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The evidence for use of direct oral anticoagulants (DOACs) in the management of post-operative cardiac surgery atrial fibrillation is limited and mostly founded on clinical trials that excluded this patient population. We performed a systematic review and meta-analysis of clinical trials and observational studies to evaluate the hypothesis that DOACs are safe compared to warfarin for the anticoagulation of patients with post-operative cardiac surgery atrial fibrillation. We searched PubMed, EMBASE, Web of Science, clinicaltrials.gov, and the Cochrane Library for clinical trials and observational studies comparing DOAC with warfarin in patients ≥18 years old who had post-cardiac surgery atrial fibrillation. Primary outcomes included stroke, systemic embolization, bleeding, and mortality. We performed a random-effects meta-analysis of all outcomes. The meta-analysis for the primary outcomes showed significantly lower risk of stroke with DOAC use (6 studies, 7143 patients, RR 0.64; 95% CI 0.50–0.81, I2: 0.0%) compared to warfarin, a trend towards lower risk of systemic embolization (4 studies, 7289 patients, RR 0.64, 95% CI 0.41–1.01, I2: 31.99%) and similar risks of bleeding (14 studies, 10182 patients, RR 0.91; 95% CI 0.74–1.10, I2: 26.6%) and mortality (12 studies, 9843 patients, relative risk [RR] 1.01; 95% CI 0.74–1.37, I2: 26.5%). Current evidence suggests that DOACs, compared to warfarin, in the management of atrial fibrillation after cardiac surgery is associated with lower risk of stroke and a strong trend for lower risk of systemic embolization, and no evidence of increased risk for hospital readmission, bleeding and mortality.

To evaluate the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on inflammatory markers and clinical outcomes in patients with COVID-19.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.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.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.The Brazilian Registry of Clinical Trials (RBR-399t4g5).

The study’s objective was to develop a clinical prediction rule that predicts a clinically significant analgesic effect on chronic knee osteoarthritis pain after transcranial direct current stimulation treatment. This is a secondary analysis from a double-blind randomized controlled trial. Data from 51 individuals with chronic knee osteoarthritis pain and an impaired descending pain inhibitory system were used. The intervention comprised a 15-session protocol of anodal primary motor cortex transcranial direct current stimulation. Treatment success was defined by the Western Ontario and McMaster Universities’ Osteoarthritis Index pain subscale. Accuracy statistics were calculated for each potential predictor and for the final model. The final logistic regression model was statistically significant (p < 0.01) and comprised five physical and psychosocial predictor variables that together yielded a positive likelihood ratio of 14.40 (95% CI: 3.66–56.69) and an 85% (95%CI: 60–96%) post-test probability of success. This is the first clinical prediction rule proposed for transcranial direct current stimulation in patients with chronic pain. The model underscores the importance of both physical and psychosocial factors as predictors of the analgesic response to transcranial direct current stimulation treatment. Validation of the proposed clinical prediction rule should be performed in other datasets.

There is tentative evidence to support the analgesic effect of transcranial direct current stimulation (tDCS) in fibromyalgia (FM), with large variability in the effect size (ES) encountered in different clinical trials. Understanding the source of the variability and exploring how it relates to the clinical results could characterize effective neuromodulation protocols and ultimately guide care in FM pain. The primary objective of this study was to determine the effect of tDCS in FM pain as compared with sham tDCS. The secondary objective was to explore the relationship of methodology, population, and intervention factors and the analgesic effect of tDCS in FM.For the primary objective, a systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized clinical trials (RCTs) investigating tDCS as an intervention for FM pain were searched in MEDLINE, Embase, and the Web Of Science. Studies were excluded if they used cross-over designs or if they did not use tDCS as an intervention for pain or did not measure clinical pain. Analysis for the main outcome was performed using a random-effects model. Risk of bias and evidence certainty were assessed for all studies using Cochrane Risk of Bias and Grading of Recommendations Assessment, Development, and Evaluation tools. For the secondary objective, a meta-regression was conducted to explore methodology, population, and intervention factors potentially related to the ES.Sixteen RCTs were included. Six studies presented a high risk of bias. Significant reduction in pain scores were found for FM (standardized mean difference = 1.22, 95% CI = 0.80-1.65, p 0.001). Subgroup analysis considering tDCS as a neural target revealed no differences between common neural sites. Meta-regression revealed that the duration of the tDCS protocol in weeks was the only factor associated with the ES, in which protocols that lasted four weeks or longer reported larger ES than shorter protocols.Results suggest an analgesic effect of tDCS in FM. tDCS protocols that last four weeks or more may be associated with larger ESs. Definite conclusions are inadequate given the large heterogeneity and limited quality of evidence of the included studies.

BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.MethodsIn a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.FindingsThe study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30(4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, pOverall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13–48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR30(10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 109 cells/L, p=0.0098).ConclusionAnti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2.

Objectives The pain related to spinal cord injury (SCI) is difficult to treat, and it is associated with significant morbidity. One aspect to improve therapeutics is to explore markers of pain and its correlates in SCI. Methods In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 39 patients with SCI were included. We analyzed conditioned pain modulation (CPM) efficiency as the index of the descending pain inhibitory system, EEG variables, and clinical pain levels as measured by the Visual Analogue Scale. Regression analyses were performed to assess the relationship among EEG variables, pain levels, and CPM. Results We included 39 SCI patients, 74% reported SCI-related pain. We found that (1) less alpha and beta power are related to pain presence, (2) less alpha and beta power are associated with higher pain levels among patients with pain, (3) patients with pain have decreased peak alpha-theta frequency compared to no-pain group, (4) more relative theta power are related to the presence of low CPM efficiency, (5) higher relative theta power is associated with lower CPM efficiency. Conclusions Our results confirm and provide additional data on the relationship between decreased alpha and beta frequencies and higher pain levels. One important finding, though, was a specific and different EEG signature for the descending inhibitory pain system, as we showed that increased theta EEG power is related to decreased CPM efficiency; suggesting that, although low CPM efficiency plays a major role in pain in these participants, it does seem to be associated with a specific oscillatory brain rhythm different from clinical pain. These findings have significant implications for future research on EEG-based biomarkers of pain in post-SCI and new interventions as neurofeedback to manage pain in this population.

Objectives To explore associations of intracortical excitability with clinical characteristics in a large sample of subjects with phantom limb pain (PLP). Methods Ancillary study using baseline and longitudinal data from a large multicenter randomized trial that investigated the effects of non-invasive brain stimulation combined with sensorimotor training on PLP. Multivariate regression modeling analyses were used to investigate the association of intracortical excitability, measured by percentages of intracortical inhibition (ICI) and facilitation (ICF) with clinical variables. Results Ninety-eight subjects were included. Phantom sensation of itching was positively associated with ICI changes and at baseline in the affected hemisphere (contralateral to PLP). However, in the non-affected hemisphere (ipsilateral to PLP), the phantom sensation of warmth and PLP intensity were negatively associated with ICI (both models). For the ICF, PLP intensity (baseline model only) and age (longitudinal model) were negatively associated, while time since amputation and amputation level (both for longitudinal model only) were positively associated in the affected hemisphere. Additionally, use of antidepressants led to lower ICF in the non-affected hemisphere for the baseline model while higher amputation level also led to less changes in the ICF. Conclusion Results revealed clear associations of clinical variables and cortical excitability in a large chronic pain sample. ICI and ICF changes appear not to be mainly explained by PLP intensity. Instead, other variables associated with duration of neuroplasticity changes (such as age and duration of amputation) and compensatory mechanisms (such as itching and phantom limb sensation) seem to be more important in explaining these variables.

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.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.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.These results underscore the promising role of combining genetic and neurophysiological markers to endotype the treatment response in this population.

