Effect of perceived injustice-targeted pain neuroscience education compared with biomedically focused education in breast cancer survivors: a study protocol for a multicentre randomised controlled trial (BCS-PI trial).

INTRODUCTION: Current treatments for pain in breast cancer survivors (BCSs) are mostly biomedically focused rather than biopsychosocially driven. However, 22% of BCSs with pain are experiencing perceived injustice, which is a known predictor for adverse pain outcomes and opioid prescription due to increased maladaptive pain behaviour. Educational interventions such as pain neuroscience education (PNE) are suggested to target perceived injustice. In addition, motivational interviewing can be an effective behavioural change technique. This trial aims to examine whether perceived injustice-targeted PNE with the integration of motivational interviewing is superior to biomedically focused pain education in reducing pain after 12 months in BCS with perceived injustice and pain. In addition, improvements in quality of life, perceived injustice and opioid use are evaluated, and a cost-effectiveness analysis will finally result in a recommendation concerning the use of perceived injustice-targeted PNE in BCSs with perceived injustice and pain. METHODS AND ANALYSIS: This two-arm multicentre randomised controlled trial will recruit female BCS (n=156) with pain and perceived injustice. Participants will be randomly assigned to perceived injustice-targeted PNE or biomedically focused pain education in each centre. Both interventions include an online session, an information leaflet and three one-to-one sessions. The primary outcome (pain), secondary outcomes (quality of life, perceived injustice and outcomes for cost-effectiveness analysis) and explanatory outcomes (pain phenotyping, sleep, fatigue and cognitive-emotional factors) will be assessed at baseline and at 0, 6, 12 and 24 months postintervention using self-reported questionnaires online. Treatment effects over time will be evaluated using linear mixed model analyses. Additionally, a cost-utility analysis will be done from a healthcare payer and societal perspective. ETHICS AND DISSEMINATION: The ethical agreement was obtained from the Main Ethics Committee (B.U.N.1432020000068) at the University Hospital Brussels and all other participating hospitals. Study results will be disseminated through presentations, conferences, social media, press and journals. TRIAL REGISTRATION NUMBER: NCT04730154.

Costly mistakes: Why and when spelling errors in resumes jeopardise interview chances.

The analysis of hiring penalties due to spelling errors has been restricted to white-collar occupations and error-laden resumes. Moreover, the mechanisms underlying these penalties remained unclear. To fill these gaps, we conducted a scenario experiment with 445 recruiters. Compared to error-free resumes, hiring penalties are inflicted for error-laden resumes (18.5 percent points lower interview probability) and resumes with fewer errors (7.3 percent points lower interview probability). Furthermore, we find heterogeneity in penalties inflicted. Half of the penalty can be explained by the perceptions that applicants making spelling errors have lower interpersonal skills (9.0%), conscientiousness (12.1%) and mental abilities (32.2%).

The Prevalence of Perceived Injustice and Factors Associated With Perceived Injustice in People With Pain: A Systematic Review With Meta-analysis.

