Autologous bone marrow mononuclear cells to treat severe traumatic brain injury in children.

Autologous bone marrow mononuclear cells (BMMNCs) infused after severe traumatic brain injury have shown promise for treating the injury. We evaluated their impact in children, particularly their hypothesized ability to preserve the blood-brain barrier and diminish neuroinflammation, leading to structural CNS preservation with improved outcomes. We performed a randomized, double-blind, placebo-sham-controlled Bayesian dose-escalation clinical trial at two children's hospitals in Houston, TX and Phoenix, AZ, USA (NCT01851083). Patients 5-17 years of age with severe traumatic brain injury (Glasgow Coma Scale score ≤ 8) were randomized to BMMNC or placebo (3:2). Bone marrow harvest, cell isolation and infusion were completed by 48 h post-injury. A Bayesian continuous reassessment method was used with cohorts of size 3 in the BMMNC group to choose the safest between two doses. Primary end points were quantitative brain volumes using MRI and microstructural integrity of the corpus callosum (diffusivity and oedema measurements) at 6 months and 12 months. Long-term functional outcomes and ventilator days, intracranial pressure monitoring days, intensive care unit days and therapeutic intensity measures were compared between groups. Forty-seven patients were randomized, with 37 completing 1-year follow-up (23 BMMNC, 14 placebo). BMMNC treatment was associated with an almost 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days and 3-day (14%) reduction in intensive care unit (ICU) days. White matter volume at 1 year in the BMMNC group was significantly preserved compared to placebo [decrease of 19 891 versus 40 491, respectively; mean difference of -20 600, 95% confidence interval (CI): -35 868 to -5332; P = 0.01], and the number of corpus callosum streamlines was reduced more in placebo than BMMNC, supporting evidence of preserved corpus callosum connectivity in the treated groups (-431 streamlines placebo versus -37 streamlines BMMNC; mean difference of -394, 95% CI: -803 to 15; P = 0.055), but this did not reach statistical significance due to high variability. We conclude that autologous BMMNC infusion in children within 48 h after severe traumatic brain injury is safe and feasible. Our data show that BMMNC infusion led to: (i) shorter intensive care duration and decreased ICU intensity; (ii) white matter structural preservation; and (iii) enhanced corpus callosum connectivity and improved microstructural metrics.

Surgical Necrotizing Enterocolitis and Spontaneous Intestinal Perforation Lead to Severe Growth Failure in Infants.

OBJECTIVE: We aimed to determine the incidence of growth failure in infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) and whether initial laparotomy versus peritoneal drainage (PD) impacted the likelihood of growth failure. SUMMARY BACKGROUND DATA: Infants with surgical NEC and SIP have high mortality, and most have neurodevelopmental impairment and poor growth. Existing literature on growth outcomes for these infants is limited. METHODS: This is a preplanned secondary study of the Necrotizing Enterocolitis Surgery Trial dataset. The primary outcome was growth failure (Z-score for weight <-2.0) at 18 to 22 months. We used logistic regression, including diagnosis and treatment, as covariates. Secondary outcomes were analyzed using the Fisher exact or Pearson χ2 test for categorical variables and the Wilcoxon rank sum test or one-way ANOVA for continuous variables. RESULTS: Among 217 survivors, 207 infants (95%) had primary outcome data. Growth failure at 18 to 22 months occurred in 24/50 (48%) of NEC infants versus 65/157 (42%) SIP (P=0.4). The mean weight-for-age Z-score at 18 to 22 months in NEC infants was -2.05±0.99 versus -1.84±1.09 SIP (P=0.2), and the predicted mean weight-for-age Z-score SIP (Beta -0.27; 95% CI: -0.53, -0.01; P=0.041). Median declines in weight-for-age Z-score between birth and 18 to 22 months were significant in all infants but most severe (>2) in NEC infants (P=0.2). CONCLUSIONS: This first ever prospective study of growth outcomes in infants with surgical NEC or SIP demonstrates that growth failure is very common, especially in infants with NEC, and persists at 18-22 months.

