setting, medical procedures, subsequent treatment use, patient disposition, clinical improvement, and outcomes were summarized descriptively. Among a total of 26,192 patients identified, the most prevalent treatments initiated were dexamethasone (35.4%) and dexamethasone + remdesivir (14.9%), and dexamethasone was the most common subsequent treatment. At day 14 post-index, <10% of patients received any treatments of interest. Mean (standard deviation [SD]) patient age was 65.6 (15.6) years, and the most prevalent comorbidities included hypertension (44.8%), obesity (35.4%), and diabetes (25.7%). At the end of follow-up, patients had a mean (SD) 8.1 (6.6) inpatient days and 1.4 (4.1) days with ICU care. Oxygen supplementation, non-invasive, or invasive ventilation was required by 4.5%, 3.0%, and 3.1% of patients, respectively. At the end of follow-up, 84.2% of patients had evidence of clinical improvement, 3.1% remained hospitalized, 83.8% were discharged, 4% died in hospital, and 9.1% died after discharge. Although the majority of patients were discharged alive, no treatments appeared to alleviate the inpatient morbidity and mortality associated with COVID-19. This highlights an unmet need for effective treatment options for patients hospitalized with COVID-19.

Characteristics and outcomes of hospitalised adults with COVID-19 in a Global Health Research Network: a cohort study.

OBJECTIVE: To examine age, gender, and temporal differences in baseline characteristics and clinical outcomes of adult patients hospitalised with COVID-19. DESIGN: A cohort study using deidentified electronic medical records from a Global Research Network. SETTING/PARTICIPANTS: 67 456 adult patients hospitalised with COVID-19 from the USA; 7306 from Europe, Latin America and Asia-Pacific between February 2020 and January 2021. RESULTS: In the US cohort, compared with patients 18-34 years old, patients ≥65 had a greater risk of intensive care unit (ICU) admission (adjusted HR (aHR) 1.73, 95% CI 1.58 to 1.90), acute respiratory distress syndrome(ARDS)/respiratory failure (aHR 1.86, 95% CI 1.76 to 1.96), invasive mechanical ventilation (IMV, aHR 1.93, 95% CI, 1.73 to 2.15), and all-cause mortality (aHR 5.6, 95% CI 4.36 to 7.18). Men appeared to be at a greater risk for ICU admission (aHR 1.34, 95% CI 1.29 to 1.39), ARDS/respiratory failure (aHR 1.24, 95% CI1.21 to 1.27), IMV (aHR 1.38, 95% CI 1.32 to 1.45), and all-cause mortality (aHR 1.16, 95% CI 1.08 to 1.24) compared with women. Moreover, we observed a greater risk of adverse outcomes during the early pandemic (ie, February-April 2020) compared with later periods. In the ex-US cohort, the age and gender trends were similar; for the temporal trend, the highest proportion of patients with all-cause mortality were also in February-April 2020; however, the highest percentages of patients with IMV and ARDS/respiratory failure were in August-October 2020 followed by February-April 2020. CONCLUSIONS: This study provided valuable information on the temporal trends of characteristics and outcomes of hospitalised adult COVID-19 patients in both USA and ex-USA. It also described the population at a potentially greater risk for worse clinical outcomes by identifying the age and gender differences. Together, the information could inform the prevention and treatment strategies of COVID-19. Furthermore, it can be used to raise public awareness of COVID-19's impact on vulnerable populations.