Social Environment and Neurobehavioral Outcomes 1 Year After Severe Pediatric TBI in the Intensive Care Unit.

OBJECTIVE: To examine the association of home and neighborhood environment with neurobehavioral outcomes after severe pediatric traumatic brain injury (TBI). SETTING: Domestic and international children's medical centers. PARTICIPANTS: Participants enrolled in the study were 18 years or younger at the time of their severe TBI (Glasgow Coma Scale [GCS] ≤ 8), admitted to the intensive care unit, and underwent placement of an intracranial pressure (ICP) monitor. Exclusionary criteria included less severe injury (GCS > 8), pregnancy, and/or ICP monitor placement occurred at a non-participating hospital. DESIGN: A multicenter, observational cohort study. MAIN MEASURES: Outcomes assessed at 12 months post-injury included measures of global functioning, intellectual ability, caregiver-report measures of family functioning, executive functioning behaviors, behavior problems, and health-related quality of life. We examined mortality risk (assessed acutely after injury), family functioning (assessed at 12 months post-injury) and parenting practices, social environment, and neighborhood stressors (all assessed > 12 months post-injury), as correlates and moderators of the 12-month post-injury outcomes. RESULTS: Home and neighborhood factors were associated with neurobehavioral outcomes (ie, intellectual ability, executive functioning, behavioral adjustment, and health-related quality of life) but not with global functioning outcomes. A negative association between a more vulnerable home and neighborhood environment and neurobehavioral outcomes was more consistent in older children compared with younger children, based on age of injury. The influence of mortality risk on neurobehavioral outcomes was variable. CONCLUSION: Parenting practices and quality of social and neighborhood environment are associated with neurobehavioral outcomes 12 months after severe pediatric TBI. More research is needed to better understand the relationship between home/neighborhood stressors and TBI recovery to develop and implement strategies for patients and families to optimize outcomes. Future intervention development should focus on addressing parenting practices and social environment in a developmentally sensitive way for children who have sustained a severe TBI.

A New Horizon for Understanding the Comparative Effectiveness for Cooling Prospectively Infants with Mild Encephalopathy.

The authors summarize the methodology for a new pragmatic comparative effectiveness research investigation, Cooling Prospectively Infants with Mild Encephalopathy (COOLPRIME), which uses sites' existing mild hypoxic-ischemic encephalopathy (HIE) treatment preference (hypothermia or normothermia) to assess hypothermia effectiveness and safety. COOLPRIME's primary aim is to determine the safety and effectiveness of hypothermia compared to normothermia in mild HIE. Engagement of Families and Community Affected by Hypoxic-Ischemic Encephalopathy strongly favored Effectiveness over Efficacy Trials leading to COOL PRIME design.

Development and validation of a stakeholder-driven, self-contained electronic informed consent platform for trio-based genomic research studies.

Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant comprehension and satisfaction with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy. iConsent development incorporated stakeholder perspectives including researchers, patient advocates, institutional review board members, and genomic data-sharing considerations. The iConsent platform integrated principles derived from prior electronic consenting research and elements of multimedia learning theory. Participant comprehension was assessed in an interactive teachback format. The iConsent application achieved nine of ten proposed desiderata for effective patient-focused electronic consenting for genomic research. Overall, participants demonstrated high comprehension and retention of key human subjects' considerations. Enrollees reported high levels of satisfaction with the iConsent, and we found that participant comprehension, iConsent clarity, privacy protections, and study goal explanations were associated with overall satisfaction. Although opportunities exist to optimize iConsent, we show that such an approach is feasible, can satisfy multiple stakeholder requirements, and can realize high participant satisfaction and comprehension while increasing study reach.

Early GFAP and UCH-L1 point-of-care biomarker measurements for the prediction of traumatic brain injury and progression in patients with polytrauma and hemorrhagic shock.

