Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

Multimodal testing reveals subclinical neurovascular dysfunction in prediabetes, challenging the diagnostic threshold of diabetes.

AIM: To explore if novel non-invasive diagnostic technologies identify early small nerve fibre and retinal neurovascular pathology in prediabetes. METHODS: Participants with normoglycaemia, prediabetes or type 2 diabetes underwent an exploratory cross-sectional analysis with optical coherence tomography angiography (OCT-A), handheld electroretinography (ERG), corneal confocal microscopy (CCM) and evaluation of electrochemical skin conductance (ESC). RESULTS: Seventy-five participants with normoglycaemia (n = 20), prediabetes (n = 29) and type 2 diabetes (n = 26) were studied. Compared with normoglycaemia, mean peak ERG amplitudes of retinal responses at low (16-Td·s: 4.05 µV, 95% confidence interval [95% CI] 0.96-7.13) and high (32-Td·s: 5·20 µV, 95% CI 1.54-8.86) retinal illuminance were lower in prediabetes, as were OCT-A parafoveal vessel densities in superficial (0.051 pixels/mm2 , 95% CI 0.005-0.095) and deep (0.048 pixels/mm2 , 95% CI 0.003-0.093) retinal layers. There were no differences in CCM or ESC measurements between these two groups. Correlations between HbA1c and peak ERG amplitude at 32-Td·s (r = -0.256, p = 0.028), implicit time at 32-Td·s (r = 0.422, p < 0.001) and 16-Td·s (r = 0.327, p = 0.005), OCT parafoveal vessel density in the superficial (r = -0.238, p = 0.049) and deep (r = -0.3, p = 0.017) retinal layers, corneal nerve fibre length (CNFL) (r = -0.293, p = 0.017), and ESC-hands (r = -0.244, p = 0.035) were observed. HOMA-IR was a predictor of CNFD (ß = -0.94, 95% CI -1.66 to -0.21, p = 0.012) and CNBD (ß = -5.02, 95% CI -10.01 to -0.05, p = 0.048). CONCLUSIONS: The glucose threshold for the diagnosis of diabetes is based on emergent retinopathy on fundus examination. We show that both abnormal retinal neurovascular structure (OCT-A) and function (ERG) may precede retinopathy in prediabetes, which require confirmation in larger, adequately powered studies.

What is the impact of microvascular complications of diabetes on severe COVID-19?

Evidence suggests severe coronavirus disease-19 (COVID-19) infection is characterised by pulmonary and systemic microvasculature dysfunction, specifically, acute endothelial injury, hypercoagulation and increased capillary permeability. Diabetes, which is also characterised by vascular injury in itself, confers an increased risk of adverse COVID-19 outcomes. It has been suggested that pre-existing endothelial dysfunction and microvascular disease in diabetes will exacerbate the vascular insults associated with COVID-19 and thus lead to increased severity of COVID-19 infection. In this article, we evaluate the current evidence exploring the impact of microvascular complications, in the form of diabetic retinopathy and nephropathy, in individuals with COVID-19 and diabetes. Future insights gained from exploring the microvascular injury patterns and clinical outcomes may come to influence care delivery algorithms for either of these conditions.

Resource use within a multidisciplinary foot team clinic.

OBJECTIVE: The establishment of multidisciplinary foot team clinics reduces the risk of amputation, but little is known about its resource requirement. This study evaluates the service's resource use for first visit attendees to an established multidisciplinary foot team clinic. METHOD: A retrospective evaluation was performed for new referrals to the clinic over six months, including demographics, resource use and clinical outcome. Data were extracted electronically with retrospective review of electronic clinical notes. RESULTS: A total of 240 first visit attendees were analysed. Mean age was 64±15years, 63% were male, 72% had type 2 diabetes, 16% had type 1 diabetes, 15% had a previous amputation, and 40% had a previous ulceration. Common presentations were ulcers (62%), osteomyelitis (11%), Charcot foot (19%), foot ischaemia (17%), post-surgical wounds (13%), and osteomyelitis (11%). At first attendance, 79% of patients required specialist services including diabetologist (45%), joint vascular review (23%), joint orthopaedics services (8%), dermatologist (2%), and orthotics services (1%). A total of 4% of patients had complex debridement, 0.4% total nail excision, 0.8% pus drainage, 3% cast-related procedures, and 1% vacuum-assisted dressing. Of the patients, 4% were admitted to hospital, 38% had vascular duplex investigations, 7% had a deep vein thrombosis scan, 16% had magnetic resonance imagine (MRI), and 5% had a bone scan. CONCLUSION: A functional multidisciplinary foot team clinic requires significant resources-both clinical and administrative-for prompt investigations and revascularisation to sustain low amputation rates. Regular appraisal of resource use helps with clinic and pathway planning.

