Randomized controlled trial of prolonged second stage: extending the time limit vs usual guidelines.

BACKGROUND: Guidelines for management of the second stage have been proposed since the 1800s and were created largely by expert opinion. Current retrospective data are mixed regarding differences in maternal and neonatal outcomes with a prolonged second stage. There are no randomized controlled trials that have evaluated whether extending the second stage of labor beyond current American College of Obstetricians and Gynecologists recommendations is beneficial. OBJECTIVE: The purpose of this study was to evaluate whether extending the length of labor in nulliparous women with prolonged second stage affects the incidence of cesarean delivery and maternal and neonatal outcomes. STUDY DESIGN: We conducted a randomized controlled trial of nulliparous women with singleton gestations at 36 0/7 to 41 6/7 weeks gestation who reached the American College of Obstetricians and Gynecologists definition of prolonged second stage of labor, which is 3 hours with epidural anesthesia or 2 hours without epidural anesthesia. Women were assigned randomly to extended labor for at least 1 additional hour, or to usual labor, which was defined as expedited delivery via cesarean or operative vaginal delivery. The exclusion criteria were intrauterine fetal death, planned cesarean delivery, ageyears, and suspected major fetal anomaly. Primary outcome was incidence of cesarean delivery. Maternal and neonatal outcomes were compared secondarily. Statistical analysis was done by intention-to-treat. RESULTS: Seventy-eight nulliparous women were assigned randomly. All of the women had epidural anesthesia. Maternal demographics were not significantly different. The incidence of cesarean delivery was 19.5% (n = 8/41 deliveries) in the extended labor group and 43.2% (n = 16/37 deliveries) in the usual labor group (relative risk, 0.45; 95% confidence interval, 0.22-0.93). The number needed-to-treat to prevent 1 cesarean delivery was 4.2. There were no statistically significant differences in maternal or neonatal morbidity outcomes. CONCLUSION: Extending the length of labor in nulliparous women with singleton gestations, epidural anesthesia, and prolonged second stage decreased the incidence of cesarean delivery by slightly more than one-half, compared with usual guidelines. Maternal or neonatal morbidity were not statistically different between the groups; however, our study was underpowered to detect small, but potentially clinical important, differences

Opioid stimulation in the ventral tegmental area facilitates the onset of maternal behavior in rats

This research investigated the effect of an increase or decrease in opioid activity in the ventral tegmental area (VTA) on the onset of maternal behavior in rats. In Experiment 1, the latency to show maternal behavior toward foster rat pups (sensitization latency) was determined in maternally naive female rats given either nothing or a unilateral intra-VTA injection of morphine sulfate (MS) (0.0, 0.01, 0.03, 0.1 or 0.3 µg), on the first three days of a 10-day period of constant exposure to pups. Rats treated with 0.03 µg MS had significantly shorter sensitization latencies than did rats treated with 0.0 µg MS, 0.01 µg MS, or receiving no treatment (higher doses of morphine produced intermediate results). The facilitating effect of intra-VTA MS on the onset of maternal behavior was blocked by pretreatment with naltrexone hydrochloride and was found to have a specific site of action in the VTA (MS injections dorsal to the VTA were ineffective). In Experiment 2, sensitization latencies were determined in periparturitional rats given a bilateral intra-VTA injection of either the opioid antagonist naltrexone methobromide (quaternary naltrexone), its vehicle, a sham injection, or left untreated 40 min after delivery of the last pup. The mothers' own pups were removed at delivery; mothers were nonmaternal at the time of testing. Quaternary naltrexone treatment produced significantly slower sensitization to foster pups than did control conditions. Total activity and pup-directed activity did not differ significantly with treatment. The results demonstrate that increased opioid activity in the VTA facilitates the onset of maternal behavior in inexperienced nonpregnant female rats, and decreased opioid activity in the VTA disrupts the rapid onset of maternal behavior at parturition

Causal Nature and Dynamics of Trapping Horizons in Black Hole Collapse

In calculations of gravitational collapse to form black holes, trapping horizons (foliated by marginally trapped surfaces) make their first appearance either within the collapsing matter or where it joins on to a vacuum exterior. Those which then move outwards with respect to the matter have been proposed for use in defining black holes, replacing the global concept of an "event horizon" which has some serious drawbacks for practical applications. We here present results from a study of the properties of both outgoing and ingoing trapping horizons, assuming strict spherical symmetry throughout. We have investigated their causal nature (i.e. whether they are spacelike, timelike or null), making contact with the Misner-Sharp- Hernandez formalism, which has often been used for numerical calculations of spherical collapse. We follow two different approaches, one using a geometrical quantity related to expansions of null geodesic congruences, and the other using the horizon velocity measured with respect to the collapsing matter. After an introduction to these concepts, we then implement them within numerical simulations of stellar collapse, revisiting pioneering calculations from the 1960s where some features of the emergence and subsequent behaviour of trapping horizons could already be seen. Our presentation here is aimed firmly at "real world" applications of interest to astrophysicists and includes the effects of pressure, which may be important for the asymptotic behaviour of the ingoing horizon.Comment: 33 pages, 11 figure

Rewriting Human History and Empowering Indigenous Communities with Genome Editing Tools.

Appropriate empirical-based evidence and detailed theoretical considerations should be used for evolutionary explanations of phenotypic variation observed in the field of human population genetics (especially Indigenous populations). Investigators within the population genetics community frequently overlook the importance of these criteria when associating observed phenotypic variation with evolutionary explanations. A functional investigation of population-specific variation using cutting-edge genome editing tools has the potential to empower the population genetics community by holding "just-so" evolutionary explanations accountable. Here, we detail currently available precision genome editing tools and methods, with a particular emphasis on base editing, that can be applied to functionally investigate population-specific point mutations. We use the recent identification of thrifty mutations in the CREBRF gene as an example of the current dire need for an alliance between the fields of population genetics and genome editing

Computer simulations explain mutation-induced effects on the DNA editing by adenine base editors.

Adenine base editors, which were developed by engineering a transfer RNA adenosine deaminase enzyme (TadA) into a DNA editing enzyme (TadA*), enable precise modification of A:T to G⋮C base pairs. Here, we use molecular dynamics simulations to uncover the structural and functional roles played by the initial mutations in the onset of the DNA editing activity by TadA*. Atomistic insights reveal that early mutations lead to intricate conformational changes in the structure of TadA*. In particular, the first mutation, Asp108Asn, induces an enhancement in the binding affinity of TadA to DNA. In silico and in vivo reversion analyses verify the importance of this single mutation in imparting functional promiscuity to TadA* and demonstrate that TadA* performs DNA base editing as a monomer rather than a dimer

Selective Cytotoxicity of Rhodium Metalloinsertors in Mismatch Repair-Deficient Cells

Mismatches in DNA occur naturally during replication and as a result of endogenous DNA damaging agents, but the mismatch repair (MMR) pathway acts to correct mismatches before subsequent rounds of replication. Rhodium metalloinsertors bind to DNA mismatches with high affinity and specificity and represent a promising strategy to target mismatches in cells. Here we examine the biological fate of rhodium metalloinsertors bearing dipyridylamine ancillary ligands in cells deficient in MMR versus those that are MMR-proficient. These complexes are shown to exhibit accelerated cellular uptake which permits the observation of various cellular responses, including disruption of the cell cycle, monitored by flow cytometry assays, and induction of necrosis, monitored by dye exclusion and caspase inhibition assays, that occur preferentially in the MMR-deficient cell line. These cellular responses provide insight into the mechanisms underlying the selective activity of this novel class of targeted anticancer agents