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Coral reefs are among the most sensitive ecosystems affected by ocean warming and acidification, and are predicted to collapse over the next few decades. Reefs are predicted to shift from net accreting calcifier-dominated systems with exceptionally high biodiversity to net eroding algal-dominated systems with dramatically reduced biodiversity. Here, we present a two-year experimental study examining the responses of entire mesocosm coral reef communities to warming (+2 °C), acidification (-0.2 pH units), and combined future ocean (+2 °C, -0.2 pH) treatments. Contrary to modeled projections, we show that under future ocean conditions, these communities shift structure and composition yet persist as novel calcifying ecosystems with high biodiversity. Our results suggest that if climate change is limited to Paris Climate Agreement targets, coral reefs could persist in an altered state rather than collapse., Competing Interests: Competing interests statement:The authors declare no competing interest.

Objective: To evaluate the accuracy of two portable ultrasound machines (PUM) in assessing fetal biometry and estimated gestational age (EGA)., Methods: This was a secondary analysis of data from the Fetal Age Machine Learning Initiative, an observational study of pregnant women in the USA and Zambia. Each participant underwent ultrasound assessment by an experienced sonographer using both a high-specification ultrasound machine (HSUM) and a PUM (Butterfly iQ or Clarius C3) to measure fetal biometry and calculate EGA at each visit. By comparing paired PUM and HSUM scans, we estimated agreement between individual biometry measurements and aggregate gestational age estimates by reporting mean difference, intraclass correlation coefficient (ICC) and Bland-Altman plots, adjusting for trend., Results: Between April and December 2021, 818 participants contributed 1386 paired PUM-HSUM ultrasound investigations, of which 991 PUM scans were obtained using the Butterfly iQ device and 395 using the Clarius C3 device. Gestational age at scan ranged from 7 to 38 weeks. Compared with HSUM, the Butterfly iQ PUM had a mean difference of -0.20 (95% CI, -0.60 to 0.20) days in the first trimester and -0.68 (95% CI, -0.93 to -0.44) days in the second/third trimesters. Compared with HSUM, the Clarius C3 PUM had a mean difference of -0.47 (95% CI, -1.11 to 0.18) days in the first trimester and -1.67 (95% CI, -2.10 to -1.25) days in the second/third trimesters. ICCs were 0.989 or greater throughout. Increasing gestational age was associated with increasing error and absolute error in EGA and fetal biometry. Both PUM devices demonstrated a modest trend toward underestimation of EGA with advancing gestational age in second/third-trimester scans, compared with HSUM., Conclusion: The Butterfly iQ and Clarius C3 PUM devices were highly accurate in performing fetal biometry in a diverse population from the USA and Zambia. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Background: The Multi-Omics for Mothers and Infants consortium aims to improve birth outcomes. Preterm birth is a major obstetrical complication globally and causes significant infant and childhood morbidity and mortality., Objective: We analyzed placental samples (basal plate, placenta or chorionic villi, and the chorionic plate) collected by the 5 Multi-Omics for Mothers and Infants sites, namely The Alliance for Maternal and Newborn Health Improvement Bangladesh, The Alliance for Maternal and Newborn Health Improvement Pakistan, The Alliance for Maternal and Newborn Health Improvement Tanzania, The Global Alliance to Prevent Prematurity and Stillbirth Bangladesh, and The Global Alliance to Prevent Prematurity and Stillbirth Zambia. The goal was to analyze the morphology and gene expression of samples collected from preterm and uncomplicated term births., Study Design: The teams provided biopsies from 166 singleton preterm (<37 weeks' gestation) and 175 term (≥37 weeks' gestation) deliveries. The samples were fixed in formalin and paraffin embedded. Tissue sections from these samples were stained with hematoxylin and eosin and subjected to morphologic analyses. Other placental biopsies (n=35 preterm, 21 term) were flash frozen, which enabled RNA purification for bulk transcriptomics., Results: The morphologic analyses revealed a surprisingly high rate of inflammation that involved the basal plate, placenta or chorionic villi, and the chorionic plate. The rate of inflammation in chorionic villus samples, likely attributable to chronic villitis, ranged from 25% (Pakistan site) to 60% (Zambia site) of cases. Leukocyte infiltration in this location vs in the basal plate or chorionic plate correlated with preterm birth. Our transcriptomic analyses identified 267 genes that were differentially expressed between placentas from preterm vs those from term births (123 upregulated, 144 downregulated). Mapping the differentially expressed genes onto single-cell RNA sequencing data from human placentas suggested that all the component cell types, either singly or in subsets, contributed to the observed dysregulation. Consistent with the histopathologic findings, gene ontology analyses highlighted the presence of leukocyte infiltration or activation and inflammatory responses in both the fetal and maternal compartments., Conclusion: The relationship between placental inflammation and preterm birth is appreciated in developed countries. In this study, we showed that this link also exists in developing geographies. In addition, among the participating sites, we found geographic- and population-based differences in placental inflammation and preterm birth, suggesting the importance of local factors., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Postpartum depression (PPD) affects nearly 20% of postpartum women in Sub-Saharan Africa (SSA), where HIV prevalence is high. Depression is associated with worse HIV outcomes in non-pregnant adults and mental health disorders may worsen HIV outcomes for postpartum women and their infants. PPD is effectively treated with psychosocial or pharmacologic interventions; however, few studies have evaluated the acceptability of treatment modalities in SSA. We analyzed interviews with 23 postpartum women with HIV to assess the acceptability of two depression treatments provided in the context of a randomized trial. Most participants expressed acceptability of treatment randomization and study visit procedures. Participants shared perceptions of high treatment efficacy of their assigned intervention. They reported ongoing HIV and mental health stigma in their communities and emphasized the importance of social support from clinic staff. Our findings suggest a full-scale trial of PPD treatment will be acceptable among women with HIV in Zambia., (© 2024. The Author(s).)

