Distinct baseline immune characteristics associated with responses to conjugated and unconjugated pneumococcal polysaccharide vaccines in older adults.

Pneumococcal infections cause serious illness and death among older adults. The capsular polysaccharide vaccine PPSV23 and conjugated alternative PCV13 can prevent these infections; yet, underlying immunological responses and baseline predictors remain unknown. We vaccinated 39 older adults (>60 years) with PPSV23 or PCV13 and observed comparable antibody responses (day 28) and plasmablast transcriptional responses (day 10); however, the baseline predictors were distinct. Analyses of baseline flow cytometry and bulk and single-cell RNA-sequencing data revealed a baseline phenotype specifically associated with weaker PCV13 responses, which was characterized by increased expression of cytotoxicity-associated genes, increased frequencies of CD16+ natural killer cells and interleukin-17-producing helper T cells and a decreased frequency of type 1 helper T cells. Men displayed this phenotype more robustly and mounted weaker PCV13 responses than women. Baseline expression levels of a distinct gene set predicted PPSV23 responses. This pneumococcal precision vaccinology study in older adults uncovered distinct baseline predictors that might transform vaccination strategies and initiate novel interventions.

Mapping systemic lupus erythematosus heterogeneity at the single-cell level.

Patients with systemic lupus erythematosus (SLE) display a complex blood transcriptome whose cellular origin is poorly resolved. Using single-cell RNA sequencing, we profiled ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls. Increased expression of interferon-stimulated genes (ISGs) distinguished cells from children with SLE from healthy control cells. The high ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, CD4+ and CD8+ T cells, natural killer cells, conventional and plasmacytoid dendritic cells, B cells and especially plasma cells. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.

Comparison of the Scope of Practice of the Army Combat Medic Specialist and Civilian National EMS Certification Levels.

INTRODUCTION: The transition of Army Combat Medic Specialists (Military Occupational Specialty Code: 68W) from military to civilian emergency medical services (EMS) is challenging, and the pathway is not clearly defined. Our objective was to evaluate the current military requirements for 68W and how they compare to the 2019 EMS National Scope of Practice Model (SoPM) for the civilian emergency medical technician (EMT) and advanced emergency medical technician (AEMT). METHODS: This was a cross-sectional evaluation of the 68W skill floor as defined by the Soldier's Manual and Trainer's Guide Healthcare Specialist and Medical Education and Demonstration of Individual Competence in comparison to the 2019 SoPM, which categorizes EMS tasks into seven skill categories. Military training documents were reviewed and extracted for specific information on military scope of practice and task-specific training requirements. Descriptive statistics were calculated. RESULTS: Army 68Ws were noted to perform all (59/59) tasks that coincide with the EMT SoPM. Further, Army 68W practiced above scope in the following skill categories: airway/ventilation (3 tasks); medication administration route (7 tasks); medical director approved medication (6 tasks); intravenous initiation maintenance fluids (4 tasks); and miscellaneous (1 task). Army 68W perform 96% (74/77) of tasks aligned with the AEMT SoPM, excluding tracheobronchial suctioning of an intubated patient, end-tidal CO2 monitoring or waveform capnography, and inhaled nitrous oxide monitoring. Additionally, the 68W scope included six tasks that were above the SoPM for AEMT; airway/ventilation (2 tasks); medication administration route (2 tasks); and medical director approved medication (2 tasks). CONCLUSIONS: The scope of practice of U.S. Army 68W Combat Medics aligns well with the civilian 2019 Scope of Practice Model for EMTs and AEMTs. Based on the comparative scope of practice analysis, transitioning from Army 68W Combat Medic to civilian AEMT would require minimal additional training. This represents a promising potential workforce to assist with EMS workforce challenges. Although aligning the scope of practice is a promising first step, future research is needed to assess the relationship of Army 68Ws training with state licensure and certification equivalency to facilitate this transition.

Factors Associated with Maternal Morbidity among Black Women in the United States.

