Can Brain Volume-Driven Characteristic Features Predict the Response of Alzheimer's Patients to Repetitive Transcranial Magnetic Stimulation? A Pilot Study.

This study is a post-hoc examination of baseline MRI data from a clinical trial investigating the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for patients with mild-moderate Alzheimer's disease (AD). Herein, we investigated whether the analysis of baseline MRI data could predict the response of patients to rTMS treatment. Whole-brain T1-weighted MRI scans of 75 participants collected at baseline were analyzed. The analyses were run on the gray matter (GM) and white matter (WM) of the left and right dorsolateral prefrontal cortex (DLPFC), as that was the rTMS application site. The primary outcome measure was the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog). The response to treatment was determined based on ADAS-Cog scores and secondary outcome measures. The analysis of covariance showed that responders to active treatment had a significantly lower baseline GM volume in the right DLPFC and a higher GM asymmetry index in the DLPFC region compared to those in non-responders. Logistic regression with a repeated five-fold cross-validated analysis using the MRI-driven features of the initial 75 participants provided a mean accuracy of 0.69 and an area under the receiver operating characteristic curve of 0.74 for separating responders and non-responders. The results suggest that GM volume or asymmetry in the target area of active rTMS treatment (DLPFC region in this study) may be a weak predictor of rTMS treatment efficacy. These results need more data to draw more robust conclusions.

Repetitive transcranial magnetic stimulation as a treatment for Alzheimer's disease: A randomized placebo-controlled double-blind clinical trial.

We report results of a large multisite double-blind randomized trial investigating the short and long-term efficacy of repetitive transcranial magnetic stimulation (rTMS) applied to patients with Alzheimer's disease (AD) at mild to moderate stages, in doses of either 2 or 4 weeks of treatment (5 days/week), whilst compared with 4 weeks of sham rTMS. Randomization to treatment group was stratified based on age and severity. The objectives of this study were to: 1) investigate the efficacy of active rTMS versus sham, 2) investigate the effect of dose of treatment (2 or 4 weeks), and 3) investigate the length of benefits from treatment. The rTMS pulses (20 â€‹Hz, 30 pulses/train, 25 trains, 10-s intertrain interval) were applied serially to the left and right dorsolateral prefrontal cortex using neuro-navigation. We compared the primary outcome measure's (ADAS-Cog) score changes from pre- to post-treatment, with assessments at baseline and 4 more times up to 6 months post-treatment. Data of 135 patients were analyzed. The mean total ADAS-Cog score at baseline did not differ between the active and sham treatment groups, nor across the three study sites. The overall results show significant cognitive improvement after treatment up to two months post-treatment with either sham or active coils. The results show both short and long-term benefits of active rTMS treatment but also show similar benefits for sham coil treatment of mild/moderate AD. We discuss this finding in the context of the existing literature on rTMS therapy for AD, as well as evidence of the sham coil's potential to induce a low-level current in the brain. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02908815.

Gray and White Matter Voxel-Based Morphometry of Alzheimer's Disease With and Without Significant Cerebrovascular Pathologies.

Alzheimer's disease (AD) is the most common type of dementia, and AD individuals often present significant cerebrovascular disease (CVD) symptomology. AD with significant levels of CVD is frequently labeled mixed dementia (or sometimes AD-CVD), and the differentiation of these two neuropathologies (AD, AD-CVD) from each other is challenging, especially at early stages. In this study, we compared the gray matter (GM) and white matter (WM) volumes in AD (n = 83) and AD-CVD (n = 37) individuals compared with those of cognitively healthy controls (n = 85) using voxel-based morphometry (VBM) of their MRI scans. The control individuals, matched for age and sex with our two dementia groups, were taken from the ADNI. The VBM analysis showed widespread patterns of significantly lower GM and WM volume in both dementia groups compared to the control group (P < .05, family-wise error corrected). While comparing with AD-CVD, the AD group mainly demonstrated a trend of lower volumes in the GM of the left putamen and right hippocampus and WM of the right thalamus (uncorrected P < .005 with cluster threshold, K = 10). The AD-CVD group relative to AD tended to present lower GM and WM volumes, mainly in the cerebellar lobules and right brainstem regions, respectively (uncorrected P < .005 with cluster threshold, K = 10). Although finding a discriminatory feature in structural MRI data between AD and AD-CVD neuropathologies is challenging, these results provide preliminary evidence that demands further investigation in a larger sample size.

