Reimagining general surgery resident selection: Collaborative innovation through design thinking.

Introduction: The process by which surgery residency programs select applicants is complex, opaque, and susceptible to bias. Despite attempts by program directors and educational researchers to address these issues, residents have limited ability to affect change within the process at present. Here, we present the results of a design thinking brainstorm to improve resident selection and propose this technique as a framework for surgical residents to creatively solve problems and generate actionable changes. Methods: Members of the Collaboration of Surgical Education Fellows (CoSEF) used the design thinking framework to brainstorm ways to improve the resident selection process. Members participated in one virtual focus group focused on identifying pain points and developing divergent solutions to those pain points. Pain points and solutions were subsequently organized into themes. Finally, members participated in a second virtual focus group to design prototypes to test the proposed solutions. Results: Sixteen CoSEF members participated in one or both focus groups. Participants identified twelve pain points and 57 potential solutions. Pain points and solutions were grouped into the three themes of transparency, fairness, and applicant experience. Members subsequently developed five prototype ideas that could be rapidly developed and tested to improve resident selection. Conclusions: The design thinking framework can help surgical residents come up with creative ideas to improve pain points within surgical training. Furthermore, this framework can supplement existing quantitative and qualitative methods within surgical education research. Future work will be needed to implement the prototypes devised during our sessions and turn them into complete interventions. Key message: In this paper, we demonstrate the results of a resident-led design thinking brainstorm on improving resident selection in which our team identified twelve pain points in resident selection, ideated 57 solutions, and developed five prototypes for further testing. In addition to sharing our results, we believe design thinking can be a useful framework for creative problem solving within surgical education.

Quality improvement initiative to increase radial artery usage as a second arterial conduit in coronary artery bypass grafting.

OBJECTIVES: Use of radial artery as a second arterial graft, compared to a saphenous vein, in coronary artery bypass grafting (CABG) can improve late outcomes. However, the radial artery remains underutilized. We initiated a quality improvement (QI) initiative to increase the usage of radial artery grafts. METHODS: During our 4-month lead period, we disseminated evidence for radial artery graft usage to surgeons, developed a radial artery decision-making algorithm and adopted endoscopic harvesting. Our QI initiative was conducted over a 6-month period and included a postoperative survey of decision-making for graft selection and obstacles to radial artery usage. RESULTS: Over the 6-month study period, 247 patients received isolated CABG which included 98 (40%) with radial arteries as a second arterial graft and 144 (58%) with greater saphenous veins. Radial artery usage increased with QI initiative implementation by 67% compared to 6 months prior to the study period (60 radial arteries/252 isolated CABG, 24%) (P = 0.006). The survey response rate was 93% (231/247). Barriers to radial artery graft usage were poor quality target vessel or stenosis <80% (24%), patient age >75 years (20%), ejection fraction ≤35% (8%) and renal insufficiency/dialysis (7%). No patients experienced significant complications from radial artery harvest. CONCLUSIONS: Our institutional QI initiative was successful in (i) increasing the usage of radial artery as a second arterial graft and (ii) understanding barriers to radial artery graft usage. Implementation of a QI program can improve radial artery usage in CABG with low risk of patient morbidity from radial artery harvest.

Roles, Responsibilities, and Expectations of Medical Students on Surgical Subinternships: A Modified Delphi Consensus Study.

PURPOSE: Surgical subinternships are important rotations for students preparing for a career in general surgery; however, these rotations often vary by institution and service. This modified Delphi study was conducted to reach a consensus set of roles, responsibilities, and expectations of fourth-year medical students on their surgical subinternships. METHOD: Candidate statements on roles, responsibilities, and expectations of subinterns were categorized into 7 domains: rotation structure, rounding and patient care, operating room conduct, technical skills, knowledge base, clinic, and professionalism. Expert panels were assembled of key stakeholders: program directors, clerkship directors, other education faculty, trainees, and recent subinterns. Three Delphi rounds were conducted from January to April 2023 to reach consensus defined a priori as a Cronbach α ≥ 0.8 and 80% or greater panel agreement. RESULTS: Forty-six expert panelists were recruited to participate in Delphi rounds, with 100%, 95.7%, and 97.8% response rates in the first, second, and third rounds, respectively. By the third round, 67 statements reached consensus as essential roles, responsibilities, and expectations of surgical subinterns. Key themes from these 67 statements included subinterns approximating the role of an intern with respect to work hours, patient care responsibilities, basic technical skills, and knowledge base. Panelists rated rounding and patient care as the most important domain, followed closely by professionalism. Additional key domains for evaluation in descending order were knowledge base, operating room conduct, clinic, and technical skills. By the third round, notable disagreements in the Delphi process included technical skills and rounding and patient care (93.3% and 88.9% agreement, respectively). CONCLUSIONS: This study provides a national consensus on core roles, responsibilities, and expectations for medical students completing surgical subinternships. Students can use these recommendations to prepare for subinternships, whereas faculty as well as residents and fellows can use them to evaluate applicants for general surgery residency positions.

