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by Fanghui Shi, Jiajia Zhang, Chengbo Zeng, Xiaowen Sun, Zhenlong Li, Xueying Yang, Sharon Weissman, Bankole Olatosi, Xiaoming Li Background Timely linkage to care (LTC) is key in the HIV care continuum, as it enables people newly diagnosed with HIV (PNWH) to benefit from HIV treatment at the earliest stage. Previous studies have found LTC disparities by individual factors, but data are limited beyond the individual level, especially at the county level. This study examined the temporal and geographic variations of county-level LTC status across 46 counties in South Carolina (SC) from 2010 to 2018 and the association of county-level characteristics with LTC status. Methods All adults newly diagnosed with HIV from 2010 to 2018 in SC were included in this study. County-level LTC status was defined as 1 = “high LTC (≥ yearly national LTC percentage)” and 0 = “low LTC (< yearly national LTC percentage)”. A generalized estimating equation model with stepwise selection was employed to examine the relationship between 29 county-level characteristics and LTC status. Results The number of counties with high LTC in SC decreased from 34 to 21 from 2010 to 2018. In the generalized estimating equation model, six out of 29 factors were significantly associated with LTC status. Counties with a higher percentage of males (OR = 0.07, 95%CI: 0.02~0.29) and persons with at least four years of college (OR = 0.07, 95%CI: 0.02~0.34) were less likely to have high LTC. However, counties with more mental health centers per PNWH (OR = 45.09, 95%CI: 6.81~298.55) were more likely to have high LTC. Conclusions Factors associated with demographic characteristics and healthcare resources contributed to the variations of LTC status at the county level. Interventions targeting increasing the accessibility to mental health facilities could help improve LTC. …

by David J. Braun, Hilaree N. Frazier, Verda A. Davis, Meggie J. Coleman, Colin B. Rogers, Linda J. Van Eldik The p38 alpha mitogen-activated protein kinase (p38α) is linked to both innate and adaptive immune responses and is under investigation as a target for drug development in the context of Alzheimer’s disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38α inhibition can protect against AD-associated neuropathology, the underlying mechanisms are not fully elucidated. Inhibitors of p38α may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to AD pathology. The present study tests this hypothesis by knocking out microglial p38α and assessing early-stage pathological changes. Conditional knockout of microglial p38α was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system under control of the Cx3cr1 promoter. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field, followed by a later radial arm water maze test and collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included quantification of proinflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics. Loss of microglial p38α did not alter behavioral outcomes, proinflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Aβ42 and reduce colocalization of Iba1 and 6E10 in a subset of microglia in close proximity to plaques. The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38α inhibition in the context of early AD-type amyloid pathology is a subtle alteration of microglia-plaque interactions. Encouragingly from a therapeutic standpoint, these data suggest no detrimental effect of even substantial decreases in microglial p38α in this context. Additionally, these results support future investigations of microglial p38α signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.

by Maia Sieverding, Caroline Krafft, Irene Selwaness, Alexandra Abi Nassif The pathways through which the COVID-19 pandemic has impacted population mental health are potentially gendered. Little research has explored these pathways in low- and middle-income country contexts, such as in the Middle East and North Africa (MENA) region, where socioeconomic roles are highly gendered. To address this gap, we examine the relationships between pandemic-related socioeconomic changes and subjective wellbeing in the MENA region. Our core hypothesis is that the COVID-19 pandemic affected men and women’s subjective wellbeing differently in part because these effects were mediated by gendered socioeconomic roles. We exploit multiple waves of longitudinal, nationally-representative phone survey data across Egypt, Jordan, Morocco, Sudan, and Tunisia. The data were collected between November 2020 and August 2021 and include 32,296 observations of 20,256 unique individuals. Mental health is measured through the WHO-5 subjective wellbeing scale. Our key independent variables capture pandemic-related employment loss, income loss, experience of limitations on food access, enrollment of children in alternative schooling modalities, and receipt of formal and informal transfers. We find significantly worse subjective wellbeing for women in Egypt and Morocco during the pandemic, but not the three other countries. There were negative associations between employment and income loss during the pandemic and subjective wellbeing, but not gender-differentiated ones. In contrast, high levels of limitations on food access were associated with worse mental health for men than women. Receipt of transfers generally did not have any association with subjective wellbeing. Further research is needed into how social assistance programs implemented in response to pandemics may be designed so as to address the negative mental health consequences of such events.