Glucose circadian rhythm assessment in pregnant women for gestational diabetes screening.

BACKGROUND: Gestational diabetes mellitus (GDM) is the most common complication during pregnancy, and it is associated with short- and long-term health impairments. Even with increasing incidence rates worldwide, to date, GDM lacks an international standard diagnosis criterion. OBJECTIVE: To elucidate whether a chronobiological perspective may improve the identification of patients at risk for neonatal complications. METHODS: We analyzed a dataset with 92 recruited pregnant patients with Continuous Glucose Monitoring (CGM) data obtained in a blinded study. The primary outcome consisted in evaluating whether the composite of adverse neonatal outcomes could be predicted by chronobiological variables derived from fitting glucose oscillation to a circadian rhythm. The secondary neonatal outcomes included preterm birth, neonatal intensive care unit admission, hypoglycemia, mechanical ventilation or continuous positive airway pressure, hyperbilirubinemia, and hospital length of stay. The secondary maternal outcomes included weight gain during pregnancy, hypertensive disorders of pregnancy, induction of labor, cesarean delivery, and postpartum complications. 87 subjects had enough data to study for glucose circadian rhythmicity. RESULTS: We developed a 3-covariate model including two chronobiological metrics, the midline estimating statistic of rhythm (MESOR) and glucose M10 start-time, and age that was predictive of the primary outcome, and associated with maternal secondary outcomes (preeclampsia with severe features and weight gain during pregnancy), and newborn secondary outcomes (preterm delivery < 37 weeks, indicated preterm delivery, NICU admission, need for CPAP, and differences in length of hospital stay). CONCLUSIONS: Chronobiological parameters might contribute to a better identification of the adverse outcomes associated with GDM in both the mother and newborn.

Proximity extension assay proteomics and renal single cell transcriptomics uncover novel urinary biomarkers for active lupus nephritis.

OBJECTIVE: To identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). METHODS: Urine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. RESULTS: Systems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). CONCLUSION: In addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.

Permissive intrapartum glucose control: an equivalence randomized control trial (PERMIT).

BACKGROUND: There is limited high-quality data on the best practices for maternal blood glucose management during labor. OBJECTIVE: We compared permissive care (target maternal blood glucose 70-180 mg/dL) to usual care (blood glucose 70-110 mg/dL) among laboring individuals with diabetes. STUDY DESIGN: This was a two-site equivalence randomized control trial for individuals with diabetes (pregestational or gestational) at ≥34 weeks in labor. Individuals were randomly allocated to usual care or permissive care. Maternal blood glucose was evaluated by capillary blood glucose monitoring in latent and active labor every 4 and 2 hours. Insulin drip was initiated if maternal blood glucose exceeded the upper bounds of the allocated target. The primary outcome was the first neonatal heel stick glucose within 2 hours of birth before feeding. We assumed a mean first neonatal blood glucose of 50±10 mg/dL. To ensure that the use of permissive care did not increase or decrease the first neonatal blood glucose >10 mg/dL (2-tailed: a=0.05, b=0.1), 96 total participants were required. We calculated adjusted relative risk and 95% confidence intervals in an intention-to-treat analysis. A preplanned Bayesian analysis was used to estimate the probability of equivalence with a neutral informative prior. RESULTS: Of deliveries with diabetes assessed for eligibility (from October 2022 to June 2023), 280 of 511 (54.8%) met eligibility criteria, and 96 of 280 (34.3%) agreed and were randomized. In the usual care group, 17% required an insulin drip compared with none in permissive care. There was equivalence in the primary outcome between usual and permissive care (57.9 vs 57.1 mg/dL; adjusted mean difference, -0.72 [95% confidence interval, -8.87 to 7.43]). Bayesian analysis indicated a 98% posterior probability of the mean difference not being >10 mg/dL. The rate of neonatal hypoglycemia was 25% in the usual care group and 29% in the permissive group (adjusted relative risk, 1.14; 95% confidence interval, 0.60-2.17). There was no difference in other neonatal or maternal outcomes. CONCLUSION: In this randomized control trial, although almost 1 in 6 individuals with diabetes required an insulin drip with usual intrapartum maternal blood glucose care, permissive care was associated with equivalent neonatal blood glucose.

