Addressing sociodemographic, socioeconomic, and gendered disparities for equity in menopause care.

Menopause experiences and care vary widely because of biological, sociodemographic, and sociocultural factors. Treatments for troublesome symptoms are not uniformly available or accessed. Intersectional factors may affect the experience and are poorly understood. Disparities across populations highlight the opportunity for a multifaceted equitable approach that includes patient-centered care, education, and policy change.

Evaluation of in silico model predictions for mammalian acute oral toxicity and regulatory application in pesticide hazard and risk assessment.

The United States Environmental Protection Agency (USEPA) uses the lethal dose 50% (LD50) value from in vivo rat acute oral toxicity studies for pesticide product label precautionary statements and environmental risk assessment (RA). The Collaborative Acute Toxicity Modeling Suite (CATMoS) is a quantitative structure-activity relationship (QSAR)-based in silico approach to predict rat acute oral toxicity that has the potential to reduce animal use when registering a new pesticide technical grade active ingredient (TGAI). This analysis compared LD50 values predicted by CATMoS to empirical values from in vivo studies for the TGAIs of 177 conventional pesticides. The accuracy and reliability of the model predictions were assessed relative to the empirical data in terms of USEPA acute oral toxicity categories and discrete LD50 values for each chemical. CATMoS was most reliable at placing pesticide TGAIs in acute toxicity categories III (>500-5000 mg/kg) and IV (>5000 mg/kg), with 88% categorical concordance for 165 chemicals with empirical in vivo LD50 values ≥ 500 mg/kg. When considering an LD50 for RA, CATMoS predictions of 2000 mg/kg and higher were found to agree with empirical values from limit tests (i.e., single, high-dose tests) or definitive results over 2000 mg/kg with few exceptions.

Healthcare providers' use of a concise summary to prescribe for lactating patients.

BACKGROUND: Most breastfeeding individuals take at least one prescription drug, yet limited data from lactation studies are available to inform the safety of these drugs during breastfeeding. As a result, healthcare providers (HCPs) rely on available information about safety of drugs used during pregnancy or on personal experiences to inform prescribing/counseling decisions for breastfeeding individuals. To improve risk communication regarding drugs used during lactation, the U.S. Food and Drug Administration published the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, which added a narrative summary of available risk information to the lactation section of Prescribing Information (PI). Prior studies on labeling in PLLR format revealed that although HCPs found these details valuable, they regarded the narrative as too long to support decision-making during patient encounters. OBJECTIVE: This qualitative study's objective was to assess the utility of adding a concise summary to the Lactation subsection of PI to complement the narrative and succinctly communicate to busy HCPs a drug's risks when used during lactation. The concise summary consisted of a bolded headline, bulleted descriptions of available study findings and potential adverse reactions, and recommendations for risk mitigation. METHODS: Twenty-five online focus groups were conducted with five segments of HCPs to obtain their feedback on the concise summary and discuss their prescribing/counseling decisions for four fictitious prescription drugs including one vaccine. RESULTS: HCPs utilized the concise summary to make initial prescribing/counseling decisions. Many also used the labeling narrative for a comprehensive benefit-risk assessment. CONCLUSION: The findings indicate a need to continue to improve communication about safety of drugs used during lactation, and that the concise summary may help facilitate this communication. The study also highlights the need to educate HCPs about PI limitations when clinical data are lacking and the need to encourage clinical studies to be conducted to support actionable recommendations about use of prescription drugs during lactation.

Key Findings from Mental Health Research During the Menopause Transition for Racially and Ethnically Minoritized Women Living in the United States: A Scoping Review.

Background: Racially and ethnically minoritized (REM) women experience social and structural factors that may affect their response to mental health treatment and menopausal symptoms during the menopause transition (MT). This scoping review on mental health during the MT for REM women in the United States was conducted to characterize factors associated with mental health challenges. Materials and Methods: Five databases were searched. Articles were included if focused on MT in REM women in the United States and its territories with specific mental illnesses and published in English from 2005 to 2021. Titles and abstracts and full text were screened. Screening and data collection were completed in duplicate by two reviewers in Covidence. Results: Sixty-five articles were included and indicate that REM women experience a disproportionate burden of depressive symptoms during the MT. Less evidence is reported about anxiety, Post-Traumatic Stress Disorder, psychosis, schizophrenia, and other mental illnesses. The risk factors associated with mental illness during MT are social, structural, and biological. Treatment response to therapeutic interventions is often underpowered to explain REM differences. Conclusion: Depression during the MT is associated with negative outcomes that may impact REM women differentially. Incorporating theoretical frameworks (e.g., intersectionality, weathering) into mental health research will reduce the likelihood that scientists mislabel race as the cause of these inequities, when racism and intersecting systems of oppression are the root causes of differential expression of mental illness among REM women during the MT. There is a need for interdisciplinary research to advance the mental health of REM women.

