Telehealth Mindfulness-Oriented Recovery Enhancement vs Usual Care in Individuals With Opioid Use Disorder and Pain: A Randomized Clinical Trial.

Importance: Methadone treatment (MT) fails to address the emotion dysregulation, pain, and reward processing deficits that often drive opioid use disorder (OUD). New interventions are needed to address these factors. Objective: To evaluate the efficacy of MT as usual (usual care) vs telehealth Mindfulness-Oriented Recovery Enhancement (MORE) plus usual care among people with an OUD and pain. Design, Setting, and Participants: This study was a randomized clinical trial conducted from August 2020 to June 2022. Participants receiving MT for OUD and experiencing chronic pain were recruited at 5 clinics in New Jersey. Interventions: In usual care, participants received MT, including medication and counseling. Participants receiving MORE plus usual care attended 8 weekly, 2-hour telehealth groups that provided training in mindfulness, reappraisal, and savoring in addition to usual care. Main Outcomes and Measure: Primary outcomes were return to drug use and MT dropout over 16 weeks. Secondary outcomes were days of drug use, methadone adherence, pain, depression, and anxiety. Analyses were based on an intention-to-treat approach. Results: A total of 154 participants (mean [SD] age, 48.5 [11.8] years; 88 female [57%]) were included in the study. Participants receiving MORE plus usual care had significantly less return to drug use (hazard ratio [HR], 0.58; 95% CI, 0.37-0.90; P = .02) and MT dropout (HR, 0.41; 95% CI, 0.18-0.96; P = .04) than those receiving usual care only after adjusting for a priori-specified covariates (eg, methadone dose and recent drug use, at baseline). A total of 44 participants (57.1%) in usual care and 39 participants (50.6%) in MORE plus usual care returned to drug use. A total of 17 participants (22.1%) in usual care and 10 participants (13.0%) in MORE plus usual care dropped out of MT. In zero-inflated models, participants receiving MORE plus usual care had significantly fewer days of any drug use (ratio of means = 0.58; 95% CI, 0.53-0.63; P < .001) than those receiving usual care only through 16 weeks. A significantly greater percentage of participants receiving MORE plus usual care maintained methadone adherence (64 of 67 [95.5%]) at the 16-week follow-up than those receiving usual care only (56 of 67 [83.6%]; χ2 = 4.49; P = .04). MORE reduced depression scores and ecological momentary assessments of pain through the 16-week follow-up to a significantly greater extent than usual care (group × time F2,272 = 3.13; P = .05 and group × time F16,13000 = 6.44; P < .001, respectively). Within the MORE plus usual care group, EMA pain ratings decreased from a mean (SD) of 5.79 (0.29) at baseline to 5.17 (0.30) at week 16; for usual care only, pain decreased from 5.19 (0.28) at baseline to 4.96 (0.29) at week 16. Within the MORE plus usual care group, mean (SD) depression scores were 22.52 (1.32) at baseline and 18.98 (1.38) at 16 weeks. In the usual care-only group, mean (SD) depression scores were 22.65 (1.25) at baseline and 20.03 (1.27) at 16 weeks. Although anxiety scores increased in the usual care-only group and decreased in the MORE group, this difference between groups did not reach significance (group × time unadjusted F2,272 = 2.10; P= .12; Cohen d = .44; adjusted F2,268 = 2.33; P = .09). Within the MORE plus usual care group, mean (SD) anxiety scores were 25.5 (1.60) at baseline and 23.45 (1.73) at 16 weeks. In the usual care-only group, mean (SD) anxiety scores were 23.27 (1.75) at baseline and 24.07 (1.73) at 16 weeks. Conclusions and Relevance: This randomized clinical trial demonstrated that telehealth MORE was a feasible adjunct to MT with significant effects on drug use, pain, depression, treatment retention, and adherence. Trial Registration: ClinicalTrials.gov Identifier: NCT04491968.

Further Exploration of Treatment Response in Latinos with Comorbid Asthma and Panic Disorder: A Brief Report of HRV and ETCO2 as Potential Mediators of Treatment Response.