BACKGROUND: Phantom limb pain (PLP) management has been a challenge due to its response heterogeneity and lack of treatment access. This study will evaluate the feasibility of a remotely home-based M1 anodal tDCS combined with motor imagery in phantom limb patients and assess the preliminary efficacy, safety, and predictors of response of this therapy. METHODS: This is a pilot, single-arm, open-label trial in which we will recruit 10 subjects with phantom limb pain. The study will include 20 sessions. All participants will receive active anodal M1 tDCS combined with phantom limb motor imagery training. Our primary outcome will be the acceptability and feasibility of this combined intervention. Moreover, we will assess preliminary clinical (pain intensity) and physiological (motor inhibition tasks and heart rate variability) changes after treatment. Finally, we will implement a supervised statistical learning (SL) model to identify predictors of treatment response (to tDCS and phantom limb motor imagery) in PLP patients. We will also use data from our previous clinical trial (total observations=224 [n=112 x timepoints = 2)) for our statistical learning algorithms. The new prospective data from this open-label study will be used as an independent test dataset. DISCUSSION: This protocol proposes to assess the feasibility of a novel, neuromodulatory combined intervention that will allow the design of larger remote clinical trials, thus increasing access to safe and effective treatments for PLP patients. Moreover, this study will allow us to identify possible predictors of pain response and PLP clinical endotypes.

International audience; Simple Summary There have been huge improvements in both vaccination and the management of COVID-19 in patients with cancer. In addition, different variants may be associated with different presentations. Therefore, we examined whether indicators of the severity of COVID-19 in patients with cancer who present to hospital varied during different waves of the pandemic and we showed that these indicators remained predictive. We validated that the COVID-19 Risk in Oncology Evaluation Tool (CORONET), which predicts the severity of COVID-19 in cancer patients presenting to hospital, performed well in all waves. In addition, we examined patient outcomes and the factors that influence them and found that there was increased vaccination uptake and steroid use for patients requiring oxygen in later waves, which may be associated with improvements in outcome. Patients with cancer have been shown to have increased risk of COVID-19 severity. We previously built and validated the COVID-19 Risk in Oncology Evaluation Tool (CORONET) to predict the likely severity of COVID-19 in patients with active cancer who present to hospital. We assessed the differences in presentation and outcomes of patients with cancer and COVID-19, depending on the wave of the pandemic. We examined differences in features at presentation and outcomes in patients worldwide, depending on the waves of the pandemic: wave 1 D614G (n = 1430), wave 2 Alpha (n = 475), and wave 4 Omicron variant (n = 63, UK and Spain only). The performance of CORONET was evaluated on 258, 48, and 54 patients for each wave, respectively. We found that mortality rates were reduced in subsequent waves. The majority of patients were vaccinated in wave 4, and 94% were treated with steroids if they required oxygen. The stages of cancer and the median ages of patients significantly differed, but features associated with worse COVID-19 outcomes remained predictive and did not differ between waves. The CORONET tool performed well in all waves, with scores in an area under the curve (AUC) of >0.72. We concluded that patients with cancer who present to hospital with COVID-19 have similar features of severity, which remain discriminatory despite differences in variants and vaccination status. Survival improved following the first wave of the pandemic, which may be associated with vaccination and the increased steroid use in those patients requiring oxygen. The CORONET model demonstrated good performance, independent of the SARS-CoV-2 variants.

Prostate cancer has huge health and societal impacts, and there is no clear consensus on the most effective and efficient treatment strategy for this disease, particularly for localized prostate cancer. We have reviewed the scientific literature describing the economic burden and cost-effectiveness of different treatment strategies for localized prostate cancer in OECD countries. We initially identified 315 articles, studying 13 of them in depth (those that met the inclusion criteria), comparing the social perspectives of cost, time period, geographical area, and severity. The economic burden arising from prostate cancer due to losses in productivity and increased caregiver load is noticeable, but clinical decision-making is carried out with more subjective variability than would be advisable. The direct cost of the intervention was the main driver for the treatment of less severe cases of prostate cancer, whereas for more severe cases, the most important determinant was the loss in productivity. Newer, more affordable radiotherapy strategies may play a crucial role in the future treatment of early prostate cancer. The interpretation of our results depends on conducting thorough sensitivity analyses. This approach may help better understand parameter uncertainty and the methodological choices discussed in health economics studies. Future results of ongoing clinical trials that are considering genetic characteristics in assessing treatment response of patients with localized prostate cancer may shed new light on important clinical and pharmacoeconomic decisions.

