Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial.

BACKGROUND: COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19. METHODS: An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry. RESULTS: The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio <1.2) of 98% and a posterior probability of inferiority (odds ratio <1.0) of 91%. Overall, there were 37 deaths (17.5%) in the crizanlizumab arm and 27 deaths (12.8%) in the standard-of-care arm (hazard ratio, 1.33 [95% CrI, 0.85-2.21]; [probability of hazard ratio>1] = 0.879). CONCLUSIONS: Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04505774.

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.

Use of Antifibrinolytics in Pediatric Life-Threatening Hemorrhage: A Prospective Observational Multicenter Study.

OBJECTIVES: To assess the impact of antifibrinolytics in children with life-threatening hemorrhage. DESIGN: Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four children's hospitals in the United States, Canada, and Italy. PATIENTS: Children 0-17 years old who received greater than 40 mL/kg of total blood products over 6 hours or were transfused under activation of massive transfusion protocol. INTERVENTION/EXPOSURE: Children were compared according to receipt of antifibrinolytic medication (tranexamic acid or aminocaproic acid) during the bleeding event. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, medications administered, and clinical outcomes were analyzed using Cox proportional hazard and Kaplan-Meier survival analysis. The primary outcome was 24-hour mortality. Of 449 patients analyzed, median age was 7 years (2-15 yr), and 55% were male. The etiology of bleeding was 46% traumatic, 34% operative, and 20% medical. Twelve percent received antifibrinolytic medication during the bleeding event (n = 54 unique subjects; n = 18 epsilon aminocaproic acid, n = 35 tranexamic acid, and n = 1 both). The antifibrinolytic group was comparable with the nonantifibrinolytic group on baseline demographic and physiologic parameters; the antifibrinolytic group had longer massive transfusion protocol duration, received greater volume blood products, and received factor VII more frequently. In the antifibrinolytic group, there was significantly less 6-hour mortality overall (6% vs 17%; p = 0.04) and less 6-hour mortality due to hemorrhage (4% vs 14%; p = 0.04). After adjusting for age, bleeding etiology, Pediatric Risk of Mortality score, and plasma deficit, the antifibrinolytic group had decreased mortality at 6- and 24-hour postbleed (adjusted odds ratio, 0.29 [95% CI, 0.09-0.93]; p = 0.04 and adjusted odds ratio, 0.45 [95% CI, 0.21-0.98]; p = 0.04, respectively). CONCLUSIONS: Administration of antifibrinolytic medications during the life-threatening event was independently associated with improved 6- and 24-hour survivals in bleeding children. Consideration should be given to use of antifibrinolytics in pediatric patients with life-threatening hemorrhage.

Transfusion Ratios and Deficits in Injured Children With Life-Threatening Bleeding.

OBJECTIVES: To assess the impact of plasma and platelet ratios and deficits in injured children with life-threatening bleeding. DESIGN: Secondary analysis of the MAssive Transfusion epidemiology and outcomes In Children study dataset, a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy. PATIENTS: Injured children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under activation of massive transfusion protocol. INTERVENTION/EXPOSURE: Weight-adjusted blood product volumes received during the bleeding event were recorded. Plasma:RBC ratio (plasma/RBC weight-adjusted volume in mL/kg) and platelet:RBC ratio (platelet/RBC weight-adjusted volume in mL/kg) were analyzed. Plasma deficit was calculated as RBC mL/kg - plasma mL/kg; platelet deficit was calculated as RBC mL/kg - platelet mL/kg. MEASUREMENTS AND MAIN RESULTS: Of 191 patients analyzed, median (interquartile range) age was 10 years (5-15 yr), 61% were male, 61% blunt mechanism, and median (interquartile range) Injury Severity Score was 29 (24-38). After adjusting for Pediatric Risk of Mortality score, cardiac arrest, use of vasoactive medications, and blunt mechanism, a high plasma:RBC ratio (> 1:2) was associated with improved 6-hour survival compared with a low plasma:RBC ratio (odds ratio [95% CI] = 0.12 [0.03-0.52]; p = 0.004). Platelet:RBC ratio was not associated with survival. After adjusting for age, Pediatric Risk of Mortality score, cardiac arrest, and mechanism of injury, 6-hour and 24-hour mortality were increased in children with greater plasma deficits (10% and 20% increased odds of mortality for every 10 mL/kg plasma deficit at 6 hr [p = 0.04] and 24 hr [p = 0.01], respectively); 24-hour mortality was increased in children with greater platelet deficits (10% increased odds of 24-hr mortality for every 10 mL/kg platelet deficit [p = 0.02)]). CONCLUSIONS: In injured children, balanced resuscitation may improve early survival according to this hypothesis generating study. Multicenter clinical trials are needed to assess whether clinicians should target ratios and deficits as optimal pediatric hemostatic resuscitation practice.

Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial.

Importance: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19. Objective: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021. Interventions: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = 293) or a therapeutic dose of heparin only (usual care) (n = 269) in a 1:1 ratio for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The composite primary outcome was organ support-free days evaluated on an ordinal scale that combined in-hospital death (assigned a value of -1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, -1 to 21 days; higher scores indicate less organ support and better outcomes). The primary safety outcome was major bleeding by 28 days as defined by the International Society on Thrombosis and Hemostasis. Results: Enrollment of non-critically ill patients was discontinued when the prespecified criterion for futility was met. All 562 patients who were randomized (mean age, 52.7 [SD, 13.5] years; 41.5% women) completed the trial and 87% received a therapeutic dose of heparin by the end of study day 1. In the P2Y12 inhibitor group, ticagrelor was used in 63% of patients and clopidogrel in 37%. The median number of organ support-free days was 21 days (IQR, 20-21 days) among patients in the P2Y12 inhibitor group and was 21 days (IQR, 21-21 days) in the usual care group (adjusted odds ratio, 0.83 [95% credible interval, 0.55-1.25]; posterior probability of futility [defined as an odds ratio <1.2], 96%). Major bleeding occurred in 6 patients (2.0%) in the P2Y12 inhibitor group and in 2 patients (0.7%) in the usual care group (adjusted odds ratio, 3.31 [95% CI, 0.64-17.2]; P = .15). Conclusions and Relevance: Among non-critically ill patients hospitalized for COVID-19, the use of a P2Y12 inhibitor in addition to a therapeutic dose of heparin, compared with a therapeutic dose of heparin only, did not result in an increased odds of improvement in organ support-free days within 21 days during hospitalization. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Life-Threatening Bleeding in Children: A Prospective Observational Study.

OBJECTIVES: The purpose of our study was to describe children with life-threatening bleeding. DESIGN: We conducted a prospective observational study of children with life-threatening bleeding events. SETTING: Twenty-four childrens hospitals in the United States, Canada, and Italy participated. SUBJECTS: Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included. INTERVENTIONS: Children were compared according bleeding etiology: trauma, operative, or medical. MEASUREMENTS AND MAIN RESULTS: Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours. CONCLUSIONS: Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.

Age and Mortality in Pediatric Severe Traumatic Brain Injury: Results from an International Study.

