Development of the CDISC Pediatrics User Guide: a CDISC and conect4children collaboration.

Introduction: The conect4children (c4c) project aims to facilitate efficient planning and delivery of paediatric clinical trials. One objective of c4c is data standardization and reuse. Interoperability and reusability of paediatric clinical trial data is challenging due to a lack of standardization. The Clinical Data Interchange Standards Consortium (CDISC) standards that are required or recommended for regulatory submissions in several countries lack paediatric specificity with limited awareness within academic institutions. To address this, c4c and CDISC collaborated to develop the Pediatrics User Guide (PUG) consisting of cross-cutting data items that are routinely collected in paediatric clinical trials, factoring in all paediatric age ranges. Methods and Results: The development of the PUG consisted of six stages. During the scoping phase, subtopics (each containing several clinically relevant concepts) were suggested and debated for inclusion in the PUG. Ninety concepts were selected for the modelling phase. Concept maps describing the Research Topic and representation procedure were developed for the 19 concepts that had no (or partial) previous modelling in CDISC. Next, metadata and implementation examples were developed for concepts. This was followed by a CDISC internal review and a public review. For both these review stages, the feedback comments were either implemented or rejected based on budget, timelines, expert review, and scope. The PUG was published on the CDISC website on February 23, 2023. Discussion: The PUG is a first step in bridging the lack of child specific CDISC standards, particularly within academia. Several academic and industrial partners were involved in the development of the PUG, and c4c has undertaken multiple steps to publicize the PUG within its academic partner organizations - in particular, the European Reference Networks (ERNs) that are developing registries and dictionaries in 24 disease areas. In the long term, continued use of the PUG in paediatric clinical trials will enable the pooling of data from multiple trials, which is particularly important for medical domains with small populations.

Dilution of humoral immunity: Results from a natural history study of healthy total knee arthroplasty patients.

The incidence of prosthetic joint infection (PJI) following elective primary total knee arthroplasty (TKA) is very low but serious risk remains. To identify unknown risk factors, we completed a natural history study of IgG specific for Staphylococcus aureus antigens previously phenotyped as protective (anti-Atl) and pathogenic (anti-Isd). Twenty-five male and 25 female optimized patients 50-85 years of age and BMI 24-39 undergoing primary TKA were prospectively enrolled. Blood sampling was performed preoperatively, postoperative Day 1, and at 2, 6, and 12 weeks, to assess serum cytokine, anti-staphylococcal IgG levels and anti-tetanus toxoid IgG measured via custom Luminex assay. Clinical, demographic, and PROMIS-10 data were collected with outcomes to 2 years postop. All participants completed the study and 2-year follow-up. No patients were readmitted or noted to develop a surgical site infection or serious adverse event, and patient-reported outcomes were improved. Serology revealed a highly significant decrease in six out of eight antibody titers against specific S. aureus antigens on Day 1 (p < 0.0001), five of which normalized to preoperative levels within 2 weeks. These changes were commensurate with a decrease and recovery of anti-tetanus toxoid titers, and a 20% drop in hemoglobin 13.8 ± 1.7 at preop to 11.1 ± 1.8 mg/dL on Day 1 (p < 0.0001). After TKA, a significant decrease in humoral immunity commensurate with blood loss and hemodilution was recorded. This decrease in circulating anti-staphylococcal antibodies in the early postop period may represent a periprosthetic joint infection risk factor for patients.

Fetal and Maternal Factors Predictive of Primary Cesarean Delivery at Term in a Low-Risk Population: NICHD Fetal Growth Studies-Singletons.