Aspirin 162 mg vs 81 mg for preeclampsia prophylaxis in high-risk obese individuals: a comparative effectiveness open-label randomized trial (ASPREO).

BACKGROUND: In the United States, leading medical societies recommend 81 mg of aspirin daily for the prevention of preeclampsia in women at risk, whereas the NICE guidelines in the United Kingdom recommend a dose as high as 150 mg of aspirin. Recent data also suggest that in the obese population, inadequate dosing or aspirin resistance may impact the efficacy of aspirin at the currently recommended doses. OBJECTIVE: We evaluated whether daily administration of 162 mg aspirin would be more effective compared with 81 mg in decreasing the rate of preeclampsia with severe features in high-risk obese pregnant individuals. STUDY DESIGN: We performed a randomized trial between May 2019 and November 2022. Individuals at 12-20 weeks of gestational age with a body mass index ≥30 kg/m2 at the time of enrollment and at least 1 of 3 high-risk factors: history of preeclampsia in a prior pregnancy, at least stage I hypertension documented in the index pregnancy, pregestational diabetes or gestational diabetes diagnosed before 20 weeks of gestational age were randomized to either 162 mg or 81 mg of aspirin daily till delivery, participants were not blinded to treatment allocation. Exclusion criteria were multifetal gestation, known major fetal anomalies, seizure disorder, baseline proteinuria, on aspirin because of other indications, or contraindication to aspirin. The primary outcome was preeclampsia with severe features (preeclampsia or superimposed preeclampsia with severe features; eclampsia; or hemolysis, elevated liver enzymes, low platelet count syndrome). Secondary outcomes included rates of preterm birth because of preeclampsia, small for gestational age, postpartum hemorrhage, abruption, and medication side effects. A sample size of 220 was needed using a preplanned Bayesian analysis of the primary outcome to estimate the posterior probability of benefit or harm with a neutral informative prior. RESULTS: Approximately 220/343 (64.1%) individuals were randomized. The primary outcome was available for 209/220 (95%) individuals. Baseline characteristics were similar between groups, with the median gestational age at enrollment being 15.9 weeks in the 162 mg aspirin group and 15.6 weeks in the 81 mg aspirin group. Enrollment before 16 weeks occurred in 55 of 110 of those assigned to 162 mg and 58 of 110 of those assigned to 81 mg of aspirin. The primary outcome occurred in n of d individuals (35%) in the 162 mg aspirin group and n of d individuals (40%) in the 81 mg aspirin group (posterior relative risk, 0.88; 95% credible interval, 0.64-1.22). Bayesian analysis indicated a 78% probability of a reduction in the primary outcome with 162 mg aspirin compared with 81 mg aspirin dose. Rates of indicated preterm birth because of preeclampsia (21% vs 21%), small for gestational age (6.5% vs 2.9%), abruption (2.8% vs 3.0%), and postpartum hemorrhage (10.0% vs 8.8%) were similar between groups. Medication adverse effects were also similar. CONCLUSION: Among high-risk obese individuals, there was a 78% probability of benefit that 162 mg aspirin compared with 81 mg will decrease the rate of preeclampsia with severe features. With the best estimate of a 12% reduction when using 162 mg of aspirin compared with 81 mg of aspirin in this population. This trial supports doing a larger multicenter trial.

Implementing a Bundle for Evidence-based Cesarean Delivery May Not Be As Beneficial as Expected: A Multi-center, Pre- and Post- Study.