Heart rate variability (HRV) and end tidal CO2 (ETCO2) in relation to treatment response have not been studied in Latino populations or in comorbid asthma and panic disorder (PD). An extension of previously published research, the current study explored psychophysiological variables as possible mediators of treatment response. Latino treatment completers (N = 32) in the Bronx with asthma-PD received either Cognitive-Behavioral Psychophysiological Therapy (CBPT) or Music Relaxation Therapy (MRT). CBPT included HRV-biofeedback (HRVB); in-the-moment heart rate data to help an individual learn to influence his/her own heart rate. The sample was primarily female (93.8%) and Puerto Rican (81.25%). Treatment groups did not differ on demographics, except for less education in CBPT. The Panic Disorder Severity Scale (PDSS) and Asthma Control Questionnaire (ACQ) assessed changes in symptoms. HRV and ETCO2 were measured at four of eight therapy sessions. Baseline ETCO2 and changes in HRV from first to last of psychophysiology sessions were investigated as mediators of change on ACQ and PDSS. Mixed model analyses indicated in the CPBT group, changes in both asthma control and PD severity were not mediated by changes in HRV. In the CBPT and MRT groups combined, changes in PD severity were not mediated by baseline ETCO2. These findings may be due to the brevity of HRVB in CBPT, multiple treatment components, ETCO2 not directly targeted, and/or unique physiological pathways in Latinos with asthma-PD.

Heart Rate Variability Biofeedback Does Not Substitute for Asthma Steroid Controller Medication.

Despite previous findings of therapeutic effects for heart rate variability biofeedback (HRVB) on asthma, it is not known whether HRVB can substitute either for controller or rescue medication, or whether it affects airway inflammation. Sixty-eight paid volunteer steroid naïve study participants with mild or moderate asthma were given 3 months of HRVB or a comparison condition consisting of EEG alpha biofeedback with relaxing music and relaxed paced breathing (EEG+), in a two-center trial. All participants received a month of intensive asthma education prior to randomization. Both treatment conditions produced similar significant improvements on the methacholine challenge test (MCT), asthma symptoms, and asthma quality of life (AQOL). MCT effects were of similar size to those of enhanced placebo procedures reported elsewhere, and were 65% of those of a course of a high-potency inhaled steroid budesonide given to a sub-group of participants following biofeedback training. Exhaled nitric oxide decreased significantly only in the HRVB group, 81% of the budesonide effect, but with no significant differences between groups. Participants reported becoming more relaxed during practice of both techniques. Administration of albuterol after biofeedback sessions produced a large improvement in pulmonary function test results, indicating that neither treatment normalized pulmonary function as a potent controller medication would have done. Impulse oscillometry showed increased upper airway (vocal cord) resistance during biofeedback periods in both groups. These data suggest that HRVB should not be considered an alternative to asthma controller medications (e.g., inhaled steroids), although both biofeedback conditions produced some beneficial effects, warranting further research, and suggesting potential complementary effects. Various hypotheses are presented to explain why HRVB effects on asthma appeared smaller in this study than in earlier studies. Clinical Trial Registration NCT02766374.

The bidirectional associations between state anger and rumination and the role of trait mindfulness.

Rumination is associated with exacerbated angry mood. Angry moods may also trigger rumination. However, research has not empirically tested the bidirectional associations of state rumination and anger, as experience sampling methodology can do. We predicted that state anger and rumination would be bi-directionally associated, both concurrently and over time, even controlling for trait anger and rumination. In addition, because mindfulness is associated with rumination and anger at the bivariate level, we examined the effect of trait mindfulness on the bidirectional association between state rumination and anger. We examined two hypotheses: (i) state rumination mediates the effect of trait mindfulness on state anger; and (ii) trait mindfulness weakens, or moderates, the bidirectional associations between state rumination and anger. In an experience-sampling study, 200 college students reported their current ruminative thinking and angry mood several times a day for 7 days. Mixed model analyses indicated that state anger and rumination predicted each other concurrently. In cross-lagged analyses, previous anger did not uniquely predict current rumination; previous rumination predicted current anger, although the effect was small. In support of our hypothesis, state rumination mediated the association between trait mindfulness and state anger. Additionally, trait mindfulness moderated the concurrent and cross-lagged associations between state rumination and anger, although the results were complex. This study contributes new information about the complex interplay of rumination and anger. Findings also add support to the theory that mindfulness decreases emotional reactivity. Aggr. Behav. 43:342-351, 2017. © 2016 Wiley Periodicals, Inc.

