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OBJECTIVE: We sought to determine whether morbid obesity is associated with increased maternal hypotension or fetal heart rate (FHR) abnormalities after epidural anesthesia placement during labor. STUDY DESIGN: This was a retrospective cohort study of women undergoing epidural anesthesia during labor at term from April 2008 through July 2010. RESULTS: A total of 125 morbidly obese patients were matched for age and race with 125 normal-weight patients. Morbidly obese patients had more frequent persistent systolic (16% vs 4%, P = .003) and diastolic (49% vs 29%, P = .002) hypotension and more prolonged (16% vs 5%, P = .006) and late (26% vs 14%, P = .03) FHR decelerations. Increasing body mass index was associated with persistent systolic (odds ratio, 1.06; 95% confidence interval, 1.02-1.10) and diastolic (odds ratio, 1.04; 95% confidence interval, 1.01-1.06) hypotension after controlling for epidural bolus dose and hypertensive disorders. CONCLUSION: Morbidly obese women have more hypotension and prolonged FHR decelerations following epidural anesthesia during labor at term. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 propagation under nirmatrelvir and ensitrelvir pressure selects for main protease (MPro) drug-resistant mutations E166V (DRM2), L50F/E166V (DRM3), E166A/L167F (DRM4), and L50F/E166A/L167F (DRM5). DRM2-DRM5 undergoes N-terminal autoprocessing to produce mature MPro with dimer dissociation constants ( K dimer ) 2-3 times larger than that of the wildtype. Co-selection of L50F restores catalytic activity of DRM2 and DRM4 from ∼10 to 30%, relative to that of the wild-type enzyme, without altering K dimer . Binding affinities and thermodynamic profiles that parallel the drug selection pressure, exhibiting significant decreases in affinity through entropy/enthalpy compensation, were compared with GC373. Reorganization of the active sites due to mutations observed in the inhibitor-free DRM3 and DRM4 structures as compared to MPro WT may account for the reduced binding affinities, although DRM2 and DRM3 complexes with ensitrelvir are almost identical to MPro WT -ensitrelvir. Chemical reactivity changes of the mutant active sites due to differences in electrostatic and protein dynamics effects likely contribute to losses in binding affinities.

Previable and periviable preterm prelabor rupture of membranes are challenging obstetrical complications to manage given the substantial risk of maternal morbidity and mortality, with no guarantee of fetal benefit. The following are the Society for Maternal-Fetal Medicine recommendations for the management of previable and periviable preterm prelabor rupture of membranes before the period when a trial of neonatal resuscitation and intensive care would be considered appropriate by the healthcare team and desired by the patient: (1) we recommend that pregnant patients with previable and periviable preterm prelabor rupture of membranes receive individualized counseling about the maternal and fetal risks and benefits of both abortion care and expectant management to guide an informed decision; all patients with previable and periviable preterm prelabor rupture of membranes should be offered abortion care, and expectant management can also be offered in the absence of contraindications (GRADE 1C); (2) we recommend antibiotics for pregnant individuals who choose expectant management after preterm prelabor rupture of membranes at ≥24 0/7 weeks of gestation (GRADE 1B); (3) antibiotics can be considered after preterm prelabor rupture of membranes at 20 0/7 to 23 6/7 weeks of gestation (GRADE 2C); (4) administration of antenatal corticosteroids and magnesium sulfate is not recommended until the time when a trial of neonatal resuscitation and intensive care would be considered appropriate by the healthcare team and desired by the patient (GRADE 1B); (5) serial amnioinfusions and amniopatch are considered investigational and should be used only in a clinical trial setting; they are not recommended for routine care of previable and periviable preterm prelabor rupture of membranes (GRADE 1B); (6) cerclage management after previable or periviable preterm prelabor rupture of membranes is similar to cerclage management after preterm prelabor rupture of membranes at later gestational ages; it is reasonable to either remove the cerclage or leave it in situ after discussing the risks and benefits and incorporating shared decision-making (GRADE 2C); and (7) in subsequent pregnancies after a history of previable or periviable preterm prelabor rupture of membranes, we recommend following guidelines for management of pregnant persons with a previous spontaneous preterm birth (GRADE 1C)., (Copyright © 2024. Published by Elsevier Inc.)

The two most abundant isoforms of amyloid-β (Aβ) are the 40- (Aβ40) and 42-residue (Aβ42) peptides. Since they coexist and there is a correlation between toxicity and the ratio of the two isoforms, quantitative characterization of their interactions is crucial for understanding the Aβ aggregation mechanism. In this work, we follow the aggregation of individual isoforms in a mixture using single-molecule FRET spectroscopy by labeling Aβ42 and Aβ40 with the donor and acceptor fluorophores, respectively. We found that there are two phases of aggregation. The first phase consists of coaggregation of Aβ42 with a small amount of Aβ40, while the second phase results mostly from aggregation of Aβ40. We also found that the aggregation of Aβ42 is slowed by Aβ40 while the aggregation of Aβ40 is accelerated by Aβ42 in a concentration-dependent manner. The formation of oligomers was monitored by incubating mixtures in a plate reader and performing a single-molecule free-diffusion experiment at several different stages of aggregation. The detailed properties of the oligomers were obtained by maximum likelihood analysis of fluorescence bursts. The FRET efficiency distribution is much broader than that of the Aβ42 oligomers, indicating the diversity in isoform composition of the oligomers. Pulsed interleaved excitation experiments estimate that the fraction of Aβ40 in the co-oligomers in a 1:1 mixture of Aβ42 and Aβ40 varies between 0 and 20%. The detected oligomers were mostly co-oligomers especially at the physiological ratio of Aβ42 and Aβ40 (1:10), suggesting the critical role of Aβ40 in oligomer formation and aggregation.

