Risk Of Neuropathy Research Articles

Nonarteritic Anterior Ischemic Optic Neuropathy and the Risk of Dementia: A Nationwide Cohort Study.

While emerging theories suggest that vascular dysfunction may occur concurrently with the amyloid cascade in Alzheimer disease (AD) pathogenesis, the role of vascular components as primary neurodegeneration triggers remains uncertain. The aim of this retrospective, population-based cohort study conducted in Korea was to explore the link between nonarteritic anterior ischemic optic neuropathy (NAION) and dementia risk. In this nationwide, population-based, retrospective cohort study, we identified newly diagnosed NAION from 2010 to 2017 in the Korean National Health Insurance Service database. The primary outcome was new dementia diagnoses confirmed by new ICD-10 claims coupled with antidementia medication prescriptions. We assessed dementia risk using hazard ratios (HRs) with 95% CIs over an average 2.69-year follow-up after a 1-year lag period. The cohort consisted of 42,943 patients with NAION and 214,715 age-matched and sex-matched controls without NAION (mean age 61.37 years ± 10.75 SD, 55.48% female). The study found a higher risk of all-cause dementia (ACD; HR 1.28, 95% CI 1.20-1.36), AD (HR 1.27, 95% CI 1.18-1.36), vascular dementia (VaD; HR 1.31, 95% CI 1.09-1.58), and other dementia (HR 1.39, 95% CI 1.11-1.73) among patients with NAION, regardless of other potential confounding factors such as age, sex, lifestyle behaviors, economic status, and preexisting health conditions. In subgroup analysis, the associations between NAION and ACD were stronger in the younger age group (HR 1.83 for those younger than 65 years vs 1.23 for those 65 years or older; p for interaction <0.001). Moreover, the association of NAION with both ACD and VaD was particularly strong among current smokers. We found a significant association between NAION and increased risk for ACD, AD, VaD, and other dementia even after adjusting for potential confounders such as lifestyle, health conditions, and demographic factors within a nationwide cohort. This study highlights the potential role of vascular pathology in dementia progression and suggests that NAION may serve as a robust predictor for dementia, highlighting the need for comprehensive neurologic assessment in patients with NAION. Further research is needed to clarify the association between NAION and dementia risk.

Nonadherence to Cardiovascular Drugs Predicts Risk for Non-Arthritic Anterior Ischemic Optic Neuropathy: A Large-Scale National Study.

Purpose: While patients with cardiovascular comorbidities are at a higher risk for the occurrence of non-arteritic anterior ischemic optic neuropathy (NAION), it is unclear whether adherence to medication results in risk reduction. The purpose of this study was to investigate whether nonadherence to medical therapy for cardiovascular morbidity correlates with a higher risk for NAION when compared to patients with strict adherence. Methods: A retrospective case-control study was conducted among members of Clalit Health Services in Israel from 2001 to 2022. For each of the 757 NAION cases, three controls (totaling 2271 patients) were matched based on birth year and sex, with a propensity score analysis employed to adjust for a range of comorbidities. A patient was deemed nonadherent with medical treatment if their purchased quantity of medication was less than 60% of the prescribed annual dosage. Mixed models were used to evaluate exposure differences, and conditional logistic regression was applied, incorporating adjustments for socioeconomic status and ethnicity, to examine the impact of medication nonadherence on NAION risk. Results: A total of 3028 patients were included in the study; 757 patients with the diagnosis of NAION and 2271 in the matched control group. The average age of NAION patients was 69 ± 9 years and 55% were male. After adjustments for socioeconomic status and ethnicity, nonadherence to calcium channel blockers (CCBs) (odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.03-1.71) and anti-arrhythmic (OR: 5.67, 95% CI: 1.89-21.2) medications emerged as significant risk factors. Similarly, nonadherence to cardioprotective medications (OR: 1.46, 95% CI: 1.23-1.74) was also identified as a significant risk factor. Conclusions: Nonadherence to treatments for cardiovascular disease, specifically to medications known to improve prognosis, is associated with a higher risk for NAION.

Pre-treatment amino acids and risk of paclitaxel-induced peripheral neuropathy in SWOG S0221.

