Strategies for secondary use of real-world clinical and administrative data for outcome ascertainment in pragmatic clinical trials.

BACKGROUND: Pragmatic trials are gaining popularity as a cost-effective way to examine treatment effectiveness and generate timely comparative evidence. Incorporating supplementary real-world data is recommended for robust outcome monitoring. However, detailed operational guidelines are needed to inform effective use and integration of heterogeneous databases. OBJECTIVE: Lessons learned from the Veterans Affairs (VA) Diuretic Comparison Project (DCP) are reviewed, providing adaptable recommendations to capture clinical outcomes from real-world data. METHODS: Non-cancer deaths and major cardiovascular (CV) outcomes were determined using VA, Medicare, and National Death Index (NDI) data. Multiple ascertainment strategies were applied, including claims-based algorithms, natural language processing, and systematic chart review. RESULTS: During a mean follow-up of 2.4 (SD = 1.4) years, 907 CV events were identified within the VA healthcare system. Slight delays (∼1 year) were expected in obtaining Medicare data. An additional 298 patients were found having a CV event outside of the VA in 2016 - 2021, increasing the CV event rate from 3.5 % to 5.7 % (770 of 13,523 randomized). NDI data required âˆ¼2 years waiting period. Such inclusion did not increase the number of deaths identified (all 894 deaths were captured by VA data) but enhanced the accuracy in determining cause of death. CONCLUSION: Our experience supports the recommendation of integrating multiple data sources to improve clinical outcome ascertainment. While this approach is promising, hierarchical data aggregation is required when facing different acquisition timelines, information availability/completeness, coding practice, and system configurations. It may not be feasible to implement comparable applications and solutions to studies conducted under different constraints and practice. The recommendations provide guidance and possible action plans for researchers who are interested in applying cross-source data to ascertain all study outcomes.

Simplified urine-based method to detect rifampin underexposure in adults with tuberculosis: a prospective diagnostic accuracy study.

Variable pharmacokinetics of rifampin in tuberculosis (TB) treatment can lead to poor outcomes. Urine spectrophotometry is simpler and more accessible than recommended serum-based drug monitoring, but its optimal efficacy in predicting serum rifampin underexposure in adults with TB remains uncertain. Adult TB patients in New Jersey and Virginia receiving rifampin-containing regimens were enrolled. Serum and urine samples were collected over 24 h. Rifampin serum concentrations were measured using validated liquid chromatography-tandem mass spectrometry, and total exposure (area under the concentration-time curve) over 24 h (AUC0-24) was determined through noncompartmental analysis. The Sunahara method was used to extract total rifamycins, and rifampin urine excretion was measured by spectrophotometry. An analysis of 58 eligible participants, including 15 (26%) with type 2 diabetes mellitus, demonstrated that urine spectrophotometry accurately identified subtarget rifampin AUC0-24 at 0-4, 0-8, and 0-24 h. The area under the receiver operator characteristic curve (AUC ROC) values were 0.80 (95% CI 0.67-0.90), 0.84 (95% CI 0.72-0.94), and 0.83 (95% CI 0.72-0.93), respectively. These values were comparable to the AUC ROC of 2 h serum concentrations commonly used for therapeutic monitoring (0.82 [95% CI 0.71-0.92], P = 0.6). Diabetes status did not significantly affect the AUC ROCs for urine in predicting subtarget rifampin serum exposure (P = 0.67-0.92). Spectrophotometric measurement of urine rifampin excretion within the first 4 or 8 h after dosing is a simple and cost-effective test that accurately predicts rifampin underexposure. This test provides critical information for optimizing tuberculosis treatment outcomes by facilitating appropriate dose adjustments.

A Centralized EHR-Based Model for the Recruitment of Rural and Lower Socioeconomic Participants in Pragmatic Trials: A Secondary Analysis of the Diuretic Comparison Project.

