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Abstract: Rare bleeding disorders can cause significant bleeding in children and adolescents. These encompass rare clotting factor deficiencies, and fibrinolytic pathway defects. Vascular anomalies can cause recurrent and refractory bleeding, and are included in this review of rare causes of abnormal bleeding in children and adolescents. Menorrhagia is often reported as a manifestation of these conditions. Succinct knowledge about these disorders, their clinical presentation, diagnostic work-up, and therapeutic options are crucial to the accurate diagnosis and optimal management of affected patients. This review provides an overview of these infrequently encountered disorders, discusses their recognition based on results of suggested screening tests and offers a general guideline for approach to therapy. [Copyright &y& Elsevier]

Venous thromboembolism (VTE) is increasingly diagnosed in pediatric patients, and anticoagulantusein thispopulationhas become common, despite the absence of US Food and Drug Administration (FDA) approval for this indication. Guidelines for the use of anticoagulants in pediatrics are largely extrapolated from large randomized controlled trials (RCTs) in adults, smaller dose-finding and observational studies in children, and expert opinion. The recently FDA-approved direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, apixaban, and edoxaban, provide potential advantages over oral vitamin K antagonists and subcutaneous low-molecular-weight heparins (LMWHs). However, key questions arise regarding their potential off-label clinical application inpediatric thromboembolic disease. In this Perspective, we provide background on the use of LMWHs such as enoxaparin as the main stay of treatment of pediatric provoked VTE; identify key questions and challenges with regard to DOAC trials and future DOAC therapy in pediatric VTE; and discuss applicable lessons learned from the recent pilot/feasibility phase of a large multicenter RCT of anticoagulant duration in pediatric VTE. The challenges and lessons learned present opportunities to improve evidence for anticoagulant therapies in pediatric VTE through future clinical trials. [ABSTRACT FROM AUTHOR]

Study Objective To compare the efficacy of oral tranexamic acid (TA) with combined oral contraceptives (COC) in reducing menstrual blood loss (MBL) and improving quality of life in adolescent heavy menstrual bleeding (HMB). Design, Setting, and Participants A prospective randomized crossover trial with 17 postmenarchal girls aged 21 years and younger with HMB who were seen at our institution. Interventions Patients were randomized to group A (TA arm) or group B (COC arm), each for 3 cycles, with crossover to the second arm after 1-month washout. Main Outcome Measures The primary end points were difference in improvement in MBL and QOL, from baseline to end of each therapy. Results Seventeen patients were enrolled (mean age 14.2 years, range 11.7 to 16.8 years). Nine patients completed both arms; 8 patients withdrew from the study due to adverse events or noncompliance. Compared with baseline, significant improvement ( P < .05) was demonstrated by TA and COC in MBL (mean Pictorial Blood Assessment Chart score decrease: TA, 536.4; COC, 430.6) and quality of life (mean Pediatric Quality of Life Inventory TM version 4.0 Generic Scales score increase: TA, 15.6; COC, 16.75), but no significant difference was noted between TA and COC ( P > .05). There was statistically significant reduction in the length of menstrual cycle for COC only (mean reduction 5.3 days; P = .04) and not for TA ( P = .18). Ten patients (58%) experienced adverse events that were possibly drug related (TA: n = 3, 30%; COCP: n = 7, 64%). Conclusion In this pilot study, oral TA appeared as efficacious as COC in the management of adolescent HMB by reducing MBL and improving quality of life. [ABSTRACT FROM AUTHOR]

Abstract: Extensive evidence of the adverse impacts of polychlorinated biphenyls (PCBs) to wildlife, domestic animals, and humans has now been documented for over 40years. Despite the ban on production and new use of PCBs in the United States in 1979, a number of fish consumption advisories remain in effect, and there remains considerable uncertainty regarding ongoing environmental sources and management alternatives. Using a blind sampling approach, 25 caulk samples were collected from the exterior of ten buildings in the San Francisco Bay Area and analyzed for PCBs using congener-specific gas chromatography–mass spectrometry (GC–MS) and chlorine using portable X-ray fluorescence (XRF). PCBs were detected in 88% of the caulk samples collected from the study area buildings, with 40% exceeding 50ppm. Detectable PCB concentrations ranged from 1 to 220,000ppm. These data are consistent with previous studies in other cities that have identified relatively high concentrations of PCBs in concrete and masonry buildings built between 1950 and 1980. Portable XRF was not a good predictor of the PCB content in caulk and the results indicate that portable XRF analysis may only be useful for identifying caulk that contains low concentrations of Cl (≤10,000ppm) and by extension low or no PCBs. A geographic information system-based approach was used to estimate that 10,500kg of PCBs remain in interior and exterior caulk in buildings located in the study area, which equates to an average of 4.7kg PCBs per building. The presence of high concentrations in the exterior caulk of currently standing buildings suggests that building caulk may be an ongoing source of PCBs to the San Francisco Bay Area environment. Further studies to expand the currently small international dataset on PCBs in caulking materials in buildings of countries that produced or imported PCBs appear justified in the context of both human health and possible ongoing environmental release. [Copyright &y& Elsevier]