Pharmacokinetic Evaluation in Pregnancy-Current Status and Future Considerations: Workshop Summary.

As pregnant individuals have traditionally been excluded from clinical trials, there is a gap in knowledge at the time of drug approval regarding safety, efficacy, and appropriate dosing for most prescription medications used during pregnancy. Physiologic changes in pregnancy can result in changes in pharmacokinetics that can impact safety or efficacy. This highlights the need to foster further research and collection of pharmacokinetic data in pregnancy to ensure appropriate drug dosing in pregnant individuals. Therefore, the US Food and Drug Administration and the University of Maryland Center of Excellence in Regulatory Science and Innovation hosted a workshop on May 16 and 17, 2022, titled "Pharmacokinetic Evaluation in Pregnancy." This is a summary of the workshop proceedings.

Evaluation of the fish acute toxicity test for pesticide registration.

The U.S. Environmental Protection Agency (USEPA) uses the in vivo fish acute toxicity test to assess potential risk of substances to non-target aquatic vertebrates. The test is typically conducted on a cold and a warm freshwater species and a saltwater species for a conventional pesticide registration, potentially requiring upwards of 200 or more fish. A retrospective data evaluation was conducted to explore the potential for using fewer fish species to support conventional pesticide risk assessments. Lethal concentration 50% (LC50) values and experimental details were extracted and curated from 718 studies on fish acute toxicity submitted to USEPA. The LC50 data were analysed to determine, when possible, the relative sensitivity of the tested species to each pesticide. One of the tested freshwater species was most sensitive in 85% of those cases. The tested cold freshwater species was the most sensitive overall among cases with established relative sensitivity and was within 3X of the LC50 value of the most sensitive species tested in 98% of those cases. The results support potentially using fewer than three fish species to conduct ecological risk assessments for the registration of conventional pesticides.

Implementing community-engaged ecological research in Proctor Creek, an urban watershed in Atlanta, Georgia, USA.

The Southeast Region of the United States Fish and Wildlife Service (USFWS) implemented community-engaged research in Proctor Creek, an urban watershed in Northwest Atlanta, Georgia, to sample for aquatic species of concern in Atlanta, Georgia's Proctor Creek Watershed as a part of the Urban Waters Federal Partnership program. This research shifted the focus of the agency from the endangered and pristine natural spaces to a major city watershed negatively impacted by urbanization and other human influences for more than a century. Team members from USFWS, Proctor Creek Watershed residents, local students, and other stakeholders in the Urban Waters Federal Partnership (UWFP) spent three months conducting stream surveys and participating in community-led events to build relationships and learn community priorities. The team collected data at 11 sites throughout the Proctor Creek Watershed, visually assessed each site, and collected aquatic species using dip nets, seines, and traps. We observed approximately 28 aquatic species, including 13 unique fish species, and eight macroinvertebrate species, including two unique crayfish species. We also observed varying degrees of ecological health throughout the watershed. Native aquatic animal species were found at all stream sites, no matter the condition of the stream. Through creating training resources and disseminating data among team members for future sampling, the team established pathways to keep natural resource stewardship sustainable without direct federal involvement. Through engaging in community-engaged research to achieve the mission of the agency, the USFWS Proctor Creek Watershed survey helped shift the paradigm of how government agencies can connect their mission statements to the ever-changing complex needs of the American public.

Freshwater Salinization Syndrome Alters Retention and Release of 'Chemical Cocktails' along Flowpaths: from Stormwater Management to Urban Streams.

