Diagnosis of childhood febrile illness using a multi-class blood RNA molecular signature.

BACKGROUND: Appropriate treatment and management of children presenting with fever depend on accurate and timely diagnosis, but current diagnostic tests lack sensitivity and specificity and are frequently too slow to inform initial treatment. As an alternative to pathogen detection, host gene expression signatures in blood have shown promise in discriminating several infectious and inflammatory diseases in a dichotomous manner. However, differential diagnosis requires simultaneous consideration of multiple diseases. Here, we show that diverse infectious and inflammatory diseases can be discriminated by the expression levels of a single panel of genes in blood. METHODS: A multi-class supervised machine-learning approach, incorporating clinical consequence of misdiagnosis as a "cost" weighting, was applied to a whole-blood transcriptomic microarray dataset, incorporating 12 publicly available datasets, including 1,212 children with 18 infectious or inflammatory diseases. The transcriptional panel identified was further validated in a new RNA sequencing dataset comprising 411 febrile children. FINDINGS: We identified 161 transcripts that classified patients into 18 disease categories, reflecting individual causative pathogen and specific disease, as well as reliable prediction of broad classes comprising bacterial infection, viral infection, malaria, tuberculosis, or inflammatory disease. The transcriptional panel was validated in an independent cohort and benchmarked against existing dichotomous RNA signatures. CONCLUSIONS: Our data suggest that classification of febrile illness can be achieved with a single blood sample and opens the way for a new approach for clinical diagnosis. FUNDING: European Union's Seventh Framework no. 279185; Horizon2020 no. 668303 PERFORM; Wellcome Trust (206508/Z/17/Z); Medical Research Foundation (MRF-160-0008-ELP-KAFO-C0801); NIHR Imperial BRC.

Non-Inferiority of Point-of-Care Ultrasound Compared to Radiography to Diagnose Upper Extremity Fractures in Children.

Conventional X-ray imaging for fracture diagnosis is time-consuming and exposes patients to ionizing radiation. Additionally, the positioning of the injured limb for standardized X-ray imaging is painful. Point-of-care ultrasound (POCUS) is increasingly available in medical offices and emergency rooms. This study aimed to prove the non-inferiority of POCUS compared to X-ray imaging with respect to diagnostic sensitivity, pain, and investigation time in the diagnosis of long-bone fractures of the upper extremity in children. Children and adolescents (1−18 years old) presenting to the UKBB emergency service between May 2020 and May 2021 with suspected upper extremity fracture were included in the study. Before obtaining X-ray images, we conducted a POCUS examination of the injured limb. Pain scores at inclusion as well as maximum pain scores during X-ray and ultrasound examinations were documented. The duration of POCUS and X-ray examinations was compared. We examined 403 children with POCUS and plain X-ray imaging. The mean age (±SD) of the children was 10.6 (±3.5) years. The non-inferiority of POCUS compared to X-ray was confirmed with an estimated sensitivity of 0.95 and a lower confidence interval of 0.93. Maximum pain during POCUS was significantly lower compared to pain at inclusion (p = 0.002) or maximum pain during radiographic examination (p = 0.03). POCUS examination took 3.9 (±2.9) min in the mean whilst the mean duration for obtaining the X-ray images was 16 (±37) min (p < 0.001). POCUS for diagnosing upper extremity fractures in children proved as sensitive as standard X-ray imaging and was significantly faster and less painful. Future prospective studies are required to confirm our findings.

Acceptance-enhanced behavior therapy for trichotillomania in adults: A randomized clinical trial.

Given the limited treatment options for trichotillomania (TTM), or Hair Pulling Disorder, this large randomized clinical trial evaluated the efficacy of acceptance-enhanced behavior therapy for TTM (AEBT-TTM) in reducing TTM severity relative to psychoeducation and supportive therapy (PST). Eighty-five adults (78 women) with TTM received 10 sessions (over 12 weeks) of either AEBT-TTM or PST. Independent evaluators masked to treatment assignment assessed participants at baseline (week 0), midpoint (week 6), and endpoint (week 12). Consistent with a priori hypotheses, 64% of the adults treated with AEBT-TTM were classified as clinical responders at post-treatment relative to 38% treated with PST. Clinical responders were identified by a score of 1 or 2 on the Clinical Global Impressions-Improvement (CGI-I) scale. Relative to the PST group, the AEBT-TTM group demonstrated significantly greater pre-to post-treatment reductions on the self-report Massachusetts General Hospital-Hairpulling Scale (MGH-HS) and the evaluator-rated National Institute of Mental Health Trichotillomania Severity Scale (NIMH-TSS). There were no significant post-treatment group differences on the Clinical Global Impressions-Severity (CGI-S) scale, or rate of TTM diagnoses. Results suggest AEBT-TTM provides greater treatment benefit than PST. Future research should continue to investigate AEBT-TTM along with mediators and moderators of its efficacy.