We analyzed eight sediment cores from wetland and subtidal locations around San Francisco (SF) Bay, terrace sediment from the Yuba River, CA and precipitation from the SF Bay region. We defined the Hg isotopic composition of uncontaminated SF Bay sediment, two contributing endmember sediments contaminated by distinct Hg sources, and regional precipitation. Deep subtidal sediments with pre-mining THg concentrations (less than 60ng/g) have δ202Hg of −0.98±0.06‰ and Δ199Hg of 0.17±0.03‰ (1 s.d.; n=5). The δ202Hg of subtidal sediment in SF Bay systematically changed between pre-mining, circa 1960, and surface sediment. In circa 1960 sediment δ202Hg ranges from −0.63 to −0.32‰ (±0.10‰) with higher δ202Hg in the south and lower δ202Hg in the north; however in surface sediment δ202Hg is nearly constant and averages −0.52±0.04‰ (1 s.d.; n=6). These latter values for SF Bay surface sediment are similar to those for terrace sediment along the Yuba River that have δ202Hg of −0.57±0.10‰ and Δ199Hg of 0.05±0.01‰ (1 s.d.; n=2) and are consistent with sediment contaminated by a metallic Hg source that was derived from Hg ore in the California Coast Ranges and used in Sierra Nevada gold mining. Wetlands adjacent to south and central SF Bay have high THg in deeper sediment layers (>3000ng/g) that vary by ~0.6‰ in δ202Hg, presumably reflective of various anthropogenic Hg sources. The three sediment endmembers (metallic Hg, Hg mining and background Hg) were defined using δ202Hg and THg concentrations. Based on the estimated contribution of endmember sediment to subtidal and intertidal locations, we suggest that the subtidal Hg stable isotope record in sediment cores is consistent with historical sediment transport to, and deposition in, SF Bay. Thus, Hg stable isotopes can be used to trace sediment transport in locations that are impacted by multiple anthropogenic Hg sources. [ABSTRACT FROM AUTHOR]

Mosquito community dynamics in urban areas are influenced by an array of both social and ecological factors. Human socioeconomic factors (SEF) can be related to mosquito abundance and diversity as urban mosquito development sites are modified by varying human activity, e.g. level of abandoned structures or amount of accumulated trash. The goal of this study was to investigate the relationships among mosquito diversity, populations of Aedes aegypti , and SEF in a tropical urban setting. Mosquitoes were collected using BG Sentinel 2 traps and CDC light traps during three periods between late 2018 and early 2019 in San Juan, Puerto Rico, and were identified to species. SEFs (i.e. median household income, population density, college-level educational attainment, unemployment, health insurance coverage, percentage of households below the poverty line, amount of trash and level of abandoned homes) were measured using foot surveys and U.S. Census data. We found 19 species with the two most abundant species being Culex quinquefasciatus (n  = 10 641, 87.6%) and Ae. aegypti (n  = 1558, 12.8%). We found a positive association between Ae. aegypti abundance and mosquito diversity, which were both negatively related to SES and ecological factors. Specifically, lower socioeconomic status neighborhoods had both more Ae. aegypti and more diverse communities, due to more favorable development habitat, indicating that control efforts should be focused in these areas. [ABSTRACT FROM AUTHOR]

Food quality and quantity serve as the basis for cycling of key chemical elements in trophic interactions; yet the role of nutrient stoichiometry in shaping host–pathogen interactions is under appreciated. Most of the emergent mosquito-borne viruses affecting human health are transmitted by mosquitoes that inhabit container systems during their immature stages, where allochthonous input of detritus serves as the basal nutrients. Quantity and type of detritus (animal and plant) were manipulated in microcosms containing newly hatched Aedes aegypti mosquito larvae. Adult mosquitoes derived from these microcosms were allowed to ingest Zika virus-infected blood and then tested for disseminated infection, transmission, and total nutrients (percent carbon, percent nitrogen, ratio of carbon to nitrogen). Treatments lacking high-quality animal (insect) detritus significantly delayed development. Survivorship to adulthood was closely associated with the amount of insect detritus present. Insect detritus was positively correlated with percent nitrogen, which affected Zika virus infection. Disseminated infection and transmission decreased with increasing insect detritus and percent nitrogen. We provide the first definitive evidence linking nutrient stoichiometry to arbovirus infection and transmission in a mosquito using a model system of invasive Ae. aegypti and emergent Zika virus. [ABSTRACT FROM AUTHOR]

