Syphilis Treatment Among People Who Are Pregnant in Six U.S. States, 2018-2021.

OBJECTIVE: To describe syphilis treatment status and prenatal care among people with syphilis during pregnancy to identify missed opportunities for preventing congenital syphilis. METHODS: Six jurisdictions that participated in SET-NET (Surveillance for Emerging Threats to Pregnant People and Infants Network) conducted enhanced surveillance among people with syphilis during pregnancy based on case investigations, medical records, and linkage of laboratory data with vital records. Unadjusted risk ratios (RRs) were used to compare demographic and clinical characteristics by syphilis stage (primary, secondary, or early latent vs late latent or unknown) and treatment status during pregnancy (adequate per the Centers for Disease Control and Prevention's "Sexually Transmitted Infections Treatment Guidelines, 2021" vs inadequate or not treated) and by prenatal care (timely: at least 30 days before pregnancy outcome; nontimely: less than 30 days before pregnancy outcome; and no prenatal care). RESULTS: As of September 15, 2023, of 1,476 people with syphilis during pregnancy, 855 (57.9%) were adequately treated and 621 (42.1%) were inadequately treated or not treated. Eighty-two percent of the cohort received timely prenatal care. Although those with nontimely or no prenatal care were more likely to receive inadequate or no treatment (RR 2.50, 95% CI, 2.17-2.88 and RR 2.73, 95% CI, 2.47-3.02, respectively), 32.1% of those with timely prenatal care were inadequately or not treated. Those with reported substance use or a history of homelessness were nearly twice as likely to receive inadequate or no treatment (RR 2.04, 95% CI, 1.82-2.28 and RR 1.83, 95% CI, 1.58-2.13, respectively). CONCLUSION: In this surveillance cohort, people without timely prenatal care had the highest risk for syphilis treatment inadequacy; however, almost a third of people who received timely prenatal care were not adequately treated. These findings underscore gaps in syphilis screening and treatment for pregnant people, especially those experiencing substance use and homelessness, and the need for systems-based interventions, such as treatment outside of traditional prenatal care settings.

Zika virus prevention behaviors and knowledge among male partners of pregnant people and lack of condom use as a prevention behavior from the Zika en Embarazadas y Niños (ZEN) prospective cohort study, Colombia.

OBJECTIVE: Zika virus (ZIKV) infection in pregnancy can cause brain and eye abnormalities and neurodevelopmental sequelae. In the absence of medical countermeasures, behavioral interventions were recommended to prevent mosquito bites and sexual transmission of ZIKV. This report uses data from the Zika en Embarazadas y Niños (ZEN) prospective cohort study in Colombia to describe the knowledge, attitudes, and behaviors (KAB) related to ZIKV prevention in male partners compared to those of their pregnant partners at study enrollment during February 2017-2018. RESULTS: Most male partners reported wearing protective clothing such as long pants (97.6%) and long sleeves (72.8%), as well as covering ankles and feet (89.1%) to prevent ZIKV infection. When comparing the preventive behavior of condom use between male and pregnant partners, 26 pairs (10.0%) both responded that they performed the behavior. Overall, 25.1% of male partners and 18.9% of pregnant people reported any condom use during the three months before enrolling in ZEN. When comparing other preventive behaviors between male and pregnant partners, the behavior which was most frequently reported by both partners was wearing long pants (85.4%), and the least frequently reported by both partners was using condoms after finding out about a partner's pregnancy (3.4%).

Pre-Delta, Delta, and Omicron Periods of the Coronavirus Disease 2019 (COVID-19) Pandemic and Health Outcomes During Delivery Hospitalization.