The assembly of two monomeric constructs spanning segments 1-199 (MPro 1-199 ) and 10-306 (MPro 10-306 ) of SARS-CoV-2 main protease (MPro) was examined to assess the existence of a transient heterodimer intermediate in the N-terminal autoprocessing pathway of MPro model precursor. Together, they form a heterodimer population accompanied by a 13-fold increase in catalytic activity. Addition of inhibitor GC373 to the proteins increases the activity further by ∼7-fold with a 1:1 complex and higher order assemblies approaching 1:2 and 2:2 molecules of MPro 1-199 and MPro 10-306 detectable by analytical ultracentrifugation and native mass estimation by light scattering. Assemblies larger than a heterodimer (1:1) are discussed in terms of alternate pathways of domain III association, either through switching the location of helix 201 to 214 onto a second helical domain of MPro 10-306 and vice versa or direct interdomain III contacts like that of the native dimer, based on known structures and AlphaFold 3 prediction, respectively. At a constant concentration of MPro 1-199 with molar excess of GC373, the rate of substrate hydrolysis displays first order dependency on the MPro 10-306 concentration and vice versa. An equimolar composition of the two proteins with excess GC373 exhibits half-maximal activity at ∼6 μM MPro 1-199 . Catalytic activity arises primarily from MPro 1-199 and is dependent on the interface interactions involving the N-finger residues 1 to 9 of MPro 1-199 and E290 of MPro 10-306 . Importantly, our results confirm that a single N-finger region with its associated intersubunit contacts is sufficient to form a heterodimeric MPro intermediate with enhanced catalytic activity., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Background: Angiogenic imbalances, characterized by an excess of antiangiogenic factors (soluble fms-like tyrosine kinase 1) and reduced angiogenic factors (vascular endothelial growth factor and placental growth factor), contribute to the mechanisms of disease in preeclampsia. The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor has been used as a biomarker for preeclampsia, but the cutoff values may vary with gestational age and assay platform., Objective: This study aimed to compare multiples of the median of the maternal plasma soluble fms-like tyrosine kinase 1 to placental growth factor ratio, soluble fms-like tyrosine kinase 1, placental growth factor, and conventional clinical and laboratory values in their ability to predict preeclampsia with severe features., Study Design: We conducted a cohort study across 18 United States centers involving hospitalized individuals with hypertension between 23 and 35 weeks' gestation. Receiver operating characteristic curve analyses of maternal plasma biomarkers, highest systolic or diastolic blood pressures, and laboratory values at enrollment were performed for the prediction of preeclampsia with severe features. The areas under the curve were compared, and quasi-Poisson regression models were fitted to estimate relative risks. The primary outcome was preeclampsia with severe features within 2 weeks of enrollment. Secondary outcomes were a composite of severe adverse maternal outcomes (elevated liver enzymes, low platelets count, placental abruption, eclampsia, disseminated intravascular coagulation, and pulmonary edema) and a composite of severe adverse perinatal outcomes (birth weight below the third percentile, very preterm birth [<32 weeks' gestation], and fetal or neonatal death)., Results: Of the 543 individuals included in the study, preeclampsia with severe features within 2 weeks was observed in 33.1% (n=180) of them. A receiver operating characteristic curve-derived cutoff of 11.5 multiples of the median for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio provided good sensitivity (90.6%), specificity (76.9%), positive predictive value (66.0%), negative predictive value (94.3%), positive likelihood ratio (3.91), negative likelihood ratio (0.12), and accuracy (81.4%) for preeclampsia with severe features within 2 weeks. This cutoff was used to compare test positive cases (≥ cutoff) and test negative cases (< cutoff). Preeclampsia with severe features (66.0% vs 5.7%; P<.001) and composites of severe adverse maternal (8.11% vs 2.7%; P=.006) or perinatal (41.3% vs 10.14%; P=.001) outcomes within 2 weeks were more frequent in test positive cases than in test negative cases. A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the median was independently associated with preeclampsia with severe features (adjusted incidence rate ratio, 9.08; 95% confidence interval, 6.11-14.06; P<.001) and a composite of severe adverse perinatal outcomes (adjusted incidence rate ratio, 9.42; 95% confidence interval, 6.36-14.53; P<.001) but not with a composite of severe adverse maternal outcomes (adjusted incidence rate ratio, 2.20; 95% confidence interval, 0.95-5.54; P=.08). The area under the curve for the soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio in multiples of the median (0.91; 95% confidence interval, 0.89-0.94) for preeclampsia with severe features within 2 weeks was significantly higher (P<.001 for all comparisons) than either plasma biomarker alone or any other parameter with the exception of absolute soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio values., Conclusion: A soluble fms-like tyrosine kinase 1 to placental growth factor plasma ratio ≥11.5 multiples of the mean among hospitalized patients with hypertension between 23 and 35 week's gestation predicts progression to preeclampsia with severe features and severe adverse perinatal outcomes within 2 weeks., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sleep is important for overall health of a person. It is always recommended that an adult should sleep for not less than 7 to 9 hours every day. However, there are a lot of adults who experience sleep deprivation, out of them mostly are women. Sleep deprivation can lead to a lot of health issues, including mortality risk, impaired metabolism, imbalance in cognitive function, and the overall quality of life. Women often face more difficulties falling asleep as compared to men, leading to greater levels of self-reported sleep deprivation and problems related to poor sleeping habits., Competing Interests: Disclosure The authors have no conflicting interests to report., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Myotonic dystrophy type 1 (DM1) is a heterogeneous multisystemic disease caused by a CTG repeat expansion in DMPK. Transcription of the expanded allele produces toxic CUG repeat RNA that sequesters the MBNL family of alternative splicing (AS) regulators into ribonuclear foci, leading to pathogenic mis-splicing. To identify genetic modifiers of toxic CUG RNA levels and the spliceopathy, we performed a genome-scale siRNA screen using an established HeLa DM1 repeat-selective screening platform. We unexpectedly identified core spliceosomal proteins as a new class of modifiers that rescue the spliceopathy in DM1. Modest knockdown of one of our top hits, SNRPD2, in DM1 fibroblasts and myoblasts, significantly reduces DMPK expression and partially rescues MBNL-regulated AS dysfunction. While the focus on the DM1 spliceopathy has centered around the MBNL proteins, our work reveals an unappreciated role for MBNL:spliceosomal protein stoichiometry in modulating the spliceopathy, revealing new biological and therapeutic avenues for DM1., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Synthetic DNA motifs form the basis of nucleic acid nanotechnology. The biochemical and biophysical properties of these motifs determine their applications. Here, we present a detailed characterization of switchback DNA, a globally left-handed structure composed of two parallel DNA strands. Compared to a conventional duplex, switchback DNA shows lower thermodynamic stability and requires higher magnesium concentration for assembly but exhibits enhanced biostability against some nucleases. Strand competition and strand displacement experiments show that component sequences have an absolute preference for duplex complements instead of their switchback partners. Further, we hypothesize a potential role for switchback DNA as an alternate structure in sequences containing short tandem repeats. Together with small molecule binding experiments and cell studies, our results open new avenues for switchback DNA in biology and nanotechnology., (© 2024. The Author(s).)

Background: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b)., Methods: Flow limitation severity scores (0%=fully obstructed, 100%=open airway), quantified from breath-by-breath airflow shape, were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and pre-eclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM) and infant birthweight., Results: Of 1939 participants with flow limitation data at both time-points (mean±sd age 27.0±5.4 years and BMI 27.7±6.1 kg·m -2 ), 5.8% developed pre-eclampsia, 12.7% developed HDP and 4.5% developed GDM. Greater flow limitation was associated with increased pre-eclampsia risk: adjusted OR 2.49 (95% CI 1.69-3.69) per 2sd increase in severity. Findings persisted in women without sleep apnoea (apnoea-hypopnoea index <5 events·h -1 ). Flow limitation was associated with HDP (OR 1.77 (95% CI 1.33-2.38)) and reduced infant birthweight (83.7 (95% CI 31.8-135.6) g), but not GDM., Conclusions: Greater flow limitation is associated with increased risk of pre-eclampsia, HDP and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy., Competing Interests: Conflict of interest: A. Azarbarzin receives personal fees as a consultant for Somnifix, Apnimed, LinguaFlex, Respicardia and Inspire, and receives grant support from Somnifix. A. Wellman has financial interest in Apnimed, a company developing pharmacologic therapies for sleep apnoea; his interests are managed by Brigham and Women's Hospital and Mass General Brigham in accordance with their conflict of interest policies; A. Wellman also consults for Apnimed, Nox Medical, Inspire, Somnifix, Mosanna and Takeda, and has received grants from Somnifix and Sanofi. P.C. Zee receives personal fees as a consultant from Eisai, Jazz, Idorsia, Harmony Bioscience, Sleep Number and CVS Caremark. S. Redline received personal fees from Jazz Pharma, Eli Lilly and Apnimed. S.A. Sands receives personal fees as a consultant for Nox Medical, Merck, Apnimed, Respicardia, Inspire, Lilly, LinguaFlex and Forepont outside the submitted work, and receives grant support from Apnimed, ProSomnus and Dynaflex for unrelated studies. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

