Active COVID-19 infection as a barrier to postpartum tubal ligation.

OBJECTIVES: To identify patients unable to obtain postpartum bilateral tubal ligations (ppBTLs) due to policy prohibiting "elective" procedures for COVID-positive patients at a single academic medical center in New Jersey. RESULTS: Upon retrospective chart review of patients requesting ppBTLS, of 110 ppBTL requests between identified via retrospective chart review between February 1, 2020, and February 28, 2022, 24 (22%) were canceled due to COVID infection. Of these patients, 10 (42%) were uninsured, 13 (54%) had Medicaid, and 22 (92%) were Hispanic/Latinx. Postpartum, five (21%) obtained interval tubal ligation, seven (37%) never received contraception, and one had a future pregnancy. CONCLUSIONS: This policy affected uninsured patients by preventing access to permanent contraception.

A randomized controlled trial to evaluate outcomes with Aggrenox in patients with SARS-CoV-2 infection.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an immunoinflammatory and hypercoagulable state that contributes to respiratory distress, multi-organ dysfunction, and mortality. Dipyridamole, by increasing extracellular adenosine, has been postulated to be protective for COVID-19 patients through its immunosuppressive, anti-inflammatory, anti-coagulant, vasodilatory, and anti-viral actions. Likewise, low-dose aspirin has also demonstrated protective effects for COVID-19 patients. This study evaluated the effect of these two drugs formulated together as Aggrenox in hospitalized COVID-19 patients. METHODS: In an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge. RESULTS: From October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05). CONCLUSION: In this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients.

Cannabis Use is an Independent Risk Factor for Manic Episode: A Report from 380,265 Bipolar Inpatients.

OBJECTIVES: To evaluate the odds for bipolar disorder (BP) mania and depression-related hospitalization due to cannabis use disorders (CUD). METHODS: We conducted a cross-sectional study using the national inpatient sample (NIS), and included adult BP hospitalizations sub-grouped by manic (N = 209,785) versus depressive episodes (N = 170480). A logistic regression model was used to evaluate adjusted odds ratio (aOR) of association between CUD and BP-mania-related hospitalizations and was adjusted for demographics confounders, psychiatric comorbidities and other substance use disorders (SUD). RESULTS: Comorbidities were less prevalent in BP mania compared to BP depression: anxiety disorders (22.7% vs. 35.3%), PTSD (8.7% vs. 14.3%), and personality disorders (15.4% vs. 20.5%). Among SUD, methamphetamine (aOR 1.27, 95%CI 1.22 - 1.32) and CUD (aOR 1.53, 95%CI 1.50 - 1.56) had increased odds for hospitalization for BP mania. CONCLUSION: CUD increases the odds for hospitalization for BP manic episode by 53%. Due to the rising prevalence of cannabis use among patients with BP it is important to provide substance use counseling/psychoeducation and discourage cannabis use among youth to prevent long-term adverse consequences.

Stimulation of phospholipase Cß1 by Gαq promotes the assembly of stress granule proteins.

During adverse conditions, mammalian cells suppress protein production by sequestering the translational machinery in membrane-less organelles known as stress granules. Here, we found that activation of the G protein subunit Gαq promoted the formation of particles that contained stress granule proteins through a mechanism linked to a cytosolic fraction of phospholipase Cß1 (PLCß1). In experiments with PC12 and A10 cells, we showed that under basal conditions, cytosolic PLCß1 bound to stress granule­associated proteins, including PABPC1, eIF5A, and Ago2. Knockdown of cytosolic PLCß1 with siRNA or promoting its relocalization to the plasma membrane by activating Gαq resulted in the formation of particles containing these stress granule­associated proteins. Our studies showed that the composition of these particles resembled those formed under osmotic stress and were distinct from those formed in response to other types of stress. Our results fit a simple thermodynamic model in which cytosolic PLCß1 solubilizes stress granule proteins such that its movement to activated Gαq releases these proteins to enable the formation of stress granules. Together, our data suggest a link between Gαq-coupled signals and protein translation through stress granule formation.

Postpartum hemorrhage caused by uterine artery pseudoaneurysm: A case report.