Treating latent autoimmune diabetes in adults in the era of cardiovascular outcomes trials: Old dog should learn new tricks.

BACKGROUND: Latent autoimmune diabetes in adults (LADA) is characterised by pathophysiological and clinical heterogeneity. Hence, the optimal treatment strategy for this type of diabetes remains a clinical challenge. AIM: To discuss the potential of a modern therapeutic approach for LADA in the context of the novel findings of cardiovascular outcomes trials and stress the controversies surrounding LADA and the barriers in the effective management of people with this type of diabetes. METHODS: We performed a literature search in major biomedical databases in order to retrieve relevant literature. The results of key studies, along with the authors' clinical experience and perspective, are summarised and discussed in this narrative, mini review article. RESULTS: Insulin remains the primary treatment choice in individuals with low C-peptide levels. Although cardiovascular outcomes trials have mainly recruited participants with type 2 diabetes, recent data suggest that the cardiorenal protective properties of the new therapies are even present in people without diabetes and thus, the extrapolation of their results on LADA individuals sounds reasonable. Therefore, sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists should be considered for the management of people with preserved insulin production being at high cardiovascular risk. The risk of diabetic ketoacidosis with SGLT2is requires increased vigilance by treating physicians. CONCLUSIONS: Individualisation, preservation of beta-cell mass and function and cardiorenal protection are the new challenges in LADA therapy.

Isolated low toe-brachial index is associated with increased mortality and morbidity: a retrospective cohort study.

OBJECTIVE: The aim was to assess the prognostic impact of perfusion assessments including ankle-brachial Index (ABI) and toe-brachial Index (TBI) on survival of patients who present with diabetic foot ulceration and to analyse clinical outcomes when patients are categorised into three levels of limb ischaemia. METHOD: This was a retrospective cohort analysis of consecutive patients presenting with foot ulceration. Patients continued with their standard of care, after having baseline assessments of limb perfusion. Patients were retrospectively categorised into three groups according to baseline ABI and TBI: Group 1 (n=31) non-ischaemic (TBI≥0.75, ABI≥0.9), Group 2 (n=67) isolated low TBI with foot ischaemia (TBI<0.75, ABI≥0.90) and Group 3 (n=30) foot-leg ischaemia (TBI<0.75, ABI<0.90). RESULTS: A total of 128 patients took part in the study. Low TBI was associated with a significant decrease in patient survival (42±20 versus 51±16 months, p=0.011). There was a progressive and significant decline in mean patient survival time (51±16 versus 44±20 versus 39±22 months, respectively, for ANOVA across the three groups, p=0.04). Patients with isolated low TBI had angioplasty and bypass at a rate similar to that of patients in Group 3 (low ABI and low TBI). The proportion of angioplasties was significantly higher in the isolated low TBI (19.4% (13/67) versus the non-ischaemic 3.2% (1/31), p=0.033). Such revascularisation resulted in ulcer healing within the foot ischaemic group that was similar to the non-ischaemic group (68% versus 60% over 12 months, p=0.454). CONCLUSION: Regardless of ABI level, measurement of TBI identifies patients with isolated low TBI who require specialised care pathways and revascularisation to achieve ulcer healing that is similar to non-ischaemic patients.

People living with diabetes are unaware of their foot risk status or why they are referred to a multidisciplinary foot team.

