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The efficacy and safety of rivipansel, a predominantly E-selectin antagonist, were studied in a phase 3, randomized, controlled trial for vaso-occlusive crisis (VOC) requiring hospitalization (RESET). A total of 345 subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an IV loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in the Open-label Extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary end point, was not different between rivipansel and placebo (-5.7 hours, P = .79; hazard ratio, 0.97), nor were differences seen in secondary end points of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use. Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a post hoc analysis, early rivipansel treatment within 26.4 hours of VOC pain onset (earliest quartile of time from VOC onset to treatment) reduced median TTRFD by 56.3 hours, reduced median TTD by 41.5 hours, and reduced median TTDIVO by 50.5 hours, compared with placebo (all P < .05). A similar subgroup analysis comparing OLE early-treatment with early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P = .062) and in TTDIVO of 30.1 hours (P = .087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE)., (© 2023 by The American Society of Hematology.)

Stormwater runoff typically contains significant quantities of metal contaminants that enter urban waterways over short durations and represent a potential risk to water quality. The origin of metals within the catchment and processes that occur over the storm can control the partitioning of metals between a range of different forms. Understanding the fraction of metals present in a form that is potentially bioavailable to aquatic organisms is useful for environmental risk assessment. To help provide this information, the forms and dynamics of metal contaminants in an urban system were assessed across a storm. Temporal patterns in the concentration of metals in dissolved and particulate (total suspended solids; TSS) forms were assessed from water samples, and diffusive gradients in thin-films (DGTs) were deployed to measure the DGT-labile time-integrated metal concentration. Results indicate that the concentrations of dissolved and TSS-associated metals increased during the storm, with the metals Al, Cd, Co, Cu, Pb and Zn representing the greatest concern relative to water quality guideline values (GVs). The portion of labile metal as measured by DGT devices indicated that during the storm a substantial fraction (∼98%) of metals were complexed and pose a lower risk of acute toxicity to aquatic organisms. Comparison of DGT results to GVs indicate that current GVs are likely quite conservative when assessing stormwater pollution risks with regards to metal contaminants. This study provides valuable insight into the forms and dynamics of metals in an urban system receiving stormwater inputs and assists with the development of improved approaches for the assessment of short-term, intermittent discharge events., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Snubnose gobies (genus Pseudogobius: Gobionellinae) are ubiquitous to, and important components of, estuarine ecosystems of the Indo-west Pacific. These small benthic fishes occur in freshwater, brackish and marine habitats such as mangroves, sheltered tide pools and lowland streams, and represent a model group for understanding the biodiversity and biogeography of estuarine fauna. To develop the species-level framework required for a concurrent morphological taxonomic appraisal, we undertook thorough sampling around the extensive Australian coastline, referenced to international locations, as part of a molecular systematic review using both nuclear and mitochondrial markers. The results indicate that while there are currently eight recognised species, the true diversity is close to double this, with a hotspot of endemism located in Australia. Complicated patterns were observed in southern Australia owing to two differing zones of introgression/admixture. Key drivers of diversity in the group appear to include plate tectonics, latitude, and historic barriers under glacial maxima, where an interplay between ready dispersal and habitat specialisation has led to regional panmixia but frequent geographic compartmentalisation within past and present landscapes. The findings have significant implications for biodiversity conservation, coastal and estuarine development, the basic foundations of field ecology, and for applied use such as in biomonitoring., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: It has been reported that patients with antiphospholipid antibodies (aPL) and refractory migraine may experience symptomatic improvement with antithrombotic therapy, but this phenomenon has not been well studied. This study was undertaken to detail the response to trials of antithrombotic therapy in these patients., Methods: This is a retrospective study of 75 patients with refractory migraine and aPL who were given a 2-4 week trial of aspirin, clopidogrel and/or anticoagulation. Major response was defined as 50-100% improvement in frequency and/or severity of migraine; minor response: 25-49% improvement; no response: <25% improvement., Results: 66 patients were given a trial of aspirin: 47% responded (21% major); 60 patients were given a trial of clopidogrel: 83% responded (67% major); and 34 patients were given a trial of anticoagulation (usually apixaban): 94% responded (85% major). The response rate to any anti-thrombotic therapy was 89% (83% major). Many patients also noted improvement in non-headache symptoms. No patient experienced stroke. There was no major bleeding during any 2-4 week treatment trial and only 3 of 69 patients maintained on an antithrombotic regimen for a median follow up of 29.9 months (5-100) experienced major bleeding., Conclusions: There was a high rate of symptomatic response to antithrombotic therapy in this context and long-term follow up suggested an individualized symptom-derived antithrombotic regimen may be associated with a low bleeding risk. Our data support consideration of a 2-4 week trial of antithrombotic therapy, usually starting with antiplatelet therapy, in aPL-positive patients with refractory migraine, particularly if other treatment options have been exhausted. As a retrospective study, our data provide only Class IV level of evidence, but they suggest randomized controlled trials are warranted to validate these encouraging findings.

