Robust analysis of stepped wedge trials using composite likelihood models.

Stepped wedge trials (SWTs) are a type of cluster randomized trial that involve repeated measures on clusters and design-induced confounding between time and treatment. Although mixed models are commonly used to analyze SWTs, they are susceptible to misspecification particularly for cluster-longitudinal designs such as SWTs. Mixed model estimation leverages both "horizontal" or within-cluster information and "vertical" or between-cluster information. To use horizontal information in a mixed model, both the mean model and correlation structure must be correctly specified or accounted for, since time is confounded with treatment and measurements are likely correlated within clusters. Alternative non-parametric methods have been proposed that use only vertical information; these are more robust because between-cluster comparisons in a SWT preserve randomization, but these non-parametric methods are not very efficient. We propose a composite likelihood method that focuses on vertical information, but has the flexibility to recover efficiency by using additional horizontal information. We compare the properties and performance of various methods, using simulations based on COVID-19 data and a demonstration of application to the LIRE trial. We found that a vertical composite likelihood model that leverages baseline data is more robust than traditional methods, and more efficient than methods that use only vertical information. We hope that these results demonstrate the potential value of model-based vertical methods for SWTs with a large number of clusters, and that these new tools are useful to researchers who are concerned about misspecification of traditional models.

Sequenced treatment effectiveness for posttraumatic stress (STEPS) trial: A protocol for a pragmatic comparative effectiveness trial with baseline results.

BACKGROUND: There have only been two efficacy trials reporting a head-to-head comparison of medications and psychotherapy for posttraumatic stress disorder (PTSD), and neither was conducted in primary care. Therefore, in this pragmatic trial we compare outcomes of primary care patients randomized to initially receive a brief trauma-focused psychotherapy or a choice of three antidepressants. In addition, because there are few trials examining the effectiveness of subsequent treatments for patients not responding to the initial treatment, we also compare the outcomes of those switching or augmenting treatments. METHOD: Patients screening positive for PTSD (n = 700) were recruited from the primary care clinics of 7 Federally Qualified Health Centers (FQHC) and 8 Department of Veterans Affairs (VA) Medical Centers and randomized in the ratio 1:1:2 to one of three treatment sequences: 1) selective serotonin reuptake inhibitor (SSRI) followed by augmentation with Written Exposure Therapy (WET), 2) SSRI followed by a switch to serotonin-norepinephrine reuptake inhibitor (SNRI), or 3) WET followed by a switch to SSRI. Participants complete surveys at baseline, 6 months, and 12 months. The primary outcome is PTSD symptom severity as measured by the PTSD Checklist (PCL-5). RESULTS: The average PCL-5 score was 52.8 (SD = 11.1), indicating considerable severity. The most common bothersome traumatic event for VA enrollees was combat (47.8%), and for FQHC enrollees was other (28.2%), followed by sexual assault (23.4%), and child abuse (19.8%). Only 22.4% were taking an antidepressant at baseline. CONCLUSION: Results will help healthcare systems and clinicians make decisions about which treatments to offer to patients. CLINICALTRIALS: govID - NCT04597190.

The association of lumbar intervertebral disc degeneration with low back pain is modified by underlying genetic propensity to pain.

BACKGROUND CONTEXT: Associations between magnetic resonance imaging (MRI)-detected lumbar intervertebral disc degeneration (LDD) and LBP are often of modest magnitude. This association may be larger in specific patient subgroups. PURPOSE: To examine whether the association between LDD and LBP is modified by underlying genetic predispositions to pain. STUDY DESIGN: Cross-sectional study in UK Biobank (UKB) and TwinsUK. PATIENT SAMPLES: A genome-wide association study (GWAS) of the number of anatomical chronic pain locations was conducted in 347,538 UKB participants. The GWAS was used to develop a genome-wide polygenic risk score (PRS) in a holdout sample of 30,000 UKB participants. The PRS model was then used in analyses of 645 TwinsUK participants with standardized LDD MRI assessments. OUTCOME MEASURES: Ever having had LBP associated with disability lasting ≥1 month (LBP1). METHODS: Using the PRS as a proxy for "genetically-predicted propensity to pain", we stratified TwinsUK participants into PRS quartiles. A "basic" model examined the association between an LDD summary score (LSUM) and LBP1, adjusting for covariates. A "fully-adjusted" model also adjusted for PRS quartile and LSUM x PRS quartile interaction terms. RESULTS: In the basic model, the odds ratio (OR) of LBP1 was 1.8 per standard deviation of LSUM (95% confidence interval [CI] 1.4 -2.3). In the fully-adjusted model, there was a statistically significant LSUM-LBP1 association in quartile 4, the highest PRS quartile (OR = 2.5 [95% CI 1.7-3.7], p=2.6×10-6), and in quartile 3 (OR=2.0, [95% CI 1.3-3.0]; p=0.002), with small-magnitude and/or non-significant associations in the lowest two PRS quartiles. PRS quartile was a significant effect modifier of the LSUM-LBP1 association (interaction p≤0.05). CONCLUSIONS: Genetically-predicted propensity to pain modifies the LDD-LBP association, with the strongest association present in people with the highest genetic propensity to pain. Lumbar MRI findings may have stronger connections to LBP in specific subgroups of people.

