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Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously ( n  = 148) or placebo ( n  = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.

Abstract Context Hypoglycemia-associated autonomic failure (HAAF), defined as blunting of counterregulatory hormone and symptom responses to recurrent hypoglycemia, remains a therapeutic challenge in diabetes treatment. The opioid system may play a role in HAAF pathogenesis since activation of opioid receptors induces HAAF. Blockade of opioid receptors with intravenous naloxone ameliorates HAAF experimentally yet is not feasible therapeutically. Objective To investigate the effects of opioid receptor blockade with intranasal naloxone on experimentally induced HAAF. Design Randomized, double-blinded, placebo-controlled crossover study. Setting Academic research center. Participants Healthy nondiabetic volunteers. Interventions Paired 2-day studies, 5 to 10 weeks apart, each consisting of 3 consecutive hypoglycemic episodes (hyperinsulinemic hypoglycemic clamps, glucose nadir: 54 mg/dL): 2 on day 1 with administration of intranasal naloxone vs placebo, followed by the third episode on day 2. Main Outcome Measures Differences in counterregulatory hormones responses and hypoglycemia symptoms between first and third hypoglycemic episodes in naloxone vs placebo studies. Results Out of 17 participants, 9 developed HAAF, confirming variable interindividual susceptibility. Among participants susceptible to HAAF, naloxone maintained some hormonal and symptomatic responses to hypoglycemia and prevented the associated requirement for increased glucose infusion. Unexpectedly, naloxone reduced plasma epinephrine and GH responses to the first hypoglycemic episode but prevented further reduction with subsequent hypoglycemia. Conclusion This is the first study to report that intranasal naloxone, a widely used opioid receptor antagonist, may ameliorate some features of HAAF. Further investigation is warranted into mechanisms of variable interindividual susceptibility to HAAF and the effects of intranasal naloxone in people with diabetes at risk for HAAF.

Background Previous studies have shown that increasing body mass index (BMI) was associated with decreased hypoglycemia in type 2 diabetes, but it remains uncertain whether this finding could be applied to patients with and without cardiac autonomic neuropathy (CAN). Methods The study included 7789 participants with type 2 diabetes from action to control cardiovascular risk in diabetes (ACCORD) trail. CAN was defined as SDNN < 8.2 ms and RMSSD < 8.0 ms. Obesity was defined as BMI ≥ 30 kg/m 2 . Outcomes were identified as severe hypoglycemia requiring any assistance (HAA) or requiring medical assistance (HMA). We assessed the association between obesity and severe hypoglycemia in type 2 diabetes with or without CAN using COX regression models adjusted for baseline characteristics. Results Over a median follow-up of 4.7 years, a total of 893 participants developed HAA and 584 participants developed HMA. Compared with non-obesity, obesity was associated with lower risk of severe hypoglycemia (HAA: hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.38–0.68, P  < 0.001; HMA: HR 0.57, 95% CI 0.40–0.82, P  = 0.002) in CAN present group, but not in CAN absent group (HAA: HR 0.98, 95% CI 0.83–1.16, P  = 0.830; HMA: HR 0.97, 95% CI 0.79–1.19, P  = 0.754). Similarly, increasing BMI was associated with reduced severe hypoglycemic events in participants with CAN, but not in participants without CAN. Conclusions CAN modifies the association between obesity and hypoglycemia in type 2 diabetes. Type 2 diabetic individuals with CAN who are under weight control should pay attention to hypoglycemic events. Trial registry http://www.clinicaltrials.gov . Unique identifier: NCT00000620.

Paroxysmal sympathetic hyperexcitation (PSH) refers to a clinical syndrome characterized by a sudden increase in sympathetic excitability caused by severe brain injury. This study aims to investigate the effectiveness and practicality of combining transcranial direct current stimulation (tDCS) with medication to treat PSH and employ non-linear electroencephalography (EEG) to assess changes in cortical activation post-intervention. 40 PSH patients were randomly assigned to receive either active tDCS or sham tDCS treatment over an 8-week period. The tDCS stimulation targeted the prefrontal area, left frontal-temporal-parietal cortex, right frontal-temporal-parietal cortex, and left dorsolateral prefrontal cortex. Both patient groups also underwent medication and other conventional therapies. The Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM), Coma Recovery Scale-Revised (CRS-R), medication dosage, and approximate entropy (ApEn) index were assessed before and after treatment. The active tDCS group exhibited more substantial improvements in changes of PSH-AM, changes of CRS-R, and medication reduction ratios compared to the sham tDCS group after the treatment. After treatment and during follow-up, a significantly greater number of patients in the active tDCS group demonstrated clinically important differences compared to the sham tDCS group. The active tDCS group showed significantly higher ApEn indices in the less affected frontal lobe compared to the control group. No significant differences in ApEn indices were noted in the sham tDCS group before and after treatment. Regression analysis revealed that the group (active tDCS/sham tDCS) was the primary factor associated with improving PSH-AM. Therefore, we believe that in patients with PSH, combining tDCS with medication therapy demonstrated superior clinical efficacy compared to medication therapy alone. Electrophysiological results also indicated enhanced cortical excitability. Therefore, this single-center pilot study suggests that multi-target, multi-session tDCS combined with medication may be an effective treatment protocol for PSH.