Importance: Participant diversity is important for reducing study bias and increasing generalizability of comparative effectiveness research. Objective: Demonstrate the operational efficiency of a centralized electronic health record (EHR)-based model for recruiting difficult-to-reach participants in a pragmatic trial. Design, Setting, and Participants: This comparative effectiveness study was a secondary analysis of Diuretic Comparison Project, a randomized clinical trial conducted between 2016 and 2022 (mean [SD] follow-up, 2.4 [1.4] years) comparing 2 commonly prescribed antihypertensives, which used an EHR-based recruitment model. Electronic study workflows, in tandem with routine clinical practice, were adapted by 72 Veteran Affairs (VA) primary care networks. Data were analyzed from August to December 2022. Main Outcomes and Measures: Measures reflecting recruitment capacity (monthly rate), operational efficiency (median time for completion of electronic procedures), and geographic reach (percentage of patients recruited from rural areas) were examined. Results: A total of 13 523 patients with hypertension (mean [SD] age, 72 [5.4] years; 13 092 male [96.8%]) were recruited from 537 outpatient clinics. Approximately 205 patients were randomized per month and a median of 35 days (Q1-Q3, 23-80 days) was needed to complete electronic recruitment. The annual income was below the national median for 69% of the cohort. Patients from all 50 states, Puerto Rico, and the District of Columbia were included and 45% resided in rural areas. Conclusions and Relevance: In this secondary analysis of a multicenter pragmatic trial, a centralized EHR-based recruitment model was associated with improved participation from underrepresented groups. These participants often are difficult to reach, with their exclusion potentially biasing trial results; eliminating in-person study visits and local site involvement can minimize barriers for the recruitment of patients from rural and lower socioeconomic areas. Trial Registration: The Diuretic Comparison Project (DCP) was registered on ClinicalTrials.gov Identifier: NCT02185417.

Ascertainment of stroke from administrative data to support a pragmatic embedded clinical trial.

The goal of this observational study was to identify stroke hospitalizations using International Classification of Disease (ICD)-10 codes and use these codes to develop an ascertainment algorithm for use in pragmatic clinical trials, reducing or eliminating the need for manual chart adjudication in future. Using VA (Veterans Affairs) electronic medical records, 9959 patient charts with ICD-10 codes indicating stroke were screened and a sample of 304 were adjudicated by three clinical reviewers. Hospitalizations were categorized as stroke or non-stroke and positive predictive value (PPV) was calculated for each ICD-10 code that was sampled. The adjudicated codes were categorized for use in a decision tool for identifying stroke in a clinical trial. Of the 304 hospitalizations adjudicated, 192 met the definition of stroke. Of the ICD-10 codes evaluated, I61 yielded the highest PPV (100%) while I63.x yielded the 2nd highest PPV (90%) with a false discovery rate of 10%. A relatively high PPV of ≥80% was associated with codes I60.1-7, I61, I62.9 and I63, which accounted for nearly half of all cases reviewed. Hospitalizations associated with these codes were categorized at positive stroke cases. The incorporation of large administrative datasets, and elimination of trial specific data collection, increases efficiencies, while reducing costs. Accurate algorithms must be developed to allow for identification of clinical endpoints from administrative databases to offer a reliable alternative to study-specific case report form completion. This study demonstrates an example of how to apply medical record data to a decision tool for clinical trial outcomes. CSP597 or clinicaltrials.gov NCT02185417.

Referral Order Placement Decreases Time to Transfer to Adult Congenital Heart Disease Care.

Pediatric patients with moderate and great complexity congenital heart disease (CHD) may benefit from coordinated transfer to adult congenital heart disease (ACHD) centers to reduce the risk of complications; however, there are a variety of transfer practices. We examined the impact of referral order placement at the last pediatric cardiology visit on time to transfer to an ACHD center. We analyzed data collected from pediatric patients with moderate and great complexity CHD who were eligible to transfer to our tertiary center's accredited ACHD center. We examined transfer outcomes and time-to-transfer between those with a referral order placed at the last pediatric cardiology visit and those without using Cox proportional hazards modeling. The sample (n = 65) was 44.6% female and mean age at study start was 19.5 years (± 2.2). Referral orders were placed for 32.3% of patients at the last pediatric cardiology visit. Those who had a referral order placed at the last visit had significantly higher number of successful transfers to the ACHD center compared to those who did not (95% vs 25%, p < 0.001). In a Cox regression model, placement of a referral order at the last pediatric cardiology visit was associated significantly with a sooner time to transfer (HR 6.0; 95% CI 2.2-16.2, p > 0.001), adjusting for age, sex, complexity, living location, and pediatric cardiology visit location. Placement of a referral order at the last pediatric cardiology visit may improve transfer occurrence and time to transfer to accredited ACHD centers.

Practical issues in pragmatic trials: the implementation of the Diuretic Comparison Project.

