What Should Students and Trainees Be Taught About Turfing and Where Patients Belong?

Turfing is a colloquialism that refers to what clinicians do to patients whose needs do not fit neatly and tidily into typical clinical placement protocols, especially during inpatient admissions from a hospital's emergency department. This term and this practice are both clinically and ethically problematic because a patient is rarely, if ever, "turfed" to their advantage. Ethically speaking, turfing constitutes deferral of responsibility for a patient's admission or care to colleagues. This article suggests when and under which circumstances it is clinically and ethically appropriate to defer a patient's care and suggests why turfing happens despite its negative influence on both physicians and patients.

Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis.

Cancer cells are dependent on cholesterol, and they possess strictly controlled cholesterol homeostasis mechanisms. These allow them to smoothly switch between cholesterol synthesis and uptake to fulfill their needs and to adapt environmental changes. Here we describe a mechanism of how cancer cells employ oncogenic growth factor signaling to promote uptake and utilization of extracellular cholesterol via Myeloid Zinc Finger 1 (MZF1)-mediated Niemann Pick C1 (NPC1) expression and upregulated macropinocytosis. Expression of p95ErbB2, highly oncogenic, standard-treatment resistant form of ErbB2 mobilizes lysosomes and activates EGFR, invasion and macropinocytosis. This is connected to a metabolic shift from cholesterol synthesis to uptake due to macropinocytosis-enabled flow of extracellular cholesterol. NPC1 increase facilitates extracellular cholesterol uptake and is necessary for the invasion of ErbB2 expressing breast cancer spheroids and ovarian cancer organoids, indicating a regulatory role for NPC1 in the process. The ability to obtain cholesterol as a byproduct of increased macropinocytosis allows cancer cells to direct the resources needed for the energy-consuming cholesterol synthesis towards other activities such as invasion. These results demonstrate that macropinocytosis is not only an alternative energy source for cancer cells but also an efficient way to provide building material, such as cholesterol, for its macromolecules and membranes.

Anesthetic Considerations for Cesarean Delivery in a Parturient With Severe Gitelman Syndrome.

Gitelman syndrome is an autosomal recessive inherited disorder that impairs the function of thiazide-sensitive sodium-chloride cotransporters in the distal convoluted tubule of the nephron. During labor and delivery, avoidance of sympathetic overactivity, meticulous hemodynamic monitoring, and expedited repletion of potassium and magnesium are required to avoid adverse outcomes. We present a parturient with severe Gitelman syndrome, requiring continuous electrolyte and fluid infusions, who underwent successful cesarean delivery. Potential severe morbidity was avoided with multidisciplinary planning and management.

Elevated midtrimester maternal plasma cytokines and preterm birth in patients with cerclage.

