A Comparison of Neonatal Outcomes Between Obese and Nonobese Women With Preterm Prelabor Rupture of Membranes.

Introduction Preterm prelabor rupture of membrane (PPROM) contributes to increasing rates of preterm birth, causing greater health risks for newborns. While the mechanisms driving PPROM are not well understood, one hypothesis is that it is due to systemic inflammation, which can be caused by obesity defined as a BMI [Formula: see text]30 kg/m2. The specific aim of the study was to compare neonatal outcomes after PPROM between patients who were obese vs not obese in early pregnancy at a tertiary medical center serving an Appalachian population. Methods An observational, descriptive retrospective review was conducted of the medical records of patients who were diagnosed with PPROM from January 2017 through December 2020. Patients with a single gestation at the time of PPROM without evidence of clinical infection requiring immediate delivery were included. Maternal characteristics, latency management, and birth outcomes were compared between obese ([Formula: see text]30 BMI) and non-obese (<30 BMI) patients. Results Of the 214 women in the study, 129 (60.3%) were obese pre-pregnancy and 85 (39.7%) were not. Most PPROM occurred between 32 and 36 weeks of gestation (145 patients, 67.8%), with 19.2% occurring at 26-31 weeks (41 patients), and 13.2% at <26 weeks of gestation (28 patients). Latency, defined as the days between PPROM and delivery, ranged from 0 to 80 days with a mean of 4.9 + 10.9 days. At least one day of latency was achieved for most patients (144/214; 67.3%). When outcomes were compared between obese and nonobese patients, the obese patients experienced significantly more complications (10.1% vs 2.4%; p=0.031), which were accompanied by greater neonatal morbidity 67 of 129 ((51.9%) vs 30 of 85 (35.3%); p=0.018). Obese women had greater odds that their newborns would experience neonatal morbidity than nonobese women (odds ratio, 1.98; 95% confidence interval, 1.1-3.5). Conclusion This study of Appalachian women found that pre-pregnancy BMI [Formula: see text]30 increased the risk of complications and neonatal morbidity after PPROM. To improve birth outcomes, healthcare workers and policymakers must work together to decrease rates of obesity in Appalachian women at or near childbearing age.

The Case for Advocacy Curricula and Opportunities in Medical Education: Past Examples to Inform Future Instruction.

ABSTRACT: With recent advances in understanding racial, socioeconomic, and mental health issues in medicine and their relation to policy and legislation, medical professionals are increasingly involved in local and national advocacy efforts. At the frontlines of these initiatives are medical students who, in addition to completing required coursework and clinical training, devote themselves to serving patients through civic participation. The burgeoning evidence concerning health care disparities and inequity, along with greater awareness of racial and socioeconomic discrimination, have made advocacy an essential aspect of many students' medical training. Every year, thousands of medical students join national medical advocacy organizations, in addition to regional, state, and local groups. Despite the rich history of medical student involvement in advocacy, there remains much speculation and skepticism about the practice as an essential component of the medical profession. From early initiatives pushing for national health insurance after World War II to encouraging antidiscrimination policies and practices, medical students have been collectively working to create change for themselves and their patients. Through efforts such as banning smoking on airplanes, creating safe syringe programs, and protesting against police brutality, many medical students work tirelessly in advocacy despite minimal educational support or guidance about the advocacy process. Given that medical student advocacy continues to grow and has shown measurable successes in the past, the authors believe that these efforts should be rewarded and expanded upon. The authors examine historical examples of medical student advocacy to suggest ways in which advocacy can be integrated into core medical school curricula and activities. They call attention to opportunities to support students' development of knowledge and skills to facilitate legislative change, expansion of interprofessional collaborations and credit, and curricular updates to promote social and health equity.

Prevalence and Spatial Distribution of Gastroschisis in an Industrial Watershed.

