Effect of vitamin D replacement on maternal and neonatal outcomes: a randomised controlled trial in pregnant women with hypovitaminosis D. A protocol

Introduction: The vitamin D recommended doses during pregnancy differ between societies. The WHO guidelines do not recommend routine prenatal supplementation, but they underscore the fact that women with the lowest levels may benefit most. The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East, where hypovitaminosis D is prevalent. Our hypothesis is that in Middle Eastern pregnant women, a vitamin D dose of 3000?IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [25(OH)D] level, and to positively impact infant bone mineral content (BMC).Methods and analysis: This is a multicentre blinded randomised controlled trial. Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached. Eligible women will be randomised to daily equivalent doses of cholecalciferol, 600?IU or 3000?IU, from 15 to 18?weeks gestation until delivery. Maternal 25(OH)D and chemistries will be assessed at study entry, during the third trimester and at delivery. Neonatal anthropometric variables and 25(OH)D level will be measured at birth, and bone and fat mass assessment by dual-energy X-ray absorptiometry scan at 1?month. A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25(OH)D level ?50?nmol/L at delivery, and a difference in infant BMC of 6 (10)g, for a 90% power and a 2.5% level of significance. The proportions of women achieving a target 25(OH)D level will be compared between the two arms, using ?2. An independent t test will be used to compare mean infant BMC between the two arms. The primary analysis is an intention-to-treat analysis of unadjusted results.Ethics and dissemination: The protocol has been approved by the Institutional Review Board at the American University of Beirut-Lebanon (IM.GEHF.22). The trial results will be published in peer-reviewed medical journals and presented at scientific conferences.Trial registration number: NCT02434380.<br/

Impact of Distribution and Network Flushing on the Drinking Water Microbiome

We sampled the tap water of seven unique, full-scale drinking water distribution systems at different locations as well as the corresponding treatment plant effluents to evaluate the impact of distribution and the potential presence of a core drinking water microbiome. The water was also sampled during network flushing to examine its effect on the microbial ecology. While a core microbiome dominated by Gammaproteobacteria was found using 16S rRNA gene pyrosequencing, an increase in biomass was detected in the networks, especially during flushing. Water age did not significantly impact the microbiology. Irrespective of differences in treatment plants, tap water bacterial communities in the distinct networks converged and highly resembled the flushed water communities. Piping biofilm and sediment communities therefore largely determine the final tap water microbial quality, attenuating the impact of water source and treatment strategy and highlighting the fundamental role of local physicochemical conditions and microbial processes within infrastructure micro-niches

Abdominal Visceral Adipose Tissue and All-Cause Mortality: A Systematic Review

Introduction Increased abdominal visceral adipose tissue (VAT) implies an adverse cardio-metabolic profile. We examined the association of abdominal VAT parameters and all-cause mortality risk. Methods We systematically searched four databases. We performed citations/articles screening, data abstraction, and quality assessment in duplicate and independently (CRD42020205021). Results We included 12 cohorts, the majority used computed tomography to assess abdominal VAT area. Six cohorts with a mean age ≤ 65 years, examining all-cause mortality risk per increment in VAT area (cm2) or volume (cm3), showed a 11-98% relative risk increase with higher VAT parameters. However, the association lost significance after adjusting for glycemic indices, body mass index, or other fat parameters. In 4 cohorts with a mean age >65 years, the findings on mortality were inconsistent. Conversely, in two cohorts (mean age 73-77 years), a higher VAT density, was inversely proportional to VAT area, and implied a higher mortality risk. Conclusion A high abdominal VAT area seems to be associated with increased all-cause mortality in individuals ≤ 65 years, possibly mediated by metabolic complications, and not through an independent effect. This relationship is weaker and may reverse in older individuals, most likely secondary to confounding bias and reverse causality. An individual participant data meta-analysis is needed to confirm our findings, and to define an abdominal VAT area cutoff implying increased mortality risk. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=205021, identifier CRD42020205021

Characterization of a Novel Compound That Stimulates STING-Mediated Innate Immune Activity in an Allele-Specific Manner.