Demonstration of 3D photon correlation spectroscopy in the hard X-ray regime.

Three-dimensional photon correlation spectroscopy (3D PCS) is a well-known technique developed to suppress multiple scattering contributions in correlation functions, which are inevitably involved when an optical laser is employed to investigate dynamics in a turbid system. Here, we demonstrate a proof-of-principle study of 3D PCS in the hard X-ray regime. We employ an X-ray optical cross-correlator to measure the dynamics of silica colloidal nanoparticles dispersed in polypropylene glycol. The obtained cross correlation functions show very good agreement with auto-correlation measurements. This demonstration provides the foundation for X-ray speckle-based studies of very densely packed soft matter systems.

Microsecond hydrodynamic interactions in dense colloidal dispersions probed at the European XFEL.

Many soft-matter systems are composed of macromolecules or nanoparticles suspended in water. The characteristic times at intrinsic length scales of a few nanometres fall therefore in the microsecond and sub-microsecond time regimes. With the development of free-electron lasers (FELs) and fourth-generation synchrotron light-sources, time-resolved experiments in such time and length ranges will become routinely accessible in the near future. In the present work we report our findings on prototypical soft-matter systems, composed of charge-stabilized silica nanoparticles dispersed in water, with radii between 12 and 15 nm and volume fractions between 0.005 and 0.2. The sample dynamics were probed by means of X-ray photon correlation spectroscopy, employing the megahertz pulse repetition rate of the European XFEL and the Adaptive Gain Integrating Pixel Detector. We show that it is possible to correctly identify the dynamical properties that determine the diffusion constant, both for stationary samples and for systems driven by XFEL pulses. Remarkably, despite the high photon density the only observable induced effect is the heating of the scattering volume, meaning that all other X-ray induced effects do not influence the structure and the dynamics on the probed timescales. This work also illustrates the potential to control such induced heating and it can be predicted with thermodynamic models.

Therapist Behavior During Exposure Tasks Predicts Habituation and Clinical Outcome in Three Randomized Controlled Trials for Pediatric OCD.

This study measured therapist behaviors in relation to subsequent habituation within exposure tasks, and also tested their direct and indirect relationships (via habituation) with clinical outcomes of exposure therapy. We observed 459 videotaped exposure tasks with 111 participants in three clinical trials for pediatric obsessive-compulsive disorder (POTS trials). Within exposure tasks, therapist behaviors and patient fear were coded continuously. Outcomes were habituation and posttreatment change in symptom severity, global improvement, and treatment response. More therapist behaviors that encourage approach-and less use of accommodation, unrelated talk, and externalizing language-predicted greater subsequent habituation during individual exposure tasks (exposure-level), and also predicted improved patient clinical outcomes via higher "total dose" of habituation across treatment (patient-level indirect effect). For six of seven therapist behaviors analyzed, the relationship with subsequent habituation within exposure differed by patient fear (low, moderate, or high) at the time the behavior was used. Two therapist behaviors had direct effects in the opposite direction expected; more unrelated talk and less intensifying were associated with greater patient symptom reduction. Results shed light on the "black box" of in-session exposure activities and point to specific therapist behaviors that may be important for clinical outcomes. These behaviors might be best understood in the context of changing patient fear during exposure tasks. Future studies should test whether therapist behaviors can be experimentally manipulated to produce improvement in clinical outcomes.

Core Motivations of Childhood Obsessive-Compulsive Disorder: The Role of Harm Avoidance and Incompleteness.

In an effort to improve patient conceptualization and targeted treatment, researchers have sought to accurately classify OCD subtypes. To date, the most common form of OCD classification has used the content of symptom topography as opposed to functional links between symptoms to categorize OCD. The aim of the current study was to explore the associations between these two forms of OCD classification. Participant topographical symptoms were self-reported using the Obsessive-Compulsive Inventory-Child Version (OCI-CV). Clinicians assessed whether participant symptoms were motivated by harm avoidance and/or incompleteness. Structural equation modeling was employed to explore the associations between harm avoidance and incompleteness and symptom dimensions in youth with OCD. Results showed that harm avoidance was significantly associated with doubting/checking, obsessing, and neutralizing symptoms, whereas incompleteness was associated with doubting/checking, ordering, and neutralizing symptoms. Findings are consistent with child and adult literature and highlight the importance of assessing the underlying function of OC behaviors.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

Emergence of anomalous dynamics in soft matter probed at the European XFEL.