The relationship between the congenital defect of gastroschisis and environmental toxins is poorly understood. We examined gastroschisis incidence, risk factors, and spatial association in a geographic region with known environmental pollution and hazardous waste sites. An observational study of fetal and neonatal gastroschisis diagnosed from 1/1/2006 to 12/31/2020 was conducted in a southern West Virginia (WV) tertiary care hospital. Emerging hot spot analysis and Ripley's K-Function examined the spatial relationship between gastroschisis cases and Environmental Protection Agency (EPA) Federal Registry Sites (FRS). A total of 63 gastroschisis cases provided a prevalence rate of 14.6 per 10000 live births. Gastroschisis was associated with younger maternal age, decreased pre-pregnancy BMI, and increased maternal tobacco use. Relative to FRS sites, spatial clusters were identified with emerging hot spot analysis. Observed Ripley K was higher at all measured bands. Results suggest a potential geographic association between gastroschisis cases and EPA-designated hazardous waste sites.

What MFTs should know about nutrition, psychosocial health, and collaborative care with nutrition professionals.

Despite sufficient evidence on the role of nutrition in psychosocial health, Marriage and Family Therapists lack the knowledge for sufficient assessment and referrals in treatment. The purpose of this article is to orient MFTs to human metabolism and the effects of various nutrients, or lack thereof, on the psychosocial health in their clients. The roles of several micronutrients and macronutrients will be described as well as the effects of eating patterns and overall metabolic health on mental health. Finally, implications for MFTs as sole practitioners, domains for assessment and psychoeducation, and recommendations for collaborating with nutrition professionals will be discussed.

Intermediate filaments enable pathogen docking to trigger type 3 effector translocation.

Type 3 secretion systems (T3SSs) of bacterial pathogens translocate bacterial effector proteins that mediate disease into the eukaryotic cytosol. Effectors traverse the plasma membrane through a translocon pore formed by T3SS proteins. In a genome-wide selection, we identified the intermediate filament vimentin as required for infection by the T3SS-dependent pathogen S. flexneri. We found that vimentin is required for efficient T3SS translocation of effectors by S. flexneri and other pathogens that use T3SS, Salmonella enterica serovar Typhimurium and Yersinia pseudotuberculosis. Vimentin and the intestinal epithelial intermediate filament keratin 18 interact with the C-terminus of the Shigella translocon pore protein IpaC. Vimentin and its interaction with IpaC are dispensable for pore formation, but are required for stable docking of S. flexneri to cells; moreover, stable docking triggers effector secretion. These findings establish that stable docking of the bacterium specifically requires intermediate filaments, is a process distinct from pore formation, and is a prerequisite for effector secretion.

Infectious Entry Pathway Mediated by the Human Endogenous Retrovirus K Envelope Protein.

UNLABELLED: Endogenous retroviruses (ERVs), the majority of which exist as degraded remnants of ancient viruses, comprise approximately 8% of the human genome. The youngest human ERVs (HERVs) belong to the HERV-K(HML-2) subgroup and were endogenized within the past 1 million years. The viral envelope protein (ENV) facilitates the earliest events of endogenization (cellular attachment and entry), and here, we characterize the requirements for HERV-K ENV to mediate infectious cell entry. Cell-cell fusion assays indicate that a minimum of two events are required for fusion, proteolytic processing by furin-like proteases and exposure to acidic pH. We generated an infectious autonomously replicating recombinant vesicular stomatitis virus (VSV) in which the glycoprotein was replaced by HERV-K ENV. HERV-K ENV imparts an endocytic entry pathway that requires dynamin-mediated membrane scission and endosomal acidification but is distinct from clathrin-dependent or macropinocytic uptake pathways. The lack of impediments to the replication of the VSV core in eukaryotic cells allowed us to broadly survey the HERV-K ENV-dictated tropism. Unlike extant betaretroviral envelopes, which impart a narrow species tropism, we found that HERV-K ENV mediates broad tropism encompassing cells from multiple mammalian and nonmammalian species. We conclude that HERV-K ENV dictates an evolutionarily conserved entry pathway and that the restriction of HERV-K to primate genomes reflects downstream stages of the viral replication cycle. IMPORTANCE: Approximately 8% of the human genome is of retroviral origin. While many of those viral genomes have become inactivated, some copies of the most recently endogenized human retrovirus, HERV-K, can encode individual functional proteins. Here, we characterize the envelope protein (ENV) of the virus to define how it mediates infection of cells. We demonstrate that HERV-K ENV undergoes a proteolytic processing step and triggers membrane fusion in response to acidic pH--a strategy common to many viral fusogens. Our data suggest that the infectious entry pathway mediated by this ENV requires endosomal acidification and the GTPase dynamin but does not require clathrin-dependent uptake. In marked contrast to other betaretroviruses, HERV-K ENV imparts broad species tropism in cultured cells. This work provides new insights into the entry pathway of an extinct human virus and provides a powerful tool to further probe the endocytic route by which HERV-K infects cells.