OBJECTIVE: Traumatic brain injury (TBI) and hemorrhage are responsible for the largest proportion of all trauma-related deaths. In polytrauma patients at risk of hemorrhage and TBI, the diagnosis, prognosis, and management of TBI remain poorly characterized. The authors sought to characterize the predictive capabilities of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase L1 (UCH-L1) measurements in patients with hemorrhagic shock with and without concomitant TBI. METHODS: The authors performed a secondary analysis on serial blood samples derived from a prospective observational cohort study that focused on comparing early whole-blood and component resuscitation. A convenience sample of patients was used in which samples were collected at three time points and the presence of TBI or no TBI via CT imaging was documented. GFAP and UCH-L1 measurements were performed on plasma samples using the i-STAT Alinity point-of-care platform. Using classification tree recursive partitioning, the authors determined the measurement cut points for each biomarker to maximize the abilities for predicting the diagnosis of TBI, Rotterdam CT imaging scores, and 6-month Glasgow Outcome Scale-Extended (GOSE) scores. RESULTS: Biomarker comparisons demonstrated that GFAP and UCH-L1 measurements were associated with the presence of TBI at all time points. Classification tree analyses demonstrated that a GFAP level > 286 pg/ml for the sample taken upon the patient's arrival had an area under the receiver operating characteristic curve of 0.77 for predicting the presence of TBI. The classification tree results demonstrated that a cut point of 3094 pg/ml for the arrival GFAP measurement was the most predictive for an elevated Rotterdam score on the initial and second CT scans and for TBI progression between scans. No significant associations between any of the most predictive cut points for UCH-L1 and Rotterdam CT scores or TBI progression were found. The predictive capabilities of UCH-L1 were limited by the range allowed by the point-of-care platform. Arrival GFAP cut points remained strong independent predictors after controlling for all potential polytrauma confounders, including injury characteristics, shock severity, and resuscitation. CONCLUSIONS: Early measurements of GFAP and UCH-L1 on a point-of-care device are significantly associated with CT-diagnosed TBI in patients with polytrauma and shock. Early elevated GFAP measurements are associated with worse head CT scan Rotterdam scores, TBI progression, and worse GOSE scores, and these associations are independent of other injury attributes, shock severity, and early resuscitation characteristics.

Understanding the Added Value of High-Resolution CT Beyond Chest X-ray in Determining Extent of Physiologic Impairment.

BACKGROUND: Sarcoidosis staging primarily has relied on the Scadding chest radiographic system, although chest CT imaging is finding increased clinical use. RESEARCH QUESTION: Whether standardized chest CT scan assessment provides additional understanding of lung function beyond Scadding stage and demographics is unknown and the focus of this study. STUDY DESIGN AND METHODS: We used National Heart, Lung, and Blood Institute study Genomics Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) cases of sarcoidosis (n = 351) with Scadding stage and chest CT scans obtained in a standardized manner. One chest radiologist scored all CT scans with a visual scoring system, with a subset read by another chest radiologist. We compared demographic features, Scadding stage and CT scan findings, and the correlation between these measures. Associations between spirometry and diffusing capacity of the lungs for carbon monoxide (Dlco) results and CT scan findings and Scadding stage were determined using regression analysis (n = 318). Agreement between readers was evaluated using Cohen's κ value. RESULTS: CT scan features were inconsistent with Scadding stage in approximately 40% of cases. Most CT scan features assessed on visual scoring were associated negatively with lung function. Associations persisted for FEV1 and Dlco when adjusting for Scadding stage, although some CT scan feature associations with FVC became insignificant. Scadding stage was associated primarily with FEV1, and inclusion of CT scan features reduced significance in association between Scadding stage and lung function. Multivariable regression modeling to identify radiologic measures explaining lung function included Scadding stage for FEV1 and FEV1 to FVC ratio (P < .05) and marginally for Dlco (P < .15). Combinations of CT scan measures accounted for Scadding stage for FVC. Correlations among Scadding stage and CT scan features were noted. Agreement between readers was poor to moderate for presence or absence of CT scan features and poor for degree and location of abnormality. INTERPRETATION: In this study, CT scan features explained additional variability in lung function beyond Scadding stage, with some CT scan features obviating the associations between lung function and Scadding stage. Whether CT scan features, phenotypes, or endotypes could be useful for treating patients with sarcoidosis needs more study.

Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial.

OBJECTIVE: To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared with standard care resuscitation in patients with hemorrhagic shock. BACKGROUND: Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury. METHODS: A phase 2, multicenter, randomized, open label, clinical trial was performed at 5 US trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days versus standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality. RESULTS: Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared with 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P =0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups. CONCLUSIONS AND RELEVANCE: In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04667468.