by Manee Chanama, Chanwit Suriyachadkun, Suchart Chanama A novel actinobacterium, designated strain SMC 277T, was isolated from the clay soil in paddy field of Chonburi Province, Thailand, and characterized using polyphasic taxonomy. Strain SMC 277T formed straight chains of nonmotile cylindrical spores with smooth surface developed on aerial mycelia. The typical chemotaxonomic properties of members of the genus Streptomyces were observed in strain SMC 277T, e.g., cell wall peptidoglycan, whole cell sugars, major menaquinones, cellular fatty acids, and polar lipids. Chemotaxonomic data combined with mycelium and spore morphologies supported the assignment of strain SMC 277T to the genus Streptomyces. The results of comparative analysis of the 16S rRNA gene sequences confirmed that strain SMC 277T represented a member of the genus Streptomyces. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SMC 277T shared the highest sequence similarity with Streptomyces bambusae NBRC 110903T (98.8%). Genome sequencing revealed a genome size of 6.55 Mbp and a digital G+C content of 73.4 mol%. In addition to the differences in phenotypic characteristics (morphology and physiology), values of ANI (ANIb and ANIm), AAI and dDDH between strain SMC 277T and its closest relative S. bambusae NBRC 110903T were 81.84, 86.77, 76.91 and 26.1%, respectively. Genome annotation and secondary metabolite gene cluster analysis predicted that SMC 277T contained 35 biosynthetic gene clusters encoding diverse bioactive secondary metabolites. It is in agreement with observed antimicrobial activity against drug-resistant bacteria associated with nosocomial infections (methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase producing Klebsiella pneumoniae, and multidrug-resistant Acinetobacter baumannii). On the basis of these genotypic and phenotypic characteristics, strain SMC 277T can be characterized to represent a novel species of the genus Streptomyces, for which the name Streptomyces antimicrobicus is proposed. The type strain is SMC 277T (= TBRC 15568T = NBRC 115422T).

by Felix Matheri, Anne Kelly Kambura, Maina Mwangi, Edward Karanja, Noah Adamtey, Kennedy Wanjau, Edwin Mwangi, Chrysantus Mbi Tanga, David Bautze, Steven Runo Thermophilic composting is a promising soil and waste management approach involving diverse micro and macro-organisms, including eukaryotes. Due to sub-optimal amounts of nutrients in manure, supplemental feedstock materials such as Lantana camara, and Tithonia diversifolia twigs are used in composting. These materials have, however, been reported to have antimicrobial activity in in-vitro experiments. Furthermore, the phytochemical analysis has shown differences in their complexities, thus possibly requiring various periods to break down. Therefore, it is necessary to understand these materials’ influence on the biological and physical-chemical stability of compost. Most compost microbiome studies have been bacterial-centric, leaving out eukaryotes despite their critical role in the environment. Here, the influence of different green feedstock on the fungal and non-fungal eukaryotic community structure in a thermophilic compost environment was examined. Total community fungal and non-fungal eukaryotic DNA was recovered from triplicate compost samples of four experimental regimes. Sequencing for fungal ITS and non-fungal eukaryotes; 18S rDNA was done under the Illumina Miseq platform, and bioinformatics analysis was done using Divisive Amplicon Denoising Algorithm version 2 workflow in R version 4.1. Samples of mixed compost and composting day 84 recorded significantly (P…

