Integrated Approach for Testing and Assessment for Developmental Neurotoxicity (DNT) to Prioritize Aromatic Organophosphorus Flame Retardants.

Organophosphorus flame retardants (OPFRs) are abundant and persistent in the environment but have limited toxicity information. Their similarity in structure to organophosphate pesticides presents great concern for developmental neurotoxicity (DNT). However, current in vivo testing is not suitable to provide DNT information on the amount of OPFRs that lack data. Over the past decade, an in vitro battery was developed to enhance DNT assessment, consisting of assays that evaluate cellular processes in neurodevelopment and function. In this study, behavioral data of small model organisms were also included. To assess if these assays provide sufficient mechanistic coverage to prioritize chemicals for further testing and/or identify hazards, an integrated approach to testing and assessment (IATA) was developed with additional information from the Integrated Chemical Environment (ICE) and the literature. Human biomonitoring and exposure data were identified and physiologically-based toxicokinetic models were applied to relate in vitro toxicity data to human exposure based on maximum plasma concentration. Eight OPFRs were evaluated, including aromatic OPFRs (triphenyl phosphate (TPHP), isopropylated phenyl phosphate (IPP), 2-ethylhexyl diphenyl phosphate (EHDP), tricresyl phosphate (TMPP), isodecyl diphenyl phosphate (IDDP), tert-butylphenyl diphenyl phosphate (BPDP)) and halogenated FRs ((Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), tris(2-chloroethyl) phosphate (TCEP)). Two representative brominated flame retardants (BFRs) (2,2'4,4'-tetrabromodiphenyl ether (BDE-47) and 3,3',5,5'-tetrabromobisphenol A (TBBPA)) with known DNT potential were selected for toxicity benchmarking. Data from the DNT battery indicate that the aromatic OPFRs have activity at similar concentrations as the BFRs and should therefore be evaluated further. However, these assays provide limited information on the mechanism of the compounds. By integrating information from ICE and the literature, endocrine disruption was identified as a potential mechanism. This IATA case study indicates that human exposure to some OPFRs could lead to a plasma concentration similar to those exerting in vitro activities, indicating potential concern for human health.

Hyperspectral dark-field microscopy of human breast lumpectomy samples for tumor margin detection in breast-conserving surgery.

Significance: Hyperspectral dark-field microscopy (HSDFM) and data cube analysis algorithms demonstrate successful detection and classification of various tissue types, including carcinoma regions in human post-lumpectomy breast tissues excised during breast-conserving surgeries. Aim: We expand the application of HSDFM to the classification of tissue types and tumor subtypes in pre-histopathology human breast lumpectomy samples. Approach: Breast tissues excised during breast-conserving surgeries were imaged by the HSDFM and analyzed. The performance of the HSDFM is evaluated by comparing the backscattering intensity spectra of polystyrene microbead solutions with the Monte Carlo simulation of the experimental data. For classification algorithms, two analysis approaches, a supervised technique based on the spectral angle mapper (SAM) algorithm and an unsupervised technique based on the K-means algorithm are applied to classify various tissue types including carcinoma subtypes. In the supervised technique, the SAM algorithm with manually extracted endmembers guided by H&E annotations is used as reference spectra, allowing for segmentation maps with classified tissue types including carcinoma subtypes. Results: The manually extracted endmembers of known tissue types and their corresponding threshold spectral correlation angles for classification make a good reference library that validates endmembers computed by the unsupervised K-means algorithm. The unsupervised K-means algorithm, with no a priori information, produces abundance maps with dominant endmembers of various tissue types, including carcinoma subtypes of invasive ductal carcinoma and invasive mucinous carcinoma. The two carcinomas' unique endmembers produced by the two methods agree with each other within <2% residual error margin. Conclusions: Our report demonstrates a robust procedure for the validation of an unsupervised algorithm with the essential set of parameters based on the ground truth, histopathological information. We have demonstrated that a trained library of the histopathology-guided endmembers and associated threshold spectral correlation angles computed against well-defined reference data cubes serve such parameters. Two classification algorithms, supervised and unsupervised algorithms, are employed to identify regions with carcinoma subtypes of invasive ductal carcinoma and invasive mucinous carcinoma present in the tissues. The two carcinomas' unique endmembers used by the two methods agree to <2% residual error margin. This library of high quality and collected under an environment with no ambient background may be instrumental to develop or validate more advanced unsupervised data cube analysis algorithms, such as effective neural networks for efficient subtype classification.