OBJECTIVE: To examine the relationship between coronavirus disease 2019 (COVID-19) diagnosis at delivery and adverse maternal health and pregnancy outcomes during pre-Delta, Delta, and Omicron variant predominance, with a focus on the time period of Omicron variant predominance. METHODS: We conducted a cross-sectional observational study with data from delivery hospitalizations in the Premier Healthcare Database from February 2020 to August 2023. The pre-Delta (February 2020-June 2021), Delta (July 2021-December 2021), and Omicron (January 2022-August 2023) periods of variant predominance were examined. Exposure to COVID-19 was identified by having a diagnostic code for COVID-19 during the delivery hospitalization. Adjusted prevalence ratios (aPRs) were calculated to compare the risks of adverse maternal and pregnancy outcomes for women with and without COVID-19 diagnoses at the time of delivery for each variant period. RESULTS: Among 2,990,973 women with delivery hospitalizations, 1.9% (n=56,618) had COVID-19 diagnoses noted at delivery admission discharge, including 26,053 during the Omicron period. Across all variant time periods, the prevalence of many adverse maternal and pregnancy outcomes during the delivery hospitalization was significantly higher for pregnant women with COVID-19 compared with pregnant women without COVID-19. In adjusted models, COVID-19 during the Omicron period was associated with significant increased risks for maternal sepsis (COVID-19: 0.4% vs no COVID-19: 0.1%; aPR 3.32, 95% CI, 2.70-4.08), acute respiratory distress syndrome (0.6% vs 0.1%; aPR 6.19, 95% CI, 5.26-7.29), shock (0.2% vs 0.1%; aPR 2.14, 95% CI, 1.62-2.84), renal failure (0.5% vs 0.2%; aPR 2.08, 95% CI, 1.73-2.49), intensive care unit admission (2.7% vs 1.7%; aPR 1.64, 95% CI, 1.52-1.77), mechanical ventilation (0.3% vs 0.1%; aPR 3.15, 95% CI, 2.52-3.93), in-hospital death (0.03% vs 0.01%; aPR 5.00, 95% CI, 2.30-10.90), stillbirth (0.7% vs 0.6%; aPR 1.17, 95% CI, 1.01-1.36), and preterm delivery (12.3% vs 9.6%; aPR 1.28, 95% CI, 1.24-1.33). CONCLUSION: Despite the possibility of some level of immunity due to previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, vaccination, or testing differences, risks of adverse outcomes associated with COVID-19 diagnosis at delivery remained elevated during the Omicron variant time period.

Pregnancy and infant outcomes following SARS-CoV-2 infection in pregnancy during delta variant predominance - Surveillance for Emerging Threats to Pregnant People and Infants.

BACKGROUND: SARS-CoV-2 infection in pregnancy is associated with an increased risk of adverse birth outcomes such as preterm birth, stillbirth, and maternal and infant complications. Previous research suggests an increased risk of severe COVID-19 illness and stillbirth in pregnant people during delta variant predominance in 2021; however, those studies did not assess timing of infection during pregnancy, and few of them described COVID-19 vaccination status. OBJECTIVE: Using a large population-based cohort, this study compared pregnancy and infant outcomes and described demographic and clinical characteristics of pregnant people with SARS-CoV-2 infection prior to and during the delta variant period. STUDY DESIGN: This retrospective cohort analysis included persons with confirmed SARS-CoV-2 infection in pregnancy from 6 US jurisdictions reporting to the Surveillance for Emerging Threats to Pregnant People and Infants Network. Data were collected through case reports of polymerase chain reaction-positive pregnant persons and linkages to birth certificates, fetal death records, and immunization records. We described clinical characteristics and compared frequency of spontaneous abortion (<20 weeks of gestation), stillbirth (≥20 weeks), preterm birth (<37 weeks), small for gestational age, and term infant neonatal intensive care unit admission between the time periods of pre-delta and delta variant predominance. Study time periods were determined by when variants constituted more than 50% of sequences isolated according to regional SARS-CoV-2 genomic surveillance data, with time periods defined for pre-delta (March 3, 2020-June 25, 2021) and Delta (June 26, 2021-December 25, 2021). Adjusted prevalence ratios were estimated for each outcome measure using Poisson regression and were adjusted for continuous maternal age, race and ethnicity, and insurance status at delivery. RESULTS: Among 57,563 pregnancy outcomes, 57,188 (99.3%) were liveborn infants, 65 (0.1%) were spontaneous abortions, and 310 (0.5%) were stillbirths. Most pregnant persons were unvaccinated at the time of SARS-CoV-2 infection, with a higher proportion in pre-delta (99.4%) than in the delta period (78.4%). Of those with infections during delta and who were previously vaccinated, the timing from last vaccination to infection was a median of 183 days. Compared to pre-delta, infections during delta were associated with a higher frequency of stillbirths (0.7% vs 0.4%; adjusted prevalence ratio, 1.55; 95% confidence interval, 1.14-2.09) and preterm births (12.8% vs 11.9%; adjusted prevalence ratio, 1.14; 95% confidence interval, 1.07-1.20). The delta period was associated with a lower frequency of neonatal intensive care unit admission (adjusted prevalence ratio, 0.74; 95% confidence interval, 0.67-0.82) than in the pre-delta period. During the delta period, infection during the third trimester was associated with a higher frequency of preterm birth (adjusted prevalence ratio, 1.41; 95% confidence interval, 1.28-1.56) and neonatal intensive care unit admission (adjusted prevalence ratio, 1.21; 95% confidence interval, 1.01-1.45) compared to the first and second trimester combined. CONCLUSION: In this US-based cohort of persons with SARS-CoV-2 infection in pregnancy, the majority were unvaccinated, and frequencies of stillbirth and preterm birth were higher during the delta variant predominance period than in the pre-delta period. During the delta period, frequency of preterm birth and neonatal intensive care unit admission was higher among infections occurring in the third trimester vs those earlier in pregnancy. These findings demonstrate population-level increases of adverse fetal and infant outcomes, specifically in the presence of a COVID-19 variant with more severe presentation.