BACKGROUND: Uterine artery pseudoaneurysms (UAPs) are a rare life-threatening complication presenting as vaginal bleeding. Transvaginal ultrasound doppler scans can diagnose UAPs in the immediate and later postpartum period. This case report highlights UAP management using minimally invasive interventions for fertility preservation. CASE: A 21-year-old woman presented on post-operative day 10 following a primary cesarean section with heavy vaginal bleeding and a UAP was confirmed on doppler sonography. A multidisciplinary approach determined the optimal management taking the patient's fertility into consideration. Initially, the UAP was injected directly with thrombin under ultrasound guidance. However, due to a subsequent hemorrhage, a uterine artery embolization was performed. CONCLUSION: Recognition of UAP is critical in the management of postpartum vaginal bleeding. Patient goals should be balanced with the severity of UAPs to determine optimal management.

Phospholipase Cß interacts with cytosolic partners to regulate cell proliferation.

Phospholipase Cß (PLCß) is the main effector of the Gαq signaling pathway relaying different extracellular sensory information to generate intracellular calcium signals. Besides this classic function, we have found that PLCß plays an important but unknown role in regulating PC12 cell differentiation by interacting with components in the RNA-induced silencing machinery. In trying to understand the role of PLCß in PC12 cell differentiation, we find that over-expressing PLCß reduces PC12 cell proliferation while down-regulating PLCß increases the rate of cell proliferation. However, this behavior is not seen in other cancerous cell lines. To determine the underlying mechanism, we carried out mass spectrometry analysis of PLCß complexes in PC12 cells. We find that in unsynchronized cells, PLCß primarily binds cyclin-dependent kinase (CDK)16 whose activity plays a key role in cell proliferation. In vitro studies show a direct association between the two proteins that result in loss in CDK16 activity. When cells are arrested in the G2/M phase, a large population of PLCß is bound to Ago2 in a complex that contains C3PO and proteins commonly found in stress granules. Additionally, another population of PLCß complexes with CDK18 and cyclin B1. Fluorescence lifetime imaging microscopy (FLIM) confirms cell cycle dependent associations between PLCß and these other protein binding partners. Taken together, our studies suggest that PLCß may play an active role in mediating interactions required to move through the cell cycle.

Survival of Mycobacterium tuberculosis and Mycobacterium bovis BCG in lysosomes in vivo.

Mycobacterium tuberculosis is one of the most successful pathogens known, having infected more than a third of the global population. An important strategy for intracellular survival of pathogenic mycobacteria relies on their capacity to resist delivery to lysosomes, instead surviving within macrophage phagosomes. Several factors of both mycobacterial and host origin have been implicated in this process. However, whether or not this strategy is employed in vivo is not clear. Here we show that in vivo, following intravenous infection, M. tuberculosis and Mycobacterium bovis BCG initially survived by resisting lysosomal transfer. However, after prolonged infection the bacteria were transferred to lysosomes yet continued to proliferate. A M. bovis BCG mutant lacking protein kinase G (PknG), that cannot avoid lysosomal transfer and is readily cleared in vitro, was found to survive and proliferate in vivo. The ability to survive and proliferate in lysosomal organelles in vivo was found to be due to an altered host environment rather than changes in the inherent ability of the bacteria to arrest phagosome maturation. Thus, within an infected host, both M. tuberculosis and M. bovis BCG adapts to infection-specific host responses. These results are important to understand the pathology of tuberculosis and may have implications for the development of effective strategies to combat tuberculosis.

Global analyses of TetR family transcriptional regulators in mycobacteria indicates conservation across species and diversity in regulated functions.

BACKGROUND: Mycobacteria inhabit diverse niches and display high metabolic versatility. They can colonise both humans and animals and are also able to survive in the environment. In order to succeed, response to environmental cues via transcriptional regulation is required. In this study we focused on the TetR family of transcriptional regulators (TFTRs) in mycobacteria. RESULTS: We used InterPro to classify the entire complement of transcriptional regulators in 10 mycobacterial species and these analyses showed that TFTRs are the most abundant family of regulators in all species. We identified those TFTRs that are conserved across all species analysed and those that are unique to the pathogens included in the analysis. We examined genomic contexts of 663 of the conserved TFTRs and observed that the majority of TFTRs are separated by 200 bp or less from divergently oriented genes. Analyses of divergent genes indicated that the TFTRs control diverse biochemical functions not limited to efflux pumps. TFTRs typically bind to palindromic motifs and we identified 11 highly significant novel motifs in the upstream regions of divergently oriented TFTRs. The C-terminal ligand binding domain from the TFTR complement in M. tuberculosis showed great diversity in amino acid sequence but with an overall architecture common to other TFTRs. CONCLUSION: This study suggests that mycobacteria depend on TFTRs for the transcriptional control of a number of metabolic functions yet the physiological role of the majority of these regulators remain unknown.

