Search Results (3,031)

Type 2 diabetes (T2D) is a prevalent disease worldwide that increases the risk of cardiovascular (CV) complications, disability and mortality. While excessive alcohol consumption is harmful, the effects of moderate wine consumption remain debated. This review evaluates whether moderate wine intake affects the risk of developing T2D and its impact on subjects with T2D. Twenty-eight studies were analysed. Evidence suggests an association between moderate wine consumption and the risk of developing T2D, with a J-shaped relationship, and reduced risk observed at low levels. This effect appears more pronounced with red wine, likely related to its higher polyphenol content, and when consumed with meals. On the other side, in patients with T2D, moderate wine consumption has been associated with a reduced risk of CV complications, nephropathy and mortality. It has also been linked to improved lipid profiles and reduced inflammatory markers, without adversely affecting body weight or glycaemic control in well-managed patients. These effects may be enhanced within a Mediterranean dietary pattern, suggesting synergistic actions. However, alcohol intake may increase the risk of hypoglycemia, particularly in patients receiving glucose-lowering therapies. It should be avoided by vulnerable individuals, and those with comorbidities such as MASLD and other significant liver diseases, peripheral neuropathy or other severe conditions. In conclusion, moderate wine consumption may be associated with a reduction in the risk of developing T2D and with several CV benefits in patients with T2D. Vulnerable patients should abstain and individuals who currently do not drink alcohol should not start drinking. If wine is consumed, intake should always remain moderate (as low as possible), within healthy meals and only after individual clinical assessment. Full article

Background/Objectives: Foot and ankle presentations during Hajj occur in a dense mass-gathering environment where prolonged walking, heat exposure, crowding, variable footwear, and limited self-care can interact with chronic disease and wound vulnerability. Previous Hajj studies have described foot injuries and diabetes-related complications, but less is known about whether simple high-risk foot documentation flags identify presentation records with higher care-pathway intensity. The primary objective was to estimate the presentation-level burden of core high-risk foot profiles among pilgrims presenting with foot and ankle conditions during Hajj 2025. Secondary objectives were to evaluate associations with a surgery-coded care-intensity indicator, hospital referral, and component heterogeneity. Methods: This observational presentation-level analysis included 3957 foot and ankle presentation records. The unit of analysis was the presentation/case record, not a unique individual pilgrim. A core high-risk foot profile was defined as diabetes, neuropathy, diabetic foot ulcer, foot ulcer, complications of open wound, or osteomyelitis. The primary outcome was a surgery-coded care-intensity indicator, defined solely from treatment documentation containing “Surgery” and interpreted as a care-pathway proxy rather than confirmed operating-room surgery. Logistic regression estimated crude and adjusted odds ratios (ORs); exploratory risk-category analyses assessed heterogeneity within the composite profile. Results: Core high-risk foot profiles were identified in 1793/3957 presentations (45.3%). The primary outcome occurred in 239/1793 high-risk presentations (13.3%) and 201/2164 non-high-risk presentations (9.3%), an absolute difference of 4.0 percentage points. The crude OR was 1.50 (95% CI 1.23–1.83; p < 0.001). The association persisted in the primary adjusted model (adjusted OR 1.47; 95% CI 1.20–1.79; p < 0.001) and in the extended clinical sensitivity model (adjusted OR 1.47; 95% CI 1.20–1.80; p < 0.001). Care pathways and secondary outcomes are summarized was also more frequent in high-risk presentations (12.2% vs. 9.8%; crude OR 1.28; 95% CI 1.05–1.57; p = 0.017). Exploratory category analysis showed that chronic-risk-only presentations had a primary outcome rate similar to non-high-risk presentations (9.0% vs. 9.3%), whereas ulcer/wound/deep-infection presentations had a higher rate (17.3%; crude OR 2.04; 95% CI 1.63–2.55; p < 0.001). Model discrimination was modest (C-statistics 0.55–0.64). Conclusions: Core high-risk foot flags were common among Hajj foot and ankle presentation records and were associated with surgery-coded care-intensity and referral documentation. However, the composite was clinically heterogeneous, the outcome was not a validated surgery endpoint, and the models were not prediction tools. These findings support cautious use of high-risk foot flags as operational prompts for assessment and pathway planning rather than as standalone clinical risk estimates. Full article

