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Oral Diseases (2012) 18, 223-235 The addition of genomic information to our understanding of oral disease is driving important changes in oral health care. It is anticipated that genome-derived information will promote a deeper understanding of disease etiology and permit earlier diagnosis, allowing for preventative measures prior to disease onset rather than treatment that attempts to repair the diseased state. Advances in genome technologies have fueled expectations for this proactive healthcare approach. Application of genomic testing is expanding and has already begun to find its way into the practice of clinical dentistry. To take full advantage of the information and technologies currently available, it is vital that dental care providers, consumers, and policymakers be aware of genomic approaches to understanding of oral diseases and the application of genomic testing to disease diagnosis and treatment. Ethical, legal, clinical, and educational initiatives are also required to responsibly incorporate genomic information into the practice of dentistry. This article provides an overview of the application of genomic technologies to oral health care and introduces issues that require consideration if we are to realize the full potential of genomics to enable the practice of personalized dental medicine. [ABSTRACT FROM AUTHOR]

The current study examined relations between parent anxiety and child anxiety, depression, and externalizing symptoms. In addition, the study tested the additive and interactive effects of parent anxiety with parent depression and externalizing symptoms in relation to child symptoms. Forty-eight parents with anxiety disorders and 49 parents without any psychiatric disorder participated with one of their children (ages 6 to 14 years; 46.4% male; 75.8% Caucasian). Parent anxiety was related to both child anxiety and depression, but not child externalizing symptoms. Hierarchical regression analyses showed that only parent externalizing symptoms had additive effects, beyond parent anxiety symptoms, in relation to child anxiety symptoms. Further, parent anxiety symptoms moderated the relationship between parent and child externalizing symptoms, such that the strength of this relationship was reduced in the presence of high levels of parent anxiety symptoms. Results of this study illuminate the role of parent comorbidity in understanding relations between parent and child symptoms. [ABSTRACT FROM AUTHOR]

Context: Tourette disorder is a chronic and typically impairing childhood-onset neurologic condition. Antipsychotic medications, the first-line treatments for moderate to severe tics, are often associated with adverse effects. Behavioral interventions, although promising, have not been evaluated in large-scale controlled trials.Objective: To determine the efficacy of a comprehensive behavioral intervention for reducing tic severity in children and adolescents.Design, Setting, and Participants: Randomized, observer-blind, controlled trial of 126 children recruited from December 2004 through May 2007 and aged 9 through 17 years, with impairing Tourette or chronic tic disorder as a primary diagnosis, randomly assigned to 8 sessions during 10 weeks of behavior therapy (n = 61) or a control treatment consisting of supportive therapy and education (n = 65). Responders received 3 monthly booster treatment sessions and were reassessed at 3 and 6 months following treatment.Intervention: Comprehensive behavioral intervention.Main Outcome Measures: Yale Global Tic Severity Scale (range 0-50, score >15 indicating clinically significant tics) and Clinical Global Impressions-Improvement Scale (range 1 [very much improved] to 8 [very much worse]).Results: Behavioral intervention led to a significantly greater decrease on the Yale Global Tic Severity Scale (24.7 [95% confidence interval {CI}, 23.1-26.3] to 17.1 [95% CI, 15.1-19.1]) from baseline to end point compared with the control treatment (24.6 [95% CI, 23.2-26.0] to 21.1 [95% CI, 19.2-23.0]) (P < .001; difference between groups, 4.1; 95% CI, 2.0-6.2) (effect size = 0.68). Significantly more children receiving behavioral intervention compared with those in the control group were rated as being very much improved or much improved on the Clinical Global Impressions-Improvement scale (52.5% vs 18.5%, respectively; P < .001; number needed to treat = 3). Attrition was low (12/126, or 9.5%); tic worsening was reported by 4% of children (5/126). Treatment gains were durable, with 87% of available responders to behavior therapy exhibiting continued benefit 6 months following treatment.Conclusion: A comprehensive behavioral intervention, compared with supportive therapy and education, resulted in greater improvement in symptom severity among children with Tourette and chronic tic disorder.Trial Registration: clinicaltrials.gov Identifier: NCT00218777. [ABSTRACT FROM AUTHOR]