OBJECTIVE: This study aimed to examine associations of fetal biometric and amniotic fluid measures with intrapartum primary cesarean delivery (PCD) and develop prediction models for PCD based on ultrasound parameters and maternal factors. STUDY DESIGN: Secondary analysis of the National Institute of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-singleton cohort (2009-2013) including patients with uncomplicated pregnancies and intent to deliver vaginally at ≥370/7 weeks. The estimated fetal weight, individual biometric parameters, fetal asymmetry measurements, and amniotic fluid single deepest vertical pocket assessed at the final scan (mean 37.5 ± 1.9 weeks) were categorized as <10th, 10th to 90th (reference), and >90th percentiles. Logistic regression analyses examined the association between the ultrasound measures and PCD. Fetal and maternal SuperLearner prediction algorithms were constructed for the full and nulliparous cohorts. RESULTS: Of the 1,668 patients analyzed, 249 (14.9%) had PCD. The fetal head circumference, occipital-frontal diameter, and transverse abdominal diameter >90th percentile (adjusted odds ratio [aOR] = 2.50, 95% confidence interval [95% CI]: 1.39, 4.51; aOR = 1.86, 95% CI: 1.02, 3.40; and aOR = 2.13, 95% CI: 1.16, 3.89, respectively) were associated with PCD. The fetal model demonstrated poor ability to predict PCD in the full cohort and in nulliparous patients (area under the receiver-operating characteristic curve [AUC] = 0.56, 95% CI: 0.52, 0.61; and AUC = 0.54, 95% CI: 0.49, 0.60, respectively). Conversely, the maternal model had better predictive capability overall (AUC = 0.79, 95% CI: 0.75, 0.82) and in the nulliparous subgroup (AUC = 0.72, 95% CI: 0.67, 0.77). Models combining maternal/fetal factors performed similarly to the maternal model (AUC = 0.78, 95% CI: 0.75, 0.82 in full cohort, and AUC = 0.71, 95% CI: 0.66, 0.76 in nulliparas). CONCLUSION: Although a few fetal biometric parameters were associated with PCD, the fetal prediction model had low performance. In contrast, the maternal model had a fair-to-good ability to predict PCD. KEY POINTS: · Fetal HC >90th percentile was associated with cesarean delivery.. · Fetal parameters did not effectively predict PCD.. · Maternal factors were more predictive of PCD.. · Maternal/fetal and maternal models performed similarly.. · Prediction models had lower performance in nulliparas..

Multiethnic growth standards for fetal body composition and organ volumes derived from 3D ultrasonography.

BACKGROUND: A major goal of contemporary obstetrical practice is to optimize fetal growth and development throughout pregnancy. To date, fetal growth during prenatal care is assessed by performing ultrasonographic measurement of 2-dimensional fetal biometry to calculate an estimated fetal weight. Our group previously established 2-dimensional fetal growth standards using sonographic data from a large cohort with multiple sonograms. A separate objective of that investigation involved the collection of fetal volumes from the same cohort. OBJECTIVE: The Fetal 3D Study was designed to establish standards for fetal soft tissue and organ volume measurements by 3-dimensional ultrasonography and compare growth trajectories with conventional 2-dimensional measures where applicable. STUDY DESIGN: The National Institute of Child Health and Human Development Fetal 3D Study included research-quality images of singletons collected in a prospective, racially and ethnically diverse, low-risk cohort of pregnant individuals at 12 U.S. sites, with up to 5 scans per fetus (N=1730 fetuses). Abdominal subcutaneous tissue thickness was measured from 2-dimensional images and fetal limb soft tissue parameters extracted from 3-dimensional multiplanar views. Cerebellar, lung, liver, and kidney volumes were measured using virtual organ computer aided analysis. Fractional arm and thigh total volumes, and fractional lean limb volumes were measured, with fractional limb fat volume calculated by subtracting lean from total. For each measure, weighted curves (fifth, 50th, 95th percentiles) were derived from 15 to 41 weeks' using linear mixed models for repeated measures with cubic splines. RESULTS: Subcutaneous thickness of the abdomen, arm, and thigh increased linearly, with slight acceleration around 27 to 29 weeks. Fractional volumes of the arm, thigh, and lean limb volumes increased along a quadratic curvature, with acceleration around 29 to 30 weeks. In contrast, growth patterns for 2-dimensional humerus and femur lengths demonstrated a logarithmic shape, with fastest growth in the second trimester. The mid-arm area curve was similar in shape to fractional arm volume, with an acceleration around 30 weeks, whereas the curve for the lean arm area was more gradual. The abdominal area curve was similar to the mid-arm area curve with an acceleration around 29 weeks. The mid-thigh and lean area curves differed from the arm areas by exhibiting a deceleration at 39 weeks. The growth curves for the mid-arm and thigh circumferences were more linear. Cerebellar 2-dimensional diameter increased linearly, whereas cerebellar 3-dimensional volume growth gradually accelerated until 32 weeks followed by a more linear growth. Lung, kidney, and liver volumes all demonstrated gradual early growth followed by a linear acceleration beginning at 25 weeks for lungs, 26 to 27 weeks for kidneys, and 29 weeks for liver. CONCLUSION: Growth patterns and timing of maximal growth for 3-dimensional lean and fat measures, limb and organ volumes differed from patterns revealed by traditional 2-dimensional growth measures, suggesting these parameters reflect unique facets of fetal growth. Growth in these three-dimensional measures may be altered by genetic, nutritional, metabolic, or environmental influences and pregnancy complications, in ways not identifiable using corresponding 2-dimensional measures. Further investigation into the relationships of these 3-dimensional standards to abnormal fetal growth, adverse perinatal outcomes, and health status in postnatal life is warranted.