BACKGROUND: Standardization of procedures improves outcomes. Though systematic reviews have summarized the evidence-based steps (EBS) of cesarean delivery (CD), their bundled implementation has not been investigated. OBJECTIVE: In this pre- and post-implementation trial, we sought to ascertain if bundled EBS of CD, compared to surgeon's preference, improves outcomes. STUDY DESIGN: A StaRI (Standards for Reporting Implementation Studies) compliant, multi-center pre- and post-implementation trial at 4 teaching hospitals was conducted. The pre-implementation period consisted of CD done based on the physicians' preferences for 3 months; educational intervention (e.g., didactics, badge cards, posters, video) occurred at the 4th month. CDs in post-implementation period employed the bundled EBS. A pre-planned 10% randomized audit of both groups assessed adherence and uptake of EBS. The primary outcome was a composite maternal morbidity (CMM), which included estimated blood loss > 1,000 mL, blood transfusion, endometritis, post-partum fever, wound complications, sepsis, thrombosis, ICU admission, hysterectomy, or death. The secondary outcome was a composite neonatal morbidity (CNM) and some of its components were 5-min Apgar score < 7, positive pressure oxygen use, hypoglycemia, or sepsis. A priori Bayesian sample size calculation indicated 700 CD in each group was needed to demonstrate 20% relative reduction (from 15% to 12%) of CMM with 75% certainty. Bayesian logistic regression with neutral priors was used to calculate likelihood of net-improvement in adjusted relative risk (aRR) with 95% credible intervals (CrI). RESULTS: A total of 1,425 consecutive CD (721 in pre- and 704 in post-implementation group) were examined. Audited data indicated that the baseline EBS utilization rate during the pre-implementation period was 79%; after the implementation bundled EBS of CD the audited adherence was 89%-an uptake of 10.0% of the EBS. In four aspects, the maternal characteristics differed significantly in the pre- and post-implementation periods: race/ethnicity, hypertensive disorder, and the relative contribution of the 4 centers to the cohorts and the gestational age at delivery, but the indications for CD and whether its duration was < versus > 60 min did not. The rates of CMM in the pre- and post-implementation groups were 26% and 22%, respectively (aRR, 0.88; 95% CrI, 0.73-1.04), with a 94 % Bayesian probability of a reduction in CMM. The CNM occurred in 37% of the pre- and in 41% of the post-implementation group (aRR, 1.12; 95% CrI 0.98-1.39), with a 95% Bayesian probability of worsening in CNM. When CMM were segregated by preterm (<37 wks) and term (> 37 weeks) CD, the improvement in maternal outcomes persisted; when CNM were segregated by gestational age subgroupsthe potential for worsening neonatal outcomes persisted as well. CONCLUSIONS: Standardization of the evidence-based bundled steps of cesarean delivery resulted in a modest reduction of the composite maternal outcome; however, a paradoxical increase in neonatal composite morbidity was noted. Although individual evidence-based steps may be of value, while awaiting additional intervention trials a formal bundling of such steps is currently not recommended.

Effect of Preoperative Bilateral Ultrasound-Guided Quadratus Lumborum Nerve Block on Quality of Recovery After Minimally Invasive Hysterectomy in an Enhanced Recovery After Surgery (ERAS) Setting.

STUDY OBJECTIVE: To assess the effect of preoperative bilateral ultrasound-guided quadratus lumborum nerve block (QLB) on quality of recovery after minimally invasive hysterectomy, in an enhanced recovery after surgery setting. DESIGN: Randomized, controlled, double-blinded trial (Canadian Task Force level I). SETTING: University-affiliated tertiary medical center. PATIENTS: All women undergoing an elective robotic or laparoscopic hysterectomy. Women with chronic pain, chronic anticoagulation, and body mass index >50 kg/m2 were excluded. INTERVENTION: Patients were randomized with a 1:1 allocation, to one of the following 2 arms, and stratified based on robotic versus laparoscopic approach. 1. QLB: QLB (bupivacaine) + sham local trocar sites infiltration (normal saline) 2. Local infiltration: sham QLB (normal saline) + local infiltration (bupivacaine) MEASUREMENTS AND MAIN RESULTS: The primary outcome was defined as the quality of recovery score based on the validated questionnaire Quality of Recovery, completed 24 hours postoperatively. Secondary outcomes included dynamic pain scores, accumulated opioid consumption up to 24 hours, postoperative nausea and vomiting, surgical complications, length of hospital stay, time to first pain medication administration in the postanesthesia care unit, and adverse events. A total of 76 women were included in the study. Demographic characteristics were similar in both groups. Median age was 44 years (interquartile range 39-50), 47% of the participants were African American, and mean body mass index was 32.8 kg/m2 (standard deviation [SD] 8.1). The mean Quality of Recovery score was 179.1 (SD ± 10.3) in the QLB and 175.6 (SD ± 9.7) for the local anesthesia group (p = .072). All secondary outcomes were comparable between groups. CONCLUSIONS: QLBs do not significantly improve quality of recovery after elective robotic or laparoscopic hysterectomy compared with local anesthetic port site infiltration.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Comprehensive proteomics and platform validation of urinary biomarkers for bladder cancer diagnosis and staging.