AIM: People with active diabetic foot disease should be rapidly referred by health professionals along a pathway of care to a multidisciplinary foot team. The aim was to investigate patients' self-reported understanding of their foot risk status and reasons for their referral to a multidisciplinary foot team. METHOD: This seven-month service evaluation included consecutive newly referred patients. Participants completed a questionnaire which asked firstly about their understanding of their foot risk status, secondly about their pathway of care before presentation to the multidisciplinary foot team, and thirdly about their interest in diabetes-related foot education and preferred learning style. RESULTS: There were 202 participants; 65% were male, mean age was 64±15 years (mean±standard deviation (SD)), 86% had type 2 diabetes, and mean HbA1c was 65±23mmol/mol (8.3±3.7%). Only 4% of participants knew their current foot risk status and 52% did not know why their care had been escalated to a multidisciplinary foot clinic. Participants with type 2 diabetes more readily expressed an interest in further foot education compared with participants with type 1 diabetes, (70% versus 29%, p=0.001). CONCLUSIONS: These findings show that people with diabetes and foot disease are less aware of their foot risk status or why they are referred to a multidisciplinary team. Participants indicated a variable interest in further learning about foot complications. These findings indicate possible communication and educational barriers between patients and health professionals which may contribute to delayed presentation or suboptimal engagement.

Effectiveness of interventions to enhance healing of chronic foot ulcers in diabetes: a systematic review.

The management of diabetic foot ulcers (DFU) remains a challenge, and there is continuing uncertainty concerning optimal approaches to wound healing. The International Working Group of the Diabetic Foot (IWGDF) working group on wound healing has previously published systematic reviews of the evidence in 2008, 2012 and 2016 to inform protocols for routine care and to highlight areas which should be considered for further study. The working group has now updated this review by considering papers on the interventions to improve the healing of DFU's published between June 2014 and August 2018. Methodological quality of selected studies was independently assessed by a minimum of two reviewers using the recently published 21-point questionnaire as recommended by IWGDF/European Wound Management Association, as well as the previously incorporated Scottish Intercollegiate Guidelines Network criteria. Of the 2275 papers identified, 97 were finally selected for grading following full text review. Overall, there has been an improvement in study design and a significant rise in the number of published studies. While previous systematic reviews did not find any evidence to justify the use of newer therapies, except for negative pressure wound therapy in post-surgical wounds, in this review we found additional evidence to support some interventions including a sucrose-octasulfate dressing, the combined leucocyte, fibrin and platelet patch as well as topical application of some placental membrane products, all when used in addition to usual best care. Nonetheless, the assessment and comparison of published trials remains difficult with marked clinical heterogeneity between studies: in patient selection, study duration, standard of usual care provision and the timing and description of the clinical endpoints.

Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. In conjunction with advice from internal and external reviewers and expert consultants in the field, this update is based on a systematic review of the literature centred on the following: the Population (P), Intervention (I), Comparator (C) and Outcomes (O) framework; the use of the SIGN guideline/Cochrane review system; and the 21 point scoring system advocated by IWGDF/EWMA. This has resulted in 13 recommendations. The recommendation on sharp debridement and the selection of dressings remain unchanged from the last recommendations published in 2016. The recommendation to consider negative pressure wound therapy in post-surgical wounds and the judicious use of hyperbaric oxygen therapy in certain non-healing ischaemic ulcers also remains unchanged. Recommendations against the use of growth factors, autologous platelet gels, bioengineered skin products, ozone, topical carbon dioxide, nitric oxide or interventions reporting improvement of ulcer healing through an alteration of the physical environment or through other systemic medical or nutritional means also remain. New recommendations include consideration of the use of sucrose-octasulfate impregnated dressings in difficult to heal neuro-ischaemic ulcers and consideration of the use of autologous combined leucocyte, platelet and fibrin patch in ulcers that are difficult to heal, in both cases when used in addition to best standard of care. A further new recommendation is the consideration of topical placental derived products when used in addition to best standard of care.

Definitions and criteria for diabetic foot disease.

Multiple disciplines are involved in the management of diabetic foot disease, and a common vocabulary is essential for clear communication. Based on the systematic reviews of the literature that form the basis of the International Working Group on the Diabetic Foot (IWGDF) Guidelines, the IWGDF has developed a set of definitions and criteria for diabetic foot disease. This document describes these definitions and criteria. We suggest these definitions be used consistently in both clinical practice and research to facilitate clear communication between professionals.

Diabetes, obesity and COVID-19: A complex interplay.

