Reduced Thalamic Gamma Aminobutyric Acid (GABA) in Painless but not Painful Diabetic Peripheral Neuropathy.

Alterations in the structure, function, and microcirculation of the thalamus, a key brain region involved in pain pathways, have previously been demonstrated in patients with Painless- and Painful-diabetic peripheral neuropathy (DPN). However, thalamic neurotransmitter levels including GABA (inhibitory neurotransmitter) and glutamate (excitatory neurotransmitter) in different DPN phenotypes are not known. We performed a Magnetic Resonance Spectroscopy study and quantified GABA and glutamate levels within the thalamus, in a carefully characterised cohort of participants with Painless- and Painful-DPN. Participants with DPN (Painful- and Painless combined) had a significantly lower GABA:H2O ratio compared to those without DPN (Healthy volunteers [HV] and diabetes without DPN [No-DPN]). Participants with Painless-DPN had the lowest GABA:H2O ratio, which reached significance compared with HV and No-DPN, but not Painful-DPN. There was no difference in GABA:H2O in Painful-DPN compared with all other groups. A significant correlation with GABA:H2O and neuropathy severity was also seen. This study demonstrates that lower levels of thalamic GABA in participants with Painless-DPN may reflect neuroplasticity due to reduced afferent pain impulses. Whereas partially preserved levels of GABA in Painful-DPN may indicate that central GABAergic pathways are involved in the mechanisms of neuropathic pain in diabetes.

Application of machine learning methods for predicting childhood anaemia: Analysis of Ethiopian Demographic Health Survey of 2016.

Childhood anaemia is a public health problem in Ethiopia. Machine learning (ML) is a growing in medicine field to predict diseases. Diagnosis of childhood anaemia is resource intensive. The aim of this study is to apply machine learning (ML) algorithm to predict childhood anaemia using socio-demographic, economic, and maternal and child related variables. The study used data from 2016 Ethiopian demographic health survey (EDHS). We used Python software version 3.11 to apply and test ML algorithms through logistic regression, Random Forest (RF), Decision Tree, and K-Nearest Neighbours (KNN). We evaluated the performance of each of the ML algorithms using discrimination and calibration parameters. The predictive performance of the algorithms was between 60% and 66%. The logistic regression model was the best predictive model of ML with accuracy (66%), sensitivity (82%), specificity (42%), and AUC (69%), followed by RF with accuracy (64%), sensitivity (79%), specificity (42%), and AUC (63%). The logistic regression and the RF models of ML showed poorest family, child age category between 6 and 23 months, uneducated mother, unemployed mother, and stunting as high importance predictors of childhood anaemia. Applying logistic regression and RF models of ML can detect combinations of predictors of childhood anaemia that can be used in primary health care professionals.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Non-pharmacological interventions to improve cardiovascular risk factors in people with diabetic foot disease: A systematic review and meta-analysis.

Cardiovascular disease (CVD) risk in those with diabetic foot disease is very high. Non-pharmacological interventions may improve this risk, though no previous evidence synthesis has been completed. This systematic review aimed to investigate the impact of non-pharmacological interventions on CVD risk factors in diabetic ulcer disease. Multiple databases and trials registers were searched from inception to December 6th 2023. We included reports of randomised controlled trials investigating the impact of non-pharmacological interventions on cardiovascular risk in those with type 1 or type 2 diabetes and current or previous diabetic foot disease. Twenty studies were included. Extracted data included: study design and setting; participant sociodemographic factors; and change in cardiovascular risk factors. Data were synthesised using random effects meta-analyses and narrative syntheses. Interventions included nutritional supplementation, collaborative care, hyperbaric oxygen therapy, patient education, nurse-led intervention, self-management, family support, relaxation and exercise, over a median duration of 12 weeks. Significant post-intervention changes were observed in fasting plasma glucose, serum insulin levels, insulin sensitivity and resistance, glycated haemoglobin, triglycerides, total cholesterol, low-density lipoprotein-cholesterol and C-reactive protein. No effects were detected in very low- or high-density lipoprotein-cholesterol or body mass index. Non-pharmacological interventions show promise in improving CVD risk in diabetic foot disease.