Approaches to address measurement error frequently rely on validation data to estimate measurement error parameters (e.g., sensitivity and specificity). Acquisition of validation data can be costly, thus secondary use of existing data for validation is attractive. To use these external validation data, however, we may need to address systematic differences between these data and the main study sample. Here, we derive estimators of the risk and the risk difference that leverage external validation data to account for outcome misclassification. If misclassification is differential with respect to covariates that themselves are differentially distributed in the validation and study samples, the misclassification parameters are not immediately transportable. We introduce two ways to account for such covariates: (1) standardize by these covariates or (2) iteratively model the outcome. If conditioning on a covariate for transporting the misclassification parameters induces bias of the causal effect (e.g., M-bias), the former but not the latter approach is biased. We provide proof of identification, describe estimation using parametric models, and assess performance in simulations. We also illustrate implementation to estimate the risk of preterm birth and the effect of maternal HIV infection on preterm birth. Measurement error should not be ignored and it can be addressed using external validation data via transportability methods., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Masimo Total Hemoglobin SpHb® is a continuous and non-invasive handheld device to measure hemoglobin levels. Previous research has found that SpHb is able to accurately detect hemoglobin levels in adult patients with a similar degree of bias and standard deviation to point-of-care invasive method measurements. Generally, limited clinical evidence, lack of validation of Masimo at higher than and lower than hemoglobin threshold values, and scientific consensus supporting the use of Masimo for accurate hemoglobin testing for the diagnosis of anemia during pregnancy calls for further research., Methods and Analysis: The proposed prospective cohort will be nested within the ongoing Pregnancy Risk and Infant Surveillance and Measurement Alliance (PRISMA) Maternal and Newborn Health (MNH) study. Three study sites (located in Zambia, Kenya, and Pakistan) will participate and collect hemoglobin data at five time points (<20 weeks, 20 weeks, 28 weeks, 36 weeks' gestation, and six weeks postpartum). We will measure hemoglobin using a venous blood sample via hematology auto-analyzer complete blood count (gold standard) and the non-invasive device. The primary objective is to assess agreement between Masimo total hemoglobin and complete blood count and on a continuous scale using Intraclass Correlation Coefficient and Bland-Altman Analysis. The second objective is to assess agreement between the two measures on a binary scale using Positive Percentage Agreement and Negative Percentage Agreement, Cohen's Kappa, and McNemar Test. On an ordinal scale, agreement will be measured using Weighted Cohen's Kappa and Harrel's Concordance Index. Lastly, we will assess factors that might affect the accuracy of Masimo total hemoglobin using linear mixed models., Conclusions: The primary aim of this study is to assess the validity of the non-invasive Masimo device compared to the gold standard method of invasive hemoglobin measurements during pregnancy and postpartum periods for the diagnosis of anemia., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Farooq F et al.)

Background: Copper (Cu), an essential trace mineral regulating multiple actions of inflammation and oxidative stress, has been implicated in risk for preterm birth (PTB)., Objectives: This study aimed to determine the association of maternal Cu concentration during pregnancy with PTB risk and gestational duration in a large multicohort study including diverse populations., Methods: Maternal plasma or serum samples of 10,449 singleton live births were obtained from 18 geographically diverse study cohorts. Maternal Cu concentrations were determined using inductively coupled plasma mass spectrometry. The associations of maternal Cu with PTB and gestational duration were analyzed using logistic and linear regressions for each cohort. The estimates were then combined using meta-analysis. Associations between maternal Cu and acute-phase reactants (APRs) and infection status were analyzed in 1239 samples from the Malawi cohort., Results: The maternal prenatal Cu concentration in our study samples followed normal distribution with mean of 1.92 μg/mL and standard deviation of 0.43 μg/mL, and Cu concentrations increased with gestational age up to 20 wk. The random-effect meta-analysis across 18 cohorts revealed that 1 μg/mL increase in maternal Cu concentration was associated with higher risk of PTB with odds ratio of 1.30 (95% confidence interval [CI]: 1.08, 1.57) and shorter gestational duration of 1.64 d (95% CI: 0.56, 2.73). In the Malawi cohort, higher maternal Cu concentration, concentrations of multiple APRs, and infections (malaria and HIV) were correlated and associated with greater risk of PTB and shorter gestational duration., Conclusions: Our study supports robust negative association between maternal Cu and gestational duration and positive association with risk for PTB. Cu concentration was strongly correlated with APRs and infection status suggesting its potential role in inflammation, a pathway implicated in the mechanisms of PTB. Therefore, maternal Cu could be used as potential marker of integrated inflammatory pathways during pregnancy and risk for PTB., (Copyright © 2023. Published by Elsevier Inc.)

FKBP25 (FKBP3 gene) is a dual-domain PPIase protein that consists of a C-terminal PPIase domain and an N-terminal basic tilted helix bundle (BTHB). The PPIase domain of FKBP25 has been shown to bind to microtubules, which has impacts upon microtubule polymerisation and cell cycle progression. Using quantitative proteomics, it was recently found that FKBP25 was expressed in the top 10% of the mouse skeletal muscle proteome. However, to date there have been few studies investigating the role of FKBP25 in non-transformed systems. As such, this study aimed to investigate potential roles for FKBP25 in myoblast viability, migration and differentiation and in adaptation of mature skeletal muscle. Doxycycline-inducible FKBP25 knockdown in C2C12 myoblasts revealed an increase in cell accumulation/viability and migration in vitro that was independent of alterations in tubulin dynamics; however, FKBP25 knockdown had no discernible impact on myoblast differentiation into myotubes. Finally, a series of in vivo models of muscle adaptation were assessed, where it was observed that FKBP25 protein expression was increased in hypertrophy and regeneration conditions (chronic mechanical overload and the mdx model of Duchenne muscular dystrophy) but decreased in an atrophy model (denervation). Overall, the findings of this study establish FKBP25 as a regulator of myoblast viability and migration, with possible implications for satellite cell proliferation and migration and muscle regeneration, and as a potential regulator of in vivo skeletal muscle adaptation., (© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The plasticity of some coral-associated microbial communities under stressors like warming and ocean acidification suggests the microbiome has a role in the acclimatization of corals to future ocean conditions. Here, we evaluated the acclimatization potential of coral-associated microbial communities of four Hawaiian coral species (Porites compressa, Porites lobata, Montipora capitata, and Pocillopora acuta) over 22-month mesocosm experiment. The corals were exposed to one of four treatments: control, ocean acidification, ocean warming, or combined future ocean conditions. Over the 22-month study, 33-67% of corals died or experienced a loss of most live tissue coverage in the ocean warming and future ocean treatments while only 0-10% died in the ocean acidification and control. Among the survivors, coral-associated microbial communities responded to the chronic future ocean treatment in one of two ways: (1) microbial communities differed between the control and future ocean treatment, suggesting the potential capacity for acclimatization, or (2) microbial communities did not significantly differ between the control and future ocean treatment. The first strategy was observed in both Porites species and was associated with higher survivorship compared to M. capitata and P. acuta which exhibited the second strategy. Interestingly, the microbial community responses to chronic stressors were independent of coral physiology. These findings indicate acclimatization of microbial communities may confer resilience in some species of corals to chronic warming associated with climate change. However, M. capitata genets that survived the future ocean treatment hosted significantly different microbial communities from those that died, suggesting the microbial communities of the survivors conferred some resilience. Thus, even among coral species with inflexible microbial communities, some individuals may already be tolerant to future ocean conditions. These findings suggest that coral-associated microbial communities could play an important role in the persistence of some corals and underlie climate change-driven shifts in coral community composition., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Price 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.)