Substance Use Among Persons with Syphilis During Pregnancy - Arizona and Georgia, 2018-2021.

Despite universal prenatal syphilis screening recommendations and availability of effective antibiotic treatment, syphilis prevalence during pregnancy and the incidence of congenital syphilis have continued to increase in the United States (1,2). Concurrent increases in methamphetamine, injection drug, and heroin use have been described in women with syphilis (3). CDC used data on births that occurred during January 1, 2018-December 31, 2021, from two states (Arizona and Georgia) that participate in the Surveillance for Emerging Threats to Pregnant People and Infants Network (SET-NET) to describe the prevalence of substance use among pregnant persons with syphilis by congenital syphilis pregnancy outcome (defined as delivery of a stillborn or live-born infant meeting the surveillance case definition for probable or confirmed congenital syphilis). The prevalence of substance use (e.g., tobacco, alcohol, cannabis, illicit use of opioids, and other illicit, nonprescription substances) in persons with a congenital syphilis pregnancy outcome (48.1%) was nearly double that among those with a noncongenital syphilis pregnancy outcome (24.6%). Persons with a congenital syphilis pregnancy outcome were six times as likely to report illicit use of opioids and four times as likely to report using other illicit, nonprescription substances during pregnancy than were persons with a noncongenital syphilis pregnancy outcome. Approximately one half of persons who used substances during pregnancy and had a congenital syphilis pregnancy outcome had late or no prenatal care. Tailored interventions should address barriers and facilitators to accessing screening and treatment for syphilis among persons who use substances. The need for syphilis screening and treatment should be addressed at any health care encounter during pregnancy, especially among persons who use substances.

Critical windows of susceptibility for the effects of prenatal exposure to heat and heat variability on gestational growth.

BACKGROUND: Studies have shown that prenatal heat exposure may impact fetal growth, but few studies have examined the critical windows of susceptibility. As extreme heat events and within season temperature variability is expected to increase in frequency, it is important to understand how this may impact gestational growth. OBJECTIVES: We investigated associations between various measures of weekly prenatal heat exposure (mean and standard deviation (SD) of temperature and heat index (HI), derived using temperature in °C and dew point) and term birthweight or odds of being born small for gestational age (SGA) to identify critical windows of susceptibility. METHODS: We analyzed data from mother-child dyads (n = 4442) in the Boston-based Children's HealthWatch cohort. Birthweights were collected from survey data and electronic health records. Daily temperature and HI values were obtained from 800 m gridded spatial climate datasets aggregated by the PRISM Climate Group. Distributed lag-nonlinear models were used to assess the effect of the four weekly heat metrics on measures of gestational growth (birthweight, SGA, and birthweight z-scores). Analyses were stratified by child sex and maternal homelessness status during pregnancy. RESULTS: HI variability was significantly associated with decreased term birthweight during gestational weeks 10-29 and with SGA for weeks 9-26. Cumulative effects for these time periods were -287.4 g (95% CI: -474.1 g, -100.8 g for birthweight and 4.7 (95% CI: 1.6, 14.1) for SGA. Temperature variability was also significantly associated with decreased birthweight between weeks 15 and 26. The effects for mean heat measures on term birthweight and SGA were not significant for any gestational week. Stratification by sex revealed a significant effect on term birthweight in females between weeks 23-28 and in males between weeks 9-26. Strongest effects of HI variability on term birthweight were found in children of mothers who experienced homelessness during pregnancy. Weekly HI variability was the heat metric most strongly associated with measures of gestational growth. The effects observed were largest in males and those who experienced homelessness during pregnancy. DISCUSSION: Given the impact of heat variability on birthweight and risk of SGA, it is important for future heat warnings to incorporate measure of heat index and temperature variability.