BACKGROUND: Although small series have suggested that younger age is associated with less favorable outcome after severe traumatic brain injury (TBI), confounders and biases have limited our understanding of this relationship. We hypothesized that there would be an association between age and mortality in children within an ongoing observational, cohort study. METHODS: The first 200 subjects from the Approaches and Decisions for Acute Pediatric TBI trial were eligible for this analysis (inclusion criteria: severe TBI (Glasgow Coma Scale [GCS] score ≤ 8], age 18 years, and intracranial pressure (ICP) monitor placed; exclusion: pregnancy). Children with suspected abusive head trauma (AHT) were excluded to avoid bias related to the association between AHT and mortality. Demographics, and prehospital and resuscitation events were collected/analyzed, and children were stratified based on age at time of injury (< 5, 5-< 11, 11-18 years) and presented as mean ± standard error of the mean (SEM). Analyses of variance were used to test the equality of the means across the group for continuous variable, and Chi-square tests were used to compare percentages for discrete variables (post hoc comparisons were made using t test and Bonferroni corrections, as needed). Kaplan-Meier curves were generated for each age subgroup describing the time of death, and log-rank was used to compare the curves. Cox proportional hazards regression models were used to assess the effect of age on time to death while controlling for covariates. RESULTS: In the final cohort (n = 155, 45 excluded for AHT), overall age was 9.2 years ± 0.4 and GCS was 5.3 ± 0.1. Mortality was similar between strata (14.0, 20.0, 20.9%, respectively, p = 0.58). Motor vehicle accidents were the most common mechanism across all strata, while falls tended to be more common in the youngest stratum (p = 0.08). The youngest stratum demonstrated increased incidence of spontaneous hypothermia at presentation and decreased hemoglobin concentrations and coagulopathies, while the oldest demonstrated lower platelet counts. CONCLUSIONS: In contrast to previous reports, we failed to detect mortality differences across age strata in children with severe TBI. We have discerned novel associations between age and various markers of injury-unrelated to AHT-that may lead to testable hypotheses in the future.

Abusive Head Trauma and Mortality-An Analysis From an International Comparative Effectiveness Study of Children With Severe Traumatic Brain Injury.

OBJECTIVES: Small series have suggested that outcomes after abusive head trauma are less favorable than after other injury mechanisms. We sought to determine the impact of abusive head trauma on mortality and identify factors that differentiate children with abusive head trauma from those with traumatic brain injury from other mechanisms. DESIGN: First 200 subjects from the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial-a comparative effectiveness study using an observational, cohort study design. SETTING: PICUs in tertiary children's hospitals in United States and abroad. PATIENTS: Consecutive children (age < 18 yr) with severe traumatic brain injury (Glasgow Coma Scale ≤ 8; intracranial pressure monitoring). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, injury-related scores, prehospital, and resuscitation events were analyzed. Children were dichotomized based on likelihood of abusive head trauma. A total of 190 children were included (n = 35 with abusive head trauma). Abusive head trauma subjects were younger (1.87 ± 0.32 vs 9.23 ± 0.39 yr; p < 0.001) and a greater proportion were female (54.3% vs 34.8%; p = 0.032). Abusive head trauma were more likely to 1) be transported from home (60.0% vs 33.5%; p < 0.001), 2) have apnea (34.3% vs 12.3%; p = 0.002), and 3) have seizures (28.6% vs 7.7%; p < 0.001) during prehospital care. Abusive head trauma had a higher prevalence of seizures during resuscitation (31.4 vs 9.7%; p = 0.002). After adjusting for covariates, there was no difference in mortality (abusive head trauma, 25.7% vs nonabusive head trauma, 18.7%; hazard ratio, 1.758; p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (abusive head trauma, 66.7% vs nonabusive head trauma, 69.0%). CONCLUSIONS: In this large, multicenter series, children with abusive head trauma had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other traumatic brain injury populations in children, female predominance was seen in abusive head trauma in our cohort. Similar mortality rates and refractory intracranial pressure deaths suggest that children with severe abusive head trauma may benefit from therapies including invasive monitoring and adherence to evidence-based guidelines.

Mood symptoms in pregnant and postpartum women with bipolar disorder: a naturalistic study.

OBJECTIVE: We conducted a prospective naturalistic study of pregnant women with bipolar disorder (BD) to evaluate symptoms of BD across childbearing and assess whether pharmacotherapy reduced their severity. METHODS: Assessments were scheduled at 20, 30, and 36 weeks' gestation and 2, 12, 26, and 52 weeks postpartum. Symptoms were assessed using the Structured Interview Guide for the Hamilton Depression Rating Scale-Atypical Depression Supplement (SIGH-ADS) and Mania Rating Scale (MRS). RESULTS: Pregnant women (N=152) with BD were evaluated; 88 women (58%) were treated and 64 untreated (42%) with psychotropic drugs during pregnancy. Among the 88 women treated, 23 (26%) discontinued their medication in the first trimester and the remaining 65 (74%) were exposed throughout pregnancy or in the second and third trimesters. More than two-thirds (73%) of the women who remained in the study took psychotropic agents postpartum. The mean scores on the SIGH-ADS were in the mild range of depressive symptoms in both the psychotropic-treated and untreated groups in both pregnancy and postpartum. The majority of women had no or few symptoms of mania. Of the pregnant women treated with psychotropic agents, 66% received a guideline-concordant drug, and 34% received either antidepressant monotherapy (for BD I) or mono- or polypharmacy with a variety of other agents. CONCLUSIONS: This sample of perinatal women with BD was characterized by mild residual symptoms of depression independent of pharmacotherapy, which poses a risk for recurrence and impaired parenting. The treatment of childbearing women with BD deserves urgent clinical and research attention to improve psychiatric outcomes.