Psychological treatment of comorbid asthma and panic disorder in Latino adults: Results from a randomized controlled trial.

Confusion between panic and asthma symptoms can result in serious self-management errors. A cognitive behavior psychophysiological therapy (CBPT) intervention was culturally adapted for Latinos consisting of CBT for panic disorder (PD), asthma education, differentiation between panic and asthma symptoms, and heart rate variability biofeedback. An RCT compared CBPT to music and relaxation therapy (MRT), which included listening to relaxing music and paced breathing at resting respiration rates. Fifty-three Latino (primarily Puerto Rican) adults with asthma and PD were randomly assigned to CBPT or MRT for 8 weekly sessions. Both groups showed improvements in PD severity, asthma control, and several other anxiety and asthma outcome measures from baseline to post-treatment and 3-month follow-up. CBPT showed an advantage over MRT for improvement in adherence to inhaled corticosteroids. Improvements in PD severity were mediated by anxiety sensitivity in CBPT and by depression in MRT, although earlier levels of these mediators did not predict subsequent improvements. Attrition was high (40%) in both groups, albeit comparable to CBT studies targeting anxiety in Latinos. Additional strategies are needed to improve retention in this high-risk population. Both CBPT and MRT may be efficacious interventions for comorbid asthma-PD, and CBPT may offer additional benefits for improving medication adherence.

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy.

PURPOSE/OBJECTIVE(S): To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. METHODS AND MATERIALS: We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. RESULTS: During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. CONCLUSIONS: Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.

Total and individual antioxidant intake and risk of epithelial ovarian cancer.

BACKGROUND: Limiting oxidative stress to the ovarian epithelium has been proposed as a first-line defense against ovarian cancer. Although evidence for an association between individual dietary antioxidant intake and ovarian cancer risk is conflicting, the combined evidence suggests a modest inverse association. Our study aimed to evaluate the association between total antioxidant capacity (TAC) and individual antioxidant intakes (vitamin C, vitamin E, beta-carotene, selenium, lutein, and lycopene) and ovarian cancer risk. METHODS: We conducted a population-based case-control study in New Jersey. Cases were women ages 21 years and older with newly diagnosed epithelial ovarian cancer who resided in six counties of New Jersey. Controls were women in the same age range who resided in the same geographic area. A total of 205 ovarian cancer cases and 390 controls were included. Dietary intake was ascertained using the Block food frequency questionnaire (FFQ), and TAC indices were constructed by linking FFQ-derived estimates to two standardized antioxidant capacity databases, the USDA Oxygen Radical Absorbance Capacity (ORAC) Database, and the University of Olso's Antioxidant Food Database. Multivariate logistic regression models were used to calculate odds ratios and 95 % confidence intervals while controlling for major ovarian cancer risk factors. RESULTS: We found a strong inverse association with selenium from food sources (OR: 0.41; 95 % CI: 0.20-0.85, for the highest vs. lowest tertile of dietary selenium intake). However, there was little evidence of an association with dietary TAC or the others individual antioxidants. In contrast, compared to non-users, supplement users had significant increased risk for all micronutrients, but no statistically significant increased risk was observed for combined intake from foods and supplements of any of these antioxidants. CONCLUSIONS: This study found an inverse association between selenium consumption from food sources and ovarian cancer risk, while there was little evidence of an association with TAC or any of the other individual antioxidants. Additional research is needed to confirm these findings.

Voluntarily produced increases in heart rate variability modulate autonomic effects of endotoxin induced systemic inflammation: an exploratory study.