Dynamics and kinetics in soft matter physics, biology, and nanoscience frequently occur on fast (sub)microsecond but not ultrafast timescales which are difficult to probe experimentally. The European X-ray Free-Electron Laser (European XFEL), a megahertz hard X-ray Free-Electron Laser source, enables such experiments via taking series of diffraction patterns at repetition rates of up to 4.5 MHz. Here, we demonstrate X-ray photon correlation spectroscopy (XPCS) with submicrosecond time resolution of soft matter samples at the European XFEL. We show that the XFEL driven by a superconducting accelerator provides unprecedented beam stability within a pulse train. We performed microsecond sequential XPCS experiments probing equilibrium and nonequilibrium diffusion dynamics in water. We find nonlinear heating on microsecond timescales with dynamics beyond hot Brownian motion and superheated water states persisting up to 100 µs at high fluences. At short times up to 20 µs we observe that the dynamics do not obey the Stokes-Einstein predictions.

Double-pulse speckle contrast correlations with near Fourier transform limited free-electron laser light using hard X-ray split-and-delay.

The ability to deliver two coherent X-ray pulses with precise time-delays ranging from a few femtoseconds to nanoseconds enables critical capabilities of probing ultra-fast phenomena in condensed matter systems at X-ray free electron laser (FEL) sources. Recent progress made in the hard X-ray split-and-delay optics developments now brings a very promising prospect for resolving atomic-scale motions that were not accessible by previous time-resolved techniques. Here, we report on characterizing the spatial and temporal coherence properties of the hard X-ray FEL beam after propagating through split-and-delay optics. Speckle contrast analysis of small-angle scattering measurements from nanoparticles reveals well-preserved transverse coherence of the beam. Measuring intensity fluctuations from successive X-ray pulses also reveals that only single or double temporal modes remain in the transmitted beam, corresponding to nearly Fourier transform limited pulses.

A Neurocognitive Comparison of Pediatric Obsessive-Compulsive Disorder and Trichotillomania (Hair Pulling Disorder).

Obsessive-compulsive disorder (OCD) and trichotillomania (hair pulling disorder, HPD) are both considered obsessive-compulsive and related disorders due to some indications of shared etiological and phenomenological characteristics. However, a lack of direct comparisons between these disorders, especially in pediatric samples, limits our understanding of divergent versus convergent characteristics. This study compared neurocognitive functioning between children diagnosed with OCD and HPD. In total, 21 children diagnosed with HPD, 40 diagnosed with OCD, and 29 healthy controls (HCs), along with their parents, completed self-/parent-report measures and a neurocognitive assessment battery, which included tasks of inhibitory control, sustained attention, planning, working memory, visual memory, and cognitive flexibility. A series of analyses of variance (or covariance) indicated significant differences between groups on tasks examining planning and sustained attention. Specifically, children in both the OCD and HPD groups outperformed HCs on a task of planning. Further, children with OCD underperformed as compared to both the HPD and HC groups on a task of sustained attention. No between group differences were found with respect to tasks of reversal learning, working memory, spatial working memory, visual memory, or inhibitory control. The implications these findings may have for future, transdiagnostic work, as well as limitations and future directions are discussed.

Coexistence of hcp and bct Phases during In Situ Superlattice Assembly from Faceted Colloidal Nanocrystals.

We study the in situ self-assembly of faceted PbS nanocrystals from colloidal suspensions upon controlled solvent evaporation using time-resolved small-angle X-ray scattering and X-ray cross-correlation analysis. In our bulk-sensitive experiment in transmission geometry, the superlattice crystallization is observed in real time, revealing a hexagonal closed-packed (hcp) structure followed by formation of a body-centered cubic (bcc) superlattice. The bcc superlattice undergoes continuous tetragonal distortion in the solvated state shortly after its formation, resulting in the body-centered tetragonal (bct) structure. Upon solvent evaporation, the bct superstructure becomes more pronounced with the still coexisting hcp phase. These findings corroborate the existing simulations of assembling cuboctahedral-shaped particles and illustrate that we observed the predicted equilibrium states. This work is essential for a deeper understanding of the fundamental forces that direct nanocrystal assembly including nanocrystal shape and ligand coverage.

