Promoter hypermethylation of RARB and GSTP1 genes in plasma cell-free DNA as breast cancer biomarkers in Peruvian women.

BACKGROUND: Promoter hypermethylation is one of the enabling mechanisms of hallmarks of cancer. Tumor suppressor genes like RARB and GSTP1 have been reported as hypermethylated in breast cancer tumors compared with normal tissues in several populations. This case-control study aimed to determine the association between the promoter methylation ratio (PMR) of RARB and GSTP1 genes (separately and as a group) with breast cancer and its clinical-pathological variables in Peruvian patients, using a liquid biopsy approach. METHODS: A total of 58 breast cancer patients and 58 healthy controls, matched by age, participated in the study. We exacted cell-free DNA (cfDNA) from blood plasma and converted it by bisulfite salts. Methylight PCR was performed to obtain the PMR value of the studied genes. We determined the association between PMR and breast cancer, in addition to other clinicopathological variables. The sensitivity and specificity of the PMR of these genes were obtained. RESULTS: A significant association was not found between breast cancer and the RARB PMR (OR = 1.90; 95% CI [0.62-6.18]; p = 0.210) or the GSTP1 PMR (OR = 6.57; 95% CI [0.75-307.66]; p = 0.114). The combination of the RARB + GSTP1 PMR was associated with breast cancer (OR = 2.81; 95% CI [1.02-8.22]; p = 0.026), controls under 50 years old (p = 0.048), patients older than 50 (p = 0.007), and postmenopausal (p = 0.034). The PMR of both genes showed a specificity of 86.21% and a sensitivity of 31.03%. CONCLUSION: Promoter hypermethylation of RARB + GSTP1 genes is associated with breast cancer, older age, and postmenopausal Peruvian patients. The methylated promoter of the RARB + GSTP1 genes needs further validation to be used as a biomarker for liquid biopsy and as a recommendation criterion for additional tests in asymptomatic women younger than 50 years.

Modeling Electric Fields in Transcutaneous Spinal Direct Current Stimulation: A Clinical Perspective.

Clinical findings suggest that transcutaneous spinal direct current stimulation (tsDCS) can modulate ascending sensitive, descending corticospinal, and segmental pathways in the spinal cord (SC). However, several aspects of the stimulation have not been completely understood, and realistic computational models based on MRI are the gold standard to predict the interaction between tsDCS-induced electric fields and anatomy. Here, we review the electric fields distribution in the SC during tsDCS as predicted by MRI-based realistic models, compare such knowledge with clinical findings, and define the role of computational knowledge in optimizing tsDCS protocols. tsDCS-induced electric fields are predicted to be safe and induce both transient and neuroplastic changes. This could support the possibility to explore new clinical applications, such as spinal cord injury. For the most applied protocol (2-3 mA for 20-30 min, active electrode over T10-T12 and the reference on the right shoulder), similar electric field intensities are generated in both ventral and dorsal horns of the SC at the same height. This was confirmed by human studies, in which both motor and sensitive effects were found. Lastly, electric fields are strongly dependent on anatomy and electrodes' placement. Regardless of the montage, inter-individual hotspots of higher values of electric fields were predicted, which could change when the subjects move from a position to another (e.g., from the supine to the lateral position). These characteristics underlines the need for individualized and patient-tailored MRI-based computational models to optimize the stimulation protocol. A detailed modeling approach of the electric field distribution might contribute to optimizing stimulation protocols, tailoring electrodes' configuration, intensities, and duration to the clinical outcome.

Chip-based digital Polymerase Chain Reaction as quantitative technique for the detection of PIK3CA mutations in breast cancer patients.

Background: PIK3CA is a gene frequently mutated in breast cancer. With the FDA approval of alpelisib, the evaluation of PIK3CA for activating mutations is becoming routinely. Novel platforms for gene analysis as digital PCR (dPCR) are emerging as a potential replacement for the traditional Sanger sequencing. However, there are still few studies on chip-based dPCR to detect mutations in tumor samples. Thus, this cross-sectional study aimed to assess the sensibility of a chip-based dPCR to detect and quantify PIK3CA mutations and compare its performance with Sanger sequencing. Materials and Methods: Tumor samples from 57 breast cancer patients (22 pre-treatment samples, 32 tumors after neoadjuvant chemotherapy, and three lymph nodes) were collected and analyzed by Sanger sequencing and dPCR for the three PIK3CA most relevant mutations (p.E545K, p. H1047R, and p. H1047L). Digital PCR sensitivity, specificity, and overall performance were estimated by contingency tables, receptor operator characteristic (ROC), and area under the curve (AUC). Association of PIK3CA mutations with clinicopathological variables was conducted. Results: Sanger sequencing identified PIK3CA mutations in six patients (10.5%), two with p. H1047R, and four with p. E545K. Digital PCR confirmed those mutations and identified 19 additional patients with at least one mutation. Comparison between dPCR and Sanger sequencing showed a sensitivity of 100% (95% CI 53-100%), and a specificity of 84.2% (95% CI 83-84.2%). Besides, p. H1047R mutation detected by dPCR showed a significant association with breast cancer phenotype (p = 0.019) and lymphatic nodes infiltration (p = 0.046). Conclusions: Digital PCR showed a high sensitivity to detect mutations in tumor samples and it might be capable to detect low-rate mutations and tumor subpopulations not detected by Sanger sequencing.

