Fasted C-Peptide Distribution and Associated Clinical Factors in Adults With Longstanding Type 1 Diabetes: Analysis of the Canadian Study of Longevity in Type 1 Diabetes.

OBJECTIVE: Although insulin production is reportedly retained in many people with longstanding type 1 diabetes (T1D), the magnitude and relevance of connecting peptide (C-peptide) production are uncertain. In this study, we aimed to define fasted C-peptide distributions and associated clinical factors. METHODS: In a cross-sectional analysis of the Canadian Study of Longevity, fasted serum and urinary C-peptide was measured in 74 patients with longstanding T1D (duration ≥50 years) and 75 age- and sex-matched controls. Extensive phenotyping for complications was performed and patient-reported variables were included. C-peptide distributions were analyzed, and multivariable logistic regression was used to assess the variable association in participants with T1D. RESULTS: The 74 participants with T1D had a mean age of 66±8 years, a disease duration of 54 (interquartile range 52 to 58) years, and a glycated hemoglobin (A1C) of 7.4%±0.8% (56.8±9.15 mmol/mol). The 75 controls had a mean age of 65±8 years and an A1C of 5.7%±0.4% (38.4±4.05 mmol/mol). Participants with T1D had lower fasted serum C-peptide than controls (0.013±0.022 vs 1.595±1.099 nmol/L, p<0.001). Of the participants with T1D, C-peptide was detectable in 30 of 73 (41%) serum samples, 32 of 74 (43%) urine samples, and 48 of 74 (65%) for either serum or urine. The variables independently associated with detectable serum or urinary C-peptide were lower total daily insulin requirement (odds ratio 2.351 [for 1 lower unit/kg], p=0.013) and lower hypoglycemia worry score (odds ratio 1.059 [for 1 point lower on the worry subscore of the Hypoglycemia Fear Survey], p=0.030). CONCLUSIONS: Although detectable C-peptide in longstanding diabetes was common, the magnitude of concentration was extremely low when compared with age- and sex-matched controls. Despite minimal detectability, its presence is validated by lower insulin requirements and strongly associated with lower hypoglycemia worry.

Pars plana vitrectomy versus intravitreal antibiotics for endophthalmitis management following intravitreal anti-VEGF agents: A meta-analysis.

In this meta-analysis, we aim to compare the efficacy and safety of pars plana vitrectomy (PPV) versus tap-and-inject (TAI) of intravitreal antibiotics for the management of endophthalmitis secondary to intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. A systematic literature search was conducted on Ovid MEDLINE, EMBASE, and Cochrane Central (January 2005-October 2022). The primary analysis compared initial PPV versus TAI and the secondary analysis examined the efficacy and safety of TAI alone compared to TAI followed by PPV. The quality of non-randomized observational studies was assessed using the Newcastle-Ottawa Scale. The quality of the evidence was assessed for each outcome. A random effects meta-analysis was performed. Weighted mean differences (WMDs) with 95% confidence intervals were reported. Of the 7474 screened studies, nine studies reporting on 153 eyes were included. The change in mean best corrected visual acuity (BCVA) between endophthalmitis presentation and last follow-up did not significantly differ between the initial TAI versus PPV groups (WMD = 0.05 units; 95% CI -0.12 to 0.22; p = 0.59; heterogeneity p = 0.41). The difference in pre- to post-treatment mean BCVA did not significantly differ between eyes that received TAI alone or TAI followed by PPV (WMD = 0.04 units; 95% CI -0.42 to 0.51; p = 0.85; heterogeneity p = 0.74). While the meta-analysis revealed no significant difference in the change in BCVA between PPV and TAI to treat endophthalmitis secondary to anti-VEGF agents, the quality of evidence was low with potential for confounding and selection bias. Further well-designed studies in this setting are needed.

Diabetic retinopathy screening integrated in a multidisciplinary diabetes care clinic: a pilot project.

