Transcutaneous vagus nerve stimulation effects on chronic pain: systematic review and meta-analysis.

Chronic pain is one of the major causes of disability with a tremendous impact on an individual's quality of life and on public health. Transcutaneous vagus nerve stimulation (tVNS) is a safe therapeutic for this condition. We aimed to evaluate its effects in adults with chronic pain. A comprehensive search was performed, including randomized controlled trials published until October 2023, which assessed the effects of noninvasive tVNS. Cohen's d effect size and 95% confidence intervals (CIs) were calculated, and random-effects meta-analyses were performed. Fifteen studies were included. The results revealed a mean effect size of 0.41 (95% CI 0.17-0.66) in favor of tVNS as compared with control, although a significant heterogeneity was observed (χ2 = 21.7, df = 10, P = 0.02, I 2 = 53.9%). However, when compared with nonactive controls, tVNS shows a larger effect size (0.79, 95% CI 0.25-1.33), although the number of studies was small (n = 3). When analyzed separately, auricular tVNS and cervical tVNS against control, it shows a significant small to moderate effect size, similar to that of the main analysis, respectively, 0.42 (95% CI 0.08-0.76, 8 studies) and 0.36 (95% CI 0.01-0.70, 3 studies). No differences were observed in the number of migraine days for the trials on migraine. This meta-analysis indicates that tVNS shows promise as an effective intervention for managing pain intensity in chronic pain conditions. We discuss the design of future trials to confirm these preliminary results, including sample size and parameters of stimulation.

Resting-state electroencephalography delta and theta bands as compensatory oscillations in chronic neuropathic pain: a secondary data analysis.

Chronic neuropathic pain (CNP) remains a significant clinical challenge, with complex neurophysiological underpinnings that are not fully understood. Identifying specific neural oscillatory patterns related to pain perception and interference can enhance our understanding and management of CNP. To analyze resting electroencephalography data from individuals with chronic neuropathic pain to explore the possible neural signatures associated with pain intensity, pain interference, and specific neuropathic pain characteristics. We conducted a secondary analysis from a cross-sectional study using electroencephalography data from a previous study, and Brief Pain Inventory from 36 patients with chronic neuropathic pain. For statistical analysis, we modeled a linear or logistic regression by dependent variable for each model. As independent variables, we used electroencephalography data with such brain oscillations: as delta, theta, alpha, and beta, as well as the oscillations low alpha, high alpha, low beta, and high beta, for the central, frontal, and parietal regions. All models tested for confounding factors such as age and medication. There were no significant models for Pain interference in general activity, walking, work, relationships, sleep, and enjoyment of life. However, the model for pain intensity during the past four weeks showed decreased alpha oscillations, and increased delta and theta oscillations were associated with decreased levels of pain, especially in the central area. In terms of pain interference in mood, the model showed high oscillatory Alpha signals in the frontal and central regions correlated with mood impairment due to pain. Our models confirm recent findings proposing that lower oscillatory frequencies, likely related to subcortical pain sources, may be associated with brain compensatory mechanisms and thus may be associated with decreased pain levels. On the other hand, higher frequencies, including alpha oscillations, may disrupt top-down compensatory mechanisms.

Age as an Effect Modifier of the Effects of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) on Heart Rate Variability in Healthy Subjects.

Background: Evidence suggests that vagus nerve stimulation can modulate heart rate variability (HRV). However, there is a lack of mechanistic studies in healthy subjects assessing the effects of bilateral transcutaneous auricular vagus nerve stimulation (taVNS) on HRV. Our study aims to investigate how taVNS can influence the HRV response, including the influence of demographic variables in this response. Methods: Therefore, we conducted a randomized controlled study with 44 subjects, 22 allocated to active and 22 to sham taVNS. Results: Our results showed a significant difference between groups in the high-frequency (HF) metric. Active taVNS increased the HF metric significantly as compared to sham taVNS. Also, we found that age was a significant effect modifier of the relationship between taVNS and HF-HRV, as a larger increase in HF-HRV was seen in the older subjects. Importantly, there was a decrease in HF-HRV in the sham group. Conclusions: These findings suggest that younger subjects can adapt and maintain a constant level of HF-HRV regardless of the type of stimulation, but in the older subjects, only the active taVNS recipients were able to maintain and increase their HF-HRV. These results are important because they indicate that taVNS can enhance physiological regulation processes in response to external events.