OBJECTIVE: Non-Hispanic Black people (NHBP) have a three-fold higher rate of maternal mortality compared to other racial groups. Racial disparities in maternal morbidity are well-described; however, there are substantial differences in cultural, economic, and social determinants of health among racial groups. We thus sought to study the at-risk, non-Hispanic Black population as its own cohort to identify factors most associated with severe maternal morbidity (SMM). STUDY DESIGN: This is a population-based retrospective case-control study of all live births in the United States between 2017 and 2019 using birth records obtained from the National Center for Health Statistics. The primary outcome for this study was to determine demographic, social, medical, and obstetric factors associated with maternal morbidity among NHBP who did and did not experience an SMM event. Multivariable logistic regression was used to estimate the adjusted odds ratio between each individual factor and the outcome of SMM among NHBP. RESULTS: Of the 1,624,744 NHBP who delivered between 2017 and 2019, 1.1% experienced an SMM event defined as a composite of blood product transfusion, eclamptic seizure, intensive care unit admission, unplanned hysterectomy, and uterine rupture. The rates of these individual SMM events per 10,000 deliveries were 50, 40, 20, 5, and 4 among NHBP, respectively. Among NHBP, factors associated in multivariable regression analysis with SMM in order of strength of association included cesarean delivery, earlier gestational age at delivery, preeclampsia, induction of labor, chronic hypertension, prior preterm birth, lower educational attainment, multifetal gestation, advanced maternal age, pregestational diabetes, and cigarette smoking. The population attributable fraction for cesarean delivery, preterm birth, and pregnancy-induced hypertensive disease for the outcome of SMM were 0.46, 0.23, and 0.07, respectively. CONCLUSION: The three factors most associated with SMM among NHBP are potentially avoidable or modifiable by aggressive screening, prevention, and treatment of preeclampsia and preterm birth as well as reducing cesarean rates in this population. KEY POINTS: · The rate of SMM in NHBP may be modifiable.. · NHBP have a three-fold higher rate of maternal mortality.. · Preeclampsia, preterm birth, and cesarean sections are most associated with maternal morbidity..

A functional mechanism for a non-coding variant near AGTR2 associated with risk for preterm birth.

BACKGROUND: Preterm birth (PTB), defined as delivery before 37 gestational weeks, imposes significant public health burdens. A recent maternal genome-wide association study of spontaneous PTB identified a noncoding locus near the angiotensin II receptor type 2 (AGTR2) gene. Genotype-Tissue Expression data revealed that alleles associated with decreased AGTR2 expression in the uterus were linked to an increased risk of PTB and shortened gestational duration. We hypothesized that a causative variant in this locus modifies AGTR2 expression by altering transcription factor (TF) binding. METHODS: To investigate this hypothesis, we performed bioinformatics analyses and functional characterizations at the implicated locus. Potential causal single nucleotide polymorphisms (SNPs) were prioritized, and allele-dependent binding of TFs was predicted. Reporter assays were employed to assess the enhancer activity of the top PTB-associated non-coding variant, rs7889204, and its impact on TF binding. RESULTS: Our analyses revealed that rs7889204, a top PTB-associated non-coding genetic variant is one of the strongest eQTLs for the AGTR2 gene in uterine tissue samples. We observed differential binding of CEBPB (CCAAT enhancer binding protein beta) and HOXA10 (homeobox A10) to the alleles of rs7889204. Reporter assays demonstrated decreased enhancer activity for the rs7889204 risk "C" allele. CONCLUSION: Collectively, these results demonstrate that decreased AGTR2 expression caused by reduced transcription factor binding increases the risk for PTB and suggest that enhancing AGTR2 activity may be a preventative measure in reducing PTB risk.

Historic and Contemporary Surface Disposal of Produced Water Likely Inputs Arsenic and Selenium to Surficial Aquifers.

Oil and gas development generates large amounts of wastewater (i.e., produced water), which in California has been partially disposed of in unlined percolation/evaporation ponds since the mid-20th century. Although produced water is known to contain multiple environmental contaminants (e.g., radium and trace metals), prior to 2015, detailed chemical characterizations of pondwaters were the exception rather than the norm. Using a state-run database, we synthesized samples (n = 1688) collected from produced water ponds within the southern San Joaquin Valley of California, one of the most productive agricultural regions in the world, to examine regional trends in pondwater arsenic and selenium concentrations. We filled crucial knowledge gaps resulting from historical pondwater monitoring by constructing random forest regression models using commonly measured analytes (boron, chloride, and total dissolved solids) and geospatial data (e.g., soil physiochemical data) to predict arsenic and selenium concentrations in historical samples. Our analysis suggests that both arsenic and selenium levels are elevated in pondwaters and thus this disposal practice may have contributed substantial amounts of arsenic and selenium to aquifers having beneficial uses. We further use our models to identify areas where additional monitoring infrastructure would better constrain the extent of legacy contamination and potential threats to groundwater quality.