Potential of stable isotope analysis to deduce anaerobic biodegradation of ethyl tert-butyl ether (ETBE) and tert-butyl alcohol (TBA) in groundwater: a review.

Understanding anaerobic biodegradation of ether oxygenates beyond MTBE in groundwater is important, given that it is replaced by ETBE as a gasoline additive in several regions. The lack of studies demonstrating anaerobic biodegradation of ETBE, and its product TBA, reflects the relative resistance of ethers and alcohols with a tertiary carbon atom to enzymatic attack under anoxic conditions. Anaerobic ETBE- or TBA-degrading microorganisms have not been characterized. Only one field study suggested anaerobic ETBE biodegradation. Anaerobic (co)metabolism of ETBE or TBA was reported in anoxic microcosms, indicating their biodegradation potential in anoxic groundwater systems. Non-isotopic methods, such as the detection of contaminant loss, metabolites, or ETBE- and TBA-degrading bacteria are not sufficiently sensitive to track anaerobic biodegradation in situ. Compound- and position-specific stable isotope analysis provides a means to study MTBE biodegradation, but isotopic fractionation of ETBE has only been studied with a few aerobic bacteria (εC -0.7 to -1.7‰, εH -11 to -73‰) and at one anoxic field site (δ2H-ETBE +14‰). Similarly, stable carbon isotope enrichment (δ13C-TBA +6.5‰) indicated TBA biodegradation at an anoxic field site. CSIA and PSIA are promising methods to detect anaerobic ETBE and TBA biodegradation but need to be investigated further to assess their full potential at field scale.

Longitudinal Integrated Clerkships and Undergraduate Surgical Education: A Scoping Review and Gap Analysis.

OBJECTIVE: Longitudinal integrated clerkships (LICs) are an increasingly popular approach to medical student clinical education, and the literature describing them is expanding. Despite this, there is a lack of understanding for how surgery didactics and skills are currently taught as a part of the LIC curriculum. DESIGN: We conducted a scoping literature review in July 2022 using terms related to LIC and surgical education. Abstract and full-length text screening followed. Data extraction was completed in August 2022. Articles published in English, focused on LIC students, and discussed any element of LIC curriculum surgical education was included. SETTING: Scoping literature review. PARTICIPANTS: A total of 282 studies describing LICs were identified from the scoping literature review. After applying inclusion and exclusion criteria, 37 (13%) studies describing some element of surgical education were included. RESULTS: Of these 37 studies, the majority did not delve into pertinent details related to students' surgery experience, expectations, and surgical skills accomplishments. Four studies (11%) reported on the outpatient surgical experience, such as minimum required time that students were expected to be in the clinic, and 8 studies (22%) described the inpatient and operating room exposure. Only 1 study (3%) described the surgical floor management of surgical patients, including tasks like documentation and wound care, and 3 studies (8%) reported formal assessment of surgical skills, such as suturing technique. CONCLUSIONS: Our study highlights the paucity LIC literature examining the relationship between this curricular innovation and the unique needs of medical students on a surgical clerkship. Surgeon educators should embrace the opportunity to contribute LIC curriculum development and subsequent investigation into how this modality interfaces with the learning objectives of undergraduate surgical education. A formal description of essential curriculum components for all surgical LIC programs is needed to ensure appropriate surgical education across the varied LIC models.