The impact of education level and socioeconomic status on the association between depressive symptoms and memory in an older population in Latin America: An exploratory analysis from the Brazilian Longitudinal Study of Aging (ELSI-BRAZIL).

Purpose: The globally increasing older population raises concerns about age-related conditions, including cognitive impairment and depressive symptoms. In Latin America, nearly one-third of the population is affected by either of these conditions. However, data investigating the association between cognitive impairment and depressive symptoms, particularly in Brazil, are limited to small-scale studies that have not carefully examined the critical effects of variables such as education level and socioeconomic status on this relationship. We aimed at exploring this association in a representative population-based cohort. Methods: We used the Brazilian Longitudinal Study of Aging (ELSI-BRAZIL) database to examine the relationship between depressive symptoms and cognitive impairment in Brazilian older adults, adjusted for potential confounders. Direct acyclic graphs and multivariable linear regression were used to build our model. Depressive symptoms were measured using a short version of the Center for Epidemiologic Studies Scale (CES D-8), and combined memory recall test as a surrogate of cognitive impairment. Results: The study included 8280 participants. Only education level was identified as a confounder for the relationship between memory loss and depressive symptoms. After adjusting for age, sex, and education level, there was strong evidence for a negative association between depressive symptoms and memory performance. For every 5-unit increase in the CES D-8 score, there was a reduction in memory capacity, translating to a loss of approximately one word in the combined words recall test (mean - 0.18, 95% CI -0.22; -0.15, P < 0.001). In addition, we found strong evidence for an interaction between socioeconomic status and depressive symptoms. Subjects belonging to medium socioeconomic status (SES) showed more pronounced memory decline, when compared to those with lower SES (mean - 0.28, 95% CI -0.42 to -0.14, P < 0.001). Conclusions: In adults aged over 50, after adjusting for sex, age, and educational level, a 5-unit increase in CES D-8 score is associated with loss of one point in the combined memory recall test. This association seems to be confounded by educational level and significantly modified by socioeconomic status.

Neuropsychiatric drugs and a neurophysiological marker as predictors of health-related quality of life in patients with phantom limb pain.

OBJECTIVE: To explore the relationship between sociodemographic, clinical, and neurophysiological variables and health-related quality of life (HR-QOL) of patients with phantom limb pain. METHODS: This is a cross-sectional analysis of a previous clinical trial. Univariate and multivariate linear and logistic regression analyses were used to model the predictors of HR-QOL. We utilized a sequential modeling approach with increasing adjustment levels, controlling for age and sex, and other relevant clinical variables (time since amputation, level of amputation, and pain). HR-QOL was assessed by the SF-36 Health Survey and its eight subdomains. RESULTS: We analyzed baseline data from 92 patients with lower-limb amputations. They were mostly male (63%), 45.2 ± 15.6 years, with a mean time since amputation of 82.7 ± 122.4 months, and an overall SF-36 score of 55.9 ± 21.5. We found an association between intracortical facilitation in the affected hemisphere (ICF), gabapentin usage, and HR-QOL. ICF is a predictor of better HRQOL, whereas gabapentin usage was associated with a poorer HR-QOL, with the main model explaining 13.4% of the variance in the outcome. For the SF-36 subdomains, ICF was also a positive predictor for social functioning, bodily pain, and vitality, while medication usage was associated with lower scores in mental health, general health perception, bodily pain, and vitality. CONCLUSION: We found firsthand two new independent predictors of HR-QOL in individuals with PLP, namely, the neurophysiological metric ICF and gabapentin usage. These results highlight the role of the motor cortex excitability in the HR-QOL and stress the need for treatments that favor the neuroplastic adaptation after amputation, for which ICF may be used as a possible marker.

Peri-ictal psychiatric manifestations in people with epilepsy: An umbrella review.