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.

Child Health Needs and the Pediatric Endocrinology Workforce: 2020-2040.

The pediatric endocrinology (PE) workforce in the United States is struggling to sustain an adequate, let alone optimal, workforce capacity. This article, one of a series of articles in a supplement to Pediatrics, focuses on the pediatric subspecialty workforce and furthers previous evaluations of the US PE workforce to model the current and future clinical PE workforce and its geographic distribution. The article first discusses the children presenting to PE care teams, reviews the current state of the PE subspecialty workforce, and presents projected headcount and clinical workforce equivalents at the national, census region, and census division level on the basis of a subspecialty workforce supply model through 2040. It concludes by discussing the educational and training, clinical practice, policy, and future workforce research implications of the data presented. Data presented in this article are available from the American Board of Pediatrics, the National Resident Matching Program, and the subspecialty workforce supply model. Aging, part-time appointments, and unbalanced geographic distribution of providers diminish the PE workforce capacity. In addition, limited exposure, financial concerns, and lifestyle perceptions may impact trainees. Additional workforce challenges are the subspecialty's increasingly complex cases and breadth of conditions treated, reliance on international medical graduates to fill fellowship slots, and high relative proportion of research careers. The recent limitations on pediatric endocrinologists providing gender-affirming care may also impact the geographic distribution of the subspecialty's workforce. Deliberate actions need to be taken now to continue serving the needs of children.

Guidance for Pharmacy Curricula to Incorporate Health, Wellness, and Health Inequities Stemming From Climate Change: The Report of the 2022-2023 AACP Argus Commission.

The 2022-2023 American Association of College of Pharmacy Argus Commission was charged to provide guidance to schools, curriculum committees, and faculty on how to incorporate health, wellness, and health inequities stemming from climate change into pharmacy curricula. The Argus Commission does not advocate for major changes in the curriculum or standards but suggests a concerted effort across the Academy to enhance the awareness of graduating students of the potential impact of climate change on health both now and in the future. Various examples, along with recommendations and suggestions, are provided of how the impact of climate change on health is currently being integrated into curricula in member schools, as well as a list of resources faculty can use to enhance their awareness of issues related to climate change and health. The Commission was also charged to provide guidance to the American Association of College of Pharmacy regarding future fundraising and business development opportunities. Recommendations in that regard are also included in this report.

Evaluation of cost data associated with pediatric cochlear implantation (CI) throughout 2016-2021.

INTRODUCTION: Cochlear Implants (CI) are a mainstay in the treatment of severe sensorineural hearing loss with proven cost-effectiveness and improved quality of life. However, costs associated with CI are variable. During the Covid-19 pandemic, elective surgeries decreased. The investigation into how the pandemic affected CI procedures, costs, and demographic utilization has not been elucidated. METHODS: A retrospective cohort study using the Pediatric Health Information System® (PHIS) database, which consists of 50 children's hospitals, was performed. Regions were defined according to PHIS guidelines. We evaluated number of CIs, total charges and costs, Charge to Cost Ratios (CCR), demographic information, and subgrouped this analysis by region throughout 2016-2021. Charges were adjusted by CMS wage index for hospital location. RESULTS: During the years of 2016-2021, there was a rising number of CIs every year except for 2020 which had a decrease, largely driven by the southern and midwestern regions. The median number of cases did not differ between the years. The median adjusted charges increased every year, but not significantly ($103,883-$125,394). The median CCR also did not differ throughout the years (2.7-3.1). Still, there was a larger interquartile range in 2021 (2.3-4.4) for the median CCR compared to all other years (2.1-3.8), particularly in the South. The percentage of white, non-Hispanic/Latino patients who underwent CI was larger in 2020-2021 (78-79.8 %) compared to 2016-2019 (73.3-77.5 %). CONCLUSIONS: The number of CIs in 2020 was lower than in 2019 or 2021. The median CCR for CI procedures increased from 2016 to 2021 but not significantly. The range of CCR was larger in 2021 compared to the years prior, suggestive of cost shifting by some hospitals to offset the loss in revenue. There was a small but significant increase in white, non-Hispanic patients receiving CI in 2020 and 2021, suggestive of a socio-economic shift in care post pandemic.