The present study addressed two specific questions: (1) Are there differences in parenting behaviors between anxious and non-anxious mothers? and (2) Are parenting behaviors within these two groups associated with adverse outcomes in children (i.e., internalizing and externalizing symptoms)? The above questions were examined concurrently (when children were in first grade) and at a six-year follow-up among a predominately African American community-based high-risk sample. Twenty-five anxious and matched non-anxious (N = 50) mothers were videotaped with their children (mean age 5.8 years) engaging in a challenging task. Blind raters coded parent behaviors. Parents and children completed measures of anxiety and/or externalizing symptoms at both time points. Contrary to expectations, results indicated no group differences in parenting behaviors in the first grade and no relation between parenting behaviors and concurrent levels of anxiety or externalizing symptoms. At the six-year follow-up, however, higher levels of criticism and lower levels of granting of autonomy were significantly related to higher anxiety (but not externalizing) symptoms in children of anxious parents. Findings are discussed in the context of existing developmental models of childhood anxiety and suggest that the interaction of parental anxiety and parenting behavior may increase children's risk for anxiety disorders. [ABSTRACT FROM AUTHOR]

Objectives To examine rates and correlates of depressive symptoms among pregnant reservation-based American Indian (AI) adolescents from the Southwestern United States ( N = 53). Methods Data were derived from a study evaluating a home-visiting program designed to promote positive parenting among young families. Participants included a volunteer, convenience sample of expectant mothers who completed behavioral and mental health self-report questionnaires. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression scale (CES-D). Three risk domains were analyzed in relation to depressive symptoms: sociodemographics, family relations, and psychosocial functioning. Results Forty-seven percent of expectant mothers scored at or above the widely accepted clinical cutoff score of 16 on the CES-D; 30% scored at or above 20, a score more likely to reflect elevated depressive symptoms among adolescents; and almost 20% scored at or above 28 (one standard deviation above the mean), a score suggestive of clinical depression. Higher levels of depressive symptoms were associated with less use of public assistance, external locus of control, less social support, and lower self-esteem. Conclusions Data suggest that a large proportion of pregnant AI adolescents reported elevated depressive symptoms, though rates are similar to non-pregnant AI adolescent samples. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have indicated a benefit of adjuvant chemotherapy for patients with stage IB, II, or IIIA--but not stage IA--non-small-cell lung cancer (NSCLC). This classification scheme is probably an imprecise predictor of the prognosis of an individual patient. Indeed, approximately 25 percent of patients with stage IA disease have a recurrence after surgery, suggesting the need to identify patients in this subgroup for more effective therapy.Methods: We identified gene-expression profiles that predicted the risk of recurrence in a cohort of 89 patients with early-stage NSCLC (the lung metagene model). We evaluated the predictor in two independent groups of 25 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0030 study and 84 patients from the Cancer and Leukemia Group B (CALGB) 9761 study.Results: The lung metagene model predicted recurrence for individual patients significantly better than did clinical prognostic factors and was consistent across all early stages of NSCLC. Applied to the cohorts from the ACOSOG Z0030 trial and the CALGB 9761 trial, the lung metagene model had an overall predictive accuracy of 72 percent and 79 percent, respectively. The predictor also identified a subgroup of patients with stage IA disease who were at high risk for recurrence and who might be best treated by adjuvant chemotherapy.Conclusions: The lung metagene model provides a potential mechanism to refine the estimation of a patient's risk of disease recurrence and, in principle, to alter decisions regarding the use of adjuvant chemotherapy in early-stage NSCLC. [ABSTRACT FROM AUTHOR]