OBJECTIVE: We aimed to conduct an umbrella review to summarize the existing evidence regarding the prevalence of peri-ictal psychiatric manifestations (PM) in people with epilepsy (PWE) including pre-ictal, ictal, and postictal stages. METHODS: Databases were searched up to June 2023 for systematic reviews (SR) of observational studies that included patients with epilepsy peri-ictal PM. Data selection, data extraction, and risk of bias assessment (with the AMSTAR-2 instrument) were performed by two independent reviewers. We performed a narrative synthesis using previous guidelines. We used a self-developed decision table according to the GRADE system adapted for narrative outcomes if the certainty of outcomes was not determined by systematic review authors. RESULTS: Four SRs were included comprising 66 primary studies (n = 10 217). Three SRs evaluated one period (pre-ictal, ictal, and postictal), and one did not determine it. During the pre-ictal period, the more prevalent symptom was confusion, although with a low certainty (due to the heterogeneity and serious risk of bias). One systematic review that only included case reports evaluated the ictal period, finding mood/anxiety disorders, psychosis, and personality changes. The postictal period included the most PM (anxiety: 45.0% and depressive symptoms: 43.0%), with very low certainty, due to risk of bias, potential publication bias, heterogeneity, and failure to report the confidence intervals. SIGNIFICANCE: With very low certainty, epileptic periods are characterized by a wide spectrum of PM, being postictal symptoms the most prevalent, predominantly anxiety, and depressive symptoms. Further understanding of these PM of epilepsy could improve the attention of the people with epilepsy. PLAIN LANGUAGE SUMMARY: In this review of reviews, we summarize the frequency in which psychiatric manifestations occur in relation to an epileptic seizure. A total of 10 217 patients were reported in the reviews. The most common manifestations included symptoms of anxiety and depression, as well as changes in the normal behavior of the patient. These manifestations occurred most frequently right after the seizure finished.

Improved all-cause mortality with left bundle branch area pacing compared to biventricular pacing in cardiac resynchronization therapy: a meta-analysis.

BACKGROUND: Left bundle branch area pacing (LBBAP) has emerged as a physiological alternative pacing strategy to biventricular pacing (BIVP) in cardiac resynchronization therapy (CRT). We aimed to assess the impact of LBBAP vs. BIVP on all-cause mortality and heart failure (HF)-related hospitalization in patients undergoing CRT. METHODS: Studies comparing LBBAP and BIVP for CRT in patients with HF with reduced left ventricular ejection fraction (LVEF) were included. The coprimary outcomes were all-cause mortality and HF-related hospitalization. Secondary outcomes included procedural and fluoroscopy time, change in QRS duration, and change in LVEF. RESULTS: Thirteen studies (12 observational and 1 RCT, n = 3239; LBBAP = 1338 and BIVP = 1901) with a mean follow-up duration of 25.8 months were included. Compared to BIVP, LBBAP was associated with a significant absolute risk reduction of 3.2% in all-cause mortality (9.3% vs 12.5%, RR 0.7, 95% CI 0.57-0.86, p < 0.001) and an 8.2% reduction in HF-related hospitalization (11.3% vs 19.5%, RR 0.6, 95% CI 0.5-0.71, p < 0.00001). LBBAP also resulted in reductions in procedural time (mean weighted difference- 23.2 min, 95% CI - 42.9 to - 3.6, p = 0.02) and fluoroscopy time (- 8.6 min, 95% CI - 12.5 to - 4.7, p < 0.001) as well as a significant reduction in QRS duration (mean weighted difference:- 25.3 ms, 95% CI - 30.9 to - 19.8, p < 0.00001) and a greater improvement in LVEF of 5.1% (95% CI 4.4-5.8, p < 0.001) compared to BIVP in the studies that reported these outcomes. CONCLUSION: In this meta-analysis, LBBAP was associated with a significant reduction in all-cause mortality as well as HF-related hospitalization when compared to BIVP. Additional data from large RCTs is warranted to corroborate these promising findings.

Distinct patterns of metabolic motor cortex activity for phantom and residual limb pain in people with amputations: A functional near-infrared spectroscopy study.

