Data extraction for evidence synthesis using a large language model: A proof-of-concept study.

Data extraction is a crucial, yet labor-intensive and error-prone part of evidence synthesis. To date, efforts to harness machine learning for enhancing efficiency of the data extraction process have fallen short of achieving sufficient accuracy and usability. With the release of large language models (LLMs), new possibilities have emerged to increase efficiency and accuracy of data extraction for evidence synthesis. The objective of this proof-of-concept study was to assess the performance of an LLM (Claude 2) in extracting data elements from published studies, compared with human data extraction as employed in systematic reviews. Our analysis utilized a convenience sample of 10 English-language, open-access publications of randomized controlled trials included in a single systematic review. We selected 16 distinct types of data, posing varying degrees of difficulty (160 data elements across 10 studies). We used the browser version of Claude 2 to upload the portable document format of each publication and then prompted the model for each data element. Across 160 data elements, Claude 2 demonstrated an overall accuracy of 96.3% with a high test-retest reliability (replication 1: 96.9%; replication 2: 95.0% accuracy). Overall, Claude 2 made 6 errors on 160 data items. The most common errors (n = 4) were missed data items. Importantly, Claude 2's ease of use was high; it required no technical expertise or labeled training data for effective operation (i.e., zero-shot learning). Based on findings of our proof-of-concept study, leveraging LLMs has the potential to substantially enhance the efficiency and accuracy of data extraction for evidence syntheses.

A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E).

BACKGROUND: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies. OBJECTIVE: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome. METHODS AND RESULTS: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias. CONCLUSION: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference.

Primary Care Interventions to Prevent Child Maltreatment: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Child maltreatment is associated with serious negative physical, psychological, and behavioral consequences. Objective: To review the evidence on primary care-feasible or referable interventions to prevent child maltreatment to inform the US Preventive Services Task Force. Data Sources: PubMed, Cochrane Library, and trial registries through February 2, 2023; references, experts, and surveillance through December 6, 2023. Study Selection: English-language, randomized clinical trials of youth through age 18 years (or their caregivers) with no known exposure or signs or symptoms of current or past maltreatment. Data Extraction and Synthesis: Two reviewers assessed titles/abstracts, full-text articles, and study quality, and extracted data; when at least 3 similar studies were available, meta-analyses were conducted. Main Outcomes and Measures: Directly measured reports of child abuse or neglect (reports to Child Protective Services or removal of the child from the home); proxy measures of abuse or neglect (injury, visits to the emergency department, hospitalization); behavioral, developmental, emotional, mental, or physical health and well-being; mortality; harms. Results: Twenty-five trials (N = 14 355 participants) were included; 23 included home visits. Evidence from 11 studies (5311 participants) indicated no differences in likelihood of reports to Child Protective Services within 1 year of intervention completion (pooled odds ratio, 1.03 [95% CI, 0.84-1.27]). Five studies (3336 participants) found no differences in removal of the child from the home within 1 to 3 years of follow-up (pooled risk ratio, 1.06 [95% CI, 0.37-2.99]). The evidence suggested no benefit for emergency department visits in the short term (<2 years) and hospitalizations. The evidence was inconclusive for all other outcomes because of the limited number of trials on each outcome and imprecise results. Among 2 trials reporting harms, neither reported statistically significant differences. Contextual evidence indicated (1) widely varying practices when screening, identifying, and reporting child maltreatment to Child Protective Services, including variations by race or ethnicity; (2) widely varying accuracy of screening instruments; and (3) evidence that child maltreatment interventions may be associated with improvements in some social determinants of health. Conclusion and Relevance: The evidence base on interventions feasible in or referable from primary care settings to prevent child maltreatment suggested no benefit or insufficient evidence for direct or proxy measures of child maltreatment. Little information was available about possible harms. Contextual evidence pointed to the potential for bias or inaccuracy in screening, identification, and reporting of child maltreatment but also highlighted the importance of addressing social determinants when intervening to prevent child maltreatment.