Effects of inpatient rehabilitation after acute care on motor, neuropsychological and behavioral outcomes in children with severe traumatic brain injury.

PURPOSE: An observational study of children with severe traumatic brain injury (TBI) (Approaches and Decisions in Acute Pediatric TBI [ADAPT] Trial) demonstrated the benefits of inpatient rehabilitation on functional outcomes for those with more severely impaired consciousness when medically stable. We conducted a secondary analysis to assess whether using an inpatient rehabilitation or skilled nursing facility after acute hospitalization was associated with better motor, neuropsychological, and behavioral outcomes compared to receiving only non-inpatient rehabilitation among children with severe TBI. MATERIALS AND METHODS: We included 180 children who used an inpatient rehabilitation or skilled nursing facility and 74 children who only received non-inpatient rehabilitation from the ADAPT trial. At 12 months post-injury, children underwent tests of motor skills, intellectual functioning, verbal learning, memory, processing speed, and cognitive flexibility. Parents/guardians rated children's executive function and behaviors. We performed inverse probability weighting to adjust for potential confounders. RESULTS: No significant differences were found in any motor, neuropsychological, or behavioral measures between children receiving inpatient rehabilitation and children receiving only non-inpatient rehabilitation. CONCLUSIONS: Analyses of comprehensive outcomes did not show differences between children receiving inpatient rehabilitation and children receiving only non-inpatient rehabilitation, suggesting a need for more research on specific components of the rehabilitation process.

Our study showed no differences in motor, neuropsychological, or behavioral outcomes at 12 months after severe traumatic brain injury (TBI) between children using an inpatient rehabilitation or skilled nursing facility and children receiving only non-inpatient rehabilitation after acute hospitalization.Children surviving severe TBI should be evaluated for the need of inpatient and outpatient rehabilitation therapies at discharge from an acute care hospital.Children with rehabilitation requirements after severe TBI should be followed up periodically to ensure the continuity of care and reduce the gaps to the needed rehabilitation therapies.

Association Between Emergency Medical Service Agency Volume and Mortality in Trauma Patients.

OBJECTIVE: The aim of this study was to evaluate the association of annual trauma patient volume on outcomes for emergency medical services (EMS) agencies. BACKGROUND: Regionalization of trauma care saves lives. The underlying concept driving this is a volume-outcome relationship. EMS are the entry point to the trauma system, yet it is unknown if a volume-outcome relationship exists for EMS. METHODS: A retrospective analysis of prospective cohort including 8 trauma centers and 20 EMS air medical and metropolitan ground transport agencies. Patients 18 to 90 years old with injury severity scores ≥9 transported from the scene were included. Patient and agency-level risk-adjusted regression determined the association between EMS agency trauma patient volume and early mortality. RESULTS: A total of 33,511 were included with a median EMS agency volume of 374 patients annually (interquartile range: 90-580). Each 50-patient increase in EMS agency volume was associated with 5% decreased odds of 6-hour mortality (adjusted odds ratio=0.95; 95% CI: 0.92-0.99, P =0.03) and 3% decreased odds of 24-hour mortality (adjusted odds ratio=0.97; 95% CI: 0.95-0.99, P =0.04). Prespecified subgroup analysis showed EMS agency volume was associated with reduced odds of mortality for patients with prehospital shock, requiring prehospital airway placement, undergoing air medical transport, and those with traumatic brain injury. Agency-level analysis demonstrated that high-volume (>374 patients/year) EMS agencies had a significantly lower risk-standardized 6-hour mortality rate than low-volume (<374 patients/year) EMS agencies (1.9% vs 4.8%, P <0.01). CONCLUSIONS: A higher volume of trauma patients transported at the EMS agency level is associated with improved early mortality. Further investigation of this volume-outcome relationship is necessary to leverage quality improvement, benchmarking, and educational initiatives.

Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life.

BACKGROUND: Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear. RESEARCH QUESTION: In the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days? STUDY DESIGN AND METHODS: This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed. RESULTS: Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR [aOR], 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96). INTERPRETATION: In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04505774; URL: www. CLINICALTRIALS: gov.

Prehospital Time Following Traumatic Injury Is Independently Associated With the Need for In-Hospital Blood and Early Mortality for Specific Injury Types.