Quality improvement strategies in pediatric ECMO.

Pediatric extracorporeal membrane oxygenation is an increasingly utilized, life-saving technology with high mortality and morbidity. A complex technology employed urgently or emergently for some of the sickest children in the hospital by a large multidisciplinary team, ECMO is an ideal area for using quality improvement strategies to reduce the variability in care and improve patient outcomes. We review critical concepts from quality improvement and apply them to patient selection and management, staffing, credentialing and continuing education, and the variability of management among providers and institutions.

Use of pediatric trauma simulations to facilitate exposure to pediatric trauma resuscitations during training.

BACKGROUND: Pediatric traumas are often high-acuity but are low-frequency compared to adult trauma activations. This is reflected in the relatively limited experience with these events during training. Although some principles of trauma resuscitation are similar between adults and children, there are also important differences in physiology, injury patterns, and presentation. Therefore, simulation can be used to supplement trainee exposure and enhance their ability to respond to these high-stakes events. METHODS: We developed a multidisciplinary pediatric trauma resuscitation simulation curriculum to increase exposure to pediatric traumas at our institution. The intervention includes monthly sessions in the pediatric resuscitation bays, during which multidisciplinary teams complete 2 full pediatric trauma resuscitation simulations. This is supplemented with formal debriefing, simulation-specific teaching, and standardized trauma cognitive aids. The comprehensiveness of trauma evaluations and resuscitation efforts are evaluated using our institutional structured trauma resuscitation observation tool, and post-simulation surveys are used to assess the impact of the teaching interventions. RESULTS: Nine simulation sessions were conducted with more than 100 participants, including surgical residents, emergency medicine residents, nursing staff, respiratory therapists, and medical students. Completeness of resuscitation efforts improved from 55% to 82% (P < .01) between initial and repeat simulations. Surveyed participants reported improvement in overall team performance on the Team Emergency Assessment Measure (P < .01). CONCLUSION: Implementing a multidisciplinary pediatric trauma simulation curriculum with structured teaching interventions and standardized trauma scripts promotes teamwork and strengthens trainees' ability to conduct comprehensive evaluations required for high-acuity pediatric traumas.

The Surgical Subinternship: A Unique Opportunity for Early Leadership Development.

Subinternships are formative rotations in the surgery-bound medical student's journey to surgical training. This experience allows for further exploration of career goals, plays an important evaluative role in the residency selection process, and offers ongoing opportunities for technical and non-technical development. The graduated responsibility experienced in this setting extends beyond what was experienced during the core surgical clerkship where students are first interfacing with the clinical environment. We review and reflect on the role of subinternships in developing the leadership skills that surgery-bound medical students will need to effectively lead interprofessional healthcare teams in the future.

Risk of Surgical Intervention in Children with Diagnoses of Cancer and Preoperative Malnutrition: A National Analysis.

BACKGROUND: Perioperative nutrition is a critical component of appropriate healing and recovery after surgery. We sought to identify perioperative risk in children with cancer and low preoperative hypoalbuminemia undergoing surgical intervention. METHODS: We queried the 2015-2019 NSQIP-Peds datasets for children with a primary diagnosis of renal or hepatic malignancy undergoing surgical resection. Postoperative outcomes were evaluated for comparative risk between patients with low albumin (albumin<3.0 g/dL) and normal albumin within 30 days of their surgical procedure. Univariate analysis and multivariable logistic regression were conducted to identify perioperative risk in patients with hypoalbuminemia. RESULTS: We identified 360 children with primary diagnosis of hepatic malignancy and 896 children with renal malignancy undergoing surgical resection. Of these, 77 children had hypoalbuminemia. Patients with renal or hepatic malignancy diagnosis and low albumin levels were more likely to experience postoperative dehiscence, need for TPN at discharge, postoperative bleeding or transfusion, unplanned reoperation, and unplanned readmission, based on univariate analysis (all P > 0.05). Postoperative bleeding, need for nutritional support at discharge, and unplanned readmission were each associated with hypoalbuminemia. CONCLUSION: We demonstrate that low preoperative albumin is associated with significant perioperative risk. More attention should focus on perioperative nutritional status of children with cancer who are undergoing major resections.