Head and neck squamous cell carcinoma (HNSCC) is a potential curative disease at its localized stage, by the use of multimodal treatment including surgery, radiation, and chemotherapy. While the metastatic stage is considered incurable and is characterized by poor prognosis. Conventional cytotoxic chemotherapy in addition to cetuximab were the only available systemic treatment with limited efficacy and modest median overall survival barely crossing the 1 year limit. Immunotherapy with PD-1 and PD-L1 inhibitors has revolutionized the treatment of multiple cancers. Recently, Immunotherapy is being extensively explored in head and neck cancer and clinical trials have shown impressive results that allowed to immune check point inhibitors to be the new standard of care. In this article we tried to explain the rationale and mechanisms of targeting the immune system in head and neck carcinoma and to report the results from the phase III clinical trials that put the immunotherapy as a new standard of care for head and neck cancer.

Background: The use of exercise is a potential treatment option to modulate pain (exercise-induced hypoalgesia). The pain threshold (PT) response is a measure of pain sensitivity that may be a useful marker to assess the effect of physical exercise on pain modulation. Aim: The aim of this systematic review and meta-analysis is to evaluate the PT response to exercise in healthy subjects. Methods: We searched in MEDLINE, EMBASE, Web of Science, Lilacs, and Scopus using a search strategy with the following search terms: "exercise" OR "physical activity" AND "Pain Threshold" from inception to December 2nd, 2019. As criteria for inclusion of appropriate studies: randomized controlled trials or quasi-experimental studies that enrolled healthy subjects; performed an exercise intervention; assessed PT. Hedge's effect sizes of PT response and their 95% confidence intervals were calculated, and random-effects meta-analyses were performed. Results: For the final analysis, thirty-six studies were included (n=1326). From this, we found a significant and homogenous increase in PT in healthy subjects (ES=0.19, 95% CI= 0.11 to 0.27, I2=7.5%). According to subgroup analysis, the effect was higher in studies: with women (ES=0.36); performing strength exercise (ES=0.34), and with moderate intensity (ES=0.27), and no differences by age were found. Confirmed by the meta-regression analysis. Conclusion: This meta-analysis provides evidence of small to moderate effects of exercise on PT in healthy subjects, being even higher for moderate strength exercise and in women. These results support the idea of modulation of the endogenous pain system due to exercise and highlight the need for clinical translation to the chronic pain population.

Introduction: The evidence for use of direct oral anticoagulants (DOACs) in the management of post-operative cardiac surgery atrial fibrillation (POAF) is limited and mostly founded on clinical trials that excluded this patient population. Hypothesis: We performed a systematic review and meta-analysis of clinical trials and observational studies to evaluate the hypothesis that DOACs are safe compared to warfarin for the anticoagulation of patients with POAF. Methods: We searched PubMed, EMBASE, Web of Science, clinicaltrials.gov, and the Cochrane Library for clinical trials and observational studies comparing DOAC with warfarin in patients ≥18 years old who had post-cardiac surgery atrial fibrillation. Primary outcomes included stroke, systemic embolization, bleeding, and mortality, with secondary outcome of hospital readmission. We performed a random-effects meta-analysis. Results: We found 3 clinical trials, 1 prospective and 12 retrospective cohort studies eligible for inclusion with a total of 10,538 patients (3,207 DOAC patients and 7,331 warfarin patients). The meta-analysis for the primary outcomes showed significantly lower risk of stroke with DOAC use (6 studies, 7143 patients, RR 0.64; 95% CI 0.50 to 0.81, I2: 0.0%) compared to warfarin, a trend towards lower risk of systemic embolization (4 studies, 7289 patients, RR 0.64, 95% CI 0.41 to 1.01, I2: 31.99%) and similar risks of bleeding (14 studies, 10182 patients, RR 0.91; 95% CI 0.74 to 1.10, I2: 26.6%) and mortality (12 studies, 9843 patients, relative risk [RR] 1.01; 95% CI 0.74 to 1.37, I2: 26.5%) The secondary outcome of hospital readmission had similar risk between groups. Conclusions: Current evidence suggests that DOACs, compared to warfarin, in the management of atrial fibrillation after cardiac surgery is associated with lower risk of stroke and a strong trend for lower risk of systemic embolization, and no evidence of increased risk for hospital readmission, bleeding or mortality.