Transdermal Estradiol Treatment for Postpartum Depression: A Pilot, Randomized Trial.

Postpartum depression occurs in 14.5% of women in the first 3 months after birth. This study was an 8-week acute phase randomized trial with 3 cells (transdermal estradiol [E2], sertraline [SERT], and placebo [PL]) for the treatment of postpartum major depressive disorder. However, the study was stopped after batch analysis revealed that the E2 serum concentrations were lower than prestudy projections. This paper explores our experiences that will inform future investigations of therapeutic E2 use. Explanations for the low E2 concentrations were as follows: (1) study patch nonadhesion, which did not explain the low concentrations across the entire sample. (2) Ineffective transdermal patch preparations, although 2 different patch preparations were used and no significant main effect of patch type on E2 concentrations was found. (3) Obesity, at study entry, E2-treated women had body mass index of 32.9 (7.4) (mean [SD]). No pharmacokinetic data comparing E2 concentrations from transdermal patches in obese women versus normal weight controls are available. (4) Induction of cytochrome P450 (CYP450) 3A4 and other E2 elimination pathways in pregnancy. CYP4503A4 is induced in pregnancy and is a pathway for the metabolism of E2. Conversion to estrone and phase II metabolism via glucuronidation and sulfation, which also increase in pregnancy, are routes of E2 elimination. The time required for these pathways to normalize after delivery has not been elucidated. The observation that transdermal E2 doses greater than 100 µg/d did not increase serum concentrations was unexpected. Another hypothesis consistent with this observation is suppression of endogenous E2 secretion with increasing exogenous E2 dosing.

DOES SCREENING WITH THE MDQ AND EPDS IMPROVE IDENTIFICATION OF BIPOLAR DISORDER IN AN OBSTETRICAL SAMPLE?

BACKGROUND: Women with bipolar disorder (BD) are at high risk for postpartum affective episodes and psychosis. Although validated screening tools are available for postpartum unipolar depression, few screening tools for hypomania/mania exist. Screening tools for BD in the postpartum period are essential for improving detection and planning appropriate treatment. We evaluated whether adding the Mood Disorders Questionnaire (MDQ) to the Edinburgh Postnatal Depression Scale (EPDS) increased the identification of BD in the early postpartum period. METHODS: Women (N = 1,279) who delivered a live infant and screened positive on the EPDS and/or MDQ at 4-6 weeks postbirth were invited to undergo an in-home Structured Clinical Interview for DSM-IV (SCID). RESULTS: Positive EPDS and/or MDQ screens occurred in 12% of the sample (n = 155). In home SCID diagnostic interviews were completed in 93 (60%) of the mothers with positive screens. BD was the primary diagnosis in 37% (n = 34). Women with BD screened positive on the EPDS and/or MDQ as follows: EPDS+/MDQ+ (n = 14), EPDS+/MDQ- (n = 17), and EPDS-/MDQ+ (n = 3). The MDQ identified 50% (17/34) of the women with BD and 6 additional cases of BD when the MDQ question regarding how impaired the mother perceived herself was excluded from the screen criterion. CONCLUSION: Addition of the MDQ to the EPDS improved the distinction of unipolar depression from bipolar depression at the level of screening in 50% of women with traditional MDQ scoring and by nearly 70% when the MDQ was scored without the impairment criterion.