Influence of Dissolved Organic Carbon on the Acute Toxicity of Copper and Zinc to White Sturgeon (Acipenser transmontanus) and a Cladoceran (Ceriodaphnia dubia).

We conducted acute lethality tests with white sturgeon (Acipenser transmontanus) and Ceriodaphnia dubia exposed to copper and zinc at dissolved organic carbon concentrations ranging from 0.5 to 5.5 mg/L. Dissolved organic carbon had minimal effects on zinc toxicity but did have a protective effect on acute copper toxicity, which was equal to that predicted by the copper biotic ligand model (BLM). The BLM-adjusted copper median effect concentrations for A. transmontanus ranged from 2.4 to 8.2 mg/L. Environ Toxicol Chem 2019;38:2682-2687. Published 2019 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work, and as such, is in the public domain in the United States of America.

A latent profile analysis of age of onset in trichotillomania.

BACKGROUND: Trichotillomania (TTM) onset may occur across the lifespan; however, adolescent onset is most frequently reported. Several studies have explored clinical differences between TTM age-of-onset groups with mixed results. We investigated empirically defined age-of-onset groups in adults with TTM, and clinical differences between groups. METHODS: Participants included 1,604 adult respondents to an internet survey who endorsed DSM-IV-TR TTM criteria. Latent profile analysis was performed to identify TTM age-of-onset subgroups, which were then compared on demographic and clinical features. RESULTS: The most optimal model was a 2-class solution comprised of a large group with average TTM onset during adolescence (n = 1,539; 95.9% of the sample; mean age of onset = 12.4) and a small group with average onset in middle adulthood (n = 65; 4.1% of the sample; mean age of onset = 35.6). The late-onset group differed from the early-onset group on several clinical variables (eg, less likely to report co-occurring bodyfocused repetitive behaviors). CONCLUSIONS: Findings suggest the presence of at least 2 distinct TTM age-of-onset subgroups: an early-onset group with onset during adolescence, and a late-onset group with onset in middle adulthood. Future research is needed to further validate these subgroups and explore their clinical utility.

Acceptance-enhanced behavior therapy for trichotillomania: Randomized controlled trial rationale, method, and strategies for recruiting minority participants.

Trichotillomania (TTM) involves the chronic pulling out of hair to the point of hair loss or thinning, which continues despite repeated attempts to stop. Behavior therapy is a promising treatment for the condition, but studies have been limited by the lack of a credible control condition, small sample sizes, follow-up periods of short duration, and low participation by underrepresented populations. In the current article, the authors describe the theoretical rationale for an acceptance-enhanced form of behavior therapy for TTM in adults and describe the methodology used to test the efficacy of this intervention against a psychoeducation and supportive control condition. In addition, the authors discuss the importance of and difficulties encountered with enrolling minority participants into TTM research, as well as strategies used to enhance minority recruitment. Finally, the authors discuss the instruments, procedures, and related outcomes of the fidelity measures used in the randomized controlled trial.

Compact hard X-ray split-and-delay line for studying ultrafast dynamics at free-electron laser sources.

A compact hard X-ray split-and-delay line for studying ultrafast dynamics at free-electron laser sources is presented. The device is capable of splitting a single X-ray pulse into two fractions to introduce time delays from -5 to 815 ps with femtosecond resolution. The split-and-delay line can operate in a wide and continuous energy range between 7 and 16 keV. Compact dimensions of 60 × 60 × 30 cm with a total weight of about 60 kg make it portable and suitable for direct installation in an experimental hutch. The concept of the device is based on crystal diffraction. The piezo-driven stages utilized in the device give nanometre positioning accuracy. On-line monitoring systems based on X-ray cameras and intensity monitors are implemented to provide active alignment feedback. Performance estimates of the system are also presented.

Modelling pathogen load dynamics to elucidate mechanistic determinants of host-Plasmodium falciparum interactions.

During infection, increasing pathogen load stimulates both protective and harmful aspects of the host response. The dynamics of this interaction are hard to quantify in humans, but doing so could improve understanding of the mechanisms of disease and protection. We sought to model the contributions of the parasite multiplication rate and host response to observed parasite load in individual subjects infected with Plasmodium falciparum malaria, using only data obtained at the time of clinical presentation, and then to identify their mechanistic correlates. We predicted higher parasite multiplication rates and lower host responsiveness in cases of severe malaria, with severe anaemia being more insidious than cerebral malaria. We predicted that parasite-growth inhibition was associated with platelet consumption, lower expression of CXCL10 and type 1 interferon-associated genes, but increased cathepsin G and matrix metallopeptidase 9 expression. We found that cathepsin G and matrix metallopeptidase 9 directly inhibit parasite invasion into erythrocytes. The parasite multiplication rate was associated with host iron availability and higher complement factor H levels, lower expression of gametocyte-associated genes but higher expression of translation-associated genes in the parasite. Our findings demonstrate the potential of using explicit modelling of pathogen load dynamics to deepen understanding of host-pathogen interactions and identify mechanistic correlates of protection.