The Association between Sleep and Depression during Late Pregnancy and the Early Postpartum Period.

Objective To assess and correlate sleep quality and depressed mood symptoms in the late pregnancy and early postpartum periods. Study Design In a prospective pilot observational study, participants completed the Pittsburgh Sleep Quality Index (PSQI) and the Edinburgh Postnatal Depression Scale (EPDS) questionnaires at delivery, 1, and 2 months postpartum. Pearson's correlation coefficients and PROC MIXED function estimated overall correlation for repeated measures. Results Twenty-six women were enrolled with a mean gestational age at delivery of 38.4 (± 2.4) weeks. Sleep quality and mood data were available at the three time points for 24, 16, and 11 participants, respectively. Poor sleep scores were noted by 75.0, 87.5, and 72.7% of women at the three time points. An elevated EPDS score of 10 or higher was claimed by 20.8, 12.5, and 18.2% of women, respectively. Higher PSQI scores were positively associated with higher EPDS scores overall ( r = 0.71, p < 0.001) and at each of the individual time points ( r = 0.79, p < 0.0001; r = 0.52, p = 0.04; and r = 0.70, p = 0.016, respectively). None of the women reporting good sleep quality had elevated EPDS scores. Conclusion Poor sleep is commonly reported around delivery, and at 1 and 2 months postpartum, and there is an association between poor sleep and depression symptoms.

Program ACTIVE II: 6- and 12-month outcomes of a treatment approach for major depressive disorder in adults with type 2 diabetes.

AIMS: To evaluate the long-term effects of behavioral treatments on glycemic and psychological outcomes for patients with major depressive disorder (MDD) and type 2 diabetes (T2D). METHODS: Program ACTIVE II was a multicenter randomized controlled comparative effectiveness trial of cognitive behavioral therapy (CBT), exercise (EXER), combination treatment (CBT + EXER) and usual care (UC) for adults with MDD and T2D. RESULTS: Primary outcomes: change in A1c and depressive symptoms at 6- (N = 87) and 12-months (N = 75) from baseline. In those with a baseline A1c ≥7.0 %, CBT + EXER showed lasting A1c benefit at 6- (-1.2 %; SE: 0.6; p = 0.032) and 12-months (-1.4 %; SE: 0.6; p = 0.025) compared to UC. All groups had clinically significant improvements in depressive symptoms. At 6 months, CBT + EXER had significant improvements in diabetes-related distress regimen burden (p = 0.005); and social support (CIRS, p = 0.043) compared to UC. CONCLUSIONS: The Program ACTIVE II CBT + EXER intervention demonstrated a sustained improvement in A1c for a subgroup of study participants with a baseline A1c ≥7.0 %. However, this finding should be considered preliminary because of small sample size. All 3 behavioral intervention groups demonstrated improvements in psychosocial outcomes one-year post-intervention. These findings point to the enduring benefits of community-based interventions to extend the availability of depression treatment for T2D patients.

Non-alcoholic fatty liver disease is not associated with impairment in health-related quality of life in virally suppressed persons with human immune deficiency virus.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in persons with HIV (PWH) (HIV-NAFLD). It is unknown if HIV-NAFLD is associated with impairment in health-related quality of life (HRQOL). We examined HRQOL in PWH with and without NAFLD, compared HRQOL in HIV- versus primary NAFLD, and determined factors associated with HRQOL in these groups. Prospectively enrolled 200 PWH and 474 participants with primary NAFLD completed the Rand SF-36 assessment which measures 8 domains of HRQOL. Individual domain scores were used to create composite physical and mental component summary scores. Univariate and multivariate analyses determined variables associated with HRQOL in PWH and in HIV- and primary NAFLD. In PWH, 48% had HIV-NAFLD, 10.2% had clinically significant fibrosis, 99.5% were on antiretroviral therapy, and 96.5% had HIV RNA <200 copies/ml. There was no difference in HRQOL in PWH with or without NAFLD. Diabetes, non-Hispanic ethnicity, and nadir CD4 counts were independently associated with impaired HRQOL in PWH. In HIV-NAFLD, HRQOL did not differ between participants with or without clinically significant fibrosis. Participants with HIV-NAFLD compared to those with primary NAFLD were less frequently cisgender females, White, more frequently Hispanic, had lower BMI and lower frequency of obesity and diabetes. HRQOL of individuals with HIV-NAFLD was not significantly different from those with primary NAFLD. In conclusion, in virally suppressed PWH, HRQOL is not different between participants with or without HIV-NAFLD. HRQOL is not different between HIV-NAFLD and primary NAFLD.