A general framework for developing computable clinical phenotype algorithms.

OBJECTIVE: Present a general framework providing high-level guidance to developers of computable algorithms for identifying patients with specific clinical conditions (phenotypes) through a variety of approaches, including but not limited to machine learning and natural language processing methods to incorporate rich electronic health record data. MATERIALS/METHODS: Drawing on extensive prior phenotyping experiences and insights derived from three algorithm development projects conducted specifically for this purpose, our team with expertise in clinical medicine, statistics, informatics, pharmacoepidemiology, and healthcare data science methods conceptualized stages of development and corresponding sets of principles, strategies, and practical guidelines for improving the algorithm development process. RESULTS: We propose five stages of algorithm development and corresponding principles, strategies, and guidelines: 1) assessing fitness-for-purpose, 2) creating gold standard data, 3) feature engineering, 4) model development, and 5) model evaluation. DISCUSSION/CONCLUSION: This framework is intended to provide practical guidance and serve as a basis for future elaboration and extension.

Mortality with concurrent treatment with gabapentin and opioids among people with spine diagnoses in the U.S. Medicare population: a propensity-matched cohort study.

IMPORTANCE: Given the negative impact of opioid use on population health, prescriptions for alternative pain-relieving medications, including gabapentin, have increased. Concurrent gabapentin and opioid prescriptions are commonly reported in retrospective studies of opioid-related overdose deaths. OBJECTIVE: To determine whether people who filled gabapentin and opioid prescriptions concurrently ('gabapentin + opioids') had greater mortality than those who filled an active control medication (tricyclic antidepressants [TCAs] or duloxetine) and opioids concurrently ('TCAs/duloxetine + opioids'). We hypothesized that people treated with gabapentin + opioids would have higher mortality rates compared to people treated with TCAs/duloxetine + opioids. DESIGN: Propensity score-matched cohort study with an incident user, active control design. The median (maximum) follow-up was 45 (1093) days. SETTING: Population-based. PARTICIPANTS: Medicare beneficiaries with spine-related diagnoses 2017-2019. The primary analysis included those who concurrently (within 30 days) filled at least 1 incident gabapentin + at least 1 opioid or at least 1 incident TCA/duloxetine + at least 1 opioid. EXPOSURES: People treated with gabapentin + opioids (n=67,133) were matched on demographic and clinical factors in a 1:1 ratio to people treated with TCAs/duloxetine + opioids (n=67,133). MAIN OUTCOMES AND MEASURES: The primary outcome was mortality at any time. A secondary outcome was occurrence of a major medical complication at any time. RESULTS: Among 134,266 participants (median age 73.4 years; 66.7% female), 2360 died before the end of follow-up. No difference in mortality was observed between groups (adjusted hazard ratio (HR) and 95% confidence interval (CI) for gabapentin + opioids was 0.98 (0.90, 1.06); p=0.63). However, people treated with gabapentin + opioids were at slightly increased risk of a major medical complication (1.02 (1.00, 1.04); p=0.03) compared to those treated with TCAs/duloxetine + opioids. Results were similar in analyses (a) restricted to less than or = 30-day follow-up and (b) that required at least 2 fills of each prescription. CONCLUSIONS AND RELEVANCE: When treating pain in older adults taking opioids, the addition of gabapentin did not increase mortality risk relative to addition of TCAs or duloxetine. However, providers should be cognizant of a small increased risk of major medical complications among opioid users initiating gabapentin compared to those initiating TCAs or duloxetine.

Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE. METHODS: Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years. RESULTS: Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies. CONCLUSIONS: Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.

Using Effect Scores to Characterize Heterogeneity of Treatment Effects.

This JAMA Guide to Statistics and Methods article explains effect score analyses, an approach for evaluating the heterogeneity of treatment effects, and examines its use in a study of oxygen-saturation targets in critically ill patients.

Can Baseline Patient Clinical and Demographic Characteristics Predict Response to Early Posttraumatic Stress Disorder Interventions After Physical Injury?