With the accumulation of observational data showing an association of metabolic co-morbidities with adverse outcomes from COVID-19, there is a need to disentangle the contributions of pre-existing macro- and microvascular disease, obesity and glycaemia. This article outlines the complex mechanistic and clinical interplay between diabetes and COVID-19, the clinical and research questions which arise from this relationship, and the types of studies needed to answer those questions. The authors are clinicians and academics working in diabetes and obesity medicine, but the article is pitched to an audience of generalists with clinical experience of or interest in the management of COVID-19.

LDIflare small fiber function in normal glucose tolerant subjects with and without hypertriglyceridemia.

INTRODUCTION: We explored determinants of small fiber function (SFF) in normoglycemic individuals to determine influence of metabolic parameters, including triglyceride (TG) levels. METHODS: Dorsal foot SFF was assessed by the LDIflare method in 79 individuals without clinical neuropathy, including 43 controls (HC, <1.7 mmol/L), 17 with mild hypertriglyceridemia (MiTG, 1.7-2.25), and 19 with significant hypertriglyceridemia (HiTG, >2.25 mmol/L). RESULTS: LDIflare was significantly smaller in HiTG compared with HC (4.4 ± 1.4 vs. 9.3 ± 2.9 cm(2) ; P < 0.0001) and compared with the MiTG (4.4 ± 1.4 vs. 7.0 ± 2.1; P < 0.0001). Over all, an inverse correlation existed between LDIflare and age (-0.42; P < 0.0001), weight (r = -0.37; P = 0.004), body mass index (BMI) (-0.51; P < 0.0001), Log10 triglycerides (r = -0.66; P < 0.0001), total cholesterol (r = -0.26; P = 0.02), and TC/HDL ratio (r = -0.40; P = 0.002). In multivariate regression analysis, Log10 triglycerides (P < 0.0001) and age (P = 0.003) were the only independent predictors. CONCLUSIONS: There is an inverse correlation between small fiber function and triglycerides in normoglycemic individuals and abnormal SFF in normoglycemic hypertriglyceridemia. Larger prospective studies are required to confirm these findings and to determine whether reduced SFF heralds later clinical neuropathy.

Validation of the modified LDIFlare technique: a simple and quick method to assess C-fiber function.

INTRODUCTION: In this study we validated a modified laser Doppler imager method (mLDIf) for assessing C-fiber function and compared it to the original (oLDIf). Both measure flare size in foot skin after heating, but the mLDIf uses 47°C (vs. 44°C), making it quicker and better suited for clinical use. METHODS: To confirm that mLDIf assesses C-fiber function, 5 healthy controls (HC) were studied before and after local anesthesia (LA). Reproducibility and comparison with oLDIf was assessed in HC (n = 16). Finally, diabetes subjects with (DN(+), n = 10) and without (DN(-), n = 16) neuropathy were studied. RESULTS: LA almost abolished the flare (9.3 ± 3.0 cm(2) vs. 1.7 ± 0.3 cm(2), P < 0.0001). mLDIf produced larger flares (9.9 ± 3.4 vs. 5.7 ± 2.3 cm(2), P < 0.0001), but correlated with oLDIf (r = 0.81, P < 0.001). mLDIf was reduced in DN(-) (6.8 ± 2.8 vs. HC, P = 0.003), markedly so in DN(+) (2.0 ± 1.1 vs. HC and DN(-), P < 0.0001). CONCLUSION: The mLDIf is a quick, practical method for assessing C-fiber function in the clinical setting.

Improving Physical, Physiological, and Psychological Health Outcomes in Patients with Diabetic Foot Ulcers - State of the Art.

Diabetic foot disease is a complex and challenging complication of diabetes mellitus, which imposes a significant burden of disease on patients, their carers, and the wider health systems. Recurrence rates are high, and current evidence indicates a high mortality associated with it. While management algorithms have primarily focused on the physical aspects of healing, there is increasing recognition of the critical role played by psychological and biomechanical factors in the development and resolution of diabetic foot disease. Therefore, in this paper, we aim to explore how diabetic foot outcomes can be improved by addressing not only the physical but also the psychological and biomechanical aspects that are integral to the development of this condition and its optimal resolution. We explore new technologies that allow for non-invasive objective assessment of the diabetic foot at risk, and we also explore the role of understanding biomechanics, which is essential to determining risk of foot disease, but also the potential for recurrence. In addition, we discuss the evidence linking depression and cognitive impairment to diabetic foot disease and offer our insight on the research direction required before implementing novel information into front-line clinics.