N-terminal autoprocessing from its polyprotein precursor enables creating the mature-like stable dimer interface of SARS-CoV-2 main protease (MPro), concomitant with the active site oxyanion loop equilibrium transitioning to the active conformation (E*) and onset of catalytic activity. Through mutagenesis of critical interface residues and evaluating noncovalent inhibitor (ensitrelvir, ESV) facilitated dimerization through its binding to MPro, we demonstrate that residues extending from Ser1 through Glu14 are critical for dimerization. Combined mutations G11A, E290A and R298A (MPro™) restrict dimerization even upon binding of ESV to monomeric MPro™ with an inhibitor dissociation constant of 7.4 ± 1.6 µM. Contrasting the covalent inhibitor NMV or GC373 binding to monomeric MPro, ESV binding enabled capturing the transition of the oxyanion loop conformations in the absence of a reactive warhead and independent of dimerization. Characterization of complexes by room-temperature X-ray crystallography reveals ESV bound to the E* state of monomeric MPro as well as an intermediate approaching the inactive state (E). It appears that the E* to E equilibrium shift occurs initially from G138-F140 residues, leading to the unwinding of the loop and formation of the 3 10 -helix. Finally, we describe a transient dimer structure of the MPro precursor held together through interactions of residues A5-G11 with distinct states of the active sites, E and E*, likely representing an intermediate in the autoprocessing pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Objective: The objective of this study is to examine the relationship between body mass index (BMI) and complications for patients undergoing postpartum permanent contraception., Study Design: Retrospective cohort study of patients aged 18 or older who had a vaginal delivery at an academic hospital between 2011 and 2016 and underwent a postpartum tubal ligation during the delivery admission. There were three comparative groups: nonobese (BMI ≤ 29 kg/m 2 ), obese (BMI 30-39 kg/m 2 ), and morbidly obese BMI (≥40 kg/m 2 ). The outcome of interest was composite operative complications which included any occurrence of an intraoperative, postoperative, or anesthesia complication., Results: A total of 921 patients were included for analysis. Average operative time was statistically longer for patients in the morbidly obese group (33 minutes) vs. the nonobese (25 minutes) and obese (29 minutes) groups ( p <  0.0001). Composite complications were greater for the obese groups, but not statistically significant (5.1 vs. 6 vs. 16%, p  = 0.06). Wound complications were significantly greater for the obese groups (0.8 vs. 1.5 vs. 5.5%, p  = 0.01). A logistic regression model demonstrated that only operative time was predictive of operative complications., Conclusion: Overall complications of postpartum tubal complications are low; however, our study did demonstrate significantly longer operative time and wound complications for patients with obesity. The findings of our study indicate that postpartum permanent contraception can remain as an option for these patients. Further studies may help identify the best practices to decrease operative time and subsequent wound complications. This study contributes to the limited data regarding obesity and postpartum permanent contraception. We found increased operative time and wound complications for obese patients. Additional studies may identity best practices to decrease these complications. Given our findings of overall low operative complications, postpartum permanent contraception can remain an option for obese patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Our objective was to determine whether objectively measured sleep-disordered breathing (SDB) during pregnancy is associated with an increased risk of adverse neonatal outcomes in a cohort of nulliparous individuals., Study Design: Secondary analysis of the nuMom2b sleep disordered breathing substudy was performed. Individuals underwent in-home sleep studies for SDB assessment in early (6-15 weeks' gestation) and mid-pregnancy (22-31 weeks' gestation). SDB was defined as an apnea-hypopnea index ≥5 events/h at either time point. The primary outcome was a composite outcome of respiratory distress syndrome, transient tachypnea of the newborn, or receipt of respiratory support, treated hyperbilirubinemia or hypoglycemia, large-for-gestational age, seizures treated with medications or confirmed by electroencephalography, confirmed sepsis, or neonatal death. Individuals were categorized into (1) early pregnancy SDB (6-15 weeks' gestation), (2) new onset mid-pregnancy SDB (22-31 weeks' gestation), and (3) no SDB. Log-binomial regression was used to calculate adjusted risk ratios (RR) and 95% confidence intervals (CIs) representing the association., Results: Among 2,106 participants, 3% ( n  = 75) had early pregnancy SDB and 5.7% ( n  = 119) developed new-onset mid-pregnancy SDB. The incidence of the primary outcome was higher in the offspring of individuals with early (29.3%) and new onset mid-pregnancy SDB (30.3%) compared with individuals with no SDB (17.8%). After adjustment for maternal age, chronic hypertension, pregestational diabetes, and body mass index, new onset mid-pregnancy SDB conferred increased risk (RR = 1.43, 95% CI: 1.05, 1.94), where there was no longer statistically significant association between early pregnancy SDB and the primary outcome., Conclusion: New onset, mid-pregnancy SDB is independently associated with neonatal morbidity., Key Points: · SDB is a common condition impacting pregnancy with known maternal risks.. · Objectively defined SDB in pregnancy was associated with a composite of adverse neonatal outcomes.. · New onset SDB in mid pregnancy conferred statistically significant increased risk.., Competing Interests: None declared., (Thieme. All rights reserved.)

Guidelines for the management of first-trimester spontaneous and induced abortion vary in terms of rhesus factor D (RhD) testing and RhD immune globulin (RhIg) administration. These existing guidelines are based on limited data that do not convincingly demonstrate the safety of withholding RhIg for first-trimester abortions or pregnancy losses. Given the adverse fetal and neonatal outcomes associated with RhD alloimmunization, prevention of maternal sensitization is essential in RhD-negative patients who may experience subsequent pregnancies. In care settings in which RhD testing and RhIg administration are logistically and financially feasible and do not hinder access to abortion care, we recommend offering both RhD testing and RhIg administration for spontaneous and induced abortion at <12 weeks of gestation in unsensitized, RhD-negative individuals. Guidelines for RhD testing and RhIg administration in the first trimester must balance the prevention of alloimmunization with the individual- and population-level harms of restricted access to abortion., (Copyright © 2024. Published by Elsevier Inc.)