BACKGROUND: Cerclage is used for the prevention of spontaneous preterm birth; however, many patients at high risk of spontaneous preterm birth who have a cerclage in place eventually deliver before term. Although inflammation, measured by biomarkers (eg, cytokines), is a known risk factor for preterm delivery, evaluation of inflammation to determine pregnancy outcomes among patients with cerclage is poorly understood. OBJECTIVE: We sought to examine levels of maternal plasma inflammatory cytokines in the midtrimester among asymptomatic patients with a cervical cerclage (placed for any indication, including history, ultrasound, and examination indications) to evaluate the association between cytokine levels and preterm birth. STUDY DESIGN: This was a prospective cohort study of singleton, nonanomalous pregnancies who had a cerclage placed at <24 weeks of gestation from 2015 to 2018 at a single tertiary institution. Maternal plasma was collected perioperatively whenever possible. A custom magnetic bead Luminex cytokine assay was used to measure plasma inflammatory cytokine levels from these stored samples. The primary outcome was preterm birth at <37 weeks of gestation. A statistical cut point was calculated for each cytokine level to assess its optimal sensitivity and specificity for spontaneous preterm birth prediction. Patients were classified as having a "high" or "low" result for each cytokine based on this cut point. Receiver operating characteristic curve analysis was performed to estimate sensitivity, specificity, and positive and negative predictive values for spontaneous preterm birth prediction. Cox proportional-hazards regression modeled the association between the number of "high" inflammatory cytokines and gestational age at delivery, adjusting for confounders. Additional analyses were performed on the subgroup of patients with history-indicated cerclage and those with an ultrasound- or examination-indicated cerclage. RESULTS: A total of 43 patients participated in this study: 20 (46.5%) had spontaneous preterm birth (median, 30.9 weeks of gestation; interquartile range, 28.4-35.0). Plasma samples were collected at a median of 0 (interquartile range, -2 to 17) days concerning cerclage placement and a median of 18 (interquartile range, 13-21) weeks of gestation. Based on the statistical cut point for each cytokine level, 7% of patients had zero, 20.9% had 1, 18.6% had 2, 20.9% had 3, and 32.6% had ≥4 "high" cytokine results. Each additional "high" cytokine level was associated with earlier delivery (hazard ratio, 1.51; 95% confidence interval, 1.25-1.81) even after controlling for ultrasound- or examination-indication for cerclage (hazard ratio, 1.73; 95% confidence interval, 0.95-3.15). The presence of ≥4 "high" cytokine levels was 70% sensitive and 74% specific for predicting spontaneous preterm birth (area under the curve, 0.846; 95% confidence interval, 0.728-0.964; positive predictive value, 70%; negative predictive value, 73.9%). CONCLUSION: Among patients with a cervical cerclage, elevated midtrimester maternal plasma cytokine profiles were associated with subsequent preterm birth and can estimate the probability of preterm birth. Confirmation and refinement of this noninvasive panel may provide insight into improved selection of individuals who may benefit from cerclage placement and investigation of therapeutic strategies to mitigate midpregnancy inflammation.

The association of skin incision placement during cesarean delivery with wound complications in obese women: a systematic review and meta-analysis.

OBJECTIVE: To determine the risk of wound complications by skin incision type in obese women undergoing cesarean delivery.Data sources: Electronic databases (MEDLINE, Scopus, and Ovid) were searched from their inception through August 2018.Methods of study selection: We included all randomized controlled trials and cohort studies reporting the placement of skin incision during cesarean section in obese women, defined as those with BMI ≥30 kg/m2. Studies were included if they compared one placement of skin incision with a different one as comparison group. The primary outcome was incidence of wound complications, while secondary outcomes included wound infection, hematoma, seroma, postpartum hemorrhage, and endometritis. Demographics and outcomes for each individual study identified were reported as part of the review. Meta-analysis was performed using the random effects model of DerSimonian and Laird, to produce summary treatment effects in terms of mean difference (MD) or relative risk (RR) with 95% confidence interval (CI). Sub-group analyses (vertical versus Pfannenstiel) were also reported.Tabulation, integration and results: Seventeen studies (including 3 RCTs; 8960 participants among the 15 non-overlapping studies) were included in the systematic review. Vertical incisions were associated with a relative risk of 2.07 (95% CI1.61-2.67) for wound complications compared to transverse incisions, however significant possible confounders were present. Studies were mildly-moderately heterogeneous (I2 44.81%, 95% CI 0.00-71.85%) with varying definitions of obesity and wound complications. High transverse incisions (3 studies, 218 participants) trend toward a lower risk of wound complications compared to low transverse incisions (RR 0.338, 95% CI 0.114-1.004). CONCLUSIONS: Vertical incisions may be associated with an increased risk for wound complications compared to transverse incisions for cesarean delivery in obese women. Randomized controlled trials are needed to evaluate optimal cesarean skin incisions for these women.

Identification of lysosome-targeting drugs with anti-inflammatory activity as potential invasion inhibitors of treatment resistant HER2 positive cancers.