OBJECTIVE: A growing evidence base supports stepped care interventions for the early treatment of posttraumatic stress disorder (PTSD) after physical injury. Few investigations have examined the characteristics of patients who do and do not respond to these interventions. METHOD: This investigation was a secondary analysis that used previously collected data from three randomized clinical trials of stepped care interventions (patient N = 498). The study hypothesized that a subgroup of patients would manifest persistent PTSD symptoms regardless of randomization to intervention or control conditions, and that characteristics present at the time of baseline injury hospitalization could distinguish patients who would develop persistent symptoms from potential treatment responders. Regression analyses identified baseline patient clinical and demographic characteristics that were associated with persistent PTSD symptoms over the 6-months post-injury. Additional analyses identified treatment attributes of intervention patients who were and were not likely to demonstrate persistent symptoms. RESULTS: A substantial subgroup of patients (n = 222, 44.6%) demonstrated persistent PTSD symptoms over time. Greater numbers of pre-injury trauma, pre-injury PTSD symptoms, elevated early post-injury PTSD symptoms, unemployment, and non-White race identified patients with persistent symptoms. Patients with ≥3 of these baseline risk characteristics demonstrated diminished treatment responses when compared to patients with <3 characteristics. Intervention patients with ≥3 risk characteristics were less likely to engage in treatment and required greater amounts of interventionist time. CONCLUSIONS: Injured trauma survivors have readily identifiable characteristics at the time of hospitalization that can distinguish responders to PTSD stepped care interventions versus patients who may be treatment refractory.

Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Esophageal Versus Rectal Temperature Monitoring During Whole-Body Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy: Association with Short- and Long-Term Outcomes.

OBJECTIVE: To compare the short- and long-term outcomes of infants with hypoxic-ischemic encephalopathy (HIE) treated with whole-body therapeutic hypothermia (TH), monitored by esophageal vs rectal temperature. STUDY DESIGN: We conducted a secondary analysis of the multicenter High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial. All infants had moderate or severe HIE and were treated with whole-body TH. The primary outcome was death or neurodevelopmental impairment (NDI) at 22-36 months of age. Secondary outcomes included seizures, evidence of brain injury on magnetic resonance imaging, and complications of hypothermia. Logistic regression was used with adjustment for disease severity and site as clustering variable because cooling modality differed by site. RESULTS: Of the 500 infants who underwent TH, 294 (59%) and 206 (41%) had esophageal and rectal temperature monitoring, respectively. There were no differences in death or NDI, seizures, or evidence of injury on magnetic resonance imaging between the 2 groups. Infants treated with TH and rectal temperature monitoring had lower odds of overcooling (OR 0.52, 95% CI 0.34-0.80) and lower odds of hypotension (OR 0.57, 95% CI 0.39-0.84) compared with those with esophageal temperature monitoring. CONCLUSIONS: Although infants undergoing TH with esophageal monitoring were more likely to experience overcooling and hypotension, the rate of death or NDI was similar whether esophageal monitoring or rectal temperature monitoring was used. Further studies are needed to investigate whether esophageal temperature monitoring during TH is associated with an increased risk of overcooling and hypotension.

Description and initial validation of a novel measure of pain intensity: the Numeric Rating Scale of Underlying Pain without concurrent Analgesic use.

ABSTRACT: Although many individuals with chronic pain use analgesics, the methods used in many randomized controlled trials (RCTs) do not sufficiently account for confounding by differential post-randomization analgesic use. This may lead to underestimation of average treatment effects and diminished power. We introduce (1) a new measure-the Numeric Rating Scale of Underlying Pain without concurrent Analgesic use (NRS-UP (A) )-which can shift the estimand of interest in an RCT to target effects of a treatment on pain intensity in the hypothetical situation where analgesic use was not occurring at the time of outcome assessment; and (2) a new pain construct-an individuals' perceived effect of analgesic use on pain intensity (E A ). The NRS-UP (A) may be used as a secondary outcome in RCTs of point treatments or nonpharmacologic treatments. Among 662 adults with back pain in primary care, participants' mean value of the NRS-UP (A) among those using analgesics was 1.2 NRS points higher than their value on the conventional pain intensity NRS, reflecting a mean E A value of -1.2 NRS points and a perceived beneficial effect of analgesics. More negative values of E A (ie, greater perceived benefit) were associated with a greater number of analgesics used but not with pain intensity, analgesic type, or opioid dose. The NRS-UP (A) and E A were significantly associated with future analgesic use 6 months later, but the conventional pain NRS was not. Future research is needed to determine whether the NRS-UP (A), used as a secondary outcome may allow pain RCTs to target alternative estimands with clinical relevance.