Cardiac troponin T (cTnT) and troponin I (cTnI) are highly sensitive and specific for detecting myocardial damage even in the presence of skeletal muscle injury. In this study, we assessed whether ultraendurance exercise induced cardiomyocyte injury using plasma cTnT and cTnI measurements, quantitative echocardiographic wall-motion analysis, and ejection fraction measurement in athletes who participated in the Hawaii Ironman Triathlon. Twenty-three athletes (11 men) who completed the triathlon (3.9 km swim, 180.2 km bike, and 42.2 km run) participated in this study. Blood samples were obtained 2 days before and immediately after the triathlon for the determination of cTnT (Enzymun, Roche Diagnostics) and cTnI (Dade Behring) concentrations. Quantitative echocardiographic wall motion analysis and ejection fraction were obtained on 12 of the 23 participants before and immediately after the race. No subject had detectable cTnT or cTnI or abnormal echo score before the race. Following the race, 2 subjects (9%) had marked increases in both cTnT (0.15 and 0.33 microg/L) and cTnI (2.09 and 4.44 microg/L). Four additional subjects (17%) had moderate increases in cTnT (0.04 to 0.05 microg/L) but no detectable cTnI. Race time correlated inversely with cTnT (r = -0.65, p <0.01). Mean change in the number of abnormal echo segments after the race was 6.5 in those with a marked increase in cTnT and cTnI, 2.3 in those with a moderate increase in cTnT, and 1.7 in those with no increase. Ejection fraction decreased by an average of 24% after the race (p <0.002). Thus, ultraendurance exercise may cause myocardial damage as indicated by biochemical cardiac-specific markers and echocardiography. The cellular nature of this damage and whether it is transient or permanent is unclear at present. [ABSTRACT FROM AUTHOR]

Fructans are commonly used as dietary fibre supplements for their ability to promote the growth of beneficial gut microbes. However, fructan consumption has been associated with various dosage-dependent side effects. We characterised side effects in an exploratory analysis of a randomised trial in healthy adults ( n  = 40) who consumed 18 g/day inulin or placebo. We found that individuals weighing more or habitually consuming higher fibre exhibited the best tolerance. Furthermore, we identified associations between gut microbiome composition and host tolerance. Specifically, higher levels of Christensenellaceae R-7 group were associated with gastrointestinal discomfort, and a machine-learning-based approach successfully predicted high levels of flatulence, with [Ruminococcus] torques group and ( Oscillospiraceae ) UCG-002 sp. identified as key predictive taxa. These data reveal trends that can help guide personalised recommendations for initial inulin dosage. Our results support prior ecological findings indicating that fibre supplementation has the greatest impact on individuals whose baseline fibre intake is lowest.

Background: Pneumonia due to typical bacterial, atypical bacterial and viral pathogens can be difficult to clinically differentiate. Host response-based diagnostics are emerging as a complementary diagnostic strategy to pathogen detection., Methods: We used murine models of typical bacterial, atypical bacterial and viral pneumonia to develop diagnostic signatures and understand the host's response to these types of infections. Mice were intranasally inoculated with Streptococcus pneumoniae , Mycoplasma pneumoniae , influenza or saline as a control. Peripheral blood gene expression analysis was performed at multiple time points. Differentially expressed genes were used to perform gene set enrichment analysis and generate diagnostic signatures. These murine-derived signatures were externally validated in silico using human gene expression data. The response to S. pneumoniae was the most rapid and robust., Results: Mice infected with M. pneumoniae had a delayed response more similar to influenza-infected animals. Diagnostic signatures for the three types of infection had 0.94-1.00 area under the receiver operator curve (auROC). Validation in five human gene expression datasets revealed auROC of 0.82-0.96., Discussion: This study identified discrete host responses to typical bacterial, atypical bacterial and viral aetiologies of pneumonia in mice. These signatures validated well in humans, highlighting the conserved nature of the host response to these pathogen classes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Substance use problems and anxiety disorders are both highly prevalent and frequently cooccur in youth. The present study examined the benefits of successful anxiety treatment at 3-12 years after treatment completion on substance use outcomes (i.e. diagnoses and lifetime expected use)., Methods: The sample was from the Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS), a naturalistic follow-up study to the Child/Adolescent Anxiety Multimodal Study (CAMS) which randomized youth to cognitive behavioral therapy (CBT; Coping cat), medication (sertraline), their combination, or pill placebo. The first CAMELS visit occurred an average of 6.5 years following CAMS randomization. Participants were 319 youth (65.4% of the CAMS sample), aged 7-17 years at CAMS baseline assessment with a mean age of 17.6 years (range: 11-26 years) at the time of the first CAMELS follow-up. Substance use outcomes included diagnoses as well as lifetime substance use (i.e. alcohol and tobacco use)., Results: Eleven of 319 (3.4%) CAMELS participants were diagnosed with a substance use disorder at the initial follow-up visit. When compared to the population lifetime rate of 11.4%, the rate of diagnoses in the posttreated sample was significantly lower. Additionally, rates of lifetime alcohol use were lower than population rates at the initial and final follow-up visits. Rates of lifetime tobacco use were similarly lower than lifetime population rates at the initial visit (driven by significantly lower rates in the CBT treatment condition), but higher by the final visit. Furthermore, treatment remission (but not treatment response) was associated with a lower rate of substance use diagnoses at the initial follow-up visit, although rates of lifetime alcohol and tobacco use did not differ by treatment outcome., Conclusions: Anxiety treatments confer a beneficial impact on problematic substance use (i.e. diagnoses) as well as on expected substance use (i.e. alcohol and tobacco use) for on average, a period of 6.5 years., (© 2024 Association for Child and Adolescent Mental Health.)

