Experiences of Patients Taking Conditioned Open-Label Placebos for Reduction of Postoperative Pain and Opioid Exposure After Spine Surgery.

BACKGROUND: Pain after spine surgery is difficult to manage, often requiring the use of opioid analgesics. While traditional "deceptive" or concealed placebo has been studied in trials and laboratory experiments, the acceptability and patient experience of taking honestly prescribed placebos, such as "open-label" placebo (non-deceptive placebo), or conditioned placebo (pairing placebo with another active pharmaceutical) is relatively unexamined. METHODS: Qualitative thematic analysis was performed using semi-structured, post-treatment interviews with spine surgery patients (n = 18) who had received conditioned open-label placebo (COLP) during the first 2-3 weeks after surgery as part of a RCT. Interview transcripts were reviewed by 3 investigators using an immersion/crystallization approach, followed by iterative large-group discussions with additional investigators, to identify, refine, and codify emergent themes. RESULTS: Patients' experiences and perceptions of COLP efficacy varied widely. Some emergent themes included the power of the mind over pain, how COLP might provide distraction from or agency over pain, bandwidth required and engagement with COLP, and its modulation of opioid tapering, as well as negative attitudes toward opioids and pill taking in general. Other themes included uncertainty about COLP efficacy, observations of how personality may relate to COLP efficacy, and a recognition of the greater impact of COLP on reduction of opioid use rather than on pain itself. Interestingly, participant uncertainty, disbelief, and skepticism were not necessarily associated with greater opioid consumption or worse pain. CONCLUSION: Participants provided insights into the experience of COLP which may help to guide its future utilization to manage acute pain and tapering from opioids.

Systematic review of burnout among healthcare providers in sub-Saharan Africa.

BACKGROUND: Burnout is characterized by physical and emotional exhaustion from long-term exposure to emotionally demanding work. Burnout affects interpersonal skills, job performance, career satisfaction, and psychological health. However, little is known about the burden of burnout among healthcare providers in sub-Saharan Africa. METHODS: Relevant articles were identified through a systematic review of PubMed, Web of Science (Thomson Reuters), and PsycINFO (EBSCO). Studies were selected for inclusion if they examined a quantitative measure of burnout among healthcare providers in sub-Saharan Africa. RESULTS: A total of 65 articles met our inclusion criteria for this systematic review. Previous studies have examined burnout in sub-Saharan Africa among physicians (N = 12 articles), nurses (N = 26), combined populations of healthcare providers (N = 18), midwives (N = 2), and medical or nursing students (N = 7). The majority of studies assessed burnout using the Maslach Burnout Inventory. The highest levels of burnout were reported among nurses, although all healthcare providers showed high burnout. Burnout among healthcare providers is associated with their work environments, interpersonal and professional conflicts, emotional distress, and low social support. CONCLUSIONS: Available studies on this topic are limited by several methodological challenges. More rigorously designed epidemiologic studies of burnout among healthcare providers are warranted. Health infrastructure improvements will eventually be essential, though difficult to achieve, in under-resourced settings. Programs aimed at raising awareness and coping with burnout symptoms through stress management and resilience enhancement trainings are also needed.

Homeopathy Use in the United States and Implications for Public Health: A Review.

Homeopathy is used by just over 2% of the U.S. population, predominantly for respiratory, otorhinolaryngology, and musculoskeletal complaints. Individual users who see a homeopathic provider for care are more likely to perceive the therapy as helpful than those who do not; however, only 19% of users in the United States see a provider. The rest presumably rely upon over-the-counter products. Recent clinical trials highlight several areas in which homeopathy may play a role in improving public health, including infectious diseases, pain management, mental health, and cancer care. This review examines recent studies in these fields, studies assessing costs associated with homeopathic care, safety, and regulations in the United States. Data suggest the potential for public health benefit from homeopathy, especially for conditions such as upper respiratory infections and fibromyalgia.

Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor.

CD8(+) T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8(+) T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8(+) T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.

Homeopathy Use by US Adults: Results of a National Survey.

We used the 2012 National Health Interview Survey to compare homeopathy users with supplement users and those using other forms of complementary and integrative medicine. Among US adults, 2.1% used homeopathy within the past 12 months. Respiratory and otorhinolaryngology complaints were most commonly treated (18.5%). Homeopathy users were more likely to use multiple complementary and integrative medicine therapies and to perceive the therapy as helpful than were supplement users. US homeopathy use remains uncommon; however, users perceive it as helpful.

Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection.

Many of the most promising tumor antigens for T-cell-based cancer immunotherapies are unmodified self-antigens. Unfortunately, the avidity of T cells specific for these antigens is limited by central tolerance during T-cell development in the thymus, resulting in decreased anti-tumor efficacy of these T cells. One approach to overcoming this obstacle is to mutate T-cell receptor (TCR) genes from naturally occurring T cells to enhance the affinity for the target antigen. These enhanced-affinity TCRs can then be developed for use in TCR gene therapy. Although TCRs with significantly enhanced affinity have been generated using this approach, it is not clear whether these TCRs, which bypass the affinity limits imposed by negative selection, remain unresponsive to the low levels of self-antigen generally expressed by some normal tissues. Here we show that 2 variants of a high-affinity WT1-specific TCR with enhanced affinity for WT1 are safe and do not mediate autoimmune tissue infiltration or damage when transduced into peripheral CD8 T cells and transferred in vivo. However, if expressed in developing T cells and subjected to thymic selection, the same enhanced-affinity TCRs signal tolerance mechanisms in the thymus, resulting in T cells with attenuated antigen sensitivity in the periphery.

Complementary and alternative medicine use by US adults with gastrointestinal conditions: Results from the 2012 National Health Interview Survey.

OBJECTIVES: Use of complementary and alternative medicine (CAM) has increased over the past two decades, and a growing body of evidence suggests that some CAM modalities may be useful in addressing gastrointestinal (GI) conditions. However, the overall pattern of CAM use for GI conditions remains unknown. We sought to elucidate the prevalence and patterns of CAM use among US adults with GI conditions. METHODS: We used the 2012 National Health Interview Survey (n=34,525), a nationally representative survey of the civilian, noninstitutionalized US population, to estimate the prevalence of CAM use among adults with GI conditions (abdominal pain, acid reflux/heartburn, digestive allergy, liver condition, nausea and/or vomiting, stomach or intestinal illness, and ulcer). We also examined the reasons for CAM use, perceived helpfulness, and disclosure of use to health-care providers among individuals who specifically used CAM to address a GI condition. Prevalence estimates were weighted to reflect the complex sampling design of the survey. RESULTS: Of the 13,505 respondents with a GI condition in the past year, 42% (n=5629) used CAM in the past year and 3% (n=407) used at least one CAM modality to address a GI condition. The top three modalities among those using CAM to address GI conditions were herbs and supplements, mind body therapies, and manipulative therapies. Of those using CAM to address a GI condition, 47% used three or more CAM therapies, and over 80% felt that it was helpful in addressing a GI condition and was important in maintaining health and well-being. Respondents told their health-care providers about use of these therapies 70% of the time. CONCLUSIONS: CAM was used by 42% of respondents with a GI condition in the past year. A small proportion use CAM specifically to address their GI condition, but the majority who do find it helpful. The most commonly used modalities in this group are herbs and supplements, and mind body and manipulative therapies.

Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors.

CD8+ T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer. Generating effective CD8+ T cell-mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8+ T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen. Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor alpha chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8+ T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.

Adoptive immunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction.

Adoptive T cell immunotherapy is an evolving technology with the potential of providing a means to safely and effectively target tumor cells for destruction.

Development and Testing of a Communication Intervention to Improve Chronic Pain Management in Primary Care: A Pilot Randomized Clinical Trial.

OBJECTIVES: Effective communication skills are essential for optimally managing chronic pain and opioids. This exploratory, sequential mixed methods study tested the effect of a novel framework designed to improve pain-related communication and outcomes. METHODS: Study 1 developed a novel 5-step framework for helping primary care clinicians discuss chronic pain and opioids with patients. Study 2 pilot tested an intervention for teaching this framework using standardized patient instructors-actors trained to portray patients and provide immediate clinician feedback-deployed during regular clinic hours. Primary care physicians were randomized to receive either the intervention or pain management recommendations from the Centers for Disease Control and Prevention. Primary outcomes were pain-related interference at 2 months and clinician use of targeted communication skills (coded from transcripts of audio-recorded visits); secondary outcomes were pain intensity at 2 months, clinician self-efficacy for communicating about chronic pain, patient experience, and clinician-reported visit difficulty. RESULTS: We enrolled 47 primary care physicians from 2 academic teaching clinics and recorded visits with 48 patients taking opioids for chronic pain who had an appointment scheduled with an enrolled physician. The intervention was not associated with significant changes in primary or secondary outcomes other than clinician self-efficacy, which was significantly greater in the intervention group. DISCUSSION: This study developed a novel framework and intervention for teaching clinician pain-related communications skills. Although the intervention showed promise, more intensive or multicomponent interventions may be needed to have a significant impact on clinicians' pain-related communication and pain outcomes.