by Ivanice D. Freire, Katherine L. Fielding, David A. J. Moore Background The growing burden of diabetes worldwide is a threat to tuberculosis (TB) control. Drug-induced liver injury (DILI) due to TB drugs is a significant concern and there is currently limited evidence on the effect of diabetes on TB DILI. This study sought to investigate the effect of diabetes as a risk factor for DILI and to further study any potential co-factors. Methods An unmatched case-control study. Cases were TB patients on 2RHZE/4RH presenting with DILI from 2013–2017 in Porto Alegre, Brazil. Controls were contemporaneous TB patients without DILI being treated in any one of the same five Porto Alegre TB clinics. The exposure variables were diabetes (main exposure variable), age, sex, alcohol misuse, human immunodeficiency virus (HIV), hepatitis C (HCV) and B (HBV) viruses, concomitant hepatotoxic drugs, other liver diseases and TB site. The outcome variable was the occurrence of DILI. Results Odds of DILI were increased by: older age group 51–60, 61–70 and 71–93 years (adjusted OR 2.39, 95%CI 1.30–4,38; adjusted OR 4.37, 2.28–8,35; adjusted OR 12.91, 5.81–28,66, respectively), HIV positive status (adjusted OR 3.59, 95%CI 2.25–5.73), HCV positive status (adjusted OR 3.49, 95%CI 1.96–6.21) and having concurrent pulmonary and extrapulmonary TB (adjusted OR 3.16, 95%CI 1.93–5.19). Diabetes, gender, and other hepatotoxic drugs were not associated with DILI. Conclusions This study confirms the association between TB DILI and well-known risk factors but did not demonstrate increased odds of TB DILI in patients with diabetes. …

Journal of Medical Virology, Volume 95, Issue 6, June 2023.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide [1]. Traditionally, CAP has been considered an acute illness in which once the initial process has been passed, the patient fully recovers with no implications for long-term survival. In contrast, some recent studies have observed a higher risk of death after recovery from the acute episode than that in the general population [2,3,4].

Infection and Immunity, Ahead of Print.

Infection and Immunity, Ahead of Print.

Infection and Immunity, Ahead of Print.

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Antimicrobial Agents and Chemotherapy, Ahead of Print.

Publication date: Available online 31 May 2023 Source: Infectious Disease Modelling Author(s): Zenebe Shiferaw Kifle, Legesse Lemecha Obsu …

Publication date: Available online 30 May 2023 Source: International Journal for Parasitology Author(s): Mélanie Duc, Tanja Himmel, Mikas Ilgūnas, Vytautas Eigirdas, Herbert Weissenböck, Gediminas Valkiūnas …

AbstractBackgroundRifampin-resistant tuberculosis is a leading cause of morbidity worldwide; only one-third of persons initiate treatment and outcomes are often inadequate. Several trials demonstrate 90% efficacy using an all-oral, six-month regimen of bedaquiline, pretomanid, and linezolid (BPaL), but significant toxicity occurred using 1200 mg linezolid. After U.S. FDA approval in 2019, some U.S. clinicians rapidly implemented BPaL using an initial linezolid 600 mg dose adjusted by serum drug concentrations and clinical monitoring.MethodsData from U.S. patients treated with BPaL between 10/14/2019 and 4/30/2022 were compiled and analyzed by the BPaL Implementation Group (BIG), including baseline examination and laboratory, electrocardiographic, and clinical monitoring throughout treatment and follow-up. Linezolid dosing and clinical management was provider-driven, and most had linezolid adjusted by therapeutic drug monitoring (TDM).ResultsOf 70 patients starting BPaL, two changed to rifampin-based therapy, 68 (97.1%) completed BPaL, and two of these 68 (2.9%) patients relapsed after completion. Using an initial 600 mg linezolid dose daily adjusted by TDM and careful clinical and laboratory monitoring for side effects, supportive care, and expert consultation throughout BPaL treatment, three (4.4%) patients with hematologic toxicity and four (5.9%) with neurotoxicity required a change in linezolid dose or frequency. The median BPaL duration was 6 months.ConclusionsBPaL has transformed treatment for rifampin-resistant or intolerant tuberculosis. In this cohort, effective treatment required less than half the duration recommended in ATS/CDC/ERS/IDSA 2019 guidelines for drug-resistant tuberculosis. Use of individualized linezolid dosing and monitoring likely enhanced safety and treatment completion. The BIG cohort demonstrates that early implementation of new tuberculosis treatments in the U.S. is feasible.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

Proceedings of the National Academy of Sciences, Volume 120, Issue 22, May 2023.