PURPOSE: Most HER2 positive invasive cancers are either intrinsic non-responsive or develop resistance when treated with 1st line HER2 targeting drugs. Both 1st and 2nd line treatments of HER2 positive cancers are aimed at targeting the HER2 receptor directly, thereby strongly limiting the treatment options of HER2/ErbB2 inhibition resistant invasive cancers. METHODS: We used phenotypic high throughput microscopy screening to identify efficient inhibitors of ErbB2-induced invasion using 1st line HER2 inhibitor trastuzumab- and pertuzumab-resistant, p95-ErbB2 expressing breast cancer cells in conjunction with the Prestwick Chemical Library®. The screening entailed a drug's ability to inhibit ErbB2-induced, invasion-promoting positioning of lysosomes at the cellular periphery, a phenotype that defines their invasiveness. In addition, we used high throughput microscopy and biochemical assays to assess the effects of the drugs on lysosomal membrane permeabilization (LMP) and autophagy, two features connected to cancer treatment. Using 2nd line HER2 inhibitor lapatinib resistant 3-dimensional model systems, we assessed the effects of the drugs on ErbB2 positive breast cancer spheroids and developed a high-throughput invasion assay for HER2 positive ovarian cancer organoids for further evaluation. RESULTS: We identified Auranofin, Colchicine, Monensin, Niclosamide, Podophyllotoxin, Quinacrine and Thiostrepton as efficient inhibitors of invasive growth of 2nd line HER2 inhibitor lapatinib resistant breast cancer spheroids and ovarian cancer organoids. We classified these drugs into four groups based on their ability to target lysosomes by inducing autophagy and/or LMP, i.e., drugs inducing early LMP, early autophagy with late LMP, late LMP, or neither. CONCLUSIONS: Our results indicate that targetable lysosome-engaging cellular pathways downstream of ErbB2 contribute to invasion. They support lysosomal trafficking as an attractive target for therapy aiming at preventing the spreading of cancer cells. Since these drugs additionally possess anti-inflammatory activities, they could serve as multipurpose drugs simultaneously targeting infection/inflammation and cancer spreading.

Is Group B Streptococcus Colonization Associated with Maternal Peripartum Infection in an Era of Routine Prophylaxis?

OBJECTIVE: This study aimed to assess whether colonization with group B streptococcus (GBS) is associated with maternal peripartum infection in an era of routine prophylaxis. STUDY DESIGN: This study presented a secondary analysis of women delivering ≥37 weeks who underwent a trial of labor from the U.S. Consortium on Safe Labor (CSL) study. The exposure was maternal GBS colonization and the outcome was a diagnosis of chorioamnionitis, and secondarily, analyses were restricted to deliveries not admitted in labor and measures of postpartum infection (postpartum fever, endometritis, and surgical site infection). Logistic regression with generalized estimating equations was used accounting for within-woman correlations. Models adjusted for maternal age, parity, race, prepregnancy body mass index, pregestational diabetes, insurance status, study site/region, year of delivery, number of vaginal exams from admission to delivery, and time (in hours) from admission to delivery. RESULTS: Among 170,804 assessed women, 33,877 (19.8%) were colonized with GBS and 5,172 (3.0%) were diagnosed with chorioamnionitis. While the frequency of GBS colonization did not vary by chorioamnionitis status (3.0% in both groups), in multivariable analyses, GBS colonization was associated with slightly lower odds of chorioamnionitis (adjusted odds ratio [AOR]: 0.89; 95% confidence interval [CI]: 0.83-0.96). In secondary analyses, this association held regardless of spontaneous labor on admission; and the odds of postpartum infectious outcomes were not higher with GBS colonization. CONCLUSION: In contrast to historical data, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis. KEY POINTS: · Data in an era prior to routine group B streptococcus (GBS) screening and prophylaxis showed that maternal GBS colonization was associated with a higher frequency of maternal peripartum infection.. · In the current study, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis.. · The results highlight potential benefits of GBS screening and intrapartum antibiotic prophylaxis beyond neonatal disease prevention, including mitigating the risk of maternal infectious morbidity..

Nitrous oxide analgesia for external cephalic version: A randomized controlled trial.