We investigate impacts of Freshwater Salinization Syndrome (FSS) on mobilization of salts, nutrients, and metals in urban streams and stormwater BMPs by analyzing original data on concentrations and fluxes of salts, nutrients, and metals from 7 urban watersheds in the Mid-Atlantic U.S. and synthesizing literature data. We also explore future critical research needs through a survey of practitioners and scientists. Our original data show: (1) sharp pulses in concentrations of salt ions and metals in urban streams directly following both road salt events and stream restoration construction (e.g., similar to the way concentrations increase during other soil disturbance activities); (2) sharp declines in pH (acidification) in response to road salt applications due to mobilization of H+ from soil exchange sites by Na+; (3) sharp increases in organic matter from microbial and algal sources (based on fluorescence spectroscopy) in response to road salt applications likely due to lysing cells and/or changes in solubility; (4) significant retention (~30-40%) of Na+ in stormwater BMP sediments and floodplains in response to salinization; (5) increased ion exchange and mobilization of diverse salt ions (Na+, Ca2+, K+, Mg2+), nutrients (N, P), and trace metals (Cu, Sr) from stormwater BMPs and restored streams in response to FSS; (6) downstream increasing loads of Cl-, SO4 2-, Br-, F-, and I- along flowpaths through urban streams, and P release from urban stormwater BMPs in response to salinization, and (7) a significant annual reduction (> 50%) in Na+ concentrations in an urban stream when road salt applications were dramatically reduced, which suggests potential for ecosystem recovery. We compared our original results to published metrics of contaminant retention and release across a broad range of stormwater management BMPs from North America and Europe. Overall, urban streams and stormwater management BMPs consistently retain Na+ and Cl- but mobilize multiple contaminants based on salt types and salinity levels. Finally, we present our top 10 research questions regarding FSS impacts on urban streams and stormwater management BMPs. Reducing diverse 'chemical cocktails' of contaminants mobilized by freshwater salinization is now a priority for effectively and holistically restoring urban waters.

Venous thromboembolism risk screening, training and provider awareness in Australian residential aged care facilities.

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in the geriatric post-surgical population, and its prevention is a public health priority. The aim of this study was to assess the use of VTE risk screening and training protocols, and VTE awareness in the Australian residential aged care sector. A cross-sectional survey was conducted that was directed at facility and policy managers of community aged care facilities with ≥10 residents in two Australian states and territories. Forty-nine of 301 (16.3%) providers responded, representing 249/871 (28.6%) aged care facilities and 20,958/66,121 (31.7%) residents. VTE risk screening protocols were used by 1.2% of facilities (3/249), and 79.5% (198/249) were unaware that VTE is an issue in this population. Only 0.8% (2/249) were aware that risk screening and prophylaxis is required to prevent VTE; none were acting upon this. No facility had specific VTE risk assessment or prevention processes in place. Most residential aged care facilities surveyed do not have VTE risk screening protocols and were unaware of the risk that may be associated with this omission. These results have implications for development and implementation of national and international VTE risk screening guidelines in community care.

Prehospital activation of a coordinated multidisciplinary hospital response in preparation for patients with severe hemorrhage: A statewide data linkage study of the New South Wales "Code Crimson" pathway.

BACKGROUND: Hemorrhage is a leading cause of preventable death in trauma. Prehospital medical teams can streamline access to massive transfusion and definitive hemorrhage control by alerting in-hospital trauma teams of suspected life-threatening bleeding in unstable patients. This study reports the initial experience of an Australian "Code Crimson" (CC) pathway facilitating early multidisciplinary care for these patients. METHODS: This data-linkage study combined prehospital databases with a trauma registry of patients with an Injury Severity Score greater than 12 between 2017 and 2019. Four groups were created; prehospital CC activation with and without in-hospital links and patients with inpatient treatment consistent with CC, without one being activated. Diagnostic accuracy was estimated using capture-recapture methodology to replace the missing cell (no prehospital CC and Injury Severity Score < 12). RESULTS: Of 72 prehospital CC patients, 50 were linked with hospital data. Of 154 potentially missed patients, 42 had a prehospital link. Most CC patients were young men who sustained blunt trauma and required more prehospital interventions than non-CC patients. Code Crimson patients had more multisystem trauma, especially complex thoracic injuries (80%), while missed CC patients more frequently had single organ injuries (59%). Code Crimson patients required fewer hemorrhage control procedures (60% vs. 86%). Lower mortality was observed in CC patients despite greater hospital and intensive care unit length of stay. Despite a low sensitivity (0.49; 95% confidence interval [CI], 0.38-0.61) and good specificity (0.92; 95% CI, 0.86-0.96), the positive likelihood ratio was acceptable (6.42; 95% CI, 3.30-12.48). CONCLUSION: The initiation of a statewide CC process was highly specific for the need for hemorrhage control intervention in hospital, but further work is required to improve the sensitivity of prehospital activation. Patients who had a CC activation sustained more multisystem trauma but had lower mortality than those who did not. These results guide measures to improve this pathway. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Urban buried streams: Abrupt transitions in habitat and biodiversity.