BACKGROUND: Perceived injustice (PI) is a multidimensional appraisal cognition comprising the severity of loss consequent to injury, blame, a sense of unfairness, and/or irreparability of loss. PI gained increasing interest in pain research since it potentially contributes to the experience and burden of (chronic) pain. OBJECTIVES: This systematic review aimed to determine the prevalence of PI and factors associated with PI in people with pain. STUDY DESIGN: Systematic review with meta-analysis. METHODS: Web of Science, PubMed, and Embase were screened for cross-sectional or cohort studies encompassing human patients who were diagnosed with a condition causing pain and reported prevalence rates for PI and/or associations between a factor and PI. Meta-analyses were carried out, and subgroup analyses were undertaken based on the methodological quality of the studies, the type of pain population, and whether the outcome measure was valid or not in case of heterogeneity (P < 0.05). RESULTS: Fifty-four studies were found eligible. The prevalence of PI ranged from 23% to 77% (I2 = 99%, P < 0.001). Association with PI, assessed using the Injustice Experienced Questionnaire, were found with pain catastrophizing (pooled Pearson's r [rp] = 0.66 [0.64, 0.69], P < 0.00001), posttraumatic stress (rp = 0.63 [0.59, 0.67], P < 0.00001), anger (rp = 0.59 [0.49, 0.67], P < 0.00001), anxiety (rp = 0.59 [0.52, 0.64], P < 0.00001), pain acceptance (rp = -0.59 [-0.66, -0.49], P < 0.00001), depressive symptoms (rp = 0.57 [0.52, 0.60], P < 0.00001), kinesiophobia (rp = 0.57 [0.50, 0.64], P < 0.00001), academic functioning (rp = -0.54 [-0.65, -0.41], P < 0.00001), disability (rp = 0.53 [0.47, 0.59], P < 0.00001), emotional functioning (rp = -0.52 [-0.64, -0.39], P < 0.00001), pain interference (rp = 0.49 [0.35, 0.60], P < 0.00001), state anger (rp = 0.48 [0.41, 0.54], P < 0.00001), mental functioning (rp = -0.48 [-0.57, -0.38], P < 0.00001), symptoms of central sensitization (rp = 0.47 [0.39, 0.55], P < 0.00001), social functioning (rp = -0.47 [-0.60, -0.31], P < 0.00001), and physical functioning (rp = -0.43 [-0.53, -0.33], P < 0.00001), pain perceptions (rp = 0.40 [0.40, 0.64], P < 0.00001), trait anger (rp = 0.40 [0.29, 0.49], P < 0.00001), pain intensity (rp = 0.37 [0.33, 0.42], P < 0.00001), and anger inhibition (rp = 0.35 [0.26, 0.43], P < 0.00001). LIMITATIONS: Some articles had to be excluded due to the absence of a full-text version. The findings can largely be applied to developed and high-income countries, but further research is needed in developing countries. Also, no validated cutoff values were available for the National Institutes of Health to determine the methodological quality of the included studies. Lastly, high heterogeneity was observed in many of the performed analyses. However, this was addressed by performing subgroup analyses, which could decrease heterogeneity in some cases. CONCLUSIONS: The prevalence of PI was >= 33% in 75% of the studies indicating that PI is important to consider in people with pain. There is evidence for the association of PI with psychological, pain, and quality of life characteristics in people with pain. The associations of PI with personal, injury, and recovery characteristics were overall not significant or negligible.

Neuromodulation Applied to Diseases: The Case of HRV Biofeedback.

The vagus or "wandering" nerve is the main branch of the parasympathetic nervous system (PNS), innervating most internal organs crucial for health. Activity of the vagus nerve can be non-invasively indexed by heart-rate variability parameters (HRV). Specific HRV parameters predict less all-cause mortality, lower risk of and better prognosis after myocardial infarctions, and better survival in cancer. A non-invasive manner for self-activating the vagus is achieved by performing a slow-paced breathing technique while receiving visual feedback of one's HRV, called HRV-biofeedback (HRV-B). This article narratively reviews the biological mechanisms underlying the role of vagal activity and vagally mediated HRV in hypertension, diabetes, coronary heart disease (CHD), cancer, pain, and dementia. After searching the literature for HRV-B intervention studies in each condition, we report the effects of HRV-B on clinical outcomes in these health conditions, while evaluating the methodological quality of these studies. Generally, the levels of evidence for the benefits of HRV-B is high in CHD, pain, and hypertension, moderate in cancer, and poor in diabetes and dementia. Limitations and future research directions are discussed.

Transcutaneous Vagal Nerve Stimulation Alone or in Combination With Radiotherapy Stimulates Lung Tumor Infiltrating Lymphocytes But Fails to Suppress Tumor Growth.

The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.

Pain and Opioid Use in Cancer Survivors: A Practical Guide to Account for Perceived Injustice.