STUDY OBJECTIVE: Our study sought to determine whether or not nitrous oxide analgesia decreases pain compared to oxygen placebo during external cephalic version for breech presentation. Procedural success may be limited by pain and anxiety. Although neuraxial anesthesia has been studied extensively for these procedures, many centers lack resources for routine use. Nitrous oxide is noninvasive, has minimal side effects and requires limited facilities. We hypothesized that its analgesic properties would decrease pain compared to oxygen placebo during external cephalic version. DESIGN: Double-blinded randomized placebo-controlled trial. SETTING: Labor and delivery triage room. PATIENTS: Forty-eight patients, ≥18 years of age, 37-weeks' gestation or beyond, singleton pregnancy, breech presentation, and American Society of Anesthesiology physical status I-III, having an external cephalic version. INTERVENTIONS: Patients undergoing external cephalic version were randomized to receive self-administered 50% nitrous oxide/50% oxygen versus 100% oxygen placebo. MEASUREMENTS: The primary outcome measured was intra-procedural pain. Secondary outcomes were intra-procedural anxiety, patient satisfaction, and procedure difficulty. MAIN RESULTS: Forty-eight patients were enrolled; 23 received nitrous oxide and 25 received oxygen. No difference was noted in mean pain scores (nitrous oxide 5.5 ± 2.3, placebo 5.4 ± 2.7, [CI95% = -1.40, 1.51]; P = 0.943) or anxiety scores (nitrous oxide 1.6 ± 2.0, placebo 1.2 ± 1.8, [CI95% = -0.74, 1.45]; P = 0.515). Procedural difficulty (1-10 scale, 1 = very easy, 10 = extremely difficult) was not different between groups (nitrous oxide 6.1 ± 2.2, placebo 6.1 ± 3.2, [CI95% = -1.54, 1.66]; P = 0.944). There was a significant increase in the number of version attempts in the nitrous oxide group (nitrous oxide 3.9 ± 1.9, placebo 2.8 ± 1.4, [CI95% = 0.05, 2]; P = 0.046). Patient satisfaction was significantly lower in the nitrous oxide group (nitrous oxide 4.3 ± 4.0, placebo 6.9 ± 3.6, [CI95% = -4.93, -0.34]; P = 0.025). CONCLUSION: Despite the desirable properties of nitrous oxide, there was no analgesic benefit over oxygen for external cephalic version. Its routine use for these procedures was not supported.

Association of chorioamnionitis and patent ductus arteriosus in a national U.S. cohort.

OBJECTIVE: To estimate the effect of clinical chorioamnionitis on the risk of patent ductus arteriosus (PDA). STUDY DESIGN: A secondary analysis of all deliveries >23 gestational weeks from the U.S. Consortium on Safe Labor (CSL) study. The primary exposure was a clinical diagnosis of chorioamnionitis, and the outcome was a diagnosis of PDA. Generalized estimating equations with estimated error variance for women with multiple deliveries were utilized. Models adjusted for age, race, region, delivery year, body mass index, infant sex, multiple gestation, mode of delivery, and antenatal corticosteroid exposure. RESULTS: Among 228,438 deliveries, a diagnosis of PDA was more frequent with chorioamnionitis exposure versus without (9.2% vs. 3.0%; OR: 3.25; 95% CI: 2.92-3.62). Chorioamnionitis was associated with higher adjusted odds of PDA (AOR: 2.18; 95% CI: 1.93-2.45). In sensitivity analyses, the association between chorioamnionitis and PDA held after adjustment for gestational age at delivery (AOR: 1.28; 95% CI: 1.13-1.44). CONCLUSIONS: Chorioamnionitis was associated with increased odds of PDA. Robust exposure and outcome ascertainment with careful assessment of confounding is needed to further investigate this epidemiologic association.

Preoperative cefazolin rather than clindamycin or metronidazole is associated with lower postpartum infection among women with chorioamnionitis delivering by cesarean delivery.