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis., Methods: Individuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS., Results: Individuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21-1.53), factor 3 (OR:1.75, 95 %CI:1.53-2.02) and factor 4 (OR:1.49; 95 %CI:1.32-1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77-0.97) and factor 5 (OR:0.74, 95 %CI:0.65-0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82-61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14-9.29) and HDL (OR:0.35, 95 %CI:0.13-0.72) were confirmed., Conclusions: Large TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V.)

Respiratory diseases are a leading cause of morbidity and mortality globally. However, existing systems of care, built around scheduled appointments, are not well designed to support the needs of people with chronic and acute respiratory conditions that can change rapidly and unexpectedly. Home-based and personal digital health technologies (DHTs) allow implementation of new models of care catering to the unique needs of individuals. The high number of respiratory triggers and unique responses to them require a personalised solution for each patient. The real-world, repetitive monitoring capabilities of DHTs enable identification of the normal operating characteristics for each individual and, therefore, recognition of the earliest deviations from that state. However, despite this potential, the number of clinical efficacy studies of DHTs is quite small. Evaluation of clinical effectiveness of DHTs in improving health quality in real-world settings is urgently needed., Competing Interests: Declaration of interests JD reports personal fees as a Scientific Advisor to Veri and grant support from AstraZeneca. AC is the CEO, co-founder, and a shareholder of HumanFirst; and was a board member of the Digital Medical Society until 2023. MF is an advisor and shareholder of HumanFirst. SRS reports financial compensation as a consultant for physIQ; declares research grant support from Janssen Research & Development; and received reimbursement as an Executive Committee member for the Heartline Study, which is a trial on wearables to detect atrial fibrillation. GSG declared no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Index-cluster studies may help characterize the spread of communicable infections in the presymptomatic state. We describe a prospective index-cluster sampling strategy (ICSS) to detect presymptomatic respiratory viral illness and its implementation in a college population., Methods: We enrolled an annual cohort of first-year undergraduates who completed daily electronic symptom diaries to identify index cases (ICs) with respiratory illness. Investigators then selected 5-10 potentially exposed, asymptomatic close contacts (CCs) who were geographically co-located to follow for infections. Symptoms and nasopharyngeal samples were collected for 5 days. Logistic regression model-based predictions for proportions of self-reported illness were compared graphically for the whole cohort sampling group and the CC group., Results: We enrolled 1379 participants between 2009 and 2015, including 288 ICs and 882 CCs. The median number of CCs per IC was 6 (interquartile range, 3-8). Among the 882 CCs, 111 (13%) developed acute respiratory illnesses. Viral etiology testing in 246 ICs (85%) and 719 CCs (82%) identified a pathogen in 57% of ICs and 15% of CCs. Among those with detectable virus, rhinovirus was the most common (IC: 18%; CC: 6%) followed by coxsackievirus/echovirus (IC: 11%; CC: 4%). Among 106 CCs with a detected virus, only 18% had the same virus as their associated IC. Graphically, CCs did not have a higher frequency of self-reported illness relative to the whole cohort sampling group., Conclusions: Establishing clusters by geographic proximity did not enrich for cases of viral transmission, suggesting that ICSS may be a less effective strategy to detect spread of respiratory infection., Competing Interests: Potential conflicts of interest. M. T. M. reports grants from the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH), and has a patent pending on “Methods to diagnose and treat acute respiratory infections.” T. W. B. reports grants from DARPA and NIH; reports owning equity in and serving as a consultant for Biomeme; and has a patent pending on Methods to diagnose and treat acute respiratory infections. E. L. T. reports consultancy fees and equity from Biomeme; has patents pending on Biomarkers for the molecular classification of bacterial infection and Methods to diagnose and treat acute respiratory infections; and is currently an employee of Danaher Diagnostics. C. W. W. and G. S. G. have patents pending on Molecular classification of bacterial infection and gene expression signatures useful to predict or diagnose sepsis and methods of using the same, and have patents issued on Methods to diagnose and treat acute respiratory disease and Methods of identifying infectious disease and assays for identifying infectious disease. C. W. W. reports owning equity in and consulting for Biomeme; reports grants from DARPA, NIH, Antibacterial Resistance Leadership Group, and Sanofi; and has received consultancy fees from bioMérieux, Roche, Biofire, Giner, and Biomeme. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk., Methods: Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events., Results: Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events., Conclusions: Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use., Competing Interests: Disclosures Coauthors (R.A. Myers, G.S. Ginsburg, and D. Voora) are listed as coinventors on an invention disclosure related to use of platelet RNA biomarkers to predict bleeding due to platelet P2Y12 inhibitors. This article was prepared while G.S. Ginsburg was employed at Duke University. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Diagnostic limitations challenge management of clinically indistinguishable acute infectious illness globally. Gene expression classification models show great promise distinguishing causes of fever. We generated transcriptional data for a 294-participant (USA, Sri Lanka) discovery cohort with adjudicated viral or bacterial infections of diverse etiology or non-infectious disease mimics. We then derived and cross-validated gene expression classifiers including: 1) a single model to distinguish bacterial vs. viral (Global Fever-Bacterial/Viral [GF-B/V]) and 2) a two-model system to discriminate bacterial and viral in the context of noninfection (Global Fever-Bacterial/Viral/Non-infectious [GF-B/V/N]). We then translated to a multiplex RT-PCR assay and independent validation involved 101 participants (USA, Sri Lanka, Australia, Cambodia, Tanzania). The GF-B/V model discriminated bacterial from viral infection in the discovery cohort an area under the receiver operator curve (AUROC) of 0.93. Validation in an independent cohort demonstrated the GF-B/V model had an AUROC of 0.84 (95% CI 0.76-0.90) with overall accuracy of 81.6% (95% CI 72.7-88.5). Performance did not vary with age, demographics, or site. Host transcriptional response diagnostics distinguish bacterial and viral illness across global sites with diverse endemic pathogens., (© 2023. The Author(s).)

The National Institutes of Health's All of Us Research Program is an accessible platform that hosts genomic and phenotypic data to be collected from 1 million participants in the United States. Its mission is to accelerate medical research and clinical breakthroughs with a special emphasis on diversity.