OBJECTIVE: To characterize patients referred for diabetic retinopathy (DR) screening in a unique multidisciplinary diabetes care clinic at a tertiary care centre. METHODS: A retrospective study was conducted involving patients who were referred to the Cardiac and Renal Endocrine Clinic at a tertiary care centre (University Health Network) for DR screening between April 2019-March 2020 and November 2020-August 2021. Patients' demographics; micro- and macrovascular disease measurements; visual acuity, intraocular pressure, fundus imaging, and optical coherence tomography results were collected and analyzed. RESULTS: Of the 64 patients who attended the clinic, 21 patients (33%) with type 2 diabetes had on-site DR screening. The remaining 43 patients had DR screening within 6 months of the appointment or were under ophthalmology care with annual screening visits elsewhere. Of the 21 patients who underwent retinopathy screening, 7 patients (33%) had DR: 4 had mild nonproliferative DR, 2 had moderate nonproliferative DR, 1 had proliferative DR, and 1 had macular edema. Patients with DR had a significantly longer diabetes duration than patients without DR (24.5 ± 10.2 years vs 12.5 ± 5.8 years; p = 0.0247). No significant differences were observed in glycemic control, blood pressure, lipid profiles, kidney function, visual acuity, or intraocular pressure. CONCLUSIONS: Our analysis suggests a potential benefit of integrated DR screening in patients with long-standing diabetes as part of a multidisciplinary diabetes care clinic to diagnose and manage DR. Future work is needed to further develop such clinics and investigate their long-term effect on patient outcomes.

Targeting Interleukin 13 for the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a common chronic inflammatory skin condition that has a significant impact on a patient's quality of life and requires ongoing management. Conventional topical and systemic therapies do not target specific components of AD pathogenesis and, therefore, have limited efficacy and may be associated with long-term toxicity. Thus, AD management is challenging, with a significant proportion of patients not achieving clear skin or a reduction in pruritus. There remains a large unmet need for effective therapeutic strategies with favorable safety profiles that can be used long-term in patients with refractory AD. The emergence of targeted biological and small molecule therapies has effectively broadened available treatment options for moderate-to-severe AD. Most recently, interleukin 13 (IL-13) inhibitors were shown to be efficacious and well-tolerated, with tralokinumab already approved for use in this patient population. It is important for dermatologists to be aware of the evidence behind this emerging class of biologic agents to guide treatment choices and improve outcomes in patients with AD. The main objective of this paper is to review the current literature regarding the efficacy and safety of current and emerging anti-IL-13 monoclonal antibodies, including tralokinumab, lebrikizumab, cendakimab, and eblasakimab, for the treatment of moderate-to-severe AD.

Review on photoprotection: a clinician's guide to the ingredients, characteristics, adverse effects, and disease-specific benefits of chemical and physical sunscreen compounds.

Photoprotection is a critical health prevention strategy to reduce the deleterious effects of ultraviolet radiation (UVR) and visible light (VL). Methods of photoprotection are reviewed in this paper, with an emphasis on sunscreen. The most appropriate sunscreen formulation for personal use depends on several factors. Active sunscreen ingredients vary in their protective effect over the UVR and VL spectrum. There are dermatologic diseases that cause photosensitivity or that are aggravated by a particular action spectrum. In these situations, sunscreen suggestions can address the specific concern. Sunscreen does not represent a single entity. Appropriate personalized sunscreen selection is critical to improve compliance and clinical outcomes. Health care providers can facilitate informed product selection with awareness of evolving sunscreen formulations and counseling patients on appropriate use. This review aims to summarize different forms of photoprotection, discuss absorption of sunscreen ingredients, possible adverse effects, and disease-specific preferences for chemical, physical or oral agents that may decrease UVR and VL harmful effects.

Biologic therapies associated with development of palmoplantar pustulosis and palmoplantar pustular psoriasis: a systematic review.