Comparing Fetal Ultrasound Biometric Measurements to Neonatal Anthropometry at the Extremes of Birthweight.

OBJECTIVE: Error in birthweight prediction by sonographic estimated fetal weight (EFW) has clinical implications, such as avoidable cesarean or misclassification of fetal risk in labor. We aimed to evaluate optimal timing of ultrasound and which fetal measurements contribute to error in fetal ultrasound estimations of birth size at the extremes of birthweight. STUDY DESIGN: We compared differences in head circumference (HC), abdominal circumference (AC), femur length, and EFW between ultrasound and corresponding birth measurements within 14 (n = 1,290) and 7 (n = 617) days of birth for small- (SGA, <10th percentile), appropriate- (AGA, 10th-90th), and large-for-gestational age (LGA, >90th) newborns. RESULTS: Average differences between EFW and birthweight for SGA neonates were: -40.2 g (confidence interval [CI]: -82.1, 1.6) at 14 days versus 13.6 g (CI: -52.4, 79.7) at 7 days; for AGA, -122.4 g (-139.6, -105.1) at 14 days versus -27.2 g (-50.4, -4.0) at 7 days; and for LGA, -242.8 g (-306.5, -179.1) at 14 days versus -72.1 g (-152.0, 7.9) at 7 days. Differences between fetal and neonatal HC were larger at 14 versus 7 days, and similar to patterns for EFW and birthweight, differences were the largest for LGA at both intervals. In contrast, differences between fetal and neonatal AC were larger at 7 versus 14 days, suggesting larger error in AC estimation closer to birth. CONCLUSION: Using a standardized ultrasound protocol, SGA neonates had ultrasound measurements closer to actual birth measurements compared with AGA or LGA neonates. LGA neonates had the largest differences between fetal and neonatal size, with measurements 14 days from delivery showing 3- to 4-fold greater differences from birthweight. Differences in EFW and birthweight may not be explained by a single fetal measurement; whether estimation may be improved by incorporation of other knowable factors should be evaluated in future research. KEY POINTS: · Ultrasound measurements may be inadequate to predict neonatal size at birth.. · Birthweight estimation error is higher for neonates >90th percentile.. · There is higher error in AC closer to birth..

Nutritional Intake in Dichorionic Twin Pregnancies: A Descriptive Analysis of a Multisite United States Cohort.