Contemporary definitions of infant growth failure and neurodevelopmental and behavioral outcomes in extremely premature infants at two years of age.

BACKGROUND: Associations of 2-year neurodevelopmental and behavioral outcomes with growth trajectories of preterm infants are unknown. METHODS: This secondary analysis of a preterm cohort examined in-hospital and discharge to 2-year changes in anthropometric z-scores. Two-year follow-up included Bayley Scales of Infant Development (BSID-III) and Child Behavior Checklist. RESULTS: Among 590 infants, adjusted in-hospital growth was not associated with any BSID-III subscale. Occipitofrontal circumference (OFC) growth failure (GF) in-hospital was associated with increased adjusted odds of attention problems (aOR 1.65 [1.03, 2.65]), aggressive behavior (aOR 2.34 [1.12, 4.89]), and attention-deficit-hyperactivity symptoms (aOR 1.86 [1.05, 3.30]). Infants with OFC GF at 2 years had lower adjusted BSID-III language scores (-4.0 [-8.0, -0.1]), increased odds of attention problems (aOR 2.29 [1.11, 4.74]), aggressive behavior (aOR 3.09 [1.00, 9.56]), and externalizing problems (aOR 3.01 [1.07, 8.45]) compared to normal OFC growth cohort. CONCLUSION: Infants with OFC GF are at risk for neurodevelopmental and behavioral impairment. CLINICAL TRIAL REGISTRATION: This study is a secondary analysis of pre-existing data from the PENUT Trial Registration: NCT01378273.

Effectiveness of Existing Insomnia Therapies for Patients Undergoing Hemodialysis : A Randomized Clinical Trial.

BACKGROUND: Chronic insomnia is common in patients undergoing in-center hemodialysis, yet there is limited evidence on effective treatments for this population. OBJECTIVE: To compare the effectiveness of cognitive behavioral therapy for insomnia (CBT-I), trazodone, and placebo for insomnia in patients undergoing long-term hemodialysis. DESIGN: Randomized, multicenter, double-blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT03534284). SETTING: 26 dialysis units in Albuquerque, New Mexico, and Seattle, Washington. PARTICIPANTS: Patients with Insomnia Severity Index (ISI) score of 10 or greater, with sleep disturbances on 3 or more nights per week for 3 or more months. INTERVENTION: Participants were randomly assigned to 6 weeks of CBT-I, trazodone, or placebo. MEASUREMENTS: The primary outcome was the ISI score at 7 and 25 weeks from randomization. RESULTS: A total of 923 patients were prescreened, and of the 411 patients with chronic insomnia, 126 were randomly assigned to CBT-I (n = 43), trazodone (n = 42), or placebo (n = 41). The change in ISI scores from baseline to 7 weeks with CBT-I or trazodone was no different from placebo: CBT-I, -3.7 (95% CI, -5.5 to -1.9); trazodone, -4.2 (CI, -5.9 to -2.4); and placebo, -3.1 (CI, -4.9 to -1.3). There was no meaningful change in ISI scores from baseline to 25 weeks: CBT-I, -4.8 (CI, -7.0 to -2.7); trazodone, -4.0 (CI, -6.0 to -1.9); and placebo, -4.3 (CI, -6.4 to -2.2). Serious adverse events (SAEs), particularly serious cardiovascular events, were more frequent with trazodone (annualized cardiovascular SAE incidence rates: CBT-I, 0.05 [CI, 0.00 to 0.29]; trazodone, 0.64 [CI, 0.34 to 1.10]; and placebo, 0.21 [CI, 0.06 to 0.53]). LIMITATION: Modest sample size and most participants had mild or moderate insomnia. CONCLUSION: In patients undergoing hemodialysis with mild or moderate chronic insomnia, there was no difference in the effectiveness of 6 weeks of CBT-I or trazodone compared with placebo. The incidence of SAEs was higher with trazodone. PRIMARY FUNDING SOURCE: National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Platelet Transfusion and Death or Neurodevelopmental Impairment in Children Born Extremely Preterm.

Importance: Infants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes. Objective: To evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm. Design, Setting, and Participants: An observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023. Exposures: Any platelet transfusion during neonatal intensive care unit hospitalization. Main Outcomes and Measures: The primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods. Results: Of the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome. Conclusions and Relevance: The findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.

Time to regain birthweight and association with neurodevelopmental outcomes among extremely preterm newborns.