Stream burial, the rerouting of streams into underground culverts, is common in industrialized and densely populated urban areas. While stream burial is common in urban environments, direct characterization of the within-culvert environment is rare and it is unclear if buried reaches reflect neighboring open reaches regarding habitat, biota, and water chemistry. Additionally, for a buried stream, the entrance and exit of the culvert are abrupt habitat transitions within the stream channel, and it is unknown if these transitions lead to similarly abrupt responses in biotic and abiotic characteristics or if responses are gradual. Quantifying the within-culvert environment and transitions upon entering/exiting the culvert has rarely been done but can help inform management practices regarding how these systems are impacted and establish a baseline for evaluating daylighting or stream restoration projects. To understand how culverts affect longitudinal biotic and abiotic characteristics of urban streams, we evaluated longitudinal patterns of physical habitat characteristics, stream water physiochemistry, periphyton biomass, and macroinvertebrate density and diversity in two urban streams that included long (>100 m) culvert reaches. Abrupt transitions in a suite of abiotic and biotic variables were observed at the entrances and exits of the culverts whereas some variables showed no response to the culvert presence. Periphyton biomass and macroinvertebrate density were reduced by 98% and 92%, respectively, by culverts in the two streams. Within the culverts, we observed greater water depths (average of 10 cm outside vs 26 cm within the culvert), finer benthic substrate, and diversity of macroinvertebrates was reduced by 50%. Nutrient concentrations, in contrast, showed no response to the presence of a culvert. Within 60-90 m downstream of the culvert exits, most of the measured parameters returned to levels similar to those observed upstream of the culvert, suggesting that the ecosystem impacts of urban culverts, though dramatic, may be spatially constrained.

Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development.

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest. Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV. Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration. Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2-13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development. Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.

The contribution of wildland fire emissions to deposition in the U S: implications for tree growth and survival in the Northwest.

Ecosystems require access to key nutrients like nitrogen (N) and sulfur (S) to sustain growth and healthy function. However, excessive deposition can also damage ecosystems through nutrient imbalances, leading to changes in productivity and shifts in ecosystem structure. While wildland fires are a known source of atmospheric N and S, little has been done to examine the implications of wildland fire deposition for vulnerable ecosystems. We combine wildland fire emission estimates, atmospheric chemistry modeling, and forest inventory data to (a) quantify the contribution of wildland fire emissions to N and S deposition across the U S, and (b) assess the subsequent impacts on tree growth and survival rates in areas where impacts are likely meaningful based on the relative contribution of fire to total deposition. We estimate that wildland fires contributed 0.2 kg N ha-1 yr-1 and 0.04 kg S ha-1 yr-1 on average across the U S during 2008-2012, with maxima up to 1.4 kg N ha-1 yr-1 and 0.6 kg S ha-1 yr-1 in the Northwest representing over ~30% of total deposition in some areas. Based on these fluxes, exceedances of S critical loads as a result of wildland fires are minimal, but exceedances for N may affect the survival and growth rates of 16 tree species across 4.2 million hectares, with the most concentrated impacts occurring in Oregon, northern California, and Idaho. Understanding the broader environmental impacts of wildland fires in the U S will inform future decision making related to both fire management and ecosystem services conservation.

The Potential for Health Information Technology Tools to Reduce Racial Disparities in Maternal Morbidity and Mortality.

Health information technology (health IT) potentially is a promising vital lever to address racial and ethnic, socioeconomic, and geographic disparities in maternal morbidity and mortality (MMM). This is especially relevant given that approximately 60% of maternal deaths are considered preventable.1-36 Interventions that leverage health IT tools to target the underlying drivers of disparities at the patient, clinician, and health care system levels potentially could reduce disparities in quality of care throughout the continuum (antepartum, intrapartum, and postpartum) of maternity care. This article presents an overview of the research (and gaps) on the potential of health IT tools to document SDoH and community-level geocoded data in EHR-based CDS systems, minimize implicit bias, and improve adherence to clinical guidelines and coordinated care to inform multilevel (patient, clinician, system) interventions throughout the continuum of maternity care for health disparity populations impacted by MMM. Telemedicine models for improving access in rural areas and new technologies for risk assessment and disease management (e.g., regarding preeclampsia) also are discussed.

Social and Structural Determinants of Health Inequities in Maternal Health.