INTRODUCTION: Twin gestations have greater nutritional demands than singleton gestations, yet dietary intakes of women with twin gestations have not been well described. METHODS: In a prospective, multi-site US study of 148 women with dichorionic twin gestations (2012-2013), we examined longitudinal changes in diet across pregnancy. Women completed a food frequency questionnaire during each trimester of pregnancy. We examined changes in means of total energy and energy-adjusted dietary components using linear mixed effects models. RESULTS: Mean energy intake (95% CI) across the three trimesters was 2010 kcal/day (1846, 2175), 2177 kcal/day (2005, 2349), 2253 kcal/day (2056, 2450), respectively (P = 0.01), whereas the Healthy Eating Index-2010 was 63.9 (62.1, 65.6), 64.5 (62.6, 66.3), 63.2 (61.1, 65.3), respectively (P = 0.53). DISCUSSION: Women with twin gestations moderately increased total energy as pregnancy progressed, though dietary composition and quality remained unchanged. These findings highlight aspects of nutritional intake that may need to be improved among women carrying twins.

The 2023 Orthopaedic Research Society's International Consensus Meeting on musculoskeletal infection: Summary from the host immunity section.

Musculoskeletal infections (MSKI), which are a major problem in orthopedics, occur when the pathogen eludes or overwhelms the host immune system. While effective vaccines and immunotherapies to prevent and treat MSKI should be possible, fundamental knowledge gaps in our understanding of protective, nonprotective, and pathogenic host immunity are prohibitive. We also lack critical knowledge of how host immunity is affected by the microbiome, implants, prior infection, nutrition, antibiotics, and concomitant therapies, autoimmunity, and other comorbidities. To define our current knowledge of these critical topics, a Host Immunity Section of the 2023 Orthopaedic Research Society MSKI International Consensus Meeting (ICM) proposed 78 questions. Systematic reviews were performed on 15 of these questions, upon which recommendations with level of evidence were voted on by the 72 ICM delegates, and another 12 questions were voted on with a recommendation of "Unknown" without systematic reviews. Two questions were transferred to another ICM Section, and the other 45 were tabled for future consideration due to limitations of available human resources. Here we report the results of the voting with internet access to the questions, recommendations, and rationale from the systematic reviews. Eighteen questions received a consensus vote of ≥90%, while nine recommendations failed to achieve this threshold. Commentary on why consensus was not achieved on these questions and potential ways forward are provided to stimulate specific funding mechanisms and research on these critical MSKI host defense questions.

Menstrual Suppression in the Myelosuppressed: A Retrospective Cohort Study.

PURPOSE: Adolescent and young adult female patients receiving myelosuppressive cancer treatments are at risk of abnormal uterine bleeding (AUB). The frequency with which patients with cancer receive menstrual suppression and the agents used have not previously been well-characterized. We studied the rate of menstrual suppression, the effect of suppression on bleeding and blood product utilization, and if there were practice pattern differences between adult and pediatric oncologists. METHODS: We established a retrospective cohort of 90 females with a diagnosis of Hodgkin or non-Hodgkin lymphoma (n = 25), AML (n = 46), or sarcoma (n = 19) and treated with chemotherapy between 2008 and 2019 at our institutions (University of Alabama at Birmingham [UAB] adult oncology: UAB hospital; UAB pediatric oncology: Children's of Alabama). Data were abstracted from the medical record including sociodemographics, primary oncologist specialty (pediatric v adult), cancer details (diagnosis and treatment) and gynecologic course (documented gynecologic history, menstrual suppression agents used, reported AUB outcomes, and treatments). RESULTS: The majority of patients (77.8%) received menstrual suppression. Compared with nonsuppressed patients, suppressed patients had similar rates of packed red blood cell transfusions but higher number of platelet transfusions. Adult oncologists were more likely to document a gynecologic history, consult gynecology, and list AUB as a problem. Among suppressed patients, there was heterogeneity in the agents used for menstrual suppression, with a predilection toward progesterone-only agents; a low rate of thrombotic events was observed. CONCLUSION: Menstrual suppression was common in our cohort with variability in agents used. Pediatric and adult oncologists demonstrated different practice patterns.

A return to responsibility: A critique of the single actor strategic model of CSR.