BACKGROUND: The presence of pain decreases survival rates in cancer. Pain management in clinical settings is often suboptimal and secondary to other cancer-related treatments, leaving many people undertreated. Opioid use is associated with side effects and decreased survival rate in cancer patients. Hence, there is an urgent need for considering factors such as perceived injustice that sustain post-cancer pain and trigger a behavioral pattern associated with opioid use. Injustice beliefs represent a maladaptive pattern of cognitive appraisal that may be a salient target for improving pain-related coping in these patients. Perceived injustice is associated with increased opioid prescription and prospectively predicted opioid use at 1-year follow-up, urging the need for targeted interventions to diminish perceived injustice. OBJECTIVES: Explain the importance of screening for perceived injustice in patients with pain following cancer treatment, its potential relevance for opioid abuse, and its potential impact on the management of pain following cancer. Also, prove clinicians with a clinical guide for an approach comprising of modified pain neuroscience education, motivational interviewing, and acceptance-based interventions to account for perceived injustice in patients having pain following cancer. STUDY DESIGN: A narrative review, perspective and treatment manual. SETTING: Several universities, a university of applied science department, a university hospital, and a private clinic (i.e., transdisciplinary pain treatment center). METHODS: Patients were cancer survivors with pain. Intervention included modified pain neuroscience education, motivational interviewing, and acceptance-based interventions. Measurements were taken through the Injustice Experience Questionnaire (IEQ). RESULTS: The IEQ can be used to assess perceived injustice in a valid way. Education about pain, including discussing perceived injustice, should be the first part of the management of pain in cancer survivors. In order to obtain the often-required behavioral change towards a more adaptive lifestyle, motivational interviewing can be used. To thoroughly tackle perceived injustice in patients having pain following cancer, special emphasis should be given to the individual reasons patients identify for experiencing (continued) pain and related symptoms. Pain acceptance should also be thoroughly addressed. LIMITATIONS: Clinical trials exploring the benefits, including cost-effectiveness, of such a multimodal approach in patients with pain following cancer treatment are needed. CONCLUSIONS: In light of its potential relevance for opioid abuse and potential impact on conservative management strategies, clinicians are advised to screen for perceived injustice in patients with pain following cancer treatment. Therapeutic targeting of perceived injustice can be done through an approach comprising of modified pain neuroscience education, motivational interviewing, and acceptance-based interventions.

Too sick or not too sick? The importance of stress and satisfaction with supervisor support on the prevalence of sickness presenteeism.

In a sample of 3274 full-time Belgian workers, this article found that 62% of workers went to work while being sick (sickness presenteeism) at least once over the past 12 months. Of all workers who did not show sickness presenteeism themselves, another 6 out of 10 saw or heard about sickness presenteeism in their own organization. Women were more likely to report sickness presenteeism than men and junior workers were more prone to sickness presenteeism than senior workers. Education did not explain the choice for sickness presenteeism. Satisfaction with the supervisor had a direct negative effect on sickness presenteeism. Finally, indirect effects were found between satisfaction with the supervisor and sickness presenteeism via the prevalence of stress. While previous studies showed that good supervisor support can make sick workers more productive when they show up at work, this study shows that good supervisor support makes sick workers stay at home.

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Stronger Correlations between Neurophysiological and Peripheral Disease Biomarkers Predict Better Prognosis in Two Severe Diseases.

: 'Mind-body' debates assume that better brain-body associations are healthy. This study examined whether degree of associations between a neurophysiological vagal nerve index and peripheral disease biomarkers predict prognosis in pancreatic cancer (PC) and multiple sclerosis (MS). Sample 1 included 272 patients with advanced PC. Sample 2 included 118 patients with MS. We measured the vagal nerve index heart rate variability (HRV) derived from electrocardiograms. We examined associations between HRV and patients' peripheral disease biomarkers: CA19-9 in PC and neurofilament light chain (NFL) in MS. Associations between HRV and each biomarker were examined separately in patients who survived or died (PC), and in those with and without relapse during 12 months (MS). In PC, HRV was significantly inversely related to the tumor marker CA19-9 in patients who later survived (r = -0.44, p < 0.05) but not in those who died (r = 0.10, NS). In MS, HRV was significantly and inversely related to NFL only in those who did not relapse (r = -0.25, p < 0.05), but not in those who relapsed (r = -0.05, NS). The degree of association between a neurophysiological vagal marker and peripheral disease biomarkers has prognostic value in two distinct diseases.

How breathing can help you make better decisions: Two studies on the effects of breathing patterns on heart rate variability and decision-making in business cases.

Deep slow breathing can increase vagal nerve activity, indexed by heart rate variability (HRV). HRV is also associated with better decision-making. This research examined the effects of two breathing patterns on HRV (Study 1) and on stress and decision-making performance (Study 2). In Study 1, 30 healthy people performed either a symmetric breathing pattern (equal ratio of inhaling/exhalation timing), a skewed pattern (exhalation longer than inhalation), or watched an emotionally neutral film (sham), following a baseline period. Both types of breathing patterns significantly increased time and frequency domain HRV parameters, while viewing the film did not. In Study 2, 56 students were randomized to perform 2 min of the skewed vagal breathing (experimental group) or to wait for 2 min (controls), before performing a 30-minute business challenging decision-making task with multiple choice answers. Stress levels were self-reported before and after the task. While controls reported elevations in stress levels, those in the experimental group did not. Importantly, participants in the experimental group provided a significantly higher percentage of correct answers than controls. These studies show that brief vagal breathing patterns reliably increase HRV and improve decision-making. Limitations, possible mechanisms and implications for business decision-making are discussed.