Exposure of healthy people to lipopolysaccharide (LPS; endotoxin) produces a pro-inflammatory response, subjective symptoms, and decreased heart rate variability (HRV). Given the efficacy of HRV biofeedback (BF) for treating asthma, the large autonomic effects of HRV BF, and the link between vagus nerve activity and inflammation, we hypothesized that HRV BF would dampen the acute manifestations of systemic inflammation induced by LPS challenge. Healthy participants age 18-40 were randomly assigned to four-one-hour training sessions of either HRV BF (n = 6) or a control 15/min paced breathing condition (n = 5) prior to acute experimentally induced LPS exposure. Participants were coached to do the procedures for 10 min each at five hourly time points after LPS injection, and then 2 h later. Subjective symptoms, HRV parameters, and plasma cytokine levels were measured at each time point, 2 h afterward, and the following morning. Participants were able to perform the procedures both during four pre-exposure training sessions and while experiencing LPS-induced symptoms. The HRV BF group showed significant attenuation of the LPS-induced decline in HRV for the 6 h following LPS exposure, suggesting that HRV BF decreased autonomic dysfunction produced by LPS-induced inflammation. HRV BF also reduced symptoms of headache and eye sensitivity to light, but did not affect LPS-induced levels of pro-inflammatory cytokines or symptoms of nausea, muscle aches, or feverishness. Further evaluation of HRV BF appears to be warranted among patients with inflammatory conditions.

Psychological treatment of comorbid asthma and panic disorder: a pilot study.

We evaluated two protocols for treating adults with comorbid asthma and panic disorder. The protocols included elements of Barlow's panic control therapy and elements of Barlow's "panic control therapy" and several asthma education programs, as well as modules designed to teach participants how to differentiate asthma and panic symptoms, and how to apply specific home management strategies for each. Fifty percent of subjects dropped out of a 14-session protocol by the eighth session; however, 83% of patients were retained in an eight-session protocol. Clinical results were mostly equivalent: significant decreases of >50% in panic symptoms, clinically significant decreases in asthma symptoms, improvement in asthma quality of life, and maintenance of clinical stability in asthma. Albuterol use decreased significantly in the 14-session protocol and at a borderline level I the 8-session protocol, while pulmonary function was maintained. A controlled evaluation of this procedure is warranted.

Analysis of failure time data with multilevel clustering, with application to the child vitamin a intervention trial in Nepal.

We consider the problem of estimating covariate effects in the marginal Cox proportional hazard model and multilevel associations for child mortality data collected from a vitamin A supplementation trial in Nepal, where the data are clustered within households and villages. For this purpose, a class of multivariate survival models that can be represented by a functional of marginal survival functions and accounts for hierarchical structure of clustering is exploited. Based on this class of models, an estimation strategy involving a within-cluster resampling procedure is proposed, and a model assessment approach is presented. The asymptotic theory for the proposed estimators and lack-of-fit test is established. The simulation study shows that the estimates are approximately unbiased, and the proposed test statistic is conservative under extremely heavy censoring but approaches the size otherwise. The analysis of the Nepal study data shows that the association of mortality is much greater within households than within villages.

Heart rate variability biofeedback: effects of age on heart rate variability, baroreflex gain, and asthma.

OBJECTIVES: To present additional analysis of data from a previously published study showing that biofeedback training to increase heart rate variability (HRV) can be an effective component in asthma treatment. HRV and intervention-related changes in HRV are negatively correlated with age. Here we assess the effects of age on biofeedback effects for asthma. DESIGN: Ten sessions of HRV biofeedback were administered to 45 adults with asthma. Medication was prescribed by blinded physicians according to National Heart, Lung, and Blood Institute criteria. Medication needs were reassessed biweekly. RESULTS: Decreases in need for controller medication were independent of age. There were larger acute decreases in forced oscillation frequency dependence in the older group but larger increases in HRV variables in the younger group. Differences between age groups were smaller among subjects trained in pursed-lips abdominal breathing as well as biofeedback, than among those receiving only biofeedback. CONCLUSIONS: Age-related attenuation of biofeedback effects on cardiovascular variability does not diminish the usefulness of the method for treating asthma among older patients. Additional training in pursed-lips abdominal breathing obliterates the effects of age on HRV changes during biofeedback.

Marginal analysis for clustered failure time data.