BACKGROUND: Phantom pain limb (PLP) has gained more attention due to the large number of people with amputations around the world and growing knowledge of the pain process, although its mechanisms are not completely understood. OBJECTIVES: The aim of this study was to understand, in patients with amputations, the association between PLP and residual limb pain (RLP), and the brain metabolic response in cortical motor circuits, using functional near-infrared spectroscopy (fNIRS). METHODS: Sixty participants were recruited from the rehabilitation program in São Paulo, Brazil. Included patients were aged over 18 years, with traumatic unilateral lower-limb amputation, with PLP for at least 3 months after full recovery from amputation surgery. PLP and RLP levels were measured using visual analogue scales. fNIRS was performed during motor execution and motor mirror tasks for 20 s. In order to highlight possible variables related to variation in pain measures, univariate linear regression analyses were performed for both experimental conditions, resulting in four fNIRS variables (two hemispheres x two experimental conditions). Later, in order to test the topographic specificity of the models, eight multivariate regression analyses were performed (two pain scales x two experimental conditions x two hemispheres), including the primary motor cortex (PMC) related channel as an independent variable as well as five other channels related to the premotor area, supplementary area, and somatosensory cortex. All models were controlled for age, sex, ethnicity, and education. RESULTS: We found that: i) there is an asymmetric metabolic activation during motor execution and mirror task between hemispheres (with a predominance that is ipsilateral to the amputated limb), ii) increased metabolic response in the PMC ipsilateral to the amputation is associated with increased PLP (during both experimental tasks), while increased metabolic response in the contralateral PMC is associated with increased RLP (during the mirror motor task only); ii) increased metabolic activity of the ipsilateral premotor region is associated with increased PLP during the motor mirror task; iii) RLP was only associated with higher metabolic activity in the contralateral PMC and lower metabolic activity in the ipsilateral inferior frontal region during motor mirror task, but PLP was associated with higher metabolic activity during both tasks. CONCLUSION: These results suggest there is both task and region specificity for the association between the brain metabolic response and the two different types of post-amputation pain. The metabolic predominance that is ipsilateral to the amputated limb during both tasks was associated with higher levels of PLP, suggesting a cortical motor network activity imbalance due to potential interhemispheric compensatory mechanisms. The present work contributes to the understanding of the underlying topographical patterns in the motor-related circuits associated with pain after amputations.

Factors associated with pain pressure threshold in both local and remote sites in knee osteoarthritis.

BACKGROUND: Knee osteoarthritis (KOA) is a prevalent condition, and its most frequent symptom is pain that often leads to disability. Pain sensitization is a core feature of KOA, and it can be measured through quantitative sensory testing protocols such as pain pressure threshold (PPT). However, there is a lack of understanding about the factors that may influence changes in PPTs in the KOA population. OBJECTIVE: To explore the clinical and functional factors associated with PPTs in a sample of people with chronic KOA pain and to compare models of local (knees) and remote (thenar regions) sites. DESIGN: Cross-sectional analysis of a prospective cohort. SETTING: Primary care in public institution. PARTICIPANTS: 113 adults with KOA. INTERVENTION: N/A. MAIN OUTCOME MEASURES: Multivariable regression analyses evaluating demographic, clinical, and functional variables that could be associated with local and remote PPTs (main outcomes) were performed. RESULTS: Both thenar region (adjusted-R2 : 0.29) and knee (adjusted-R2 : 0.45) models had the same significant negative association with being a female, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain levels (thenar: ß: -0.15, p = .002; knee: ß: -0.2, p < .001), and the 10-Meter Walking Test (thenar: ß: -0.05, p = .038; knee: ß: -0.08, p = .004). A small significant positive association with depressive symptoms was identified in both models, which acted as a confounder for WOMAC pain and was likely affected by unmeasured confounders. CONCLUSIONS: PPTs in KOA pain are associated with functional outcomes such as the 10-Meter Walking Test and activity-related pain intensity; thus more disability is associated with smaller pain thresholds. Similarity between models may suggest central sensitization.

Association between weight status and migraine in the paediatric population: a systematic review and meta-analysis.