Revascularisation Options for Chronic Limb Threatening Ischaemia in Diabetes: Implications From Two Recent Trials.

Chronic limb-threatening ischaemia (CLTI) is a severe form of peripheral arterial disease (PAD) and is associated with an increased risk of amputation, mortality, and significantly impaired quality of life. International guidelines recommend considering timely revascularisation and optimal medical therapy to improve limb perfusion in individuals with CLTI. The 2 primary revascularization approaches for CLTI are open bypass surgery (BS) and endovascular therapy (EV), however, there is currently no consensus on the best initial treatment strategy for CLTI, leading to uncertainty among clinicians. To shed light on this issue, 2 recent trials, namely best endovascular versus best surgical therapy in patients with CLI (BEST-CLI) and bypass versus angioplasty for severe ischaemia of the leg (BASIL-2), have tried to provide valuable insights. While a definitive conclusion on the optimal revascularisation approach is still pending, these trials offer immediate and clinically relevant information to the diabetic foot multidisciplinary team. The trials encompassed a distinct range of patient cohorts and included participants with varying degrees of medical and physical frailty. Taken together, their findings, highlight the need for an individualised revascularisation strategy which accounts for underlying comorbidities, risk factors, disease severity, availability of suitable bypass conduits, surgical risks, and timely access to procedures. Regardless of the chosen strategy, early referral of patients with diabetes and CLTI to a specialist team within a multidisciplinary environment is crucial. Comprehensive care should encompass essential elements such as adequate debridement, infection control, offloading, glycaemic control, smoking cessation, and patient education. By addressing these aspects, healthcare providers can optimise the management and outcomes for individuals with CLTI and diabetes.

Evaluation of Adjuvant Antibiotic Loaded Injectable Bio-Composite Material in Diabetic Foot Osteomyelitis and Charcot Foot Reconstruction.

The management of diabetic foot osteomyelitis (DFO) is extremely challenging with high amputation rates reported alongside a five-year mortality risk of more than fifty percent. We describe our experience in using adjuvant antibiotic-loaded bio-composite material (Cerament) in the surgical management of DFO and infected Charcot foot reconstruction. We undertook a retrospective evaluation of 53 consecutive patients (54 feet) who underwent Gentamicin or Vancomycin-loaded Cerament application during surgery. The feet were categorised into two groups: Group 1, with infected ulcer and DFO, managed with radical debridement only (n = 17), and Group 2, requiring reconstruction surgery for infected and deformed Charcot foot. Group 2 was further subdivided into 2a, with feet previously cleared of infection and undergoing a single-stage reconstruction (n = 19), and 2b, with feet having an active infection managed with a two-stage reconstruction (n = 18). The mean age was 56 years (27-83) and 59% (31/53) were males. The mean BMI was 30.2 kg/m2 (20.8-45.5). Foot ulcers were present in 69% (37/54) feet. At a mean follow-up of 30 months (12-98), there were two patients lost to follow up and the mortality rate was 11% (n = 5). The mean duration of post-operative systemic antibiotic administration was 20 days (4-42). Thirteen out of fifteen feet (87%) in group 1 achieved complete eradication of infection. There was a 100% primary ulcer resolution, 100% limb salvage and 76% bony union rate within Group 2. However, five patients, all in group 2, required reoperations due to problems with bone union. The use of antibiotic-loaded Cerament resulted in a high proportion of patients achieving infection clearance, functional limb salvage and decrease in the duration of postoperative antibiotic therapy. Larger, preferably randomised, studies are required to further validate these observations.

Onset of an Active Charcot Foot in a Person with Longstanding Type 1 Diabetes and Normal Vibration Perception Threshold-A Case Report.

Charcot neuro-osteoarthropathy (CNO), or Charcot foot, is a disabling complication of diabetes, which is poorly understood and frequently overlooked. We describe an atypical presentation of an active Charcot foot in a woman with a long-standing type 1 diabetes who did not exhibit loss of protective sensation (sensate to a 10-gram monofilament) or loss of vibration sensation. These standard measures of large nerve fibre function ruled out "classical" neuropathy. However, additional testing showed reduced sweat gland function most likely related to degeneration of c-fibres (small fibre neuropathy). This case raises the awareness that in addition to the "textbook" description, in diabetes, Charcot foot can develop in individuals with "minimal" or "no signs" of clinical neuropathy. The onset of active Charcot foot should be suspected in every person with diabetes and history of trauma even when foot and ankle x-rays are normal. Offloading should be initiated until the diagnosis is proven otherwise.