Background: Cancer pain affects approximately 44.5% of all patients with malignancy and up to 55–65% of those with advanced or metastatic disease; a substantial proportion remain inadequately controlled with conventional pharmacological approaches alone. Peripheral nerve stimulation (PNS), a minimally invasive neuromodulatory strategy, has emerged as a potential opioid-sparing analgesic option for the perioperative management of oncologic surgical patients. Objectives: This narrative review synthesizes current evidence on the application, mechanisms, clinical efficacy, safety, and integration of temporary and permanent PNS systems in cancer patients, with specific focus on cancer-specific pain syndromes, key clinical studies, opioid-sparing immunological implications, evidence quality, and directions for future research. Methods: As a narrative review, this work was structured in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA) to ensure methodological transparency. A focused, non-systematic literature search of PubMed/MEDLINE, Embase, and the Cochrane Library was performed from database inception through March 2026, supplemented by hand-searching of reference lists and targeted retrieval of clinical practice guidelines. Sources were selected on the basis of relevance to PNS or closely analogous peripheral neurostimulation modalities in oncologic, perioperative, or chronic pain contexts. Evidence was synthesized narratively, with each cited study graded using the Oxford Centre for Evidence-Based Medicine (OCEBM) 2011 Levels of Evidence framework to enable transparent calibration of confidence. Results: Available preliminary and largely extrapolated evidence supports PNS as a promising but not yet established useful adjunct in oncologic perioperative care; because cancer-specific data rest substantially on a single pilot study (n = 12), one retrospective review (n = 15), and extrapolation from non-cancer populations, these conclusions should be regarded as hypothesis-generating. Randomized controlled trial data from non-cancer cohorts demonstrate opioid consumption reductions of approximately 80–90% in the PAINfRE trial, while the post-amputation trial demonstrated ≥50% pain-relief responder rates and reductions in pain interference, with clinically meaningful improvements in pain and function. Oncologic-specific pilot and retrospective evidence confirms feasibility and a 58–67% success rate across diverse cancer pain subtypes. Conclusions: The opioid-sparing properties of PNS carry additional biological plausibility for preserving perioperative antitumor immune function. High-quality prospective trials specifically designed for oncologic surgical populations remain needed to establish evidence-based recommendations. Full article

Laser acupuncture, defined as photobiomodulation or low-level laser therapy applied to specific acupuncture points, has been proposed as a non-invasive adjunctive strategy in oral and dental care. This umbrella review aimed to synthesize and critically appraise systematic reviews evaluating laser acupuncture in dental and orofacial conditions. The review followed PRISMA 2020 recommendations and was prospectively registered in PROSPERO. PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 12 May 2026. Systematic reviews with or without meta-analysis were included. Methodological quality was assessed using AMSTAR 2, and findings were narratively synthesized considering methodological quality, overlap, consistency, dosimetric heterogeneity, and clinical applicability. From 263 records identified, six systematic reviews published between 2021 and 2024 met the eligibility criteria. The included reviews addressed three main domains: temporomandibular disorders, dental-related neuropathies, and pediatric dental outcomes. Laser acupuncture protocols used red to near-infrared wavelengths, mainly between 690 and 980 nm, but varied substantially in fluence, energy delivery, irradiation time, session frequency, and acupoint selection. The most consistent signal was observed for short-term pain reduction in temporomandibular disorders, although comparative evidence did not support laser acupuncture as superior to established conservative therapies. Evidence for dental-related neuropathies was associated with possible improvements in neurosensory and motor outcomes, while pediatric evidence suggested possible short-term changes in gag reflex, procedural pain, and bruxism-related outcomes; however, both domains were supported by only one systematic review each and should be considered preliminary and hypothesis-generating. No serious adverse events were reported, but harm reporting was limited. Overall, this umbrella review should be interpreted as an evidence map rather than as a source of high-certainty clinical recommendations. Laser acupuncture may represent an emerging adjunctive approach for selected dental and orofacial indications; however, current evidence remains limited and heterogeneous and does not support standardized protocols, stand-alone use, or definitive clinical recommendations. Full article

