Assessment of treatment response in tuberculosis

Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities

Convex Treatment Response and Treatment Selection

This paper analyzes the identifying power of weak convexity assumptions in treatment effect models with endogenous selection. The counterfactual distributions are constrained either in terms of the response function, or conditional on the realized treatment, and sharp bounds on the potential outcome distributions are derived. The methods are applied to bound the effect of education on smoking.nonparametric bounds, causality, endogeneity, instrumental variables

Benchmarking Treatment Response in Tourette’s Disorder: A Psychometric Evaluation and Signal Detection Analysis of the Parent Tic Questionnaire

This study assessed the psychometric properties of a parent-reported tic severity measure, the Parent Tic Questionnaire (PTQ), and used the scale to establish guidelines for delineating clinically significant tic treatment response. Participants were 126 children ages 9 to 17 who participated in a randomized controlled trial of Comprehensive Behavioral Intervention for Tics (CBIT). Tic severity was assessed using the Yale Global Tic Severity Scale (YGTSS), Hopkins Motor/Vocal Tic Scale (HMVTS) and PTQ; positive treatment response was defined by a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impressions – Improvement (CGI-I) scale. Cronbach’s alpha and intraclass correlations (ICC) assessed internal consistency and test-retest reliability, with correlations evaluating validity. Receiver- and Quality-Receiver Operating Characteristic analyses assessed the efficiency of percent and raw-reduction cutoffs associated with positive treatment response. The PTQ demonstrated good internal consistency (α = 0.80 to 0.86), excellent test-retest reliability (ICC = .84 to .89), good convergent validity with the YGTSS and HM/VTS, and good discriminant validity from hyperactive, obsessive-compulsive, and externalizing (i.e., aggression and rule-breaking) symptoms. A 55% reduction and 10-point decrease in PTQ Total score were optimal for defining positive treatment response. Findings help standardize tic assessment and provide clinicians with greater clarity in determining clinically meaningful tic symptom change during treatment

Neurocognitive Correlates of Treatment Response in Children with Tourette\u27s Disorder

This paper examined neurocognitive functioning and its relationship to behavior treatment response among youth with Tourette\u27s Disorder (TD) in a large randomized controlled trial. Participants diagnosed with TD completed a brief neurocognitive battery assessing inhibitory functions, working memory, and habit learning pre- and post-treatment with behavior therapy (CBIT, Comprehensive Behavioral Intervention for Tics) or psychoeducation plus supportive therapy (PST). At baseline, youth with tics and Attention Deficit Hyperactivity Disorder (ADHD) exhibited some evidence of impaired working memory and simple motor inhibition relative to youth with tics without ADHD. Additionally, a small negative association was found between antipsychotic medications and youth\u27s performance speed. Across treatment groups, greater baseline working memory and aspects of inhibitory functioning were associated with a positive treatment response; no between-group differences in neurocognitive functioning at post-treatment were identified. Within the behavior therapy group, pre-treatment neurocognitive status did not predict outcome, nor was behavior therapy associated significant change in neurocognitive functioning post-treatment. Findings suggest that co-occurring ADHD is associated with some impairments in neurocognitive functioning in youth with Tourette\u27s Disorder. While neurocognitive predictors of behavior therapy were not found, participants who received behavior therapy exhibited significantly reduced tic severity without diminished cognitive functioning

HPA axis related genes and response to psychological therapies: genetics and epigenetics

Background Hypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress-related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT). Methods Children with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response). Results Treatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response. Conclusions Allele-specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner

Treatment Response in Couple Therapy: Relationship Adjustment and Individual Functioning Change Processes

This study, a naturalistic investigation of the process of change in relationship adjustment and individual functioning during conjoint therapy, examined the first 8 sessions of a multisystemic model of couple therapy, integrative problem-centered metaframeworks (Breunlin, Pinsof, Russell, & Lebow, 2011; Pinsof, Breunlin, Russell, & Lebow, 2011). The sample consisted of 125 heterosexual couples who reported on their relationship adjustment and individual functioning before every session using the Systemic Therapy Inventory of Change (Pinsof et al., 2009; Pinsof, Zinbarg, et al., in press). Data were analyzed using dyadic latent growth curve and cross-lagged models. For both men and women, relationship adjustment and individual functioning showed nonlinear change, increasing during Sessions 1–4 and stabilizing during Sessions 5–8. At pretreatment, women reported lower levels of relationship adjustment than men; no gender differences existed in initial levels of individual functioning or in the change trajectories of relationship adjustment or individual functioning. Higher relationship adjustment predicted positive change in individual functioning for men (but not for women). In contrast, there were no cross-lagged effects of individual functioning on relationship adjustment for men or women. The results demonstrate the importance of examining the processes by which relational and individual pathology respond to couple-based interventions

Treatment response in relation to inflammatory and axonal surrogate marker in multiple sclerosis

BACKGROUND: This study aimed to investigate if treatment response could retrospectively be related to inflammatory or axonal pathology as measured by plasma surrogate markers. METHODS: In this 1-year observational study 30 multiple sclerosis (MS) patients with relapsing-remitting disease were treated with intramuscular IFNbeta-1a or subcutaneous IFNbeta-1b. Responders and nonresponders were defined according to clinical and magnetic resonance imaging criteria. The control group consisted of 14 healthy subjects. Plasma levels of surrogate markers for inflammation (nitric oxide metabolites (NOx)), astrocytic activation (S100B) and axonal damage (NfH(SM135)) were measured using standard assays. RESULTS: There were 11 nonresponders and 19 responders to IFNbeta treatment. Median S100B levels were elevated in a higher proportion of treatment responders (63%, 42.9 pg/mL) compared to nonresponders (18%, 11.7 pg/mL, P < 0.05, Fisher's exact test) and controls (0%, 2 pg/mL, P < 0.001). Levels of NOx were found to be more frequently elevated in nonresponders (72%, 39 microM) compared to healthy controls (0%, 37 microM, P < 0.05). Levels of NfH(SM135) were more frequently elevated in responders (58%, 300 pg/mL, P < 0.001) and nonresponders (72%, 500 pg/mL, P < 0.001) compared to controls (0%, 4.5 pg/mL). CONCLUSION: Patients with relapsing-remitting MS who had surrogate marker supported evidence for astrocytic activation responded more frequently to treatment with IFNbeta