Brain alterations in regions associated with end-organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study.

BACKGROUND: Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). METHODS: This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. RESULTS: We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). INTERPRETATION: This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM.

Efficacy and safety of eliapixant in diabetic neuropathic pain and prediction of placebo responders with an exploratory novel algorithm: results from the randomized controlled phase 2a PUCCINI study.

ABSTRACT: Phase 2a of the PUCCINI study was a placebo-controlled, double-blind, parallel-group, multicenter, proof-of-concept study evaluating the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with diabetic neuropathic pain (DNP) ( ClinicalTrials.gov NCT04641273). Adults with type 1 or type 2 diabetes mellitus with painful distal symmetric sensorimotor neuropathy of >6 months' duration and neuropathic pain were enrolled and randomized 1:1 to 150 mg oral eliapixant twice daily or placebo for 8 weeks. The primary endpoint was change from baseline in weekly mean 24-hour average pain intensity score at week 8. In total, 135 participants completed treatment, 67 in the eliapixant group and 68 in the placebo group. At week 8, the change from baseline in posterior mean 24-hour average pain intensity score (90% credible interval) in the eliapixant group was -1.56 (-1.95, -1.18) compared with -2.17 (-2.54, -1.80) for the placebo group. The mean treatment difference was 0.60 (0.06, 1.14) in favor of placebo. The use of a model-based framework suggests that various factors may contribute to the placebo-responder profile. Adverse events were mostly mild or moderate in severity and occurred in 51% of the eliapixant group and 48% of the placebo group. As the primary endpoint was not met, the PUCCINI study was terminated after completion of phase 2a and did not proceed to phase 2b. In conclusion, selective P2X3 antagonism in patients with DNP did not translate to any relevant improvement in different pain intensity outcomes compared with placebo. Funding: Bayer AG.

Serum levels of endocannabinoids and related lipids in painful vs painless diabetic neuropathy: results from the Pain in Neuropathy Study.

ABSTRACT: N-arachidonoylethanolamine (also known as anandamide) and 2-arachidonoylglycerol are activators of the cannabinoid receptors. The endocannabinoid system also includes structurally and functionally related lipid mediators that do not target cannabinoid receptors, such as oleoylethanolamide, palmitoylethanolamide, and stearoylethanolamide. These bioactive lipids are involved in various physiological processes, including regulation of pain. The primary aim of the study was to analyze associations between serum levels of these lipids and pain in participants in the Pain in Neuropathy Study, an observational, cross-sectional, multicentre, research project in which diabetic patients with painless or painful neuropathy underwent deep phenotyping. Our hypothesis was that painful neuropathy would be associated with higher levels of the 5 lipids compared with painless neuropathy. Secondary aims were to analyze other patient-reported outcome measures and clinical data in relationship to lipid levels. The lipid mediators were analyzed in serum samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Serum levels of anandamide were significantly higher in the painful group, but the effect size was small (Cohen d = 0.31). Using cluster analysis of lipid data, patients were dichotomized into a "high-level" endocannabinoid group and a "low-level" group. In the high-level group, 61% of patients had painful neuropathy, compared with 45% in the low-level group ( P = 0.039). This work is of a correlative nature only, and the relevance of these findings to the search for analgesics targeting the endocannabinoid system needs to be determined in future studies.

Female sex is a risk factor for painful diabetic peripheral neuropathy: the EURODIAB prospective diabetes complications study.