IntroductionCardiovascular autonomic neuropathy (CAN) is a serious, untreatable complication of diabetes that contributes to excess cardiovascular mortality and morbidity. CAN is associated with increased fibrosis and inflammation, possibly driven by increased sympathetic activity and overactive mineralocorticoid receptors (MRs). These may represent a potential therapeutic target. MR antagonists (MRAs) improve autonomic function in non-diabetic diseases, and finerenone, a non-steroidal MRA, has demonstrated promising results in managing diabetic kidney disease and cardiovascular complications, suggesting its potential as a novel therapy for early-stage CAN. This trial aims to evaluate whether daily administration of finerenone can modify the disease progression of early-stage CAN.Methods and analysisThis trial is a two-centre, double-blind, parallel-group, 1:1 randomised, placebo-controlled study evaluating the effect of 78 weeks of intervention with finerenone or placebo on early-stage CAN in 100 individuals with type 2 diabetes in Denmark. The primary endpoint is the between-group difference in the expiration:inspiration ratio of the cardiovascular autonomic reflex tests (CARTs). Secondary endpoints are the between-group differences in the remaining CARTs, heart rate variability measures and fibrosis markers. Treatment effects on other forms of neuropathy and related pathological mechanisms will be explored.Ethics and disseminationThe study complies with the Declaration of Helsinki and the International Counsil for Harmonisation good clinical practice guidelines, with ethics approval obtained from the Danish Medical Research Ethics Committee. All participants will provide written informed consent. Due to the risk of hyperkalaemia associated with finerenone, safety will be closely monitored throughout the study. Findings will be disseminated through peer-reviewed publications, conference presentations and clinical trial registries. A lay summary will be provided to participants on study completion.Trial registration numberClinicalTrials.gov: NCT06906081; registration date: 25 March 2025. Clinical Trials Information System: EUCT no. 2024-516597-30-00; registration date: 3 September 2024.

Purpose This study aimed to explore the possible range of change of a single-session music intervention (SMI) on symptom clusters and neurological reactivity for women with breast cancer undergoing chemotherapy. Methods A parallel and randomized, controlled study with repeated measures design was used. A total of 100 women with breast cancer were randomly assigned to the SMI or a control group. The outcome measurements of symptom cluster were collected using the Multidimensional Fatigue Symptom Inventory, Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the neurological reactivity with heart rate variability at four time points: before commencement of the intervention (T0), immediately afterward (T1), 1 week later (T2), and 3 weeks after the intervention (T3). Results Of the 50 women in each group, 46 in the SMI and 48 in the control group completed the post-test at T3. Multivariate analysis of variance indicated that the SMI group had a medium effect in change of symptom clusters compared to the control group at T2. Moreover, after adjusting for baseline between normal and higher levels of sympathetic tone activity, significant differences existed in fatigue and depression at T2 and sleep disturbance at T3. Conclusions A single-session music intervention can be effectively used to reduce symptom clusters for women with breast cancer. Targeting those who have a higher level of sympathetic tone activity is recommended.

Multiple sclerosis (MS) can induce cardiac autonomic dysfunction identified by a decreased heart rate variability (HRV) which was linked to oxidative stress, vitamin D deficiency and sleep disturbance. Previous MS studies revealed the antioxidant and anti-inflammatory effects of exogenous melatonin, as well as its benefits on sleep and vitamin D. We aimed to investigate the change in HRV, oxidative stress, systemic inflammation and sleep following melatonin supplementation in MS patients. Participants were randomly allocated to either a melatonin group (MG, n = 15) or a placebo group (PG, n = 12) (3 mg/night during 12 weeks). Pre- and post-tests included HRV analysis (Kubios software), sleep dairy and biological analysis [oxidative stress biomarkers (malondialdehyde (MDA), advanced oxidation protein products (AOPP) and reduced glutathione (GSH)); 25-hydroxyvitamin D; C-reactive protein and cholinesterase Gen.2 (CHE2)]. Based on the pre-post supplementation change (Δ (T1₋T0)), melatonin increased the root mean square of successive differences between normal heartbeats [ΔMG (14.17 ± 16.93) vs. ΔPG (₋8.61 ± 12.67), p = 0.0007] and the HRV high-frequency band [ΔMG (6.86 ± 14.85) vs. ΔPG (₋12.58 ± 13.30), p = 0.0016] comparatively with placebo. MG showed a decrease in the HRV low-frequency band [ΔMG (₋4.96 ± 10.08) vs. ΔPG (10.22 ± 13.54), p = 0.003] as well as in the MDA [ΔMG (₋2.27 ± 1.92) vs. ΔPG (0.22 ± 2.30), p = 0.005] and AOPP levels [ΔMG (₋113.97 ± 137.72) vs. ΔPG (156.46 ± 230.52), p = 0.0008] compared with PG. Melatonin enhanced the GSH [ΔMG (10.51 ± 14.93) vs. ΔPG (₋5.05 ± 10.18), p = 0.004] and CHE2 levels [ΔMG (407.07 ± 723.26) vs. ΔPG (₋22.92 ± 506.52), p = 0.029] as well as sleep quality [scores: ΔMG (1.50 ± 1.28) vs. ΔPG (₋1.05 ± 2.05), p = 0.0006] and quantity [weighted total sleep time: ΔMG (0.74 ± 1.14) vs. ΔPG (₋1.04 ± 1.00), p = 0.0003] comparatively with placebo. Caregivers may recommend 12-week nocturnal melatonin intake to attenuate cardiac autonomic dysfunction, oxidative stress and sleep disorders in MS patients.Clinical registration This study was prospectively registered in the Pan African Clinical Trial Registry database (PACTR202007465309582) on 23 July 2020 (https://pactr.samrc.ac.za/.).Highlights• 12-week melatonin supplementation (3 mg per night) alleviated cardiac autonomic dysfunction (i.e., it increased heart rate variability) in multiple sclerosis patients.• Exogenous melatonin had benefits on oxidative stress biomarkers (reduced glutathione, malondialdehyde and advanced oxidation protein products).• Chronic nocturnal melatonin intake enhanced sleep quality, efficiency and quantity.