BACKGROUND: Palmoplantar pustulosis (PPP) and palmoplantar pustular psoriasis (PPPP) are chronic inflammatory skin conditions characterized by eruptions of sterile pustules on the palms and/or soles. Biologic use has been associated with PPP and PPPP development in the literature. OBJECTIVES: To identify PPP and PPPP associated with biologics and summarize reported treatments and outcomes. METHODS: We systematically searched in MEDLINE and Embase for articles that reported PPP or PPPP during biologic treatment. After a full-text review, 53 studies were included for analysis. RESULTS: We identified 155 patients with PPP/PPPP onset during biologic treatment, with a mean age of 44.1 years and a female preponderance (71.6%). The most frequently reported biologics were adalimumab (43.9%) and infliximab (33.3%). IL-17 inhibitors, secukinumab (7.6%) and brodalumab (1.5%), were reported only in association with PPPP. Overall, 58.8% of patients had complete remission (CR) in 3.6 months and 23.5% had partial remission (PR) in 3.7 months. The most common treatments that led to CR were topical corticosteroids (n = 16) and biologic switching (n = 8). CONCLUSIONS: Clinicians should anticipate PPP or PPPP as potential drug reactions to biologics such as adalimumab and infliximab. Large-scale studies are required to confirm our findings and further explore the pathogenesis for biologic-associated PPP and PPPP.

Efficacy and Safety of Upadacitinib for Management of Moderate-to-Severe Atopic Dermatitis: An Evidence-Based Review.

Atopic dermatitis (AD) is a common skin condition characterized by inflammation that presents with erythematous and pruritic skin. Its chronic relapse-remitting nature has a significant impact on the quality of life, and often requires ongoing management. Given the limited treatments available for AD, there remains a large need for effective and safe alternative therapies for long-term use. Janus kinase (JAK) inhibitors are a new class of agents that target the JAK-STAT pathway, which plays an important role in the production of proinflammatory cytokines involved in AD pathogenesis. Phase II and III clinical trials revealed that JAK inhibitors, such as upadacitinib, are effective and well-tolerated agents for the treatment of moderate-to-severe AD. As a result, upadacitinib was approved for use in patients with moderate-to-severe AD by the European Medicines Agency (2021), Health Canada (2021) and the FDA (2022) in the last year. It is important for dermatologists to be aware of the clinical evidence to continue incorporating the use of upadacitinib into the treatment algorithm for AD, which will ultimately lead to improved patient outcomes. Therefore, this review is an up-to-date summary of the clinical data available on the efficacy and safety of upadacitinib treatment for AD.

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.

Renal and Vascular Effects of Combined SGLT2 and Angiotensin-Converting Enzyme Inhibition.

BACKGROUND: The cardiorenal effects of sodium-glucose cotransporter 2 inhibition (empagliflozin 25 mg QD) combined with angiotensin-converting enzyme inhibition (ramipril 10 mg QD) were assessed in this mechanistic study in patients with type 1 diabetes with potential renal hyperfiltration. METHODS: Thirty patients (out of 31 randomized) completed this double-blind, placebo-controlled, crossover trial. Recruitment was stopped early because of an unexpectedly low proportion of patients with hyperfiltration. Measurements were obtained after each of the 6 treatment phases over 19 weeks: (1) baseline without treatment, (2) 4-week run-in with ramipril treatment alone, (3) 4-week combined empagliflozin-ramipril treatment, (4) a 4-week washout, (5) 4-week combined placebo-ramipril treatment, and (6) 1-week follow-up. The primary end point was glomerular filtration rate (GFR) after combination treatment with empagliflozin-ramipril compared with placebo-ramipril. GFR was corrected for ramipril treatment alone before randomization. At the end of study phase, the following outcomes were measured under clamped euglycemia (4 to 6 mmol/L): inulin (GFR) and para-aminohippurate (effective renal plasma flow) clearances, tubular sodium handling, ambulatory blood pressure, arterial stiffness, heart rate variability, noninvasive cardiac output monitoring, plasma and urine biochemistry, markers of the renin-angiotensin-aldosterone system, and oxidative stress. RESULTS: Combination treatment with empagliflozin-ramipril resulted in an 8 mL/min/1.73 m2 lower GFR compared with placebo-ramipril treatment (P=0.0061) without significant changes to effective renal plasma flow. GFR decrease was accompanied by a 21.3 mL/min lower absolute proximal fluid reabsorption rate (P=0.0092), a 3.1 mmol/min lower absolute proximal sodium reabsorption rate (P=0.0056), and a 194 ng/mmol creatinine lower urinary 8-isoprostane level (P=0.0084) relative to placebo-ramipril combination treatment. Sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor combination treatment resulted in additive blood pressure-lowering effects (clinic systolic blood pressure lower by 4 mm Hg [P=0.0112]; diastolic blood pressure lower by 3 mm Hg [P=0.0032]) in conjunction with a 94.5 dynes × sex/cm5 lower total peripheral resistance (P=0.0368). There were no significant changes observed to ambulatory blood pressure, arterial stiffness, heart rate variability, or cardiac output with the addition of empagliflozin. CONCLUSIONS: Adding sodium-glucose cotransporter 2 inhibitor treatment to angiotensin-converting enzyme inhibitor resulted in an expected GFR dip, suppression of oxidative stress markers, additive declines in blood pressure and total peripheral resistance. These changes are consistent with a protective physiologic profile characterized by the lowering of intraglomerular pressure and related cardiorenal risk when adding a sodium-glucose cotransporter 2 inhibitor to conservative therapy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02632747.