Chemotherapy-induced peripheral neuropathy (CIPN) is a treatment-limiting and debilitating neurotoxicity of many commonly used anti-cancer agents, including paclitaxel. The objective of this study was to confirm the previously found inverse association between pre-treatment blood concentrations of histidine and CIPN occurrence and examine relationships of other amino acids with CIPN severity. Pre-treatment serum concentrations of 20 amino acids were measured in the SWOG S0221 (NCT00070564) trial of patients with early-stage breast cancer receiving paclitaxel. The associations between amino acids and CIPN severity were tested in regression analysis adjusted for paclitaxel schedule, age, self-reported race, and body mass index with Bonferroni correction. The network of metabolic pathways of amino acids was analyzed using over-representation analysis. The partial correlation network of amino acids was evaluated using a debiased sparse partial correlation algorithm. In the primary analysis, histidine concentration was not associated with CIPN occurrence (odds ratio (OR) = 0.97 [0.83, 1.13], p = 0.72). In secondary analyses, higher concentrations of four amino acids, glutamate (β = 0.58 [0.23, 0.93], p = 0.001), phenylalanine (β = 0.54 [0.19, 0.89], p = 0.002), tyrosine (β = 0.57 [0.23, 0.91], p = 0.001), and valine (β = 0.58 [0.24, 0.92], p = 0.001) were associated with more severe CIPN, but none of these associations retained significance after adjustment. In the over-representation analysis, no amino acid metabolic pathways were significantly enriched (all FDR > 0.05). In the network of enriched pathways, glutamate metabolism had the highest centrality. This analysis showed that pre-treatment serum amino acid concentrations are not strongly predictive of CIPN severity. Prospectively designed studies that assess non-amino acid metabolomics predictors are encouraged.

Patterns of Physical Therapy Referral and Subsequent Attendance Among Childhood Cancer Survivors with Chemotherapy-Induced Peripheral Neuropathy at a Regional Childhood Cancer Survivorship Clinic

ObjectivesChildhood cancer survivors are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Physical therapy (PT) improves CIPN symptoms, but little is known about survivors’ PT utilization. We described characteristics of survivors with ≥ grade 2 CIPN, investigated PT referral and attendance, and described characteristics of survivors who attended and did not attend PT. MethodsChildhood cancer survivors <21 years old at cancer diagnosis and ≥2 years posttherapy, living in the United States, evaluated at a regional survivorship clinic were included in this retrospective analysis if they had motor CIPN. Symptomatic CIPN (≥grade 2 by Common Terminology Criteria for Adverse Events) and PT referral/attendance were tabulated. Patient characteristics from the medical record, and neighborhood characteristics (retrieved using survivors’ zip code from the National Neighborhood Data Archive) were described by group. ResultsAmong 91 survivors with CIPN (median 17.5 years old, 8.1 years postcancer diagnosis, 45.1% female), 35 (38.5%) had ≥ grade 2 CIPN. Survivors with ≥ grade 2 CIPN were 28.6% female, and 45.7% were <13 years old. Twenty-four (68.6%) survivors with ≥ grade 2 CIPN agreed to PT referral, and 15 (42.9%) attended PT. Among survivors who attended PT, 73.3% were <13 years old. Neighborhood characteristics of survivors included median percentage of adults without a high school diploma (6.7% PT attendees, 12.5% nonattendees), median percentage of adults who are foreign-born (11.5% PT attendees, 16.4% nonattendees), and median percentage of households with an annual income of <$15,000 (3.2% PT attendees, 6.5% nonattendees). ConclusionsWhile 68.6% of survivors with ≥ grade 2 CIPN were referred to PT, only 42.9% attended. Studies to better understand barriers to PT attendance and interventions to improve attendance are needed, especially in older survivors. Implications for Nursing PracticeNurses can play a key role in survivor education and care coordination to help optimize PT attendance.

Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials

ObjectiveTo evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis.MethodsThe literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens.ResultsA total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs.ConclusionIn summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.

Estimating risk of consequences following hypoglycaemia exposure using the Hypo-RESOLVE cohort: a secondary analysis of pooled data from insulin clinical trials