Any functional utility gained through corporate social responsibility (CSR) depends on "responsibility" as the governing principle between "corporate" and "social" interests. We argue that Porter and Kramer's highly popularised notion of "shared value" has been pivotal to the erosion of responsibility as a moderating concept in CSR. Under this approach, "strategic" CSR becomes an instrument to leverage corporate advantage, rather than fulfil social responsibilities and address business-related harms. In mining, this approach has supported shallow, derivative ideas including the wellknown CSR artefact: "social license to operate" (SLTO). We argue that CSR, and the related concept corporate social irresponsibility (CSI), suffer from the single actor problem, where the corporation too easily becomes the exclusive focus of analysis. We advocate for a reinvigorated debate about mining and social responsibility in which the corporation is but one actor in the (ir)responsibility landscape.

A new method for customized fetal growth reference percentiles.

BACKGROUND: Customized fetal growth charts assume birthweight at term to be normally distributed across the population with a constant coefficient of variation at earlier gestational ages. Thus, standard deviation used for computing percentiles (e.g., 10th, 90th) is assumed to be proportional to the customized mean, although this assumption has never been formally tested. METHODS: In a secondary analysis of NICHD Fetal Growth Studies-Singletons (12 U.S. sites, 2009-2013) using longitudinal sonographic biometric data (n = 2288 pregnancies), we investigated the assumptions of normality and constant coefficient of variation by examining behavior of the mean and standard deviation, computed following the Gardosi method. We then created a more flexible model that customizes both mean and standard deviation using heteroscedastic regression and calculated customized percentiles directly using quantile regression, with an application in a separate study of 102, 012 deliveries, 37-41 weeks. RESULTS: Analysis of term optimal birthweight challenged assumptions of proportionality and that values were normally distributed: at different mean birthweight values, standard deviation did not change linearly with mean birthweight and the percentile computed with the normality assumption deviated from empirical percentiles. Composite neonatal morbidity and mortality rates in relation to birthweight < 10th were higher for heteroscedastic and quantile models (10.3% and 10.0%, respectively) than the Gardosi model (7.2%), although prediction performance was similar among all three (c-statistic 0.52-0.53). CONCLUSIONS: Our findings question normality and constant coefficient of variation assumptions of the Gardosi customization method. A heteroscedastic model captures unstable variance in customization characteristics which may improve detection of abnormal growth percentiles. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00912132.

Prenatal weight and regional body composition trajectories and neonatal body composition: The NICHD Foetal Growth Studies.

BACKGROUND: Gestational weight gain (GWG) and anthropometric trajectories may affect foetal programming and are potentially modifiable. OBJECTIVES: To assess concomitant patterns of change in weight, circumferences and adiposity across gestation as an integrated prenatal exposure, and determine how they relate to neonatal body composition. METHODS: Data are from a prospective cohort of singleton pregnancies (n = 2182) enrolled in United States perinatal centres, 2009-2013. Overall and by prepregnancy BMI group (overweight/obesity and healthy weight), joint latent trajectory models were fit with prenatal weight, mid-upper arm circumference (MUAC), triceps (TSF) and subscapular (SSF) skinfolds. Differences in neonatal body composition by trajectory class were assessed via weighted least squares. RESULTS: Six trajectory patterns reflecting co-occurring changes in weight and MUAC, SSF and TSF across pregnancy were identified overall and by body mass index (BMI) group. Among people with a healthy weight BMI, some differences were observed for neonatal subcutaneous adipose tissue, and among individuals with overweight/obesity some differences in neonatal lean mass were found. Neonatal adiposity measures were higher among infants born to individuals with prepregnancy overweight/obesity. CONCLUSIONS: Six integrated trajectory patterns of prenatal weight, subcutaneous adipose tissue and circumferences were observed that were minimally associated with neonatal body composition, suggesting a stronger influence of prepregnancy BMI.

Early outcomes from a national Train-the-Trainer Interprofessional Team Development Program.