The Vagus Nerve Can Predict and Possibly Modulate Non-Communicable Chronic Diseases: Introducing a Neuroimmunological Paradigm to Public Health.

Global burden of diseases (GBD) includes non-communicable conditions such as cardiovascular diseases, cancer and chronic obstructive pulmonary disease. These share important behavioral risk factors (e.g., smoking, diet) and pathophysiological contributing factors (oxidative stress, inflammation and excessive sympathetic activity). This article wishes to introduce to medicine and public health a new paradigm to predict, understand, prevent and possibly treat such diseases based on the science of neuro-immunology and specifically by focusing on vagal neuro-modulation. Vagal nerve activity is related to frontal brain activity which regulates unhealthy lifestyle behaviors. Epidemiologically, high vagal activity, indexed by greater heart rate variability (HRV), independently predicts reduced risk of GBD and better prognosis in GBD. Biologically, the vagus nerve inhibits oxidative stress, inflammation and sympathetic activity (and associated hypoxia). Finally, current non-invasive methods exist to activate this nerve for neuro-modulation, and have promising clinical effects. Indeed, preliminary evidence exists for the beneficial effects of vagal nerve activation in diabetes, stroke, myocardial infarction and possibly cancer. Thus, we propose to routinely implement measurement of HRV to predict such GBD in populations, and to test in randomized controlled trials effects of non-invasive vagal nerve activation on prevention and treatment of GBD, reflecting possible neuro-modulation of health.

Therapeutic potential of the vagus nerve in cancer.

Accumulating evidence points to a beneficial effect ofvagus nerve activity in tumor development. The vagus nerve is proposed to slow tumorigenesis because of its anti-inflammatory properties mediated through ACh and the α7nAChR. Since α7nAChRs are widely expressed by many types of immune cells we hypothesized that the vagus nerve affects the tumor microenvironment and anticancer immunity. We found direct evidence in studies using animal cancer models that vagus nerve stimulation alters immunological responses relevant to the tumor microenvironment. Also studies in pathologies other than cancer suggest a role for the vagus nerve in altering immunological responses relevant to anticancer immunity. These results provide a rationale to expect that vagus nerve stimulation, in combination with conventional cancer treatments, may improve the prognosis of cancer patients by promoting anticancer immunity.

The Role of the Vagus Nerve in Cancer Prognosis: A Systematic and a Comprehensive Review.

This article reviews the role of the vagus nerve in tumor modulation and cancer prognosis. We present a systematic review of 12 epidemiological studies examining the relationship between heart rate variability, the main vagus nerve index, and prognosis in cancer patients (survival and tumor markers). These studies show that initially high vagal nerve activity predicts better cancer prognosis, and, in some studies, independent of confounders such as cancer stage and treatments. Since the design of the epidemiological studies is correlational, any causal relationship between heart rate variability and cancer prognosis cannot be inferred. However, various semi-experimental cohort studies in humans and experimental studies in animals have examined this causal relationship. The second part of this paper presents a comprehensive review including human and animal cohort and experimental studies showing that vagotomy accelerates tumor growth, while vagal nerve activation improves cancer prognosis. Based on all reviewed studies, it is concluded that the evidence supports a protective role of the vagus nerve in cancer and specifically in the metastatic stage.

Vagal nerve activity predicts overall survival in metastatic pancreatic cancer, mediated by inflammation.

Recent research findings suggest neuro-modulation of tumors. Finding new modifiable prognostic factors paves the way for additional treatments, which is crucial in advanced cancer, particularly pancreatic cancer. This study examined the relationship between vagal nerve activity, indexed by heart rate variability (HRV), and overall survival (OS) in patients (N=272) with advanced pancreatic cancer. A "historical prospective" design was employed, where vagal activity and other confounders were retroactively obtained from medical charts at diagnosis, and subsequent OS was examined. HRV was obtained from 10 sec ECGs near diagnosis. Levels of C-reactive protein (CRP) were measured as an inflammatory marker. OS and survival date were obtained from medical charts and the Belgian national registry. Patients with high HRV (>20 msec) survived on average more than double the days (133.5) than those with low HRV (64.0). In a multivariate cox regression, higher initial HRV was significantly correlated with lower risk of death, independent of confounders including age and cancer treatments. This relationship was statistically mediated (accounted for) by CRP levels. Importantly, in patients who lived up to one month from diagnosis only, HRV was unrelated to CRP, while in patients surviving longer, HRV was significantly inversely related to CRP (r=-0.20, p<0.05). These results are in line with possible vagal nerve protection in a fatal cancer, and propose that the mechanism may involve neuroimmuno-modulation. Future studies must test whether vagal nerve activation may help patients with advanced cancers.