IVIVE: Facilitating the Use of In Vitro Toxicity Data in Risk Assessment and Decision Making.

During the past few decades, the science of toxicology has been undergoing a transformation from observational to predictive science. New approach methodologies (NAMs), including in vitro assays, in silico models, read-across, and in vitro to in vivo extrapolation (IVIVE), are being developed to reduce, refine, or replace whole animal testing, encouraging the judicious use of time and resources. Some of these methods have advanced past the exploratory research stage and are beginning to gain acceptance for the risk assessment of chemicals. A review of the recent literature reveals a burst of IVIVE publications over the past decade. In this review, we propose operational definitions for IVIVE, present literature examples for several common toxicity endpoints, and highlight their implications in decision-making processes across various federal agencies, as well as international organizations, including those in the European Union (EU). The current challenges and future needs are also summarized for IVIVE. In addition to refining and reducing the number of animals in traditional toxicity testing protocols and being used for prioritizing chemical testing, the goal to use IVIVE to facilitate the replacement of animal models can be achieved through their continued evolution and development, including a strategic plan to qualify IVIVE methods for regulatory acceptance.

Defining a Patient-Centred Core Outcome Domain Set for the Assessment of Hearing Rehabilitation With Clients and Professionals.

Background: A variety of outcome domains are currently measured for the assessment of hearing rehabilitation. To date, there is no consensus about which outcome domains should be measured, when they should be measured, and how they should be measured. In addition, most studies seeking to develop core outcome sets and measures for hearing rehabilitation services have primarily focussed on the opinions and expertise of researchers, and, to a lesser extent, clinicians, rather than also involving clients of those services. The principles of experience-based co-design suggest that health services, researchers, and policymakers should come together with clients and their families to design health services and define what metrics should be used for their success. Objectives: This study aimed to seek views and consensus from a range of key stakeholders to define which client-centred self-report outcome domains should be measured, when they should be measured, and how they should be measured, in a national publicly funded hearing rehabilitation scheme. In addition, the study aimed to identify current and future potential mechanisms and systems to standardise the collection of data and reporting of outcomes, to enable comparison across clients and hearing service providers. Methods: Two stakeholder groups participated in a three-round online Delphi process: (1) 79 professional stakeholders involved in the delivery of hearing services in Australia, and (2) 64 hearing rehabilitation services' clients identified by not-for-profit consumer organisations. An initial set of in-person workshops scoped the key issues upon which to develop the initial open-ended questions and subsequent Likert-scale statements addressing these issues. These statements were then distributed to both groups in an online survey. The respondent ratings were summarised, and the summary was returned to respondents along with a second round of the survey. This process was then repeated once more. The five most important outcome domains from both groups were then combined, and a consensus workshop of seven professionals and three client advocates agreed on the top four ranked domains. Results: A range of potential outcome domains were identified as relevant indicators of successful hearing rehabilitation. Communication ability, personal relationships, wellbeing, and participation restrictions were identified as a core outcome domain set that should be measured as a minimum for patients receiving hearing rehabilitation. There was little agreement on the preferred timepoints for collection of outcome measures, with respondents expressing the view that this should be established by research once a set of outcome measures has been selected. However, there was broad agreement that measurements of these domains should be collected at baseline (before the provision of hearing rehabilitation) and no earlier than 3 months following the completion of rehabilitation. Potential benefits and issues with the development of a national outcomes database/collection system were also identified and prioritised, with participants highlighting the importance of valid, high-quality, trustworthy, and comprehensive data collection. Conclusion: These results provide a Core Outcome Domain Set for the self-reported evaluation of hearing rehabilitation and provide important background information for the design of methods to implement them across hearing healthcare systems. However, the wide range of outcome domains identified as potentially providing important additional information and the lack of specific measures to address these domains strongly suggest that there is still more research to be done. Ongoing stakeholder engagement will continue to be vital for future implementation. In addition, further research is required to determine the optimal time following hearing rehabilitation to utilise any particular outcome measure.

The multidisciplinary team severe asthma day case assessment and its impact on patient care.