Rapid reviews methods series: Guidance on assessing the certainty of evidence.

This paper is part of a series of methodological guidance from the Cochrane Rapid Reviews Methods Group. Rapid reviews (RRs) use modified systematic review methods to accelerate the review process while maintaining systematic, transparent and reproducible methods. This paper addresses considerations for rating the certainty of evidence (COE) in RRs. We recommend the full implementation of GRADE (Grading of Recommendations, Assessment, Development and Evaluation) for Cochrane RRs if time and resources allow.If time or other resources do not permit the full implementation of GRADE, the following recommendations can be considered: (1) limit rating COE to the main intervention and comparator and limit the number of outcomes to critical benefits and harms; (2) if a literature review or a Delphi approach to rate the importance of outcomes is not feasible, rely on informal judgements of knowledge users, topic experts or team members; (3) replace independent rating of the COE by two reviewers with single-reviewer rating and verification by a second reviewer and (4) if effect estimates of a well-conducted systematic review are incorporated into an RR, use existing COE grades from such a review. We advise against changing the definition of COE or the domains considered part of the GRADE approach for RRs.

Advancing health equity through social care interventions.

OBJECTIVE: To use evidence on addressing racism in social care intervention research to create a framework for advancing health equity for all populations with marginalized social identities (e.g., race, gender, and sexual orientation). Such groups have disproportionate social needs (e.g., food insecurity) and negative social determinants of health (SDOH; e.g., poverty). We recommend how the Agency for Healthcare Research and Quality (AHRQ) could advance health equity for marginalized populations through social care research and care delivery. DATA SOURCES AND STUDY SETTING: This commentary is informed by a literature review of social care interventions that were affiliated with healthcare systems; input from health equity researchers, policymakers, and community leaders attending the AHRQ Health Equity Summit; and consensus of the authors. PRINCIPAL FINDINGS: We recommend that AHRQ: (1) create an ecosystem that values research on SDOH and the effectiveness and implementation of social care interventions in the healthcare sector; (2) work with other federal agencies to (a) develop position statements with actionable recommendations about racism and other systems that perpetuate marginalization based on social identity and (b) develop aligned, complementary approaches to research and care delivery that address social marginalization; (3) advance both inclusive care delivery and inclusive research teams; (4) advance understanding of racism as a social determinant of health and effective strategies to mitigate its adverse impact on health; (5) advance the creation and scaling of effective strategies for addressing SDOH in healthcare systems, particularly in co-creation with community partners; and (6) require social care intervention researchers to use methods that advance our understanding of social health equity. CONCLUSIONS: AHRQ, as a federal agency, could help advance health equity using a range of strategies, including using the agency's levers to ensure AHRQ stakeholders examine and address the unique experiences of socially marginalized populations in SDOH and social care intervention research.

Psychotherapies for the treatment of borderline personality disorder: A systematic review.