The WHO has recommended self-isolation and social distancing measures for containing the coronavirus 19 (COVID-19) pandemic, and the Centers of Disease Control and Prevention (CDC) and the vast majority of countries have adopted it, with strategies varying in terms of degrees of containment (Wilder-Smith and Freedman, 2020). Despite the worldwide efforts in understanding and combating the disease, many uncertainties remain, including the precise rates of transmission and mortality, not to mention the proper treatment, leading to concerns and confusion regarding the necessary duration of the isolation measures. The possible need to adopt intermittent strategies of social distancing has also been raised, alternating periods of stricter and looser isolation (Kissler et al., 2020) until the discovery of a vaccine or efficient treatment is made. Social isolation by itself leads to stress and negative mood (Brooks et al., 2020). The uncertainties mentioned above potentiate these effects, particularly in patients with a history of mental health disorders. Social isolation and loneliness are also associated with increased overall mortality (Steptoe et al., 2013), worse cardiovascular, and mental health outcomes (Leigh-Hunt et al., 2017) and cognitive decline (Evans et al., 2019). Furthermore, the recent Covid-19 outbreak has been associated with post-traumatic stress disorder (PTSD) symptoms, which were identified both in medical staff and the general population (Wang et al., 2020). Numerous studies have demonstrated how non-invasive neuromodulatory techniques such as rTMS and tDCS can help prevent and ameliorate stress, with effects not only on emotion, cognition, and behavior but also on the cardiovascular (Makovac et al., 2017) and autonomic nervous systems (Schestatsky et al., 2013). Although non-invasive, repetitive TMS is expensive and not portable (the only portable option applies a very short train of pulses). Therefore, it is not appropriate during the context of social isolation since patients would have to leave their homes to receive the treatment. On the other hand, tDCS is potentially portable, and its feasibility in home-based settings has been previously studied with promising results regarding its safety and effectiveness (Martens et al., 2018; Brietzke et al., 2020). Our objective in this short communication is to provide a comment on the potential tDCS application on preventing and treating stress-related symptoms during social isolation, while addressing the feasibility and efficacy of home-based tDCS.