Regularly administering outcome measures to clients to inform clinical decision making, referred to as measurement-based care (MBC), has the potential to improve mental health treatment due to its applicability across disorders and treatment settings. Given the utility of MBC, understanding predictors of high-fidelity MBC implementation is important. Training and consultation are widely used implementation strategies to increase the fidelity of evidence-based practice delivery but have rarely been studied with MBC. The current study will examine the relationship between time clinicians spent discussing a case in consultation ("dosage") and MBC fidelity. Thirty clinicians and 56 youth were in the MBC condition of a randomized controlled trial and completed baseline questionnaires. Consultation dosage was extracted from call notes. MBC fidelity was measured using the implementation index, which combines rates of administering and viewing questionnaires, using objective data from the online MBC system. Multi-level modeling was used. Greater consultation dosage significantly predicted a higher implementation index (ß = 0.27, SE = 0.06, p < .001). For every 30 min spent discussing a case in consultation, the case's MBC fidelity increased by 8.1%. Greater consultation dosage significantly predicted higher rates of administration (ß = 0.07, SE = 0.03, p = 0.033) and feedback report viewing (ß = 0.24, SE = 0.06, p < .001). More consultation at the case level predicts greater MBC fidelity using objective measures. The greatest impact was increasing the clinician feedback report viewing rate. The results of this study can help inform future efforts to increase the fidelity with which MBC is delivered and to make consultation as efficient and effective as possible., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Effectiveness trials aim to increase the generalizability and public health impact of interventions. However, challenges associated with this design present threats to external and internal validity. This paper illustrates these challenges using data from a two-site randomized effectiveness trial, the Community Study of Outcome Monitoring for Emotional Disorders in Teens (COMET) and presents recommendations for future research., Method: COMET was a randomized effectiveness trial conducted in 19 community mental health clinics in two states comparing three interventions: treatment as usual (TAU), TAU with measurement-based care (TAU+), and the Unified Protocol forTransdiagnostic Treatment of Emotional Disorders in Adolescents with MBC (UPA). Participants included 176 clinicians (mean age = 35.5; 85.8% cisgender female; 53.0% racially and/or ethnically minorized) and 196 adolescents (mean age = 14.7; 65.3% cisgender female; 69.4% racially and/or ethnically minorized). Analyses outlined participant flow from recruitment to study completion, described participant characteristics, and examined site differences., Results: Analysis of participant flow suggested that recruitment and retention of clinicians and adolescents was challenging, raising questions about whether participants were representative of participating clinics. Both the clinician and adolescent samples were racially and ethnically diverse and adolescents were low income and clinically complex. Significant site differences were observed in clinician and adolescent characteristics., Conclusions: While this study was successful in recruiting a diverse and historically under-represented sample, difficulties in recruitment and retention raise questions about external validity and site differences present challenges to internal validity of study findings. Suggestions for future effectiveness studies, drawing from implementation science approaches, are discussed.

Objective: The current study examined trajectories of anxiety during (a) acute treatment and (b) extended follow-up to better characterize the long-term symptom trajectories of youth who received evidence-based intervention for anxiety disorders using a person-centered approach., Method: Participants were 319 youth (age 7-17 years at enrollment), who participated in a multicenter randomized controlled trial for the treatment of pediatric anxiety disorders, Child/Adolescent Anxiety Multimodal Study, and a 4-year naturalistic follow-up, Child/Adolescent Anxiety Multimodal Extended Long-term Study, an average of 6.5 years later. Using growth mixture modeling, the study identified distinct trajectories of anxiety across acute treatment (Weeks 0-12), posttreatment (Weeks 12-36), and the 4-year-long follow-up, and identified baseline predictors of these trajectories., Results: Three nonlinear anxiety trajectories emerged: "short-term responders" who showed rapid treatment response but had higher levels of anxiety during the extended follow-up; "durable responders" who sustained treatment gains; and "delayed remitters" who did not show an initial response to treatment, but showed low levels of anxiety during the maintenance and extended follow-up periods. Worse anxiety severity and better family functioning at baseline predicted membership in the delayed remitters group. Caregiver strain differentiated short-term responders from durable responders., Conclusions: Findings suggest that initial response to treatment does not guarantee sustained treatment gains over time for some youth. Future follow-up studies that track treated youth across key developmental transitions and in the context of changing social environments are needed to inform best practices for the long-term management of anxiety., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Objective: To examine the associations between sociodemographic characteristics, perceived barriers to treatment, clinical impairment, and youth treatment engagement., Method: Participants included 196 families (youth: ages 12 to 18; 64.3% cis-gender female; 23.5% Black, 60.7% White, and 12.2% Mixed/Other race; 41.3% Hispanic or Latinx ethnicity) recruited as part of a comparative effectiveness trial for adolescent anxiety and depression. Self-report measures of sociodemographic characteristics and caregiver perceived barriers were completed at intake. Youth clinical impairment was assessed at baseline via clinical interview. Measures of engagement were collected throughout treatment, including initiation status, session attendance, and termination status. Relationships were examined using analyses of variances and hierarchal linear and logistic modeling., Results: Perceived barriers did not differ by sociodemographic characteristics. Greater perceived stressors and obstacles predicted fewer sessions attended and a lower likelihood of successful termination. Youth of caregivers with an advanced degree and those with caregivers who were employed part time attended more sessions and were more likely to initiate and terminate treatment successfully compared to youth with caregivers of a lower education level or student or unemployed status. At higher levels of youth clinical impairment, greater perceived treatment demands and issues predicted reduced likelihood of treatment initiation., Conclusions: Perceived barriers, sociodemographic characteristics, and clinical impairment were all associated with levels of engagement in the treatment process. Baseline and continued assessment of perceived and experienced barriers to treatment may promote individualized strategies for families identified as at-risk for reduced engagement.