Racial and socioeconomic status differences in stress, posttraumatic growth, and mental health in an older adult cohort during the COVID-19 pandemic.

Background: The COVID-19 pandemic has disproportionately impacted the most vulnerable and widened the health disparity gap in both physical and mental well-being. Consequentially, it is vital to understand how to best support elderly individuals, particularly Black Americans and people of low socioeconomic status, in navigating stressful situations during the COVID-19 pandemic and beyond. The aim of this study was to investigate perceived levels of stress, posttraumatic growth, coping strategies, socioeconomic status, and mental health between Black and non-Hispanic, White older adults, the majority over the age of 70. Additionally, we investigated which variables, if any, were associated with posttraumatic growth in these populations. Methods: One hundred seventy-six community dwelling older adults (mean age = 76.30 ±8.94), part of two observational studies (The Harvard Aging Brain Study and Instrumental Activities of Daily Living Study) in Massachusetts, US, were included in this cross-sectional study. The survey, conducted from March 23, 2021 to May 13, 2021, measured perceived stress, behavioral coping strategies, posttraumatic growth, and mental health during the COVID-19 pandemic. We investigated associations with post-traumatic growth in a multiple linear regression model and examined their differences by race with t-tests, Wilcoxon rank-sum tests, and Fisher's exact tests. A second multiple linear regression model was used to examine which coping strategies were associated with posttraumatic growth. Findings: Our results indicated no significant difference between the groups in terms of mental health or stress. However, Black participants showed significantly greater posttraumatic growth compared to non-Hispanic, White participants. Additionally, the coping strategies of religion and positive reframing were found to be significantly associated with posttraumatic growth. Furthermore, even with the effects of stress and coping strategies controlled for, race remained significantly associated with posttraumatic growth. Interpretation: The COVID-19 pandemic has differentially impacted Black and non-Hispanic White older adults. These results may help encourage further analysis on geriatric psychiatry as well as understanding how cultural values and adaptations impact posttraumatic growth and mental health in diverse populations. Funding: The Harvard Aging Brain Study (HABS) has been funded by NIH-NIA P01 AG036694 (PI: Reisa Sperling). The IADL study is funded by the National Institute on Aging (R01 AG053184, PI: Gad A. Marshall).

Stress Management and Resiliency Training for Healthcare Professionals: A Mixed-Methods, Quality-Improvement, Cohort Study.

OBJECTIVE: To assess the effects of a multi-modal resilience program, the Stress Management and Resiliency Training (SMART) Program, on healthcare professional well-being and job satisfaction. METHODS: This pilot, mixed-methods, quality improvement, cohort study assessed perceived stress, physical and mental health, job satisfaction, burnout, and value of the curriculum to attendees. RESULTS: Participants experienced a significant reduction in perceived stress (P < 0.001) and significant improvements in global mental health (P = 0.001), physical health (P = 0.045), and job satisfaction (P = 0.047). There was no significant improvement in burnout. Qualitative analysis of free text responses revealed appreciation for the skills taught, increased resiliency, and a positive impact on relationships. CONCLUSIONS: Delivering the SMART Program to healthcare professionals is feasible and may serve as a useful tool for reducing stress and increasing resilience.

Improved health outcomes in integrative medicine visits may reflect differences in physician and patient behaviors compared to standard medical visits.