Since the World Health Organization launched its commission on the social determinants of health (SDOH) over a decade ago, a large body of research has proven that social determinants-defined as the conditions in which people are born, grow, live, work, and age-are significant drivers of disease risk and susceptibility within clinical care and public health systems. Unfortunately, the term has lost meaning within systems of care because of misuse and lack of context. As many disparate health outcomes remain, including higher risk of maternal mortality among Black women, a deeper understanding of the SDOH-and what forces underlie their distribution-is needed. In this article, we will expand our review of social determinants of maternal health to include the terms "structural determinants of health" and "root causes of inequities" as we assess the literature on this topic. We hypothesize that the addition of structural determinants and root causes will identify racism as a cause of inequities in maternal health outcomes, as many of the social and political structures and policies in the United States were born out of racism, classism, and gender oppression. We will conclude with proposed practice and policy solutions to end inequities in maternal health outcomes.

The Importance of Clinical Research in Pregnant Women to Inform Prescription Drug Labeling.

Pregnant women have historically been an understudied population and have been excluded from clinical trials. Recent efforts by stakeholders have raised awareness of the importance of clinical research in pregnant women to inform prescribing decisions. The Food and Drug Administration continues working to improve the format and content of prescription drug labeling for pregnant and lactating women, as demonstrated with the Pregnancy and Lactation Labeling Rule (PLLR), effective in 2015. The pregnancy labeling subsection now includes a subheading dedicated to the inclusion of pharmacokinetic (PK) data that inform the need for dose adjustments during pregnancy and the postpartum period. In addition, the PLLR also requires prescription drug labeling to be updated when important pregnancy information becomes available. Although PLLR improved the presentation of pregnancy-related information in labeling, there is a need to increase the quality and quantity of human data on the use of prescription drugs during pregnancy. PK studies in pregnant women should be incorporated into drug development programs and prioritized to obtain important information about safe and appropriate doses of a drug when used during pregnancy. In addition, opportunistic PK studies, postapproval pregnancy safety studies, ex vivo studies, and in silico modeling can be leveraged to better inform the risks and benefits of using a drug during pregnancy to inform study design and to further understand various mechanisms impacting pharmacokinetic/pharmacodynamic of drugs during pregnancy. It is important to address the significant existing data gaps and better inform the safety and dosing of prescription drugs for pregnant women.

Preventing Perinatal Depression Now: A Call to Action.

In the United States, perinatal depression (PD) affects an estimated 11.5% of pregnant and postpartum individuals annually and is one of the most common complications of pregnancy and the postpartum period. Alarmingly, up to 51% of people with PD are undiagnosed. Despite the availability of tools to screen for PD, there is no consensus on which tool is most accurate, nor is there a universal policy on when and how to best screen patients with PD. Screening to identify PD is essential, but prevention of depression is even more critical, yet traditionally not well addressed until recently with the US Preventive Services Task Force (USPSTF) recommendation in 2019. When the USPSTF recommended implementing programs to prevent PD in at-risk individuals, the recommendation cited two evidence-based PD prevention programs by name. One of these, ROSE (Reach Out, Stay Strong, Essentials for mothers of newborns), is a four-session class taught in prenatal settings. The second program mentioned is the Mothers and Babies program, which has been shown to be effective in using a cognitive behavioral therapy approach to prevent PD. Although scientists develop effective mental health interventions to prevent PD, community-based advocacy groups are engaged in grassroots efforts to provide support and encouragement to racially and ethnically diverse pregnant and postpartum women. To increase the number of pregnant and postpartum women who are screened and supported so that they do not develop PD, research supports three key strategies: (1) Establish a standard combination of multicultural PD screening tools with evidence-based timepoints for screening administration. (2) Introduce an evidence-based definition of PD that accurately captures the prevalence and incidence of this mental health condition. (3) Improve our understanding of PD by incorporating the psychosocial context in which mental health complications occur into routine clinical practice for pregnant and postpartum women.

Clinicians' Perspective of the New Pregnancy and Lactation Labeling Rule (PLLR): Results from an AAAAI/FDA Survey.