OBJECTIVE: Borderline personality disorder (BPD) is the most common personality disorder, affecting 1.8% of the general population, 10% of psychiatric outpatients, and 15%-25% of psychiatric inpatients. Practice guidelines recommend psychotherapies as first-line treatments. However, psychotherapies commonly used for the treatment of BPD are numerous, and little is known about the comparative effectiveness of each individual psychotherapy versus treatment as usual (TAU) or other psychotherapies. To systematically assess the comparative effectiveness of commonly used psychotherapies versus TAU or versus other psychotherapies for BPD treatment. METHOD: We conducted systematic literature searches in MEDLINE, EMBASE, the Cochrane Library, and APA PsycINFO up to July 14, 2022, and searched reference lists of pertinent articles and reviews. Inclusion criteria were (a) patients 13 years or older with a diagnosis of BPD, (b) treatment with commonly used psychotherapies, (c) comparison with TAU or another psychotherapy, (d) assessment of relevant BPD-related health outcomes, and (e) randomized or nonrandomized trials or controlled observational studies. Two investigators independently screened abstracts and full-text articles and graded the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: We found 25 psychotherapy studies meeting inclusion criteria with data on 2,545 participants. Seventeen studies compared nine psychotherapies with TAU and nine studies compared eight psychotherapies with another psychotherapy for the treatment of BPD. Overall, both TAU and included psychotherapies were effective in treating the severity and symptoms of BPD. Moderate certainty of evidence suggests that systems training for emotional predictability and problem solving is more effective than TAU for the treatment of BPD; low certainty of evidence suggests that dialectical behavior therapy, schema therapy, transference-focused psychotherapy, acceptance and commitment therapy, manual-assisted cognitive therapy, and cognitive behavioral therapy are more effective than TAU for treating BPD. We were unable to draw conclusions from head-to-head comparisons of psychotherapies, which were limited to single studies with very low to low certainty of evidence. CONCLUSIONS: All commonly used psychotherapies improve BPD severity, symptoms, and functioning. Our assessment found no strong evidence suggesting that any one psychotherapy is more beneficial than another. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Definitions, terminology, and related concepts of "racial health equity": a scoping review protocol.

BACKGROUND: In the USA, access to quality healthcare varies greatly across racial and ethnic groups, resulting in significant health disparities. A new term, "racial health equity" (RHE), is increasingly reported in the medical literature, but there is currently no consensus definition of the term. Additionally, related terms such as "health disparities," "health inequities," and "equality" have been inconsistently used when defining RHE. METHODS: The primary purpose of this scoping review is to investigate the current use and underlying concepts used to define racial health equity. The study will address two key questions: (1) "What terminology and definitions have been used to characterize RHE?" and (2) "What knowledge gaps and challenges are present in the current state of RHE research and theory?" The review will collect and analyze data from three sources: (1) websites from key national and international health organizations, (2) theoretical and narrative published articles, and (3) evidence synthesis studies addressing interventions targeting racial health equity and minority stakeholder engagement. DISCUSSION: Defining "racial health equity" and related terminology is the first step to advancing racial health equity within the USA. This review aims to offer an improved understanding of RHE constructs and definitions, bringing greater unity to national racial health equity research efforts across disciplines. SYSTEMATIC REVIEW REGISTRATION: This protocol is registered with the Open Science Framework at https://osf.io/7pvzq .

Folic Acid Supplementation to Prevent Neural Tube Defects: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Neural tube defects are among the most common birth defects in the US. Objective: To review new evidence on the benefits and harms of folic acid supplementation for the prevention of neural tube defects to inform the US Preventive Services Task Force. Evidence Review: Sources included PubMed, Cochrane Library, Embase, and trial registries from July 1, 2015, through July 2, 2021; references; and experts, with surveillance through February 10, 2023. Two investigators independently reviewed English-language randomized studies and nonrandomized cohort studies in very highly developed countries that focused on the use of folic acid supplementation for the prevention of neural tube defect-affected pregnancies; methodological quality was dually and independently assessed. Findings: Twelve observational studies (reported in 13 publications) were eligible for this limited update (N = 1 244 072). Of these, 3 studies (n = 990 372) reported on the effect of folic acid supplementation on neural tube defects. For harms, 9 studies were eligible: 1 randomized clinical trial (n = 431) reported on variations in twin delivery, 7 observational studies (n = 761 125) reported on the incidence of autism spectrum disorder, and 1 observational study (n = 429 004) reported on maternal cancer. Two cohort studies and 1 case-control study newly identified in this update reported on the association between folic acid supplementation and neural tube defects (n = 990 372). One cohort study reported a statistically significant reduced risk of neural tube defects associated with folic acid supplementation taken before pregnancy (adjusted relative risk [aRR], 0.54 [95% CI, 0.31-0.91]), during pregnancy (aRR, 0.62 [95% CI, 0.39-0.97]), and before and during pregnancy (aRR, 0.49 [95% CI, 0.29-0.83]), but this association occurred for only the later of 2 periods studied (2006-2013 and not 1999-2005). No other statistically significant benefits were reported overall. No study reported statistically significant harms (multiple gestation, autism, and maternal cancer) associated with pregnancy-related folic acid exposure. Conclusions and Relevance: New evidence from observational studies provided additional evidence of the benefit of folic acid supplementation for preventing neural tube defects and no evidence of harms related to multiple gestation, autism, or maternal cancer. The new evidence was consistent with previously reviewed evidence on benefits and harms.