OBJECTIVE: To identify differences in patient-physician interactions associated with improvements in GERD symptoms in a randomized controlled trial comparing integrative medicine and primary care/standard visits. METHODS: We analyzed video recordings of 2-minute excerpts (thin slices) from the beginning, middle, and end of 21 study visits (11 standard, 10 integrative medicine). RESULTS: According to blind coders' analysis of the excerpts, prospective improvement in GERD symptoms was most highly correlated with patients appearing pleased (r = 0.71, p < 0.01) and friendly (r = 0.67, p < 0.01) at the end of the visit, controlling for visit type. The combination of patient and physician smiling at the end of the visit was associated with improvement in GERD symptoms (r2 = 0.45, p = 0.004). The physician in the integrative visits was more engaged (p = 0.009), friendly (p = 0.005), relaxed (p = 0.002), smiled longer (p = 0.006), gazed longer (p = 0.02), and gestured more (p = 0.007), compared to standard visits. Patients in integrative visits also smiled longer (p = 0.004). CONCLUSION: The expanded history-taking questions asked by integrative clinicians may enhance relationship building, modifying patients' responses and improving patient-centered behaviors from clinicians,ultimately facilitating symptom improvement. PRACTICE IMPLICATIONS: Analysis of nonverbal behaviors may facilitate a better understanding of patient-clinician interactions in integrative medicine visits and yield insights to improve clinical interactions in conventional medicine.

A SMART approach to reducing paroxysmal atrial fibrillation symptoms: Results from a pilot randomized controlled trial.

BACKGROUND: Stress and negative emotions contribute to atrial fibrillation (AF). Mind-body practices decrease stress and negative emotions and may reduce AF episodes and improve quality of life for patients with AF. OBJECTIVE: We examined the effects of a multimodal mind-body program, the SMART Program, on AF-related quality of life in patients with paroxysmal AF (PAF). METHODS: In this randomized, waitlist-controlled pilot trial, 18 subjects with PAF participated in an 8-week SMART Program delivered online immediately or 3 months later. Validated measures were completed at baseline and at 3 and 6 months (waitlist group only). RESULTS: Comparing pre- vs post-program scores among all 18 participants, subjects reported improvement in AF-related quality of life (Cohen's d = 0.75, P = .005) and depression (d = 0.50, P = .05) but not anxiety (d = 0.35, P = .16). Subjects also reported improvements in AF symptom severity (P = .026), distress (P = .014), positive affect (P = .003), and ability to cope with stress (P = .001). Compared to waitlist control subjects, those in the immediate group reported improvement in positive affect (d = 1.20, P = .021) and coping with stress (d = 1.36, P = .011) after participating in the program. CONCLUSION: The SMART Program, delivered virtually, may enhance positive emotions and coping with stress as well as decrease negative emotions and AF symptoms. These results warrant a larger trial to better understand the potential benefits of such programs for patients with PAF.

Stress, resilience, and coping strategies in a sample of community-dwelling older adults during COVID-19.

Assessing the impact of the COVID-19 pandemic on perceived stress in older adults is critical to understanding how to best support elderly individuals navigating stressful situations, with the aim to lessen the impact of stressors on their brain health. Here, we collected measures on perceived stress, resilience, and behavioral coping strategies, in the context of the COVID-19 pandemic, in a cross-sectional sample of 141 community dwelling older adults (mean age = 74.4 ± 8.4, 59% females) who were part of two longitudinal observational studies in Massachusetts, U.S. Our results indicate that participants demonstrated moderate levels of stress related to COVID-19 and showed relatively high levels of resilience. Higher resilience was associated with greater use of adaptive coping behaviors and less use of maladaptive coping behaviors. The use of maladaptive coping strategies was associated with more stress. Moreover, hierarchical regression analyses revealed that resilience was the strongest unique predictor of stress, thus, largely accounting for the observed coping-outcome associations. Individual differences in resilience levels moderated the effects of two coping strategies (planning and self-blame) on stress. Specifically, planning was associated with increased levels of stress for people with low resilience. In contrast, high personal resilience attenuated the negative effect of self-blame on their stress levels. Taken together, our findings suggest that resilience is critical for coping with stress during the COVID-19 pandemic. Future approaches for augmenting resilience could prove to be important potential interventions to help support older adults navigating stressful situations as well as lessen adverse effects on neurocognitive and mental health in the future.

Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR.