Burden of Stroke and Population-Attributable Fractions of Risk Factors in Latin America and the Caribbean.

Background Stroke burden characterization studies in low- and middle-income countries are scarce. We estimated the burden of stroke and its risk factors in Latin America and the Caribbean (LAC). Methods and Results We extracted GBD (Global Burden of Disease) study 2019 data on overall stroke and 3 subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) for 20 LAC countries. We estimated absolute and age-standardized rates of disability-adjusted life years, years of life lost, years lived with disability, and deaths. The population-attributable fractions of 17 risk factors were estimated. All analyses were performed at regional and national levels by stroke subtype, sex, and age subgroups. In 2019, the LAC region had the fourth largest stroke burden worldwide (6.8 million disability-adjusted life years), predominantly attributable to premature deaths (89.5% of disability-adjusted life years). Intracerebral hemorrhage was the primary cause of the overall stroke burden (42% of disability-adjusted life years), but ischemic stroke was the leading cause of disability (69% of total years lived with disability). Haiti and Honduras had the highest age-standardized rates. Older adults and men had the largest burdens, although women had the highest rate of disability. Socioeconomic development level did not influence the burden. The major risk factor clusters were metabolic (high systolic blood pressure [population-attributable fraction=53%] and high body mass index [population-attributable fraction=37%]), which were more influential in hemorrhagic events, women, and older adults. Household air pollution was an important risk factor in low-income countries in LAC. Conclusions The stroke burden and stroke-related mortality in LAC are higher than the worldwide averages. However, stroke is a highly preventable disease in this region. Up to 90% of the burden could be reduced by targeting 2 modifiable factors: blood pressure and body mass index. Further research and implementation of primary and secondary prevention interventions are needed, as well as integrated national stroke care programs for acute, subacute, and rehabilitation management in LAC.

Electroencephalography Signatures for Conditioned Pain Modulation and Pain Perception in Nonspecific Chronic Low Back Pain-An Exploratory Study.

Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship. OBJECTIVE: To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms. DESIGN: Cross-sectional analysis. PARTICIPANTS: Thirty NSCLBP patients participated. METHODS: Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis. RESULTS: CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression. CONCLUSIONS: Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.

Recruitment characteristics and non-adherence associated factors of fibromyalgia patients in a randomized clinical trial: A retrospective survival analysis.

INTRODUCTION: Fibromyalgia is a complex pain condition that affects mostly women. Given the disease's lack of understanding, patients report poor adherence to medication and mistrust of medical services. This study aims to describe the recruitment characteristics and non-adherence associated factors of fibromyalgia patients to an RCT. METHODS: We performed a retrospective longitudinal analysis with data from our ongoing RCT. We investigated characteristics of subjects recruited, consented, and randomized. Adherence was studied using survival analysis techniques, and its associated factors were identified using Cox proportional hazards regression model. RESULTS: 524 subjects were contacted, 269 were eligible, 61 consented and 40 subjects were randomized. Thirty-eight percent were non-adherent to the protocol with a median of visits of five. The recruitment survey reported that 90% would likely participate in RCTs, 52% had previous participation, and 19% were aware of RCTs by their physicians. Some barriers were investigator-related (staff's friendliness and receiving the results of their trial participation) and center-related (privacy-confidentiality issues and the institution's reputation), without difference between adherent and non-adherent participants. We report significant factors for non-adherence as VAS anxiety score of 5 or more (5.3 HR, p = 0.01), Body Mass Index (BMI) (0.91 HR, p = 0.041) and Quality of Life (QoL) - Personal development subdomain (0.89 HR, p = 0.046). CONCLUSION: Recruitment and adherence of fibromyalgia patients is a challenge; however, they seem eager to participate in RCTs. We recommend creating a comfortable, friendly and trusting environment to increase the recruitment rate. Higher anxiety, lower BMI and lower quality of life were associated with a higher attrition rate.