Racial Health Equity and Social Needs Interventions: A Review of a Scoping Review.

Importance: Social needs interventions aim to improve health outcomes and mitigate inequities by addressing health-related social needs, such as lack of transportation or food insecurity. However, it is not clear whether these studies are reducing racial or ethnic inequities. Objective: To understand how studies of interventions addressing social needs among multiracial or multiethnic populations conceptualize and analyze differential intervention outcomes by race or ethnicity. Evidence Review: Sources included a scoping review of systematic searches of PubMed and the Cochrane Library from January 1, 1995, through November 29, 2021, expert suggestions, and hand searches of key citations. Eligible studies evaluated interventions addressing social needs; reported behavioral, health, or utilization outcomes or harms; and were conducted in multiracial or multiethnic populations. Two reviewers independently assessed titles, abstracts, and full text for inclusion. The team developed a framework to assess whether the study was "conceptually thoughtful" for understanding root causes of racial health inequities (ie, noted that race or ethnicity are markers of exposure to racism) and whether analyses were "analytically informative" for advancing racial health equity research (ie, examined differential intervention impacts by race or ethnicity). Findings: Of 152 studies conducted in multiracial or multiethnic populations, 44 studies included race or ethnicity in their analyses; of these, only 4 (9%) were conceptually thoughtful. Twenty-one studies (14%) were analytically informative. Seven of 21 analytically informative studies reported differences in outcomes by race or ethnicity, whereas 14 found no differences. Among the 7 that found differential outcomes, 4 found the interventions were associated with improved outcomes for minoritized racial or ethnic populations or reduced inequities between minoritized and White populations. No studies were powered to detect differences. Conclusions and Relevance: In this review of a scoping review, studies of social needs interventions in multiracial or multiethnic populations were rarely conceptually thoughtful for understanding root causes of racial health inequities and infrequently conducted informative analyses on intervention effectiveness by race or ethnicity. Future work should use a theoretically sound conceptualization of how race (as a proxy for racism) affects social drivers of health and use this understanding to ensure social needs interventions benefit minoritized racial and ethnic groups facing social and structural barriers to health.

Parent perceptions and decision making about treatments for epilepsy: a qualitative evidence synthesis.

OBJECTIVES: Epilepsy treatment decision making is complex and understanding what informs caregiver decision making about treatment for childhood epilepsy is crucial to better support caregivers and their children. We synthesised evidence on caregivers' perspectives and experiences of treatments for childhood epilepsy. DESIGN: Systematic review of qualitative studies using a best-fit framework and Grading of Recommendations Assessment, Development and Evaluation Confidence in the Evidence from Reviews of Qualitative Research (GRADE-CERQual) approach. DATA SOURCES: Searched Embase, PubMed, CINAHL, PsycINFO, SocINDEX and Web of Science from 1 January 1999 to 19 August 2021. ELIGIBILITY CRITERIA: We included qualitative studies examining caregiver's perspectives on antiseizure medication, diet or surgical treatments for childhood epilepsy. We excluded studies not reported in English. DATA EXTRACTION AND SYNTHESIS: We extracted qualitative evidence into 1 of 14 domains defined by the Theoretical Domains Framework (TDF). One reviewer extracted study data and methodological characteristics, and two reviewers extracted qualitative findings. The team verified all extractions. We identified themes within TDF domains and synthesised summary statements of these themes. We assessed our confidence in our summary statements using GRADE-CERQual. RESULTS: We identified five studies (in six reports) of good methodological quality focused on parent perceptions of neurosurgery; we found limited indirect evidence on parents' perceptions of medications or diet. We identified themes within 6 of the 14 TDF domains relevant to treatment decisions: knowledge, emotion; social/professional role and identity; social influence; beliefs about consequences; and environmental context and resources. CONCLUSIONS: Parents of children with epilepsy navigate a complex process to decide whether to have their child undergo surgery. Educational resources, peer support and patient navigators may help support parents through this process. More qualitative studies are needed on non-surgical treatments for epilepsy and among caregivers from different cultural and socioeconomic backgrounds to fully understand the diversity of perspectives that informs treatment decision making.