BACKGROUND: Bladder cancer (BC) is among the most common cancers diagnosed in men in the USA. The current gold standards for the diagnosis of BC are invasive or lack the sensitivity to correctly identify the disease. METHODS: An aptamer-based screen analyzed the expression of 1317 proteins in BC compared to urology clinic controls. The top hits were subjected to systems biology analyses. Next, 30 urine proteins were ELISA-validated in an independent cohort of 68 subjects. Three of these proteins were next validated in an independent BC cohort of differing ethnicity. RESULTS: Systems biology analysis implicated molecular functions related to the extracellular matrix, collagen, integrin, heparin, and transmembrane tyrosine kinase signaling in BC susceptibility, with HNF4A and NFKB1 emerging as key molecular regulators. STEM analysis of the dysregulated pathways implicated a functional role for the immune system, complement, and interleukins in BC disease progression. Of 21 urine proteins that discriminated BC from urology clinic controls (UC), urine D-dimer displayed the highest accuracy (0.96) and sensitivity of 97%. Furthermore, 8 urine proteins significantly discriminated MIBC from NMIBC (AUC = 0.75-0.99), with IL-8 and IgA being the best performers. Urine IgA and fibronectin exhibited the highest specificity of 80% at fixed sensitivity for identifying advanced BC. CONCLUSIONS: Given the high sensitivity (97%) of urine D-dimer for BC, it may have a role in the initial diagnosis or detection of cancer recurrence. On the other hand, urine IL-8 and IgA may have the potential in identifying disease progression during patient follow-up. The use of these biomarkers for initial triage could have a significant impact as the current cystoscopy-based diagnostic and surveillance approach is costly and invasive when compared to a simple urine test.

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Generalizability of the Necrotizing Enterocolitis Surgery Trial to the Target Population of Eligible Infants.

OBJECTIVE: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results. STUDY DESIGN: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized. RESULTS: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31]). CONCLUSION: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01029353.

Oral combined hydrochlorothiazide and lisinopril vs nifedipine for postpartum hypertension: a comparative-effectiveness pilot randomized controlled trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors and diuretics may be underutilized for postpartum hypertension because of their teratogenicity during pregnancy. OBJECTIVE: We evaluated whether combined oral hydrochlorothiazide and lisinopril therapy produced superior short-term blood pressure control when compared with nifedipine among postpartum individuals with hypertension requiring pharmacologic treatment. STUDY DESIGN: We performed a pilot randomized controlled trial (October 2021 to June 2022) that included individuals with chronic hypertension or hypertensive disorders of pregnancy with 2 systolic blood pressure measurements ≥150 mm Hg and/or diastolic blood pressure measurements ≥100 mm Hg within 72 hours after delivery. Participants were randomized to receive either combined hydrochlorothiazide and lisinopril therapy or nifedipine therapy after stratifying the participants by diagnosis (chronic hypertension vs hypertensive disorders of pregnancy). The primary outcome was stage 2 hypertension (systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg) determined using a home blood pressure monitor on days 7 to 10 after delivery or at readmission to the hospital for blood pressure control. The secondary outcomes included severe maternal morbidity (any of the following: intensive care unit admission; hemolysis, elevated liver enzymes, low platelet count syndrome; eclampsia; stroke; cardiomyopathy; or maternal death), need for intravenous medications after randomization, hospital length of stay, blood pressure during first clinic visit, medication compliance, and adverse events. A pilot trial with 70 individuals was planned given the limited available data on combined hydrochlorothiazide and lisinopril therapy use in postpartum care. We calculated relative risks and 95% credible intervals in an intention-to-treat analysis. Finally, we conducted a preplanned Bayesian analysis to estimate the probability of benefit or harm with a neutral informative prior. RESULTS: Of 111 eligible individuals, 70 (63%) agreed and were randomized (31 in the hydrochlorothiazide and lisinopril group and 36 in the nifedipine group; 3 withdrew consent after randomization), and the characteristics were similar at baseline between the groups. The primary outcome was unavailable for 9 (12.8%) participants. The primary outcome occurred in 27% of participants in the hydrochlorothiazide and lisinopril group and in 43% of the participants in the nifedipine group (posterior adjusted relative risk, 0.74; 95% credible interval, 0.40-1.31). Bayesian analysis indicated an 85% posterior probability of a reduction in the primary outcome with combined hydrochlorothiazide and lisinopril therapy relative to nifedipine treatment. No differences were noted in the secondary outcomes or adverse medication events. CONCLUSION: The results of the pilot trial suggest a high probability that combined hydrochlorothiazide and lisinopril therapy produces superior short-term BP control when compared with nifedipine. These findings should be confirmed in a larger trial.