Maternal-Infant interaction in women with unipoloar and bipolar depression.

BACKGROUND: One percent of women experience bipolar disorder and are likely to suffer from mood disorders during the postpartum period, potentially impacting interaction with their infants. The purpose of this study was to describe maternal-infant interactions in women with bipolar depression at 12 months postpartum and to compare interactions to women with unipolar depression and a control group. METHODS: Using a descriptive design, maternal-infant interactions in women with bipolar disorder (n=40) were videotaped, coded, and analyzed for maternal sensitivity and maternal-infant reciprocity and compared to maternal-infant interaction in women with unipolar depression (n=50) and women without depression (n=40). RESULTS: Women with bipolar depression had lower scores on both maternal sensitivity and infant reciprocity, but differences were nonsignificant. CONCLUSIONS: This research is the first study to examine maternal-infant interaction in women with bipolar disorder, and important trends were noted. Future research should examine maternal-infant interaction at earlier time periods.

Theoretical approaches to maternal-infant interaction: which approach best discriminates between mothers with and without postpartum depression?

OBJECTIVE: The purpose of this study was to determine which of the four common approaches to coding maternal-infant interaction best discriminates between mothers with and without postpartum depression. METHODS: After extensive training, four research assistants coded 83 three minute videotapes of maternal infant interaction at 12month postpartum visits. Four theoretical approaches to coding (Maternal Behavior Q-Sort, the Dyadic Mini Code, Ainsworth Maternal Sensitivity Scale, and the Child-Caregiver Mutual Regulation Scale) were used. Twelve month data were chosen to allow the maximum possible exposure of the infant to maternal depression during the first postpartum year. The videotapes were created in a laboratory with standard procedures. Inter-rater reliabilities for each coding method ranged from .7 to .9. The coders were blind to depression status of the mother. RESULTS: Twenty-seven of the women had major depressive disorder during the 12month postpartum period. Receiver operating characteristics analysis indicated that none of the four methods of analyzing maternal infant interaction discriminated between mothers with and without major depressive disorder. CONCLUSION: Limitations of the study include the cross-sectional design and the low number of women with major depressive disorder. Further analysis should include data from videotapes at earlier postpartum time periods, and alternative coding approaches should be considered. Nurses should continue to examine culturally appropriate ways in which new mothers can be supported in how to best nurture their babies.

Disturbed sleep and inflammatory cytokines in depressed and nondepressed pregnant women: an exploratory analysis of pregnancy outcomes.

OBJECTIVE: Disturbed sleep and depression are potential risk factors for pregnancy complications. Both conditions are known to dysregulate biological pathways responsible for maintaining homeostatic balance and pregnancy health. Depression during pregnancy is associated with poor sleep. Thus, we explored whether disturbed sleep was associated with inflammatory cytokines and risk for adverse pregnancy outcomes, as well as whether depression augmented the sleep-cytokine relationship, thereby additively contributing to risk for adverse outcomes. METHODS: Interview-assessed sleep and plasma cytokine concentrations were evaluated in a cohort of depressed and nondepressed pregnant women (n = 168) at 20 and 30 weeks' gestation. Outcomes evaluated included preterm birth, birth weight, and peripartum events. RESULTS: Among depressed women, short sleep duration (<7 hours) was associated with higher interleukin (IL)-8 across time (ß = 0.506, p = .001), poor sleep efficiency (<85%) was associated with higher IL-6 (ß = 0.205, p = .006), and daytime naps were associated with higher tumor necrosis factor α (ß = 0.105, p = .024). Aspects of poor sleep were associated with having a lower weight baby (p values <.053). Among depressed women, interferon-γ increased risk for preterm birth (odds ratio = 1.175, p = .032). Trends for IL-6 and higher birth weight (ß = 105.2, p = .085), interferon-γ and lower birth weight (ß = -19.92, p < .069), and increased IL-8 and babies weighing less than 4000 grams (odds ratio = 0.72, p < .083) were observed. CONCLUSIONS: Although speculative, disturbed sleep may disrupt normal immune processes and contribute to adverse pregnancy outcomes. Exploratory analyses indicate that depression modifies these relationships.