Background/Objectives: Paclitaxel is a chemotherapy drug used to treat various tumours, but its use is often limited by an acute and chronic pain syndrome that is poorly managed. Naringin and its aglycone, naringenin, exhibit antioxidant, antitumour, anti-inflammatory, and antinociceptive effects, making them potential alternative treatments. However, their low water solubility limits their oral bioavailability in humans. Micronisation in a supercritical medium reduces particle size and enhances the dissolution of compounds, offering a possible solution. In this study, we investigated whether micronising naringin and naringenin via supercritical technology could improve their dissolution and oral efficacy against paclitaxel-induced pain syndrome. Methods: Micronisation was performed using supercritical CO₂. Molecular docking was used to analyse the binding of naringin and naringenin to TRPV1, a key target for pain relief. Swiss mice were used in capsaicin (TRPV1 agonist)-induced nociception and paclitaxel-caused acute and chronic pain models. We assessed mechanical, cold, and heat sensitivity, potential adverse effects, and TRPV1 mRNA expression. Results: Micronisation improved the apparent dissolution profile of molecules. Docking results showed that naringin and naringenin bind to TRPV1. Both micronised compounds reduced capsaicin-induced nociception without affecting locomotion or body temperature. Micronised naringin and naringenin alleviated mechanical and cold allodynia, as well as thermal hyperalgesia in both acute and chronic paclitaxel-induced pain, outperforming their conventional forms. They also downregulated TRPV1 mRNA expression in the mice’s sciatic nerve. Conclusions: Taken together, these results show that supercritical micronisation improved the apparent dissolution and oral antinociceptive efficacy of naringin and naringenin, emphasising their potential as promising alternatives for managing paclitaxel-induced pain, with TRPV1 being a probable contributor to the observed antinociceptive effects. Full article

Diabetic neuropathy is a common and multifactorial complication of type 2 diabetes, in which genetic susceptibility is increasingly recognized as a contributing factor. This study (cross-sectional case–control) aimed to investigate the associations between previously identified genetic variants and clinically relevant neurophysiological and symptomatic parameters. A total of 48 individuals with type 2 diabetes (24 with neuropathy and 24 without) were included. Neuropathy was assessed using standardized neurological, sensory, and cardiovascular autonomic function tests. Genetic variants were selected in a prior discovery analysis of this same cohort and re-tested here, precluding independent validation. Associations between genetic variants and clinical parameters were assessed through group-based comparisons using Mann–Whitney U tests and Fisher’s exact test, correlation analysis using Spearman’s rank correlation, permutation-based testing to improve robustness, and multivariable linear regression adjusted for age and sex to account for potential demographic confounding (q < 0.1). Mann–Whitney U test analysis identified several associations between genetic variants and neuropathy-related clinical parameters. In the Mann–Whitney U test analysis, only the rs6682221 variant remained significantly associated with heat detection threshold in the left hand after false discovery rate correction (p = 0.000150; q = 0.02736), although this association did not remain significant in the complementary permutation analysis based on median differences. Spearman’s rank correlation analysis identified a significant positive association between rs6682221 allele burden and heat detection threshold in the left hand, which remained significant after permutation correction (r = 0.552, p = 0.000086, q = 0.016). Multivariable regression adjusted for age and sex revealed several independent associations between selected variants and sensory neuropathy-related parameters. These findings should be considered exploratory, as all analyses were performed within the original discovery cohort and no independent validation cohort was available. Independent replication and functional studies are required before any clinical relevance can be inferred. Full article

This study aimed to characterize cortical dysfunction and frequency-specific network reorganization following optic nerve injury using spin-exchange relaxation-free magnetoencephalography (SERF-MEG), and to assess the potential of MEG-derived multiscale features as sensitive functional biomarkers for clinical evaluation. In this prospective case–control study, SERF-MEG recordings were acquired during a pattern-reversal visual stimulation paradigm. Time-domain evoked components (M100/M135), global electrophysiological indices, energy-based metrics, and alpha- and beta-band phase-based functional connectivity were extracted. Network topology was quantified using graph-theoretical measures, including global and local efficiency, clustering coefficient, and assortativity. Group-level differences between patients and healthy controls were statistically analyzed. Patients showed significantly reduced M100/M135 amplitudes, prolonged M100 latency, and a lower early-component energy ratio. Functional connectivity was significantly decreased in the alpha and beta bands, accompanied by reduced global and local efficiency, mean strength, and clustering coefficient. Seed-based analyses revealed reduced connectivity predominantly in occipito-parietal and occipito-temporal pathways. SERF-MEG provides sensitive identification of cortical- and network-level functional impairments following optic nerve damage. MEG has significant clinical potential for disease diagnosis and therapy monitoring, providing a novel objective assessment tool for neuro-ophthalmological disorders. Full article