Preliminary Findings from the Gulf War Women's Cohort: Reproductive and Children's Health Outcomes among Women Veterans.

Reproductive outcomes, such as preterm birth, miscarriage/stillbirth, and pre-eclampsia, are understudied in veterans, particularly among Gulf War veterans (GWVs). During deployment, women GWVs were exposed to toxicant and nontoxicant exposures that may be associated with adverse reproductive and developmental outcomes. The data come from a survey of 239 participants from northeastern and southern U.S. cohorts of women veterans. The questionnaire collected information about the service history, current and past general health, reproductive and family health, demographic information, and deployment exposures. Odds ratios were computed with 95% confidence intervals between exposures in theater and reproductive/children's health outcomes. GWVs experienced adverse reproductive outcomes: 25% had difficulty conceiving, and 31% had a pregnancy that ended in a miscarriage or stillbirth. Pregnancy complications were common among GWVs: 23% had a high-risk pregnancy, and 16% were diagnosed with pre-eclampsia. About a third of GWVs reported their children (38%) had a developmental disorder. Use of pesticide cream during deployment was associated with higher odds of all reproductive and developmental outcomes. The results demonstrate that GWVs experienced reproductive and children's health outcomes at potentially high rates, and exploratory analyses suggest pesticide exposure as associated with higher odds of adverse reproductive outcomes. Future longitudinal studies of women veterans should prioritize examining reproductive and children's health outcomes.

Host gut resistome in Gulf War chronic multisymptom illness correlates with persistent inflammation.

Chronic multisymptom illness (CMI) affects a subsection of elderly and war Veterans and is associated with systemic inflammation. Here, using a mouse model of CMI and a group of Gulf War (GW) Veterans' with CMI we show the presence of an altered host resistome. Results show that antibiotic resistance genes (ARGs) are significantly altered in the CMI group in both mice and GW Veterans when compared to control. Fecal samples from GW Veterans with persistent CMI show a significant increase of resistance to a wide class of antibiotics and exhibited an array of mobile genetic elements (MGEs) distinct from normal healthy controls. The altered resistome and gene signature is correlated with mouse serum IL-6 levels. Altered resistome in mice also is correlated strongly with intestinal inflammation, decreased synaptic plasticity, reversible with fecal microbiota transplant (FMT). The results reported might help in understanding the risks to treating hospital acquired infections in this population.

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals.

Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelopmental outcomes in offspring. US federal risk assessments rely almost exclusively on apical endpoints in animal models for deriving points of departure (PODs). New approach methodologies (NAMs) such as high-throughput screening (HTS) and mechanistically informative in vitro human cell-based systems, combined with in vitro to in vivo extrapolation (IVIVE), supplement in vivo studies and provide an alternative approach to calculate/determine PODs. We examine how parameterization of IVIVE models impacts the comparison between IVIVE-derived equivalent administered doses (EADs) from thyroid-relevant in vitro assays and the POD values that serve as the basis for risk assessments. Pesticide chemicals with thyroid-based in vitro bioactivity data from the US Tox21 HTS program were included (n = 45). Depending on the model structure used for IVIVE analysis, up to 35 chemicals produced EAD values lower than the POD. A total of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVE-derived EAD values and the in vivo-derived POD values is highly dependent on model parameterization. Here, we derive a range of potentially thyroid-relevant doses that incorporate uncertainty in modeling choices and in vitro assay data.