Background: Blood proteins are frequently measured in serum or plasma, because they provide a wealth of information. Differences in the ex vivo processing of serum and plasma raise concerns that proteomic health and disease signatures derived from serum or plasma differ in content and quality. However, little is known about their respective power to predict feto-maternal health outcomes. Predictive power is a sentinel characteristic to determine the clinical use of biosignatures., Objective: This study aimed to compare the power of serum and plasma proteomic signatures to predict a physiological pregnancy outcome., Study Design: Paired serum and plasma samples from 73 women were obtained from biorepositories of a multinational prospective cohort study on pregnancy outcomes. Gestational age at the time of sampling was the predicted outcome, because the proteomic signatures have been validated for such a prediction. Multivariate and cross-validated models were independently derived for serum and plasma proteins., Results: A total of 1116 proteins were measured in 88 paired samples from 73 women with a highly multiplexed platform using proximity extension technology (Olink Proteomics Inc, Watertown, MA). The plasma proteomic signature showed a higher predictive power (R=0.64; confidence interval, 0.42-0.79; P =3.5×10 -6 ) than the serum signature (R=0.45; confidence interval, 0.18-0.66; P =2.2×10 -3 ). The serum signature was validated in plasma with a similar predictive power (R=0.58; confidence interval, 0.34-0.75; P =4.8×10 -5 ), whereas the plasma signature was validated in serum with reduced predictive power (R=0.53; confidence interval, 0.27-0.72; P =2.6×10 -4 ). Signature proteins largely overlapped in the serum and plasma, but the strength of association with gestational age was weaker for serum proteins., Conclusion: Findings suggest that serum proteomics are less informative than plasma proteomics. They are compatible with the view that the partial ex-vivo degradation and modification of serum proteins during sample processing are an underlying reason. The rationale for collecting and analyzing serum and plasma samples should be carefully considered when deriving proteomic biosignatures to ascertain that specimens of the highest scientific and clinical yield are processed. Findings suggest that plasma is the preferred matrix., (© 2023 The Authors.)

The process of macroautophagy plays a pivotal role in the degradation of long-lived, superfluous, and damaged proteins and organelles, which are later recycled for cellular use. Normal cells rely on autophagy to combat various stressors and insults to ensure survival. However, autophagy is often upregulated in cancer cells, promoting a more aggressive phenotype that allows mutated cells to evade death after exposure to therapeutic treatments. As a result, autophagy has emerged as a significant factor in therapeutic resistance across many cancer types, with underlying mechanisms such as DNA damage, cell cycle arrest, and immune evasion. This review provides a comprehensive summary of the role of autophagy in therapeutic resistance and the limitations of available autophagic inhibitors in cancer treatment. It also highlights the urgent need to explore new inhibitors that can synergize with existing therapies to achieve better patient treatment outcomes. Advancing research in this field is crucial for developing more effective treatments that can help improve the lives of cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tonkin-Reeves, Giuliani and Price.)

Preterm birth (PTB) is the leading cause of death in children under five, yet comprehensive studies are hindered by its multiple complex etiologies. Epidemiological associations between PTB and maternal characteristics have been previously described. This work used multiomic profiling and multivariate modeling to investigate the biological signatures of these characteristics. Maternal covariates were collected during pregnancy from 13,841 pregnant women across five sites. Plasma samples from 231 participants were analyzed to generate proteomic, metabolomic, and lipidomic datasets. Machine learning models showed robust performance for the prediction of PTB (AUROC = 0.70), time-to-delivery ( r = 0.65), maternal age ( r = 0.59), gravidity ( r = 0.56), and BMI ( r = 0.81). Time-to-delivery biological correlates included fetal-associated proteins (e.g., ALPP, AFP, and PGF) and immune proteins (e.g., PD-L1, CCL28, and LIFR). Maternal age negatively correlated with collagen COL9A1, gravidity with endothelial NOS and inflammatory chemokine CXCL13, and BMI with leptin and structural protein FABP4. These results provide an integrated view of epidemiological factors associated with PTB and identify biological signatures of clinical covariates affecting this disease.

Objective: To compare the performance of mid upper arm circumference (MUAC) and body mass index (BMI) for prediction of small for gestational age (SGA) in Zambia., Methods: This is a secondary analysis of an ongoing clinical cohort that included women with a single gestation and MUAC measured before 24 weeks of pregnancy. We assessed relationships between maternal MUAC and birth weight centile using regression. The performance of MUAC and BMI to predict SGA was compared using receiver operating characteristic curves and the effect of maternal HIV was investigated in sub-group analyses., Results: Of 1117 participants, 847 (75%) were HIV-negative (HIV-) and 270 (24%) were HIV-positive (HIV+). Seventy-four (7%) delivered severe SGA infants (<3rd centile), of whom 56 (76%) were HIV- and 18 (24%) were HIV+ (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.58-1.75). MUAC was associated with higher birth weight centile (+1.2 centile points, 95% CI 0.7-1.6; P < 0.001); this relationship was stronger among HIV+ women (+1.7 centile points, 95% CI 0.8-2.6; P < 0.001) than HIV- women (+0.9 centile points, 95% CI 0.4-1.4; P = 0.001). The discriminatory power was similar, albeit poor (area under the curve [AUC] < 0.7), between MUAC and BMI for the prediction of SGA. In stratified analysis, MUAC and BMI showed excellent discrimination predicting severe SGA among HIV+ (AUC 0.83 and 0.81, respectively) but not among HIV- women (AUC 0.64 and 0.63, respectively)., Conclusion: Maternal HIV infection increased the discrimination of both early pregnancy MUAC and BMI for prediction of severe SGA in Zambia., Clinical Trial Number: ClinicalTrials.gov (NCT02738892)., (© 2022 International Federation of Gynecology and Obstetrics.)

Background: Since the declaration of COVID-19 as a global pandemic, several studies have been conducted to examine associated factors. However, few studies have focused on pregnant women infected with COVID-19 in sub-Saharan Africa. Therefore, this study investigated the prevalence and factors associated with COVID-19 infection among pregnant women at the Levy Mwanawasa University Teaching Hospital and Women and Newborn Hospital of the University Teaching Hospitals in Lusaka, Zambia., Methods: A cross-sectional study was conducted between March and July 2021. Women were recruited as they presented for antenatal care. Data was collected using a structured questionnaire to capture variables of interest (socio-demographic, clinical and obstetric). COVID-19 diagnosis was made using a nasopharyngeal swab by PCR test. Multivariable logistic regression was used to control for confounding and calculate the odds ratios for each explanatory variable and respective 95% confidence intervals., Results: The study enrolled 352 participants with a mean (standard deviation [SD]) age of 30.1 years (5.6). One hundred thirty of 352 (36.9%; 95% CI: 31.9 to 42.2) participants had a confirmed positive SARS-CoV-2 test result. At univariable analysis, factors associated with COVID-19 were increased gestational age, education status and maternal HIV serostatus. Women with a secondary level of education were less likely to have COVID-19 infection than those with a primary level of education (AOR = 0.23, 95% CI: 0.09-0.63). On the other hand, a one-week increase in gestational age was associated with higher odds of COVID-19 infection (AOR = 1.03, 95% CI: 1.01-1.06)., Conclusion: The results showed that the prevalence of COVID-19 infection among pregnant women was 36.9% and was associated with increased gestational age and a lower level of education. To mitigate adverse maternal outcomes, there is a need to screen for COVID-19 strictly and broadly monitor prenatal women presenting for healthcare., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Background: Accurate estimates of gestational age (GA) at birth are important for preterm birth surveillance but can be challenging to obtain in low income countries. Our objective was to develop machine learning models to accurately estimate GA shortly after birth using clinical and metabolomic data., Methods: We derived three GA estimation models using ELASTIC NET multivariable linear regression using metabolomic markers from heel-prick blood samples and clinical data from a retrospective cohort of newborns from Ontario, Canada. We conducted internal model validation in an independent cohort of Ontario newborns, and external validation in heel prick and cord blood sample data collected from newborns from prospective birth cohorts in Lusaka, Zambia and Matlab, Bangladesh. Model performance was measured by comparing model-derived estimates of GA to reference estimates from early pregnancy ultrasound., Results: Samples were collected from 311 newborns from Zambia and 1176 from Bangladesh. The best-performing model accurately estimated GA within about 6 days of ultrasound estimates in both cohorts when applied to heel prick data (MAE 0.79 weeks (95% CI 0.69, 0.90) for Zambia; 0.81 weeks (0.75, 0.86) for Bangladesh), and within about 7 days when applied to cord blood data (1.02 weeks (0.90, 1.15) for Zambia; 0.95 weeks (0.90, 0.99) for Bangladesh)., Conclusions: Algorithms developed in Canada provided accurate estimates of GA when applied to external cohorts from Zambia and Bangladesh. Model performance was superior in heel prick data as compared to cord blood data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hawken 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.)