BACKGROUND/AIMS: The US Department of Veterans Affairs Point of Care Clinical Trial Program conducts studies that utilize informatics infrastructure to integrate clinical trial protocols into routine care delivery. The Diuretic Comparison Project compared hydrochlorothiazide to chlorthalidone in reduction of major cardiovascular events in subjects with hypertension. Here we describe the cultural, technical, regulatory, and logistical challenges and solutions that enabled successful implementation of this large pragmatic comparative effectiveness Point of Care clinical trial. METHODS: Patients were recruited from 72 Veterans Affairs Healthcare Systems using centralized processes for subject identification, obtaining informed consent, data collection, safety monitoring, site communication, and endpoint identification with minimal perturbation of the local clinical care ecosystem. Patients continued to be managed exclusively by their clinical care providers without protocol specified study visits, treatment recommendations, or data collection extraneous to routine care. Centralized study processes were operationalized through the application layer of the electronic health record via a data coordinating center staffed by clinical nurses, data scientists, and statisticians without site-based research coordinators. Study data was collected from the Veterans Affairs electronic health record supplemented by Medicare and National Death Index data. RESULTS: The study exceeded its enrolled goal (13,523 subjects) and followed subjects for the 5-year study duration. The key determinant of program success was collaboration between researchers, regulators, clinicians, and administrative staff at the site level to customize study procedures to align with local clinical practice. This flexibility was enabled by designation of the study as minimal risk and determination that clinical care providers were not engaged in research by the Veterans Affairs Central Institutional Review Board. Cultural, regulatory, technical, and logistical problems were identified and solved through iterative collaboration between clinical and research entities. Paramount among these problems was customization of the Veterans Affairs electronic health record and data systems to accommodate study procedures. CONCLUSIONS: Leveraging clinical care for large-scale clinical trials is feasible but requires a rethinking of traditional clinical trial design (and regulation) to better meet requirements of clinical care ecosystems. Study designs must accommodate site-specific practice variation to reduce the impact on clinical care. A tradeoff thus exists between designing trial processes tailored to expedite local study implementation versus those to produce a more refined response to the research question. The availability of a uniform and flexible electronic health record in the Department of Veterans Affairs played a major role in the success of the trial. Conducting Point of Care research in other healthcare systems without such research-friendly infrastructure presents a more formidable challenge.

Patient- reported reasons for non-participation in a COVID-19 therapeutics clinical trial: Findings from a multi-center investigation.

BACKGROUND: Early in the pandemic, there were no evidence-based treatments for SARS-CoV-2, creating an urgent need to identify effective therapeutics. However, public participation in medical research is low; trial enrollment in the US is typically 10-20%. Thus, the aim of this study was to identify common themes underpinning patient reasons to decline participation and evaluate the impact of specific contextual factors. METHODS: This sub-study was conducted in five VISN-1 Clinical Trials Network participating facilities from 4/10/2020-2/3/2021. The trial evaluated the addition of the IL-6-inhibitor, Sarilumab, to the current standard of care for inpatients with moderate-to-severe SARS-CoV-2. Consent procedures varied by site and included fully in-person and fully remote processes. Reasons for declining enrollment were collected among eligible patients who declined to participate but agreed to answer a short follow-up question. Qualitative data were analyzed using directed content analysis. Enrollment rates were assessed using simple, descriptive statistics. RESULTS: N = 417 COVID-19 positive inpatients were screened and 53/162 eligible patients enrolled. Enrollment varied across study sites and by study period. Prior to identification of effective treatment, the enrollment rate was 10/11 (91%) versus 43/144 (30%) during the later period of the study. N = 85/102 patients who did not enroll answered the follow-up question. The most commonly reported responses were: concerns about the study drug and participation in clinical research in general, comorbidity concerns, competing priorities, external factors, and external advice and influence from family members and clinicians. CONCLUSIONS: Identifying reasons behind declining to enroll may help investigators develop strategies to increase research participation.

Chlorthalidone vs. Hydrochlorothiazide for Hypertension-Cardiovascular Events.

BACKGROUND: Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear. METHODS: In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed. RESULTS: A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P<0.001). CONCLUSIONS: In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

Long-Term Outcomes After Atrial Switch Operation for Transposition of the Great Arteries.