Neuropsychological effects in children exposed to anticonvulsant monotherapy during gestation: Phenobarbital, carbamazepine, and phenytoin.

OBJECTIVE: Usage during pregnancy of the antiseizure medication (ASM), phenobarbital (PB), carbamazepine (CBZ), and phenytoin (PHT), has been associated with adverse pregnancy outcomes. While morphological effects on offspring are well-documented, inconsistent findings have been reported on neuropsychological development, possibly due to differences in attention to maternal demographics, and other design characteristics. Herein, we report the results of a carefully designed protocol used to examine the effects of gestational monotherapy with PB, CBZ, or PHT upon children's general mental abilities, when compared to age- and gender- matched children born to unexposed women of similar age, education, and socioeconomic status. METHODS: For each ASM, we selected qualifying cases from children born to PB, CBZ, or PHT monotherapy-exposed and unexposed women. Following the application of inclusion, exclusion, and matching criteria, our sample included 34 PB-exposed, 40 PHT-exposed, and 41 CBZ-exposed children along with matched unexposed children for each drug group. Criteria were applied through examination of maternal medical and educational histories, parental socioeconomic characteristics, and child's age and gender. Each child's physical and neuropsychological characteristics were examined, using standardized protocols. We report on the cognitive performance of the children as assessed by the Wechsler Intelligence Scale for Children - III (WISC-III), the leading measure of mental ability in the U.S. RESULTS: An overall mixed model ANOVA of the adjusted performance of the children across all groups controlling for maternal IQ revealed significant effects on verbal IQ, but not full-scale IQ or performance IQ. In the individual drug and unexposed group comparisons, only reduced verbal and full-scale IQ scores in PB-exposed versus matched unexposed children were found. Comparisons between drug groups revealed a significant reduction in verbal IQ and full-scale IQ in PB-exposed versus PHT-exposed children, but not in other drug-drug comparisons. SIGNIFICANCE: These results demonstrate effects on children's mental ability due to prenatal PB exposure, such that analyses adjusted for maternal IQ scores, revealed reduced verbal mental abilities and reduced full-scale IQ scores when scores in exposed children were compared to scores from children of the same age and sex born to demographically similar, healthy unexposed women. When comparisons were made between drug groups, children exposed prenatally to PB performed significantly worse than prenatally PHT-exposed children, but CBZ-exposed children's scores were not significantly different from those of PB or PHT-exposed groups. In light of shared effects on structural teratogenicity, these findings suggest that use of PB monotherapy for the management of seizures during pregnancy may be associated with increased risk in comparison to PHT when neurobehavioral functioning is considered, and that only PB-exposed children have reduced performance compared to matched controls. Attention to these effects is critical in the developing world where use of these older medications remains predominant, and prudent choices can be made to reduce impact on cognitive development.

Pre-pregnancy body mass index and parent and teacher-reported behavioral outcomes among offspring in childhood.