Background The interplay between branched-chain amino acid (BCAA) metabolism, an important pathway in adiposity and cardiometabolic disease, and visceral adipose depots such as hepatic steatosis (HS) and epicardial adipose tissue is unknown. We leveraged the PROMISE clinical trial with centrally adjudicated coronary computed tomography angiography imaging to determine relationships between adipose depots, BCAA dysregulation, and coronary artery disease (CAD). Methods and Results The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10 003 outpatients with stable chest pain to computed tomography angiography versus standard-of-care diagnostics. For this study, we included 1798 participants with available computed tomography angiography data and biospecimens. Linear and logistic regression were used to determine associations between a molar sum of BCAAs measured by nuclear magnetic resonance spectroscopy with body mass index, adipose traits, and obstructive CAD. Mendelian randomization was then used to determine if BCAAs are in the causal pathway for adipose depots or CAD. The study sample had a mean age of 60 years (SD, 8.0), body mass index of 30.6 (SD, 5.9), and epicardial adipose tissue volume of 57.3 (SD, 21.3) cm 3 /m 2 ; 27% had HS, and 14% had obstructive CAD. BCAAs were associated with body mass index (multivariable beta 0.12 per SD increase in BCAA [95% CI, 0.08-0.17]; P =4×10 -8 ). BCAAs were also associated with HS (multivariable odds ratio [OR], 1.46 per SD increase in BCAAs [95% CI, 1.28-1.67]; P =2×10 -8 ), but BCAAs were associated only with epicardial adipose tissue volume (odds ratio, 1.18 [95% CI, 1.07-1.32]; P =0.002) and obstructive CAD (OR, 1.18 [95% CI, 1.04-1.34]; P =0.009) in univariable models. Two-sample Mendelian randomization did not support the role of BCAAs as within the causal pathways for HS or CAD. Conclusions BCAAs have been implicated in the pathogenesis of cardiometabolic diseases, and adipose depots have been associated with the risk of CAD. Leveraging a large clinical trial, we further establish the role of dysregulated BCAA catabolism in HS and CAD, although BCAAs did not appear to be in the causal pathway of either disease. This suggests that BCAAs may serve as an independent circulating biomarker of HS and CAD but that their association with these cardiometabolic diseases is mediated through other pathways.

Introduction: Stress generation suggests a reciprocal relationship between depression and prospective stressful life events. However, the applicability of stress generation to anxiety disorders has been understudied, particularly among youth. We address this gap by examining stress generation in youth at high-risk of developing anxiety disorders., Methods: Participants were one-hundred thirty-six at-risk youth ( M age = 8.69, 84.6% Caucasian; 55.9% female), each of whom had a parent with an anxiety disorder. We examined the role of an anxiety disorder diagnosis, anxiety symptoms, and cognitive distortions in youth's prospective one and six-year stressful life events (i.e., stress generation)., Results: Anxiety symptoms and cognitive distortions were significant predictors of one-year total dependent stress. Anxiety diagnosis and anxiety symptoms were significant predictors of one-year dependent interpersonal stress. Anxiety diagnosis and anxiety symptoms were significant predictors of six-year independent stress., Conclusion: Support for the stress generation model was found in high-risk youth, but only over a one-year period. This suggests important effects of anxiety and cognitive distortions on stress generation, though their implications might be time-capped.