OBJECTIVE: Determine association between time to regain birthweight and 2-year neurodevelopment among extremely preterm (EP) newborns. STUDY DESIGN: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial evaluating time to regain birthweight, time from birth to weight nadir, time from nadir to regain birthweight, and cumulative weight loss with 2-year corrected Bayley Scales of Infant and Toddler Development 3rd edition. RESULTS: Among n = 654 EP neonates, those with shorter nadir-to-regain had lower cognitive scores (≤1 day versus ≥8 days: -5.0 points, [CI -9.5, -0.6]) and lower motor scores (≤1 day versus ≥8 days: -4.6 points [CI -9.2, -0.03]) in adjusted stepwise forward regression modeling. Increasingly cumulative weight loss was associated with lower cognitive scores (≤-50 percent-days: -5.6, [CI -9.4, -1.8]), motor scores (≤-50 percent-days: -4.2, [CI -8.2, -0.2]); and language scores (≤-50 percent-days: -6.0, [CI -10.1, -1.9]). CONCLUSION: Faster nadir-to-regain and excessive cumulative weight loss are associated with adverse 2-year neurodevelopmental outcomes. TRIAL REGISTRATION: PENUT Trial Registration: NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 . CLINICAL TRIAL REGISTRATION: This study is a post-hoc secondary analysis of pre-existing data from the PENUT Trial (NCT #01378273).

Evolution of the Sarnat exam and association with 2-year outcomes in infants with moderate or severe hypoxic-ischaemic encephalopathy: a secondary analysis of the HEAL Trial.

OBJECTIVE: To study the association between the Sarnat exam (SE) performed before and after therapeutic hypothermia (TH) and outcomes at 2 years in infants with moderate or severe hypoxic-ischaemic encephalopathy (HIE). DESIGN: Secondary analysis of the High-dose Erythropoietin for Asphyxia and EncephaLopathy Trial. Adjusted ORs (aORs) for death or neurodevelopmental impairment (NDI) based on SE severity category and change in category were constructed, adjusting for sedation at time of exam. Absolute SE Score and its change were compared for association with risk for death or NDI using locally estimated scatterplot smoothing curves. SETTING: Randomised, double-blinded, placebo-controlled multicentre trial including 17 centres across the USA. PATIENTS: 479/500 enrolled neonates who had both a qualifying SE (qSE) before TH and a SE after rewarming (rSE). INTERVENTIONS: Standardised SE was used across sites before and after TH. All providers underwent standardised SE training. MAIN OUTCOME MEASURES: Primary outcome was defined as the composite outcome of death or any NDI at 22-36 months. RESULTS: Both qSE and rSE were associated with the primary outcome. Notably, an aOR for primary outcome of 6.2 (95% CI 3.1 to 12.6) and 50.3 (95% CI 13.3 to 190) was seen in those with moderate and severe encephalopathy on rSE, respectively. Persistent or worsened severity on rSE was associated with higher odds for primary outcome compared with those who improved, even when qSE was severe. CONCLUSION: Both rSE and change between qSE and rSE were strongly associated with the odds of death/NDI at 22-36 months in infants with moderate or severe HIE.

Stepped collaborative care versus American College of Surgeons Committee on Trauma required screening and referral for posttraumatic stress disorder: Clinical trial protocol.

BACKGROUND: Each year in the US, approximately 1.5-2.5 million individuals are so severely injured that they require inpatient hospital admissions. The American College of Surgeons Committee on Trauma (College) now requires that trauma centers have in place protocols to identify and refer hospitalized patients at risk injury psychological sequelae. Literature review revealed no investigations that have identified optimal screening, intervention, and referral procedures in the wake of the College requirement. METHODS: The single-site pragmatic trial investigation will individually randomize 424 patients (212 intervention and 212 control) to a brief stepped care intervention versus College required mental health screening and referral control conditions. Blinded follow-up interviews at 1-, 3-, 6-, and 12-months post-injury will assess the symptoms of PTSD and related comorbidity for all patients. The emergency department information exchange (EDIE) will be used to capture population-level automated emergency department and inpatient utilization data for the intent-to-treat sample. The investigation aims to test the primary hypotheses that intervention patients will demonstrate significant reductions in PTSD symptoms and emergency department/inpatient utilization when compared to control patients. The study incorporates a Rapid Assessment Procedure-Informed Clinical Ethnography (RAPICE) implementation process assessment. CONCLUSIONS: The overarching goal of the investigation is to advance the sustainable delivery of high-quality trauma center mental health screening, intervention, and referral procedures for diverse injury survivors. An end-of-study policy summit will harness pragmatic trial data to inform the capacity for US trauma centers to implement high-quality acute care mental health screening, intervention and referral services for diverse injured patient populations. TRIAL REGISTRATION: Clinicaltrials.govNCT05632770.