Background: In nonpregnant individuals, the rate-pressure product, the product of heart rate and systolic blood pressure, is used as a noninvasive surrogate of myocardial O 2 consumption during cardiac stress testing. Pregnancy is considered a physiological cardiovascular stress test. Evidence describing the impact of pregnancy on myocardial O 2 demand, as assessed by the rate-pressure product, is limited., Objective: This study aimed to describe changes in the rate-pressure product for each pregnancy trimester, during labor and delivery, and the postpartum period among low-risk pregnancies., Study Design: This was a retrospective cohort study that assessed uncomplicated pregnancies delivered vaginally at term. We collected rate-pressure product (heart rate × systolic blood pressure) values preconception, during pregnancy for each trimester (at ≤13 weeks + 6/7 days, at 14 weeks + 0/7 days through 27 weeks + 6/7 days, and at ≥28 weeks + 0/7 days), during the labor and delivery encounter (hospital admission until complete cervical dilation, complete cervical dilation until placental delivery, and after placental delivery until hospital discharge), and during the outpatient postpartum visit at 2 to 6 weeks after delivery. We calculated the percentage change at each time point from the preconception rate-pressure product (delta rate-pressure product). We used a mixed-linear model to analyze differences in the mean delta rate-pressure product over time and the influence of prepregnancy age, prepregnancy body mass index, and neuraxial anesthesia status during labor and delivery on these estimates., Results: Our cohort comprised 316 patients. The mean rate-pressure product increased significantly from preconception starting at the third trimester of pregnancy and during labor and delivery (P≤.05). The mean delta rate-pressure product peaked at 12% and 38% in the third trimester and during labor and delivery, respectively. Prepregnancy body mass index was inversely correlated with the mean delta rate-pressure product changes (estimate, -0.308; 95% confidence interval, -0.536 to -0.80; P=.008). In contrast, neither the prepregnancy age, nor neuraxial anesthesia status during labor had a significant influence on this parameter., Conclusion: This study validates the transient but significant increase in the rate-pressure product, a clinical estimate of myocardial O 2 demand, during uncomplicated pregnancies delivered vaginally at term. Pregnant individuals with lower prepregnancy body mass index experienced a sharper increase in this parameter. Patients who receive neuraxial anesthesia during labor and delivery experience similar changes in the rate-pressure product as those who did not., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hypertensive disorders of pregnancy are increasing in prevalence and a leading cause of early postpartum readmissions. Stricter blood pressure target goals for treatment of hypertension during pregnancy have recently been proposed, however, the treatment goals for management of postpartum hypertension are less well established., Objective: We sought to evaluate the clinical factors associated with early postpartum readmissions for hypertensive disease and to evaluate blood pressure thresholds associated with these readmissions., Study Design: We conducted a retrospective cohort study of women delivering at a tertiary care center between January 2018 and May 2022 who experienced a hospital readmission for postpartum hypertension or new onset postpartum preeclampsia. Charts were reviewed for clinical and sociodemographic data. Patients with early readmission (<72 hours after discharge) were compared with patients readmitted after 3 days of initial discharge. Data were analyzed using chi-square, Student t test, Mann-Whitney U test, and logistic regression where appropriate. The P value <.05 was considered significant., Results: During the study period, 23,372 deliveries occurred. Postpartum readmission due to worsening of a known diagnosis of hypertension or new onset postpartum preeclampsia occurred in 1.1% and 0.49% respectively. Patients with early readmission were more likely to have hypertensive disorders of pregnancy as the indication for delivery. Among patients readmitted, 93% had 2 or more systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, and 73% had blood pressure of either systolic between 130 and 139 mmHg or diastolic between 80 and 89 mmHg within 24 hours before initial discharge. Only 27 patients met criteria (blood pressure ≥160/110 mmHg on >1 vitals check during their hospitalization) to be started on antihypertensives before initial delivery discharge; of those 25 (93%) were discharged with a new prescription for an antihypertensive. After controlling for confounding variables, predischarge blood pressure between 130-140 mmHg/80-90 mmHg (adjusted odds ratio, 2.4 [1.5-4.0]) was associated with an increased likelihood of early readmission., Conclusion: Patients with delivery for hypertensive disorders of pregnancy and predischarge blood pressure ≥140/90 mmHg were less likely to have an early readmission within 3 days of initial discharge, however, patients with predischarge blood pressure 130-139 mmHg/80-89 mmHg were more likely to have an early readmission for hypertensive disorders of pregnancy and postpartum preeclampsia. Further research is indicated to evaluate interventions to prevent postpartum readmission in patients at high risk for persistent hypertension or new onset postpartum preeclampsia., (© 2024 The Authors.)

Malaria eradication efforts in resource-limited areas require a rapid, economical, and accurate tool for detecting of the low parasitemia. The malaria rapid diagnostic test (mRDT) is the most suitable for on-site detection of the deadliest form of malaria, Plasmodium falciparum. However, the deletions of histidine rich protein 2 and 3 genes are known to compromise the effectiveness of mRDT. One of the approaches that have been explored intensively for on-site diagnostics is the loop-mediated isothermal amplification (LAMP). LAMP is a one-step amplification that allows the detection of Plasmodium species in less than an hour. Thus, this study aims to present a new primer set to enhance the performance of a colorimetric LAMP (cLAMP) for field application. The primer binding regions were selected within the A-type of P. falciparum 18S rRNA genes, which presents a dual gene locus in the genome. The test result of the newly designed primer indicates that the optimal reaction condition for cLAMP was 30 minutes incubation at 65°C, a shorter incubation time compared to previous LAMP detection methods that typically takes 45 to 60 minutes. The limit of detection (LoD) for the cLAMP using our designed primers and laboratory-grown P. falciparum (3D7) was estimated to be 0.21 parasites/μL which was 1,000-fold higher than referencing primers. Under optimal reaction condition, the new primer sets showed the sensitivity (100%, 95% CI: 80.49-100%) and specificity (100%, 95% CI: 94.64-100%) with 100% (95% CI: 95.70-100%) accuracy on the detection of dried blood spots from Malawi (n = 84). Briefly, the newly designed primer set for P. falciparum detection exhibited high sensitivity and specificity compared to referenced primers. One great advantage of this tool is its ability to be detected by the naked eye, enhancing field approaches. Thus, this tool has the potential to be effective for accurate early parasite detection in resource-limited endemic areas., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nguyen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Respiratory syncytial virus is a leading cause of lower respiratory tract illness globally in children aged <5 years. Each year, approximately 58,000 hospitalizations in the United States are attributed to respiratory syncytial virus. Infants aged ≤6 months experience the most severe morbidity and mortality. Until recently, prevention with the monoclonal antibody, palivizumab, was only offered to infants with high-risk conditions, and treatment primarily consisted of supportive care. Currently, 2 products are approved for the prevention of respiratory syncytial virus in infants. These include the Pfizer bivalent recombinant respiratory syncytial virus prefusion F protein subunit vaccine, administered seasonally to the pregnant person between 32 0/7 and 36 6/7 weeks of gestation, and the monoclonal antibody, nirsevimab, administered to infants aged up to 8 months entering their first respiratory syncytial virus season. With few exceptions, administering both the vaccine to the pregnant person and the monoclonal antibody to the infant is not recommended. All infants should be protected against respiratory syncytial virus using one of these strategies. Key considerations for pregnant individuals include examining available safety and efficacy data, weighing accessibility and availability, and patient preferences for maternal vaccination vs infant monoclonal antibody treatment. It will be critical for maternal-fetal medicine physicians to provide effective and balanced counseling to aid patients in deciding on a personalized approach to the prevention of respiratory syncytial virus in their infants., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: As many as one in four pregnant women may experience sleep-disordered breathing (SDB) during pregnancy. The same sequelae of SDB, such as insulin resistance and inflammation, have been implicated in the development of certain birth defects., Methods: This is a secondary analysis of the SDB substudy of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be study, which included 2106 participants who had a sufficiency sleep study at two visits at different time points in pregnancy. SDB was based on a self-administered home sleep apnea test with data scored by trained, blinded research polysomnologists. SDB was defined as an apnea-hypopnea index (AHI) ≥5. The primary outcome of this analysis was any of the 45 non-chromosomal birth defects included in the National Birth Defects Prevention Network Annual Report., Results: In this cohort, the overall rate of birth defects was 3.1%. The prevalence was similar between those without SDB (3.0%) and those with only mid-pregnancy SDB (3.4%), but was higher in those with early-pregnancy SDB (6.7%). After adjusting for maternal age, chronic hypertension, pregestational diabetes, and body mass index (BMI), there were no statistically significant differences in the risk of birth defects by subject SDB status., Conclusions: Further studies to evaluate the effect of prepregnancy and early-pregnancy SDB on the fetus, as well as the risk of specific birth defects and neonatal outcomes in those with an objectively measured diagnosis of SDB, are still needed., (© 2023 Wiley Periodicals LLC.)