AbstractIntroductionPrevious studies reported inconsistent findings regarding the association between respiratory syncytial virus (RSV) subgroup distribution and timing of RSV seasonal epidemics, possibly due to not accounting for confounders such as meteorological factors. We aimed to improve the understanding of the association through a global-level systematic analysis that accounted for these potential confounders.MethodsWe compiled published data on RSV seasonality through a systematic literature review, and supplemented with unpublished data shared by international collaborators. RSV seasonal characteristics were defined for each study-year based on the annual cumulative proportion (ACP) of RSV-positive cases, with ACP of 10% and 90% being defined as season onset and offset, respectively. Linear regression models with study-level clustered standard errors were conducted to analyse the association of proportion of RSV-A with the corresponding RSV season onset and offset separately, while accounting for meteorological factors.ResultsWe included a total of 36 studies from 36 sites in 20 countries, which cumulatively provided data for 179 study-years in 1995–2019. Overall, year-on-year variations in RSV season onset, offset, and duration were generally comparable among tropical, sub-tropical, and temperate regions. Regression analysis by latitude groups showed that RSV subgroup distribution was not significantly associated with RSV season onset or offset globally; the only exception was for RSV season offset in the tropics in one model, possibly by chance. Models that included both RSV subgroup distribution and meteorological factors only jointly explained 2–4% of the variations in RSV season onset and offset.ConclusionGlobally, RSV subgroup distribution had negligible impact on the RSV seasonal characteristics. RSV subgroup distribution and meteorological factors jointly could only explain limited year-on-year variations in RSV season onset and offset. The role of population susceptibility, mobility, and viral interference should be examined in future studies.

AbstractBackgroundRespiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in adults that can result in hospitalisations. Estimating RSV-associated hospitalisation is critical for planning RSV-related healthcare across Europe.MethodsWe gathered RSV-associated hospitalisation estimates from the RSV Consortium in Europe (RESCEU) for adults in Denmark, England, Finland, Norway, Netherlands, and Scotland from 2006-2017. We extrapolated these estimates to 28 EU countries using nearest-neighbour matching, multiple imputations, and two sets of 10 indicators.ResultsOn average, 158229 (95%CI:140865-175592) RSV-associated hospitalisations occur annually among adults in the EU (≥18years); 92% of these hospitalisations occur in adults ≥65years. Among 75-84years, the annual average is estimated at 74519 (69923-79115) at a rate of 2.24 (2.10-2.38) per 1000. Among ≥85years, the annual average is estimated at 37904 (32444-43363) at a rate of 2.99 (2.56-3.42).ConclusionOur estimates of RSV-associated hospitalisations in adults are the first analysis integrating available data to provide the disease burden across the EU. Importantly, for a condition considered in the past to be primarily a disease of young children, the average annual hospitalisation estimate in adults was lower but of a similar magnitude to the estimate in young children(0-4years): 158229 (140865–175592) versus 245244 (224688–265799).