BACKGROUND: The optimal antibiotic regimen to prevent maternal postpartum infection among high-risk women treated for chorioamnionitis delivering by cesarean delivery remains to be defined. Emerging data suggest that cefazolin decreases the risk of cesarean surgical site infection. OBJECTIVE: To investigate whether intrapartum antibiotic therapy with cefazolin versus the current standard clindamycin or metronidazole decreases the risk of postpartum infectious morbidity among women delivering by cesarean delivery who were receiving a base regimen of ampicillin or penicillin with gentamicin for chorioamnionitis. MATERIALS AND METHODS: A secondary analysis from the Maternal-Fetal Medicine Units Network (MFMU) Cesarean Registry. We included women who delivered by cesarean delivery with presumptive chorioamnionitis (intrapartum fever >100.4°F and receipt of intrapartum antibiotics). All women received a base regimen of penicillin or ampicillin with gentamicin. We compared antibiotic therapy with cefazolin versus clindamycin or metronidazole. The primary outcome was a composite of postpartum maternal infection, including endometritis and surgical site infection. Multivariable logistic regression was used, adjusting for age, parity, race/ethnicity, insurance, body mass index at delivery, tobacco use, pregestational diabetes, American Society of Anesthesiologists classification, trial of labor prior to cesarean delivery, and postpartum antibiotics. RESULTS: Among 1105 women with presumptive chorioamnionitis who delivered by cesarean delivery, 22.0% (n = 244) received cefazolin and 77.9% (n = 861) received clindamycin or metronidazole. Most women were in labor prior to cesarean delivery (93.8%) and received postpartum antibiotics (88.4%). Almost one-tenth (9.5%) were diagnosed with a postpartum infection, most commonly endometritis (80.9%), followed by surgical site infection (20.9%) (not mutually exclusive). Women treated with cefazolin rather than clindamycin or metronidazole had lower odds of postpartum infectious morbidity (adjusted odds ratio, 0.49; 95% confidence interval, 0.26-0.90). This association held when the outcome was restricted to surgical site infection (adjusted odds ratio, 0.11; 95% confidence interval, 0.01-0.92) but not endometritis. Similar results were observed with propensity score analysis. CONCLUSION: Among women delivering by cesarean delivery who were treated for chorioamnionitis, additional antibiotic therapy with cefazolin decreased the risk of postpartum infection, primarily surgical site infection, compared to the current standard clindamycin or metronidazole.

SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells.

Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.

Association Between Maternal Obesity and Group B Streptococcus Colonization in a National U.S. Cohort.

Objective: To investigate the association between maternal obesity as measured by prepregnancy body mass index (BMI) and group B streptococcus (GBS) colonization. Methods: We conducted a secondary analysis from the Consortium on Safe Labor Study (CSL) in the United States cohort study (2002-2008). Pregnant women with deliveries at ≥37 weeks of gestation who attempted labor were included (115,070 assessed deliveries). The association between maternal prepregnancy BMI, categorized as normal weight or below (<25 kg/m2), overweight (25 to <30 kg/m2), class I obesity (30 to <35 kg/m2), class II obesity (35 to <40 kg/m2), and class III obesity (≥40 kg/m2), and GBS colonization was modeled using logistic regression with generalized estimating equations. Models adjusted for maternal age, parity, race, pregestational diabetes, insurance status, study site/region, and year of delivery. Results: The overall prevalence of GBS colonization was 20.5% (23,625/115,070), which increased with rising maternal BMI, normal weight 19.3% (13,543/70,098), overweight 20.8% (5,353/25,733), class I obesity 23.0% (2,596/11,275), class II obesity 26.1% (1,270/4,850), and class III obesity 27.7% (863/3,114). In multivariable analysis, increasing maternal obesity severity was associated with higher odds of GBS colonization, namely overweight (adjusted odds ratio [AOR]: 1.09, 95% confidence interval [CI]: 1.05-1.13), class I obesity (AOR: 1.20, 95% CI: 1.15-1.26), class II obesity (AOR: 1.42, 95% CI: 1.33-1.51), and class III obesity (AOR: 1.50; 95% CI: 1.38-1.62) compared with normal weight. In secondary analyses, these associations persisted when stratified by maternal race. Conclusions: In a national U.S. sample, increasing maternal obesity severity as assessed by prepregnancy BMI was associated with a higher likelihood of maternal GBS colonization during pregnancy.

The effect of orthognathic surgery on facial recognition algorithm analysis.