Continuous glucose monitoring in individuals undergoing gestational diabetes screening.

BACKGROUND: Among guidelines on gestational diabetes mellitus, there is an incongruity about the threshold of maternal hyperglycemia to diagnose gestational diabetes mellitus. OBJECTIVE: This study aimed to ascertain the association between continuous glucose monitoring metrics and adverse outcomes among individuals undergoing gestational diabetes mellitus screening. STUDY DESIGN: This was a prospective study (from June 2020 to January 2022) of individuals who underwent 2-step gestational diabetes mellitus screening at ≤30 weeks of gestation. The participants wore a blinded continuous glucose monitoring device (Dexcom G6 Pro; Dexcom, Inc, San Diego, CA) for 10 days starting when they took the 50-g glucose challenge test. The primary outcome was a composite of adverse neonatal outcomes (large for gestational age, shoulder dystocia or neonatal injury, respiratory distress, need for intravenous glucose treatment for hypoglycemia, or fetal or neonatal death). The secondary neonatal outcomes included preterm birth, neonatal intensive care unit admission, hypoglycemia, mechanical ventilation or continuous positive airway pressure, hyperbilirubinemia, and hospital length of stay. The secondary maternal outcomes included weight gain during pregnancy, hypertensive disorders of pregnancy, induction of labor, cesarean delivery, and postpartum complications. Time within the target range (63-140 mg/dL), time above the target range (>140 mg/dL) expressed as a percentage of all continuous glucose monitoring readings, and mean glucose level were analyzed. The Youden index was used to choose the threshold of ≥10% for the time above the target range and association with adverse outcomes. RESULTS: Of 136 participants recruited, data were available from 92 individuals (67.6%). The 2-step method diagnosed gestational diabetes mellitus in 2 individuals (2.2%). Continuous glucose monitoring indicated that 17 individuals (18.5%) had time above the target range of ≥10%. Individuals with time above the target range of ≥10% had a significantly higher likelihood of composite adverse neonatal outcomes than individuals with time above the target range of <10% (63% vs 18%; P=.001). Furthermore, compared with neonates born to individuals with time above the target range of <10%, neonates born to individuals with time above the target range of ≥10% had an increased likelihood for hypoglycemia (14.5% vs 47%; P=.009) and had a longer length of stay (2 vs 4 days; P=.03). No difference in maternal outcomes was noted between the groups. CONCLUSION: In this prospective study of individuals undergoing gestational diabetes mellitus screening, a cutoff of the time above the target range of ≥10% using continuous glucose monitoring was associated with a higher rate of neonatal adverse outcomes. A randomized trial of continuous glucose monitoring vs 2-step screening for gestational diabetes mellitus to lower the rate of adverse outcomes is underway (identification number: NCT05430204).