BACKGROUND Chronic pain is the leading cause of disability, affecting between 20% and 50% of the global population. The key recommended treatment is physical activity, which can be measured in daily life using a pedometer. However, poor adherence to pedometer use can result in incorrect measurements. Furthermore, only a few studies have investigated a possible curvilinear association between physical activity and chronic pain. OBJECTIVE In this study, we developed the Pain-Note smartphone app to collect real-world data on step count, using the smartphone’s built-in pedometer. The aims of our research are (1) to evaluate the association between daily step count and pain level among patients with chronic pain and (2) determine if the association between daily step count and pain level was curvilinear. METHODS We conducted a cross-sectional study based on step count data collected with the app and on the results of questionnaires, which measured the duration and intensity of pain, the widespread pain index, the symptom severity score, and the insomnia severity scale, including 7 questions for symptoms of depression. We analyzed the association between step count and pain level as a nonlinear relationship using a restricted cubic spline model. A prespecified subgroup analysis was also conducted based on fibromyalgia criteria. RESULTS Between June 1, 2018, and June 11, 2020, a total of 6138 records were identified, of which 1273 were analyzed. The mean age of the participants was 38.7 years, 81.9% (1043/1273) were female, and chronic pain was present for more than 5 years in 43.2% (550/1273) of participants. Participants in the third and fourth quartiles for step count (more than 3045 and 5668 steps a day, respectively) showed a significant positive association between higher step count and lower numerical pain rating scale (mean difference –0.43, 95% CI –0.78 to –0.08, P=.02; –0.45; 95% CI –0.8 to –0.1, P=.01, respectively) than those in the first quartile (less than or equal to 1199 steps a day). The restricted cubic spline model for the association between step count and pain scale displayed a steep decline followed by a moderate decrease as the step count increased; the inflection point was 5000 steps. However, this association was not observed among participants who met the fibromyalgia criteria (491/1273), who showed a steep positive increase below 2000 steps. Data were collected between June 1, 2018, and June 11, 2020, and were analyzed on November 18, 2021. CONCLUSIONS Step count measured with the Pain-Note app showed a nonlinear association with pain level. Although participants with and without fibromyalgia showed a negative correlation between step count and pain level, participants who meet the criteria for fibromyalgia may present a different relationship between walking and pain perception compared to those in the general chronic pain population.

Summary 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.

Fibromyalgia (FM) is a common and refractory chronic pain condition with multiple clinical phenotypes. The current diagnosis is based on a syndrome identification which can be subjective and lead to under or over-diagnosis. Therefore, there is a need for objective biomarkers for diagnosis, phenotyping, and prognosis (treatment response and follow-up) in fibromyalgia. Potential biomarkers are measures of cortical excitability indexed by transcranial magnetic stimulation (TMS). However, no systematic analysis of current evidence has been performed to assess the role of TMS metrics as a fibromyalgia biomarker. Therefore, this study aims to evaluate evidence on corticospinal and intracortical motor excitability in fibromyalgia subjects and to assess the prognostic role of TMS metrics as response biomarkers in FM. We conducted systematic searches on PubMed/Medline, Embase, and Cochrane Central databases for observational studies and randomized controlled trials on fibromyalgia subjects that used TMS as an assessment. Three reviewers independently selected and extracted the data. Then, a random-effects model meta-analysis was performed to compare fibromyalgia and healthy controls in observational studies. Also, to compare active versus sham treatments, in randomized controlled trials. Correlations between changes in TMS metrics and clinical improvement were explored. The quality and evidence certainty were assessed following standardized approaches. We included 15 studies (696 participants, 474 FM subjects). The main findings were: (1) fibromyalgia subjects present less intracortical inhibition (mean difference (MD) = -0.40, 95% confidence interval (CI) -0.69 to -0.11) and higher resting motor thresholds (MD = 6.90 μV, 95% CI 4.16 to 9.63 μV) when compared to controls; (2) interventions such as exercise, pregabalin, and non-invasive brain stimulation increased intracortical inhibition (MD = 0.19, 95% CI 0.10 to 0.29) and cortical silent period (MD = 14.92 ms, 95% CI 4.86 to 24.98 ms), when compared to placebo or sham stimulation; (3) changes on intracortical excitability are correlated with clinical improvements - higher inhibition moderately correlates with less pain, depression, and pain catastrophizing; lower facilitation moderately correlates with less fatigue. Measures of intracortical inhibition and facilitation indexed by TMS are potential diagnostic and treatment response biomarkers for fibromyalgia subjects. The disruption in the intracortical inhibitory system in fibromyalgia also provides additional evidence that fibromyalgia has some neurophysiological characteristics of neuropathic pain. Treatments inducing an engagement of sensorimotor systems (e.g., exercise, motor imagery, and non-invasive brain stimulation) could restore the cortical inhibitory tonus in FM and induce clinical improvement.