Objective: To illustrate the difference between exposure effects and population attributable effects., Methods: We examined the effect of mid-pregnancy short cervical length (<25 mm) on preterm birth using data from a prospective cohort of pregnant women in Lusaka, Zambia. Preterm birth was live birth or stillbirth before 37 weeks of pregnancy. For estimation, we used multivariable regression and parametric g-computation., Results: Among 1409 women included in the analysis, short cervix was rare (2.4%); 13.6% of births were preterm. Exposure effect estimates were large (marginal risk ratio 2.86, 95% confidence interval [CI] 1.80-4.54), indicating that the preterm birth risk was substantially higher among women with a short cervix compared with women without a short cervix. However, the population attributable effect estimates were close to the null (risk ratio 1.06, 95% CI 1.02-1.10), indicating that an intervention to counteract the impact of short cervix on preterm birth would have minimal effect on the population risk of preterm birth., Conclusion: Although authors often refer to "the" effect, there are actually different types of effects, as we have illustrated here. In planning research, it is important to consider which effect to estimate to ensure that the estimate aligns with the research objective., (© 2022 International Federation of Gynecology and Obstetrics.)

Background: Antiretroviral therapy (ART) is associated with high rates of adverse birth outcomes, including preterm birth and low birthweight. Studies suggest that progesterone and prolactin may play important intermediary roles., Methods: We analyzed data from the Antenatal Component of the PROMISE trial, a multi-center study of pregnant women taking antiretroviral regimens (lopinavir/ritonavir-containing ART or zidovudine alone) to prevent mother-to-child HIV transmission. In a nested case-control study, we compared data from women who gave birth to preterm (<37 weeks gestation) and/or low birthweight (<2500 g) infants to matched individuals who did not. We measured serum progesterone and prolactin at 24-34 weeks gestation. We used conditional logistic regression to describe relationships between hormone levels, birth outcomes, and antiretroviral regimens., Results: 299 women and their newborns were included (146 cases, 153 controls). When compared to women receiving zidovudine alone, those on ART had higher odds of progesterone levels under the 10th percentile (adjusted odds ratio [AOR]:2.34, 95%CI:1.41-3.89) and 25th percentile (AOR:2.07, 95%CI:1.46-2.94). However, higher levels of progesterone-rather than lower levels-were associated with our composite case outcome at the 10th percentile (AOR:1.88, 95%CI:0.77-4.59) and 25th percentile (AOR:1.96, 95%CI:1.06-3.61). Associations were not observed between prolactin, antiretroviral regimen, and birth outcomes., Conclusion: We observed lower progesterone levels among women allocated to ART regimens; however, higher progesterone levels were associated with preterm birth and/or low birthweight. While features of the study design may have contributed to these findings, they nevertheless highlight the potentially complex mechanisms underpinning adverse birth outcomes and HIV., Competing Interests: The study products in the PROMISE trial were provided free of charge by Abbott, Gilead Sciences, Boehringer Ingelheim, and GlaxoSmithKline. Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Chi 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.)

Missing data are pandemic and a central problem for epidemiology. Missing data reduce precision and can cause notable bias. There remain too few simple published examples detailing types of missing data and illustrating their possible impact on results. Here we take an example randomized trial that was not subject to missing data and induce missing data to illustrate 4 scenarios in which outcomes are 1) missing completely at random, 2) missing at random with positivity, 3) missing at random without positivity, and 4) missing not at random. We demonstrate that accounting for missing data is generally a better strategy than ignoring missing data, which unfortunately remains a standard approach in epidemiology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Each year, nearly 300,000 women and 5 million fetuses or neonates die during childbirth or shortly thereafter, a burden concentrated disproportionately in low- and middle-income countries. Identifying women and their fetuses at risk for intrapartum-related morbidity and death could facilitate early intervention. Methods: The Limiting Adverse Birth Outcomes in Resource-Limited Settings (LABOR) Study is a multi-country, prospective, observational cohort designed to exhaustively document the course and outcomes of labor, delivery, and the immediate postpartum period in settings where adverse outcomes are frequent. The study is conducted at four hospitals across three countries in Ghana, India, and Zambia. We will enroll approximately 12,000 women at presentation to the hospital for delivery and follow them and their fetuses/newborns throughout their labor and delivery course, postpartum hospitalization, and up to 42 days thereafter. The co-primary outcomes are composites of maternal (death, hemorrhage, hypertensive disorders, infection) and fetal/neonatal adverse events (death, encephalopathy, sepsis) that may be attributed to the intrapartum period. The study collects extensive physiologic data through the use of physiologic sensors and employs medical scribes to document examination findings, diagnoses, medications, and other interventions in real time. Discussion: The goal of this research is to produce a large, sharable dataset that can be used to build statistical algorithms to prospectively stratify parturients according to their risk of adverse outcomes. We anticipate this research will inform the development of new tools to reduce peripartum morbidity and mortality in low-resource settings., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Adu-Amankwah A et al.)