You may need a nerve to treat pain: the neurobiological rationale for vagal nerve activation in pain management.

OBJECTIVES: Pain is a complex common health problem, with important implications for quality of life and with huge economic consequences. Pain can be elicited due to tissue damage, as well as other multiple factors such as inflammation and oxidative stress. Can there be 1 therapeutic pathway that may target multiple etiologic factors in pain? METHODS: In the present article, we review evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and 5 factors that are etiologic to or protective in pain. RESULTS: Vagal nerve activity inhibits inflammation, oxidative stress, and sympathetic activity, activates brain regions that can oppose the brain "pain matrix," and finally it might influence the analgesic effects of opioids. Together, these can explain the antinociceptive effects of vagal nerve activation or of acetylcholine, the principal vagal nerve neurotransmitter. These findings form an evidence-based neurobiological rationale for testing and possibly implementing different vagal nerve-activating treatments in pain conditions. DISCUSSION: In this article, we show evidence for the relationships between vagal nerve activity and pain, and between vagal nerve activity and 5 factors that are etiologic to pain. Given the evidence and effects of the vagus nerve activation in pain, people involved in pain therapy may need to seriously consider activation of this nerve.

The relationship between vagal nerve activity and clinical outcomes in prostate and non-small cell lung cancer patients.

Recent studies suggest that vagal nerve activity, indexed by heart rate variability (HRV), could have a prognostic role in cancer. However, most studies did not control adequately for confounders and included cardiac patients. Furthermore, the validity of this prognostic role needs to be tested in different types of cancer. The present study tested the prognostic role of HRV in prostate cancer (PC) and non-small cell lung cancer (NSCLC) patients, using a historical prospective design. HRV was derived from brief 10 sec ECGs obtained at approximately the time of diagnosis in 113 PC patients and 133 NSCLC patients. Outcomes included prostate-specific antigen (PSA) at 6 and 24 months in PC, and overall survival (OS) (for the full sample) and survival time (for the deceased patients) in NSCLC. Furthermore, the possible mediating role of C-reactive protein (CRP) was tested (in NSCLC), as well as whether age and stage moderated the relationship between HRV and prognosis in both types of cancer. In the PC patients, HRV significantly inversely predicted PSA levels at 6 and 24 months, independent of confounders. Furthermore, this was particularly significant in metastatic PC patients, indicating moderation by stage. In NSCLC patients, HRV did not predict OS and survival time, but it did positively predict survival time in patients under the age of 65, independent of confounders. Additionally, CRP was not found to mediate the relationship between HRV and OS or survival time in NSCLC. The present results partly support previous studies and extend them to two additional common types of cancer, using a more rigorous control over confounders. Together with recent experimental findings, these results propose a modulatory role of vagal nerve activity in cancer. Therefore, routine measurement of HRV in estimating prognosis in cancer may be considered.

You may need the vagus nerve to understand pathophysiology and to treat diseases.

Can different pathophysiological mechanisms and risk factors leading to various diseases be linked with altered transmission of signals by one common pathway? The present article provides evidence for the hypothesis that adequate vagal nerve activity reduces the risk of major diseases, via common basic mechanisms and interim risk factors. These diseases include cardiovascular disease, cancer, Alzheimer's disease and the metabolic syndrome. Three basic mechanisms contribute to such illnesses: local oxidative stress and DNA damage, inflammatory reactions and excessive sympathetic responses, all of which are inhibited by vagal nerve activity. Efferent vagal activity that can be non-invasively measured by HRV (heart rate variability), derived from an ECG, is inversely related to all three basic mechanisms, to various risk factors (e.g. diabetes and dyslipidaemia) and, more broadly, to the diseases as well. Finally, vagal activity is proposed to moderate the effects of risk factors on developing such illnesses. By proposing an integrative neurobiological model of major diseases, identifying people at risk for, and treating patients with, such diseases may be done more efficiently. People with low HRV may be identified and subsequently treated by vagus nerve activation to possibly prevent or treat such illnesses. This proposed disease paradigm may have important preventative and therapeutic implications, whose clinical effects need to be investigated.