Association of Antenatal Corticosteroid Exposure and Infant Survival at 22 and 23 Weeks.

OBJECTIVE: In 2014, the leading obstetric societies published an executive summary of a joint workshop to establish obstetric interventions to be considered for periviable births. Antenatal corticosteroid administration between 220/7 and 226/7 weeks was not recommended given existing evidence. We sought to evaluate whether antenatal steroid exposure was associated with improved survival among resuscitated newborns delivered between 22 and 23 weeks of gestation. STUDY DESIGN: We conducted a population-based cohort study of all resuscitated livebirths delivered between 220/7 and 236/7 weeks of gestation in the United States during 2009 to 2014 utilizing National Center for Health Statistics data. The primary outcome was rate of survival to 1 year of life (YOL) between infant cohorts based on antenatal steroid exposure. Multivariable logistic regression estimated the association of antenatal steroid exposure on survival outcomes. RESULTS: In the United States between 2009 and 2014, there were 2,635 and 7,992 infants who received postnatal resuscitation after delivery between 220/7 to 226/7 and 230/7 to 236/7 weeks of gestation, respectively. Few infants born at 22 (15.9%) and 23 (26.0%) weeks of gestation received antenatal corticosteroids (ANCS). Among resuscitated neonates, survival to 1 YOL was 45.2 versus 27.8% (adjusted relative risk [aRR]: 1.6, 95% confidence interval [CI]: 1.2-2.1) and 57.9 versus 47.7% (aRR: 1.3, 95% CI: 1.1-1.5) for infants exposed to ANCS compared with those not exposed at 22 and 23 weeks of gestation, respectively. When stratified by 100 g birth weight category, ANCS were associated with survival among neonates weighing 500 to 599 g (aRR: 1.9, 95% CI: 1.3-2.9) and 600 to 699 g (aRR: 1.7, 95% CI: 1.1-2.6) at 22 weeks. CONCLUSION: Exposure to ANCS was associated with higher survival rates to 1 YOL among resuscitated infants born at 22 and 23 weeks. National guidelines recommending against ANCS utilization at 22 weeks should be re-evaluated given emerging evidence of benefit. KEY POINTS: · Exposure to antenatal steroids was associated with higher survival rates at 22 and 23 weeks of gestation.. · Women exposed to antenatal steroids were more likely to have an adverse outcome.. · The association between steroids and survival was observed among infants with birth weights > 500 g..

Factors Associated with Receiving No Maternal or Neonatal Interventions among Periviable Deliveries.

OBJECTIVE: The aim of this study was to quantify the influence of maternal sociodemographic, medical, and pregnancy characteristics on not receiving maternal and neonatal interventions with deliveries occurring at 22 to 23 weeks of gestation. STUDY DESIGN: This was a case-control study of U.S. live births at 220/6 to 236/7 weeks of gestation using vital statistics birth records from 2012 to 2016. We analyzed births that received no interventions for periviable delivery. Births were defined as having no interventions if they did not receive maternal (cesarean delivery, maternal hospital transfer, or antenatal corticosteroid administration) or neonatal interventions (neonatal intensive care unit admission, surfactant administration, antibiotic administration, or assisted ventilation). Logistic regression estimated the influence of maternal and pregnancy factors on the receipt of no interventions when delivery occurred at 22 to 23 weeks. RESULTS: Of 19,844,580 U.S. live births in 2012-2016, 24,379 (0.12%) occurred at 22 to 23 weeks; 54.3% of 22-week deliveries and 15.7% of 23-week deliveries received no interventions. Non-Hispanic Black maternal race was associated with no maternal interventions at 22 and 23 weeks. Private insurance, singleton pregnancy, and small for gestational age were associated with receiving no neonatal interventions at 22 and 23 weeks of gestation. CONCLUSIONS: Withholding or refusing maternal and neonatal interventions occurs frequently at the threshold of viability. Our data highlight various sociodemographic, pregnancy, and medical factors associated with decisions to not offer or receive maternal or neonatal interventions when birth occurs at the threshold of viability. The data elucidate observed practices and may assist in the development of further research. KEY POINTS: · Non-Hispanic Black race was associated with receiving no maternal interventions.. · Indicators of high socioeconomic status were associated with no neonatal inventions.. · Patient-level factors influence the receipt of no interventions for periviable birth..