AIMS/HYPOTHESIS: While the risk factors for diabetic peripheral neuropathy (DPN) are now well recognised, the risk factors for painful DPN remain unknown. We performed analysis of the EURODIAB Prospective Complications Study data to elucidate the incidence and risk factors of painful DPN. METHODS: The EURODIAB Prospective Complications Study recruited 3250 participants with type 1 diabetes who were followed up for 7.3±0.6 (mean ± SD) years. To evaluate DPN, a standardised protocol was used, including clinical assessment, quantitative sensory testing and autonomic function tests. Painful DPN (defined as painful neuropathic symptoms in the legs in participants with confirmed DPN) was assessed at baseline and follow-up. RESULTS: At baseline, 234 (25.2%) out of 927 participants with DPN had painful DPN. At follow-up, incident DPN developed in 276 (23.5%) of 1172 participants. Of these, 41 (14.9%) had incident painful DPN. Most of the participants who developed incident painful DPN were female (73% vs 48% painless DPN p=0.003) and this remained significant after adjustment for duration of diabetes and HbA1c (OR 2.69 [95% CI 1.41, 6.23], p=0.004). The proportion of participants with macro- or microalbuminuria was lower in those with painful DPN compared with painless DPN (15% vs 34%, p=0.02), and this association remained after adjusting for HbA1c, diabetes duration and sex (p=0.03). CONCLUSIONS/INTERPRETATION: In this first prospective study to investigate the risk factors for painful DPN, we definitively demonstrate that female sex is a risk factor for painful DPN. Additionally, there is less evidence of diabetic nephropathy in incident painful, compared with painless, DPN. Thus, painful DPN is not driven by cardiometabolic factors traditionally associated with microvascular disease. Sex differences may therefore play an important role in the pathophysiology of neuropathic pain in diabetes. Future studies need to look at psychosocial, genetic and other factors in the development of painful DPN.

The potential of Ethiopian medicinal plants to treat emergent viral diseases.

Ethiopians have deep-rooted traditions of using plants to treat ailments affecting humans and domesticated animals. Approximately 80% of the population continues to rely on traditional medicine, including for the prevention and treatment of viral diseases. Many antiviral plants are available to and widely used by communities in areas where access to conventional healthcare systems is limited. In some cases, pharmacological studies also confirm the potent antiviral properties of Ethiopian plants. Building on traditional knowledge of medicinal plants and testing their antiviral properties may help to expand options to address the global pandemic of COVID-19 including its recently isolated virulent variants and prepare for similar outbreaks in the future. Here, we provide an ethnobotanical and pharmacological inventory of Ethiopian medicinal plants that might contribute to the prevention and treatment of viral diseases. We identified 387 species, about 6% of Ethiopia's known flora, for which records of use by local communities and traditional herbalists have been documented for the treatment of viral diseases. We provide a framework for further investigation and development of this vital resource much anticipated to help combat emergent viral diseases along with existing ones in Ethiopia and elsewhere.

Psychosocial Care for People With Diabetic Neuropathy: Time for Action.

Psychological factors and psychosocial care for individuals with diabetic neuropathy (DN), a common and burdensome complication of diabetes, are important but overlooked areas. In this article we focus on common clinical manifestations of DN, unremitting neuropathic pain, postural instability, and foot complications, and their psychosocial impact, including depression, anxiety, poor sleep quality, and specific problems such as fear of falling and fear of amputation. We also summarize the evidence regarding the negative impact of psychological factors such as depression on DN, self-care tasks, and future health outcomes. The clinical problem of underdetection and undertreatment of psychological problems is described, together with the value of using brief assessments of these in clinical care. We conclude by discussing trial evidence regarding the effectiveness of current pharmacological and nonpharmacological approaches and also future directions for developing and testing new psychological treatments for DN and its clinical manifestations.

Are we missing pancreatic exocrine insufficiency in 'at-risk' groups? Prospective assessment of the current practice and yield of faecal elastase testing in patients with diabetes mellitus, HIV and/or high alcohol intake.