Impact of Ventricular Dominance on Long-Term Fontan Outcomes: A 25-year Single-institution Study.

BACKGROUND: The long-term impact of ventricular dominance on Fontan outcomes is controversial. This study examined this issue in a 25-year cohort. METHODS: Patients undergoing the Fontan operation at a single institution (Duke University Medical Center, Durham, NC) from October 1998 to February 2022 were reviewed. Primary outcomes were transplant-free survival and Fontan failure (death, heart transplantation, takedown, protein-losing enteropathy, or plastic bronchitis). Secondary outcomes included hospital and intensive care lengths of stay. Kaplan-Meier methodology compared outcomes by ventricular dominance. Multiphase parametric risk hazard analysis identified risk factors for primary outcomes. RESULTS: There were 195 patients (104 right ventricular dominant) included in the study. Baseline characteristics were comparable. Perioperative survival was similar (right ventricular dominant, 98%; non-right ventricular dominant, 100%; P = .51). The proportion of patients experiencing death or heart transplantation was 8.7%, and the rate of Fontan failure was 11.8% during a median follow-up of 4.5 years (interquartile range, 0.3-9.8 years). Right ventricular-dominant patients had reduced transplant-free survival (10-year estimates: 80% [95% CI, 70%-91%] vs 92% [95% CI, 83%-100%]; P = .04) and freedom from Fontan failure (73% [95% CI, 62%-86%] vs 92% [95% CI, 83%-100%]; P = .04). Multiphase hazard modeling resolved 2 risk phases. The early phase spanned from surgery to approximately 6 months afterward. The late phase spanned from approximately 6 months after surgery onward. In multivariable analysis, right ventricular dominance was an independent risk factor for death or heart transplantation (parameter estimate, 1.3 ± 0.6; P = .04) and Fontan failure (1.1 ± 0.5; P = .04) during the second phase, with no significant first-phase risk factors. CONCLUSIONS: Right ventricular dominance was associated with long-term complications after Fontan procedures, including mortality, heart transplantation, and Fontan failure. This cohort may benefit from heightened surveillance in a multidisciplinary Fontan clinic after the perioperative period.

Improved survival and higher rates of surgical resection associated with hepatocellular carcinoma in children as compared to young adults.

Hepatocellular adenocarcinoma (HCC) is the second most common primary hepatic malignancy in children with a 5-year overall survival of 30%. Few studies have examined the similarities and differences between pediatric and adult HCC. This article aims to examine the relationship between tumor characteristics, treatments and outcomes in pediatric and adult patients with HCC. The 2019 National Cancer Database was queried for patients with HCC. Patients were stratified by age: pediatric <21 years (n = 214) and young adults 21 to 40 (n = 1102). Descriptive statistics and chi square were performed. The mean age at diagnosis was 15.5 years (SD 5.6) in the pediatric and 33 years (5.3) in the adult group. Children had a comparable rate of metastasis (30% vs 28%, P = .47) and increased fibrolamellar histology (32% vs 9%). Surgical resection was more common in children compared to adults (74% vs 62%, P < .001), children also had more lymph nodes examined (39% vs 19%, P < .001), positive lymph nodes (35% vs 17%, P = .02) and surgical resection when metastasis were present at diagnosis (46% vs 18%, P < .001). The 1-, 3- and 5-year overall survival was higher for pediatric patients than adults (81%, 65%, 55%, vs 70%, 54%, 48%). Despite higher prevalence of fibrolamellar histology, greater number of positive lymph nodes and comparable rates of metastasis at diagnosis, children with HCC have improved overall survival compared to adults. Age did not significantly contribute to survivorship, so it is likely that the more aggressive surgical approach contributed to the improved overall survival in pediatric patients.

Use of a Structured Observation Tool to Promote Medical Student Engagement in Trauma Resuscitations.