Aims/hypothesisWhether hypoglycaemia increases the risk of other adverse outcomes in diabetes remains controversial, especially for hypoglycaemia episodes not requiring assistance from another person. An objective of the Hypoglycaemia REdefining SOLutions for better liVEs (Hypo-RESOLVE) project was to create and use a dataset of pooled clinical trials in people with type 1 or type 2 diabetes to examine the association of exposure to all hypoglycaemia episodes across the range of severity with incident event outcomes: death, CVD, neuropathy, kidney disease, retinal disorders and depression. We also examined the change in continuous outcomes that occurred following a hypoglycaemia episode: change in eGFR, HbA1c, blood glucose, blood glucose variability and weight.MethodsData from 84 trials with 39,373 participants were pooled. For event outcomes, time-updated Cox regression models adjusted for age, sex, diabetes duration and HbA1c were fitted to assess association between: (1) outcome and cumulative exposure to hypoglycaemia episodes; and (2) outcomes where an acute effect might be expected (i.e. death, acute CVD, retinal disorders) and any hypoglycaemia exposure within the last 10 days. Exposures to any hypoglycaemia episode and to episodes of given severity (levels 1, 2 and 3) were examined. Further adjustment was then made for a wider set of potential confounders. The within-person change in continuous outcomes was also summarised (median of 40.4 weeks for type 1 diabetes and 26 weeks for type 2 diabetes). Analyses were conducted separately by type of diabetes.ResultsThe maximally adjusted association analysis for type 1 diabetes found that cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of neuropathy, kidney disease, retinal disorders and depression, with risk ratios ranging from 1.55 (p=0.002) to 2.81 (p=0.002). Associations of a similar direction were found when level 1 episodes were examined separately but were significant for depression only. For type 2 diabetes cumulative exposure to hypoglycaemia episodes of any level was associated with higher risks of death, acute CVD, kidney disease, retinal disorders and depression, with risk ratios ranging from 2.35 (p<0.0001) to 3.00 (p<0.0001). These associations remained significant when level 1 episodes were examined separately. There was evidence of an association between hypoglycaemia episodes of any kind in the previous 10 days and death, acute CVD and retinal disorders in both type 1 and type 2 diabetes, with rate ratios ranging from 1.32 (p=0.017) to 2.68 (p<0.0001). These associations varied in magnitude and significance when examined separately by hypoglycaemia level. Within the range of hypoglycaemia defined by levels 1, 2 and 3, we could not find any evidence of a threshold at which risk of these consequences suddenly became pronounced.Conclusions/interpretationThese data are consistent with hypoglycaemia being associated with an increased risk of adverse events across several body systems in diabetes. These associations are not confined to severe hypoglycaemia requiring assistance.Graphical

Volar versus Dorsal Plating for Fracture Distal Radius (A Systematic Review/Meta-Analysis)

Abstract Background Fractures of the distal radius are the most common of all orthopedic injuries accounting for nearly 16–20% of all fractures presenting to the emergency department. Treatment of distal radius fractures historically has been predominantly by inexpensive means as some surgeons advocate treatment by manipulation and plaster immobilization. Aim of the Work This study aims to review systematically and to meta-analyze the currently available literature regarding volar and dorsal plating for distal radial fractures regarding functional outcome and complications. Patients and Methods This study was approved by the Ethical Committee of Ain Shams University Faculty of Medicine. Written informed consent was not needed because of the study design(systematic review). Results The results of our study showed that there were significant difference between volar and dorsal groups regarding ROM (Flexion, Extension, Ulnar deviation and Radial deviation). Also we found significant difference regarding PRWE Score, DASH Score and complication rate. Also the results showed non significant difference between volar and dorsal plating groups regarding VAS Score for Pain, Grip Strength and ROM (Supination and Pronation). We also found the dorsal fixation offers a lower risk of neuropathy and carpal tunnel syndrome than the volar fixation, But a higher risk of tendon irritation and rupture in dorsal group so we recommend removal of dorsal plates after good healing and regain good range of motion. Conclusion In conclusion, Based on our outcomes of current systematic review and meta-analysis, it appears that fractures of distal radius treated previously with dorsal plating showed poor outcomes and unclear results, meanwhile more recent studies favored volar plating for fixation compared to indicated dorsal plating biased by these studies.

The synergistic impact of type 2 diabetes and MASLD on cardiovascular, liver, diabetes-related and cancer outcomes.

We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes. Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper .1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related, and cancer events over 5 years. Analysis 1 (n = 95 275): a co-diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver-related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co-diagnosis of MASLD significantly increased risk of all-cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation. T2D significantly potentiates the risk of cardiovascular, malignancy and liver-related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy.