The innate immune response to cytosolic DNA involves transcriptional activation of type I interferons (IFN-I) and proinflammatory cytokines. This represents the culmination of intracellular signaling pathways that are initiated by pattern recognition receptors that engage DNA and require the adaptor protein Stimulator of Interferon Genes (STING). These responses lead to the generation of cellular and tissue states that impair microbial replication and facilitate the establishment of long-lived, antigen-specific adaptive immunity. Ultimately this can lead to immune-mediated protection from infection but also to the cytotoxic T cell-mediated clearance of tumor cells. Intriguingly, pharmacologic activation of STING-dependent phenotypes is known to enhance both vaccine-associated immunogenicity and immune-based anti-tumor therapies. Unfortunately, the STING protein exists as multiple variant forms in the human population that exhibit differences in their reactivity to chemical stimuli and in the intensity of molecular signaling they induce. In light of this, STING-targeting drug discovery efforts require an accounting of protein variant-specific activity. Herein we describe a small molecule termed M04 that behaves as a novel agonist of human STING. Importantly, we find that the molecule exhibits a differential ability to activate STING based on the allelic variant examined. Furthermore, while M04 is inactive in mice, expression of human STING in mouse cells rescues reactivity to the compound. Using primary human cells in ex vivo assays we were also able to show that M04 is capable of simulating innate responses important for adaptive immune activation such as cytokine secretion, dendritic cell maturation, and T cell cross-priming. Collectively, this work demonstrates the conceivable utility of a novel agonist of human STING both as a research tool for exploring STING biology and as an immune potentiating molecule

A Novel Agonist of the TRIF Pathway Induces a Cellular State Refractory to Replication of Zika, Chikungunya, and Dengue Viruses.

The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy\u27s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3

Using a composite maternal-infant outcome measure in tuberculosis prevention studies among pregnant women

CITATION: Montepiedra, G. et al. 2021. Using a Composite Maternal-Infant Outcome Measure in Tuberculosis-Prevention Studies Among Pregnant Women. Clinical infectious diseases, 73(3):587–e593. doi:10.1093/cid/ciaa1674The original publication is available at https://academic.oup.com/cid/Background: Tuberculosis (TB-)-preventive therapy (TPT) among pregnant women reduces risk of TB in mothers and infants, but timing of initiation should consider potential adverse effects. We propose an analytical approach to evaluate the risk-benefit of interventions. Methods: A novel outcome measure that prioritizes maternal and infant events was developed with a 2-stage Delphi survey, where a panel of stakeholders assigned scores from 0 (best) to 100 (worst) based on perceived desirability. Using data from TB APPRISE, a trial among pregnant women living with human immunodeficiency virus (WLWH) that randomized the timing of initiation of isoniazid, antepartum versus postpartum, was evaluated. Results: The composite outcome scoring/ranking system categorized mother-infant paired outcomes into 8 groups assigned identical median scores by stakeholders. Maternal/infant TB and nonsevere adverse pregnancy outcomes were assigned similar scores. Mean (SD) composite outcome scores were 43.7 (33.0) and 41.2 (33.7) in the antepartum and postpartum TPT initiation arms, respectively. However, a modifying effect of baseline antiretroviral regimen was detected (P = .049). When women received nevirapine, composite scores were higher (worse outcomes) in the antepartum versus postpartum arms (adjusted difference, 14.3; 95% confidence interval [CI], 2.4-26.2; P = .02), whereas when women received efavirenz there was no difference by timing of TPT (adjusted difference, .62; 95% CI, -3.2-6.2; P = .53). Conclusions: For TPT, when used by otherwise healthy persons, preventing adverse events is paramount from the perspective of stakeholders. Among pregnant WLWH in high-TB-burden regions, it is important to consider the antepartum antiretroviral regimen taken when deciding when to initiate TPT. Clinical Trials Registration. NCT01494038 (IMPAACT P1078).https://academic.oup.com/cid/article/73/3/e587/5955952?login=truePublishers versio

Etravirine pharmacokinetics in HIV-infected pregnant women

__Background__ The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. __Methods__ IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). __Results__ Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred. __Conclusion__ Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. __Clinical Trial registration:__ The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929

Association of prolactin receptor (PRLR) variants with prolactinomas

Prolactinomas are the most frequent type of pituitary tumors, which represent 10–20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P 1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms

Prevention of HIV-1 transmission through breastfeeding: efficacy and safety of maternal antiretroviral therapy versus infant nevirapine prophylaxis for duration of breastfeeding in HIV-1-infected women with high CD4 cell count (IMPAACT PROMISE): a randomized, open label, clinical trial.

CAPRISA, 2018.Abstract available in pdf

Management of stillbirth delivery

Stillbirth is a common adverse outcome of pregnancy. Management should be individualized based on gestational age, maternal condition, prior uterine surgery, availability of skilled professionals, and maternal desires. This article discusses available data on management by gestational age and prior uterine surgery. Expectant management is a viable option for women and families who desire it and do not have any contraindications. In the second trimester, misoprostol induction and dilatation and evacuation are effective in the evacuation of the uterus. In the third trimester, induction of labor with prostaglandins, mechanical dilators, and augmentation with oxytocin is appropriate. Care should be taken with women with prior cesarean delivery; prostaglandins ideally should be avoided. Delivery by cesarean section should be performed selectively, i.e., when there is a maternal indication