Factors Associated with Occurrence of Stillbirth before 32 Weeks of Gestation in a Contemporary Cohort.

OBJECTIVE: We sought to quantify the distribution of stillbirths by gestational age (GA) in a contemporary cohort and to determine identifiable risk factors associated with stillbirth prior to 32 weeks of gestation. STUDY DESIGN: Population-based case-control study of all stillbirths in the United States during the year 2014, utilizing vital statistics data, obtained from the National Center for Health Statistics. Distribution of stillbirths were stratified by 20 to 44 weeks of GA, in women diagnosed with stillbirth in the antepartum period. Pregnancy characteristics were compared between those diagnosed with stillbirth <32 versus ≥32 weeks of gestation. Multivariate logistic regression estimated the relative influence of various factors on the outcome of stillbirth prior to 32 weeks of gestation. RESULTS: There were 15,998 nonlaboring women diagnosed with stillbirth during 2014 in the United States between 20 and 44 weeks. Of them, 60.1% (n = 9,618) occurred before antenatal fetal surveillance (ANFS) is typically initiated (<32 weeks) and 39.9% (n = 6,380) were diagnosed at ≥32 weeks. Women with stillbirth prior to 32 weeks were more likely to be of non-Hispanic Black race (29.0 vs. 23.9%, p < 0.001), nulliparous (53.8 vs. 50.6%, p = 0.001), have chronic hypertension (CHTN; 6.0 vs. 4.3%, p < 0.001), and fetal growth restriction as evidenced by small for GA (SGA < 10th%) birth weight (44.8 vs. 42.1%, p < 0.001) as opposed to women with stillbirth after 32 weeks. After adjustment, SGA birth weight (adjusted odds ratio [aOR] = 1.2, 95% confidence interval [CI]: 1.1-1.3), Black race (aOR = 1.2, 95% CI: 1.1-1.3), and CHTN (aOR = 1.3, 95% CI: 1.1-1.5) were associated with stillbirth prior to 32 weeks of gestation as opposed to stillbirth after 32 weeks. CONCLUSION: More than 6 out of 10 stillbirths in this study occurred <32 weeks of gestation, before ANFS is typically initiated under American College of Obstetricians and Gynecologists recommendations. Among identifiable risk factors, CHTN, Black race, and fetal growth restriction were associated with higher risk of stillbirth before 32 weeks of gestation. Earlier ANFS may be warranted at in certain "at risk" women. KEY POINTS: · Six out of 10 stillbirths occur before 32 weeks of gestation.. · We evaluated factors associated with stillbirth <32 weeks.. · Hypertension and fetal growth restriction were associated with early stillbirth..

Vulnerability of Groundwater Resources Underlying Unlined Produced Water Ponds in the Tulare Basin of the San Joaquin Valley, California.

The San Joaquin Valley (SJV) in California is one of the most agriculturally productive regions in the world relying in part on groundwater for irrigation and for domestic or municipal water supply for nearly 4 million residents. One area of growing concern in the SJV is potential impact to groundwater resources from ongoing and historical disposal of oilfield-produced water into unlined produced water ponds (PWPs). In this investigation, we utilized available information on composition of produced water disposed into unlined PWPs and levels of total dissolved solids in underlying groundwater to demonstrate that this disposal practice, both past and present, poses risks to groundwater resources, especially in the Tulare Basin in the southern SJV. Groundwater monitoring at unlined PWP facilities is relatively sparse, but where monitoring has occurred, impact to aquifers used for public and agricultural water supply has been observed and has proven to be too expensive to actively remediate. Results of this investigation should inform policy discussions in California and other locations where disposal of produced water into unlined impoundments occurs, especially at locations that overlie groundwater resources.

Effect of Needle Exchange Program on Maternal Hepatitis C Virus Prevalence.