AbstractBackgroundNo overall estimate of RSV-associated hospitalisations in children under 5 years has been published for the European Union (EU). We aimed to estimate the RSV hospitalisation burden in children under 5 years in EU countries and Norway, by age group.MethodsWe collated national RSV-associated hospitalisation estimates calculated using linear regression models via the RESCEU project for Denmark, England, Finland, Norway, the Netherlands and Scotland during 2006-2018. Additional estimates were obtained from a systematic review. Using the multiple imputation and nearest neighbour matching methods, we estimated overall RSV-associated hospitalisations and rates in the EU.ResultsAdditional estimates for only two countries (France and Spain) were found in the literature. In the EU, an average of 245,244 (95%CI 224,688-265,799) yearly hospital admissions with a respiratory infection per year were associated with RSV in children under the age of 5, with most cases occurring among children aged less than 1 year (75%). Infants aged less than 2 months represented the most affected group (71.6 per 1,000 children; 66.6-76.6).ConclusionOur findings will help support decisions regarding prevention efforts and represent an important benchmark to understand changes in the RSV burden following the introduction of RSV immunisation programs in Europe.

AbstractBackgroundPulmonary tuberculosis (TB) and lung cancer (LC) have similar clinical symptoms and atypical imaging findings which are easily misdiagnosed. There is an urgent need for a noninvasive and accurate biomarker to distinguish LC from TB.MethodsA total of 694 subjects were enrolled and divided into discovery set (n = 122), identification set (n = 214), and validation set (n = 358). Metabolites were identified by multivariate and univariate analyses. Receiver operating characteristic curve were used to evaluate the diagnostic efficacy of biomarkers.ResultsSeven metabolites were identified and validated. Phenylalanylphenylalanine for distinguish LC from TB yielded an area under the curve of 0.89, sensitivity of 71%, and specificity of 92%. It also showed good diagnostic abilities in discovery set and identification set. Compared with that in healthy volunteers (1.57 (1.01, 2.34) μg·mL-1), it was elevated in LC (4.76 (2.74-7.08) μg·mL-1; ratio of median, ROM = 3.03, p 

Dogma is defined as “a belief or set of beliefs that is accepted by the members of a group without being questioned or doubted” (https://www.britannica.com/dictionary/dogma; accessed May 2, 2023). Everyone who has worked in different healthcare institutions, maybe even in different countries, knows that there are local ‘dogmas’ that are not evidence-based.(1) Indeed, one may identify dogmas as such only once one has been confronted with other, possibly opposing ‘dogmas’ elsewhere. The question of whether, for which patients, at what interval(s), and how often to repeat blood cultures in the case of Gram-negative bacteremia may be an example.

Abstract Background Although tuberculosis (TB) patients coinfected with HIV are at risk of poor treatment outcomes, there is paucity of data on changing trends of TB/HIV co-infection and their treatment outcomes. This study aims to estimate the burden of TB/HIV co-infection over time, describe the treatment available to TB/HIV patients and estimate the effect of TB/HIV co-infection on TB treatment outcomes. Methods This was a retrospective data analyses from TB surveillance in two counties in Kenya (Nyeri and Kilifi): 2012‒2020. All TB patients aged ≥ 18 years were included. The main exposure was HIV status categorised as infected, negative or unknown status. World Health Organization TB treatment outcomes were explored; cured, treatment complete, failed treatment, defaulted/lost-to-follow-up, died and transferred out. Time at risk was from date of starting TB treatment to six months later/date of the event and Cox proportion with shared frailties models were used to estimate effects of TB/HIV co-infection on TB treatment outcomes. Results The study includes 27,285 patients, median (IQR) 37 (29‒49) years old and 64% male. 23,986 (88%) were new TB cases and 91% were started on 2RHZE/4RH anti-TB regimen. Overall, 7879 (29%, 95% 28‒30%) were HIV infected. The proportion of HIV infected patient was 32% in 2012 and declined to 24% in 2020 (trend P-value = 0.01). Uptake of ARTs (95%) and cotrimoxazole prophylaxis (99%) was high. Overall, 84% patients completed six months TB treatment, 2084 (7.6%) died, 4.3% LTFU, 0.9% treatment failure and 2.8% transferred out. HIV status was associated with lower odds of completing TB treatment: infected Vs negative (aOR 0.56 (95%CI 0.52‒0.61) and unknown vs negative (aOR 0.57 (95%CI 0.44‒0.73). Both HIV infected and unknown status were associated with higher hazard of death: (aHR 2.40 (95%CI 2.18‒2.63) and 1.93 (95%CI 1.44‒2.56)) respectively and defaulting treatment/LTFU: aHR 1.16 (95%CI 1.01‒1.32) and 1.55 (95%CI 1.02‒2.35)) respectively. HIV status had no effect on hazard of transferring out and treatment failure. Conclusion The overall burden of TB/HIV coinfection was within previous pooled estimate. Our findings support the need for systematic HIV testing as those with unknown status had similar TB treatment outcomes as the HIV infected. …