Physiotherapy is an evidence-based healthcare occupation aiming to collaborate in the diagnosis, prevention and treatment of a myriad of diseases and clinical scenarios throughout all stages of human life. Its development has been accelerated over the last two decades. The scope of physiotherapy is continuously evolvig. However, the accumulated evidence in the context of rare diseases is scarce. Remarkably, the opportunity for improvement and potential benefit for complex diseases with low prevalence is also very high, both as an isolated approach or within multidisciplinary specialized units. Systemic light-chain (AL) amyloidosis is a rare, chronic, complex, heterogeneous, incurable, and challenging disease, which may involve different organs and systems, including the heart, kidney, liver, peripheral nerves, lung, muscle, skin, and others. Heart is the most frequently involved organ leading to failure and arrhythmias. Peripheral neuropathy is a relatively frequent symptom. Renal, respiratory, and hepatic failure may also occur. The aim of this narrative review is summarizing, updating, and critically underlining potential new avenues of development on the role of physiotherapy in systemic light-chain (AL) amyloidosis, compared with its application in multiple myeloma, a closely related but not so rare entity. Full article

In 1988, plastic surgeon Lee Dellon in Annals of Plastic Surgery hypothesized that there was “A Cause for Optimism in Diabetic Neuropathy”. He noted that entrapment neuropathy is common in diabetic peripheral neuropathy (DPN) and explained that multiple sites of local nerve entrapment can also produce the classically described clinical picture of progressive and irreversible ‘length dependent axonopathy’. This observation has justified for him the use of nerve decompression (ND) surgery for beneficial treatment of DPN pain, diabetic foot ulcer (DFU), ulcer recurrences and their subsequent complications. Subsequent observational and controlled reports have consistently demonstrated post-operative benefit for these problems, but ND has not yet been widely adopted. The lack of an etiologic explanation of the physiology changes which would allow surgery to modify the metabolic disturbances of diabetes has likely been involved in such hesitance. Recent explanations that glycolysis is altered in diabetes through intensified polyol metabolism which produces swollen nerves, local peripheral entrapments and compression neuropathy now provide plausible associations of hyperglycemia with epidermal hypoxia and nutrition deficit. Recognition that nerve enlargements can create secondary fibro-osseous compressions explains the well-known association of diabetes and compression syndromes. Peripheral nerve entrapments damage small c-fibers and produce sympathetic autonomic as well as sensorimotor dysfunction. This explains the diminished skin microcirculation, epidermal hypoxia and nutrition deficit seen in diabetes, DPN, DFU and Charcot neuroarthropathy. Laboratory and clinical evidence has demonstrated that ND in diabetes rejuvenates at least two sympathetically commanded skin microcirculation processes and explains how surgery is producing beneficial results. This article recapitulates the literature which clarifies the processes by which ND surgery can modify painful DPN, DFU occurrence, ulcer healing, DFU recurrence risk, amputations after DFU healing, and bilateral pain relief after unilateral surgery. Full article

Background: Diabetic neuropathy (DN) is a common complication of diabetes mellitus that remains frequently undetected by conventional diagnostic methods. Sudomotor dysfunction, reflecting small-fiber impairment, has emerged as a potential early marker. SUDOSCAN, a rapid and non-invasive device measuring electrochemical skin conductance (ESC), has been proposed as a screening tool for early DN. The objective of this study was to systematically evaluate the diagnostic performance and clinical utility of SUDOSCAN in the early detection of DN. Methods: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. Studies assessing SUDOSCAN-derived ESC in adults with diabetes were included. Data on diagnostic accuracy, correlations with established neuropathy measures, and clinical applicability were extracted. Where feasible, pooled sensitivity and specificity were estimated using a random-effects model. Results: Fifteen studies (n = 7343 participants) were included in the qualitative synthesis, with five of them contributing to the quantitative analysis. Reduced ESC values were consistently associated with DN, including early and asymptomatic cases. Pooled sensitivity and specificity for detecting DN were 0.81 (95% CI 0.73–0.87) and 0.73 (95% CI 0.57–0.85), respectively. ESC values correlated with neuropathy severity scores and autonomic dysfunction measures. However, substantial heterogeneity was observed due to variability in diagnostic criteria, ESC thresholds, and study populations. Conclusions: SUDOSCAN is a feasible, rapid, and non-invasive tool for detecting DN, particularly in the early-stage or small-fiber disease. It shows promise as a screening and adjunctive diagnostic modality, especially when combined with established clinical tools. Nevertheless, the lack of standardized thresholds limits its standalone use. Full article