Electrodiagnosis of polyneuropathy, organmegaly, endocrinopathy, M-protein, skin changes syndrome patients with peripheral neuropathy and potential-related risk factors

Objectives: To explore the correlation between classification and electrophysiology of polyneuropathy, organmegaly, endocrinopathy, M-protein, skin changes syndrome (POEMS)-related peripheral neuropathy (PN). Methods: We analyzed the data of 30 POEMS patients admitted to Zhongshan Hospital affiliated with Fudan University between February 2017 and February 2023. The degree of PN was determined according to its classification. All three groups of patients underwent neuroelectromyography, and the nerve conduction velocity and amplitude of the three groups were analyzed. Results: The compound motor active potentials (CMAP) of the peroneal, tibial, and ulnar nerves decreased significantly with increasing disease grade, and the motor conduction velocity of the peroneal, median, and tibial nerves decreased significantly in grade 3 compared with grade 1 and 2. The action potential of sensory nerves (sensory nerve action potential) and the conduction speed of sensory impulses (sensory conduction velocity (SCV) in the sural nerve in grade 3 were significantly lower than those in grades 1 and 2. Linear regression analysis showed that there was a linear correlation between CMAP of peroneal nerve and vascular endothelial growth factor. The SCV of the ulnar nerve significantly correlated with the course of the disease. Discussion: Neuroelectromyography can effectively evaluate the degree of PN in patients with POEMS, providing a reliable reference for further clinical treatment.

Risk of peripheral neuropathy in patients with psoriasis and psoriatic arthritis. A prospective cohort study.

Laboratory and clinical data suggest a link between neurologically mediated inflammation and psoriasis, but the risk and features of peripheral neuropathy in psoriasis or psoriatic arthritis remain unknown. The aim of this exploratory study was to evaluate the risk and to describe the features of peripheral neuropathy in patients with psoriasis and psoriatic arthritis. One hundred patients with psoriasis and/or psoriatic arthritis and 100 control subjects were consecutively enrolled. Diagnostic confirmation included electrophysiological examination, skin biopsy, and nerve ultrasound for confirmed polyneuropathy. Nine patients were diagnosed with confirmed polyneuropathy, while none of the control subjects had the condition (relative risk [RR] = 19.00, 95% confidence interval [CI] = 1.12-322.11). Specific relative risks for polyneuropathy were 22.09 (95% CI = 1.17-416.43) in psoriasis patients and 18.75 (95% CI = 1.07-327.62) in psoriatic arthritis patients. The observed polyneuropathy in all nine patients was length-dependent, symmetrical, and predominantly sensory, with minimal or no disability. Comorbidities and exposure to therapies known to increase the risk of polyneuropathy were more frequent in psoriasis and/or psoriatic arthritis patients compared to controls (42% vs. 4%, p = .0001). Analyzing data after excluding possible contributory causes, the risk of polyneuropathy in patients with psoriasis and/or psoriatic arthritis was not significant. Psoriasis and psoriatic arthritis appear to be associated with an increased risk of polyneuropathy. This increased risk seems to be linked to the higher prevalence of contributing factors for polyneuropathy, rather than a direct increase in neuropathy risk specifically related to psoriasis and psoriatic arthritis.

Graves' orbitopathy as the cause of diplopia in old age-Differences between young and old

Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue. The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 ≤50 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses. Younger patients (n = 484) presented significantly more frequently with milder EO (53% vs. 33%, p < 0.0001), whereas older patients (n = 448) more frequently suffered from moderate or severe forms (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310° vs. 330°, both p < 0.0001, CAS 2.1 vs. 1.7, p = 0.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR = 0.12, 95 % CI 0.1-0.2, p < 0.0001), followed by orbital irradiation and age. In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age.

Prediabetes: A Benign Intermediate Stage or a Risk Factor in Itself?

Prediabetes is a condition when the blood glucose levels are above the normal range but below the threshold for defining diabetes. Previously considered benign, it is now recognized to be associated with various macrovascular and microvascular complications, with increases in the risk of cardiovascular events, nephropathy neuropathy, and retinopathy. Early identification of prediabetics may help detect the risk for these future complications at an earlier stage. Moreover, therapeutic options for prediabetes are available, which can retard its progression to diabetes and the subsequent development of complications. Hence, we make a case for the early identification of prediabetes through screening methods and appropriate institution of management strategies.

ECOG-ACRIN EAZ171: Prospective validation trial of germline variants and taxane type in association with taxane-induced peripheral neuropathy (TIPN) in Black women with early-stage breast cancer.