OBJECTIVE: This study aimed to quantify the prevalence of maternal hepatitis C virus (HCV) before and after implementation of the needle exchange program (NEP) in Scioto County, Ohio. STUDY DESIGN: We conducted a population-based retrospective cohort study of all live births in Ohio (2006-2015). Frequency of maternal HCV was compared before (2006-2011) and after (2012-2015) the implementation of an NEP (2011) in Portsmouth, Ohio (Scioto County). Trends in maternal HCV prevalence in neighboring counties both physically adjacent and regional to Scioto County were also evaluated before and after NEP implementation. RESULTS: During the study period, there were 7,069 reported cases of maternal HCV infection at the time of delivery among 1,463,506 (0.5%) live births in Ohio. The rate of maternal HCV infection increased 137% in Scioto County between 2006 and 2011. After initiation of the NEP in Portsmouth, Ohio, in 2011, the rate of increase in the following 4 years (2012-2015) was 12%. The rate of increase in maternal HCV declined precipitously in counties physically adjacent to Scioto County, whereas regional counties continued to have substantial increases in maternal HCV. CONCLUSION: Rate of maternal HCV infection increased 137% versus 12% (rate difference: 125%) between pre- and post-NEP implementation time periods in Scioto County.

Mode of Delivery in Previable Births.

OBJECTIVE: Preterm birth before 23 weeks of gestation typically results in neonatal death (5% survival). Society for Maternal-Fetal Medicine and American College of Obstetricians and Gynecologists published consensus guidelines recommending cesarean delivery (CD) not be performed for fetal indications between 20 and 226/7 weeks given the lack of proven benefit. We sought to quantify the previable CD rate and identify characteristics associated with previable CD. METHODS: We performed a population-based retrospective cohort study of all live births in Ohio (2006-2015). Frequency of previable CD was stratified by week of gestation, defined as delivery between 16 and < 23 weeks of gestation. Maternal, obstetric, and neonatal characteristics were compared between women who underwent vaginal delivery versus CD. Multivariable logistic regression estimated the relative influence of maternal and fetal factors on the outcome of CD among previable live births. RESULTS: Of 1,463,506 live births in Ohio during the 10-year study period, 2,865 births (0.2%) occurred during the previable period of 16 to 22 weeks. Nearly 1 in 10 live births at less than 23 weeks was delivered by cesarean (n = 273/2,865), CD rate 9.5% (95% confidence interval, 8.5-10.7). At 16 to 22 weeks of gestation, the CD rates were 0, 5.5, 7.6, 3.5, 5.4, 10.1, and 15.1%, respectively. Factors associated with CD included increasing parity, increasing birth weight, maternal corticosteroid administration, and fetal malpresentation. Previable neonates born by CD were more likely to be admitted to the NICU, receive ventilator support, and more likely to be living at the time of birth certificate filing. CONCLUSION: Nearly 1 out of 10 births during the previable period was delivered via cesarean. Factors associated with previable CD suggest intent for neonatal interventions, such as NICU admission and supportive therapies. Our findings support that education and adherence with guidelines for care of previable births are a potential area of focus for perinatal quality improvement efforts.

Obstetric Outcomes Associated with Fetal Cyanotic Congenital Heart Disease.

OBJECTIVE: To characterize obstetric outcomes associated with cyanotic congenital heart disease (CCHD) in a contemporary population. STUDY DESIGN: We conducted a population-based retrospective cohort study of all livebirths in Ohio (2006-2015). Obstetric characteristics of pregnancies complicated by fetal CCHD were compared with those without CCHD, excluding those with other anomalies and aneuploidy. The primary objective was to determine the risk of cesarean delivery among CCHD affected pregnancies. Multivariate logistic regression estimated the influence of CCHD on these obstetric outcomes. RESULTS: Among 1,463,506 live births in Ohio, there were 863 (0.06%) CCHD affected births. The overall cesarean rate was 45.9 versus 31.0% (p< 0.001) in CCHD compared with non-CCHD pregnancies. After adjusting for various confounders, CCHD affected pregnancies were associated with a higher risk for cesarean delivery (adjusted relative risk [aRR]: 2.0, 95% confidence interval [CI]: 1.6-2.4), preterm birth (PTB) (aRR: 1.5, 95% CI: 1.1-2.0), induction of labor (aRR: 1.2, 95% CI: 1.04-1.4), small for gestational age (SGA) birthweight (aRR: 2.4, 95% CI: 2.0-2.9), and fetal intolerance of labor (FIOL; aRR: 2.0, 95% CI: 1.6-2.4). Women with CCHD affected pregnancies were also less likely to undergo a trial of labor (aRR: 0.4, 95% CI: 0.3-0.5) prior to cesarean delivery. CONCLUSION: Obstetric outcomes associated with CCHD include higher risk for cesarean delivery, PTB, SGA, and FIOL.

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance.