The immune response is essential in the protection of our body against pathogens; however, the inflammatory response caused by the immune system can become a disease itself. In fact, anti-inflammatory and immune-suppressive drugs are applied to limit the immune response to treat inflammatory diseases. Flavonoids are plant-derived polyphenols extensively investigated for their anti-inflammatory and antioxidant properties in inflammatory diseases. Studies applying isolated compounds as well as using supplements as nutraceuticals based on flavonoids have been conducted. Our review systematically analyzed the top five studied flavonoids between 2020 and 2025: quercetin (1742 articles), kaempferol (642), luteolin (589), apigenin (419), and epicatechin (354), highlighting their major therapeutic applications in diseases affecting the liver (12%), nervous system (11%), and lungs (10%). Mechanistically, these compounds act as multi-target agents mainly by inhibiting NF-κB and inducing Nrf2-dependent antioxidant programs. Application of advanced delivery systems, which increase oral bioavailability by up to 20-fold, overcomes pharmacokinetic bottlenecks. Clinical highlights demonstrated promising therapeutic effects, including reduced intrahepatic lipid accumulation in non-alcoholic fatty liver disease patients following quercetin supplementation (11.5% to 9.6%) and accelerated SARS-CoV-2 clearance after quercetin phytosome administration. The translation of flavonoids into standardized clinical therapies remains limited by the lack of large-scale, well-controlled clinical trials. Full article

Diabetic neuropathy (DN) is a multifactorial complication of diabetes mellitus driven by chronic hyperglycemia, insulin resistance, and disturbed metabolic homeostasis, leading to progressive injury of both the peripheral and central nervous systems. This study investigated whether L-serine supplementation could attenuate DN through dose-dependent metabolic and neuroprotective mechanisms in a high-fat diet (HFD) plus streptozotocin (STZ)-induced diabetic rat model. Male Wistar rats (n = 8 per group) were allocated to five groups: normal control (NC), diabetic control (DC), pioglitazone (PIO; 1.5 mg/kg/day), low-dose L-serine (S1; 200 mg/kg/day), and high-dose L-serine (S2; 400 mg/kg/day). After 60 days of oral gavage, behavioural testing, glucose and insulin profiling, HOMA-IR calculation, brain histopathology, nerve growth factor (NGF) immunohistochemistry, and LC–MS/MS-based proteomic analysis of cerebral tissue were performed. Diabetic rats exhibited marked hyperglycaemia (355.33 ± 4.72 mg/dL), hyperinsulinaemia, severe insulin resistance (HOMA-IR 16.8 ± 3.2; a 14-fold increase), impaired thermal nociception, motor dysfunction, and pronounced neuronal degeneration. L-serine supplementation significantly improved metabolic status: S1 reduced HOMA-IR by 77.4% and S2 by 87.5% relative to diabetic controls (p < 0.001). High-dose L-serine produced greater improvements in thermal sensitivity, motor coordination (rotarod latency 26.67 ± 1.52 s vs. 16.1 ± 0.85 s in DC; p < 0.05), and NGF expression (8.6-fold increase vs. DC). Histopathology confirmed attenuation of neuronal injury and gliosis in both treatment groups. Exploratory, group-level proteomic profiling identified dose-specific molecular signatures: S1 was predominantly associated with carbohydrate, lipid, and biosynthetic pathways, whereas S2 was associated with synaptic, neurotransmission-related, and proteostasis pathways. Within the constraints of an exploratory design—group-level pooled proteomics, analysis of cerebral rather than peripheral-nerve tissue, and only two doses—these findings indicate that L-serine attenuates the metabolic and behavioural features of experimental diabetic neuropathy and generates the testable hypothesis of dose-dependent neuro-metabolic remodelling. The proteomic signatures are hypothesis-generating and require orthogonal validation before any mechanistic or translational inference can be drawn. Full article