Adoptive T-cell immunotherapy has shown promise in the treatment of human malignancies, but the challenge of isolating T cells with high avidity for tumor antigens in each patient has limited application of this approach. The transfer into T cells of T-cell receptor (TCR) genes encoding high-affinity TCRs recognizing defined tumor-associated antigens can potentially circumvent this obstacle. Using a well-characterized murine model of adoptive T-cell immunotherapy for widely disseminated leukemia, we demonstrate that TCR gene-modified T cells can cure mice of disseminated tumor. One goal of such adoptive therapy is to establish a persistent memory response to prevent recurrence; however, long-term function of transferred TCR-transduced T cells is limited due to reduced expression of the introduced TCR in vivo in quiescent resting T cells. However, by introducing the TCR into a cell with a known endogenous specificity, activation of these T cells by stimulation through the endogenous TCR can be used to increase expression of the introduced TCR, potentially providing a strategy to increase the total number of tumor-reactive T cells in the host and restore more potent antitumor activity.

Structural features of T cell receptor variable regions that enhance domain stability and enable expression as single-chain ValphaVbeta fragments.

The variable (V) domains of antibodies and T cell receptors (TCRs) share sequence homology and striking structural similarity. Single-chain antibody V domain constructs (scFv) are routinely expressed in a variety of heterologous systems, both for production of soluble protein as well as for in vitro engineering. In contrast, single-chain T cell receptor V domain constructs (scTCR) are prone to aggregation and misfolding and are refractory to display on phage or yeast in their wild-type form. However, through random mutagenesis and yeast display engineering, it has been possible to isolate scTCR mutants that are properly folded and displayed on the yeast surface. These displayed mutants can serve not only as a scaffold for further engineering but also as scTCR variants that exhibit favorable biophysical properties in Escherichia coli expression. Thus, a more comprehensive understanding of the V domain mutations that allowed display would be beneficial. Our goal here was to identify generalizable patterns of important mutations that can be applied to different TCRs. We compared five different scTCRs, four from mice and one from a human, for yeast surface display. Analysis of a collection of mutants revealed four distinct regions of TCR V domains that were most important for enabling surface expression: the Valpha-Vbeta interface, the HV4 of Vbeta, and the region of the Valpha and Vbeta domains normally apposed against the constant (C) domains. Consistent with the role of the V-C interface in surface display, reconstitution of this interface, by including the constant domains of each chain, allowed V domain display and alphabeta chain association on the yeast surface, thus providing an alternative TCR scaffold. However, the surface levels of TCR achieved with engineered scTCR mutants were superior to that of the ValphaCalpha/VbetaCbeta constructs. Therefore, we describe further optimization of the current strategy for surface display of the single-chain format in order to facilitate yeast display engineering of a broader range of scTCRs.

Primary care providers' use of and attitudes towards placebos: An exploratory focus group study with US physicians.

OBJECTIVE: To examine how primary care physicians define placebo concepts, use placebos in clinical practice, and view open-label placebos (OLPs). DESIGN: Semi-structured focus groups that were audio-recorded and content-coded. METHODS: Two focus groups with a total of 15 primary care physicians occurred at medical centres in the New England region of the United States. Prior experience using placebo treatments and attitudes towards open-label placebos were explored. Themes were analysed using an inductive data-driven approach. RESULTS: Physicians displayed a nuanced understanding of placebos and placebo effects in clinical contexts which sometimes focused on relational factors. Some respondents reported that they prescribed treatments with no known pharmacological effect for certain conditions and symptoms ('impure placebos') and that such prescriptions were more common for pain disorders, functional disorders, and medically unexplained symptoms. Opinions about OLP were mixed: Some viewed OLPs favourably or considered them 'harmless'; however, others strongly rejected OLPs as disrespectful to patients. Other issues in relation to OLPs included the following: lack of guidelines, legal and reputational concerns, and the notion that such treatments would run counter to customary medical practice. CONCLUSIONS: A number of physicians reported prescribing impure placebos in clinical care. Although some primary care physicians were resistant to the possibility of recommending OLPs, others regarded OLPs more favourably, viewing them as potential treatments, albeit with restricted potential. Statement of contribution What is already known? Many physicians report prescribing drugs for the purposes of eliciting a placebo effect. Initial evidence for the efficacy of open-label placebos is promising. What does this study add? A more nuanced description of the circumstances under which primary care physicians report placebo prescribing. A qualitative account of physician attitudes about using open-label placebos in clinical practice.