Pre-pregnancy obesity and maternal nutritional biomarker status during pregnancy: a factor analysis.

OBJECTIVE: Pre-pregnancy obesity has been associated with adverse birth outcomes. Poor essential fatty acid (EFA) and micronutrient status during pregnancy may contribute to these associations. We assessed the associations between pre-pregnancy BMI and nutritional patterns of maternal micronutrient and EFA status during mid-pregnancy. DESIGN: A cross-sectional analysis from a prospective cohort study. Women provided non-fasting blood samples at ≥ 20 weeks' gestation that were assayed for red cell EFA; plasma folate, homocysteine and ascorbic acid; and serum retinol, 25-hydroxyvitamin D, a-tocopherol, soluble transferrin receptors and carotenoids. These nutritional biomarkers were employed in a factor analysis and three patterns were derived: EFA, Micronutrients and Carotenoids. SETTING: The Antidepressant Use During Pregnancy Study, Pittsburgh, PA, USA. SUBJECTS: Pregnant women (n 129). RESULTS: After adjustment for parity, race/ethnicity and age, obese pregnant women were 3.0 (95% CI 1.1, 7.7) times more likely to be in the lowest tertile of the EFA pattern and 4.5 (95% CI 1.7, 12.3) times more likely to be in the lowest tertile of the Carotenoid pattern compared with their lean counterparts. We found no association between pre-pregnancy obesity and the Micronutrient pattern after confounder adjustment. CONCLUSIONS: Our results suggest that obese pregnant women have diminished EFA and carotenoid concentrations.

Unhealthy alcohol use and brief intervention rates among high and low complexity veterans seeking primary care services in the Veterans Health Administration.

INTRODUCTION: Brief intervention (BI) is recommended for all primary care (PC) patients who screen positive for unhealthy alcohol use; however, patients with multiple chronic health conditions who are at high-risk of hospitalization (i.e., "high complexity" patients) may face disparities in receiving BIs in PC. The current study investigated whether high complexity and low complexity patients in the Veterans Health Administration (VHA) differed regarding screening positive for unhealthy alcohol use, alcohol-use severity, and receipt of BI for those with unhealthy alcohol use. METHODS: Patients were veterans receiving PC services at the VHA in a mid-Atlantic region of the United States. The study extracted VHA administrative and clinical data for a total of 282,242 patients who had ≥1 PC visits between 1/1/2014 and 12/31/2014, during which they were screened for unhealthy alcohol use by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C). The study defined high complexity patients as those within and above the 90th percentile of risk for hospitalization per the VHA's Care Assessment Need Score. Logistic regression models assessed if being a high complexity patient was associated with screening positive for unhealthy alcohol use (AUDIT-C ≥ 5), severity of unhealthy alcohol use in those who screened positive (AUDIT-C score range 5-12), and receipt of BI in those who screened positive. RESULTS: Our sample was 94.5% male, 83% White, 13% Black, 4% other race, and 1.7% Hispanic. A total of 10,813 (3.8%) patients screened positive for unhealthy alcohol use from which we identified 569 (5.3%) high complexity and 10,128 (93.6%) low complexity patients (n = 116 removed due to missing complexity data). Relative to low complexity patients, high complexity patients were less likely to screen positive for unhealthy alcohol use (3.3% vs. 4.1%, AOR = 0.59, p < .001); however, in patients who screened positive, high complexity patients had higher AUDIT-C scores (Mean AUDIT-C = 7.75 vs. 6.87, AOR = 1.46, p < .001) and were less likely to receive a BI (78.0% vs. 92.6%, AOR = 0.42, p < .001). CONCLUSIONS: Disparities in BI exist for highly complex patients despite having more severe unhealthy alcohol use. Future research should examine the specific patient- and/or clinic-level factors impeding BI delivery for complex patients.

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.

Effect of P2Y12 Inhibitors on Organ Support-Free Survival in Critically Ill Patients Hospitalized for COVID-19: A Randomized Clinical Trial.