Effects of Transcutaneous Spinal Direct Current Stimulation (tsDCS) in Patients With Chronic Pain: A Clinical and Neurophysiological Study.

Background and Aims: Chronic pain is a complex clinical condition, often devastating for patients and unmanageable with pharmacological treatments. Converging evidence suggests that transcutaneous spinal Direct Current Stimulation (tsDCS) might represent a complementary therapy in managing chronic pain. In this randomized, double-blind and sham-controlled crossover study, we assessed tsDCS effects in chronic pain patients. Methods: Sixteen patients (aged 65.06 ± 16.16 years, eight women) with chronic pain of different etiology underwent sham and anodal tsDCS (anode over the tenth thoracic vertebra, cathode over the somatosensory cortical area: 2.5 mA, 20 min, 5 days for 1 week). As outcomes, we considered the Visual Analog Scale (VAS), the Neuropathic Pain Symptom Inventory (NPSI), and the components of the lower limb flexion reflex (LLFR), i.e., RIII threshold, RII latency and area, RIII latency and area, and flexion reflex (FR) total area. Assessments were conducted before (T0), immediately at the end of the treatment (T1), after 1 week (T2) and 1 month (T3). Results: Compared to sham, anodal tsDCS reduced RIII area at T2 (p = 0.0043) and T3 (p = 0.0012); similarly, FR total area was reduced at T3 (p = 0.03). Clinically, anodal tsDCS dampened VAS at T3 (p = 0.015), and NPSI scores at T1 (p = 0.0012), and T3 (p = 0.0015), whereas sham condition left them unchanged. Changes in VAS and NPSI scores linearly correlated with the reduction in LLFR areas (p = 0.0004). Conclusions: Our findings suggest that tsDCS could modulate nociceptive processing and pain perception in chronic pain syndromes.

Barriers and facilitators for clinical trial participation of underrepresented and non-underrepresented fibromyalgia patients: A cross-sectional internet survey.

BACKGROUND: There is a need of well-powered randomized clinical trials in fibromyalgia. However, challenges for recruitment are presented. This study aims to describe and assess the perception of barriers and facilitators and the associated factors for the participation of underrepresented and non-underrepresented fibromyalgia patients. METHODS: We performed an online survey through REDCap (Research Electronic Data Capture) targeting fibromyalgia patients from April 7 to July 3, 2020 during the COVID-19 stay home mandate and it was restricted to the United States of America. We described and compared the survey characteristics between underrepresented and non-underrepresented participants, and we performed logistic regression models to assess the associated factors with clinical trial participation. RESULTS: In total, 481 completed the survey including 168 underrepresented fibromyalgia patients. Only (1) 11.09 % reported previous participation in clinical trials and the significant perceived barriers were investigator-related (lack of friendliness of research staff and the opportunity to receive the results) and center-related (privacy and confidentiality policies, and the institution's reputation); (2) the participation rate and perceived barriers and facilitators were similar between underrepresented and non-underrepresented patients; and was positively associated with low income, higher age, and clinical trial awareness from their physician; and negatively associated with the perception of investigator-related barriers; and (4) for the underrepresented population, the presence of emotional support. CONCLUSION: Our findings suggest low rates of participation, regardless of underrepresented population status. Strategies as involving their physician as liaison to increase the awareness of clinical trials, as well as improving patient-researcher communication should be considered in this population.

Effects of Combined and Alone Transcranial Motor Cortex Stimulation and Mirror Therapy in Phantom Limb Pain: A Randomized Factorial Trial.

Phantom limb pain (PLP) is a frequent complication in amputees, which is often refractory to treatments. We aim to assess in a factorial trial the effects of transcranial direct current stimulation (tDCS) and mirror therapy (MT) in patients with traumatic lower limb amputation; and whether the motor cortex plasticity changes drive these results. In this large randomized, blinded, 2-site, sham-controlled, 2 × 2 factorial trial, 112 participants with traumatic lower limb amputation were randomized into treatment groups. The interventions were active or covered MT for 4 weeks (20 sessions, 15 minutes each) combined with 2 weeks of either active or sham tDCS (10 sessions, 20 minutes each) applied to the contralateral primary motor cortex. The primary outcome was PLP changes on the visual analogue scale at the end of interventions (4 weeks). Motor cortex excitability and cortical mapping were assessed by transcranial magnetic stimulation (TMS). We found no interaction between tDCS and MT groups (F = 1.90, P = .13). In the adjusted models, there was a main effect of active tDCS compared to sham tDCS (beta coefficient = -0.99, P = .04) on phantom pain. The overall effect size was 1.19 (95% confidence interval: 0.90, 1.47). No changes in depression and anxiety were found. TDCS intervention was associated with increased intracortical inhibition (coefficient = 0.96, P = .02) and facilitation (coefficient = 2.03, P = .03) as well as a posterolateral shift of the center of gravity in the affected hemisphere. MT induced no motor cortex plasticity changes assessed by TMS. These findings indicate that transcranial motor cortex stimulation might be an affordable and beneficial PLP treatment modality.