People with severe and difficult to control asthma can be a complex and heterogenous group of patients often with multiple comorbidities. Living with this disease imposes a huge physical and psychological burden upon the patient which requires a comprehensive, systematic and patient-focused assessment, using a wide range of clinical expertise from within the multidisciplinary team. This article describes a severe asthma systematic and multidimensional day case assessment, and the positive benefits that the authors perceive it offers for patient care. These benefits include a confirmed diagnosis, consideration of alternative diagnosis, enhanced adherence, medication optimisation, access to and gatekeeping of high-cost specialist medications, improved patient self-management skills and signposting to appropriate therapies. As a consequence, they believe that this facilitates better patient outcomes through a reduction in corticosteroid exposure, exacerbations and hospitalisation. This severe asthma multidisciplinary team day case approach offers more than just physical benefits when compared with the traditional medical model. Patient feedback reports an excellent patient experience, feeling listened to, understood, empowered and hopeful for the future.

Comorbidity Burden and Adverse Outcomes After Transcatheter Aortic Valve Replacement.

Background Transcatheter aortic valve replacement (TAVR) has become the preferred treatment for symptomatic patients with aortic stenosis and elevated procedural risk. Many deaths following TAVR are because of noncardiac causes and comorbid disease burden may be a major determinant of postprocedure outcomes. The prevalence of comorbid conditions and associations with outcomes after TAVR has not been studied. Methods and Results This was a retrospective single-center study of patients treated with TAVR from January 2015 to October 2018. The association between 21 chronic conditions and short- and medium-term outcomes was assessed. A total of 341 patients underwent TAVR and had 1-year follow-up. The mean age was 81.4 (SD 8.0) years with a mean Society of Thoracic Surgeons predicted risk of mortality score of 6.7% (SD 4.8). Two hundred twenty (65%) patients had ≥4 chronic conditions present at the time of TAVR. There was modest correlation between Society of Thoracic Surgeons predicted risk of mortality and comorbid disease burden (r=0.32, P<0.001). After adjusting for Society of Thoracic Surgeons predicted risk of mortality, age, and vascular access, each additional comorbid condition was associated with increased rates of 30-day rehospitalizations (odds ratio, 1.21; 95% CI, 1.02-1.44), a composite of 30-day rehospitalization and 30-day mortality (odds ratio, 1.20; 95% CI, 1.02-1.42), and 1-year mortality (odds ratio, 1.29; 95% CI, 1.05-1.59). Conclusions Comorbid disease burden is associated with worse clinical outcomes in high-risk patients treated with TAVR. The risks associated with comorbid disease burden are not adequately captured by standard risk assessment. A systematic assessment of comorbid conditions may improve risk stratification efforts.

Assessment of the effects of straw burning bans in China: Emissions, air quality, and health impacts.

Open biomass burning (OBB) plays an important role in air pollution and climate change by releasing short-term but intensive amounts of particulate matter and gaseous air pollutants. During past years, policies with respect to prohibition on open straw burning have been issued in China in order to mitigate the air pollution problems and the effectiveness of these straw burning bans in different regions remains to be evaluated. In this study, open crop straw burning (OCSB) emissions during 2010-2018 were analyzed based on a commonly used emission inventory with high spatial and temporal resolution. High emissions concentrated over Northeast China (31.8% of national total PM2.5 emissions in 2018), East China (24.0%), and North China (16.6%). Simulations based on an integrated meteorology-air quality modeling system and an exposure-response function show that OCSB emissions could increase monthly PM2.5 concentration by as much as 10 µg/m3 during burning seasons in Northeast China and were associated with 4741 premature deaths in 2018. Spatial heterogeneities were observed with respect to the trends of OCSB emissions during 2010-2018. In East China, North China, and Central China, OCSB emissions showed a general declining trend since 2013 while an opposing increasing trend was observed in Northeast China with peak emissions in 2017. Comparing 2013 (before intensive implementation of straw burning bans) and 2018 (after), national total PM2.5 emissions from OCSB activities decreased by 46.9%, ranging from -14.1% to +70% depending on the specific regions. Northeast China is the only region that showed higher OCSB emissions in 2018 compared to 2013, probably associated with the relatively delayed implementation of the straw burning bans. Avoided number of premature deaths due to reduced OCSB emissions was estimated to be 4256 on a national scale, with most health benefits gained in East and Central China. Results from this study demonstrate the importance of OCSB contribution to PM2.5 concentrations and spatial heterogeneities exist in terms of the effectiveness of the straw burning bans in reducing OCSB emissions and gained health benefits.

Responding to COVID-19: how an academic infectious diseases division mobilized in Singapore.