Introduction: An association between weight status and migraine has been previously reported; however, this relationship has only been studied in adults, not in the paediatric population. Objective: To evaluate the association between weight status and migraine in the paediatric population. Methods: We searched PubMed/Medline, Scopus, Web of Science, Ovid Medline, and Embase using a cut-off date of May 2023. We included observational studies that evaluated the association between weight status (underweight, overweight, obese, and excess weight) and migraine in the paediatric population (children and adolescents). Normal weight was the comparator. The outcome was migraine (all types, episodic and chronic). We performed meta-analyses using a random-effects model to estimate the pooled effects for each outcome. Sensitivity analysis was performed based on study design and risk of bias (using the Newcastle-Ottawa Scale). Certainty of evidence was assessed using the GRADE approach. Results: Eight studies (6 cross-sectional, 1 case-control and 1 cohort) covering 16,556 patients were included. The overall certainty of evidence was very low for the association between overweight, obesity, and excess weight with migraine. In the sensitivity analysis, meta-analyses of studies with a low risk of bias found that the overweight population probably had an increased odds of migraine (OR: 1.70; 95% CI: 1.14 to 2.53; I2 = 32.3%, p = 0.224) and that excess weight may increase the odds of migraine (OR: 1.58; 95% CI: 1.06 to 2.35; I2 = 83.7%, p = 0.002). Additionally, cohort and case-control studies found that obesity probably increases the odds of migraine. No studies analysed the association between underweight and migraine. Conclusion: The associations between overweight, obesity, excess weight and migraine were uncertain, but studies with better methodological quality reported increased odds. Future longitudinal studies with proper confounding control are needed to disentangle their causal relationship. Systematic review registration: PROSPERO, identifier CRD42021271533.

Is brain perfusion correlated to switching mood states and cognitive impairment in bipolar disorder type I? A longitudinal study using perfusion imaging approach.

Type I Bipolar disorder (BD-I) is a neuropsychiatric disorder characterized by manic or mixed-featured episodes, impaired cognitive functioning, and persistent work and social functioning impairment. This study aimed to investigate within-subject; (i) differences in brain perfusion using Single-photon emission computed tomography (SPECT) between manic and euthymic states in BD-I patients; (ii) explore potential associations between altered brain perfusion and cognitive status; and (iii) examine the relationship between cerebral perfusion and mania symptom ratings. Seventeen adult patients diagnosed with BD-I in a manic episode were recruited, and clinical assessments, cognitive tests, and brain perfusion studies were conducted at baseline (mania state) and a follow-up visit 6 months later. The results showed cognitive impairment during the manic episode, which persisted during the euthymic state at follow-up. However, no significant changes in brain perfusion were observed between the manic and euthymic states. During mania, trends toward decreased perfusion in the left cerebellum and right superior parietal lobule were noted. Additionally, trends indicated a higher perfusion imbalance in the left superior and middle frontal gyrus during mania and the right superior and middle frontal gyrus during euthymia. No significant correlations existed between brain perfusion, mania symptom ratings, and cognitive performance, indicating that symptomatology might represent more than neural hemodynamics. These findings suggest that cognitive impairment may persist in BD-I patients and highlight the need for therapeutic interventions targeting cognitive deficits. More extensive studies with extended follow-up periods are warranted further to investigate brain perfusion and cognitive functioning in BD-I patients.

Functional and Neural Correlates Associated with Conditioned Pain Modulation in Patients with Chronic Knee Osteoarthritis Pain: A Cross-Sectional Study.

Background: In this study, we aimed to assess the factors that predict a dysfunctional conditioned pain modulation (CPM) in chronic knee OA. Methods: This is a cross-sectional analysis of patients with chronic knee OA from a prospective cohort study in Brazil (n = 85). We performed linear and logistic multivariate regression models using the purposeful selection approach to test the relationship between the CPM in both knees (average) as a dependent variable and demographics, clinical, and neurophysiological as independent variables. Results: A significant negative association between WOMAC pain scores and CPM (ß: -0.13) was found. This association was modified by the subjects' race, being stronger in the non-white subjects. In our logistic regression models, pain intensity indexed with the WOMAC pain scale remained a significant association with dichotomized CPM. Furthermore, a significant CPM association with balance, indexed with the Berg Balance score, was evidenced (ß: 0.04). Neurophysiological variables showed a significant negative relationship with CPM, such as the relative power of delta oscillations in the frontal area (ß: -3.11) and central area (ß: -3.23). There was no significant relationship between CPM and the following domains: cognitive, emotion, sleep, opioid receptor polymorphisms, and intrinsic variables of OA disease. There was no association of CPM with TMS-indexed inhibitory markers. Conclusions: These results may indicate that less function of the pain descending inhibitory system in patients with OA is correlated with higher activity-related pain (WOMAC), less balance, and cortical plasticity especially with increased low-frequency (delta) brain oscillations. These associations seem modified by race.