BACKGROUND: For patients with d-loop transposition of the great arteries (d-TGA) with a systemic right ventricle after an atrial switch operation, there is a need to identify risks for end-stage heart failure outcomes. OBJECTIVES: The authors aimed to determine factors associated with survival in a large cohort of such individuals. METHODS: This multicenter, retrospective cohort study included adults with d-TGA and prior atrial switch surgery seen at a congenital heart center. Clinical data from initial and most recent visits were obtained. The composite primary outcome was death, transplantation, or mechanical circulatory support (MCS). RESULTS: From 1,168 patients (38% female, age at first visit 29 ± 7.2 years) during a median 9.2 years of follow-up, 91 (8.8% per 10 person-years) met the outcome (66 deaths, 19 transplantations, 6 MCS). Patients experiencing sudden/arrhythmic death were younger than those dying of other causes (32.6 ± 6.4 years vs 42.4 ± 6.8 years; P < 0.001). There was a long duration between sentinel clinical events and end-stage heart failure. Age, atrial arrhythmia, pacemaker, biventricular enlargement, systolic dysfunction, and tricuspid regurgitation were all associated with the primary outcome. Independent 5-year predictors of primary outcome were prior ventricular arrhythmia, heart failure admission, complex anatomy, QRS duration >120 ms, and severe right ventricle dysfunction based on echocardiography. CONCLUSIONS: For most adults with d-TGA after atrial switch, progress to end-stage heart failure or death is slow. A simplified prediction score for 5-year adverse outcome is derived to help identify those at greatest risk.

Design of a pragmatic clinical trial embedded in the Electronic Health Record: The VA's Diuretic Comparison Project.

BACKGROUND: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].

Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial.

IMPORTANCE AND OBJECTIVE: The aim of this pragmatic, embedded, adaptive trial was to measure the effectiveness of the subcutaneous anti-IL-6R antibody sarilumab, when added to an evolving standard of care (SOC), for clinical management of inpatients with moderate to severe COVID-19 disease. DESIGN: Two-arm, randomized, open-label controlled trial comparing SOC alone to SOC plus sarilumab. The trial used a randomized play-the-winner design and was fully embedded within the electronic health record (EHR) system. SETTING: 5 VA Medical Centers. PARTICIPANTS: Hospitalized patients with clinical criteria for moderate to severe COVID-19 but not requiring mechanical ventilation, and a diagnostic test positive for SARS-CoV-2. INTERVENTIONS: Sarilumab, 200 or 400 mg subcutaneous injection. SOC was not pre-specified and could vary over time, e.g., to include antiviral or other anti-inflammatory drugs. MAIN OUTCOMES AND MEASURES: The primary outcome was intubation or death within 14 days of randomization. All data were extracted remotely from the EHR. RESULTS: Among 162 eligible patients, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death. This occurred in 5/20 and 1/30 of participants in the sarilumab and SOC arms respectively, with the majority occurring in the initial 9 participants (3/4 in the sarilumab and 1/5 in the SOC) before the sarilumab dose was increased to 400 mg and before remdesivir and dexamethasone were widely adopted. After interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. CONCLUSIONS AND RELEVANCE: This randomized trial of patients hospitalized due to respiratory compromise from COVID-19 but not mechanical ventilation found no benefit from subcutaneous sarilumab when added to an evolving SOC. The numbers of patients and events were too low to allow definitive conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6R inhibition in the treatment of hospitalized COVID-19 patients. Methods developed and piloted during this trial will be useful in conducting future studies more efficiently. TRIAL REGISTRATION: Clinicaltrials.gov-NCT04359901; https://clinicaltrials.gov/ct2/show/NCT04359901?cond=NCT04359901&draw=2&rank=1.

Implementation of documented and written informed consent for clinical trials of communicable diseases: Lessons learned, barriers, solutions, future directions identified during the conduct of a COVID-19 clinical trial.

BACKGROUND AND OBJECTIVE: The communicable nature of many infectious diseases, including SARS-CoV-2, creates challenges for implementing and obtaining regulatory-compliant written informed consent. The goal of this project was to identify and evaluate processes that address these barriers while maintaining clinical and research staff safety. METHODS: We reviewed Federal Drug Administration (FDA), World Health Organization (WHO), and VA Office of Research and Development (ORD) guidance about informed consent during the COVID-19 pandemic, and identified and pilot-tested several mechanisms for obtaining regulatory-compliant consent during our COVID-19 therapeutics clinical trial. RESULTS: Several processes were identified. These included a standard face-to-face consent with a plan for maintaining a paper copy of the signed consent form, a phone or video chat consent process that included taking a picture of the signed consent form or a screen shot of the signed document during a video chat, integration of the consent forms into software embedded within the electronic health record, and secure software programs with electronic signature. These processes are FDA-compliant but time-intensive, often requiring four or more hours of coordination between the clinical team, research staff, patients, and legally authorized representatives. CONCLUSIONS: Future studies could evaluate how to improve efficiency, and whether some elements of the consenting process, such as the requirement for documented written signed consent, rather than a witnessed oral consent, is an acceptable standard for research participants with communicable diseases.