INTRODUCTION: The purpose of this study was to evaluate the ability of a publicly available facial recognition application program interface to calculate similarity scores for presurgical and postsurgical photographs of patients who underwent orthognathic surgeries. Our primary objective was to identify which surgical procedure(s) had the greatest effect(s) on the similarity score. METHODS: Existing photographs for 25 orthodontic-orthognathic patients were analyzed using the application program interface to calculate similarity scores between the presurgical and postsurgical photographs. Photographs from 2 presurgical timepoints were compared as controls. Both relaxed and smiling photographs were included to assess the added impact of a facial pose. Patient characteristics and surgery types were recorded for statistical analysis. Nonparametric Kruskal-Wallis rank-sum tests were performed to analyze the relationship between patient characteristics and similarity scores. Multiple comparisons Wilcoxon rank-sum tests were performed on the statistically significant characteristics. RESULTS: Recognition scores were significantly lower after orthognathic surgery at rest (P = 0.009) and smiling (P <0.001). Patients receiving both LeFort I and bilateral sagittal split osteotomy (BSSO) surgeries had a lower median similarity score compared with those that received only BSSO (P = 0.009) when comparing relaxed photographs before and after surgery. Similarly, for the score comparing presurgical relaxed photographs to postsurgical smiling photographs, patients that received both surgeries were found to have lower similarity scores compared with those receiving only BSSO (P = 0.036). CONCLUSIONS: Two-jaw surgeries were associated with a statistically significant decrease in similarity score when compared with 1-jaw procedure. Pose was also found to be a factor influencing similarity scores, especially when comparing presurgical relaxed photographs to postsurgical smiling photographs.

Adverse maternal and neonatal outcomes among women with preeclampsia with severe features <34 weeks gestation with versus without comorbidity.

OBJECTIVES: To determine adverse maternal and neonatal outcomes among women with preeclampsia with severe features who delivered <34 weeks comparing those with versus without a comorbid condition. STUDY DESIGN: A retrospective analysis from the U.S. Consortium on Safe Labor Study of deliveries <34 weeks with preeclampsia with severe features. We examined the association of each comorbid condition versus none with adverse maternal and neonatal outcomes. The comorbidities (not mutually exclusive) were chronic hypertension, pregestational diabetes, gestational diabetes, twin gestation, and fetal growth restriction. MAIN OUTCOMES: Maternal outcome: eclampsia, thromboembolism, ICU admission, and/or death; and neonatal outcome: intracranial/periventricular hemorrhage, hypoxic-ischemic encephalopathy/periventricular leukomalacia, stillbirth, and/or perinatal death. RESULTS: Among 2217 deliveries, 50% had a comorbidity, namely chronic hypertension (30%), pregestational diabetes (8%), gestational diabetes (8%), twin gestation (10%), and fetal growth restriction (7%). Adverse maternal and neonatal outcomes occurred in 10% and 12% of pregnancies, respectively. Pregnancies with preeclampsia with severe features delivered <34 weeks complicated by gestational diabetes (adjusted risk difference, aRD: -4.9%, 95%CI: -9.11 to -0.71), twin gestation (aRD: -5.1%, 95%CI: -8.63 to -1.73), and fetal growth restriction (aRD: -4.7%, 95%CI: -7.96 to -1.62) were less likely to result in adverse maternal outcome compared to pregnancies without comorbidity, but not chronic hypertension and pregestational diabetes. A pregnancy complicated by fetal growth restriction (aRD: 12.2%, 95%CI: 5.48 to 19.03) was more likely to result in adverse neonatal outcome, but not other comorbid conditions. CONCLUSIONS: Preeclampsia with severe features <34 weeks complicated by comorbidity was generally not associated with an increased risk of adverse maternal and neonatal outcomes, with the exception of fetal growth restriction.

Machine Learning and Statistical Models to Predict Postpartum Hemorrhage.

OBJECTIVE: To predict a woman's risk of postpartum hemorrhage at labor admission using machine learning and statistical models. METHODS: Predictive models were constructed and compared using data from 10 of 12 sites in the U.S. Consortium for Safe Labor Study (2002-2008) that consistently reported estimated blood loss at delivery. The outcome was postpartum hemorrhage, defined as an estimated blood loss at least 1,000 mL. Fifty-five candidate risk factors routinely available on labor admission were considered. We used logistic regression with and without lasso regularization (lasso regression) as the two statistical models, and random forest and extreme gradient boosting as the two machine learning models to predict postpartum hemorrhage. Model performance was measured by C statistics (ie, concordance index), calibration, and decision curves. Models were constructed from the first phase (2002-2006) and externally validated (ie, temporally) in the second phase (2007-2008). Further validation was performed combining both temporal and site-specific validation. RESULTS: Of the 152,279 assessed births, 7,279 (4.8%, 95% CI 4.7-4.9) had postpartum hemorrhage. All models had good-to-excellent discrimination. The extreme gradient boosting model had the best discriminative ability to predict postpartum hemorrhage (C statistic: 0.93; 95% CI 0.92-0.93), followed by random forest (C statistic: 0.92; 95% CI 0.91-0.92). The lasso regression model (C statistic: 0.87; 95% CI 0.86-0.88) and logistic regression (C statistic: 0.87; 95% CI 0.86-0.87) had lower-but-good discriminative ability. The above results held with validation across both time and sites. Decision curve analysis demonstrated that, although all models provided superior net benefit when clinical decision thresholds were between 0% and 80% predicted risk, the extreme gradient boosting model provided the greatest net benefit. CONCLUSION: Postpartum hemorrhage on labor admission can be predicted with excellent discriminative ability using machine learning and statistical models. Further clinical application is needed, which may assist health care providers to be prepared and triage at-risk women.