Estimating mortality and disability in Peru before the COVID-19 pandemic: a systematic analysis from the Global Burden of the Disease Study 2019.

Background: Estimating and analyzing trends and patterns of health loss are essential to promote efficient resource allocation and improve Peru's healthcare system performance. Methods: Using estimates from the Global Burden of Disease (GBD), Injuries, and Risk Factors Study (2019), we assessed mortality and disability in Peru from 1990 to 2019. We report demographic and epidemiologic trends in terms of population, life expectancy at birth (LE), mortality, incidence, prevalence, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) caused by the major diseases and risk factors in Peru. Finally, we compared Peru with 16 countries in the Latin American (LA) region. Results: The Peruvian population reached 33.9 million inhabitants (49.9% women) in 2019. From 1990 to 2019, LE at birth increased from 69.2 (95% uncertainty interval 67.8-70.3) to 80.3 (77.2-83.2) years. This increase was driven by the decline in under-5 mortality (-80.7%) and mortality from infectious diseases in older age groups (+60 years old). The number of DALYs in 1990 was 9.2 million (8.5-10.1) and reached 7.5 million (6.1-9.0) in 2019. The proportion of DALYs due to non-communicable diseases (NCDs) increased from 38.2% in 1990 to 67.9% in 2019. The all-ages and age-standardized DALYs rates and YLLs rates decreased, but YLDs rates remained constant. In 2019, the leading causes of DALYs were neonatal disorders, lower respiratory infections (LRIs), ischemic heart disease, road injuries, and low back pain. The leading risk factors associated with DALYs in 2019 were undernutrition, high body mass index, high fasting plasma glucose, and air pollution. Before the COVID-19 pandemic, Peru experienced one of the highest LRIs-DALYs rates in the LA region. Conclusion: In the last three decades, Peru experienced significant improvements in LE and child survival and an increase in the burden of NCDs and associated disability. The Peruvian healthcare system must be redesigned to respond to this epidemiological transition. The new design should aim to reduce premature deaths and maintain healthy longevity, focusing on effective coverage and treatment of NCDs and reducing and managing the related disability.

Exercise effects on motor function, manual dexterity, and brain oscillatory activity in individuals with Parkinson's disease: Randomized controlled trial protocol.

BACKGROUND: Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. Exercise protocols are promising interventions to improve PD symptoms, however, the best modality and its neural correlates are still unknown. OBJECTIVES: To evaluate the effects of the aerobic, strength and task-oriented upper-limb exercises in motor function, manual dexterity, and brain oscillations of individuals with PD. METHOD: In this clinical trial, 44 PD patients aged 40-80 years will be randomized in four groups: aerobic training (AT), strength training (ST), task-oriented training (TOT), and waiting list group (CG). The AT group will perform 30 min of a cycle ergometer on 50%-70% of the reserve heart rate. The ST group will use equipment for upper limb muscles and will perform two series of 8-12 repetitions for each exercise, and intensity between 50% and 70% of one maximum repetition will be used. The TOT group will perform a program consisting of three activities to enhance reaching, grasping, and manipulation. All the groups will perform three sessions per week for 8 weeks. We will use the UPDRS Motor function section, Nine-Hole Peg Test, and quantitative electroencephalography to measure motor function, manual dexterity, and brain oscillations, respectively. ANOVA and regression models will be used to compare outcomes within and between groups.

Primary headache disorders in Latin America and the Caribbean: A meta-analysis of population-based studies.