Observational study using video recordings to explore the first hour after admission to a neonatal intensive care unit.

AIM: To explore the admission process to our neonatal intensive care unit. METHODS: A first phase quality improvement initiative was conducted. We utilised observational video recording of a convenience sample of inborn admissions. Two remote GoPro cameras were placed, one giving an overview of activity and the other focussed on the infant. Recordings captured the first hour after admission including transfer to the neonatal intensive care unit by the birthing team. The video footage of each case study was reviewed by a multidisciplinary panel using an agreed semi-quantitative analysis of events. RESULTS: Ten admissions to the neonatal intensive care unit were video recorded between June and October 2018. Gestational age 282 -401 . A focus on maintaining airway support was inconsistent as was the ability to provide continuous monitoring of vital signs. Overall leadership of the process was lacking and handover often appeared fragmented. Median temperature on admission was 362 (354 -373 ) °C. Vascular access and fluid management occurred at a median of 36 (13-67) minutes. CONCLUSIONS: Planning and approval for this study were protracted, particularly negotiating the use of video recording. Anecdotally, this delay is thought to have contributed to an improvement in managing admissions, particularly when maintaining airway support and monitoring. However, our baseline data have highlighted a lack of leadership, fragmented handover, low admission temperatures and broad time frames to achieve vascular access. A guideline to streamline handover and nursery transition is currently being implemented; a subsequent evaluation cycle is planned.

Early lung ultrasound affords little to the prediction of bronchopulmonary dysplasia.

OBJECTIVE: To test the hypothesis that lung ultrasound (LUS) performed in the first week of life would predict bronchopulmonary dysplasia (BPD). Secondary outcomes included the utility of LUS in predicting interim respiratory interventions. DESIGN: A prospective observational cohort study in preterm infants born <28 weeks' gestation in the single tertiary statewide neonatal intensive care unit in Western Australia. METHODS: A rigorous protocol for LUS acquisition on day 1, day 3-4, day 7, day 28 and 36 weeks' postmenstrual age (PMA) was implemented with blinded analysis using a modified, previously validated LUS score. BPD was defined by both recent National Institute of Child Health and Human Development categorical criteria and a continuous physiological variable using a modified Shift test. RESULTS: Of the 100 infants studies, primary outcome data were available for the 96 infants, surviving to 36 weeks' PMA. In a univariate logistic regression analysis, LUS on days 3-4 and day 7 accurately predicted BPD (day 3-4 OR (95% CI)=1.54 (1.03 to 2.42), p=0.044; day 7 OR (95% CI)=1.66 (1.07 to 2.70), p=0.031). The predictive value of LUS was insignificant in a multivariate model in which gestational age was the dominant predictor. LUS accurately predicted interim respiratory outcomes including surfactant administration, duration of intubation and extubation to non-invasive support at 48 hours. CONCLUSIONS: LUS in the first week of life predicted BPD. However, LUS offers little additive accuracy to current gestational age-based models. TRIAL REGISTRATION NUMBER: ACTRN12617000208303.

A Pilot RCT of A Body-Oriented Group Therapy For Complex Trauma Survivors: An Adaptation of Sensorimotor Psychotherapy.

This study is a pilot randomized controlled trial that examined the efficacy of a body-oriented group therapy designed to address chronic fear states in the body due to complex trauma. The Trauma and the Body Group (TBG) is a 20-session group psychotherapy that draws upon the principles and techniques of sensorimotor psychotherapy. Thirty-two women with a history of childhood trauma were randomized to immediate treatment or a waitlist control condition. Assessments were conducted one month prior to treatment, immediately after treatment, and six months post-treatment. Significant improvements were found in body awareness, anxiety, and soothing receptivity when comparing treatment to no treatment. The TBG appears to be a valuable tool for helping clients acquire mindfulness and self soothing skills that they can use to reduce posttraumatic symptoms. This study provides preliminary evidence that the TBG provides complex trauma survivors an opportunity to challenge their avoidance of two prominent trauma-related triggers - their bodies and interpersonal relationships - and in so doing may help survivors develop greater body awareness, increase their capacity for self and relational soothing, and reduce their anxiety symptoms.

Left ventricular strain and fibrosis in adults with repaired tetralogy of Fallot: A case-control study.