Bayesian regularization to predict neuropsychiatric adverse events in smoking cessation with pharmacotherapy.

BACKGROUND: Research on risk factors for neuropsychiatric adverse events (NAEs) in smoking cessation with pharmacotherapy is scarce. We aimed to identify predictors and develop a prediction model for risk of NAEs in smoking cessation with medications using Bayesian regularization. METHODS: Bayesian regularization was implemented by applying two shrinkage priors, Horseshoe and Laplace, to generalized linear mixed models on data from 1203 patients treated with nicotine patch, varenicline or placebo. Two predictor models were considered to separate summary scores and item scores in the psychosocial instruments. The summary score model had 19 predictors or 26 dummy variables and the item score model 51 predictors or 58 dummy variables. A total of 18 models were investigated. RESULTS: An item score model with Horseshoe prior and 7 degrees of freedom was selected as the final model upon model comparison and assessment. At baseline, smokers reporting more abnormal dreams or nightmares had 16% greater odds of experiencing NAEs during treatment (regularized odds ratio (rOR) = 1.16, 95% credible interval (CrI) = 0.95 - 1.56, posterior probability P(rOR > 1) = 0.90) while those with more severe sleep problems had 9% greater odds (rOR = 1.09, 95% CrI = 0.95 - 1.37, P(rOR > 1) = 0.85). The prouder a person felt one week before baseline resulted in 13% smaller odds of having NAEs (rOR = 0.87, 95% CrI = 0.71 - 1.02, P(rOR < 1) = 0.94). Odds of NAEs were comparable across treatment groups. The final model did not perform well in the test set. CONCLUSIONS: Worse sleep-related symptoms reported at baseline resulted in 85%-90% probability of being more likely to experience NAEs during smoking cessation with pharmacotherapy. Treatment for sleep disturbance should be incorporated in smoking cessation program for smokers with sleep disturbance at baseline. Bayesian regularization with Horseshoe prior permits including more predictors in a regression model when there is a low number of events per variable.

Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial.

BACKGROUND: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels. OBJECTIVE: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered. METHODS: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis. DISCUSSION: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing. TRIAL REGISTRATION: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022).

Determinants and Trends of the Use of Intravenous Thrombolysis for Minor Stroke: A Population-Based Study, 2016 to 2020.

BACKGROUND: We analyzed the main factors associated with intravenous thrombolysis (IVT) in patients with minor ischemic stroke. METHODS: Data were obtained from a prospective, government-mandated, population-based registry of stroke code patients in Catalonia (6 Comprehensive Stroke Centers, 8 Primary Stroke Centers, and 14 TeleStroke Centers). We selected patients diagnosed with ischemic stroke and National Institutes of Health Stroke Scale (NIHSS) ≤5 at hospital admission from January 2016 to December 2020. We excluded patients with a baseline modified Rankin Scale score of ≥3, absolute contraindication for IVT, unknown stroke onset, or admitted to hospital beyond 4.5 after stroke onset. The main outcome was treatment with IVT. We performed univariable and binary logistic regression analyses to identify the most important factors associated with IVT. RESULTS: We included 2975 code strokes; 1433 (48.2%) received IVT of which 30 (2.1%) had a symptomatic hemorrhagic transformation. Patients treated with IVT as compared to patients who did not receive IVT were more frequently women, had higher NIHSS, arrived earlier to hospital, were admitted to a Comprehensive Stroke Centers, and had large vessel occlusion. After binary logistic regression, NIHSS score 4 to 5 (odds ratio, 40.62 [95% CI, 31.73-57.22]; P<0.001) and large vessel occlusion (odds ratio, 16.39 [95% CI, 7.25-37.04]; P<0.001) were the strongest predictors of IVT. Younger age, female sex, baseline modified Rankin Scale score of 0, earlier arrival to hospital (<120 minutes after stroke onset), and the type of stroke center were also independently associated with IVT. The weight of large vessel occlusion on IVT was higher in patients with lower NIHSS. CONCLUSIONS: Minor stroke female patients, with higher NIHSS, arriving earlier to the hospital, presenting with large vessel occlusion and admitted to a Comprehensive Stroke Centers were more likely to receive intravenous thrombolysis.