Burden of fatty liver and hepatic fibrosis in persons with HIV: A diverse cross-sectional US multicenter study.

BACKGROUND AIMS: The current prevalence of fatty liver disease (FLD) due to alcohol-associated (AFLD) and nonalcoholic (NAFLD) origins in US persons with HIV (PWH) is not well defined. We prospectively evaluated the burden of FLD and hepatic fibrosis in a diverse cohort of PWH. APPROACH RESULTS: Consenting participants in outpatient HIV clinics in 3 centers in the US underwent detailed phenotyping, including liver ultrasound and vibration-controlled transient elastography for controlled attenuation parameter and liver stiffness measurement. The prevalence of AFLD, NAFLD, and clinically significant and advanced fibrosis was determined. Univariate and multivariate logistic regression models were used to evaluate factors associated with the risk of NAFLD. Of 342 participants, 95.6% were on antiretroviral therapy, 93.9% had adequate viral suppression, 48.7% (95% CI 43%-54%) had steatosis by ultrasound, and 50.6% (95% CI 45%-56%) had steatosis by controlled attenuation parameter ≥263 dB/m. NAFLD accounted for 90% of FLD. In multivariable analysis, old age, higher body mass index, diabetes, and higher alanine aminotransferase, but not antiretroviral therapy or CD4 + cell count, were independently associated with increased NAFLD risk. In all PWH with fatty liver, the frequency of liver stiffness measurement 8-12 kPa was 13.9% (95% CI 9%-20%) and ≥12 kPa 6.4% (95% CI 3%-11%), with a similar frequency of these liver stiffness measurement cutoffs in NAFLD. CONCLUSIONS: Nearly half of the virally-suppressed PWH have FLD, 90% of which is due to NAFLD. A fifth of the PWH with FLD has clinically significant fibrosis, and 6% have advanced fibrosis. These data lend support to systematic screening for high-risk NAFLD in PWH.

Real world experience with ropeginterferon alpha-2b (Besremi) in essential thrombocythaemia and polycythaemia vera following exposure to pegylated interferon alfa-2a (Pegasys).

Despite widespread use of Pegylated forms of Inteferon in the management of Myeloproliferative Neoplasms (MPN), most clinicians have experience predominantly with peginterferon alfa-2a (Pegasys). Third generation pegylated IFNα, ropeginterferon alfa-2b (ropegIFN; Besremi), was recommended by the European Medicine Authority (EMA) for treatment of Polycythaemia Vera (PV) following a Phase III trial (PROUD-PV / CONTINUATION-PV). FDA approval for PV, regardless of treatment history, was subsequently granted in November 2021. We hereby demonstrate the safety and tolerability of ropegIFN in a series of MPN patients at variable doses. It corroborates reports of efficacy of ropegIFN in patients with PV and use in pregnancy.

Effect of Medication Optimization vs Cognitive Behavioral Therapy Among US Veterans With Chronic Low Back Pain Receiving Long-term Opioid Therapy: A Randomized Clinical Trial.

Importance: Medication management and cognitive behavioral therapy (CBT) are commonly used treatments for chronic low back pain (CLBP). However, little evidence is available comparing the effectiveness of these approaches. Objective: To compare collaborative care medication optimization vs CBT on pain intensity, interference, and other pain-related outcomes. Design, Setting, and Participants: The Care Management for the Effective Use of Opioids (CAMEO) trial was a 12-month, comparative effectiveness randomized clinical trial with blinded outcome assessment. Recruitment of veterans with CLBP prescribed long-term opioids occurred at 7 Veterans Affairs primary care clinics from September 1, 2011, to December 31, 2014, and follow-up was completed December 31, 2015. Analyses were based on intention to treat in all randomized participants and were performed from March 22, 2015, to November 1, 2021. Interventions: Patients were randomized to receive either collaborative care with nurse care manager-delivered medication optimization (MED group) (n = 131) or psychologist-delivered CBT (CBT group) (n = 130) for 6 months, with check-in visits at 9 months and final outcome assessment at 12 months. Main Outcomes and Measures: The primary outcome was change in Brief Pain Inventory (BPI) total score, a composite of the pain intensity and interference subscales at 6 (treatment completion) and 12 (follow-up completion) months. Scores on the BPI range from 0 to 10, with higher scores representing greater pain impact and a 30% improvement considered a clinically meaningful treatment response. Secondary outcomes included pain-related disability, pain catastrophizing, self-reported substance misuse, health-related quality of life, depression, and anxiety. Results: A total of 261 patients (241 [92.3%] men; mean [SD] age, 57.9 [9.5] years) were randomized and included in the analysis. Baseline mean (SD) BPI scores in the MED and CBT groups were 6.45 (1.79) and 6.49 (1.67), respectively. Improvements in BPI scores were significantly greater in the MED group at 12 months (between-group difference, -0.54 [95% CI, -1.18 to -0.31]; P = .04) but not at 6 months (between-group difference, -0.46 [95% CI, -0.94 to 0.11]; P = .07). Secondary outcomes did not differ significantly between treatment groups. Conclusions and Relevance: In this randomized clinical trial among US veterans with CLBP who were prescribed long-term opioid therapy, collaborative care medication optimization was modestly more effective than CBT in reducing pain impact during the 12-month study. However, this difference may not be clinically meaningful or generalize to nonveteran populations. Trial Registration: ClinicalTrials.gov Identifier: NCT01236521.