The IPOP trial demonstrated a reduced risk of severe small for gestational age among infants born to women with HIV who received weekly intramuscular 17 alpha-hydroxyprogesterone caproate. This secondary analysis examined the 17P treatment effect in subgroups of maternal BMI, parity, timing of antiretroviral therapy (ART) initiation, and ART regimen. We found that 17P was more effective among nulliparous women, women who started ART before pregnancy, and those taking protease inhibitors., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate the effect of HIV co-infection on non-treponemal titers during pregnancy in women with syphilis., Methods: This is a secondary analysis of pregnant women with syphilis in the prospective, observational Zambian Preterm Birth Prevention Study (ZAPPS). Treponemal (Treponema pallidum particle agglutination) and non-treponemal (rapid plasma reagin; RPR) testing were performed on serum biospecimens, resulting in 47 participants with serologically confirmed syphilis (27 HIV-positive, 20 HIV-negative). The primary outcome, achievement of RPR titer seroreduction during pregnancy, was analyzed by logistic regression. Secondary outcomes included overall titer reduction, seroreduction rate, serologic cure, and adverse pregnancy outcomes., Results: Seroreduction of RPR titer occurred in 78% (21/27) of women with HIV versus 45% (9/20) of women without (adjusted odds ratio 4.66; 95% confidence interval [CI] 1.14 - 19.08). Overall RPR titer reduction, rate of seroreduction per week, and the proportion achieving serologic cure each trended higher among women with HIV compared with those without HIV. There was a trend toward decreased stillbirth incidence in participants achieving seroreduction (odds ratio 0.15, 95% CI 0.01-1.58)., Conclusion: HIV co-infection in this cohort of Zambian women with syphilis was associated with greater odds of RPR titer seroreduction during pregnancy. Pregnant women with syphilis and HIV may not be at increased risk for a delayed syphilis treatment response compared with women without HIV., (© 2022 International Federation of Gynecology and Obstetrics.)

Background: Fetal ultrasound is an important component of antenatal care, but shortage of adequately trained healthcare workers has limited its adoption in low-to-middle-income countries. This study investigated the use of artificial intelligence for fetal ultrasound in under-resourced settings., Methods: Blind sweep ultrasounds, consisting of six freehand ultrasound sweeps, were collected by sonographers in the USA and Zambia, and novice operators in Zambia. We developed artificial intelligence (AI) models that used blind sweeps to predict gestational age (GA) and fetal malpresentation. AI GA estimates and standard fetal biometry estimates were compared to a previously established ground truth, and evaluated for difference in absolute error. Fetal malpresentation (non-cephalic vs cephalic) was compared to sonographer assessment. On-device AI model run-times were benchmarked on Android mobile phones., Results: Here we show that GA estimation accuracy of the AI model is non-inferior to standard fetal biometry estimates (error difference -1.4 ± 4.5 days, 95% CI -1.8, -0.9, n  = 406). Non-inferiority is maintained when blind sweeps are acquired by novice operators performing only two of six sweep motion types. Fetal malpresentation AUC-ROC is 0.977 (95% CI, 0.949, 1.00, n  = 613), sonographers and novices have similar AUC-ROC. Software run-times on mobile phones for both diagnostic models are less than 3 s after completion of a sweep., Conclusions: The gestational age model is non-inferior to the clinical standard and the fetal malpresentation model has high AUC-ROCs across operators and devices. Our AI models are able to run on-device, without internet connectivity, and provide feedback scores to assist in upleveling the capabilities of lightly trained ultrasound operators in low resource settings., Competing Interests: Competing interestsThe authors declare the following competing interests: this study was partially funded by Google Inc. R.G.G., C. Lee, A.W., M.S., J.A.T., S.M.M., C.C., S.S., D.T., A.U., K.C., J.G., G.E.D., T. Sp., T. Sa., K.L., T.T., G.C., L.P., J.W., and R.P. are employees of Google Inc. and own stock as part of the standard employee compensation package. The remaining authors declare no competing interests., (© The Author(s) 2022.)

Competing Interests: Competing interests: The authors have completed the ICMJE declaration of Interest Form (available upon request from the corresponding author) and declare no conflicts of interest.

Introduction: Postpartum depression (PPD) is a prevalent and debilitating disease that may affect medication adherence and thus maternal health and vertical transmission among women with HIV. We assessed the feasibility of a trial of interpersonal psychotherapy (IPT) versus antidepressant medication (ADM) to treat PPD and/or anxiety among postpartum women with HIV in Lusaka, Zambia., Methods: Between 29 October 2019 and 8 September 2020, we pre-screened women 6-8 weeks after delivery with the Edinburgh Postnatal Depression Scale (EPDS) and diagnosed PPD or anxiety with the Mini International Neuropsychiatric Interview. Consenting participants were randomized 1:1 to up to 11 sessions of IPT or daily self-administered sertraline and followed for 24 weeks. We assessed EPDS score, Clinical Global Impression-Severity of Illness (CGI-S) and medication side effects at each visit and measured maternal HIV viral load at baseline and final study visit. Retention, visit adherence, change in EPDS, CGI-S and log viral load were compared between groups with t-tests and Wilcoxon signed rank tests; we report mean differences, relative risks and 95% confidence intervals. A participant satisfaction survey assessed trial acceptability., Results: 78/80 (98%) participants were retained at the final study visit. In the context of the COVID-19 pandemic, visit adherence was greater among women allocated to ADM (9.9 visits, SD 2.2) versus IPT (8.9 visits, SD 2.4; p = 0.06). EPDS scores decreased from baseline to final visit overall, though mean change was greater in the IPT group (-13.8 points, SD 4.7) compared to the ADM group (-11.4 points, SD 5.5; p = 0.04). Both groups showed similar changes in mean log viral load from baseline to final study visit (mean difference -0.43, 95% CI -0.32, 1.18; p = 0.48). In the IPT group, viral load decreased significantly from baseline (0.9 log copies/ml, SD 1.7) to final visit (0.2 log copies/ml, SD 0.9; p = 0.01)., Conclusions: This pilot study demonstrates that a trial of two forms of PPD treatment is feasible and acceptable among women with HIV in Zambia. IPT and ADM both improved measures of depression severity; however, a full-scale trial is required to determine whether treatment of PPD and anxiety improves maternal-infant HIV outcomes., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objective: To investigate whether angiogenic biomarker concentrations differ between women who deliver small-for-gestational-age (SGA) infants (<10th centile birth weight for gestational age) compared with controls, because identifying SGA risk early could improve outcomes., Methods: This case-control study compared serum concentrations of angiogenic biomarkers before 24 weeks of pregnancy from 62 women who delivered SGA infants (cases) and 62 control women from an urban Zambian cohort. Odds of delivering an SGA infant were calculated using conditional logistic regression., Results: Placental growth factor (PlGF), soluble fms-like tyrosine kinase (sFLT-1) and soluble endoglin (sEng) in controls were 37.74 pg/mL (interquartile range [IQR] 23.12-63.15), 2525.18 pg/mL (IQR 1502.21-4265.54) and 2408.18 pg/mL (IQR 1854.87-3017.94), respectively. SGA cases had higher PlGF (40.50 pg/mL, IQR 22.81-67.94) and sFLT-1 (2613.06 pg/mL, IQR 1720.58-3722.50), and lower sEng (2038.06 pg/mL, IQR 1445.25-3372.26). Participants with sEng concentration below and concomitant sFLT-1 concentration above their respective thresholds (n = 40) had five-fold higher odds of SGA (adjusted odds ratio 4.77, 95% confidence interval 1.61-14.1; P = 0.005)., Conclusion: Biomarker concentrations were similar between cases and controls. Participants with concomitant low sEng and high sFLT-1 had the highest odds of SGA, suggesting that a combination of biomarkers may better for predicting SGA than single biomarkers., (© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