OBJECTIVE: Treating traumatic hemorrhage is time sensitive. Prehospital care and transport modes (eg, helicopter and ground) may influence in-hospital events. We hypothesized that prehospital time (on-scene time [OST] and total prehospital time [TPT]) and transport mode are associated with same-day transfusion and mortality. Furthermore, we sought to identify regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. METHODS: We obtained prehospital, in-hospital, and trauma registry data from an 8-center cohort of adult nonburn trauma patients from 2017 to 2022 directly transported from the scene to the hospital and having an Injury Severity Score (ISS) > 9 for the Task Order 1 project of the Linking Investigators in Trauma and Emergency Services research network. We excluded patients missing prehospital times, patients < 18 years of age, patients from interfacility transfers, and recipients of prehospital blood. Our same-day outcomes were in-hospital transfusions within 4 hours and 24-hour mortality. Each outcome was adjusted using multivariable logistic regression for covariates of prehospital phases (OST and TPT), mode of transport (helicopter and ground), age, sex, ISS, Glasgow Coma Scale motor subscale score < 6, and field hypotension (systolic blood pressure < 90 mm Hg). We evaluated the association of prehospital time on outcomes for scene missions by transport mode across severe injury patterns defined by Abbreviated Injury Scale > 2 body regions. RESULTS: Of 78,198 subjects, 34,504 were eligible for the study with a mean age of 47.6 ± 20.3 years, ISS of 18 ± 11, OST of 15.9 ± 9.5 minutes, and TPT of 48.7 ± 20.3 minutes. Adjusted for injury severity and demographic factors, transport type significantly modified the relationship between prehospital time and outcomes. The association of OST and TPT with the odds of 4-hour transfusion was absent for the ground emergency medical services (GEMS) cohort and present for the helicopter emergency medical services (HEMS) ambulance cohort, whereas these times were associated with decreased 24-hour mortality for both transport types. When stratifying by injury to most anatomic regions, OST and TPT were associated with a decreased need for 4-hour transfusions in the GEMS cohort. However, OST was associated with increased early transfusion only among patients with severe injuries of the thorax, and this association persisted after adjusting additionally for injury type (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.00-1.05; P = .02). The presence of polytrauma supported an association between prehospital time and decreased 24-hour mortality for the GEMS cohort (OST: OR = 0.97; 95% CI, 0.95-0.99; P < .01; TPT: OR = 0.99; 95% CI, 0.98-0.99; P = .02), whereas no injuries showed significant association of helicopter prehospital time on mortality after adjustment. CONCLUSION: We determined that transport type affects the relationship between prehospital time and hospital outcomes (4-hour transfusion: positive relationship for HEMS and negative for GEMS, 24-hour mortality: negative for both transport types). Furthermore, we identified regions of anatomic injury that modify the relationship between prehospital time and outcomes in strata corresponding to transport types. Of these regions, most notable were severe isolated injuries to the thorax that supported a positive relationship between HEMS OST and 4-hour transfusions and polytrauma that showed a negative relationship between GEMS OST or TPT and 24-hour mortality after adjustment.

Lifestyle Intervention and Excess Weight in Chronic Obstructive Pulmonary Disease (COPD): INSIGHT COPD Randomized Clinical Trial.

Rationale: Being overweight or obese is common among patients with chronic obstructive pulmonary disease (COPD), but whether interventions targeted at weight loss improve functional impairments is unknown. Objectives: INSIGHT (Intervention Study in Overweight Patients with COPD) tested whether a pragmatic low-intensity lifestyle intervention would lead to better physical functional status among overweight or obese participants with COPD. Methods: The trial was a 12-month, multicenter, patient-level pragmatic clinical trial. Participants were recruited from April 2017 to August 2019 from 38 sites across the United States and randomized to receive usual care or usual care plus lifestyle intervention. The intervention was a self-directed video program delivering the Diabetes Prevention Program's Group Lifestyle Balance curriculum. Results: The primary outcome was 6-minute-walk test distance at 12 months. Priority secondary outcomes were postwalk modified Borg dyspnea at 12 months and weight at 12 months. Participants (N = 684; mean age, 67.0 ± 8.0 yr [standard deviation]; 41.2% female) on average were obese (body mass index, 33.0 ± 4.6 kg/m2) with moderate COPD (forced expiratory volume in 1 second % predicted, 58.1 ± 15.7%). At 12 months, participants randomized to the intervention arm walked farther (adjusted difference, 42.3 ft [95% confidence interval (CI), 7.9-76.7 ft]; P = 0.02), had less dyspnea at the end of the 6-minute-walk test (adjusted difference, -0.36 [95% CI, -0.63 to -0.09]; P = 0.008), and had greater weight loss (adjusted difference, -1.34 kg [95% CI, -2.33 to -0.34 kg]; P = 0.008) than control participants. The intervention did not improve the odds of achieving clinically meaningful thresholds of walk distance (98.4 ft) or dyspnea (1 unit) but did achieve meaningful thresholds of weight loss (3% and 5%). Conclusions: Among participants with COPD who were overweight or obese, a self-guided low-intensity video-based lifestyle intervention led to modest weight loss but did not lead to clinically important improvements in physical functional status and dyspnea. Clinical trial registered with www.clinicaltrials.gov (NCT02634268).