The imperative need to train health professions faculty (educators and clinicians) to lead interprofessional education efforts and promote interprofessional team-based care is widely recognized. This need stems from a growing body of research that suggests collaboration improves patient safety and health outcomes. This short report provides an overview of a Train-the-Trainer Interprofessional Team Development Program (T3 Program) that equips faculty leaders with the skills to lead interprofessional education and interprofessional collaborative practice across the learning continuum. We also describe the history, approach, and early outcomes of this innovative program.

Combination of Fundal Height and Ultrasound to Predict Small for Gestational Age at Birth.

OBJECTIVE: The objective of the study was to determine whether adding longitudinal measures of fundal height (FH) to the standard cross-sectional FH to trigger third trimester ultrasound estimated fetal weight (EFW) would improve small for gestational age (SGA) prediction. STUDY DESIGN: We developed a longitudinal FH calculator in a secondary analysis of a prospective cohort study of 1,939 nonobese pregnant women who underwent serial FH evaluations at 12 U.S. clinical sites. We evaluated cross-sectional FH measurement ≤ -3 cm at visit 3 (mean: 32.0 ± 1.6 weeks) versus the addition of longitudinal FH up to and including visit 3 to trigger an ultrasound to diagnose SGA defined as birth weight <10th percentile. If the FH cut points were not met, the SGA screen was classified as negative. If FH cut points were met and EFW was <10th percentile, the SGA screen was considered positive. If EFW was ≥10th percentile, the SGA screen was also considered negative. Sensitivity, specificity, and positive predictive value (PPV) and negative predictive value (NPV) were computed. RESULTS: In a comparison of methods, 5.8% of women were classified as at risk of SGA by both cross-sectional and longitudinal classification methods; cross-sectional FH identified an additional 4.0%, and longitudinal fundal height identified a separate, additional 4.5%.Using cross-sectional FH as an ultrasound trigger, EFW had a PPV and NPV for SGA of 69 and 92%, respectively. After adding longitudinal FH, PPV increased to 74%, whereas NPV of 92% remained unchanged; however, the number of women who underwent triggered EFW decreased from 9.7 to 5.7%. CONCLUSION: An innovative approach for calculating longitudinal FH to the standard cross-sectional FH improved identification of SGA birth weight, while simultaneously reducing the number of triggered ultrasounds. As an essentially free-of-charge screening test, our novel method has potential to decrease costs as well as perinatal morbidity and mortality (through better prediction of SGA). KEY POINTS: · We have developed an innovative calculator for fundal height trajectory.. · Longitudinal fundal height improves detection of SGA.. · As a low cost screening test, the fundal height calculator may decrease costs and morbidity through better prediction of SGA..

Autologous bone marrow-derived MSCs engineered to express oFVIII-FLAG engraft in adult sheep and produce an effective increase in plasma FVIII levels.

Introduction: Hemophilia A (HA) is the most common X-linked bleeding disorder, occurring in 1 in 5,000 live male births and affecting >1 million individuals worldwide. Although advances in protein-based HA therapeutics have improved health outcomes, current standard-of-care requires infusion 2-3 times per week for life, and 30% of patients develop inhibitors, significantly increasing morbidity and mortality. There are thus unmet medical needs requiring novel approaches to treat HA. Methods: We tested, in a highly translational large animal (sheep) model, whether the unique immunological and biological properties of autologous bone marrow (BM)-derived mesenchymal stromal cells (MSCs) could enable them to serve as cellular delivery vehicles to provide long-term expression of FVIII, avoiding the need for frequent infusions. Results: We show that autologous BM-MSCs can be isolated, transduced with a lentivector to produce high levels of ovine (o)FVIII, extensively expanded, and transplanted into adult animals safely. The transplanted cells engraft in multiple organs, and they stably produce and secrete sufficient quantities of FVIII to yield elevated plasma FVIII levels for at least 15 weeks. Discussion: These studies thus highlight the promise of cellular-based gene delivery approaches for treating HA.

Decarbonization, population disruption and resource inventories in the global energy transition.