OBJECTIVE: We describe a novel approach to promoting medical student learning and engagement during trauma resuscitation with implementation of a structured observation and debriefing tool. DESIGN: In the context of a multifaceted quality improvement effort in our emergency room, we implemented a structured trauma observation tool (SOT) for medical students based on ATLS trauma guidelines. The SOT reflects the American College of Surgeons and Association for Surgical Education (ACS/ASE) trauma evaluation module for medical students. Two medical students from our quality improvement working group undertook a proof-of-concept study to determine whether the SOT facilitated accurate observations of trauma resuscitations and promoted educational debriefs with precepting providers. Results were encouraging, so the tool was implemented for elective use on surgical clerkships. Clerkship students who used the SOT were given the opportunity to share its impact on their experience. Institutional Review Board approval was obtained under Pro00109569. SETTING: A large level 1 trauma center at an academic hospital in the southeastern United States. PARTICIPANTS: An interdisciplinary working group including surgeons, emergency medicine physicians, nurses, and students developed the observation tool. Two medical students from this team showed that the tool was effective at guiding observations and facilitating debriefs prior to its broader implementation on the general surgery clerkship. RESULTS: A total of 630 resuscitation tasks were observed during 15 trauma activations prior to implementation on the surgery clerkship. There was over 97% agreement between students observations and evaluating physicians self-reporting on which tasks were completed. Tasks on which there was disagreement were discussed to aid student learning. The tool was implemented for elective use on the surgery clerkship where students reported positive experiences. CONCLUSIONS: Early data suggest that this structured observation tool facilitates accurate trauma assessment observations and provides an opportunity for high-yield debriefs with the evaluating physician. This promotes student comprehension of ATLS principles. The SOT is being implemented as a pedagogic tool for students on the surgery clerkship to guide their observations, improve comprehension of decisions made in a hyperacute setting, and offer real time feedback as part of their learning in the trauma bay. The tool appears to be a valuable supplement which supports the ACS/ASE curriculum.

Minimally Invasive Approach for Cardiac Hemangioma Resection in a Teenager.

Cardiac hemangiomas are a rare tumor traditionally resected by median sternotomy. We performed a minimally invasive right ventricular cardiac hemangioma resection via a left anterior mini-incision (LAMI). The procedure was without complication, and the patient was discharged on postoperative day 2. The LAMI has been used broadly by our team for operations involving the right ventricular outflow tract, as an alternative to median sternotomy. Here we show that it can also be used for the resection of a cardiac tumor.

Biliary atresia in a neonate with a history of COVID-19: A case report.

INTRODUCTION AND IMPORTANCE: Biliary Atresia is the progressive destruction of the neonatal intra- and extra- hepatic bile ducts. The novel coronavirus has shown dramatic hepatic tropism, and patients experiencing liver injury appear to have worse outcomes. We present the first documented case of a neonate diagnosed with Biliary Atresia and a prior history of COVID-19. CASE PRESENTATION: A two-month-old female presented with increasing scleral icterus. Her laboratory testing demonstrated direct hyperbilirubinemia, with elevated alkaline phosphatase and increased ALT. She tested positive for COVID-19 at that time, requiring a two-week quarantine during which time she did not develop respiratory symptoms. Two weeks later, she presented to the hospital with emesis and an evaluation concerning for biliary atresia. She ultimately underwent a Kasai repair and recovered well with no significant post-operative complications. CLINICAL DISCUSSION: Biliary Atresia is a heterogenous disease of unknown etiology, though viral triggers are suggested to contribute. COVID-19 disease is frequently associated with liver damage, though its relationship to Biliary Atresia is unexplored. We present a case of a neonate who contracted COVID-19 infection, and subsequently developed biliary atresia. CONCLUSION: Considering this child's concurrent COVID-19 infection, viral mediated hepatic and biliary inflammation may have contributed to the development of Biliary Atresia in this case. The proposed relationship requires additional investigation but may suggest value in COVID-19 testing for patients presenting with Biliary Atresia.

MAVRIC: a multicenter randomized controlled trial of transabdominal vs transvaginal cervical cerclage.