Diabetic foot ulcers represent a severe complication of diabetes mellitus, affecting millions of adults worldwide and often leading to hospitalization and amputation. Diabetic neuropathy increases the risk of plantar injuries, while the lack of continuous monitoring and delayed detection contributes to the progression of these lesions. This study presents a low-cost smart insole system for continuous plantar pressure monitoring and screening of plantar pressure patterns associated with diabetic neuropathy. The system integrates piezoresistive sensors distributed across key regions of the foot, connected to a low-power ESP32 microcontroller for data acquisition. Measurements are transmitted via Bluetooth Low Energy to a mobile application that enables real-time visualization, user management, and storage in a MySQL database for historical data consultation. Data processing employs a convolutional neural network configured to classify plantar pressure patterns between non-diabetic individuals and diabetic patients presenting neuropathic alterations. System validation demonstrated 88% accuracy, 88% recall, and 87% F1-score in classifying plantar pressure patterns. The results confirm that the combination of low-cost hardware and open-source software constitutes a viable and scalable solution for screening biomechanical alterations associated with diabetic foot complications. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

Background: Diabetic peripheral neuropathy (DPN) is a progressive complication of type 2 diabetes mellitus (T2DM) for which no approved disease-modifying therapy exists. Palmitoylethanolamide/Baicalin (PEA/Bai; Neuridase^®) is a nutraceutical formulation with anti-neuroinflammatory and antioxidant properties; however, real-world evidence on its associations with objective neuropathy biomarkers remains limited; nutraceutical approaches to DPN remain exploratory and adjunctive in the absence of randomised controlled trial evidence of disease modification. Methods: We conducted a single-centre, retrospective, 1:1 matched-cohort study at an Internal Medicine outpatient clinic. Forty-eight T2DM patients with clinically diagnosed DPN who received PEA/Bai supplementation (Neuridase^® group) were matched to 48 untreated controls drawn from a large institutional database, using age, sex, BMI, and diabetes duration as matching variables. Acknowledged a priori limitations include baseline imbalance in neuropathy severity (VAS and ESC) and SGLT2 inhibitor use, reflecting real-world prescribing patterns (confounding by indication) and constituting potential sources of residual confounding that preclude causal inference. The primary outcome was change in VAS neuropathic pain score from baseline (T0) to 6-month follow-up (T6). Secondary outcomes were changes in electrochemical skin conductance (ESC, µS) in hands, feet, and four-limb sum measured by Sudoscan. Results: At baseline, the Neuridase^® group exhibited significantly greater neuropathic burden: higher VAS scores (median 5.5 [IQR 3.8–7.2] vs. 2.0 [0.0–5.0]; p < 0.001) and lower ESC in both hands (53.0 vs. 72.2 µS; p < 0.001) and feet (74.5 vs. 81.0 µS; p < 0.001), reflecting real-world prescribing patterns. Over 6 months, VAS decreased significantly in the Neuridase^® group (5.5→3.0; p < 0.0001; median Δ = −2.5 points, exceeding the clinically important difference), with no change in controls (2.0→2.0; p = 0.85). Differential Sudoscan trajectories were observed: the Neuridase^® group showed significant improvement in hand ESC (53.0→60.0 µS; p = 0.035) and preservation of foot ESC (p = 0.888), while controls exhibited significant deterioration across all three sudomotor indices (hand p = 0.038; foot p = 0.008; four-limb sum p = 0.004). In a complementary categorical pain trajectory analysis, VAS worsening occurred in 31.3% of controls compared with 0% of Neuridase^®-treated patients (p = 0.00022). Among patients with pathological hand ESC at baseline (<60 µS), 27.8% of Neuridase^® patients (n = 36) transitioned to non-pathological values at T6 versus 0% of controls (n = 32; p = 0.001). Conclusions: In a real-world matched cohort, PEA/Baicalin supplementation was associated with clinically meaningful pain reduction and with differential longitudinal sudomotor trajectories compared to matched untreated controls. These exploratory, hypothesis-generating findings from a retrospective non-randomised design are consistent with possible modulatory effects of PEA/Baicalin on objective sudomotor autonomic biomarkers in DPN. Confounding by indication, baseline severity imbalance, and residual confounders including SGLT2 inhibitor use preclude causal interpretation. These observations provide a rationale for adequately powered, prospective, randomised placebo-controlled trials with extended follow-up and structural neuropathy endpoints. Full article