A Lactobacillus-deficient, anaerobe-rich vaginal microbiome has been associated with local inflammation and spontaneous preterm birth (sPTB), but few studies have assessed this association in the setting of HIV. We performed metagenomic sequencing and inflammatory marker assays on vaginal swabs collected in pregnancy. We grouped samples into 7 metagenomic clusters (mgClust) using the non-redundant VIRGO catalogue, and derived inflammatory scores by factor analysis. Of 221 participants, median Shannon diversity index (SDI) was highest in HIV+ with detectable viral load (1.31, IQR: 0.85-1.66; p < 0.001) and HIV+ with undetectable virus (1.17, IQR: 0.51-1.66; p = 0.01) compared to HIV- (0.74, IQR: 0.35-1.26). Inflammatory scores positively correlated with SDI (+ 0.66, 95%CI 0.28, 1.03; p = 0.001), highest among anaerobe-rich mgClust2-mgClust6. HIV was associated with predominance of anaerobe-rich mgClust5 (17% vs. 6%; p = 0.02) and mgClust6 (27% vs. 11%; p = 0.002). Relative abundance of a novel Gardnerella metagenomic subspecies > 50% predicted sPTB (RR 2.6; 95%CI: 1.1, 6.4) and was higher in HIV+ (23% vs. 10%; p = 0.001). A novel Gardnerella metagenomic subspecies more abundant in women with HIV predicted sPTB. The risk of sPTB among women with HIV may be mediated by the vaginal microbiome and inflammation, suggesting potential targets for prevention., (© 2022. The Author(s).)

The development of peptide inhibitors against intracellular targets depends upon the dual challenge of achieving a high affinity and specificity for the target and maintaining cellular permeability for biological activity. Previous efforts to develop bicyclic peptides targeted to the Grb7 signalling protein implicated in HER2+ve cancer progression have resulted in improved affinity. However, these same peptides demonstrated a lowered activity due to their decreased ability to penetrate cell membranes. Here, we report the testing of a new series of bicyclic G7 peptides designed to possess improved bioactivity. We discovered that the incorporation of two amino acids (Phe-Pro, Phe-Trp or Phe-Arg) within the bicyclic peptide framework maintains an enhanced binding affinity for the Grb7-SH2 domain compared to that of the first-generation monocyclic peptide G7-18NATE. Structure determination using X-ray crystallography revealed that the mode of binding by the expanded bicyclic G7 peptide is analogous to that of G7-18NATE. Interestingly, while the bicyclic peptide containing Phe-Trp did not display the highest affinity for Grb7-SH2 in the series, it was the most potent inhibitor of HER2+ve SKBR3 breast cancer cell migration when coupled to Penetratin. Together, this demonstrates that peptide flexibility as well as the amino acid tryptophan can play important roles in the uptake of peptides into the cell.

Assessment of gestational age (GA) is key to provide optimal care during pregnancy. However, its accurate determination remains challenging in low- and middle-income countries, where access to obstetric ultrasound is limited. Hence, there is an urgent need to develop clinical approaches that allow accurate and inexpensive estimations of GA. We investigated the ability of urinary metabolites to predict GA at time of collection in a diverse multi-site cohort of healthy and pathological pregnancies (n = 99) using a broad-spectrum liquid chromatography coupled with mass spectrometry (LC-MS) platform. Our approach detected a myriad of steroid hormones and their derivatives including estrogens, progesterones, corticosteroids, and androgens which were associated with pregnancy progression. We developed a restricted model that predicted GA with high accuracy using three metabolites (rho = 0.87, RMSE = 1.58 weeks) that was validated in an independent cohort (n = 20). The predictions were more robust in pregnancies that went to term in comparison to pregnancies that ended prematurely. Overall, we demonstrated the feasibility of implementing urine metabolomics analysis in large-scale multi-site studies and report a predictive model of GA with a potential clinical value., (© 2022. The Author(s).)

Background: A trial of progesterone to prevent preterm birth among HIV-infected Zambian women [Improving Pregnancy Outcomes with Progesterone (IPOP)] found no treatment effect, but the risk of the primary outcome was among the lowest ever documented in women with HIV. In this secondary analysis, we compare the risks of preterm birth (<37 weeks), stillbirth, and a composite primary outcome comprising the two in IPOP versus an observational pregnancy cohort [Zambian Preterm Birth Prevention Study (ZAPPS)] in Zambia, to evaluate reasons for the low risk in IPOP., Methods: Both studies enrolled women before 24 gestational weeks, during August 2015-September 2017 (ZAPPS) and February 2018-January 2020 (IPOP). We used linear probability and log-binomial regression to estimate risk differences and risk ratios (RR), before and after restriction and standardization with inverse probability weights., Results: The unadjusted risk of composite outcome was 18% in ZAPPS (N = 1450) and 9% in IPOP (N = 791) (RR = 2.0; 95% CI = 1.6, 2.6). After restricting and standardizing the ZAPPS cohort to the distribution of IPOP baseline characteristics, the risk remained higher in ZAPPS (RR = 1.6; 95% CI = 1.0, 2.4). The lower risk of preterm/stillbirth in IPOP was only partially explained by measured risk factors., Conclusions: Possible benefits in IPOP of additional monetary reimbursement, more frequent visits, and group-based care warrant further investigation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ultrasound is indispensable to gestational age estimation and thus to quality obstetrical care, yet high equipment cost and the need for trained sonographers limit its use in low-resource settings., Methods: From September 2018 through June 2021, we recruited 4695 pregnant volunteers in North Carolina and Zambia and obtained blind ultrasound sweeps (cineloop videos) of the gravid abdomen alongside standard fetal biometry. We trained a neural network to estimate gestational age from the sweeps and, in three test data sets, assessed the performance of the artificial intelligence (AI) model and biometry against previously established gestational age., Results: In our main test set, the mean absolute error (MAE) (±SE) was 3.9±0.12 days for the model versus 4.7±0.15 days for biometry (difference, -0.8 days; 95% confidence interval [CI], -1.1 to -0.5; P<0.001). The results were similar in North Carolina (difference, -0.6 days; 95% CI, -0.9 to -0.2) and Zambia (-1.0 days; 95% CI, -1.5 to -0.5). Findings were supported in the test set of women who conceived by in vitro fertilization (MAE of 2.8±0.28 vs. 3.6±0.53 days for the model vs. biometry; difference, -0.8 days; 95% CI, -1.7 to 0.2) and in the set of women from whom sweeps were collected by untrained users with low-cost, battery-powered devices (MAE of 4.9±0.29 vs. 5.4±0.28 days for the model vs. biometry; difference, -0.6; 95% CI, -1.3 to 0.1)., Conclusions: When provided blindly obtained ultrasound sweeps of the gravid abdomen, our AI model estimated gestational age with accuracy similar to that of trained sonographers conducting standard fetal biometry. Model performance appears to extend to blind sweeps collected by untrained providers in Zambia using low-cost devices. (Funded by the Bill and Melinda Gates Foundation.).