BACKGROUND: Vaginal cerclage (a suture around the cervix) commonly is placed in women with recurrent pregnancy loss. These women may experience late miscarriage or extreme preterm delivery, despite being treated with cerclage. Transabdominal cerclage has been advocated after failed cerclage, although its efficacy is unproved by randomized controlled trial. OBJECTIVE: The objective of this study was to compare transabdominal cerclage or high vaginal cerclage with low vaginal cerclage in women with a history of failed cerclage. Our primary outcome was delivery at <32 completed weeks of pregnancy. STUDY DESIGN: This was a multicenter randomized controlled trial. Women were assigned randomly (1:1:1) to receive transabdominal cerclage, high vaginal cerclage, or low vaginal cerclage either before conception or at <14 weeks of gestation. RESULTS: The data for 111 of 139 women who were recruited and who conceived were analyzed: 39 had transabdominal cerclage; 39 had high vaginal cerclage, and 33 had low vaginal cerclage. Rates of preterm birth at <32 weeks of gestation were significantly lower in women who received transabdominal cerclage compared with low vaginal cerclage (8% [3/39] vs 33% [11/33]; relative risk, 0.23; 95% confidence interval, 0.07-0.76; P=.0157). The number needed to treat to prevent 1 preterm birth was 3.9 (95% confidence interval, 2.32-12.1). There was no difference in preterm birth rates between high and low vaginal cerclage (38% [15/39] vs 33% [11/33]; relative risk, 1.15; 95% confidence interval, 0.62-2.16; P=.81). No neonatal deaths occurred. In an exploratory analysis, women with transabdominal cerclage had fewer fetal losses compared with low vaginal cerclage (3% [1/39] vs 21% [7/33]; relative risk, 0.12; 95% confidence interval, 0.016-0.93; P=.02). The number needed to treat to prevent 1 fetal loss was 5.3 (95% confidence interval, 2.9-26). CONCLUSION: Transabdominal cerclage is the treatment of choice for women with failed vaginal cerclage. It is superior to low vaginal cerclage in the reduction of risk of early preterm birth and fetal loss in women with previous failed vaginal cerclage. High vaginal cerclage does not confer this benefit. The numbers needed to treat are sufficiently low to justify transabdominal surgery and cesarean delivery required in this select cohort.

Does progesterone prophylaxis to prevent preterm labour improve outcome? A randomised double-blind placebo-controlled trial (OPPTIMUM).

BACKGROUND: Progesterone prophylaxis is widely used to prevent preterm birth but is not licensed and there is little information on long-term outcome. OBJECTIVE: To determine the effect of progesterone prophylaxis in women at high risk of preterm birth on obstetric, neonatal and childhood outcomes. DESIGN: Double-blind, randomised placebo-controlled trial. SETTING: Obstetric units in the UK and Europe between February 2009 and April 2013. PARTICIPANTS: Women with a singleton pregnancy who are at high risk of preterm birth because of either a positive fibronectin test or a negative fibronectin test, and either previous spontaneous birth at ≤ 34 weeks+0 of gestation or a cervical length of ≤ 25 mm. INTERVENTIONS: Fibronectin test at 18+0 to 23+0 weeks of pregnancy to determine risk of preterm birth. Eligible women were allocated (using a web-based randomisation portal) to 200 mg of progesterone or placebo, taken vaginally daily from 22+0 to 24+0 until 34+0 weeks' gestation. Participants, caregivers and those assessing the outcomes were blinded to group assignment until data collection was complete. MAIN OUTCOME MEASURES: There were three primary outcomes, as follows: (1) obstetric - fetal death or delivery before 34+0 weeks' gestation; (2) neonatal - a composite of death, brain injury on ultrasound scan (according to specific criteria in the protocol) and bronchopulmonary dysplasia; and (3) childhood - the Bayley-III cognitive composite score at 22-26 months of age. RESULTS: In total, 96 out of 600 (16%) women in the progesterone group and 108 out of 597 (18%) women in the placebo group had the primary obstetric outcome [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.61 to 1.22]. Forty-six out of 589 (8%) babies of women in the progesterone group and 62 out of 587 (11%) babies of women in the placebo group experienced the primary neonatal outcome [OR 0.72, 95% CI 0.44 to 1.17]. The mean Bayley-III cognitive composite score of the children at 2 years of age was 97.3 points [standard deviation (SD) 17.9 points; n = 430] in the progesterone group and 97.7 points (SD 17.5 points; n = 439) in the placebo group (difference in means -0.48, 95% CI -2.77 to 1.81). LIMITATIONS: Overall compliance with the intervention was 69%. HARMS: There were no major harms, although there was a trend of more deaths from trial entry to 2 years in the progesterone group (20/600) than in the placebo group (16/598) (OR 1.26, 95% CI 0.65 to 2.42). CONCLUSIONS: In this study, progesterone had no significant beneficial or harmful effects on the primary obstetric, neonatal or childhood outcomes.The OPPTIMUM trial is now complete. We intend to participate in a comprehensive individual patient-level data meta-analysis examining women with a singleton pregnancy with a variety of risk factors for preterm birth. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14568373. FUNDING: This trial was funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC-NIHR partnership.