Predicting the risk of pre-eclampsia between 11 and 13 weeks' gestation by combining maternal characteristics and serum analytes, PAPP-A and free ß-hCG.

OBJECTIVE: To determine if a simplified model for predicting pre-eclampsia (PEC) can be developed by combining first-trimester serum analytes, pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (ß-hCG), and maternal characteristics. METHODS: A retrospective cohort study of patients seen for first-trimester aneuploidy screening from 2003 to 2009. The 5th, 10th, 90th, and 95th percentiles for the analyte multiples of the medians (MoMs) for our population were determined and evaluated for association with PEC. Univariate and backward stepwise logistic regression analyses were performed and the area under the receiver operating characteristic (ROC) curves [area under curve (AUC)] used to determine the best models for predicting PEC. RESULTS: Among 4020 women meeting the inclusion criteria, outcome data was available for 3716 (93%). There were 293 cases of PEC. The final model identified a history of pre-gestational diabetes [aOR 2.6, 95% confidence interval (CI) 1.7-3.9], chronic hypertension (cHTN) (aOR 2.6, 95% CI 1.7-3.9), maternal body mass index (BMI) > 25 (aOR 2.5, 95% CI 1.9-3.4), African American race (aOR 1.8, 95% CI 1.3-2.6), and PAPP-A MoM < 10th percentile (aOR 1.6, 95% CI 1.1-2.4) to be significant predictors of PEC (AUC = 0.70, 95% CI 0.65-0.72). CONCLUSION: Low first-trimester PAPP-A levels are associated with the development of PEC; however, the model was only modestly efficient in its predictive ability.

Is chorionic villus sampling associated with hypertensive disorders of pregnancy?

OBJECTIVE: Our objective is to evaluate for potential associations between chorionic villus sampling (CVS) and hypertensive disorders of pregnancy. METHODS: Using our genetic database, we compared the rates of hypertensive disorders between women who underwent CVS at 10-13 and 6/7 weeks with those seen for other indications at similar gestational ages who had no invasive procedure. Only singleton and euploid pregnancies were included. Statistical methods including univariable and multivariable logistic regression, supplemented by stratified analyses were used for comparisons. RESULTS: Among 11 012 pregnant women seen between 1990 and 2006 in our center and meeting the inclusion criteria, information on hypertensive disorders of pregnancy were available in 9386, and 9098 met the inclusion criteria. The overall incidence of hypertensive disorders was 421/9098 (4.6%), with 138/5096 (2.7%) in the CVS group and 283/4002 (7.1%) in the control group [adjusted odds ratio (adjOR) 0.47, 95% confidence interval (CI), 0.38-0.59]. Similar findings were seen on stratified analyses for gestational age of procedure and the type or severity of hypertensive disorder, and other potential confounders. CONCLUSION: The rate of hypertensive disorders of pregnancy is significantly lower in women having CVS compared with the control group. Placental disruption from CVS is not associated with preeclampsia or gestational hypertension.

The efficiency of first-trimester serum analytes and maternal characteristics in predicting fetal growth disorders.

OBJECTIVE: To evaluate the association between first-trimester serum analytes, pregnancy-associated plasma protein A and free beta-human chorionic gonadotropin, and fetal growth disorders, and to determine whether a prediction model for these growth disorders can be developed. STUDY DESIGN: Retrospective cohort study of patients seen for first-trimester aneuploidy screening. Pregnancy-associated plasma protein A and free beta-human chorionic gonadotropin multiples of the median were evaluated for association with small- and large-for-gestational-age infants in combination with maternal characteristics. Univariate and backward stepwise logistic regression analyses were performed and the area under the receiver-operator curves used to determine the best prediction models. RESULTS: Neither pregnancy-associated plasma protein A nor free beta-human chorionic gonadotropin levels were associated with an increased risk of large-for-gestational-age infants. For small-for-gestational-age infants, the final model included black race, free beta-human chorionic gonadotropin multiples of the median >90th percentile, and pregnancy-associated plasma protein A multiples of the median <5th percentile as significant predictors (area under the curve = 0.58). CONCLUSION: Low pregnancy-associated plasma protein A and high free beta-human chorionic gonadotropin levels are associated with a small-for-gestational-age growth pattern; however, additional factors to improve the prediction model are needed.