The zinc finger transcription factor EGR4 has previously been identified as having a critical role in the proliferation of small cell lung cancer. Here, we have identified a novel, shortened splice variant of this transcription factor (EGR4-S) that is regulated by Heat Shock Factor-1 (HSF1). Our findings demonstrate that the shortened variant (EGR4-S) is upregulated with high EGFR, HER2, and H-Ras v12 -expressing breast cell lines, and its expression is inhibited in response to HER pathway inhibitors. Protein and mRNA analyses of HER2+ human breast tumours indicated the novel EGR4-S splice variant to be preferentially expressed in tumour tissue and not detectable in patient-matched normal tissue. Knockdown of EGR4-S in the HER2-amplified breast cancer cell line SKBR3 reduced cell growth, suggesting that EGR4-S supports the growth of HER2+ tumour cells. In addition to chemical inhibitors of the HER2 pathway, EGR4-S expression was also found to be suppressed by chemical stressors and the overexpression of HSF1. Under these conditions, reduced EGR4-S levels were associated with the observed lower cell growth rate, but the augmentation of properties associated with higher metastatic potential. Taken together, these findings identify EGR4-S as a potential biomarker for HER2 pathway activation in human tumours that is regulated by HSF1.

Climate change poses a major threat to coral reefs. We conducted an outdoor 22-month experiment to investigate if coral could not just survive, but also physiologically cope, with chronic ocean warming and acidification conditions expected later this century under the Paris Climate Agreement. We recorded survivorship and measured eleven phenotypic traits to evaluate the holobiont responses of Hawaiian coral: color, Symbiodiniaceae density, calcification, photosynthesis, respiration, total organic carbon flux, carbon budget, biomass, lipids, protein, and maximum Artemia capture rate. Survivorship was lowest in Montipora capitata and only some survivors were able to meet metabolic demand and physiologically cope with future ocean conditions. Most M. capitata survivors bleached through loss of chlorophyll pigments and simultaneously experienced increased respiration rates and negative carbon budgets due to a 236% increase in total organic carbon losses under combined future ocean conditions. Porites compressa and Porites lobata had the highest survivorship and coped well under future ocean conditions with positive calcification and increased biomass, maintenance of lipids, and the capacity to exceed their metabolic demand through photosynthesis and heterotrophy. Thus, our findings show that significant biological diversity within resilient corals like Porites, and some genotypes of sensitive species, will persist this century provided atmospheric carbon dioxide levels are controlled. Since Porites corals are ubiquitous throughout the world's oceans and often major reef builders, the persistence of this resilient genus provides hope for future reef ecosystem function globally., (© 2022. The Author(s).)

Objective: There is a paucity of data on the psychosocial issues and coping mechanisms among pregnant and postnatal women with COVID-19 infection. We, therefore, aimed to explore the psychosocial issues and coping mechanisms of pregnant and postnatal women diagnosed with COVID-19 at tertiary-level hospitals., Methods: This was a qualitative phenomenological study conducted in 2021 with a sample size of 16 women admitted at two referral hospitals serving as COVID-19 admission facilities for pregnant and postnatal women in Lusaka, Zambia. In-depth interviews were conducted via telephone to understand what these women experienced when diagnosed with COVID-19. All the interviews were audio-recorded and transcribed verbatim. Thematic analysis was conducted using the six steps approach to develop emerging themes., Results: Two major themes emerged: psychosocial issues and coping mechanisms. The primary psychosocial issues were worry and stigma. Women worried about infecting their unborn baby or neonate, being separated from the baby, the general safety of the baby, and the health of other family members. Women also worried about the attitude of health care providers and faced discrimination or stigma because of their infection. Thus, some coping mechanisms were developed that helped them, such as a positive attitude, keeping the disease secret, reliance on family members for support and using positive information from social media., Conclusion: This study provides unique insights into the psychosocial experiences of pregnant and postnatal women diagnosed with COVID-19. Women were particularly concerned about the unborn baby's well-being and discrimination.This study suggests the need for policy and clinical practice to consider the integration of effective mental health services into the provision of maternal health and COVID-19 services.

Background: Women with HIV face an increased risk of preterm birth. 17 alpha-hydroxyprogesterone caproate (17P) has been shown in some trials to reduce early delivery among women with a history of spontaneous preterm birth. We investigated whether 17P would reduce this risk among women with HIV., Methods: We did a randomised, double-blind, placebo-controlled trial in pregnant women with HIV at the University Teaching Hospital and Kamwala District Health Centre in Lusaka, Zambia. Eligible patients were women aged 18 years or older with confirmed HIV-1 infection, viable intrauterine singleton pregnancy at less than 24 weeks of gestation, and were receiving or intending to commence antiretroviral therapy during pregnancy. Exclusion criteria were major uterine or fetal anomaly; planned or in situ cervical cerclage; evidence of threatened miscarriage, preterm labour, or ruptured membranes at screening; medical contraindication to 17P; previous participation in the trial; or history of spontaneous preterm birth. Eligible participants provided written informed consent and were randomly assigned (1:1) to receive 250 mg intramuscular 17P or placebo once per week, starting between 16 and 24 weeks of gestation until delivery, stillbirth, or reaching term (37 weeks). Participants and study staff were masked to assignment, except for pharmacy staff who did random assignment and prepared injections but did not interact with participants. The primary outcome was a composite of delivery before 37 weeks or stillbirth at any gestational age. Patients attended weekly visits for study drug injections and antenatal care. We estimated the absolute and relative difference in risk of the primary outcome and safety events between treatment groups by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03297216, and is complete., Findings: Between Feb 7, 2018 and Jan 13, 2020, we assessed 1042 women for inclusion into the study. 242 women were excluded after additional assessments, and 800 eligible patients were enrolled and randomly assigned to receive intramuscular 17P (n=399) or placebo (n=401). Baseline characteristics were similar between groups. Adherence to study drug injections was 98% in both groups, no patients were lost to follow-up, and the final post-partum visit was on Aug 6, 2020. 36 (9%) of 399 participants assigned to 17P had preterm birth or stillbirth, compared with 36 (9%) of 401 patients assigned to placebo (risk difference 0·1, 95% CI -3·9 to 4·0; relative risk 1·0, 95% CI 0·6 to 1·6; p=0·98). Intervention-related adverse events were reported by 140 (18%) of 800 participants and occurred in similar proportions in both randomisation groups. No serious adverse events were reported., Interpretation: Although 17P seems to be safe and acceptable to participants, available data do not support the use of the drug to prevent preterm birth among women whose risk derives solely from HIV infection. The low risk of preterm birth in both randomisation groups warrants further investigation., Funding: US National Institutes of Health and the Bill and Melinda Gates Foundation., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations., Methods: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis., Findings: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi., Interpretation: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Maternal HIV increases the risk of adverse birth outcomes including preterm birth, fetal growth restriction, and stillbirth, but the biological mechanism(s) underlying this increased risk are not well understood. We hypothesized that maternal HIV may lead to adverse birth outcomes through an imbalance in angiogenic factors involved in the vascular endothelial growth factor (VEGF) signaling pathway., Methods: In a case-control study nested within an ongoing cohort in Zambia, our primary outcomes were serum concentrations of VEGF-A, soluble endoglin (sEng), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFLT-1). These were measured in 57 women with HIV (cases) and 57 women without HIV (controls) before 16 gestational weeks. We used the Wilcoxon rank-sum and linear regression controlling for maternal body mass index (BMI) and parity to assess the difference in biomarker concentrations between cases and controls. We also used logistic regression to test for associations between biomarker concentration and adverse pregnancy outcomes (preeclampsia, preterm birth, small for gestational age, stillbirth, and a composite of preterm birth or stillbirth)., Results: Compared to controls, women with HIV had significantly lower median concentrations of PlGF (7.6 vs 10.2 pg/mL, p = 0.02) and sFLT-1 (1647.9 vs 2055.6 pg/mL, p = 0.04), but these findings were not confirmed in adjusted analysis. PlGF concentration was lower among women who delivered preterm compared to those who delivered at term (6.7 vs 9.6 pg/mL, p = 0.03) and among those who experienced the composite adverse birth outcome (6.2 vs 9.8 pg/mL, p = 0.02). Median sFLT-1 concentration was lower among participants with the composite outcome (1621.0 vs 1945.9 pg/mL, p = 0.04), but the association was not significant in adjusted analysis. sEng was not associated with either adverse birth outcomes or HIV. VEGF-A was undetectable by Luminex in all specimens., Conclusions: We present preliminary findings that HIV is associated with a shift in the VEGF signaling pathway in early pregnancy, although adjusted analyses were inconclusive. We confirm an association between angiogenic biomarkers and adverse birth outcomes in our population. Larger studies are needed to further elucidate the role of HIV on placental angiogenesis and adverse birth outcomes., (© 2021. The Author(s).)