Studies examining whether measures of cognition are related to the presence of diabetic peripheral neuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) are lacking, as are data regarding factors potentially explaining such associations. Participants were from the Glycemia Reduction Approaches in Diabetes Study (GRADE) that examined 5047 middle-aged people with type 2 diabetes of <10 years of known duration. Verbal learning and immediate and delayed recall (memory) were assessed with the Spanish English Verbal Learning Test; frontal executive function and processing speed with the Digit Symbol Substitution Test; and ability to concentrate and organize data with word and animal fluency tests. DPN was assessed with the Michigan Neuropathy Screening Instrument and CAN by indices of heart rate variability (standard deviation of normal beat to beat variation [SDNN] and root mean square of successive differences [RMSSD]). DPN was significantly inversely related to measures of immediate recall and processing speed. The percent of cognitive variation explained by DPN was small. Tests of CAN had an inconsistent or absent association with measures of cognition. Higher waist circumference and urine albumin creatinine (UACR) levels were the strongest correlates in the relationship between DPN and cognitive impairment. DPN, but not CAN, was cross-sectionally associated with lower performance in measures of cognition in people with type 2 diabetes of <10 years of known duration. Greater waist circumference and UACR were important variables in this association. The mechanisms underlying the cross-sectional association of DPN with cognitive impairment are unknown. Clinicaltrials.gov: NCT01794143 •We examined the association of diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (AN) with cognitive impairment.•DPN was significantly and inversely associated with measures of immediate recall and processing speed.•Higher urine albumin creatinine (UACR) levels and waist circumference were the strongest correlates of this association.•AN had an inconsistent or absent association with measures of cognition.

Background Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO 4 ) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). Methods During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO 4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO 4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO 4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. Results Between June 2014 and September 2016, 14 and 12 participants received MgSO 4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO 4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO 4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p  = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p  = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. Conclusion Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO 4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO 4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. Trial registration ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor : University of Oxford

To assess the role of oxidative stress in mediating adverse outcomes in metabolic syndrome (MetS) and resultant cardiovascular autonomic neuropathy (CAN), and to evaluate the effects of lifestyle interventions on measures of oxidative stress and CAN in subjects with MetS. Pilot study in 25 non-diabetic subjects with MetS (age 49±10years, 76% females) participating in a 24-week lifestyle intervention (supervised aerobic exercise/Mediterranean diet), and 25 age-matched healthy controls. CAN was assessed by cardiovascular reflex tests, heart rate variability (HRV) and PET imaging with sympathetic analog [11C] meta-hydroxyephedrine ([11C]HED). Specific oxidative fingerprints were measured by liquid-chromatography/mass-spectrometry (LC/MS). At baseline, MetS subjects had significantly higher oxidative stress markers [3-nitrotyrosine (234±158 vs. 54±47μmol/mol tyrosine), ortho-tyrosine (59±38 vs. 18±10μmol/molphenylalanine, all P<0.0001], and impaired HRV at rest and during deep breathing (P=0.039 and P=0.021 respectively) compared to controls. Twenty-four-week lifestyle intervention significantly reduced all oxidative stress markers (all P<0.01) but did not change any of the CAN measures. Subjects with MetS present with signs of CAN and increased oxidative stress in the absence of diabetes. The 24-week lifestyle intervention was effective in ameliorating oxidative stress, but did not improve measures of CAN. Larger clinical trials with longer duration are required to confirm these findings.