Fedratinib, the first selective JAK2 inhibitor approved for treatment of myelofibrosis - an option beyond ruxolitinib.

INTRODUCTION: Myelofibrosis, a life shortening clonal disorder, presents with a constellation of features: bone marrow fibrosis, abnormal blood counts, extramedullary hematopoiesis, splenomegaly, thrombohemorrhagic complications, and constitutional symptoms. Until recently Ruxolitinib, a JAK1 and 2 inhibitor, has been the only targeted therapy available for transplant-ineligible patients requiring treatment for splenomegaly and disease-related symptoms. However, most patients discontinue Ruxolitinib after 3-5 years, mostly due to loss of response. There has been an unmet need for this patient group. In August 2019, Fedratinib (INREBIC® capsules, Impact Biomedicines, Inc., a wholly owned subsidiary of Bristol Meyer Squibb), a JAK2 inhibitor, was approved by US FDA for treatment of myelofibrosis in both JAK inhibitor naïve and pre-treated patients for the management of symptoms and splenomegaly. AREAS COVERED: Here, we discuss the development, evidence base to date for Fedratinib. Including early and late phase, and ongoing trials, safety issues, potential role and current position of Fedratinib in the treatment of myelofibrosis, as well as future direction of targeted therapy in myelofibrosis. EXPERT OPINION: Fedratinib presents a much needed option of treatment, particularly, for patients failing Ruxolitinib, with response rates that are quite similar. Nonetheless, there remain important questions including sequencing and options for combining therapy.

Addressing the challenges of accelerated and blast phase myeloproliferative neoplasms in 2022 and beyond.

Accelerated and blast phase myeloproliferative neoplasms present many challenges despite the advent of more novel and targeted therapeutic approaches. Outcome following transformation is frequently dismal, and the only curative approach remains allogeneic stem cell transplantation, applicable to a relatively small proportion of cases. Historically, potential risk factors for transformation from chronic phase disease have been based loosely on increasing age, long disease duration, use of sequential DNA-damaging agents, cytogenetic anomalies and advancing disease burden and limited genomic profiling which frequently reveals disparate signatures. Overall, the risk of these transformation events remains unpredictable, can occur in young individuals even without detectable high risk genomic profiles. Enhanced prognostic approaches would optimise monitoring and early intervention with potential to improve overall outcomes. Within this review we will summarise advances on disease biology, prognostication and molecular annotation and how this may ultimately lead to more rationale, stratified and forward-thinking therapeutic approaches.

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Morpho-phenetical study of high yielding tossa jute variety BJRI Tossa Pat 7 (MG-1) for bast fibre yield and qualities.