End-user understanding of qualitative comparative analysis used within evidence synthesis: A mixed-methods study.

BACKGROUND: Enhanced uptake of systematic reviews that use qualitative comparative analyses (QCA) requires knowing how end-users interpret such findings. The study purpose was to identify effective approaches to communicating results from a QCA within a systematic review. METHODS: Sequential exploratory mixed methods design; thematic analysis of interviews with 11 end-users followed by a randomized experiment with 254 participants that provided QCA results for a hypothetical review presented through three formats (text, table, and figure). A survey administered after the experiment assessed subjective and objective comprehension of QCA results. RESULTS: Interview themes included use of jargon; appropriate use of appendices, tables, figures; and integration of QCA results within the systematic review. In the experiment, we observed a significant difference (p = 0.035) in subjective comprehension across the three presentation formats. Participants randomized to the figure and text formats scored higher compared to the table. No significant differences were observed for objective comprehension overall (p = 0.11). However, for parameter interpretation (a unique component of QCA results), scores among participants that received the figure format were significantly higher than scores for participants who received the text (p = 0.001) or table (p = 0.004). No significant differences (p = 0.09) were observed in objective comprehension for configuration interpretation. CONCLUSIONS: End-users of systematic reviews saw value in the use of QCA, but unfamiliar methods and terminology were barriers to full understanding of the findings. When presenting results, a figure format appears to be superior to text or table formats based on measures of subjective comprehension and some measures of objective comprehension.

Inclusion of nonrandomized studies of interventions in systematic reviews of interventions: updated guidance from the Agency for Health Care Research and Quality Effective Health Care program.

OBJECTIVES: We developed guidance to inform decisions regarding the inclusion of nonrandomized studies of interventions (NRSIs) in systematic reviews (SRs) of the effects of interventions. STUDY DESIGN AND SETTING: The guidance workgroup comprised SR experts and used an informal consensus generation method. RESULTS: Instead of recommending NRSI inclusion only if randomized controlled trials (RCTs) are insufficient to address the SR key question, different topics may require different decisions regarding NRSI inclusion. We identified important considerations to inform such decisions from topic refinement through protocol development. During topic scoping and refinement, considerations were related to the clinical decisional dilemma, adequacy of RCTs to address the key questions, risk of bias in NRSIs, and the extent to which NRSIs are likely to complement RCTs. When NRSIs are included, during SR team formation, familiarity with topic-specific data sources and advanced analytic methods for NRSIs should be considered. During protocol development, the decision regarding NRSI inclusion or exclusion should be justified, and potential implications explained. When NRSIs are included, the protocol should describe the processes for synthesizing evidence from RCTs and NRSIs and determining the overall strength of evidence. CONCLUSION: We identified specific considerations for decisions regarding NRSI inclusion in SRs and highlight the importance of flexibility and transparency.