COVID-19 pandemic and Farr's law: A global comparison and prediction of outbreak acceleration and deceleration rates.

The COVID-19 outbreak has forced most of the global population to lock-down and has put in check the health services all over the world. Current predictive models are complex, region-dependent, and might not be generalized to other countries. However, a 150-year old epidemics law promulgated by William Farr might be useful as a simple arithmetical model (percent increase [R1] and acceleration [R2] of new cases and deaths) to provide a first sight of the epidemic behavior and to detect regions with high predicted dynamics. Thus, this study tested Farr's Law assumptions by modeling COVID-19 data of new cases and deaths. COVID-19 data until April 10, 2020, was extracted from available countries, including income, urban index, and population characteristics. Farr's law first (R1) and second ratio (R2) were calculated. We constructed epidemic curves and predictive models for the available countries and performed ecological correlation analysis between R1 and R2 with demographic data. We extracted data from 210 countries, and it was possible to estimate the ratios of 170 of them. Around 42·94% of the countries were in an initial acceleration phase, while 23·5% already crossed the peak. We predicted a reduction close to zero with wide confidence intervals for 56 countries until June 10 (high-income countries from Asia and Oceania, with strict political actions). There was a significant association between high R1 of deaths and high urban index. Farr's law seems to be a useful model to give an overview of COVID-19 pandemic dynamics. The countries with high dynamics are from Africa and Latin America. Thus, this is a call to urgently prioritize actions in those countries to intensify surveillance, to re-allocate resources, and to build healthcare capacities based on multi-nation collaboration to limit onward transmission and to reduce the future impact on these regions in an eventual second wave.

Decreased neural inhibitory state in fibromyalgia pain: A cross-sectional study.

OBJECTIVES: Chronic pain is one of the most common and challenging symptoms in fibromyalgia (FM). Currently, self-reported pain is the main criterion used by clinicians assessing patients with pain. However, it is subjective, and multiple factors can affect pain levels. In this study, we investigated the neural correlates of FM pain using conditioned pain modulation (CPM), electroencephalography (EEG), and transcranial magnetic stimulation (TMS). METHODS: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 36 patients with fibromyalgia were included. We analyzed CPM, EEG variables and TMS measures and their correlation with pain levels as measured by a visual analog scale. Univariate and multivariate linear regression analyses were performed to identify the predictors of pain severity. RESULTS: We found: (1) no association between pain levels and CPM; (2) an association between reduced alpha and beta power over the central region in resting-EEG and higher pain levels; (3) an association between smaller event-related desynchronization (ERD) responses in theta and delta bands over the central region and higher pain levels; (4) an association between smaller ERD responses in theta and delta bands and smaller intracortical inhibition and higher intracortical facilitation ratios; (5) an association between smaller ERD responses in delta band and reduced CPM. CONCLUSIONS: Our results do not support CPM as a biomarker for pain intensity in FM. However, our specific EEG findings showing the relationship between pain, CPM and TMS measures suggest that FM leads to a disruption of inhibitory neural modulators and thus support CPM as a likely predictive marker of disrupted pain modulation system. These neurophysiological markers need to be further explored in potential future trials as to find novel targets for the treatment of FM.

Noninvasive motor cortex stimulation effects on quantitative sensory testing in healthy and chronic pain subjects: a systematic review and meta-analysis.