The Geography of Injuries in Trauma Systems: Using Home as a Proxy for Incident Location.

INTRODUCTION: Effective trauma system organization is crucial to timely access to care and requires accurate understanding of injury and resource locations. Many systems rely on home zip codes to evaluate geographic distribution of injury; however, few studies have evaluated the reliability of home as a proxy for incident location after injury. METHODS: We analyzed data from a multicenter prospective cohort collected from 2017 to 2021. Injured patients with both home and incident zip codes were included. Outcomes included discordance and differential distance between home and incident zip code. Associations of discordance with patient characteristics were determined by logistic regression. We also assessed trauma center catchment areas based on home versus incident zip codes and variation regionally at each center. RESULTS: Fifty thousand one hundred seventy-five patients were included in the analysis. Home and incident zip codes were discordant in 21,635 patients (43.1%). Injuries related to motor vehicles (aOR: 4.76 [95% CI 4.50-5.04]) and younger adults 16-64 (aOR: 2.46 [95% CI 2.28-2.65]) were most likely to be discordant. Additionally, as injury severity score increased, discordance increased. Trauma center catchment area differed up to two-thirds of zip codes when using home versus incident location. Discordance rate, discordant distance, and catchment area overlap between home and incident zip codes all varied significantly by geographic region. CONCLUSIONS: Home location as proxy for injury location should be used with caution and may impact trauma system planning and policy, especially in certain populations. More accurate geolocation data are warranted to further optimize trauma system design.

Whole Blood Resuscitation and Association with Survival in Injured Patients with an Elevated Probability of Mortality.

BACKGROUND: Low-titer group O whole blood (LTOWB) resuscitation is becoming common in both military and civilian settings and may represent the ideal resuscitation intervention. We sought to characterize the safety and efficacy of LTOWB resuscitation relative to blood component resuscitation. STUDY DESIGN: A prospective, multicenter, observational cohort study was performed using 7 trauma centers. Injured patients at risk of massive transfusion who required both blood transfusion and hemorrhage control procedures were enrolled. The primary outcome was 4-hour mortality. Secondary outcomes included 24-hour and 28-day mortality, achievement of hemostasis, death from exsanguination, and the incidence of unexpected survivors. RESULTS: A total of 1,051 patients in hemorrhagic shock met all enrollment criteria. The cohort was severely injured with >70% of patients requiring massive transfusion. After propensity adjustment, no significant 4-hour mortality difference across LTOWB and component patients was found (relative risk [RR] 0.90, 95% CI 0.59 to 1.39, p = 0.64). Similarly, no adjusted mortality differences were demonstrated at 24 hours or 28 days for the enrolled cohort. When patients with an elevated prehospital probability of mortality were analyzed, LTOWB resuscitation was independently associated with a 48% lower risk of 4-hour mortality (relative risk [RR] 0.52, 95% CI 0.32 to 0.87, p = 0.01) and a 30% lower risk of 28-day mortality (RR 0.70, 95% CI 0.51 to 0.96, p = 0.03). CONCLUSIONS: Early LTOWB resuscitation is safe but not independently associated with survival for the overall enrolled population. When patients were selected with an elevated probability of mortality based on prehospital injury characteristics, LTOWB was independently associated with a lower risk of mortality starting at 4 hours after arrival through 28 days after injury.