Abstract Background Liver failure is severe hepatic cellular damage caused by multiple factors that leads to clinical manifestations. Hepatic infiltration by malignancy is rarely reported as a cause of liver failure. Case presentation A 51-year-old male patient was admitted to the Wuhan Union Hospital complaining of bloating and jaundice. He had been diagnosed with polymyositis ten prior and was taking oral glucocorticoids. Physical examination revealed seroperitoneum and icteric sclera; laboratory tests revealed liver dysfunction, a coagulopathy, and negative results for the common causes of liver failure. Moreover, an ascitic tap and bone marrow aspirate and trephine confirmed a metastatic, poorly differentiated adenocarcinoma. These findings indicate that malignant infiltration is the most likely cause of liver failure. Regrettably, the patient refused complete liver and lymph node biopsies and was discharged on day 31. Conclusion Clinicians should consider the possibility of malignant infiltration when approaching a case of liver failure with prodromal symptoms or imaging abnormalities, especially in patients with autoimmune diseases, such as polymyositis. …

Abstract Aim Until now, the performance of interferon-γ release assay (IGRA) and Mantoux tests remains unclear in infant tuberculous meningitis (TBM). Therefore, a systematic review is performed to evaluate the sensitivity of IGRA and Mantoux tests for the diagnosis of infant TBM in low and intermediate tuberculosis (TB) burden countries, while following PRISMA. Methods Several databases, including PubMed, EBSCO, Embase, Scopus, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials, were searched. Articles describing the results of IGRA or Mantoux tests among infant TBM were included for analysis. Data, such as age, sex, Mantoux test or IGRA, and cerebrospinal fluid (CSF) microbiological examinations (such as acid-fast bacilli (AFB) smear, TB PCR, and TB culture), were extracted from each study. Results A total of 31 articles were enrolled for further analysis, including 48 cases. The mean age was 9.4 ± 5.8 months and boys accounted for 57.1% of infants (24/42). Mantoux test was positive in 57.4% (27/47) of tested infants and IGRA was positive in 77.8% (7/9) of infants. In addition, among the infants with confirmed TB, 18 (52.9%, 18/34) of them have positive Mantoux responses and 7 (20.0%, 7/35) have positive IGRA results. Conclusions In low or intermediate TB burden countries, the Mantoux test has a poor performance for diagnosing TBM among infants, and IGRAs appear to have a moderate sensitivity for the diagnosis of infant TBM. …

Once integrated in the genome of infected cells, HIV-1 provirus is transcribed by the cellular transcription machinery. This process is regulated by both viral and cellular factors, which are necessary for an ...

Some people do not believe long COVID (also known as post-COVID-19 condition) is real. In fact, patients have reported that there are even doctors who sit in this camp, who might dismiss their symptoms as psychosomatic, or do not know how to recognise or treat long COVID. It is complicated, even for researchers. People might not have had severe symptoms when infected with SARS-CoV-2 virus, they might be young, without a significant medical history or risk factors. Although studies suggest around 10–20% of individuals who did not have severe acute disease might develop long COVID symptoms, the number of people who are facing long-term effects is hard to quantify.

In patients who underwent delivery during their ICU stay, maternal outcome deteriorated following delivery among those defined as critical compared with non-critical patients, who improved following delivery. Interventional delivery should be considered for maternal indications before patients deteriorate and require mechanical ventilation.