There is cumulative evidence that pancreatic exocrine insufficiency (PEI) is under-recognised and can occur in patients with 'at-risk' conditions. Thus, we aimed to assess the current practice and yield of requesting faecal elastase (FEL-1), an indicator of PEI, in patients with 'at-risk' conditions. We prospectively recruited patients attending secondary care clinics with diabetes mellitus (DM), people living with HIV (PLHIV) and inpatients admitted to hospital with high alcohol intake (HAI). All patients underwent testing with FEL-1. Those patients with PEI (FEL-1 <200 µg/g) were contacted and offered a follow-up review in gastroenterology clinic. In total, 188 patients were recruited (HAI, n=78; DM, n=64; and PLHIV, n=46). Previous FEL-1 testing had not been performed in any of the patients. The return rate of samples was 67.9% for patients with HAI, 76.6% for those with DM and 56.5% for those with PLHIV. The presence of PEI was shown in 20.4% of patients with DM, 15.4% of patients with PLHIV and 22.6% in those with HAI. Diarrhoea and bloating were the most reported symptoms in followed-up patients with low FEL-1 (31.8% and 22.7% of patients, respectively). Follow-up computed tomography (CT) scans in those patients with PEI identified chronic pancreatitis changes in 13.6% and pancreatic atrophy in 31.8% of patients. These results suggest that there is a lack of testing for PEI in 'at-risk' groups. Our findings also suggest that using FEL-1 to test for PEI in patients with DM, PLHIV and HAI has a significant impact, although further studies are required to validate these findings.

Chemopreventive Activity of 80% Methanol Leaf Extract of Vernonia auriculifera Hiern (Asteraceae) Against Dimethylhydrazine-Induced Colorectal Carcinogenesis in Rats.

Background: Vernonia auriculifera Hiern (Asteraceae) is among Ethiopian herbal medicines that are traditionally used to treat skin and gastrointestinal cancers. In this study, the chemopreventive potential of Vernonia auriculifera leaf extract in dimethylhydrazine (DMH)-induced colorectal carcinogenesis in rats was investigated. Methods: Rats were assigned to nine groups (normal, positive, and negative control groups, and three pre- and three post-initiation groups). Except for the normal control group (administered with 1 mL/100 g distilled water), the remaining eight groups were given DMH (20 mg/kg) intraperitoneally (ip) for 15 consecutive weeks to induce colorectal tumours. The extract was given orally to the pre-initiation and post-initiation groups at doses of 100, 200, and 400 mg/kg before and after the induction of cancer, respectively. The positive control group was treated with aspirin (60 mg/kg/day) orally for the whole experimental period. Parameters including body weight, average tumour number, size, progression, incidence, total cholesterol, serum total protein, and triglyceride levels were determined. The cytotoxic activity of the extract in Caco-2 cells was evaluated using the MTT assay, and the antioxidant activity of the extract was also assessed using 2.2-diphenyl-1-picrylhydrazine (DPPH) and reducing power methods. Moreover, total phenol and flavonoid contents were determined using appropriate methods. Results: Rats treated with the extract showed a lower incidence of up to 50% in the pre-initiation higher dose, average number (p<0.05),and size (p<0.05) of tumours compared to untreated rats. It also inhibited colorectal cancer-associated increases in serum total cholesterol and triglycerides. The extract's IC50 value in the MTT assay was found to be higher than 200 µg/mL. The extract had an IC50 of 74.88 ± 0.86 µg/mL and 84.69 ± 2.02 µg/mL in the reducing power and DPPH assays, respectively. Total flavonoid and phenol contents were 14.51 ± 0.41 mg quercetin acid equivalent/gm and 47.37 ± 0.72 mg gallic acid equivalent/gm of the crude extract, respectively. Conclusion: The findings collectively indicated that the leaves of V. auriculifera possess chemopreventive activity, probably mediated through antioxidant mechanisms, which supports the traditional claim.

War and Health Care Services Utilization for Chronic Diseases in Rural and Semiurban Areas of Tigray, Ethiopia.