BACKGROUND: In this manuscript, we aim to systematically estimate the pooled prevalence and incidence of primary headaches and its subtypes (migraine, tension-type headache, and chronic headaches) in Latin America and the Caribbean, describing its epidemiological profile and associated factors. METHODS: We systematically searched PubMed/MEDLINE, Scopus, and LILACS (From conception to March 2021), for populational studies reporting the epidemiology of primary headaches and their associated factors in Latin America and the Caribbean. The data extraction was conducted independently. We performed random-effect model meta-analysis of prevalence (overall primary headaches and by subtypes) and associated factors, assessed potential sources of heterogeneity, the risk of bias, publication bias, and the evidence certainty (GRADE methodology). RESULTS: We included 32 populational studies (38 subpopulations, n = 63,813). The prevalence of primary headaches was 41.4% (95% CI 31.1-52.2%; n = 54,357), 15% for migraine (95% CI 12.0-18.3; n = 53,658 individuals), 20.6% for tension-type headache (95% CI 12.4-30.2; n = 25,840), and 6% for chronic headaches (95% CI 3.3-9.6; n = 21,720), with high between-study heterogeneity. No incidence data was found. Female sex, white ethnicity, high BMI, comorbid mental health disorders, and low-back pain were associated with higher prevalence of primary headaches. The prevalence was less in rural areas. CONCLUSION: In Latin America and the Caribbean, primary headaches are highly prevalent affecting young females disproportionally. The prevalence of chronic headaches is higher than in other systematic global and regional estimations. The presence of comorbidities as modifiable risk factors should encourage their integration as targets for community-based preventive and therapeutic interventions. PROTOCOL REGISTRATION NUMBER: CRD42018105116.

Burden of disease due to amphetamines, cannabis, cocaine, and opioid use disorders in South America, 1990-2019: a systematic analysis of the Global Burden of Disease Study 2019.

BACKGROUND: South America's substance use profile, poverty, income inequality, and cocaine-supplier role make it a unique place for substance use research. This study investigated the burden of disease attributable to amphetamine use disorder, cannabis use disorder (CAD), cocaine use disorder, and opioid use disorder (OUD) in South America from 1990 to 2019, on the basis of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019. METHODS: GBD 2019 estimated the incidence, prevalence, mortality, years of life lost (YLL), years of life lived with disability (YLD), and disability-adjusted life-years (DALYs) due to substance use disorders in each of the 12 South American countries (Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Guyana, Paraguay, Peru, Suriname, Uruguay, and Venezuela). Data were modelled using standardised tools (ie, the Cause of Death Ensemble model, spatio-temporal Gaussian process regression, and disease modelling meta-regression) to generate estimates of each quantity of interest by sex, location, and year. The analysis included comparisons by sex and country, and against regional and global estimates. FINDINGS: In 2019, the highest amphetamine use disorder burden per 100 000 population in South America was in Peru (66 DALYs). CAD DALY rates per 100 000 in South America were stable between 1990 and 2019, except in Chile and Colombia, which had the highest rates in 2019 (19 DALYs for Chile and 18 DALYs for Colombia). OUD DALYs per 100 000 increased during the period in Brazil and Peru, which in 2019 had the highest rates in South America (82 DALYs for Brazil and 70 DALYs for Peru). In 2019, Brazil had the highest cocaine use disorder DALYs per 100 000 (45 DALYs), nearly double its rate in 1990. DALY rates were higher in males than females for each substance use disorder, except in Paraguay. The overall burden of substance use disorders was higher in males than in females, mainly because of cocaine use disorder and CAD, whereas for amphetamine use disorder, the difference between sexes was minimal, and for OUD there was no difference. For males and females, the highest rate of substance use disorders DALYs per 100 000 was for OUD except in Argentina (in males, 58 DALYs for cocaine use disorder vs 52 DALYs for OUD) and in Paraguay (in females, 77 for amphetamine use disorder vs 50 for OUD). CAD DALY rates were generally the lowest among the substance use disorders for males and females. Amphetamine use disorder YLD rates were reasonably stable throughout the period and were highest in Peru, Paraguay, and Uruguay (>40 YLD per 100 000). For CAD, YLD rates were stable in all countries except Chile and Colombia. Cocaine use disorder YLD rates per 100 000 for the top four countries (Argentina, Uruguay, Chile, and Brazil) increased from 1990 to 2010 (eg, from 19 to 33 in Brazil), but decreased between 2010 and 2019 (eg, from 36 to 31 in Chile). For OUD, YLD rates showed a slight increase in most countries apart from Brazil, which increased from 52 in 1990 to 80 in 2019 and was top among the countries. Amphetamine use disorder YLL rates per 100 000 were highest in Suriname and Peru during the period, although in Suriname it increased from 2·7 in 2010 to 3·2 in 2019, whereas in Peru it decreased from 2·1 to 1·7. The highest YLL rate for cocaine use disorder was in Brazil, which increased from 3·7 in 1990 to 18·1 in 2019. Between 2000 and 2019, Chile and Uruguay showed the highest OUD YLL rates (11·6 for Chile and 10·9 for Uruguay). A high incidence of CAD was found in Chile, Colombia, Guyana, and Suriname. There were high incidences of amphetamine use disorder in Paraguay, cocaine use disorder in Argentina, and OUD in Ecuador. A decrease in annual prevalence for substance use disorders during the period was observed in Venezuela (amphetamine use disorder, CAD, and OUD), Brazil (CAD and amphetamine use disorder), Colombia (amphetamine use disorder and cocaine use disorder), Peru (amphetamine use disorder and cocaine use disorder), Chile and Suriname (amphetamine use disorder), Uruguay (CAD), and Bolivia (OUD). Overall, the cocaine use disorder burden stabilised then decreased. OUD was less prevalent than other substance use disorders but its burden was the highest. INTERPRETATION: The decrease in the burden of cocaine use disorder probably reflects the success of national standardised treatment programmes. Programmes for amphetamine use disorder, CAD, and OUD management should be improved. We did not find an increase in CAD burden in Uruguay, the country with the highest degree of cannabis decriminalisation in the region. Countries in South America should improve monitoring of substance use disorders, including regular surveys to provide more accurate data on which to base policy decisions. FUNDING: The Bill & Melinda Gates Foundation.