Urban watersheds are significantly anthropogenically-altered landscapes. Most previous studies cover relatively short periods, without addressing concentrations, loads, and yields in relation to annual climate fluctuations, and datasets on Ag, Se, PBDEs, and PCDD/Fs are rare. Intensive storm-focused sampling and continuous turbidity monitoring were employed to quantify pollution at two locations in the Guadalupe River (California, USA). At a downstream location, we determined loads of suspended sediment (SS) for 14 yrs., mercury (HgT), PCBs, and total organic carbon (TOC) (8 yrs), total methylmercury (MeHgT) (6 yrs), nutrients, and trace elements including Ag and Se (3 yrs), DDTs, chlordanes, dieldrin, and PBDEs (2 yrs), and PCDD/Fs (1 yr). At an upstream location, we determined loads of SS for 4 yrs. and HgT, MeHgT, PCBs and PCDD/Fs for 1 yr. These data were compared to previous studies, climatically adjusted, and used to critically assess the use of small datasets for estimating annual average conditions. Concentrations and yields in the Guadalupe River appear to be atypical for total phosphorus, DDTs, dieldrin, HgT, MeHgT, Cr, Ni, and possibly Se due to local conditions. Other pollutants appear to be similar to other urban systems. On average, wet season flow varied by 6.5-fold and flow-weighted mean (FWM) concentrations varied 4.4-fold, with an average 7.1-fold difference between minimum and maximum annual loads. Loads for an average runoff year for each pollutant were usually less than the best estimate of long-term average. The arithmetic average of multiple years of load data or a FWM concentration combined with mean annual flow was also usually below the best estimate of long-term average load. Mean annual loads using sampled years were also less than the best estimate of long-term average by a mean of 2.2-fold. Climatic adjustment techniques are needed for computing estimates of long-term average annual loads. [ABSTRACT FROM AUTHOR]

Aims Antithrombin is increasingly used in paediatric patients, yet there are few age-specific pharmacokinetic data to guide dosing. We aimed to describe the pharmacokinetic profile of human (plasma-derived) antithrombin concentrate in paediatric patients. Methods A 5-year retrospective review was performed of patients <19 years of age admitted to our institution who received antithrombin concentrate, were not on mechanical circulatory support and had baseline (predose) and postdose plasma antithrombin activity levels available for analysis. Demographic and laboratory variables, antithrombin dosing information and data on the use of continuous infusion unfractionated heparin were collected. Population pharmacokinetic analysis was performed with bootstrap analysis. The model developed was tested against a validation dataset from a cohort of similar patients, and a predictive value was calculated. Results A total 184 patients met the study criteria {46.7% male, median age [years] 0.35 [interquartile range (IQR) 0.07-3.9]}. A median of two antithrombin doses (IQR 1-4) were given to patients (at a dose of 46.3 ± 13.6 units kg-1), with median of three (IQR 2-7) postdose levels per patient. Continuous infusion unfractionated heparin was administered in 87.5% of patients, at a mean dose of 34.1 ± 22.7 units kg-1 h-1. A one-compartment exponential error model best fit the data, and significant covariates included allometrically scaled weight on clearance and volume of distribution, unfractionated heparin dose on clearance, and baseline antithrombin activity level on volume of distribution. The model resulted in a median −1.75% prediction error (IQR -11.75% to 6.5%) when applied to the validation dataset ( n = 30). Conclusions Antithrombin pharmacokinetics are significantly influenced by the concurrent use of unfractionated heparin and baseline antithrombin activity. [ABSTRACT FROM AUTHOR]