Importance: Platelet activation is a potential therapeutic target in patients with COVID-19. Objective: To evaluate the effect of P2Y12 inhibition among critically ill patients hospitalized for COVID-19. Design, Setting, and Participants: This international, open-label, adaptive platform, 1:1 randomized clinical trial included critically ill (requiring intensive care-level support) patients hospitalized with COVID-19. Patients were enrolled between February 26, 2021, through June 22, 2022. Enrollment was discontinued on June 22, 2022, by the trial leadership in coordination with the study sponsor given a marked slowing of the enrollment rate of critically ill patients. Intervention: Participants were randomly assigned to receive a P2Y12 inhibitor or no P2Y12 inhibitor (usual care) for 14 days or until hospital discharge, whichever was sooner. Ticagrelor was the preferred P2Y12 inhibitor. Main Outcomes and Measures: The primary outcome was organ support-free days, evaluated on an ordinal scale that combined in-hospital death and, for participants who survived to hospital discharge, the number of days free of cardiovascular or respiratory organ support up to day 21 of the index hospitalization. The primary safety outcome was major bleeding, as defined by the International Society on Thrombosis and Hemostasis. Results: At the time of trial termination, 949 participants (median [IQR] age, 56 [46-65] years; 603 male [63.5%]) had been randomly assigned, 479 to the P2Y12 inhibitor group and 470 to usual care. In the P2Y12 inhibitor group, ticagrelor was used in 372 participants (78.8%) and clopidogrel in 100 participants (21.2%). The estimated adjusted odds ratio (AOR) for the effect of P2Y12 inhibitor on organ support-free days was 1.07 (95% credible interval, 0.85-1.33). The posterior probability of superiority (defined as an OR > 1.0) was 72.9%. Overall, 354 participants (74.5%) in the P2Y12 inhibitor group and 339 participants (72.4%) in the usual care group survived to hospital discharge (median AOR, 1.15; 95% credible interval, 0.84-1.55; posterior probability of superiority, 80.8%). Major bleeding occurred in 13 participants (2.7%) in the P2Y12 inhibitor group and 13 (2.8%) in the usual care group. The estimated mortality rate at 90 days for the P2Y12 inhibitor group was 25.5% and for the usual care group was 27.0% (adjusted hazard ratio, 0.96; 95% CI, 0.76-1.23; P = .77). Conclusions and Relevance: In this randomized clinical trial of critically ill participants hospitalized for COVID-19, treatment with a P2Y12 inhibitor did not improve the number of days alive and free of cardiovascular or respiratory organ support. The use of the P2Y12 inhibitor did not increase major bleeding compared with usual care. These data do not support routine use of a P2Y12 inhibitor in critically ill patients hospitalized for COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04505774.

Depression treatment in patients with general medical conditions: results from the CO-MED trial.

PURPOSE: We studied the effect of 3 antidepressant treatments on outcomes (depressive severity, medication tolerability, and psychosocial functioning) in depressed patients having comorbid general medical conditions in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial. METHODS: Adult outpatients who had chronic and/or recurrent major depressive disorder (MDD) with and without general medical conditions were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram plus placebo, (2) bupropion-SR plus escitalopram, or (3) venlafaxine-XR plus mirtazapine. At weeks 12 and 28, we compared response and tolerability between participants with 0, 1, 2, and 3 or more general medical conditions. RESULTS: Of the 665 evaluable patients, 49.5% reported having no treated general medical conditions, 23.8% reported having 1, 14.8% reported having 2, and 11.9% reported having at least 3. We found only minimal differences in antidepressant treatment response between these groups having different numbers of conditions; patients with 3 or more conditions reported higher rates of impairment in social and occupational functioning at week 12 but not at week 28. Additionally, we found no significant differences between the 3 antidepressant treatments across these groups. CONCLUSIONS: Patients with general medical conditions can be safely and effectively treated for MDD with antidepressants with no additional adverse effect or tolerability burden relative to their counterparts without such conditions. Combination therapy is not associated with an increased treatment response beyond that found with traditional monotherapy in patients with MDD, regardless of the presence and number of general medical conditions.