Sleep is a critical aspect of one's daily life for overall health, with a recommended 7 to 9 hours in adulthood (ages 26-64). Up to a third of women do not sleep sufficiently, and pregnant women are at an increased risk for sleep deficiency. Throughout pregnancy, sleep is affected in differing ways. For example, in the first trimester, hormones affect sleep cycles, but by the third trimester, physical complaints such as increasing frequent urination and fetal movement create frequent awakenings. Associations between sleep deficiency and gestational diabetes, hypertensive disorders, depression, and some evidence regarding preterm birth exist. A woman's labor course and perception of delivery are also negatively affected by short sleep duration., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Silver dressings have been associated with a decrease in postoperative pain in selected populations, but it is unknown if the benefit can be observed after cesarean deliveries. We sought to evaluate the impact of silver nylon dressings in reducing postoperative pain after cesarean delivery., Study Design: A secondary analysis of data from a blinded randomized clinical trial of women undergoing cesarean delivery scheduled and unscheduled at a single site was conducted. Women were recruited for participation from a single site and randomized to a silver nylon dressing or an identical-appearing gauze wound dressing. Wounds were evaluated in the outpatient clinic at 1 and 6 weeks after delivery and patient responded to the modified patient scar assessment scale. The primary outcome of this analysis was inpatient opioid and nonopioid analgesic dispensed. The secondary outcome was patient-reported pain at the 1- and 6-week postpartum visits. Data were analyzed using chi-square test, Student's t -test, Fisher's exact test, Wilcoxon-Mann-Whitney's test, and logistic regression where appropriate. A p -value of < 0.05 was considered significant., Results: Among the 649 participants, women allocated to the silver nylon dressing group, when compared with the gauze group, were similar in the amount of dispensed opioid and nonopioid analgesic medications (morphine equivalent milligrams of opioids dispensed [82.5 vs. 90 mg, p  = 0.74], intravenous nonsteroidal anti-inflammatory drugs (NSAIDs) [120 vs. 120 mg, p  = 0.55], and oral NSAIDs [4,800 vs. 5,600 mg in the gauze group, p  = 0.65]). After adjusting for confounding variables, postoperative wound infection (adjusted odds ratio [aOR]: 11.70; 95% confidence interval [CI]: 4.51-30.31) at 1-week postoperative and again at 6-week postoperative (aOR: 5.59; 95% CI: 1.03-30.31) but not gauze dressing was associated with patient-reported postoperative pain., Conclusion: Among women undergoing cesarean delivery, silver nylon dressing was not associated with a reduction in postoperative pain., Key Points: · Silver dressings showed no decrease in pain medications.. · Wound infection is associated with pain postoperatively.. · Silver dressings did not reduce postoperative pain.., Competing Interests: None declared., (Thieme. All rights reserved.)

A critical step for SARS-CoV-2 assembly and maturation involves the autoactivation of the main protease (MPro WT ) from precursor polyproteins. Upon expression, a model precursor of MPro WT mediates its own release at its termini rapidly to yield a mature dimer. A construct with an E290A mutation within MPro exhibits time dependent autoprocessing of the accumulated precursor at the N-terminal nsp4/nsp5 site followed by the C-terminal nsp5/nsp6 cleavage. In contrast, a precursor containing E290A and R298A mutations (MPro M ) displays cleavage only at the nsp4/nsp5 site to yield an intermediate monomeric product, which is cleaved at the nsp5/nsp6 site only by MPro WT . MPro M and the catalytic domain (MPro 1-199 ) fused to the truncated nsp4 region also show time-dependent conversion in vitro to produce MPro M and MPro 1-199 , respectively. The reactions follow first-order kinetics indicating that the nsp4/nsp5 cleavage occurs via an intramolecular mechanism. These results support a mechanism involving an N-terminal intramolecular cleavage leading to an increase in the dimer population and followed by an intermolecular cleavage at the C-terminus. Thus, targeting the predominantly monomeric MPro precursor for inhibition may lead to the identification of potent drugs for treatment., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Clonorchis sinensis is commonly found in East Asian countries. Clonorchiasis is prevalent in these countries and can lead to various clinical symptoms. In this study, we used overlap extension polymerase chain reaction (PCR) and the Xenopus laevis oocyte expression system to isolate a cDNA encoding the choline transporter of C. sinensis (CsChT). We subsequently characterized recombinant CsChT. Expression of CsChT in X. laevis oocytes enabled efficient transport of radiolabeled choline, with no detectable uptake of arginine, α-ketoglutarate, p-aminohippurate, taurocholate, and estrone sulfate. Influx and efflux experiments showed that CsChT-mediated choline uptake was time- and sodium-dependent, with no exchange properties. Concentration-dependent analyses of revealed saturable kinetics consistent with the Michaelis-Menten equation, while nonlinear regression analyses revealed a Km value of 8.3 μM and a Vmax of 61.0 pmol/oocyte/h. These findings contribute to widen our understanding of CsChT transport properties and the cascade of choline metabolisms within C. sinensis.

Maternal sepsis is a significant cause of maternal morbidity and mortality, and is a potentially preventable cause of maternal death. This Consult aims to summarize what is known about sepsis and provide guidance for the management of sepsis during pregnancy and the postpartum period. Most studies cited are from the nonpregnant population, but where available, pregnancy data are included. The following are the Society for Maternal-Fetal Medicine recommendations: (1) we recommend that clinicians consider the diagnosis of sepsis in pregnant or postpartum patients with otherwise unexplained end-organ damage in the presence of a suspected or confirmed infectious process, regardless of the presence of fever (GRADE 1C); (2) we recommend that sepsis and septic shock in pregnancy be considered medical emergencies and that treatment and resuscitation begin immediately (Best Practice); (3) we recommend that hospitals and health systems use a performance improvement program for sepsis in pregnancy with sepsis screening tools and metrics (GRADE 1B); (4) we recommend that institutions develop their own procedures and protocols for the detection of maternal sepsis, avoiding the use of a single screening tool alone (GRADE 1B); (5) we recommend obtaining tests to evaluate for infectious and noninfectious causes of life-threatening organ dysfunction in pregnant and postpartum patients with possible sepsis (Best Practice); (6) we recommend that an evaluation for infectious causes in pregnant or postpartum patients in whom sepsis is suspected or identified includes appropriate microbiologic cultures, including blood, before starting antimicrobial therapy, as long as there are no substantial delays in timely administration of antibiotics (Best Practice); (7) we recommend obtaining a serum lactate level in pregnant or postpartum patients in whom sepsis is suspected or identified (GRADE 1B); (8) in pregnant or postpartum patients with septic shock or a high likelihood of sepsis, we recommend administration of empiric broad-spectrum antimicrobial therapy, ideally within 1 hour of recognition (GRADE 1C); (9) after a diagnosis of sepsis in pregnancy is made, we recommend rapid identification or exclusion of an anatomic source of infection and emergency source control when indicated (Best Practice); (10) we recommend early intravenous administration (within the first 3 hours) of 1 to 2 L of balanced crystalloid solutions in sepsis complicated by hypotension or suspected organ hypoperfusion (GRADE 1C); (11) we recommend the use of a balanced crystalloid solution as a first-line fluid for resuscitation in pregnant and postpartum patients with sepsis or septic shock (GRADE 1B); (12) we recommend against the use of starches or gelatin for resuscitation in pregnant and postpartum patients with sepsis or septic shock (GRADE 1A); (13) we recommend ongoing, detailed evaluation of the patient's response to fluid resuscitation guided by dynamic measures of preload (GRADE 1B); (14) we recommend the use of norepinephrine as the first-line vasopressor during pregnancy and the postpartum period with septic shock (GRADE 1C); (15) we suggest using intravenous corticosteroids in pregnant or postpartum patients with septic shock who continue to require vasopressor therapy (GRADE 2B); (16) because of an increased risk of venous thromboembolism in sepsis and septic shock, we recommend the use of pharmacologic venous thromboembolism prophylaxis in pregnant and postpartum patients in septic shock (GRADE 1B); (17) we suggest initiating insulin therapy at a glucose level >180 mg/dL in critically ill pregnant patients with sepsis (GRADE 2C); (18) if a uterine source for sepsis is suspected or confirmed, we recommend prompt delivery or evacuation of uterine contents to achieve source control, regardless of gestational age (GRADE 1C); and (19) because of an increased risk of physical, cognitive, and emotional problems in survivors of sepsis and septic shock, we recommend ongoing comprehensive support for pregnant and postpartum sepsis survivors and their families (Best Practice)., (Copyright © 2023. Published by Elsevier Inc.)