INTRODUCTION: Fibromyalgia affects more than 5 million people in the United States and has a detrimental impact on individuals’ quality of life. Current pharmacological treatments provide limited benefits to relieve fibromyalgia’s pain, along with risks of adverse effects, a scenario that explains the increasing interest for multimodal approaches. A tailored strategy to focus on this dysfunctional endogenous pain inhibitory system is transcranial direct current stimulation (tDCS) of the primary motor cortex. By combining tDCS with aerobic exercise, the effects can be optimized. AREAS COVERED: The relevant literature was reviewed and discussed the methodological issues for designing a mechanistic clinical trial to test this combined intervention. Also, we reviewed the neural control of different pathways that integrate the endogenous pain inhibitory system, as well as the effects of tDCS and aerobic exercise both alone and combined. In addition, potential neurophysiological assessments are addressed: Conditioned Pain Modulation, Temporal Slow Pain Summation, Transcranial Magnetic Stimulation and Electroencephalography in the context of fibromyalgia. EXPERT COMMENTARY: By understanding the neural mechanisms underlying pain processing and potential optimized interventions in fibromyalgia with higher accuracy, the field has an evident potential of advancement in the direction of new neuromarkers and tailored therapies.

International audience; There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data - emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.

Esophageal cancer and gastric cancer are aggressive diseases for which treatment approaches are facing a new era. Some molecular pathways, such as VEGF, EGFR, fibroblast growth factor receptor, PIK3CA, and PARP-1, have been studied, and novel targeted drugs are presumed to be developed in the near future. From The Cancer Genome Atlas report, 80% of Epstein-Barr virus tumors and 42% of tumors with microsatellite instability have PIK3CA mutations, suggesting that this pathway could be reevaluated as a possible target for new systemic treatment of gastric cancer. Notably, higher PARP-1 expression can be found in gastric cancer, which might be related to more advanced disease and worse prognosis. In addition, PD-L1 expression, high microsatellite instability, and mismatch repair deficiency can be found in gastric cancer, thus suggesting that immunotherapy may also play a role in those patients. We discuss trends related to the potential of novel therapies for patients with esophageal and gastric cancers in the near future.

IntroductionFibromyalgia (FM) is a common debilitating condition with limited therapeutic options. Medications have low efficacy and are often associated with adverse effects. Given that FM is associated with a defective endogenous pain control system and central sensitisation, combining interventions such as transcranial direct current stimulation (tDCS) and aerobic exercise (AE) to modulate pain-processing circuits may enhance pain control.Methods and analysisA prospective, randomised (1:1:1:1), placebo-controlled, double-blind, factorial clinical trial will test the hypothesis that optimised tDCS (16 anodal tDCS sessions combined with AE) can restore of the pain endogenous control system. Participants with FM (n=148) will undergo a conditioning exercise period and be randomly allocated to one of four groups: (1) active tDCS and AE, (2) sham tDCS and AE, (3) active tDCS and non-aerobic exercise (nAE) or (4) sham tDCS and nAE. Pain inhibitory activity will be assessed using conditioned pain modulation (CPM) and temporal slow pain summation (TSPS)—primary outcomes. Secondary outcomes will include the following assessments: Transcranial magnetic stimulation and electroencephalography as cortical markers of pain inhibitory control and thalamocortical circuits; secondary clinical outcomes on pain, FM, quality of life, sleep and depression. Finally, the relationship between the two main mechanistic targets in this study—CPM and TSPS—and changes in secondary clinical outcomes will be tested. The change in the primary efficacy endpoint, CPM and TSPS, from baseline to week 4 of stimulation will be tested with a mixed linear model and adjusted for important demographic variables.Ethics and disseminationThis study obeys the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Partners Healthcare under the protocol number 2017P002524. Informed consent will be obtained from participants. Study findings will be reported in conferences and peer-reviewed journal publications.Trial registration numberNCT03371225.