Monitoring Nanocrystal Self-Assembly in Real Time Using In Situ Small-Angle X-Ray Scattering.

Self-assembled nanocrystal superlattices have attracted large scientific attention due to their potential technological applications. However, the nucleation and growth mechanisms of superlattice assemblies remain largely unresolved due to experimental difficulties to monitor intermediate states. Here, the self-assembly of colloidal PbS nanocrystals is studied in real time by a combination of controlled solvent evaporation from the bulk solution and in situ small-angle X-ray scattering (SAXS) in transmission geometry. For the first time for the investigated system a hexagonal closed-packed (hcp) superlattice formed in a solvent vapor saturated atmosphere is observed during slow solvent evaporation from a colloidal suspension. The highly ordered hcp superlattice is followed by a transition into the final body-centered cubic superlattice upon complete drying. Additionally, X-ray cross-correlation analysis of Bragg reflections is applied to access information on precursor structures in the assembly process, which is not evident from conventional SAXS analysis. The detailed evolution of the crystal structure with time provides key results for understanding the assembly mechanism and the role of ligand-solvent interactions, which is important both for fundamental research and for fabrication of superlattices with desired properties.

Complement Factor H Levels Associate With Plasmodium falciparum Malaria Susceptibility and Severity.

BACKGROUND: Plasmodium falciparum may evade complement-mediated host defense by hijacking complement Factor H (FH), a negative regulator of the alternative complement pathway. Plasma levels of FH vary between individuals and may therefore influence malaria susceptibility and severity. METHODS: We measured convalescent FH plasma levels in 149 Gambian children who had recovered from uncomplicated or severe P. falciparum malaria and in 173 healthy control children. We compared FH plasma levels between children with malaria and healthy controls, and between children with severe (n = 82) and uncomplicated malaria (n = 67). We determined associations between FH plasma levels and laboratory features of severity and used multivariate analyses to examine associations with FH when accounting for other determinants of severity. RESULTS: FH plasma levels differed significantly between controls, uncomplicated malaria cases, and severe malaria cases (mean [95% confidence interval], 257 [250 to 264], 288 [268 to 309], and 328 [313 to 344] µg/mL, respectively; analysis of variance P < .0001). FH plasma levels correlated with severity biomarkers, including lactate, parasitemia, and parasite density, but did not correlate with levels of PfHRP2, which represent the total body parasite load. Associations with severity and lactate remained significant when adjusting for age and parasite load. CONCLUSIONS: Natural variation in FH plasma levels is associated with malaria susceptibility and severity. A prospective study will be needed to strengthen evidence for causation, but our findings suggest that interfering with FH binding by P. falciparum might be useful for malaria prevention or treatment.

Evidence Base Update of Psychosocial Treatments for Pediatric Obsessive-Compulsive Disorder: Evaluating, Improving, and Transporting What Works.

Pediatric obsessive-compulsive disorder is a chronic and impairing condition that often persists into adulthood. This review refreshes the state of support for psychosocial treatments and the predictors or moderators that relate to their efficacy and evaluates how the literature has improved since the last update in 2014. A secondary goal is to propose an additional framework for the categorization of studies based on central research questions rather than treatment format. Psychosocial treatment studies conducted since the last review are described and evaluated according to methodological rigor and evidence-based classification using the Journal of Clinical Child and Adolescent Psychology evidence-based treatment evaluation criteria. Findings again converge in support of cognitive-behavioral therapy (CBT) as an effective and appropriate first-line treatment for youth with obsessive-compulsive disorder. Family-focused CBT is now well-established. A number of other treatments including CBT+ D-Cycloserine, CBT+ Sertraline, CBT+ positive family interaction therapy, and technology-based CBT are now probably efficacious. Demographic, clinical, and family factors are consistent predictors of CBT outcome with conflicting findings for neurocognitive predictors. The field has advanced significantly since the last review, but there is still room for improvement. Some of the conclusions that can be drawn may be limited by our evaluation criteria. Future directions are proposed to advance treatment outcome research beyond a focus on which treatments work to exploring factors that account for how and why they work.