Climate change is projected to have significant effects on the distribution of species globally, but research into the implications in parts of Africa has been limited. Using species distribution modelling, this study models climate change-related risks to the terrestrial biodiversity (birds, mammals, reptiles, amphibians and plants) of Kenya's economically-important and ecologically diverse Tana River Basin. Large reductions in species richness are projected with just 2°C warming (relative to preindustrial levels) with birds and plants seeing the greatest impact. Potential climate refugia for biodiversity are identified within the basin, but often overlap with areas already converted to agriculture or set aside for agricultural expansion, and the majority are outside protected areas. Similarly, some protected areas contain no projected refugia at higher levels of global warming, showing they may be insufficient to protect the basin's biodiversity as climate changes. However, risks to biodiversity are much smaller if the Paris Agreement's goal of limiting global warming to 'well below 2°C' warming, rather than 2°C only, is met. The potential for refugia for plants and animals decreases strongly with warming. For example, 82% of the basin remaining climatically suitable for at least 75% of the plants currently present at 1.5°C warming, as compared with 23% at 2°C and 3% at 4.5°C. This research provides the first assessment of the combined effects of development plans and climate change on biodiversity of the Tana River Basin, including identifying potential areas for restoration, and contributes to a greater understanding of biodiversity protection and adaptation options in Kenya., Competing Interests: The authors have declared that no competing interests exist.

The WHO guideline on the integration of family planning (FP) and pre-exposure HIV prophylaxis (PrEP) to enhance the health of women and adolescent girls is reflected in the Zambia Consolidated Guidelines for Treatment and Prevention of HIV Infection, 2020. There is however a dearth of data on the integration of PrEP and FP in Zambia. We describe the integration of oral PrEP in FP services using the Evidence for Contraceptive Options and HIV Outcomes (ECHO) study experience at Kamwala District Health Center in Lusaka, Zambia. The provision of oral PrEP at Kamwala started in October 2017, lasting for ~11 months, and utilized the model where initial processes to offer PrEP were on-site followed by off-site referral to laboratory and PrEP provider services. The characteristics of 658 women who enrolled in ECHO at Kamwala are representative of women accessing FP services in Lusaka. About 644 of the enrollees were offered oral PrEP. The proportion of women accepting PrEP was low at 1.08% and the proportion of study visits at which PrEP was requested was also low at 0.57%. Those who accepted PrEP were above 20 years old, married, with at least primary education, sexual behavior, and risk comparable to decliners. The ECHO study experience indicates that the setup and integration of oral PrEP and FP services are feasible in the setting. However, uptake of PrEP was very low. Possible contributory factors were as follows: (1) timing of introduction of PrEP midway in the study, (2) PrEP being a new intervention, (3) challenges of autonomy of young women to include a daily pill into their lives and anticipated challenges to adherence because of fear of adverse events, (4) possible underdetermined risk due to use of an unvalidated risk assessment tool and assessment by health care provider vs. self-assessment, and (5) extra layer of challenges to negotiate due to needing for off-site referrals. Following these findings, we conclude that further research through demonstration projects of integration of oral PrEP and FP may provide solutions to low uptake. This information is critical for scaling up of integration HIV prevention services and sexual and reproductive health (SRH) services., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kasaro, Sindano, Chinyama, Mudenda, Chilaisha, Price and Chileshe.)

Objective: We investigated the effect of maternal HIV and its treatment on spontaneous and provider-initiated preterm birth (PTB) in an urban African cohort., Methods: The Zambian Preterm Birth Prevention Study enrolled pregnant women at their first antenatal visit in Lusaka. Participants underwent ultrasound, laboratory testing, and clinical phenotyping of delivery outcomes. Key exposures were maternal HIV serostatus and timing of antiretroviral therapy initiation. We defined the primary outcome, PTB, as delivery between 16 and 37 weeks' gestational age, and differentiated spontaneous from provider-initiated parturition., Results: Of 1450 pregnant women enrolled, 350 (24%) had HIV. About 1216 (84%) were retained at delivery, 3 of whom delivered <16 weeks. Of 181 (15%) preterm deliveries, 120 (66%) were spontaneous, 56 (31%) were provider-initiated, and 5 (3%) were unclassified. In standardized analyses using inverse probability weighting, maternal HIV increased the risk of spontaneous PTB [RR 1.68; 95% confidence interval (CI): 1.12 to 2.52], but this effect was mitigated on overall PTB [risk ratio (RR) 1.31; 95% CI: 0.92 to 1.86] owing to a protective effect against provider-initiated PTB. HIV reduced the risk of preeclampsia (RR 0.32; 95% CI: 0.11 to 0.91), which strongly predicted provider-initiated PTB (RR 17.92; 95% CI: 8.13 to 39.53). The timing of antiretroviral therapy start did not affect the relationship between HIV and PTB., Conclusion: The risk of HIV on spontaneous PTB seems to be opposed by a protective effect of HIV on provider-initiated PTB. These findings support an inflammatory mechanism underlying HIV-related PTB and suggest that published estimates of PTB risk overall underestimate the risk of spontaneous PTB., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)