BACKGROUND: On January 30, COVID-19 was declared a Public Health Emergency of International Concern-a week after Singapore's first imported case and 5 days before local transmission. The National University Hospital (NUH) is Singapore's third largest hospital with 1200 beds, heavy clinical workloads, and major roles in research and teaching. MAIN BODY: With memories of SARS still vivid, there was an urgent requirement for the NUH Division of Infectious Diseases to adapt-undergoing major reorganization to face rapidly changing priorities while ensuring usual essential services and standards. Leveraging on individual strengths, our division mobilized to meet the demands of COVID-19 while engaging in high-level coordination, strategy, and advocacy. We present our experience of the 60 days since the nation's first case. During this time, our hospital has managed 3030 suspect cases, including 1300 inpatients, 37 confirmed cases, and overseen 4384 samples tested for COVID-19. CONCLUSION: Complex hospital adaptations were supported by an unprecedented number of workflows and coordination channels essential to safe and effective operations. The actions we describe, aligned with international recommendations and emerging evidence-based best practices, may serve as a framework for other divisions and institutions facing the spread of COVID-19 globally.

Systematic Assessment of Difficult-to-Treat Asthma: Principles and Perspectives.

Difficult-to-treat asthma affects a minority of adults and children with asthma but represents a challenging mix of misdiagnosis, multimorbidity, inadequate self-management, severe airway pathobiology, and treatment complications. Management of these patients extends beyond asthma pharmacotherapy, because multiple other patient-related domains need to be addressed as well. Such complexity can hinder adequate clinical assessment even when performed in specialist practice. Systematic assessment undertaken by specialized multidisciplinary teams brings a broad range of resources to bear on patients with difficult-to-treat asthma. Although the concept of systematic assessment is not new, practices vary considerably and implementation is not universal. Nevertheless, assessment protocols are already in place in several institutions worldwide, and outcomes after such assessments have been highly encouraging. This review discusses the rationale, components, and benefits of systematic assessment, outlining its clinical utility and the available evidence for improved outcomes. It describes a range of service configurations and assessment approaches, drawing examples from severe asthma centers around the world to highlight common essential elements. It also provides a framework for establishing such services and discusses practical considerations for implementation.

External quality assessment demonstrates that PD-L1 22C3 and SP263 assays are systematically different.

PD-L1 inhibitors are part of first line treatment options for patients with advanced non-small cell lung cancer. PD-L1 immunohistochemistry (IHC) assays act as either a companion or a complementary diagnostic. The purpose of this study is to describe the experience of external quality assurance (EQA) provider UK NEQAS ICC and ISH with the comparison of different PD-L1 assays used in daily practice. Three EQA rounds (pilot, run A and run B) were carried out using formalin fixed paraffin embedded samples with sample sets covering a range of epitope concentrations, including 'critical samples' near to clinical threshold cut-offs. An expert panel (n = 4) evaluated all returned slides simultaneously and independently on a multi-header microscope together with the participants own in-house control material. The tonsil sample was evaluated as 'acceptable' or 'unacceptable', and for the other samples the percentage of PD-L1 stained tumour cells were estimated in predetermined categories (<1%, 1 to <5%, 5 to <10%, 10 to <25%, 25 to <50%, 50 to <80%, 80 to 100%). In the pilot and the two subsequent runs the number of participating laboratories was 43, 69 and 76, respectively. The pass rate for the pilot run was 67%; this increased to 81% at run A and 82% at run B. For two 'critical samples', in runs A and B, 22C3 IHC had significantly higher PD-L1 expression than SP263 IHC (p < 0.001), whilst the PD-L1 scores for the other six samples were similar for all assays. In run A the laboratory developed tests (LDTs) using 22C3 scored lower than the commercial 22C3 tests (p = 0.01). After the initial testing, improvement in performance of PD-L1 IHC is shown for approved and LDT PD-L1 assays. Equivalency of approved PD-L1 22C3 and SP263 assays cannot be assumed as the scores cross the clinically relevant thresholds of 1% and 50% PD-L1 expression.