LBA503 Background: Black women experience higher rates of TIPN compared to White women when receiving weekly paclitaxel (WP) for early-stage breast cancer. This disparity impacts health equity, as TIPN leads to more frequent dose reductions and higher recurrence rates in Black women. Conversely, disparities in TIPN by race are not seen in women receiving every three-week docetaxel (3D). Further, retrospective analyses have identified specific genotypes associated with differential risk of grade 2-4 TIPN in women of African ancestry receiving WP . The primary aim of EAZ171 was to prospectively validate germline predictors of TIPN in Black women receiving WP. Secondary objectives included comparing rates of TIPN and dose reductions in Black women receiving WP compared to 3D. Methods: Women with early-stage breast cancer who self-identified as Black and were planned by physician choice to receive (neo)adjuvant WP (80mg/m2 x 12 doses) or 3D (75 mg/m2 x 4-6 doses) were eligible. Genotyping determined germline neuropathy risk, defined as high ( FCAMR homozygous wt or SBF2 mutated) or low (variant allele in FCAMR and SBF2 wt). Grade 2-4 TIPN by physician-reported CTCAE v.5 was compared between high vs. low risk genotypes, and between the WP vs. 3D arms at one year using Fisher exact tests with two-sided alpha of 0.1. Patient-rated TIPN was captured using PRO-CTCAE items, and patient-reported outcomes (PROs) assessed TIPN symptoms and functional interference (FACT/GOG-NTx, EORTC CIPN20). Results: 249 patients were enrolled between 6/27/19-3/31/22, including 121 receiving at least one dose of WP and 118 receiving a dose of 3D. Of those with genotype data, 91/117 (77.8%) in the WP arm and 87/118 (73.7%) in the 3D arm were classified as high risk. Physician-reported grade 2-4 TIPN was not significantly different in the high vs. low risk genotype groups with WP (47% vs. 35% p=0.27) nor with 3D (28% vs. 19% p=0.47). Grade 2-4 TIPN was significantly higher in the WP vs. 3D arm by physician-rated CTCAE (45% vs. 29% p=0.02) and PRO-CTCAE (40% vs. 24% p=0.03). Trends in worsening neuropathy scores were similar over time using the FACT/GOG-NTx and EORTC CIPN20 questionnaires, but were not significantly different between the two arms at 1 year. Patients receiving WP required more dose reductions due to TIPN (28% vs. 9% p&lt;0.001) or due to any cause (39% vs. 25% p=0.02) than patients receiving 3D. Conclusions: In this prospective trial enrolling only Black women with breast cancer, germline variation did not significantly impact risk of TIPN with WP or 3D. However, 3D was more tolerable evidenced by less grade 2-4 TIPN and fewer dose reductions compared to WP. Given the disparate burden of TIPN and its potential impact on cure rates, this trial suggests docetaxel should be considered the preferred taxane for Black women with early-stage breast cancer. Clinical trial information: NCT04001829 .

Long-term sensorimotor changes after a sciatic nerve block with bupivacaine and liposomal bupivacaine in a high-fat diet/low-dose streptozotocin rodent model of diabetes

IntroductionIt is unclear whether patients with diabetes are more susceptible to nerve toxicity of local anesthetics or whether nerve blocks can accelerate the progression of diabetic peripheral neuropathy. Bupivacaine is one of the most widely used local anesthetics for regional anesthesia despite many pre-clinical studies demonstrating neurotoxicity. Herein, we report the long-term functional consequences of sciatic nerve block with bupivacaine and liposomal bupivacaine (Exparel®) in an animal model of diabetes.MethodsMale Sprague Dawley rats were subject to standard chow/vehicle or high-fat diet/low-dose streptozotocin to induce a diabetic phenotype. Animals were then subdivided into groups that received repeated sciatic nerve blocks of saline, bupivacaine, or liposomal bupivacaine. Mechanical allodynia and thermal hyperalgesia were assessed prior to and 12 weeks following nerve blocks utilizing the von Frey and Hargreaves tests, respectively. Exploratory and locomotor activity were assessed with open field testing, and nerve conduction velocity testing was conducted prior to the termination of the study at 28 weeks.ResultsAnimals in the diabetic group developed sustained hyperglycemia &amp;gt;200 mg/dl and signs of peripheral neuropathy six weeks after treatment with streptozotocin, which persisted until the end of the study. Twelve weeks after a repeated sciatic nerve block with saline, bupivacaine, or liposomal bupivacaine, results indicate significant interaction effects of the disease group (control vs. diabetic) and local anesthetic treatment. Overall, diabetic status resulted in worse sensorimotor function compared to control animals. Treatment with perineural bupivacaine resulted in worse sensorimotor functions in both control and diabetic animals. Furthermore, bupivacaine treatment in diabetic animals with pre-existing neuropathy exacerbated sensorimotor function in some measures. In contrast, liposomal bupivacaine did not appear to cause any negative effects on functional outcomes for control or diabetic animals.ConclusionOur data indicate that bupivacaine, and not liposomal bupivacaine, causes long-term changes in tactile allodynia, thermal hyperalgesia, locomotor behaviors, and nerve conduction velocity in control as well as a high-fat diet/low-dose streptozotocin rodent model of diabetes. These results highlight the necessity to investigate safe peripheral nerve block strategies to preserve long-term functional independence in patients with or at risk for diabetic peripheral neuropathy.

ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-Induced Peripheral Neuropathy in Black Women With Early-Stage Breast Cancer.

Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer. Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity. Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02). Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel.

Evaluation of the Relationship Between Microalbuminuria/Creatinine Ratio and QTc Dispersion in Type 2 Diabetes Mellitus

Objective: The assessment of QTc dispersion (QTd) is of importance in determining the risk of ventricular arrhythmias and cardiac autonomic neuropathy (CAN) in patients with diabetic nephropathy (DN). Our study explored the relationship between the microalbumin/creatinine (MA/crea) ratio and QT(cd) in the context of CAN development in DN. Material and Methods: We selected fifty individuals with a spot urine MA/crea ratio of less than 30 as the control group and fifty individuals with an MA/crea ratio between 30 and 300 as the patient group. QT intervals were calculated using the Bazett formula, taking into account the heart rate. Results: In contrast to the control group, the patient group exhibited a considerably higher median QTc min value (380.63 msn, 361.44–397.30, p: 0.042) and a statistically significant increase in the median QTc max value (439.98 msn, 420.17–460.22, p=0.005). Furthermore, the median MA/crea value (82, 60–300, p&lt;0.0001) was found to be highly significant. However, the median QT(cd) value (61.25 msn, 49.91–81.70, p=0.066) was only marginally significant, with no statistically significant difference between the two groups. It is worth noting that both groups showed a significant difference in terms of QTd (p&lt;0.001). In the control group, where DN had not yet developed, the QT(cd) value could be detected before an increase in the MA/crea value. Conclusion: The findings that both the control group and the patient group exhibited elevated QTcd values suggest that this parameter may be a viable predictor of cardiovascular risk. Furthermore, it is conceivable that QTcd could serve as an early warning sign for cardiovascular risk in diabetic patients who have not yet reached the stage of microalbuminuria.

Comparison of intraocular pressure and anterior segment parameters in subjects with asymmetrical primary angle closure disease.

To compare intraocular pressure (IOP) and anterior segment parameters between eyes with unilateral primary angle closure glaucoma (PACG) and their fellow eyes with primary angle closure (PAC) or primary angle closure suspect (PACS). Subjects underwent anterior segment imaging using 360-degree swept-source optical coherence tomography (SS-OCT, CASIA Tomey, Nagoya, Japan) and ocular investigations including gonioscopy and IOP measurement. Each SS-OCT scan (divided into 8 frames, 22.5 degrees apart) was analysed and an average was obtained for the following anterior segment parameters: iridotrabecular contact (ITC), angle opening distance (AOD750), iris thickness and curvature, anterior chamber width, depth and area (ACW, ACD and ACA) and lens vault (LV). Among 132 unilateral PACG subjects (mean age: 62.91 ± 7.2 years; 59.1% male), eyes with PACG had significantly higher presenting IOP (24.81 ± 0.94 vs. 18.43 ± 0.57 mmHg, p < 0.001), smaller gonioscopic Shaffer grade (2.07 ± 0.07 vs. 2.31 ± 0.07, p < 0.001) and a greater extent of peripheral anterior synechiae (PAS, 1.21 ± 0.21 vs. 0.54 ± 0.16 clock hours, p = 0.001). PACG eyes also exhibited increased ITC, ITC area, greater LV and smaller AOD750, ACD and ACA (all p < 0.05). Using the forward stepwise regression model, an increase in 1 mmHg in presenting IOP before laser peripheral iridotomy (LPI)increases the odds of having PACG by 9% (95% confidence interval 5%-14%). PACG eyes have higher presenting IOP, smaller anterior segment parameters, greater extent of PAS, and larger LV compared to their fellow eyes with angle closure. Narrower anterior chamber dimensions and higher presenting IOP before LPI may increase risk of chronic elevated IOP and glaucomatous optic neuropathy after LPI.