BACKGROUND AND AIM OF THE STUDY: Tossa jute (Corchorus olitorius) is a natural fibre crop produces good quality fiber having great demand for industrial uses. High yielding tossa jute variety is very important in Bangladesh. MATERIALS AND METHODS: Bangladesh Jute Research Institute (BJRI) has developed a new tossa jute variety (BJRI Tossa Pat 7) through pure line selection (PLS) from another pre-released variety named OM-1 during 2017. The new variety was evaluated for fiber yield and attributing phonological traits through comparing with another pre-released variety named BJRI Tossa Pat 5 (O-795) in RCB design at six locations during 2015-2018. RESULTS: Distinct morphological traits i.e. ovate lanceolate glossy leaves; full green plant were found in MG-1 and stem & stipule red; ovate lanceolate leaves in O-795. MG-1 showed higher fiber yield (3.39-3.40 t ha-1) where, O-795 showed 3.10-3.22 t ha-1 as means of their maximum performances for three years at both farmers' plots and research fields. MG-1 gave higher plant height, base diameter, fiber yield than O-795 at both research stations and farmers' fields. Even after sowing at 10-15 March, MG-1 gave late flowering; lower leaf size, leaf angle, green leaf biomass and node number; maximum inter-nodal length, bark diameter, bark thickness and fiber bundle cells; and finally golden bright quality fiber than O-795. If both varieties were sown at 2nd to 3rd week of March, and harvested at 110 days old, MG-1 gave 5-7% higher fiber yield than O-795. CONCLUSION: Undoubtedly, MG-1 is a good tossa jute variety for its fiber yield and quality than pre-released varieties. RECOMMENDATION: MG-1 having good fiber yield would be used for commercial cultivation by the farmers to contribute to the national economy.

Design and methods of the Care Management for the Effective Use of Opioids (CAMEO) trial.

Low back pain is the most common pain condition seen in primary care, with the most common treatment being analgesic medications, including opioids. A dramatic increase in opioid prescriptions for low back pain over the past few decades has led to increased non-medical use and opioid overdose deaths. Cognitive behavioral therapy (CBT) for chronic pain is an evidence-based non-pharmacological treatment for pain with demonstrated efficacy when delivered using collaborative care models. No previous studies have tested CBT compared to analgesic optimization that includes opioid management in primary care. This paper describes the study design and methods of the CAre Management for the Effective use of Opioids (CAMEO) trial, a 2-arm, randomized comparative effectiveness trial in seven primary care clinics. CAMEO enrolled 261 primary care veterans with chronic (6 months or longer) low back pain of at least moderate severity who were receiving long-term opioid therapy and randomized them to either nurse care management focused on analgesic treatment and optimization (MED) or cognitive behavioral therapy (CBT). All subjects undergo comprehensive outcome assessments at baseline, 3, 6, 9, and 12 months by interviewers blinded to treatment assignment. The primary outcome is pain severity and interference, measured by the Brief Pain Inventory (BPI) total score. Secondary outcomes include health-related quality of life, fatigue, sleep, functional improvement, pain disability, pain beliefs, alcohol and opioid problems, depression, anxiety, and stress.

Cost-effectiveness of Community-Based Depression Interventions for Rural and Urban Adults With Type 2 Diabetes: Projections From Program ACTIVE (Adults Coming Together to Increase Vital Exercise) II.

OBJECTIVE: We estimated the cost-effectiveness of the Program ACTIVE (Adults Coming Together to Increase Vital Exercise) II community-based exercise (EXER), cognitive behavioral therapy (CBT), and EXER+CBT interventions in adults with type 2 diabetes and depression relative to usual care (UC) and each other. RESEARCH DESIGN AND METHODS: Data were integrated into the Michigan Model for Diabetes to estimate cost and health outcomes over a 10-year simulation time horizon from the health care sector and societal perspectives, discounting costs and benefits at 3% annually. Primary outcome was cost per quality-adjusted life-year (QALY) gained. RESULTS: From the health care sector perspective, the EXER intervention strategy saved $313 (USD) per patient and produced 0.38 more QALY (cost saving), the CBT intervention strategy cost $596 more and gained 0.29 more QALY ($2,058/QALY), and the EXER+CBT intervention strategy cost $403 more and gained 0.69 more QALY ($585/QALY) compared with UC. Both EXER and EXER+CBT interventions dominated the CBT intervention. Compared with EXER, the EXER+CBT intervention strategy cost $716 more and gained 0.31 more QALY ($2,323/QALY). From the societal perspective, compared with UC, the EXER intervention strategy saved $126 (cost saving), the CBT intervention strategy cost $2,838/QALY, and the EXER+CBT intervention strategy cost $1,167/QALY. Both EXER and EXER+CBT interventions still dominated the CBT intervention. In comparison with EXER, the EXER+CBT intervention strategy cost $3,021/QALY. Results were robust in sensitivity analyses. CONCLUSIONS: All three Program ACTIVE II interventions represented a good value for money compared with UC. The EXER+CBT intervention was highly cost-effective or cost saving compared with the CBT or EXER interventions.