Pregnancy and Postpartum Drug Overdose Deaths in the US Before and During the COVID-19 Pandemic.

Importance: Knowledge about characteristics of US pregnancy-associated decedents is needed to guide responses. Objective: To examine individual sociodemographic characteristics and residing county's health care resources and socioeconomic factors among pregnancy-associated overdose decedents in comparison with obstetric decedents and overdose decedents who were not pregnant in the past year. Design, Setting, and Participants: This cross-sectional, exploratory study included 1457 pregnant and postpartum overdose decedents, 4796 obstetric decedents, and 11 205 nonpregnant overdose decedents aged 10 to 44 years from 2018 to 2021. Data were analyzed August 2023. Exposures: Decedents from the 2018-2021 Multiple Cause of Death Files linked to the 2021 Area Health Resources Files and the 2018-2021 County Health Rankings data at the county level. Main Outcomes and Measures: Pregnancy-associated deaths were defined as deaths during pregnancy or within 1 year of pregnancy termination. This study focused on unintentional drug overdoses or drug overdoses with undetermined intent involving the most common psychotropic drugs of misuse. Results: From 2018 to 2021, across the pregnancy-postpartum continuum, pregnancy-associated overdose mortality ratios consistently increased among women aged 10 to 44 years. Mortality ratio more than tripled among pregnant and postpartum women aged 35 to 44 years from 4.9 (95% CI, 3.0-8.0) per 100 000 mothers aged 35 to 44 years with a live birth in January to June 2018 to 15.8 (95% CI, 12.3-20.4) in July to December 2021 (average semiannual percentage changes, 15.9; 95% CI, 8.7-23.6; P < .001). Compared with pregnant obstetric decedents, pregnant overdose decedents had increased odds of being aged 10 to 34 years (75.4% vs 59.5%; range of odds ratios [ORs], 1.8 [95% CI, 1.3-2.5] for ages 10 to 24 years to 2.2 [95% CI, 1.7-2.8] for ages 25 to 34 years), being non-college graduates (72.1% vs 59.4%; range of ORs, 2.7 [95% CI, 1.7-4.3] for those with some college education to 3.9 [95% CI, 2.4-6.1] for those with less than high school education), being unmarried (88.0% vs 62.1%; OR, 4.5; 95% CI, 3.7-6.0), and dying in nonhome, non-health care settings (25.9% vs 4.5%; OR, 2.5; 95% CI, 1.8-3.6) and were associated with decreased odds of dying in health care settings (34.7% vs 77.6%; range of ORs, 0.1 [95% CI, 0.1-0.1] for those who died in hospital inpatient settings to 0.4 [95% CI, 0.3-0.6] for those who died in hospital outpatient/emergency room settings). Conclusions and Relevance: From 2018 to 2021, the mortality ratio more than tripled among pregnant and postpartum women aged 35 to 44 years, consistent with increases in overdose mortality across US populations. Most pregnancy-associated overdose deaths occurred outside health care settings, indicating the need for strengthening community outreach and maternal medical support. To reduce pregnancy-associated overdose mortality, evidence-based interventions are urgently needed at individual, health care, local, and national levels, along with nonpunitive approaches incentivizing pregnant and postpartum women to seek substance use disorder treatments.

Evaluation of the contribution of the transmembrane region to the ectodomain conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein.

BACKGROUND: The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env), a Type 1 transmembrane protein, assembles into a trimeric spike complex that mediates virus entry into host cells. The high potential energy of the metastable, unliganded Env trimer is maintained by multiple non-covalent contacts among the gp120 exterior and gp41 transmembrane Env subunits. Structural studies suggest that the gp41 transmembrane region forms a left-handed coiled coil that contributes to the Env trimer interprotomer contacts. Here we evaluate the contribution of the gp41 transmembrane region to the folding and stability of Env trimers. METHODS: Multiple polar/charged amino acid residues, which hypothetically disrupt the stop-transfer signal, were introduced in the proposed lipid-interactive face of the transmembrane coiled coil, allowing release of soluble cleavage-negative Envs containing the modified transmembrane region (TMmod). We also examined effects of cleavage, the cytoplasmic tail and a C-terminal fibritin trimerization (FT) motif on oligomerization, antigenicity and functionality of soluble and membrane-bound Envs. RESULTS: The introduction of polar/charged amino acids into the transmembrane region resulted in the secretion of soluble Envs from the cell. However, these TMmod Envs primarily formed dimers. By contrast, control cleavage-negative sgp140 Envs lacking the transmembrane region formed soluble trimers, dimers and monomers. TMmod and sgp140 trimers were stabilized by the addition of a C-terminal FT sequence, but still exhibited carbohydrate and antigenic signatures of a flexible ectodomain structure. On the other hand, detergent-solubilized cleaved and uncleaved Envs isolated from the membranes of expressing cells exhibited "tighter" ectodomain structures, based on carbohydrate modifications. These trimers were found to be unstable in detergent solutions, but could be stabilized by the addition of a C-terminal FT moiety. The C-terminal FT domain decreased Env cleavage and syncytium-forming ability by approximately three-fold; alteration of the FT trimerization interface restored Env cleavage and syncytium formation to near-wild-type levels. CONCLUSION: The modified transmembrane region was not conducive to trimerization of soluble Envs. However, for HIV-1 Env ectodomains that are minimally modified, membrane-anchored Envs exhibit the most native structures and can be stabilized by appropriately positioned FT domains.