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2 Minute Medicine Rewind April 22, 2019
Fetal presentation has long been determined by way of clinical examination only, despite the relative ease with which breech presentation can be identified through ultrasound screening. As such, many women continue to present in labor with an undiagnosed breech presentation, associated with increased fetal morbidity and mortality. In this prospective cohort study (2008-2012), 3879 nulliparous women were assessed by way of ultrasound examination at 36 weeks gestation for fetal presentation. Where breech presentation was detected, an external cephalic version (ECV) was routinely offered. If unsuccessful or not performed, women were offered either planned cesarean section (C-section) at 39 weeks or attempted vaginal breech delivery. To compare the likelihood of different modes of delivery and associated long-term health outcomes for universal ultrasound as compared to current practice, a probabilistic economic simulation model was constructed. Researchers found that 4.6% of women were diagnosed with breech presentation at 36 weeks. In these women, ECV was attempted in 46.9%, with a 14.3% success rate. Overall, 19 of the 179 women delivered vaginally (10.6%), 110 delivered by elective C-section (61.5%), and 50 delivered by emergency C-section (27.9%). There were no women with undiagnosed breech presentation in labor in the entire cohort. Based on the authors’ economic analysis, on a population level, the use of ultrasound would identify roughly 14,826 otherwise diagnosed breech presentations in England annually, reducing emergency C-sections and vaginal breech deliveries by 0.7% and 1.0%, respectively. Universal use of ultrasound would also prevent 7.89 neonatal mortalities annually in England. This study therefore shows that universal late-pregnancy ultrasound effectively assessed fetal presentation and may eliminate undiagnosed intrapartum breech presentation in nulliparous women. This has important implications in reducing fetal morbidity and mortality associated with breech presentation at delivery.
Convulsive status epilepticus (SE) is the most common life-threatening neurological emergency in pediatrics. It is associated with significant morbidity and mortality, with 22% of patients ultimately requiring intubation and intensive care unit admission. Benzodiazepines are used first-line in terminating seizure activity. However, when this fails, phenytoin is the current standard of care for second-line treatment. The evidence for using phenytoin, however, is limited to observational studies and expert opinion. Given the high risk of adverse neurological outcomes and potential adverse effects linked to the use of phenytoin, however, appropriately powered and designed randomized controlled trials are needed in evaluating this drug and others in second-line management of convulsive SE. In this randomized controlled trial, 233 children age 3 months to 16 years with convulsive SE that failed first-line benzodiazepine treatment were randomly assigned 1:1 to receive 20 mg/kg phenytoin (intravenous or intraosseous infusion over 20 minutes) or 40 mg/kg levetiracetam (intravenous or intraosseous infusion over 5 minutes) to determine which agent is superior as a second-line treatment for emergency management of convulsive SE in children. Researchers found that clinical cessation of seizure activity after 5 minutes of completion of infusion occurred in 60% of patients in the phenytoin group, as compared to 50% of patients in the levetiracetam group (risk difference -9.2%, 95% CI -21.9 to 3.5, p=0.16). One participant in the phenytoin group died at 27 days because of hemorrhagic encephalitis, however, this death was not attributed to the study drug. There were no other serious adverse events. This study therefore shows that levetiracetam is not superior to phenytoin for second-line management of pediatric convulsive SE.
Recent advances have been demonstrated with the administration of intraperitoneal (IP) cisplatin and paclitaxel, where women with stage III ovarian disease conferred additional survival benefit as compared to conventional intravenous (IV) chemotherapy. However, due to concerns surrounding toxicity and difficulty administering IP therapy, less than half of the eligible women treated at National Cancer Institute (NCI) comprehensive cancer centers have received it. This points to a need for a less complicated, less toxic, and more feasible outpatient regimen to increase access. In this randomized controlled trial, 1560 patients with newly diagnosed advanced ovarian carcinoma were randomly assigned to receive IV carboplatin, IP carboplatin, or IP cisplatin to evaluate the impact of two different IP chemotherapy regimens on progression-free survival (PFS). The specific treatment regimens consisted of the following: 1) 6 cycles of IV paclitaxel 80 mg/m2 once weekly with IV carboplatin, 2) IV paclitaxel 80 mg/m2 once weekly with IP carboplatin, or 3) once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8. All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22. Researchers found that the median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 months (IV-carboplatin), 28.7 months (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Compared to IV carboplatin, time to first progression or death was 7.5% lower in the IP carboplatin arm (HR 0.925, 95% CI 0.802 to 1.07) and 2.3% lower in the IP cisplatin arm (HR 0.977, 95% CI 0.847 to 1.13); neither of these differences were statistically significant. The median PFS for patients with stage II/III and no residual disease was 35.9 months for carboplatin, 38.8 months for IP carboplatin, and 35.5 months for IP cisplatin; again there were no statistically significant differences in this subgroup of patients. The median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively. The mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores were similar for all treatment arms, however, the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm. In terms of safety, grade 3 of worse infections were more frequent in the IP arms (p=0.008), as was the incidence of nausea and vomiting, particularly in the IP cisplatin group at 11.0%. Grade 3 or worse hypertension was also significantly worse in the IP cisplatin arm (p<0.005) as compared to the IV carboplatin reference group. This study therefore shows that compared to IV carboplatin, PFS is not statistically increased with either IP carboplatin or IP cisplatin when combined with bevacizumab, putting into question the role of IP administration of chemotherapy in this patient population.