Dermatology: how to manage psoriasis and recognize differences in pathophysiology and presentation in patients with skin of colour.

Psoriasis is a chronic inflammatory skin condition that affects diverse ethnic groups with a wide spectrum of skin colours. There are significant differences in how psoriasis presents and impacts the quality of life in non-White individuals. Genetic variations as well as cultural and socioeconomic factors all play a role in such differences and have important implications for the management of psoriasis in skin of colour. Despite these differences, the current psoriasis management is similar across different ethnic backgrounds and is mainly guided by factors such as disease severity, medical comorbidities and patient preferences. This is largely due to the lack of sufficient evidence for psoriasis treatment tailored for patients with skin of colour as most clinical trials are composed of mainly White individuals. Therefore, the focus of this article is to review the current evidence on how epidemiology, clinical presentation and genetic differences in patients with skin of colour with psoriasis may impact treatment strategies. Additionally, pharmacological therapies available to date in these diverse patient cohorts are summarized in this article. The limited data published on this topic reveal a significant need for more investigations with the ultimate goal of incorporating recommendations for patients with skin of colour into the current guidelines for psoriasis treatment. Moreover, awareness of differences in psoriasis presentation amongst individuals with skin of colour may support patients to seek medical care sooner, which could result in earlier diagnosis and lead to improved patient outcomes.

Onset of Pyoderma Gangrenosum in Patients on Biologic Therapies: A Systematic Review.

OBJECTIVE: To summarize clinical outcomes of paradoxical pyoderma gangrenosum (PG) onset in patients on biologic therapy. METHODS: The authors conducted MEDLINE and EMBASE searches using PRISMA guidelines to include 57 patients (23 reports). RESULTS: Of the included patients, 71.9% (n = 41/57) noted PG onset after initiating rituximab, 21.1% (n = 12/57) noted tumor necrosis factor α (TNF-α) inhibitors, 5.3% (n = 3/57) reported interleukin 17A inhibitors, and 1.8% (n = 1/57) reported cytotoxic T-lymphocyte-associated protein 4 antibodies. The majority of patients (94.3%) discontinued biologic use. The most common medications used to resolve rituximab-associated PG were intravenous immunoglobulins, oral corticosteroids, and antibiotics, with an average resolution time of 3.3 months. Complete resolution of PG in TNF-α-associated cases occurred within an average of 2.2 months after switching to another TNF-α inhibitor (n = 1), an interleukin 12/23 inhibitor (n = 2), or treatment with systemic corticosteroids and cyclosporine (n = 3), systemic corticosteroids alone (n = 1), or cyclosporine alone (n = 1). CONCLUSIONS: Further investigations are warranted to determine whether PG onset is associated with underlying comorbidities, the use of biologic agents, or a synergistic effect. Nevertheless, PG may develop in patients on rituximab or TNF-α inhibitors, suggesting the need to monitor and treat such adverse effects.