Association of Mu opioid receptor (A118G) and BDNF (G196A) polymorphisms with rehabilitation-induced cortical inhibition and analgesic response in chronic osteoarthritis pain.

Background/objective: Chronic pain due to osteoarthritis (OA) is a prevalent cause of global disability. New biomarkers are needed to improve treatment allocation, and genetic polymorphisms are promising candidates. Method: We aimed to assess the association of OPRM1 (A118G and C17T) and brain-derived neurotrophic factor (BDNF [G196A]) polymorphisms with pain-related outcomes and motor cortex excitability metrics (measured by transcranial magnetic stimulation) in 113 knee OA patients with chronic pain. We performed adjusted multivariate regression analyses to compare carriers versus non-carriers in terms of clinical and neurophysiological characteristics at baseline, and treatment response (pain reduction and increased cortical inhibitory tonus) after rehabilitation. Results: Compared to non-carriers, participants with polymorphisms on both OPRM1 (A118G) and BDNF (G196A) genes were less likely to improve pain after rehabilitation (85 and 72% fewer odds of improvement, respectively). Likewise, both carriers of OPRM1 polymorphisms (A118G and C17T) were also less likely to improve cortical inhibition (short intracortical inhibition [SICI], and intracortical facilitation [ICF], respectively). While pain and cortical inhibition improvement did not correlate in the total sample, the presence of OPRM1 (A118G) and BDNF (G196A) polymorphisms moderated this relationship. Conclusions: These results underscore the promising role of combining genetic and neurophysiological markers to endotype the treatment response in this population.

Transcutaneous auricular vagus nerve stimulation effects on inflammatory markers and clinical evolution of patients with COVID-19: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19. METHODS: A randomized blinded pilot study was carried out with 21 individuals hospitalized with COVID-19 who received 14 sessions of active (a-taVNS) or sham taVNS (s-taVNS). The level of interleukin-6 (IL-6), interleukin-10 (IL-10), cortisol, and C-reactive protein (CRP) in plasma and clinical evolution pre- and post-intervention were evaluated. The memory and attention levels were evaluated 14 days after the end of the treatment. RESULTS: After treatment, significant intragroup differences were found in the CRP (p = 0.01), IL-6 (p = 0.01), and cortisol (p = 0.01) levels; however, in the comparison between the groups, only the CRP level was statistically lower for the a-taVNS (p = 0.04). The impression of improvement in memory and attention was greater in the a-taVNS than in the s-taVNS (p = 0.01, p = 0.04, respectively). There was no difference between the other clinical outcomes. CONCLUSIONS: taVNS is a viable and safe intervention in the acute care of patients with COVID-19, which can modulate their inflammatory profile and improve cognitive symptoms. However, improvements in overall clinical outcomes were not detected. Larger sample sizes and longer follow-ups are needed to confirm the anti-inflammatory and clinical effects of taVNS in patients with COVID-19. TRIALS REGISTRY: The Brazilian Registry of Clinical Trials (RBR-399t4g5).