A mechanistic paradigm for broad-spectrum antivirals that target virus-cell fusion.

LJ001 is a lipophilic thiazolidine derivative that inhibits the entry of numerous enveloped viruses at non-cytotoxic concentrations (IC50 ≤ 0.5 µM), and was posited to exploit the physiological difference between static viral membranes and biogenic cellular membranes. We now report on the molecular mechanism that results in LJ001's specific inhibition of virus-cell fusion. The antiviral activity of LJ001 was light-dependent, required the presence of molecular oxygen, and was reversed by singlet oxygen ((1)O2) quenchers, qualifying LJ001 as a type II photosensitizer. Unsaturated phospholipids were the main target modified by LJ001-generated (1)O2. Hydroxylated fatty acid species were detected in model and viral membranes treated with LJ001, but not its inactive molecular analog, LJ025. (1)O2-mediated allylic hydroxylation of unsaturated phospholipids leads to a trans-isomerization of the double bond and concurrent formation of a hydroxyl group in the middle of the hydrophobic lipid bilayer. LJ001-induced (1)O2-mediated lipid oxidation negatively impacts on the biophysical properties of viral membranes (membrane curvature and fluidity) critical for productive virus-cell membrane fusion. LJ001 did not mediate any apparent damage on biogenic cellular membranes, likely due to multiple endogenous cytoprotection mechanisms against phospholipid hydroperoxides. Based on our understanding of LJ001's mechanism of action, we designed a new class of membrane-intercalating photosensitizers to overcome LJ001's limitations for use as an in vivo antiviral agent. Structure activity relationship (SAR) studies led to a novel class of compounds (oxazolidine-2,4-dithiones) with (1) 100-fold improved in vitro potency (IC50<10 nM), (2) red-shifted absorption spectra (for better tissue penetration), (3) increased quantum yield (efficiency of (1)O2 generation), and (4) 10-100-fold improved bioavailability. Candidate compounds in our new series moderately but significantly (p≤0.01) delayed the time to death in a murine lethal challenge model of Rift Valley Fever Virus (RVFV). The viral membrane may be a viable target for broad-spectrum antivirals that target virus-cell fusion.

N-Glycans on the Nipah virus attachment glycoprotein modulate fusion and viral entry as they protect against antibody neutralization.