Screening for Depression and Suicide Risk in Children and Adolescents: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Depression, suicidal ideation, and self-harm behaviors in youth are associated with functional impairment and suicide. Objective: To review the evidence on screening for depression or suicide risk in children and adolescents to inform the US Preventive Services Task Force (USPSTF). Data Sources: PubMed, Cochrane Library, PsycINFO, CINAHL, and trial registries through July 19, 2021; references, experts, and surveillance through June 1, 2022. Study Selection: English-language, randomized clinical trials (RCTs) of screening for depression or suicide risk; diagnostic test accuracy studies; RCTs of psychotherapy and first-line pharmacotherapy; RCTs, observational studies, and systematic reviews reporting harms. Data Extraction and Synthesis: Two reviewers assessed titles/abstracts, full-text articles, and study quality and extracted data; when at least 3 similar studies were available, meta-analyses were conducted. Main Outcomes and Measures: Test accuracy, symptoms, response, remission, loss of diagnosis, mortality, functioning, suicide-related events, and adverse events. Results: Twenty-one studies (N = 5433) were included for depression and 19 studies (N = 6290) for suicide risk. For depression, no studies reported on the direct effects of screening on health outcomes, and 7 studies (n = 3281) reported sensitivity of screening instruments ranging from 0.59 to 0.94 and specificity from 0.38 to 0.96. Depression treatment with psychotherapy was associated with improved symptoms (Beck Depression Inventory pooled standardized mean difference, -0.58 [95% CI, -0.83 to -0.34]; n = 471; 4 studies; and Hamilton Depression Scale pooled mean difference, -2.25 [95% CI, -4.09 to -0.41]; n = 262; 3 studies) clinical response (3 studies with statistically significant results using varying thresholds), and loss of diagnosis (relative risk, 1.73 [95% CI, 1.00 to 3.00; n = 395; 4 studies). Pharmacotherapy was associated with improvement on symptoms (Children's Depression Rating Scale-Revised mean difference, -3.76 [95% CI, -5.95 to -1.57; n = 793; 3 studies), remission (relative risk, 1.20 [95% CI, 1.00 to 1.45]; n = 793; 3 studies) and functioning (Children's Global Assessment Scale pooled mean difference, 2.60 (95% CI, 0.78 to 4.42; n = 793; 3 studies). Other outcomes were not statistically significantly different. Differences in suicide-related outcomes and adverse events for pharmacotherapy when compared with placebo were not statistically significant. For suicide risk, no studies reported on the direct benefits of screening on health outcomes, and 2 RCTs (n = 2675) reported no harms of screening. One study (n = 581) reported on sensitivity of screening, ranging from 0.87 to 0.91; specificity was 0.60. Sixteen RCTs (n = 3034) reported on suicide risk interventions. Interventions were associated with lower scores for the Beck Hopelessness Scale (pooled mean difference, -2.35 [95% CI, -4.06 to -0.65]; n = 644; 4 RCTs). Findings for other suicide-related outcomes were mixed or not statistically significantly different. Conclusion and Relevance: Indirect evidence suggested that some screening instruments were reasonably accurate for detecting depression. Psychotherapy and pharmacotherapy were associated with some benefits and no statistically significant harms for depression, but the evidence was limited for suicide risk screening instruments and interventions.