BACKGROUND: Left ventricular (LV) systolic dysfunction and myocardial fibrosis have prognostic implications in repaired tetralogy of Fallot (rTOF), but their relationship with myocardial strain is not well understood. We evaluated systolic strain and fibrosis (extracellular volume fraction, ECV) of the left ventricle (LV) using feature tracking with magnetic resonance and determine their association with each other and clinical outcome. METHOD: Adults with rTOF and age-matched controls underwent CMR to measure LV-ECV. Feature-tracking was used to quantify radial, circumferential, and longitudinal strain in both 2 and 3 dimensions. Clinical events (death, arrhythmia and heart-failure hospitalization) were obtained through chart review. Associations between strain, ECV and clinical events were explored. RESULTS: 48 rTOF subjects (age 40.5 ± 14.3, 42% female) and 20 healthy controls were included. Both LV 2D and 3D global circumferential strain (GCS) and global longitudinal strain (GLS) were lower in rTOF subjects (p ≤0.01 for all). There was no association between strain and LV-ECV. Strain parameters correlated with ventricular volumes and function. After a median follow-up of 8.5 years (range 1-10.9 years) there were 5 deaths, 6 hospitalizations and 9 new arrhythmias. By multivariate Cox-regression, GLS was an independent predictor of both hospitalization and death, whereas LV-ECV was an independent predictor of arrhythmia. CONCLUSION: While both LV strain abnormalities and fibrosis are present in rTOF, they are associated with different types of clinical outcome, and not to each other. The findings suggest that these measures reflect different long-term adverse adaptations to abnormal hemodynamics.

Changes in physiological reactivity in response to the trauma memory during prolonged exposure and virtual reality exposure therapy for posttraumatic stress disorder.

OBJECTIVE: A key symptom of posttraumatic stress disorder (PTSD) is hyperreactivity to trauma-relevant stimuli. Though physiological arousal is reliably elevated in PTSD, the question remains whether this arousal responds to treatment. Virtual reality (VR) has been posited to increase emotional engagement during prolonged exposure therapy (PE) for PTSD by augmenting imaginal exposures with trauma-relevant sensory information. However, the comparative effects of VR exposure therapy (VRE) have received limited empirical inquiry. METHOD: Ninety active-duty soldiers with combat-related PTSD participating in a randomized-controlled trial to receive PE, VRE, or a waitlist-control (WL) condition had their physiological reactivity, indexed by galvanic skin response (GSR), to their trauma memories assessed at pre-, mid-, and posttreatment. RESULTS: Although both VRE and PE conditions showed reduced GSR reactivity to trauma memories from pre- to posttreatment, only the VRE group differed significantly from WL. Across the sample, reductions in GSR were significantly correlated with reductions in self-reported PTSD and anxiety symptoms. CONCLUSIONS: This was the first study comparing effects of VRE and PE on psychophysiological variables. Given previous research finding limited differences between VRE and PE in PTSD symptom reduction, these findings lend support to the rationale for including VR in exposure therapy protocols while raising important questions about the potential benefits of VRE. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.

OBJECTIVE: To explore the efficacy and risks of oral paracetamol in later (>2 weeks old) treatment of patent ductus arteriosus (PDA). STUDY DESIGN: A multicentre double-blind placebo-controlled randomised pilot trial in three neonatal intensive care units in Australia. Infants born <33 weeks with haemodynamically significant PDA were treated with a 5-day course of oral paracetamol or placebo. Cardiac ultrasounds were used to document haemodynamic parameters. The primary outcome analysed was ductal closure by 48 h after treatment completion. Secondary outcomes included reduction in ductal diameter >25% and safety. RESULTS: Fifty-five infants were enrolled, of whom 27 received paracetamol and 28 placebo. Eighty percent had received previous non-steroidal anti-inflammatory drug. Mean postnatal age was 25 days. Four of the 27 ducts treated with paracetamol closed vs. 0/28 treated with placebo (p = 0.05). An additional 13/27 given  paracetamol vs. 7/28 given placebo showed significant constriction (p = 0.008). No adverse effects were observed . CONCLUSIONS: There was some evidence of increased closure with oral paracetamol at postnatal age >2 weeks; however, the overall efficacy was not high.

Correction: A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus.

In the published version of this paper the author Yan Chen was missed out of the author list. This has now been corrected in the HTML and PDF versions of the paper.

Utility of lung ultrasound scanning in neonatology.

The utility of point-of-care lung ultrasound in neonatology is rapidly expanding. This review summarises current evidence of a diagnostic, procedural and observational tool valuable in the management of newborns requiring intensive care. Approaching a patient, probe in-hand with focused clinical question is essential, and barriers to implication together with important research questions are explored.