A data-driven approach finds RNA polymerase III antibody and tendon friction rubs as enrichment tools for early diffuse scleroderma trials.

OBJECTIVE: Clinical trials in early diffuse SSc have consistently shown a placebo group response with a declining modified Rodnan skin score (mRSS), with negative outcomes. Our objective was to identify strategies using clinical characteristics or laboratory values to improve trial design. METHODS: We identified early diffuse SSc patients first seen at the University of Pittsburgh from 1980-2015. Eligible patients had ≥3 visits, with at least two mRSS scores within the first year of follow-up. We performed Kaplan-Meier analyses, group-based trajectory analysis of mRSS scores, followed by multivariable regression analysis and classification tree analysis. We applied the results to the abatacept in early diffuse systemic sclerosis (ASSET) trial outcome data. RESULTS: We identified 403 patients with <18 months, and 514 with <36 months disease duration. The median number of mRSS follow-up scores was 14 (interquartile range 8, 25). All methodologic approaches identified skin thickness progression rate, RNA polymerase III (RNAP3) antibody positivity and presence of tendon friction rubs (TFR) as predictors of mRSS trajectory over 5 years of follow-up, and thereby as potential enrichment variables. When applied to the ASSET data, adjustment for both RNAP3 and TFR demonstrated reduction of the placebo mRSS response, particularly at 6 months. A significant difference in the ACR Composite Response Index in Systemic Sclerosis (CRISS) score was found with adjustment by RNAP3 at 6 months, and TFR or RNAP3 at 12 months. CONCLUSION: Adjustment for both RNAP3 and TFR predicts mRSS trajectory and diminished the mRSS decline in ASSET placebo group, and identified significant differences in CRISS. RNAP3, particularly, is a stratification or enrichment approach to improve early diffuse SSc trial design.

The association between sleep-disordered breathing and maternal endothelial and metabolic markers in pregnancies complicated by obesity.

STUDY OBJECTIVES: To evaluate the impact of sleep-disordered breathing (SDB) on vascular, angiogenic and metabolic analytes in pregnancy. METHODS: Participants with a body mass index ≥30 kg/m2 underwent polysomnography at 14-20 weeks gestation (visit 1). Participants with SDB (defined as an apnea-hypopnea index ≥5 events/h) were then enrolled in a separate trial. SDB-negative participants returned for a polysomnogram at 28-31 weeks (visit 2) and were recategorized as persistent-negative SDB or new-onset SDB. Mean arterial blood pressure, mean uterine artery Doppler pulsatility index, endoglin, soluble Feline McDonough Sarcoma-like tyrosine kinase 1, placental growth factor, and the homeostatic model assessment for insulin resistance were measured after each visit. Our primary outcome was a composite of uterine artery Doppler pulsatility index, soluble FMS-like tyrosine kinase 1/placental growth factor ratio, and homeostatic model assessment for insulin resistance. For secondary analyses, each outcome variable was analyzed independently. RESULTS: A total of 242 and 130 participants completed visit 1 and visit 2, respectively. Newly diagnosed SDB was present in 37% of individuals at visit 1 and 31% of individuals at visit 2. No significant differences in our composite outcome vector were observed in individuals with and without SDB at either visit. In our secondary analysis, mean arterial blood pressure (88.7 ± 7.3 mm Hg vs 85.4 ± 7.1 mm Hg, P = .04) and fasting glucose (92.4 ± 15.2 mg/dL vs 86.6 ± 11.5 mg/dL, P = .05) were higher in participants with early pregnancy SDB. These associations were not observed for new-onset SDB. No associations were observed between uterine artery Doppler pulsatility index and angiogenic markers and SDB in pregnancy. CONCLUSIONS: SDB in early pregnancy was not associated with our composite primary outcome but was associated with higher mean arterial blood pressure and fasting glucose. The pathophysiologic changes that occur in pregnant individuals with SDB and how they lead to an increased risk of preeclampsia and gestational diabetes remain poorly understood. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Sleep Disordered Breathing, Obesity and Pregnancy Study (SOAP); URL: https://clinicaltrials.gov/ct2/show/NCT02086448; Identifier: NCT02086448. CITATION: Onslow ML, Wolsk J, Wisniewski S, et al. The association between sleep-disordered breathing and maternal endothelial and metabolic markers in pregnancies complicated by obesity. J Clin Sleep Med. 2023;19(1):97-109.