Importance: The war in Tigray, Ethiopia, has disrupted the health care system of the region. However, its association with health care services disruption for chronic diseases has not been well documented. Objective: To assess the association of the war with the utilization of health care services for patients with chronic diseases. Design, Setting, and Participants: Of 135 primary health care facilities, a registry-based cross-sectional study was conducted on 44 rural and semiurban facilities of Tigray. Data on health services utilization were extracted for patients with tuberculosis, HIV, diabetes, hypertension, and psychiatric disorders in the prewar period (September 1, to October 31, 2020) and during the first phase of the war period (November 4, 2020, to June 30, 2021). Main Outcomes and Measures: Records on the number of follow-up, laboratory tests, and patients undergoing treatment of the aforementioned chronic diseases were counted during the prewar and war periods. Results: Of 4645 records of patients with chronic diseases undergoing treatment during the prewar period, 998 records (21%) indicated having treatment during the war period. Compared with the prewar period, 59 of 180 individuals (33%; 95% CI, 26%-40%) had tuberculosis, 522 of 2211 (24%; 95% CI, 22%-26%) had HIV, 228 of 1195 (19%; 95% CI, 17%-21%) had hypertension, 123 of 632 (20%; 95% CI, 16%-22%) had psychiatric disorders, and 66 of 427 (15%; 95% CI, 12%-18%) had type 2 diabetes records, which revealed continued treatment during the war period. Of 174 records of patients with type 1 diabetes in the prewar period, at 2 to 3 months into the war, the numbers dropped to 10 with 94% decline compared with prewar observations. Conclusions and Relevance: This study found that the war in Tigray has resulted in critical health care service disruption and high loss to follow-up for patients with chronic disease, likely leading to increased morbidity and mortality. Local, national, and global policymakers must understand the extent and impact of the service disruption and urge their efforts toward restoration of those services.

Bridging the "Know-Do" Gaps in Five Non-Communicable Diseases Using a Common Framework Driven by Implementation Science.

According to the United Nations High-Level Meeting 2018, five non-communicable diseases (NCDs) including cardiovascular diseases, chronic respiratory diseases, diabetes mellitus, cancer, and mental health conditions accounted for two-thirds of global deaths. These five NCDs share five common risk factors including tobacco use, unhealthy diets, physical inactivity, alcohol use, and air pollution. Low- and middle-income countries (LMICs) face larger burden of NCDs than high-income countries (HICs), due to differences in ecological, technological, socioeconomic and health system development. Based on high-level evidence albeit mainly from HICs, the burden caused by NCDs can be reduced by affordable medicines and best practices. However, "know-do" gaps, ie, gaps between what we know in science and what we do in practice, has limited the impact of these strategies, especially in LMICs. Implementation science advocates the use of robust methodologies to evaluate sustainable solutions in health, education and social care aimed at informing practice and policies. In this article, physician researchers with expertise in NCDs reviewed the common challenges shared by these five NCDs with different clinical courses. They explained the principles of implementation science and advocated the use of an evidence-based framework to implement solutions focusing on early detection, prevention and empowerment, supplemented by best practices in HICs and LMICs. These successful stories can be used to motivate policymakers, payors, providers, patients and public to co-design frameworks and implement context-relevant, multi-component, evidence-based practices. In pursuit of this goal, we propose partnership, leadership, and access to continuing care as the three pillars in developing roadmaps for addressing the multiple needs during the journey of a person with or at risk of these five NCDs. By transforming the ecosystem, raising awareness and aligning context-relevant practices and policies with ongoing evaluation, it is possible to make healthcare accessible, affordable and sustainable to reduce the burden of these five NCDs.

Spatial patterns and spatially-varying factors associated with childhood acute respiratory infection: data from Ethiopian demographic and health surveys (2005, 2011, and 2016).