Ongoing and Focused Provider Performance Evaluations in Emergency Medicine: Current Practices and Modified Delphi to Guide Future Practice.

The Joint Commission requires ongoing and focused provider performance evaluations (OPPEs/FPPEs). The authors aim to describe current approaches in emergency medicine (EM) and identify consensus-based best practice recommendations. An online survey was distributed to leaders in EM to gain insight into current practices. A modified Delphi approach was then used to develop consensus to recommend best practice. A variety of strategies are currently in use for OPPE/FPPE. "Peer reviewed cases with opportunity for improvement" was identified as a preferred metric for OPPE. Although the preference was for use of peer review in OPPE, a consistent and standard adoption of robust internal care review processes is needed to establish expected norms. National benchmarking is not available currently. This was a limited survey of self-identified leaders, and there is an opportunity for additional engagement of leaders in EM to identify a unified approach that appropriately relates to patient outcomes.

Antihistamines and Ovarian Cancer Survival: Nationwide Cohort Study and in Vitro Cell Viability Assay.

Antihistamines with cationic amphiphilic drug (CAD) characteristics induce cancer-specific cell death in experimental studies. Epidemiologic evidence is, however, limited. In a Danish nationwide cohort of ovarian cancer patients diagnosed during 2000-2015 (n = 5075), we evaluated the association between filled antihistamine prescriptions and cancer mortality. We used Cox regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) for ovarian cancer mortality. In an in vitro cell viability assay, we evaluated cell death in three ovarian cancer cell lines after treatment with clinically relevant doses of eight antihistamines. In our cohort study, CAD antihistamine use (≥1 prescription; n = 133) was associated with a hazard ratio of 0.63 (95% CI = 0.40 to 0.99) compared to use of non-CAD antihistamines (n = 304), and we found a tendency toward a dose-response association. In our cell viability assay, we found consistent and dose-dependent cytotoxicity for all CAD but not non-CAD antihistamines. In this nationwide cohort study, use of antihistamines with CAD characteristics is associated with a prognostic benefit in ovarian cancer patients.

Perturbation of mitochondrial bioenergetics by polycations counteracts resistance to BRAFE600 inhibition in melanoma cells.

Acquired resistance to the oncogenic BRAFE600 inhibitor vemurafenib is a major clinical challenge in the treatment of melanoma. Vemurafenib resistance is poorly understood; however, available evidence indicates that reprogrammed mitochondrial metabolism could contribute to the resistance mechanism. Here we show that synthetic polycations, such as polyethylenimines and poly(l-lysine)s, prevent vemurafenib resistance in melanoma cells through induction of mitochondrial bioenergetic crisis. Polycations accumulate to a higher degree in hyperpolarized mitochondria (i.e. mitochondria with greater negative charge) which partly explains greater cellular uptake and mitochondrial accumulation of polycations in melanoma cells compared with epidermal melanocytes. Combined treatment of polycations and vemurafenib diminishes the metabolic flexibility of melanoma cells, making them unable to shift between glycolysis and mitochondrial oxidative phosphorylation according to energy demands. Thus, polycations exert considerable detrimental effects on melanoma cells at concentrations better tolerated by epidermal melanocytes and act synergistically with vemurafenib in effectuating bioenergetic crisis, DNA damage and cell death selectively in melanoma cells. Mechanistic understanding of this synergy could lead to the development of macromolecular and polymer therapeutics with structural attributes that encompass even greater cancer-specific cytotoxicity, and provide strategies for tailor-made combination therapies.