ABSTRACT: One of the potential mechanisms of motor cortex stimulation by noninvasive brain stimulation (NIBS) effects on pain is through the restoration of the defective endogenous inhibitory pain pathways. However, there are still limited data on quantitative sensory testing (QST), including conditioned pain modulation (CPM), supporting this mechanism. This systematic review and meta-analysis aimed to evaluate the effects of noninvasive motor cortex stimulation on pain perception as indexed by changes in QST outcomes. Database searches were conducted until July 2019 to include randomized controlled trials that performed sham-controlled NIBS on the motor cortex in either the healthy and/or pain population and assessed the QST and CPM. Quality of studies was assessed through the Cochrane tool. We calculated the Hedge's effect sizes of QST and CPM outcomes and their 95% confidence intervals (95% CIs) and performed random-effects meta-analyses. Thirty-eight studies were included (1178 participants). We found significant increases of pain threshold in healthy subjects (ES = 0.16, 95% CI = 0.02-0.31, I2 = 22.2%) and pain populations (ES = 0.48, 95% CI = 0.15-0.80, I2 = 68.8%), and homogeneous higher CPM effect (pain ratings reduction) in healthy subjects (ES = -0.39, 95% CI = -0.64 to -0.14, I2 = 17%) and pain populations (ES = -0.35, 95% CI = -0.60 to -0.11, I2 = 0%) in the active NIBS group compared with sham. These results support the idea of top-down modulation of endogenous pain pathways by motor cortex stimulation as one of the main mechanisms of pain reduction assessed by QST, which could be a useful predictive and prognostic biomarker for chronic pain personalized treatment with NIBS.

Noninvasive brain stimulation combined with exercise in chronic pain: a systematic review and meta-analysis.

Background: The use of noninvasive brain stimulation (NIBS) combined with exercise could produce synergistic effects on chronic pain conditions. This study aims to evaluate the efficacy and safety of NIBS combined with exercise to treat chronic pain as well as to describe the parameters used to date in this combination.Methods: The search was carried out in Medline, Central, Scopus, Embase, and Pedro until November 2019. Randomized clinical trials (RCTs) and quasi-experimental studies reporting the use of noninvasive brain stimulation and exercise on patients with chronic pain were selected and revised.Results: The authors included eight studies (RCTs), reporting eight comparisons (219 participants). Authors found a significant and homogeneous pain decrease (ES: -0.62, 95% CI:-0.89 to -0.34; I2 = 0.0%) in favor of the combined intervention compared to sham NIBS + exercise, predominantly by excitatory (anodal tDCS/rTMS) motor cortex stimulation. Regarding NIBS techniques, the pooled effect sizes were significant for both tDCS (ES: -0.59, 95% CI: -0.89 to -0.29, I2 = 0.0%) and rTMS (ES: -0.76, 95% CI: -1.41 to -0.11, I2 = 0.0%).Conclusions: This meta-analysis suggests a significant moderate to large effects of the NIBS and exercise combination in chronic pain. The authors discuss the potential theoretical framework for this synergistic effect.

Características de los factores de riesgo cardiovascular en una población urbana y rural de la selva peruana, julio - 2014 / Characteristics of cardiovascular risk factors in an urban and rural population of the Peruvian jungle - July, 2014

Objetivo: Determinar las características del lugar de residencia y los factores de riesgo cardiovascular en una población de la selva peruana en julio 2014. Materiales y métodos: Estudio descriptivo transversal realizado en individuos entre 30 y 74 años sin diagnóstico ni tratamiento de enfermedad cardiovascular en una población urbana y una rural del distrito de Yantaló. La muestra se obtuvo a partir del programa Power Analysis and Sample Size Software (PASS) y estuvo conformada por 268 personas (152 habitantes urbanos y 116 rurales). Los factores estudiados fueron hipertensión arterial (HTA), diabetes mellitus (DM), índice de masa corporal (IMC), índice cintura-cadera (ICC) y tabaquismo. Resultados: La población urbana presentó un mayor porcentaje de HTA (18,4%), mientras que los otros factores de riesgo no presentaron diferencias significativas. Conclusiones: El único factor de riesgo que mostró asociación significativa con el lugar de residencia fue la HTA. En contraste, los otros factores de riesgo del estudio no presentaron diferencias entre ambas poblaciones, lo que demostraría que el distrito de Yantaló se encuentra inmerso en un proceso de transición epidemiológica debido a la urbanización.

Objective: To determine the characteristics of the place of residence and the cardiovascular risk factors in a Peruvian jungle population in July 2014. Materials and methods: A descriptive cross-sectional study conducted in individuals between 30 and 74 years old without a diagnosis of or treatment for a cardiovascular disease in an urban and rural population of the district of Yantaló. The sample was obtained using the Power Analysis and Sample Size Software (PASS) program, and consisted of 268 people (152 urban and 116 rural residents). The studied factors were hypertension (HBP), diabetes mellitus (DM), body mass index (BMI), waist-hip ratio (WHR) and smoking. Results: The urban population had higher rates of hypertension (18.4%), while the other risk factors showed no significant differences between the two populations. Conclusions: The only risk factor that showed a significant association with the place of residence was hypertension. In contrast, the other risk factors of the study showed no differences between the two populations, which demonstrates that the district of Yantaló is involved in a process of epidemiological transition due to urbanization.