Intimate partner homicide of adolescents
Approximately 43 million adults in the US are affected by intimate partner violence (IPV). Data from the 2017 national Youth Risk Behavior Survey indicated that among high school students who dated, 6.9% experienced sexual violence, and 8.0% experienced physical violence by someone they were dating or going out with in the past year. The National Survey on Teen Relationships and Intimate Violence also showed that over 60% of adolescents in a current or past-year dating relationship have experienced some form of IPV, which includes physical, sexual, and/or psychological abuse. Intimate partner homicide (IPH) is the most extreme form of IPV, with most existing literature on IPH focusing on the adult population. In this multistate study of homicides of 2188 individuals age 11 to 18 years captured in the National Violent Death Reporting System (2003-2016), investigators aimed to determine the proportion of adolescent homicides perpetrated by intimate partners, to describe the victims, perpetrators, and incident characteristics of IPH in this population. Researchers found that of adolescent homicides, 6.9% were classified as IPH. Of these, 90% were female (mean age 16.8 years, SD 1.3 years). In terms of perpetrators, 77.9% were age 18 years and older (mean 20.6 years, SD 5.0 years). A total of 62.7% were current intimate partners of the victim, 26.7% were former intimate partners, and the relationship status at the time of death was unspecified for the remaining 10.7%. Compared with IPHs of young adults aged 19 to 24 years, perpetrators of adolescent victims were younger and less likely to be a current intimate partner. Firearms were the most common mechanism of injury (61.2%), followed by sharp or blunt instruments (25.2%). Based on available narrative information from the coroner/medical examiner and law enforcement reports, IPH was most often related to broken/desired relationship or jealousy (27.3%) and altercation (24.7%), followed by reckless firearm behavior (8.0%), and pregnancy (6.7%). This study therefore shows that adolescent victims of IPH are largely female and that the circumstances leading to IPH are commonly due to broken/desired relationship or jealousy and altercation, where perpetrators have access to firearms. This has important implications in informing prevention and intervention efforts tailored to adolescents at high risk of IPV/IPH.
Tuberculosis (TB) is the leading cause of death by an infectious disease. Identifying affected individuals, particularly if they are asymptomatic, however, remains a challenge as the infectious organisms are primarily contained within lung granulomas and/or draining lymph nodes. Biomarkers in the host’s blood compartment may be used in identifying individuals that are progressing from M. tuberculosis infection or latent disease, to active TB disease. In this longitudinal cohort study, 6,363 M. tuberculosis-infected, HIV-negative South African adolescents age 12 to 18 years who participated in the Adolescent Cohort Study (ACS, 2005-2007) were followed up for 2 years to identify proteomic biomarkers of TB progression, with the aim of developing a non-sputum, blood-based, point-of-care diagnostic. Researchers found that 46 individuals developed microbiologically confirmed TB disease within 2 years of follow-up. These participants were selected as progressors; 106 non-progressors, who remained healthy, were matched to the progressors. Using a highly multiplexed proteomic assay (SOMAscan), 3,000 human proteins were quantified in plasma. Of these, 361 proteins were of differential abundance between the progressors and non-progressors. A 5-protein signature, TB Risk Model 5 (TRM5), was discovered in the ACS training set and verified by blind prediction in the ACS test set. Poor performance on samples 13-24 months before TB diagnosis motivated discovery of a second 3-protein signature, 3-protein pair-ratio (3PR). The prognostic performance of both signatures was subsequently validated in an independent cohort of 1,948 HIV-negative household TB contacts from The Gambia, a small West African country, where individuals age 15 to 60 years were followed up for 2 years, sampled at baseline, month 6, and month 18. Researchers found that the prognostic performance of the TRM5 signature in the ACS training set was excellent within 6 months of TB diagnosis (AUC 0.96, 95% CI 0.93 to 0.99) and 6-12 months (AUC 0.76, 95% CI 0.65 to 0.87) before TB diagnosis. In the Gambian validation cohort, TRM5 validated with an AUC of 0.66 (95% CI 0.56 to 0.75) within 1 year of TB diagnosis, while the 3PR signature yielded an AUC of 0.89 (95% CI 0.84 to 0.95) within 6 months of TB diagnosis and 0.72 (95% CI 0.64 to 0.81) 7-12 months before TB diagnosis in the entire South African discovery cohort and validated with an AUC of 0.65 (95% CI 0.55 to 0.75) within 1 year of TB diagnosis in the Gambian validation cohort. This study therefore shows that proteomic biomarkers such as TRM5 and 3PR may play a role in predicting progression to incident TB. Further validation, particularly in cohorts from non-African countries, is necessary in determining the utility of these proteomic biomarkers in other affected populations.
Image: PD
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