Nipah virus (NiV) is the deadliest known paramyxovirus. Membrane fusion is essential for NiV entry into host cells and for the virus' pathological induction of cell-cell fusion (syncytia). The mechanism by which the attachment glycoprotein (G), upon binding to the cell receptors ephrinB2 or ephrinB3, triggers the fusion glycoprotein (F) to execute membrane fusion is largely unknown. N-glycans on paramyxovirus glycoproteins are generally required for proper protein conformational integrity, transport, and sometimes biological functions. We made conservative mutations (Asn to Gln) at the seven potential N-glycosylation sites in the NiV G ectodomain (G1 to G7) individually or in combination. Six of the seven N-glycosylation sites were found to be glycosylated. Moreover, pseudotyped virions carrying these N-glycan mutants had increased antibody neutralization sensitivities. Interestingly, our results revealed hyperfusogenic and hypofusogenic phenotypes for mutants that bound ephrinB2 at wild-type levels, and the mutant's cell-cell fusion phenotypes generally correlated to viral entry levels. In addition, when removing multiple N-glycans simultaneously, we observed synergistic or dominant-negative membrane fusion phenotypes. Interestingly, our data indicated that 4- to 6-fold increases in fusogenicity resulted from multiple mechanisms, including but not restricted to the increase of F triggering. Altogether, our results suggest that NiV-G N-glycans play a role in shielding virions against antibody neutralization, while modulating cell-cell fusion and viral entry via multiple mechanisms.

Endothelial galectin-1 binds to specific glycans on nipah virus fusion protein and inhibits maturation, mobility, and function to block syncytia formation.

Nipah virus targets human endothelial cells via NiV-F and NiV-G envelope glycoproteins, resulting in endothelial syncytia formation and vascular compromise. Endothelial cells respond to viral infection by releasing innate immune effectors, including galectins, which are secreted proteins that bind to specific glycan ligands on cell surface glycoproteins. We demonstrate that galectin-1 reduces NiV-F mediated fusion of endothelial cells, and that endogenous galectin-1 in endothelial cells is sufficient to inhibit syncytia formation. Galectin-1 regulates NiV-F mediated cell fusion at three distinct points, including retarding maturation of nascent NiV-F, reducing NiV-F lateral mobility on the plasma membrane, and directly inhibiting the conformational change in NiV-F required for triggering fusion. Characterization of the NiV-F N-glycome showed that the critical site for galectin-1 inhibition is rich in glycan structures known to bind galectin-1. These studies identify a unique set of mechanisms for regulating pathophysiology of NiV infection at the level of the target cell.

A quantitative and kinetic fusion protein-triggering assay can discern distinct steps in the nipah virus membrane fusion cascade.

The deadly paramyxovirus Nipah virus (NiV) contains a fusion glycoprotein (F) with canonical structural and functional features common to its class. Receptor binding to the NiV attachment glycoprotein (G) triggers F to undergo a two-phase conformational cascade: the first phase progresses from a metastable prefusion state to a prehairpin intermediate (PHI), while the second phase is marked by transition from the PHI to the six-helix-bundle hairpin. The PHI can be captured with peptides that mimic F's heptad repeat regions, and here we utilized a NiV heptad repeat peptide to quantify PHI formation and the half-lives (t(1/2)) of the first and second fusion cascade phases. We found that ephrinB2 receptor binding to G triggered approximately 2-fold more F than that triggered by ephrinB3, consistent with the increased rate and extent of fusion observed with ephrinB2- versus ephrinB3-expressing cells. In addition, for a series of hyper- and hypofusogenic F mutants, we quantified F-triggering capacities and measured the kinetics of their fusion cascade phases. Hyper- and hypofusogenicity can each be manifested through distinct stages of the fusion cascade, giving rise to vastly different half-lives for the first (t(1/2), 1.9 to 7.5 min) or second (t(1/2), 1.5 to 15.6 min) phase. While three mutants had a shorter first phase and a longer second phase than the wild-type protein, one mutant had the opposite phenotype. Thus, our results reveal multiple critical parameters that govern the paramyxovirus fusion cascade, and our assays should help efforts to elucidate other class I membrane fusion processes.

Private sector response to improving oral health care access.

Despite vast improvements in the oral health status of the United States population over the past 50 years, disparities in oral health status continue, with certain segments of the population carrying a disproportionate disease burden. This article attempts to describe the problem, discuss various frameworks for action, illustrate some solutions developed by the private sector, and present a vision for collaborative action to improve the health of the nation. No one sector of the health care system can resolve the problem. The private sector, the public sector, and the not-for-profit community must collaborate to improve the oral health of the nation.