OBJECTIVE: Pre-pregnancy obesity has been linked to childhood neurodevelopmental outcomes, including autism and attention-deficit hyperactivity disorder. The aim of our study was to examine the association between pre-pregnancy body mass index (BMI) and scores on behavioral scales according to both mother and teacher report. METHODS: We conducted a longitudinal study of 469 mother-child pairs. Information on pre-pregnancy body mass index (BMI) was collected from standardized maternal interviews conducted after delivery and assessment of childhood behavioral problems was measured at 5-12 years of age according to maternal-report using the Child Behavior Checklist (CBCL) and teacher-report using the Teacher Report Form (TRF). Using normal pre-pregnancy BMI (18.5-24.9 kg/m2) as the reference (n = 305), we calculated adjusted mean differences (MD) for t-scores on broadband and syndrome scales of behavior for children of mothers with pre-pregnancy overweight (n = 101) or obese (n = 63) BMI. We also examined associations with scores in the clinical range using risk ratios (RR) and compared results across informants. To account for loss to follow-up between the initial interview and the childhood behavioral assessment, we weighted models using stabilized inverse probability weights. RESULTS: Pre-pregnancy obesity was associated with a mean increase in child's total behavior problem t-scores according to both mother and teacher report, after adjustment for confounders and weighted for loss to follow-up (MD: 0.7, 95% CI: -2.2, 3.6 on CBCL; MD: 3.1, 95% CI: 0.5, 5.7 on TRF), indicating poorer behavioral outcomes. Comparing the magnitude of associations between mother and teacher-report, mean differences for pre-pregnancy obesity and most behavioral problem scales were larger for teacher-reported outcomes than mother-reported outcomes. Pre-pregnancy obesity was associated with increased risks of externalizing behaviors in the clinical range regardless of informant (CBCL RR: 1.6, 95% CI: 0.8, 3.2 and TRF RR: 1.7, 95% CI: 0.8, 3.5). Pre-pregnancy obesity was also associated with increased risks of internalizing behaviors according to teacher-report (TRF RR: 2.6, 95% CI:1.5, 4.6). CONCLUSIONS: Pre-pregnancy obesity, compared to pre-pregnancy normal weight, is associated with generally higher scores on both mother and teacher reported childhood behavioral assessments, indicating an increased likelihood of behavioral problems.

The SuperCam Instrument Suite on the NASA Mars 2020 Rover: Body Unit and Combined System Tests.

The SuperCam instrument suite provides the Mars 2020 rover, Perseverance, with a number of versatile remote-sensing techniques that can be used at long distance as well as within the robotic-arm workspace. These include laser-induced breakdown spectroscopy (LIBS), remote time-resolved Raman and luminescence spectroscopies, and visible and infrared (VISIR; separately referred to as VIS and IR) reflectance spectroscopy. A remote micro-imager (RMI) provides high-resolution color context imaging, and a microphone can be used as a stand-alone tool for environmental studies or to determine physical properties of rocks and soils from shock waves of laser-produced plasmas. SuperCam is built in three parts: The mast unit (MU), consisting of the laser, telescope, RMI, IR spectrometer, and associated electronics, is described in a companion paper. The on-board calibration targets are described in another companion paper. Here we describe SuperCam's body unit (BU) and testing of the integrated instrument. The BU, mounted inside the rover body, receives light from the MU via a 5.8 m optical fiber. The light is split into three wavelength bands by a demultiplexer, and is routed via fiber bundles to three optical spectrometers, two of which (UV and violet; 245-340 and 385-465 nm) are crossed Czerny-Turner reflection spectrometers, nearly identical to their counterparts on ChemCam. The third is a high-efficiency transmission spectrometer containing an optical intensifier capable of gating exposures to 100 ns or longer, with variable delay times relative to the laser pulse. This spectrometer covers 535-853 nm ( 105 - 7070 cm - 1 Raman shift relative to the 532 nm green laser beam) with 12 cm - 1 full-width at half-maximum peak resolution in the Raman fingerprint region. The BU electronics boards interface with the rover and control the instrument, returning data to the rover. Thermal systems maintain a warm temperature during cruise to Mars to avoid contamination on the optics, and cool the detectors during operations on Mars. Results obtained with the integrated instrument demonstrate its capabilities for LIBS, for which a library of 332 standards was developed. Examples of Raman and VISIR spectroscopy are shown, demonstrating clear mineral identification with both techniques. Luminescence spectra demonstrate the utility of having both spectral and temporal dimensions. Finally, RMI and microphone tests on the rover demonstrate the capabilities of these subsystems as well.

Urinary Isoflavones Levels in Relation to Serum Thyroid Hormone Concentrations in Female and Male Adults in the U.S. General Population.

Isoflavones are phytoestrogens found in plant-based foods and nutritional supplements. Experimental studies show a positive association between isoflavones and hypothyroidism, but epidemiological findings are conflicting. We used multivariable linear regression to examine the association between urinary isoflavone concentrations and serum thyroid hormone concentrations in the National Health and Nutrition Examination Survey (2007-2010). In this study, we found that Daidzein and O-DMA associations with free T4 were stronger among women: a 10-fold increase in daidzein was associated with a 3.2% (95% CI: 1.9%, 4.5%) increase in women and a 0.6% (95% CI: -1.7%, 0.6%) decrease in men and a 10-fold increase in O-DMA was related to a 2.0% (95% CI: 1.1%, 2.9%) increase in women and a 0.3% (95% CI: -1.2%, 0.5%) decrease in men. In this study, selected urinary isoflavone concentrations were associated with serum thyroid hormone concentration in a sex-dependent fashion.