Screening for Anxiety in Children and Adolescents: Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Anxiety in children and adolescents is associated with impaired functioning, educational underachievement, and future mental health conditions. Objective: To review the evidence on screening for anxiety in children and adolescents to inform the US Preventive Services Task Force. Data Sources: PubMed, Cochrane Library, PsycINFO, CINAHL, and trial registries through July 19, 2021; references, experts, and surveillance through June 1, 2022. Study Selection: English-language, randomized clinical trials (RCTs) of screening; diagnostic test accuracy studies; RCTs of cognitive behavioral therapy (CBT) or US Food and Drug Administration-approved pharmacotherapy; RCTs, observational studies, and systematic reviews reporting harms. Data Extraction and Synthesis: Two reviewers assessed titles/abstracts, full-text articles, and study quality and extracted data; when at least 3 similar studies were available, meta-analyses were conducted. Main Outcomes and Measures: Test accuracy, symptoms, response, remission, loss of diagnosis, all-cause mortality, functioning, suicide-related symptoms or events, adverse events. Results: Thirty-nine studies (N = 6065) were included. No study reported on the direct benefits or harms of screening on health outcomes. Ten studies (n = 3260) reported the sensitivity of screening instruments, ranging from 0.34 to 1.00, with specificity ranging from 0.47 to 0.99. Twenty-nine RCTs (n = 2805) reported on treatment: 22 on CBT, 6 on pharmacotherapy, and 1 on CBT, sertraline, and CBT plus sertraline. CBT was associated with gains on several pooled measures of symptom improvement (magnitude of change varied by outcome measure), response (pooled relative risk [RR], 1.89 [95% CI, 1.17 to 3.05]; n = 606; 6 studies), remission (RR, 2.68 [95% CI, 1.48 to 4.88]; n = 321; 4 studies), and loss of diagnosis (RR range, 3.02-3.09) when compared with usual care or wait-list controls. The evidence on functioning for CBT was mixed. Pharmacotherapy, when compared with placebo, was associated with gains on 2 pooled measures of symptom improvement-mean difference (Pediatric Anxiety Rating Scale mean difference, -4.0 [95% CI, -5.5 to -2.5]; n = 726; 5 studies; and Clinical Global Impression-Severity scale mean difference, -0.84 [95% CI, -1.13 to -0.55]; n = 550; 4 studies) and response (RR, 2.11 [95% CI, 1.58 to 2.98]; n = 370; 5 studies)-but was mixed on measures of functioning. Eleven RCTs (n = 1293) reported harms of anxiety treatments. Suicide-related harms were rare, and the differences were not statistically significantly different. Conclusions and Relevance: Indirect evidence suggested that some screening instruments were reasonably accurate. CBT and pharmacotherapy were associated with benefits; no statistically significant association with harms was reported.

The R369 Myosin Residue within Loop 4 Is Critical for Actin Binding and Muscle Function in Drosophila.

The myosin molecular motor interacts with actin filaments in an ATP-dependent manner to yield muscle contraction. Myosin heavy chain residue R369 is located within loop 4 at the actin-tropomyosin interface of myosin's upper 50 kDa subdomain. To probe the importance of R369, we introduced a histidine mutation of that residue into Drosophila myosin and implemented an integrative approach to determine effects at the biochemical, cellular, and whole organism levels. Substituting the similarly charged but bulkier histidine residue reduces maximal actin binding in vitro without affecting myosin ATPase activity. R369H mutants exhibit impaired flight ability that is dominant in heterozygotes and progressive with age in homozygotes. Indirect flight muscle ultrastructure is normal in mutant homozygotes, suggesting that assembly defects or structural deterioration of myofibrils are not causative of reduced flight. Jump ability is also reduced in homozygotes. In contrast to these skeletal muscle defects, R369H mutants show normal heart ultrastructure and function, suggesting that this residue is differentially sensitive to perturbation in different myosin isoforms or muscle types. Overall, our findings indicate that R369 is an actin binding residue that is critical for myosin function in skeletal muscles, and suggest that more severe perturbations at this residue may cause human myopathies through a similar mechanism.

Pharmacologic Treatment for Perinatal Mental Health Disorders.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019124057.