The Society of Anesthesia and Sleep Medicine and the Society for Obstetric Anesthesia and Perinatology tasked an expert group to review existing evidence and to generate recommendations on the screening, diagnosis, and treatment of patients with obstructive sleep apnea during pregnancy. These recommendations are based on a systematic review of the available scientific evidence and expert opinion when scientific evidence is lacking. This guideline may not be appropriate for all clinical situations and patients, and physicians must decide whether these recommendations are appropriate for their patients on an individual basis. We recognize that not all pregnant people may identify as women. However, data on non-cisgendered pregnant patients are lacking, and many published studies use gender-binary terms; therefore, depending on the study referenced, we may refer to pregnant individuals as women. This guideline may inform the creation of clinical protocols by individual institutions that consider the unique considerations of their patient populations and the available resources., Competing Interests: Financial Disclosure Jennifer E. Dominguez is a member of the Board of Directors of the Society for Anesthesia and Sleep Medicine. Ashraf S. Habib has grants funded by Haisco USA, Pacira Pharmaceuticals, and Heron Therapeutics. He has served on a data safety monitoring or advisory board for MDoloris, Heron Therapeutics, and Vertex Therapeutics, and is on the Board of Directors for the Society of Obstetric Anesthesia and Perinatology. Bilgay Izci-Balserak has received honoraria from the World Sleep Day Research Symposium and research equipment from Itamar Medical, Ltd. Ellen Lockhart is a consultant for AMN Healthcare. Judette M. Louis has received an honorarium from Hologic, is a member of the medical advisory board for the Preeclampsia Foundation, and is an unpaid member of the Board of Trustees of the March of Dimes. Louise M. O'Brien has received grant support from the NIH, Star Legacy Foundation, ResMed, the American Academy of Sleep Medicine, and the American Sleep Medicine Foundation. She has received research equipment from Itamar Medical Ltd, and Smart Human Dynamics, and serves on the board of the Star Legacy Foundation. Christine Won has received consulting fees from EBSCO Dynamed, Flo.com , and Jazz Pharmaceuticals and honoraria from the Canadian Anesthesiology Society, and is on the Board of Directors of the Society of Anesthesia and Sleep Medicine. Ghada Bourjeily has received grant support from NHLBI, NICHD, and NICCH, consulting fees from EBSCO, and research equipment from Dreem, and serves on the Sleep Network and Women and Pulmonary advisory groups for Chest. The other authors did not report any potential conflicts of interest., (Copyright © 2023 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The effect of mutations of the catalytic dyad residues of SARS-CoV-2 main protease (MPro WT ) on the thermodynamics of binding of covalent inhibitors comprising nitrile [nirmatrelvir (NMV), NBH2], aldehyde (GC373), and ketone (BBH1) warheads to MPro is examined together with room temperature X-ray crystallography. When lacking the nucleophilic C145, NMV binding is ∼400-fold weaker corresponding to 3.5 kcal/mol and 13.3 °C decrease in free energy (ΔG) and thermal stability (T m ), respectively, relative to MPro WT . The H41A mutation results in a 20-fold increase in the dissociation constant (K d ), and 1.7 kcal/mol and 1.4 °C decreases in ΔG and T m , respectively. Increasing the pH from 7.2 to 8.2 enhances NMV binding to MPro H41A , whereas no significant change is observed in binding to MPro WT . Structures of the four inhibitor complexes with MPro 1-304/C145A show that the active site geometries of the complexes are nearly identical to that of MPro WT with the nucleophilic sulfur of C145 positioned to react with the nitrile or the carbonyl carbon. These results support a two-step mechanism for the formation of the covalent complex involving an initial non-covalent binding followed by a nucleophilic attack by the thiolate anion of C145 on the warhead carbon. Noncovalent inhibitor ensitrelvir (ESV) exhibits a binding affinity to MPro WT that is similar to NMV but differs in its thermodynamic signature from NMV. The binding of ESV to MPro C145A also results in a significant, but smaller, increase in K d and decrease in ΔG and T m , relative to NMV., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Children exposed to parental intimate partner violence (IPV) are at high risk in terms of their mental health during the COVID-19 pandemic. Therefore, online interventions are imperative in a crisis situation. Empirical studies indicate a significant relationship between self-esteem and children exposed to parental IPV. This research aimed to develop, and pilot test an online intervention program to enhance the self-esteem of Adolescents exposed to parental IPV. Conklin's developmental model was used to develop the online program and the Coopersmith Self Esteem Inventory scale, interview, and focus group discussion was used to understand the key issues. The developed Cognitive Self Compassion (CSC) Online Intervention Program that integrates the theories and techniques of social cognitive theory and self-compassion was implemented over 6 weeks at a rate of 60 min per session to the 10 participants. Results of the single-group pilot experiment showed a significant difference in the pre & post-test scores of the participants. The self-esteem of the adolescents exposed to parental IPV was significantly enhanced after undergoing the CSC Online Intervention Program.

Insomnia is prevalent in pregnancy and is associated with increased use of health services. We aimed to evaluate the association between insomnia diagnosed at the delivery hospitalization and risk of 30-day postpartum readmission. We conducted a retrospective analysis of inpatient hospitalizations from the 2010-2019 Nationwide Readmissions Database. The primary exposure was a coded diagnosis of insomnia at delivery as determined by ICD-9-CM and ICD-10-CM codes. Obstetric comorbidities and indicators of severe maternal morbidity were also determined through coding. The primary outcome was all-cause 30-day postpartum readmission. Survey-weighted logistic regression was used to generate crude and adjusted odds ratios representing the association between maternal insomnia and postpartum readmission. Of over 34 million delivery hospitalizations, 26,099 (7.6 cases per 10,000) had a coded diagnosis of insomnia. People with insomnia experienced a 3.0% all-cause 30-day postpartum readmission rate, compared to 1.4% among those without insomnia. After controlling for sociodemographic, clinical, and hospital-level factors, insomnia was associated with 1.64 times higher odds of readmission (95% CI 1.47-1.83). After adjustment for obstetric comorbidity burden and severe maternal morbidity, insomnia was independently associated with 1.33 times higher odds of readmission (95% CI 1.18-1.48). Pregnant patients with insomnia have higher rates of postpartum readmission, and diagnosis of insomnia is independently associated with increased odds of readmission. Additional postpartum support may be warranted for pregnancies affected by insomnia.