Clinical Decision Support to Reduce Contrast-Induced Kidney Injury During Cardiac Catheterization: Design of a Randomized Stepped-Wedge Trial.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a common and serious complication of invasive cardiac procedures. Quality improvement programs have been associated with a lower incidence of CI-AKI over time, but there is a lack of high-quality evidence on clinical decision support for prevention of CI-AKI and its impact on processes of care and clinical outcomes. METHODS: The Contrast-Reducing Injury Sustained by Kidneys (Contrast RISK) study will implement an evidence-based multifaceted intervention designed to reduce the incidence of CI-AKI, encompassing automated identification of patients at increased risk for CI-AKI, point-of-care information on safe contrast volume targets, personalized recommendations for hemodynamic optimization of intravenous fluids, and follow-up information for patients at risk. Implementation will use cardiologist academic detailing, computerized clinical decision support, and audit and feedback. All 31 physicians practicing in all 3 of Alberta's cardiac catheterization laboratories will participate using a cluster-randomized stepped-wedge design. The order in which they are introduced to this intervention will be randomized within 8 clusters. The primary outcome is CI-AKI incidence, with secondary outcomes of CI-AKI avoidance strategies and downstream adverse major kidney and cardiovascular events. An economic evaluation will accompany the main trial. CONCLUSIONS: The Contrast RISK study leverages information technology systems to identify patient risk combined with evidence-based protocols, audit, and feedback to reduce CI-AKI in cardiac catheterization laboratories across Alberta. If effective, this intervention can be broadly scaled and sustained to improve the safety of cardiac catheterization.

Cost-Conscious Growth-Promoting Treatment: When Discretion Is the Better Part of Value.

Assessing cost-effectiveness of human growth hormone (hGH) treatment to augment height is complicated by uncertainty about how best to measure its therapeutic effect. Cost-conscious growth promotion practice, however, is possible and likely an emerging practical requisite as health care payers increasingly deny the medical necessity of and restrict support for short stature treatment. The increase in denials is not surprising given the expansion and continued high cost of hGH treatment, debate about the value of such treatment, and universal need to restrain burgeoning health care costs. Renunciation of sweeping payer rejection of hGH-for-height treatment is strengthened by cost-conscious practices that (1) recommend no treatment for most short children and restrict treatment to severe, likely disabling short stature; (2) initiate hGH treatment only after evidence-based informed assent; (3) utilize alternative less costly and less invasive options when possible; (4) minimize hGH treatment duration and dosage; and (5) resist enhancement of normal adult stature. A new era of cost-conscious hGH prescribing that prompts thoughtful restraint in hGH use could help preserve hGH approval for children most in need of treatment.

Toward More Targeted and Cost-Effective Gonadotropin-Releasing Hormone Analog Treatment in Girls with Central Precocious Puberty.

The use of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of central precocious puberty (CPP), especially in girls, has increased rapidly in recent years. In the context of a secular trend towards earlier puberty onset, many girls now treated for CPP are healthy children experiencing puberty onset within the early end of the normal range. Justifications for GnRHa treatment include the preservation of adult height (AH) potential and the alleviation of presumed distress of early maturation and menarche. With a case of a family requesting treatment for an 8-year-old girl in early puberty as a background, studies of the effect of untreated CPP and of GnRHa treatment of CPP on AH are reviewed. In addition, the limited evidence relating CPP to significant psychological distress - in part due to early menses, and for the amelioration of such distress by GnRHa treatment - is discussed. Taken together, current information suggests that for girls with mildly early onset of puberty (ages 7-9 years), an informed assent discussion with the family should include the consideration of reassurance and observation for many girls who might otherwise receive 2-4 years of GnRHa treatment for a poorly defined benefit and at a cost of at least $20-30,000 per year.

Assessment of methane emissions from the U.S. oil and gas supply chain.

Methane emissions from the U.S. oil and natural gas supply chain were estimated by using ground-based, facility-scale measurements and validated with aircraft observations in areas accounting for ~30% of U.S. gas production. When scaled up nationally, our facility-based estimate of 2015 supply chain emissions is 13 ± 2 teragrams per year, equivalent to 2.3% of gross U.S. gas production. This value is ~60% higher than the U.S. Environmental Protection Agency inventory estimate, likely because existing inventory methods miss emissions released during abnormal operating conditions. Methane emissions of this magnitude, per unit of natural gas consumed, produce radiative forcing over a 20-year time horizon comparable to the CO2 from natural gas combustion. Substantial emission reductions are feasible through rapid detection of the root causes of high emissions and deployment of less failure-prone systems.