Clustered failure time data are commonly encountered in biomedical research where the study subjects from the same cluster (e.g., family) share the common genetic and/or environmental factors such that the failure times within the same cluster are correlated. Two approaches that are commonly used to account for the intra-cluster association are frailty models and marginal models. In this paper, we study the marginal proportional hazards model, where the structure of dependence between individuals within a cluster is unspecified. An estimation procedure is developed based on a pseudo-likelihood approach, and a risk set sampling method is proposed for the formulation of the pseudo-likelihood. The asymptotic properties of the proposed estimators are studied, and the related issues regarding the statistical efficiencies are discussed. The performances of the proposed estimator are demonstrated by the simulation studies. A data example from a child vitamin A supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or NNIPS) is used to illustrate this methodology.

Biofeedback treatment for asthma.

STUDY OBJECTIVES: We evaluated the effectiveness of heart rate variability (HRV) biofeedback as a complementary treatment for asthma. PATIENTS: Ninety-four adult outpatient paid volunteers with asthma. SETTING: The psychophysiology laboratory at The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, and the private outpatient offices of participating asthma physicians. INTERVENTIONS: The interventions were as follows: (1) a full protocol (ie, HRV biofeedback and abdominal breathing through pursed lips and prolonged exhalation); (2) HRV biofeedback alone; (3) placebo EEG biofeedback; and (4) a waiting list control. DESIGN: Subjects were first prestabilized using controller medication and then were randomly assigned to experimental groups. Medication was titrated biweekly by blinded asthma specialists according to a protocol based on National Heart, Lung, and Blood Institute guidelines, according to symptoms, spirometry, and home peak flows. MEASUREMENTS: Subjects recorded daily asthma symptoms and twice-daily peak expiratory flows. Spirometry was performed before and after each weekly treatment session under the HRV and placebo biofeedback conditions, and at triweekly assessment sessions under the waiting list condition. Oscillation resistance was measured approximately triweekly. RESULTS: Compared with the two control groups, subjects in both of the two HRV biofeedback groups were prescribed less medication, with minimal differences between the two active treatments. Improvements averaged one full level of asthma severity. Measures from forced oscillation pneumography similarly showed improvement in pulmonary function. A placebo effect influenced an improvement in asthma symptoms, but not in pulmonary function. Groups did not differ in the occurrence of severe asthma flares. CONCLUSIONS: The results suggest that HRV biofeedback may prove to be a useful adjunct to asthma treatment and may help to reduce dependence on steroid medications. Further evaluation of this method is warranted.

Heart rate variability biofeedback increases baroreflex gain and peak expiratory flow.

OBJECTIVE: We evaluated heart rate variability biofeedback as a method for increasing vagal baroreflex gain and improving pulmonary function among 54 healthy adults. METHODS: We compared 10 sessions of biofeedback training with an uninstructed control. Cognitive and physiological effects were measured in four of the sessions. RESULTS: We found acute increases in low-frequency and total spectrum heart rate variability, and in vagal baroreflex gain, correlated with slow breathing during biofeedback periods. Increased baseline baroreflex gain also occurred across sessions in the biofeedback group, independent of respiratory changes, and peak expiratory flow increased in this group, independently of cardiovascular changes. Biofeedback was accompanied by fewer adverse relaxation side effects than the control condition. CONCLUSIONS: Heart rate variability biofeedback had strong long-term influences on resting baroreflex gain and pulmonary function. It should be examined as a method for treating cardiovascular and pulmonary diseases. Also, this study demonstrates neuroplasticity of the baroreflex.

Cohort case-control design and analysis for clustered failure-time data.

Cohort case-control design is an efficient and economical design to study risk factors for disease incidence or mortality in a large cohort. In the last few decades, a variety of cohort case-control designs have been developed and theoretically justified. These designs have been exclusively applied to the analysis of univariate failure-time data. In this work, a cohort case-control design adapted to multivariate failure-time data is developed. A risk set sampling method is proposed to sample controls from nonfailures in a large cohort for each case matched by failure time. This method leads to a pseudolikelihood approach for the estimation of regression parameters in the marginal proportional hazards model (Cox, 1972, Journal of the Royal Statistical Society, Series B 34, 187-220), where the correlation structure between individuals within a cluster is left unspecified. The performance of the proposed estimator is demonstrated by simulation studies. A bootstrap method is proposed for inferential purposes. This methodology is illustrated by a data example from a child vitamin A supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or NNIPS).