BACKGROUND: In Ethiopia, acute respiratory infections (ARIs) are a leading cause of morbidity and mortality among children under five years. Geographically linked data analysis using nationally representative data is crucial to map spatial patterns of ARIs and identify spatially-varying factors of ARI. Therefore, this study aimed to investigate spatial patterns and spatially-varying factors of ARI in Ethiopia. METHODS: Secondary data from the Ethiopian Demographic Health Survey (EDHS) of 2005, 2011, and 2016 were used. Kuldorff's spatial scan statistic using the Bernoulli model was used to identify spatial clusters with high or low ARI. Hot spot analysis was conducted using Getis-OrdGi statistics. Eigenvector spatial filtering regression model was carried out to identify spatial predictors of ARI. RESULTS: Acute respiratory infection spatially clustered in 2011 and 2016 surveys year (Moran's I:-0.011621-0.334486). The magnitude of ARI decreased from 12.6% (95%, CI: 0.113-0.138) in 2005 to 6.6% (95% CI: 0.055-0.077) in 2016. Across the three surveys, clusters with a high prevalence of ARI were observed in the North part of Ethiopia. The spatial regression analysis revealed that the spatial patterns of ARI was significantly associated with using biomass fuel for cooking and children not initiating breastfeeding within 1-hour of birth. This correlation is strong in the Northern and some areas in the Western part of the country. CONCLUSION: Overall there has been a considerable decrease in ARI, but this decline in ARI varied in some regions and districts between surveys. Biomass fuel and early initiation of breastfeeding were independent predictors of ARI. There is a need to prioritize children living in regions and districts with high ARI.

Higher Sensory Cortical Energy Metabolism in Painful Diabetic Neuropathy: Evidence From a Cerebral Magnetic Resonance Spectroscopy Study.

Alterations in the resting-state functional connectivity and hyperperfusion of pain processing areas of the brain have been demonstrated in painful diabetic peripheral neuropathy (DPN). However, the mechanisms underlying these abnormalities are poorly understood; thus there is good rationale to explore whether there is higher energy consumption in the pain processing areas of the brain. We performed a 31P magnetic resonance spectroscopy study to explore cellular energy usage (bioenergetics) in the primary somatosensory (S1) cortex in a well-characterized cohort of participants with painful and painless DPN. S1 phosphocreatine (PCr):ATP, a measure of energy consumption, was significantly reduced in painful compared with painless DPN. This is indicative of greater S1 cortical energy consumption in painful DPN. Furthermore, S1 PCr:ATP correlated with pain intensity during the MRI. S1 PCr:ATP was also significantly lower in painful-DPN individuals with moderate/severe pain compared with those with low pain. To our knowledge, this is the first study to demonstrate higher S1 cortical energy metabolism in painful compared with painless DPN. Moreover, the relationship between PCr:ATP and neuropathic pain measures shows that S1 bioenergetics is related to the severity of neuropathic pain. S1 cortical energetics may represent a biomarker of painful DPN and could have the potential to serve as a target for therapeutic interventions. ARTICLE HIGHLIGHTS: Energy consumption within the primary somatosensory cortex appears to be greater in painful compared with painless diabetic peripheral neuropathy. The measure of energy metabolism, PCr:ATP, within the somatosensory cortex correlated with pain intensity and was lower in those with moderate/severe compared with low pain. To our knowledge. this is the first study to indicate higher cortical energy metabolism in painful compared with painless diabetic peripheral neuropathy, and thus has the potential to act as a biomarker for clinical pain trials.

Combination therapy for painful diabetic neuropathy is safe and effective.

The studyTesfaye S, Sloan G, Petrie J, et al. 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. Lancet 2022;400:680-90.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/combination-therapy-for-painful-diabetic-neuropathy-is-safe-and-effective/.

Diagnosis, management and impact of painful diabetic peripheral neuropathy: A patient survey in four European countries.

AIMS: The aim of this study was to assess patient perspectives and experiences of the impact of neuropathic pain, painful diabetic neuropathy (pDPN) diagnosis and treatment, and the patient-healthcare professional (HCP) relationship. METHODS: We conducted a quantitative online survey in Germany, the Netherlands, Spain, and the UK among adults with diabetes who responded "yes" to at least four of ten questions of in the Douleur Neuropathique en 4 Questions (DN4) questionnaire. RESULTS: Of 3626 respondents, 576 met the eligibility criteria. Daily pain was rated as moderate or severe by 79 % of respondents. Most participants reported a negative impact of their pain on sleep (74 %), mood (71 %), exercise (69 %), concentration (64 %) and daily activities (62 %), and 75 % of those in employment had missed work because of their pain in the past year. Overall, 22 % of respondents avoided discussing pain with their HCP, 50 % had not received formal pDPN diagnosis, and 56 % had not used prescribed pain medications. Although two-thirds (67 %) of respondents reported feeling satisfied or very satisfied with treatment, 82 % of these patients still experienced daily moderate or severe pain. CONCLUSIONS: Neuropathic pain in people with diabetes affects daily life and remains underdiagnosed and undertreated in clinical practice.