Clinical Predictors of Failed Medical Treatment in Patients with Tubo-ovarian Abscess: External Validation of a Recently Published Risk Score.

STUDY OBJECTIVE: To assess the external validity of a recently published clinical risk score estimating the risk of failed medical treatment in patients with tubo-ovarian abscess (TOA) based on 4 clinical variables on admission. DESIGN: The probability of failed medical treatment predicted from the reference risk score was compared with the observed rates in a retrospective cohort of patients with TOA. Results were assessed using rigorous methods for clinical prediction models. SETTING: Safety-net teaching hospital system in Houston, Texas. PATIENTS: One hundred and sixty nine consecutive patients admitted with TOA between 2011 and 2018 were included. Some were treated conservatively with intravenous antibiotic agents; others required a drainage procedure. INTERVENTION: Electronic health records were reviewed and the 4 clinical predictors of failed conservative treatment were captured (age, white blood cell count on admission, abscess size, and presence of bilateral abscess). A clinical risk score was calculated for each patient. The prediction model was created using the risk score in a multivariate logistic regression. Then the calibration, discrimination, and accuracy of the model were evaluated to perform the external validation analysis. MEASUREMENTS AND MAIN RESULTS: Among 169 eligible patients, 50.2% were successfully treated with intravenous antibiotic agents and 49.8% needed abscess drainage. Patients undergoing drainage were more likely to be older, be diabetic, to present with elevated white blood cell count and fever, and to have a larger abscess size on univariate analysis. Among the 4 known predictors of drainage, abscess size was found to be the strongest. Significant difference in clinical characteristics was noted between our cohort and the reference cohort, and the model needed recalibration to adjust for these differences. The area under the receiver operating characteristic curve was 0.77 (0.71-0.84) indicating good discrimination. The Brier score was favorable (0.19) and the observed and predicted rates were similar ranging across different risk scores. CONCLUSIONS: Our results provide external validation of a simple clinical risk score predicting failed medical treatment in patients with TOA.

Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma.

BACKGROUND: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. METHODS: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. RESULTS: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. CONCLUSIONS: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Age-related Opioid Exposure in Trauma: A Secondary Analysis of the Multimodal Analgesia Strategies for Trauma (MAST) Randomized Trial.

OBJECTIVE: Evaluate the effect of age on opioid consumption after traumatic injury. SUMMARY BACKGROUND DATA: Older trauma patients receive fewer opioids due to decreased metabolism and increased complications, but adequacy of pain control is unknown. We hypothesized that older trauma patients require fewer opioids to achieve adequate pain control. METHODS: A secondary analysis of the multimodal analgesia strategies for trauma Trial evaluating the effectiveness of 2 multimodal pain regimens in 1561 trauma patients aged 16 to 96 was performed. Older patients (≥55 years) were compared to younger patients. Median daily oral morphine milligram equivalents (MME) consumption, average numeric rating scale pain scores, complications, and death were assessed. Multivariable analyses were performed. RESULTS: Older patients (n = 562) had a median age of 68 years (interquartile range 61-78) compared to 33 (24-43) in younger patients. Older patients had lower injury severity scores (13 [9-20] vs 14 [9-22], P = 0.004), lower average pain scores (numeric rating scale 3 [1-4] vs 4 [2-5], P < 0.001), and consumed fewer MME/day (22 [10-45] vs 52 [28-78], P < 0.001). The multimodal analgesia strategies for trauma multi-modal pain regimen was effective at reducing opioid consumption at all ages. Additionally, on multivariable analysis including pain score adjustment, each decade age increase after 55 years was associated with a 23% reduction in MME/day consumed. CONCLUSIONS: Older trauma patients required fewer opioids than younger patients with similar characteristics and pain scores. Opioid dosing for post-traumatic pain should consider age. A 20 to 25% dose reduction per decade after age 55 may reduce opioid exposure without altering pain control.