Problem: Medication for opioid use disorder (MOUD) is recommended for persons with opioid use disorder (OUD) during pregnancy. However, knowledge gaps exist about best practices for management of OUD during pregnancy and these data are needed to guide clinical care., Period Covered: 2014-2021., Description of the System: Established in 2019, the Maternal and Infant Network to Understand Outcomes Associated with Medication for Opioid Use Disorder During Pregnancy (MAT-LINK) is a surveillance network of seven clinical sites in the United States. Boston Medical Center, Kaiser Permanente Northwest, The Ohio State University, and the University of Utah were the initial clinical sites in 2019. In 2021, three clinical sites were added to the network (the University of New Mexico, the University of Rochester, and the University of South Florida). Persons receiving care at the seven clinical sites are diverse in terms of geography, urbanicity, race and ethnicity, insurance coverage, and type of MOUD received. The goal of MAT-LINK is to capture demographic and clinical information about persons with OUD during pregnancy to better understand the effect of MOUD on outcomes and, ultimately, provide information for clinical care and public health interventions for this population. MAT-LINK maintains strict confidentiality through robust information technology architecture. MAT-LINK surveillance methods, population characteristics, and evaluation findings are described in this inaugural surveillance report. This report is the first to describe the system, presenting detailed information on funding, structure, data elements, and methods as well as findings from a surveillance evaluation. The findings presented in this report are limited to selected demographic characteristics of pregnant persons overall and by MOUD treatment status. Clinical and outcome data are not included because data collection and cleaning have not been completed; initial analyses of clinical and outcome data will begin in 2023., Results: The MAT-LINK surveillance network gathered data on 5,541 reported pregnancies with a known pregnancy outcome during 2014-2021 among persons with OUD from seven clinical sites. The mean maternal age was 29.7 (SD = ±5.1) years. By race and ethnicity, 86.3% of pregnant persons were identified as White, 25.4% as Hispanic or Latino, and 5.8% as Black or African American. Among pregnant persons, 81.6% had public insurance, and 84.4% lived in urban areas. Compared with persons not receiving MOUD during pregnancy, those receiving MOUD during pregnancy were more likely to be older and White and to have public insurance. The evaluation of the surveillance system found that the initial four clinical sites were not representative of demographics of the South or Southwest regions of the United States and had low representation from certain racial and ethnic groups compared with the overall U.S. population; however, the addition of three clinical sites in 2021 made the surveillance network more representative. Automated extraction and processing improved the speed of data collection and analysis. The ability to add new clinical sites and variables demonstrated the flexibility of MAT-LINK., Interpretation: MAT-LINK is the first surveillance system to collect comprehensive, longitudinal data on pregnant person-infant dyads with perinatal outcomes associated with MOUD during pregnancy from multiple clinical sites. Analyses of clinical site data demonstrated different sociodemographic characteristics between the MOUD and non-MOUD treatment groups., Public Health Actions: MAT-LINK is a timely and flexible surveillance system with data on approximately 5,500 pregnancies. Ongoing data collection and analyses of these data will provide information to support clinical and public health guidance to improve health outcomes among pregnant persons with OUD and their children., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. The Maternal and Infant Network to Understand Outcomes Associated with Medication for Opioid Use Disorder During Pregnancy (MAT-LINK) is funded by the Assistant Secretary for Planning and Evaluation’s Office of the Secretary Patient-Centered Outcomes Research Trust Fund. All clinical site coauthors report funding for MAT-LINK. Katherine A. Sward reports funding from the National Institutes of Health for work with the Helping to End Addiction Long-Term (HEAL) Pain Management Effectiveness Research Network as a Data Coordinating Center. Vikrant G. Deshmukh reports a National Cancer Institute/University of Wisconsin subaward for investigating COVID-19 complications among smokers. Pilar M. Sanjuan reports funding as a principal investigator from the National Institute on Alcohol Abuse and Alcoholism for Project REACT (neural underpinnings of emotional regulation and drinking to cope); the National Institute on Drug Abuse for Project Vida (prenatal opioid use disorder and posttraumatic stress disorder); and the National Institute of Mental Health for Project Raptor (attention and post-traumatic stress disorder) and as a coinvestigator from the National Institute on Alcohol Abuse and Alcoholism on Project AsCENd (neuroimaging of child attention development); the National Institute on Drug Abuse Helping to End Addiction Long-Term initiative for Integrative Management of chronic Pain and OUD for Whole Recovery (pain and prenatal opioid use) and for the HEALthy Brain and Child Development study; and relationships with New Mexico Postpartum Support International as a board chair and the New Mexico Perinatal Collaborative as a board member. Jessie R. Maxwell reports funding from the National Institute on Drug Abuse for work as a coinvestigator on the HEALthy Brain and Childhood Development studies; the National Institutes of Health for work as a Helping to End Addiction Long-Term initiative alternate principal investigator; the National Institute on Alcohol Abuse and Alcoholism for work as a principal investigator on a project; the National Institute on Alcohol Abuse and Alcoholism for work as a coinvestigator on a local project; and the IDeA States Pediatric Clinical Trials Network for work as site principal investigator, work as a junior investigator, and meeting attendance as a member of the leadership committee. Neil S. Seligman reports funding from PreTel Inc. and Mae Stone Goode for work not related to this report; Natera for consulting fees; UpToDate for writing; and various legal reviews. Judette Louis reports funding from TD Bank for an institutional grant; Wolters Kluwer for an UpToDate piece on sleep apnea during pregnancy; Hologic for a one-time fee; Elsevier for serving as a textbook editor; Goldasich, Vick & Fulk for a fee; Sleep Disorder Research Advisory Board for being a member; the National Institutes of Health for work on a personalized integrated chronotherapy for perinatal depression; March of Dimes for travel expenses related to being a board member; Society for Maternal-Fetal Medicine for travel expenses related to being a board member; American Board of Obstetrics and Gynecology for travel expenses related to being a board member; and Preeclampsia Foundation for blood pressure cuffs for her institution. Tanner Wright reports funding from Duke University for a National Institutes of Health–funded project on Eating, Sleeping, Consoling for Neonatal Opioid Withdrawal Syndrome (ESC-NOW): a Function-Based Assessment and Management Approach; the National Institute on Drug Abuse for CADENCE (Continuous and Data-driven Care); the American Academy of Pediatrics for work as a subject matter expert on maternal–infant health and opioid use; and the National Advanced Practice and Low Risk Neonatal Nurses Conferences for presentations on neonatal opioid withdrawal syndrome. No other potential conflicts of interest were disclosed.