The Gut-Microbiome in Gulf War Veterans: A Preliminary Report.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting the central nervous system (CNS), immune and gastrointestinal (GI) systems of Gulf War veterans (GWV). We assessed the relationships between GWI, GI symptoms, gut microbiome and inflammatory markers in GWV from the Boston Gulf War Illness Consortium (GWIC). Three groups of GWIC veterans were recruited in this pilot study; GWV without GWI and no gastrointestinal symptoms (controls), GWV with GWI and no gastrointestinal symptoms (GWI-GI), GWV with GWI who reported gastrointestinal symptoms (GW+GI). Here we report on a subset of the first thirteen stool samples analyzed. Results showed significantly different gut microbiome patterns among the three groups and within the GWI +/-GI groups. Specifically, GW controls had a greater abundance of firmicutes and the GWI+GI group had a greater abundance of the phyla bacteroidetes, actinobacteria, euryarchaeota, and proteobacteria as well as higher abundances of the families Bacteroidaceae, Erysipelotrichaceae, and Bifidobacteriaceae. The GWI+GI group also showed greater plasma levels of the inflammatory cytokine TNF-RI and they endorsed significantly more chemical weapons exposure during the war and reported significantly greater chronic pain, fatigue and sleep difficulties than the other groups. Studies with larger samples sizes are needed to confirm these initial findings.

Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury.

Reactive astrocytes are associated with every form of neurological injury. Despite their ubiquity, the molecular mechanisms controlling their production and diverse functions remain poorly defined. Because many features of astrocyte development are recapitulated in reactive astrocytes, we investigated the role of nuclear factor I-A (NFIA), a key transcriptional regulator of astrocyte development whose contributions to reactive astrocytes remain undefined. Here, we show that NFIA is highly expressed in reactive astrocytes in human neurological injury and identify unique roles across distinct injury states and regions of the CNS. In the spinal cord, after white matter injury (WMI), NFIA-deficient astrocytes exhibit defects in blood-brain barrier remodeling, which are correlated with the suppression of timely remyelination. In the cortex, after ischemic stroke, NFIA is required for the production of reactive astrocytes from the subventricular zone (SVZ). Mechanistically, NFIA directly regulates the expression of thrombospondin 4 (Thbs4) in the SVZ, revealing a key transcriptional node regulating reactive astrogenesis. Together, these studies uncover critical roles for NFIA in reactive astrocytes and illustrate how region- and injury-specific factors dictate the spectrum of reactive astrocyte responses.

A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models.

Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor-infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM.

HIF2α-Targeted RNAi Therapeutic Inhibits Clear Cell Renal Cell Carcinoma.

Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%-90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an overabundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvß3 and αvß5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2α-specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model. Mol Cancer Ther; 17(1); 140-9. ©2017 AACR.

Glia-specific enhancers and chromatin structure regulate NFIA expression and glioma tumorigenesis.

Long-range enhancer interactions critically regulate gene expression, yet little is known about how their coordinated activities contribute to CNS development or how this may, in turn, relate to disease states. By examining the regulation of the transcription factor NFIA in the developing spinal cord, we identified long-range enhancers that recapitulate NFIA expression across glial and neuronal lineages in vivo. Complementary genetic studies found that Sox9-Brn2 and Isl1-Lhx3 regulate enhancer activity and NFIA expression in glial and neuronal populations. Chromatin conformation analysis revealed that these enhancers and transcription factors form distinct architectures within these lineages in the spinal cord. In glioma models, the glia-specific architecture is present in tumors, and these enhancers are required for NFIA expression and contribute to glioma formation. By delineating three-dimensional mechanisms of gene expression regulation, our studies identify lineage-specific chromatin architectures and associated enhancers that regulate cell fate and tumorigenesis in the CNS.