Current treatments to control pathological or unwanted immune responses often use broadly immunosuppressive drugs. New approaches to induce antigen-specific immunological tolerance that control both cellular and humoral immune responses are desirable. Here we describe the use of synthetic, biodegradable nanoparticles carrying either protein or peptide antigens and a tolerogenic immunomodulator, rapamycin, to induce durable and antigen-specific immune tolerance, even in the presence of potent Toll-like receptor agonists. Treatment with tolerogenic nanoparticles results in the inhibition of CD4+ and CD8+ T-cell activation, an increase in regulatory cells, durable B-cell tolerance resistant to multiple immunogenic challenges, and the inhibition of antigen-specific hypersensitivity reactions, relapsing experimental autoimmune encephalomyelitis, and antibody responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized to antigen. Only encapsulated rapamycin, not the free form, could induce immunological tolerance. Tolerogenic nanoparticle therapy represents a potential novel approach for the treatment of allergies, autoimmune diseases, and prevention of antidrug antibodies against biologic therapies.

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses.

Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients.

Reconstructing Early Industrial Contributions to Legacy Trace Metal Contamination in Southwestern Pennsylvania.

Early industrial trace metal loadings are poorly characterized but potentially substantial sources of trace metals to the landscape. The magnitude of legacy contamination in southwestern Pennsylvania, the cradle of North American fossil fuel industrialization, is reconstructed from trace metal concentrations in a sediment core with proxies including major and trace metal chemistry, bulk density, and magnetic susceptibility. Trace metal chemistry in this sediment record reflects 19th and 20th century land use and industry. In particular, early 19th century arsenic loadings to the lake are elevated from pesticides used by early European settlers at a lakeside tannery. Later, sediment barium concentrations rise, likely reflecting the onset of acidic mine drainage from coal operations. Twentieth century zinc, cadmium, and lead concentrations are dominated by emissions from the nearby, infamous Donora Zinc Works yet record both the opening of a nearby coal-fired power plant and amendments to the Clean Air Act. The impact of early industry is substantial and rivals more recent metal fluxes, resulting in a significant potential source of contaminated sediments. Thus, modern assessments of trace metal contamination cannot ignore early industrial inputs, as the potential remobilization of legacy contamination would impact ecosystem and human health.

Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation.

The immune response of hemophilia A patients to administered FVIII is a major complication that obviates this very therapy. We have recently described the use of synthetic, biodegradable nanoparticles carrying rapamycin and FVIII peptide antigens, to induce antigen-specific tolerance. Herein we test the tolerogenicity of nanoparticles that contains full length FVIII protein in hemophilia A mice, focusing on anti-FVIII humoral immune response. As expected, recipients of tolerogenic nanoparticles remained unresponsive to FVIII despite multiple challenges for up to 6 months. Furthermore, therapeutic treatments in FVIII-immunized mice with pre-existing anti-FVIII antibodies resulted in diminished antibody titers, albeit efficacy required longer therapy with the tolerogenic nanoparticles. Interestingly, durable FVIII-specific tolerance was also achieved in animals co-administered with FVIII admixed with nanoparticles encapsulating rapamycin alone. These results suggest that nanoparticles carrying rapamycin and FVIII can be employed to induce specific tolerance to prevent and even reverse inhibitor formation.

An examination of onshore produced water spills in the state of California: incident frequency, spatial distribution, and shortcomings in available data.

Accidental releases (i.e., spills) of produced water can occur at any point during oil and gas development operations, potentially resulting in chronic and/or catastrophic loadings of produced water to nearby ecosystems and exposures of human populations to toxic constituents including trace metals (e.g., arsenic), organic compounds (e.g., benzene), and/or radionuclides (e.g., radium). Despite California being one of the largest oil and gas producing states in the USA, no comprehensive reviews of produced water spills in the peer-reviewed literature have been published. To address this knowledge gap, produced water spill incident data contained within the California HazMat database were synthesized to elucidate trends in produced water spills in California. During the period of 2006-2020, a total of 1029 incidents involving produced water spills were reported. Despite the potential threat to environmental and human receptors, there are significant knowledge gaps concerning these incidents. Specifically, only ~ 6% of spill incidents contained geographic coordinates, greatly hindering assessments of the impacts of these events to public health and the environment. Moreover, updated spill volumes are not rapidly retrievable from the HazMat database, and during the years 2018-2020 volumes of produced water spilled were underreported in initial reports anywhere from 35-2750%. Further, it is unclear if groundwater monitoring is performed following spill events. This study highlights significant shortcomings in produced water spill reporting in California and recommends improvements to aid future investigations that assess the environmental and public health impacts of spill incidents.