Incidence and visual outcomes of acute endophthalmitis post intravitreal injection of anti-vascular endothelial growth factors in a single referral center.

BACKGROUND: To describe the incidence and factors predicting visual outcome in patients with infectious endophthalmitis following intravitreal anti-VEGF injection. METHODS: Retrospective, single-site, cohort study. Patients with acute endophthalmitis within 6 weeks of intravitreal anti-VEGF injection who were referred to our practice after inciting injection or were injected by us between January 2010 and July 2017 were included. All patients received intravitreal antibiotics with either vitreous/anterior chamber tap (TAP) or pars plana vitrectomy. Visual outcomes pre/post treatment, baseline variables (age, gender, ocular disease) and cultures results were studied. RESULTS: Seventy eyes of 69 patients were included. Presenting VA was the strongest factor associated with final visual outcome after adjusting for other variables including culture status and baseline VA (p = .0002). Cultures were positive in 62.8% of eyes and were associated with worse visual outcome (p = .0087). Growth of Streptococcus or microorganisms other than coagulase negative Staphylococci (CNS) was also associated with worse prognosis, regardless of baseline and presenting VA (p = .0002). The crude incidence of post-injection endophthalmitis was 0.028% in our practice (40 eyes in 143,628 injections) during the study time. No significant difference was found between pre-filled bevacizumab versus ranibizumab or aflibercept drawn from a vial. CONCLUSIONS: In a large, single center, retrospective study, the incidence of acute endophthalmitis post anti-VEGF injection was relatively low. Worse visual acuity at presentation of endophthalmitis and growth of Streptococcus or organisms other than CNS were associated with the worst visual outcomes.

Blood component ratios in children with non-traumatic life-threatening bleeding.

BACKGROUND AND OBJECTIVES: In paediatric trauma patients, there are limited prospective data regarding blood components and mortality, with some literature suggesting decreased mortality with high ratios of plasma and platelets to red blood cells (RBCs) in massive transfusions; however, most paediatric massive transfusions occur for non-traumatic aetiologies and few studies assess blood product ratios in these children. This study's objective was to evaluate whether high blood product ratios or low deficits conferred a survival benefit in children with non-traumatic life-threatening bleeding. MATERIALS AND METHODS: This is a secondary analysis of the five-year, multicentre, prospective, observational massive transfusion epidemiology and outcomes in children study of children with life-threatening bleeding from US, Canadian and Italian medical centres. Primary interventions were plasma:RBC and platelets:RBC (high ratio ≥1:2 ml/kg) and plasma and platelet deficits. The primary outcome was mortality at 6 h, 24 h and 28 days. Multivariate logistic regression models were used to determine independent associations with mortality. RESULTS: A total of 222 children were included from 24 medical centres: 145 children (median [interquartile range] age 2.1 years [0.3-11.8]) with operative bleeding and 77 (8.0 years [1.2-14.7]) with medical bleeding. In adjusted analyses, neither blood product ratios nor deficits were associated with mortality at 6 h, 24 h or 28 days. CONCLUSION: This paper addresses a lack of prospective data in children regarding optimal empiric massive transfusion strategies in non-traumatic massive haemorrhage and in finding no decrease in mortality with high plasma or platelet to RBC ratios or lower deficits supports an exploratory analysis for mortality.

A trial of positive airway pressure for the treatment of sleep apnea in pregnancy.