Fibrils formed by the 42-residue amyloid-β peptide (Aβ42), a main component of amyloid deposits in Alzheimer's disease (AD), are known to be polymorphic, i.e., to contain multiple possible molecular structures. Previous studies of Aβ42 fibrils, including fibrils prepared entirely in vitro or extracted from brain tissue and using solid-state NMR (ssNMR) or cryogenic electron microscopy (cryo-EM) methods, have found polymorphs with differences in amino acid sidechain orientations, lengths of structurally ordered segments, and contacts between cross-β subunit pairs within a single filament. Despite these differences, Aβ42 molecules adopt a common S-shaped conformation in all previously described high-resolution Aβ42 fibril structures. Here we report two cryo-EM-based structures of Aβ42 fibrils that are qualitatively different, in samples derived from AD brain tissue by seeded growth. In type A fibrils, residues 12 to 42 adopt a ν-shaped conformation, with both intra-subunit and intersubunit hydrophobic contacts to form a compact core. In type B fibrils, residues 2 to 42 adopt an υ-shaped conformation, with only intersubunit contacts and internal pores. Type A and type B fibrils have opposite helical handedness. Cryo-EM density maps and molecular dynamics simulations indicate intersubunit K16-A42 salt bridges in type B fibrils and partially occupied K28-A42 salt bridges in type A fibrils. The coexistence of two predominant polymorphs, with differences in N-terminal dynamics, is supported by ssNMR data, as is faithful propagation of structures from first-generation to second-generation brain-seeded Aβ42 fibril samples. These results demonstrate that Aβ42 fibrils can exhibit a greater range of structural variations than seen in previous studies.

Centers for Disease Control and Prevention data from 2020 demonstrate the continued upward trend in the mean age of pregnant individuals in the United States. Observational studies demonstrate that pregnancy in older individuals is associated with increased risks of adverse pregnancy outcomes-for both the pregnant patient and the fetus-that might differ from those found in younger pregnant populations, even in healthy individuals with no other comorbidities. There are several studies that suggest that advancing age at the time of pregnancy is associated with greater disparities in severe maternal morbidity and mortality. This document seeks to provide evidence-based clinical recommendations for minimizing adverse outcomes associated with pregnancy with anticipated delivery at an advanced maternal age. The importance and benefits of accessible health care from prepregnancy through postpartum care for all pregnant individuals cannot be overstated. However, this document focuses on and addresses the unique differences in pregnancy-related care for women and all those seeking obstetrical care with anticipated delivery at the age of 35 years or older within the framework of routine pregnancy care. This Obstetric Care Consensus document was developed using an a priori protocol in conjunction with the authors listed above., (Copyright © 2022 American College of Obstetricians and Gynecologists. Published by Elsevier Inc. All rights reserved.)

The importance of a fully functioning placenta for a good pregnancy outcome is unquestioned. Loss of function can lead to pregnancy complications and is often detected by a thorough placental pathologic examination. Placental pathology has advanced the science and practice of obstetrics and neonatal-perinatal medicine by classifying diseases according to underlying biology and specific patterns of injury. Many past obstacles have limited the incorporation of placental findings into both clinical studies and day-to-day practice. Limitations have included variability in the nomenclature used to describe placental lesions, a shortage of perinatal pathologists fully competent to analyze placental specimens, and a troubling lack of understanding of placental diagnoses by clinicians. However, the potential use of placental pathology for phenotypic classification, improved understanding of the biology of adverse pregnancy outcomes, the development of treatment and prevention, and patient counseling has never been greater. This review, written partly in response to a recent critique published in a major obstetrics-gynecology journal, reexamines the role of placental pathology by reviewing current concepts of biology; explaining the most recent terminology; emphasizing the usefulness of specific diagnoses for obstetrician-gynecologists, neonatologists, and patients; previewing upcoming changes in recommendations for placental submission; and suggesting future improvements. These improvements should include further consideration of overall healthcare costs, cost-effectiveness, the clinical value added of placental assessment, improvements in placental pathology education and practice, and leveraging of placental pathology to identify new biomarkers of disease and evaluate novel therapies tailored to specific clinicopathologic phenotypes of both women and infants., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Exposure of children to their parents' intimate partner violence (IPV) is recognized as an adverse childhood experience that has a significant impact on the overall healthy development of the children and this research summarizes all relevant literature to determine the prevalence, impacts, risks, and protective factors of adolescents subjected to parental IPV since childhood. The literature in this scoping was scrutinized based on both inclusion, exclusion criteria. Almost 15 articles were reviewed out of 118 related literature sourced from electronic databases such as PubMed, Scopus, Research Gate, and Google Scholar published in the year 2016-2021. The search method followed Mays, Roberts, and Popay's process of gathering relevant literature and mapping important ideas to capture the available data in a study topic, especially the one which lacked proper evaluation. The results of this review of the literature indicate that parental IPV is a pervasive problem that impairs the adolescent's overall well-being. It also highlights a range of protective factors that can mitigate the impact of parental IPV. The findings of this scoping review have implications for practice and policy. Given the enormous scope and burden of children's parental IPV exposure, intervention techniques to safeguard this vulnerable population and enhance well-being are urgently needed.

We recently demonstrated that inhibitor binding reorganizes the oxyanion loop of a monomeric catalytic domain of SARS CoV-2 main protease (MPro) from an unwound (E) to a wound (active, E*) conformation, independent of dimerization. Here we assess the effect of the flanking N-terminal residues, to imitate the MPro precursor prior to its autoprocessing, on conformational equilibria rendering stability and inhibitor binding. Thermal denaturation (T m ) of C145A mutant, unlike H41A, increases by 6.8 °C, relative to wild-type mature dimer. An inactivating H41A mutation to maintain a miniprecursor containing TSAVL[Q or E] of the flanking nsp4 sequence in an intact form [ (-6) MPro H41A and (-6*) MPro H41A , respectively], and its corresponding mature MPro H41A were systematically examined. While the H41A mutation exerts negligible effect on T m and dimer dissociation constant (K dimer ) of MPro H41A , relative to the wild type MPro, both miniprecursors show a 4-5 °C decrease in T m and > 85-fold increase in K dimer as compared to MPro H41A . The K d for the binding of the covalent inhibitor GC373 to (-6*) MPro H41A increases ∼12-fold, relative to MPro H41A , concomitant with its dimerization. While the inhibitor-free dimer exhibits a state in transit from E to E* with a conformational asymmetry of the protomers' oxyanion loops and helical domains, inhibitor binding restores the asymmetry to mature-like oxyanion loop conformations (E*) but not of the helical domains. Disorder of the terminal residues 1-2 and 302-306 observed in both structures suggest that N-terminal autoprocessing is tightly coupled to the E-E* equilibrium and stable dimer formation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

BACKGROUND: Among women with hypertensive disorders of pregnancy, biomarkers may stratify risk for developing preeclampsia with severe features (sPE). METHODS: Across 18 U.S. centers, we prospectively measured the ratio of serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) in pregnant women hospitalized between 23 and 35 weeks of gestation. The primary outcome was predicting sPE, and secondary outcomes included predicting adverse outcomes within 2 weeks. The prognostic performance of the sFlt-1:PlGF ratio was assessed by using a derivation/validation design. RESULTS: A total of 1014 pregnant women were evaluated; 299 were included in the derivation cohort and 715 in the validation cohort. In the derivation cohort, the median sFlt-1:PlGF ratio was 200 (interquartile range, 53 to 458) among women who developed sPE compared with 6 (interquartile range, 3 to 26) in those who did not (P<0.001). The discriminatory ratio of ≥40 was then tested in the validation cohort and yielded a 65% positive (95% confidence interval [CI], 59 to 71) and a 96% negative (95% CI, 93 to 98) predictive value for the primary outcome. The ratio performed better than standard clinical measures (area under the receiver-operating characteristic curve, 0.92 versus <0.75 for standard-of-care tests). Compared with women with a ratio <40, women with a ratio ≥40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2). CONCLUSIONS: In women with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1:PlGF provided stratification of the risk of progressing to sPE within the coming fortnight. (Funded by Cedars-Sinai Medical Center and Thermo Fisher Scientific; ClinicalTrials.gov NCT03815110.)