Objective To study the prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young females referred to a multidisciplinary clinic for evaluation of heavy menstrual bleeding (HMB). Methods Retrospective chart review was undertaken for 131 post-menarchal girls with HMB, 7 to 17 years of age, enrolled in the institutional ‘Menorrhagia Data Registry’ protocol. The diagnostic approach included: (1) complete blood count, prothrombin time, partial thromboplastin time, fibrinogen, von Willebrand panel (2) platelet aggregometry, specific clotting factor assay, fibrinolytic pathway analysis, and factor XIII level as needed. The prevalence of hemostatic abnormalities and the prognostic significance of clinical variables associated with hemostatic abnormalities in young girls with HMB were evaluated. Results A hemostatic abnormality was identified in 69 (53%) young girls with HMB. Of these, 27 (21%) had an underlying bleeding disorder and 42 (32%) had a risk factor for bleeding, namely low von Willebrand factor activity. A larger number of girls with underlying bleeding disorder had personal history of other bleeding symptoms (48% vs 31%) and bleeding after surgical or dental procedure (25% vs 8%) when compared to females without hemostatic abnormality. Furthermore, girls with risk factor for bleeding (low vWF activity) were more likely to have bleeding after surgical or dental procedure (15% vs 8%) and family history of bleeding (79% vs 60%) than patients without hemostatic abnormality. Conclusions There is high prevalence of hemostatic abnormalities, including bleeding disorders and risk factors, in young girls with HMB. These findings support comprehensive and systematic hemostatic evaluation in this group of patients. [ABSTRACT FROM AUTHOR]

Abstract: Novel methods utilizing liquid chromatography–tandem mass spectrometry and gas chromatography–mass spectrometry were validated for low-level detection of 104 pharmaceuticals and personal care products ingredients (PPCPs) and four alkylphenols (APs) in environmental samples. The methods were applied to surface water, sediment, and mussel tissue samples collected from San Francisco Bay, CA, USA, an urban estuary that receives direct discharge from over forty municipal and industrial wastewater outfalls. Among the target PPCPs, 35% were detected in at least one sample, with 31, 10, and 17 compounds detected in water, sediment, and mussels, respectively. Maximum concentrations were 92ng/L in water (valsartan), 33ng/g dry weight (dw) in sediments (triclocarban), and 14ng/g wet weight (ww) in mussels (N,N-diethyl-m-toluamide). Nonylphenol was detected in water (<2–73ng/L), sediments (22–86ng/g dw), and mussels (<0.04–95ng/g ww), and nonylphenol mono- and diethoxylates were detected in sediments (<1–40ng/g dw) and mussels (<5–192ng/g ww). The concentrations of PPCPs and APs detected in the San Francisco Bay samples were generally at least an order of magnitude below concentrations expected to elicit toxic effects in aquatic organisms. This study represents the first reconnaissance of PPCPs in mussels living in an urban estuary and provides the first field-derived bioaccumulation factors (BAFs) for select compounds in aquatic organisms. [Copyright &y& Elsevier]

Abstract: Atmospheric mercury (Hg) species, including gaseous elemental mercury (GEM), reactive gaseous mercury (RGM) and particulate-bound mercury (Hgp), were monitored near three sites, including a cement plant (monitored in 2007 and 2008), an urban site and a rural site (both monitored in 2005 and 2008). Although the cement plant was a significant source of Hg emissions (for 2008, GEM: 2.20 ± 1.39 ng m−3, RGM: 25.2 ± 52.8 pg m−3, Hgp 80.8 ± 283 pg m−3), average GEM levels and daytime average dry depositional RGM flux were highest at the rural site, when all three sites were monitored sequentially in 2008 (rural site, GEM: 2.37 ± 1.26 ng m−3, daytime RGM flux: 29 ± 40 ng m−2 day−1). Photochemical conversion of GEM was not the primary RGM source, as highest net RGM gains (75.9 pg m−3, 99.0 pg m−3, 149 m−3) occurred within 3.0–5.3 h, while the theoretical time required was 14–23 h. Instead, simultaneous peaks in RGM, Hgp, ozone (O3), nitrogen oxides, and sulfur dioxide in the late afternoon suggested short-range transport of RGM from the urban center to the rural site. The rural site was located more inland, where the average water vapor mixing ratio was lower compared to the other two sites (in 2008, rural: 5.6 ± 1.4 g kg−1, urban: 9.0 ± 1.1 g kg−1, cement plant: 8.3 ± 2.2 g kg−1). Together, these findings suggested short-range transport of O3 from an urban area contributed to higher RGM deposition at the rural site, while drier conditions helped sustain elevated RGM levels. Results suggested less urbanized environments may be equally or perhaps more impacted by industrial atmospheric Hg emissions, compared to the urban areas from where Hg emissions originated. [Copyright &y& Elsevier]