The association between distal symmetric polyneuropathy in diabetes with all-cause mortality - a meta-analysis.

Background: Distal symmetric polyneuropathy (DSPN) is a common microvascular complication of both type 1 and 2 diabetes with substantial morbidity burden and reduced quality of life. Its association with mortality is equivocal. Purpose: To describe the association between DSPN and all-cause mortality in people with diabetes and further stratify by the type of diabetes based on a meta-analysis of published observational studies. Data Sources: We searched Medline from inception to May 2021. Study Selection: Original data were collected from case-control and cohort studies that reported on diabetes and DSPN status at baseline and all-cause mortality during follow-up. Data Extraction: was completed by diabetes specialists with clinical experience in neuropathy assessment. Data Synthesis: Data was synthesized using random-effects meta-analysis. The difference between type 1 and 2 diabetes was investigated using meta-regression. Results: A total of 31 cohorts (n=155,934 participants, median 27.4% with DSPN at baseline, all-cause mortality 12.3%) were included. Diabetes patients with DSPN had an almost twofold mortality (HR: 1.96, 95%CI: 1.68-2.27, I2 = 91.7%), I2 = 91.7%) compared to those without DSPN that was partly explained by baseline risk factors (adjusted HR: 1.60, 95%CI: 1.37-1.87, I2 = 78.86%). The association was stronger in type 1 compared to type 2 diabetes (HR: 2.22, 95%CI: 1.43-3.45). Findings were robust in sensitivity analyses without significant publication bias. Limitations: Not all papers reported multiple adjusted estimates. The definition of DSPN was heterogeneous. Conclusions: DSPN is associated with an almost twofold risk of death. If this association is causal, targeted therapy for DSPN could improve life expectancy of diabetic patients.

Structural Brain Alterations in Key Somatosensory and Nociceptive Regions in Diabetic Peripheral Neuropathy.

OBJECTIVE: Despite increasing evidence demonstrating structural and functional alterations within the central nervous system in diabetic peripheral neuropathy (DPN), the neuroanatomical correlates of painful and painless DPN have yet to be identified. Focusing on structural MRI, the aims of this study were to 1) define the brain morphological alterations in painful and painless DPN and 2) explore the relationships between brain morphology and clinical/neurophysiological assessments. RESEARCH DESIGN AND METHODS: A total of 277 participants with type 1 and 2 diabetes (no DPN [n = 57], painless DPN [n = 77], painful DPN [n = 77]) and 66 healthy volunteers (HVs) were enrolled. All underwent detailed clinical/neurophysiological assessment and brain 3T MRI. Participants with painful DPN were subdivided into the irritable (IR) nociceptor and nonirritable (NIR) nociceptor phenotypes using the German Research Network on Neuropathic Pain protocol. Cortical reconstruction and volumetric segmentation were performed with FreeSurfer software and voxel-based morphometry implemented in FSL. RESULTS: Both participants with painful and painless DPN showed a significant reduction in primary somatosensory and motor cortical thickness compared with HVs (P = 0.02; F[3,275] = 3.36) and participants with no DPN (P = 0.01; F[3,275] = 3.80). Somatomotor cortical thickness correlated with neurophysiological measures of DPN severity. There was also a reduction in ventrobasal thalamic nuclei volume in both painless and painful DPN. Participants with painful DPN with the NIR nociceptor phenotype had reduced primary somatosensory cortical, posterior cingulate cortical, and thalamic volume compared with the IR nociceptor phenotype. CONCLUSIONS: In this largest neuroimaging study in DPN to date, we demonstrated significant structural alterations in key somatomotor/nociceptive brain regions specific to painless DPN and painful DPN, including the IR and NIR nociceptor phenotypes.