BACKGROUND: On June 30, 2015, the US Food and Drug Administration (FDA) began implementation of the Pregnancy and Lactation Labeling Rule (PLLR), which replaced the pregnancy letter category system (A, B, C, D, and X) with integrated narrative summaries of the risks of using a drug or biological product during pregnancy and lactation. The letter category system, first established in 1979, was regarded as overly simplistic and misinterpreted as a grading system. The PLLR labeling format was created to improve the presentation of available data on use of the drug during pregnancy and/or lactation. OBJECTIVE: To survey clinician awareness, assessment, and use of this new labeling format. METHODS: In January 2018, an online survey, developed in collaboration between the American Academy of Allergy, Asthma & Immunology and the FDA, was sent to a random sample of the US membership of the American Academy of Allergy, Asthma & Immunology. The survey content consisted of questions addressing the following: demographic characteristics, awareness and use of the PLLR, and value and understanding of the PLLR format on the basis of an example of the "Pregnancy" subsection of labeling. RESULTS: Of the 1500 members who received the survey via an email, 184 (12%) completed the survey. Respondents had a mean age of 56 years and treated on average 2 pregnant women per month. Less than half (46%) of the respondents were aware that the pregnancy letter category system was replaced with a narrative summary. After reading the example, most of the respondents (68%) did not feel that the narrative summary was concise. However, 71% of the respondents found the background risk and disease-associated risk information helpful. Most of the respondents (95%) continued to use the pregnancy letter category system to make prescribing decisions. CONCLUSIONS: These survey results suggest that the PLLR format was not known by most prescribers and that the pregnancy letter category format is continuing to be used despite significant flaws in the old system. However, the survey did not address why prescribers were continuing to rely on the pregnancy letter category system. Whether this is due to the PLLR format itself or the lack of quality data to inform the safe use of medications in pregnancy cannot be determined from these survey results. The FDA will use these survey results to refine the communication of pregnancy safety information in labeling and will expand outreach efforts to educate health care providers in the new labeling system.

Making 'Chemical Cocktails' - Evolution of Urban Geochemical Processes across the Periodic Table of Elements.

Urbanization contributes to the formation of novel elemental combinations and signatures in terrestrial and aquatic watersheds, also known as 'chemical cocktails.' The composition of chemical cocktails evolves across space and time due to: (1) elevated concentrations from anthropogenic sources, (2) accelerated weathering and corrosion of the built environment, (3) increased drainage density and intensification of urban water conveyance systems, and (4) enhanced rates of geochemical transformations due to changes in temperature, ionic strength, pH, and redox potentials. Characterizing chemical cocktails and underlying geochemical processes is necessary for: (1) tracking pollution sources using complex chemical mixtures instead of individual elements or compounds; (2) developing new strategies for co-managing groups of contaminants; (3) identifying proxies for predicting transport of chemical mixtures using continuous sensor data; and (4) determining whether interactive effects of chemical cocktails produce ecosystem-scale impacts greater than the sum of individual chemical stressors. First, we discuss some unique urban geochemical processes which form chemical cocktails, such as urban soil formation, human-accelerated weathering, urban acidification-alkalinization, and freshwater salinization syndrome. Second, we review and synthesize global patterns in concentrations of major ions, carbon and nutrients, and trace elements in urban streams across different world regions and make comparisons with reference conditions. In addition to our global analysis, we highlight examples from some watersheds in the Baltimore-Washington DC region, which show increased transport of major ions, trace metals, and nutrients across streams draining a well-defined land-use gradient. Urbanization increased the concentrations of multiple major and trace elements in streams draining human-dominated watersheds compared to reference conditions. Chemical cocktails of major and trace elements were formed over diurnal cycles coinciding with changes in streamflow, dissolved oxygen, pH, and other variables measured by high-frequency sensors. Some chemical cocktails of major and trace elements were also significantly related to specific conductance (p<0.05), which can be measured by sensors. Concentrations of major and trace elements increased, peaked, or decreased longitudinally along streams as watershed urbanization increased, which is consistent with distinct shifts in chemical mixtures upstream and downstream of other major cities in the world. Our global analysis of urban streams shows that concentrations of multiple elements along the Periodic Table significantly increase when compared with reference conditions. Furthermore, similar biogeochemical patterns and processes can be grouped among distinct mixtures of elements of major ions, dissolved organic matter, nutrients, and trace elements as chemical cocktails. Chemical cocktails form in urban waters over diurnal cycles, decades, and throughout drainage basins. We conclude our global review and synthesis by proposing strategies for monitoring and managing chemical cocktails using source control, ecosystem restoration, and green infrastructure. We discuss future research directions applying the watershed chemical cocktail approach to diagnose and manage environmental problems. Ultimately, a chemical cocktail approach targeting sources, transport, and transformations of different and distinct elemental combinations is necessary to more holistically monitor and manage the emerging impacts of chemical mixtures in the world's fresh waters.