People With Type 1 Diabetes of African Caribbean Ethnicity Are at Increased Risk of Developing Sight-Threatening Diabetic Retinopathy.

OBJECTIVE: There is limited information on the effect of ethnicity on the development of referable sight-threatening diabetic retinopathy (STDR) in people with type 1 diabetes. This study describes the risk factors for STDR in a diverse cohort of people with type 1 diabetes attending a regional diabetes eye screening service. RESEARCH DESIGN AND METHODS: Clinical and digital retinal imaging data from 1,876 people with type 1 diabetes (50% women, 72.1% Caucasian, 17.3% African Caribbean, 2.9% Asian, and 7.6% other) with no retinopathy at baseline, attending surveillance eye screening were reviewed. Referable STDR was defined as the presence of any moderate to severe nonproliferative or preproliferative diabetic retinopathy or proliferative diabetic retinopathy or maculopathy in either eye as per U.K. National Diabetic Eye Screening criteria. Median follow-up was 6 years. RESULTS: The median (interquartile range) age of the cohort was 29 (21, 41) years. Of the cohort of 1,876 people, 359 (19%) developed STDR. People who developed STDR had higher baseline HbA1c, raised systolic blood pressure (SBP), longer diabetes duration, and were more often of African Caribbean origin (24% vs. 15.6%; P < 0.05 for all). In multivariable Cox regression analyses, African Caribbean ethnicity (hazard ratio [HR] 1.39, 95% CI 1.09-1.78, P = 0.009), baseline SBP (HR 1.01, 95% CI 1.00-1.01, P = 0.033), and baseline HbA1c (HR 1.01, 95% CI 1.00-1.01, P = 0.0001) emerged as independent risk factors for STDR. CONCLUSIONS: We observed that people with type 1 diabetes of African Caribbean ethnicity are at significantly greater risk of STDR. Further research is required to understand the mechanisms that explain this novel observation.

Small Fiber Neuropathy in Diabetes Polyneuropathy: Is It Time to Change?

Diabetes polyneuropathy is an important complication of diabetes polyneuropathy, and its notable sequelae of foot ulceration, autonomic dysfunction, and neuropathic pain are associated with significant morbidity and mortality. Despite the major impact on quality of life and health economic costs, it remains underdiagnosed until late in its natural history, and there is lack of any intervention that can reverse its clinical progress. Assessment of small fiber neuropathy (SFN) in diabetes offers an opportunity to detect abnormalities at an early stage so that both interventional studies and preventative measures can be enacted to prevent progression to the devastating complications of foot ulceration and cardiac dysautonomic death. Over the last two decades, significant advances have been made in understanding the pathophysiology of diabetes neuropathy and its assessment. In this review, we discuss limitations of the screening methods recommended in current clinical guidelines which are based on large nerve fiber assessments. Thereafter, we discuss in detail the various methods currently available to assess small fiber structure and function and examine their individual strength and limitations. Finally, we discuss the reasons why despite the considerable body of evidence available, legislators and global experts have yet to incorporate the assessment of SFN as routine clinical surveillance in diabetes management. We hope that these insights will stimulate further discussion and be instrumental in the early adoption of these methods so as to reduce the burden of complications arising due to diabetes polyneuropathy.

COVID-19 Toes and Other Skin Lesions During the Pandemic: Emerging Entities?

There is accumulating evidence to indicate an association between coronavirus infectious disease 2019 (COVID-19) and clusters of incident cutaneous eruptions. Of these, chilblains-like perniosis have received widespread medical and media attention. These typically affect the toes, and have been called "COVID-toes." Other acral lesions such as large bullae have also been reported. However, a definitive causal relationship with the severe acute respiratory syndrome coronavirus 2 has not yet been definitively proven, nor has a pathogenic mechanism been established. These episodes are self-limiting, but we need to know whether long-term sequelae exist.