Causal relationships between gut microbiota, gut metabolites, and diabetic neuropathy: A mendelian randomization study

BackgroundPrevious studies have shown a strong correlation between gut microbiota and diabetes and its associated complications. We aimed to evaluate the causal relationships between the gut microbiota, gut metabolites, and diabetic neuropathy. MethodsSummary statistics of 211 gut microbiota and 12 gut-related metabolites (β-hydroxybutyric acid, betaine, trimethylamine-N-oxide, carnitine, choline, glutamate, kynurenine, phenylalanine, propionic acid, serotonin, tryptophan, and tyrosine) were obtained from previous genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) design was used to estimate the effects of gut microbiota and gut metabolites on the risk of diabetic neuropathy based on FinnGen GWAS. ResultsHigher levels of Acidaminococcaceae (OR=0.62; 95%CI=0.46 to 0.84; P=0.002), Peptococcaceae (OR=0.70; 95%CI=0.54 to 0.90; P=0.006), and Eubacterium coprostanoligenes group (OR=0.68; 95%CI=0.50 to 0.93; P=0.016) are genetically determined to provide protection against diabetic neuropathy. Conversely, the presence of Alistipes (OR=1.65; 95%CI=1.18 to 2.31; P=0.003), Christensenellaceae R7 group (OR=1.52; 95%CI=1.03 to 2.23; P=0.033), Eggerthella (OR=1.28; 95%CI=1.05 to 1.55; P=0.014), Ruminococcaceae UCG013 (OR=1.35; 95%CI=1.01 to 1.82; P=0.046), and Firmicutes (OR=1.42; 95%CI=1.05 to 1.93; P=0.023) increases the risk of diabetic neuropathy. Moreover, a correlation has been identified between diabetic neuropathy and two gut metabolites: betaine (OR=0.95; 95%CI=0.90 to 1.00; P=0.033) and tyrosine (OR=1.03; 95%CI=1.01 to 1.06; P=0.019). Sensitivity analysis indicated robust results with no sign of heterogeneity or pleiotropy. ConclusionThe present study elucidated the impact of specific gut microbiota and gut metabolites on the susceptibility to diabetic neuropathy. Interventions targeting the improvement of the gut microbiota diversity and composition hold considerable promise as a potential strategy.

Fabrication of Ciprofloxacin-Loaded Sodium Alginate Nanobeads Coated with Thiol-Anchored Chitosan Using B-390 Encapsulator Following Optimization by DoE.

Most infectious diseases of the gastrointestinal tract can easily be treated by exploiting the already available antibiotics with the change in administration approach and delivery system. Ciprofloxacin (CIP) is used as a drug of choice for many bacterial infections; however, long-term therapy and off-site drug accumulation lead to an increased risk of tendinitis and peripheral neuropathy. To overcome this issue, nanotechnology is being exploited to encapsulate antibiotics within polymeric structures, which not only facilitates dose maintenance at the infection site but also limits off-site side effects. Here, sodium alginate (SA) and thiol-anchored chitosan (TC) were used to encapsulate CIP via a calcium chloride (CaCl2) cross-linker. For this purpose, the B-390 encapsulator was employed in the preparation of nanobeads using a simple technique. The hydrogel-like sample was then freeze-dried, using trehalose or mannitol as a lyoprotectant, to obtain a fine dry powder. Design of Experiment (DoE) was utilized to optimize the nanobead production, in which the influence of different independent variables was studied for their outcome on the polydispersity index (PDI), particle size, zeta potential, and percentage encapsulation efficiency (% EE). In vitro dissolution studies were performed in simulated saliva fluid, simulated gastric fluid, and simulated intestinal fluid. Antibacterial and anti-inflammatory studies were also performed along with cytotoxicity profiling. By and large, the study presented positive outcomes, proving the advantage of using nanotechnology in fabricating new delivery approaches using already available antibiotics.

Abstract PS02-05: Trajectories and predictors of peripheral neuropathy after neoadjuvant chemotherapy in a prospective cohort of 11,014 patients with early breast cancer