Gestational Age and Birth Outcomes in Term Singleton Pregnancies Conceived With Infertility Treatment.

Importance: Despite the increased perinatal risks associated with pregnancies conceived with infertility treatment, there are no recommendations for timing of delivery among this at-risk population. Objective: To identify the gestational age at which the ongoing risks of stillbirth are optimally balanced with the risks of neonatal comorbidities and infant deaths in term singleton pregnancies conceived with infertility treatment. Design, Setting, and Participants: This cohort study used birth and death data from January 1, 2014, to December 31, 2018, in the US obtained from the National Center for Health Statistics. Singleton pregnancies conceived with infertility treatment delivered at term (37-42 weeks' gestation) were eligible for inclusion. The exclusion criteria were deliveries at less than 37 weeks' or at least 43 weeks' gestation and pregnancies with unknown history of infertility treatment, congenital anomalies, pregestational diabetes, pregestational hypertension, gestational hypertension, and preeclampsia. Data were analyzed from July 22, 2022, to June 24, 2023. Exposure: Gestational age at delivery between 37 and 42 weeks. Main Outcomes and Measures: The primary outcome was optimal timing of delivery. To ascertain this timing, the risk of delivery (rate of neonatal morbidity and infant death) at a given gestational week was compared with the risk of delivery in the subsequent week of gestation for an additional week (rate of stillbirth during the given week per 10 000 ongoing pregnancies plus rate of neonatal morbidity and infant death in the subsequent week of gestation per 10 000 deliveries). The rates of stillbirth, neonatal morbidity, and infant death (within 1 year of life) were compared at each week. Neonatal morbidity included an Apgar score of 3 or lower at 5 minutes, requirement of ventilation for 6 hours or more, neonatal intensive care unit admission, and seizures. Results: Of the 178 448 singleton term pregnancies conceived with infertility treatment (maternal mean [SD] age, 34.2 [5.2] years; mean [SD] gestational age, 39.2 [1.2] weeks; 130 786 [73.5%] were non-Hispanic White patients). The risk of delivery in the subsequent week of gestation was lower than the risk of delivery at both 37 weeks (628 [95% CI, 601-656] vs 1005 [95% CI, 961-1050] per 10 000 live births) and 38 weeks (483 [95% CI, 467-500 vs 625 [95% CI, 598-652] per 10 000 live births). The risks of delivery in subsequent week of gestation significantly exceeded the risk of delivery at 39 weeks (599 [95% CI, 576-622] vs 479 [95% CI, 463-495] per 10 000 live births) and were not significant at 40 weeks (639 [95% CI, 605-675] vs 594 [95% CI, 572-617] per 10 000 live births) and 41 weeks (701 [95% CI, 628-781] vs 633 [95% CI, 599-669] per 10 000 live births). Conclusions and Relevance: Results of this study suggest that, in pregnancies conceived with infertility treatment, delivery at 39 weeks provided the lowest perinatal risk when comparing risk of delivery at this week of gestation vs the subsequent week of gestation.

Pond Sediments Reveal the Increasing Importance of Road Runoff as a Source of Metal Contamination in Industrialized Urban Environments Downwind of Pittsburgh, Pennsylvania (USA).

Toxic levels of trace metals from human activities accumulate in natural environments, yet these metal mixtures are rarely characterized or quantified. Metal mixtures accumulate in historically industrial urban areas and change as economies shift. Previous research has often focused on the sources and fate of a specific element, which limits our understanding of metal contaminant interactions in our environment. Here, we reconstruct the history of metal contamination in a small pond downstream of an interstate highway and downwind of fossil fuel and metallurgical industries that have been active since the middle of the nineteenth century. Metal contamination histories were reconstructed from the sediment record using metal ratio mixing analysis to attribute the relative contributions of contamination sources. Cadmium, copper, and zinc concentrations in sediments accumulated since the construction of major road arteries in the 1930s and 40s are, respectively, 3.9, 2.4, and 6.6 times more concentrated than those during industry-dominated time periods. Shifts in elemental ratios suggest these changes in metal concentrations coincide with increased contributions from road and parking lot traffic, and to a lesser extent, from airborne sources. The metal mixture analysis demonstrates that in near-road environments, contributions from modern surface water pathways can obscure historical atmospheric industrial inputs.