We develop a novel approach to analysing decarbonisation strategies by linking global resource inventories with demographic systems. Our 'mine-town systems' approach establishes an empirical basis for examining the spatial extent of the transition and demographic effects of changing energy systems. The research highlights an urgent need for targeted macro-level planning as global markets see a decline in thermal coal and a ramp up of other mining commodities. Our findings suggest that ramping up energy transition metals (ETM) could be more disruptive to demographic systems than ramping down coal. The data shows asymmetry in the distribution of risks: mine-town systems within the United States are most sensitive to coal phase-out, while systems in Australia and Canada are most sensitive to ETM phase-in. A complete phase-out of coal could disrupt demographic systems with a minimum of 33.5 million people, and another 115.7 million people if all available ETM projects enter production.

Operative vaginal delivery as an independent risk factor for maternal postpartum infectious morbidity.

BACKGROUND: A recent study from the United Kingdom suggested that a single dosage of adjunctive amoxicillin/clavulanic acid with operative vaginal delivery reduces maternal infectious morbidity by 40% (from 19% to 11%). However, 89% of their study population received an episiotomy. OBJECTIVE: This study aimed to evaluate whether operative vaginal delivery is an independent risk factor for composite maternal postpartum infectious morbidity in a population with a low episiotomy rate. STUDY DESIGN: This was a retrospective cohort study of patients with viable singleton vaginal deliveries after ≥34 weeks gestation at a single perinatal center (2013-2018). The patients were categorized by the mode of delivery: spontaneous vaginal delivery or operative vaginal delivery (forceps or vacuum-assisted). The primary outcome was a composite of maternal infectious morbidity up to 6 weeks after delivery, defined as (1) endometritis, (2) perineal wound morbidity (infection, breakdown, or dehiscence), or (3) culture-proven urinary tract infection. The patient characteristics and outcomes were compared between the groups using appropriate tests. Multivariable models were used to estimate the association between operative vaginal delivery and study outcomes compared with spontaneous vaginal delivery, with adjustment for selected confounders. RESULTS: Of 14,647 deliveries meeting the inclusion criteria, 732 (5.0%) were operative vaginal deliveries: 354 (48%) forceps and 378 (52%) vacuums. Overall, 210 (1.4%) patients developed the morbidity composite. Patients having an operative vaginal delivery were more likely to be nulliparous, have labor inductions, develop intrapartum chorioamnionitis, receive an episiotomy, and sustain a third- or fourth-degree laceration. After adjusting for confounding factors, no significant association was observed between operative vaginal delivery and composite morbidity (adjusted odds ratio, 1.4 [0.8-2.4]) or any of its individual components. Administration of postpartum antibiotics and documented fever were also similar between groups. There was also no significant association between instrument (forceps vs vacuum) and the maternal infection composite. CONCLUSION: In this single-center US cohort, operative vaginal delivery was not an independent risk factor for maternal composite postpartum infectious morbidity.

Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation.

Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial, and its role in patients with S. aureus osteomyelitis is unknown. To address this knowledge gap, we completed a clinical study and observed elevated serum IL-27 levels (20-fold higher, P < 0.05) in patients compared with healthy controls. Remarkably, IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients (P < 0.05), suggesting a pathogenic role of IL-27. To test this hypothesis, we evaluated S. aureus osteomyelitis in WT and IL-27Rα-/- mice with and without exogenous IL-27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP, respectively. We found that IL-27 was induced at the surgical site within 1 day of S. aureus infection of bone and was expressed by M0, M1 and M2 macrophages and osteoblasts but not by osteoclasts. Unexpectedly, exogenous IL-27p28 (~2 ng·mL-1 in serum) delivery ameliorated soft tissue abscesses and peri-implant bone loss during infection, accompanied by enhanced local IL-27 expression, significant accumulation of RORγt+ neutrophils at the infection site, a decrease in RANK+ cells, and compromised osteoclast formation. These effects were not observed in IL-27Rα-/- mice compared with WT mice, suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection. In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1, nos2, il17a, il17f, and rorc expression but did not directly stimulate chemotaxis. Collectively, these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S. aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.