Abstract Background Peripheral neuropathy (PN) is a debilitating adverse event in patients with early breast cancer (BC) receiving (neo)adjuvant chemotherapy (CT). We harnessed the CANTO cohort study to detail clinical trajectories and explore clinical and genetic predictors of PN. Methods CANTO (CANcer TOxicities - NCT01993498) prospectively enrolled invasive stage I-III BC patients (pts) of 26 French comprehensive cancer centers. Pts were assessed at diagnosis, 3-6 (M6), 12 (M12), 36 (M36), and 60 (M60) months after treatment, defined as completion of surgery, CT or radiotherapy, whichever comes last. At each time point, PN events including paresthesia, sensory and motor neuropathy were collected according to NCI-CTC v4.0 criteria. A genome-wide association study (GWAS) was conducted to identify genetic predictors of PN, using Illumina GSA BeadChips. Minimac4/1000G was used to impute additional single nucleotide polymorphisms (SNPs). After stringent quality control measures, 1,894,475 SNPs with a minor allele frequency (MAF) &amp;gt;0.05 were evaluated. Longitudinal trajectories of PN events were descriptively examined. Statistical associations between each SNP and PN events measured at different time points, and between SNPs and trajectories, were performed with logistic regression assuming a log-additive genetic model. All analyses were adjusted for key clinical parameters and the first ten axes of principal component analysis of the genetic data to control for population stratification. Results Of 12,012 included pts (data lock Aug. 2022), 11,014 (91.7%) were analyzed. Age was &amp;lt; 50 and &amp;gt;65 in 3407 and 2759 pts (31% and 25%, respectively). Overweight/obesity and diabetes were recorded in 5328 (48%) and 458 pts (4%). A neurologic history was observed in 1360 pts (13%). Stage 0-I and II-III were observed in 5356 (49%) and 5512 pts (51%), and 4011 pts had an axillary dissection (37%). CT was administered in 5790 pts (53%), including a taxane (tax) in 5542 pts (96%). Shortly, all grade and grade 2+ PN was observed in 29% and 12%; 27% and 10%; 20% and 10%; 13% and 10% of pts at M6, M12, M36 and M60, respectively. We derived 5 trajectories of overall PN, deemed “never”, “always”, “appears”, “transient” and “disappears”, in respectively 54%, 10%, 9%, 7% and 19% of the pts. Similar trajectories were built for the 3 categories of PN events. We built 9 predictive nomograms including key clinical parameters and time of analysis. E.g., grade 2+ PN at M6 was independently predicted by a medical history of carpal tunnel syndrome, past neurologic history and exposure to tax. Grade 2+ PN at M36 was predicted by past neurologic history and exposure to tax, and largely by previous PN at M6 or M12. The GWAS analysis included 7633 pts (84%). Four independent SNPs adding predictive value to the clinical nomograms were identified at a suggestive level of association (p &amp;lt; 1e-6), including one SNP in the NCAM1 gene (involved in neurogenesis) for M6 PN (OR=1.40, 95%CI 1.23-1.60, p=4.8e-7, see table) and one SNP in the CLDN11 gene (regulates oligodendrocytes) for M12 sensory PN (OR=1.32; 95%CI 1.17-1.49, p=7.5e-6). For rare ( &amp;lt; 5%) toxicities, 10 independent suggestive SNPs were identified, including one SNP in the NELL1 gene (neural cell growth regulation and differentiation) for the “always” trajectory (OR=1.61, 95%CI 1.31-1.99, p=7.6e-6) and one SNP in the KCNIP1 gene (neuronal sensor) for M36 motor PN (OR=1.5, 95%CI 1.7-3.5, p=3.1e-07). Conclusions Risk of early peripheral neuropathy is associated with previous neurological history and taxane exposure. Patients with PN at M6 or M12 are highly exposed to long-term PN. Some key SNPs may add independent predictive value for specific PN endpoints. Exploratory results of interest were produced for rarer toxicities and typical clinical trajectories. Detailed results will be presented at the meeting. All PN, M6 Multivariate analyses of the risk of peripheral neuropathy, all grades, at M6, without and with GWAS input. Citation Format: Youenn Drouet, Emilie Thomas, Florence Lerebours, Barbara Pistilli, Olivier Trédan, Christelle Jouannaud, Marion Fournier, Philippe Rouanet, Laurence Vanlemmens, CHARLES COUTANT, Asma Dhaini Merimeche, Baptiste Sauterey, Christelle Levy, Mario Campone, Carole Tarpin, Marie-Ange Mouret-Reynier, Olivier Rigal, Thierry Petit, Sophie Guillermet, Antoine Arnaud, Mahmoud Ibrahim, Sylvie Giacchetti, Florence Dalenc, Johanna Wassermann, Olivier Arsène, Ariane Darut-Jouve, Sibille Everhard, Ines Vaz Luis, Anne-Laure Martin, Fabrice André, Jean-François Deleuze, Alain Viari, Matthieu Carton, Paul Cottu. Trajectories and predictors of peripheral neuropathy after neoadjuvant chemotherapy in a prospective cohort of 11,014 patients with early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-05.