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial.

BACKGROUND: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child. METHODS: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373. FINDINGS: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27). INTERPRETATION: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age. FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Oxytocin activates NF-κB-mediated inflammatory pathways in human gestational tissues.

Human labour, both at term and preterm, is preceded by NF-κB-mediated inflammatory activation within the uterus, leading to myometrial activation, fetal membrane remodelling and cervical ripening. The stimuli triggering inflammatory activation in normal human parturition are not fully understood. We show that the neurohypophyseal peptide, oxytocin (OT), activates NF-κB and stimulates downstream inflammatory pathways in human gestational tissues. OT stimulation (1 pM-100 nM) specifically via its receptor (OTR) in human myometrial and amnion primary cells led to MAPK and NF-κB activation within 15 min and maximal p65-subunit nuclear translocation within 30 min. Both in human myometrium and amnion, OT-induced activation of the canonical NF-κB pathway upregulated key inflammatory labour-associated genes including IL-8, CCL5, IL-6 and COX-2. IKKß inhibition (TPCA1; 10 µM) suppressed OT-induced NF-κB-p65 phosphorylation, whereas p65-siRNA knockdown reduced basal and OT-induced COX-2 levels in myometrium and amnion. In both gestational tissues, MEK1/2 (U0126; 10 µM) or p38 inhibition (SB203580; 10 µM) suppressed OT-induced COX-2 expression, but OT-induced p65-phosphorylation was only inhibited in amnion, suggesting OT activation of NF-κB in amnion is MAPK-dependent. Our data provide new insight into the OT/OTR system in human parturition and suggest that its therapeutic modulation could be a strategy for regulating both contractile and inflammatory pathways in the clinical context of term/preterm labour.

Whole cell bioreporter application for rapid detection and evaluation of crude oil spill in seawater caused by Dalian oil tank explosion.

Accidents involving the release of crude oil to seawater pose serious threat to human and animal health, fisheries and marine ecosystems. A whole cell bioreporter detection method, which has unique advantages for the rapid evaluation on toxicity and bioavailability, is a useful tool to provide environmental risk assessments at crude oil-contaminated sites. Acinetobacter baylyi ADPWH_alk and ADPWH_recA are chromosomally-based alkane and genotoxicity bioreporters which can be activated to express bioluminescence in the presence of alkanes and genotoxic compounds. In this study, we applied Acinetobacter ADPWH_alk and ADPWH_recA bioreporters to examine six seawater and six sediment samples around the Dalian Bay four weeks after an oil tank explosion in Dalian, China in 2010, and compared the results with samples from the same sites one year after. The results of bioreporter detection suggest that seawater and sediments from five sites (DB, NT, JSB, XHP and FJZ) four weeks after the oil-spill were contaminated by the crude oil with various extents of genotoxicity. Among these six sites, DB and NT had high oil contents and genotoxicity, and JSB had high oil content but low genotoxicity in comparison with an uncontaminated site LSF, which is located at other side of the peninsula. These three sites (DB, NT and JSB) with detectable genotoxicity are within 30 km away from the oil spill point. The far-away two sites XHP (38.1 km) and FJZ (31.1 km) were lightly contaminated with oil but no genotoxicity suggesting that they are around the contamination boundary. Bioreporter detection also indicates that all six sites were clean one year after the oil-spill as the alkane and genotoxicity were below detection limit. This study demonstrates that bioreporter detection can be used as a rapid method to estimate the scale of a crude oil spill accident and to evaluate bioavailability and genotoxicity of contaminated seawater and sediments, which are crucial to risk assessment and strategic decision-making for environmental management and clean-up.