BACKGROUND: The pathophysiology of obstructive sleep apnea in pregnancy remains poorly understood and studies examining the effect of treatment with positive airway pressure on pregnancy have been limited. OBJECTIVE: This study aimed to perform a randomized controlled trial of positive airway pressure treatment for obstructive sleep apnea in pregnancy. STUDY DESIGN: Participants with a body mass index ≥30 kg/m2 underwent polysomnography at 14 to 20 weeks' gestation (visit 1) and those with obstructive sleep apnea (apnea-hypopnea index ≥5 but <50) were enrolled. In phase 1, participants were randomized to autotitrating positive airway pressure vs sham positive airway pressure; in phase 2, the sham arm was replaced with a sleep hygiene control. Participants returned at 28 to 31 weeks' gestation (visit 2). The mean arterial blood pressure, uterine artery Doppler pulsatility index, endoglin, soluble FMS-like tyrosine kinase 1 levels, and placental growth factor levels were measured, as well as fasting glucose and insulin to calculate insulin resistance (homeostatic model assessment for insulin resistance). The primary outcome was a composite of the uterine artery Doppler pulsatility index, soluble FMS-like tyrosine kinase 1 to placental growth factor ratio, and the homeostatic model assessment for insulin resistance. For secondary analyses, each outcome variable was analyzed independently. Adherence to treatment was examined. RESULTS: A total of 241 participants completed visit 1, and 89 (37%) had an apnea-hypopnea index between 5 and 50. Of the those, 51 participants were randomized in phase 1 and 38 in phase 2. There was no significant difference in our primary outcome by treatment group. In secondary analyses, the uterine artery Doppler pulsatility index was lower in participants on autotitrating positive airway pressure when compared with sleep hygiene controls. Otherwise, there were no differences in the mean arterial blood pressure, angiogenic markers, or metabolic markers in phase 1, phase 2, or across the entire study. The overall adherence to autotitrating positive airway pressure therapy was low, but the mean use was greater in phase 2 (0.3±0.6 hours/night vs 1.3±2.3 hours/night; P=.10). For those on active therapy, fasting glucose values decreased as adherence increased. CONCLUSION: This randomized controlled trial of autotitrating positive airway pressure in pregnancy did not find any differences in a composite primary cardiometabolic risk profile between the treatment groups. Higher autotitrating positive airway pressure adherence was associated with lower fasting glucose levels. The use of a sham positive airway pressure control arm in phase1 may have negatively impacted adherence to active treatment.

Bronchodilators in Tobacco-Exposed Persons with Symptoms and Preserved Lung Function.

BACKGROUND: Many persons with a history of smoking tobacco have clinically significant respiratory symptoms despite an absence of airflow obstruction as assessed by spirometry. They are often treated with medications for chronic obstructive pulmonary disease (COPD), but supporting evidence for this treatment is lacking. METHODS: We randomly assigned persons who had a tobacco-smoking history of at least 10 pack-years, respiratory symptoms as defined by a COPD Assessment Test score of at least 10 (scores range from 0 to 40, with higher scores indicating worse symptoms), and preserved lung function on spirometry (ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity [FVC] ≥0.70 and FVC ≥70% of the predicted value after bronchodilator use) to receive either indacaterol (27.5 µg) plus glycopyrrolate (15.6 µg) or placebo twice daily for 12 weeks. The primary outcome was at least a 4-point decrease (i.e., improvement) in the St. George's Respiratory Questionnaire (SGRQ) score (scores range from 0 to 100, with higher scores indicating worse health status) after 12 weeks without treatment failure (defined as an increase in lower respiratory symptoms treated with a long-acting inhaled bronchodilator, glucocorticoid, or antibiotic agent). RESULTS: A total of 535 participants underwent randomization. In the modified intention-to-treat population (471 participants), 128 of 227 participants (56.4%) in the treatment group and 144 of 244 (59.0%) in the placebo group had at least a 4-point decrease in the SGRQ score (difference, -2.6 percentage points; 95% confidence interval [CI], -11.6 to 6.3; adjusted odds ratio, 0.91; 95% CI, 0.60 to 1.37; P = 0.65). The mean change in the percent of predicted FEV1 was 2.48 percentage points (95% CI, 1.49 to 3.47) in the treatment group and -0.09 percentage points (95% CI, -1.06 to 0.89) in the placebo group, and the mean change in the inspiratory capacity was 0.12 liters (95% CI, 0.07 to 0.18) in the treatment group and 0.02 liters (95% CI, -0.03 to 0.08) in the placebo group. Four serious adverse events occurred in the treatment group, and 11 occurred in the placebo group; none were deemed potentially related to the treatment or placebo. CONCLUSIONS: Inhaled dual bronchodilator therapy did not decrease respiratory symptoms in symptomatic, tobacco-exposed persons with preserved lung function as assessed by spirometry. (Funded by the National Heart, Lung, and Blood Institute and others; RETHINC ClinicalTrials.gov number, NCT02867761.).