Pharmacological Treatments for Borderline Personality Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Borderline personality disorder (BPD) is a debilitating psychiatric disorder that affects 0.4-3.9% of the population in Western countries. Currently, no medications have been approved by regulatory agencies for the treatment of BPD. Nevertheless, up to 96% of patients with BPD receive at least one psychotropic medication. OBJECTIVES: The objective of this systematic review was to assess the general efficacy and the comparative effectiveness of different pharmacological treatments for BPD patients. METHODS: We conducted systematic literature searches limited to English language in MEDLINE, EMBASE, the Cochrane Library, and PsycINFO up to April 6, 2021, and searched reference lists of pertinent articles and reviews. Inclusion criteria were (i) patients 13 years or older with a diagnosis of BPD, (ii) treatment with anticonvulsive medications, antidepressants, antipsychotic medications, benzodiazepines, melatonin, opioid agonists or antagonists, or sedative or hypnotic medications for at least 8 weeks, (iii) comparison with placebo or an eligible medication, (iv) assessment of health-relevant outcomes, (v) randomized or non-randomized trials or controlled observational studies. Two investigators independently screened abstracts and full-text articles and graded the certainty of evidence based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. For meta-analyses, we used restricted maximum likelihood random effects models to estimate pooled effects. RESULTS: Of 12,062 unique records, we included 21 randomized controlled trials (RCTs) with data on 1768 participants. Nineteen RCTs compared pharmacotherapies with placebo; two RCTs assessed active treatments head-to-head. Out of 87 medications in use in clinical practice, we found studies on just nine. Overall, the evidence indicates that the efficacy of pharmacotherapies for the treatment of BPD is limited. Second-generation antipsychotics, anticonvulsants, and antidepressants were not able to consistently reduce the severity of BPD. Low-certainty evidence indicates that anticonvulsants can improve specific symptoms associated with BPD such as anger, aggression, and affective lability but the evidence is mostly limited to single studies. Second-generation antipsychotics had little effect on the severity of specific BPD symptoms, but they improved general psychiatric symptoms in patients with BPD. CONCLUSIONS: Despite the common use of pharmacotherapies for patients with BPD, the available evidence does not support the efficacy of pharmacotherapies alone to reduce the severity of BPD. REGISTRATION: PROSPERO registration number, CRD42020194098.

Myosin dilated cardiomyopathy mutation S532P disrupts actomyosin interactions, leading to altered muscle kinetics, reduced locomotion, and cardiac dilation in Drosophila.

Dilated cardiomyopathy (DCM), a life-threatening disease characterized by pathological heart enlargement, can be caused by myosin mutations that reduce contractile function. To better define the mechanistic basis of this disease, we employed the powerful genetic and integrative approaches available in Drosophila melanogaster. To this end, we generated and analyzed the first fly model of human myosin-induced DCM. The model reproduces the S532P human ß-cardiac myosin heavy chain DCM mutation, which is located within an actin-binding region of the motor domain. In concordance with the mutation's location at the actomyosin interface, steady-state ATPase and muscle mechanics experiments revealed that the S532P mutation reduces the rates of actin-dependent ATPase activity and actin binding and increases the rate of actin detachment. The depressed function of this myosin form reduces the number of cross-bridges during active wing beating, the power output of indirect flight muscles, and flight ability. Further, S532P mutant hearts exhibit cardiac dilation that is mutant gene dose-dependent. Our study shows that Drosophila can faithfully model various aspects of human DCM phenotypes and suggests that impaired actomyosin interactions in S532P myosin induce contractile deficits that trigger the disease.

CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution.

Antagonistic pleiotropy is a foundational theory that predicts aging-related diseases are the result of evolved genetic traits conferring advantages early in life. Here we examine CaMKII, a pluripotent signaling molecule that contributes to common aging-related diseases, and find that its activation by reactive oxygen species (ROS) was acquired more than half-a-billion years ago along the vertebrate stem lineage. Functional experiments using genetically engineered mice and flies reveal ancestral vertebrates were poised to benefit from the union of ROS and CaMKII, which conferred physiological advantage by allowing ROS to increase intracellular Ca2+ and activate transcriptional programs important for exercise and immunity. Enhanced sensitivity to the adverse effects of ROS in diseases and aging is thus a trade-off for positive traits that facilitated the early and continued evolutionary success of vertebrates.