Per- and poly-fluoroalkyl substances (PFAS) are ubiquitously distributed throughout aquatic environments and can bioaccumulate in organisms. We examined dietary uptake and depuration of a mixture of 3 PFAS: perfluorooctanoic acid (PFOA; C 8 HF 15 O 2 ), perfluorooctane sulfonate (PFOS; C 8 HF 17 SO 3 ), and hexafluoropropylene oxide dimer acid (HPFO-DA; C 6 HF 11 O 3 ; trade name GenX). Benthic fish (blue spot gobies, Pseudogobius sp.) were fed contaminated food (nominal dose 500 ng g -1 ) daily for a 21-d uptake period, followed by a 42-d depuration period. The compounds PFOA, linear-PFOS (linear PFOS), and total PFOS (sum of linear and branched PFOS) were detected in freeze-dried fish, whereas GenX was not, indicating either a lack of uptake or rapid elimination (<24 h). Depuration rates (d -1 ) were 0.150 (PFOA), 0.045 (linear-PFOS), and 0.042 (linear+branched-PFOS) with corresponding biological half-lives of 5.9, 15, and 16 d, respectively. The PFOS isomers were eliminated differently, resulting in enrichment of linear-PFOS (70-90%) throughout the depuration period. The present study is the first reported study of GenX dietary bioaccumulation potential in fish, and the first dietary study to investigate uptake and depuration of multiple PFASs simultaneously, allowing us to determine that whereas PFOA and PFOS accumulated as expected, GenX, administered in the same way, did not appear to bioaccumulate. Environ Toxicol Chem 2020;39:595-603. © 2019 SETAC., (© 2019 SETAC.)

This exploratory study aims to investigate the health of sand flathead ( Platycephalus bassensis ) sampled from five sites in Port Phillip Bay, Australia using gas chromatography-mass spectrometry (GC-MS) metabolomics approaches. Three of the sites were the recipients of industrial, agricultural, and urban run-off and were considered urban sites, while the remaining two sites were remote from contaminant inputs, and hence classed as rural sites. Morphological parameters as well as polar and free fatty acid metabolites were used to investigate inter-site differences in fish health. Significant differences in liver somatic index (LSI) and metabolite abundance were observed between the urban and rural sites. Differences included higher LSI, an increased abundance of amino acids and energy metabolites, and reduced abundance of free fatty acids at the urban sites compared to the rural sites. These differences might be related to the additional energy requirements needed to cope with low-level contaminant exposure through energy demanding processes such as detoxification and antioxidant responses as well as differences in diet between the sites. In this study, we demonstrate that metabolomics approaches can offer a greater level of sensitivity compared to traditional parameters such as physiological parameters or biochemical markers of fish health, most of which showed no or little inter-site differences in the present study. Moreover, the metabolite responses are more informative than traditional biomarkers in terms of biological significance as disturbances in specific metabolic pathways can be identified.

Since the use of the zebrafish Danio rerio genetic model organism within the scientific research community continues to grow rapidly, continued procedural refinement to support high-quality, reproducible research and improve animal welfare remains an important focus. As such, anesthesia remains one of the most frequent procedures conducted. Here, we compared the effectiveness of clove oil (active ingredient eugenol) and AQUI-S (active ingredient iso-eugenol) with the currently most commonly used tricaine/MS-222 (ethyl 3-aminobenzoate methanesulfonate) and benzocaine anesthesia. We focused on embryos (1 day postfertilization), larvae (5 days postfertilization), and adults (9-11 months) and for the first time used exposure times that are the most relevant in research settings by using zebrafish as a genetic model system. For each age, tricaine and benzocaine achieved the most reproducible, robust anesthesia with the quickest induction and recovery. For some experimental procedures, specific clove oil concentrations in embryos and larvae may represent suitable alternatives. Although different aquatic species at specific ages respond differentially to these agents, the systematic study of comparable effective dosages for procedures most commonly employed represent an important step toward refinement.

Biomonitoring microplastics in freshwater ecosystems has been insufficient in comparison with its practice in marine environments. It is an important first step to understand microplastic uptake in organisms when assessing risk in natural freshwater habitats. We conducted microplastic biomonitoring within the Greater Melbourne Area; where the microplastic baseline pollution in freshwater organisms was largely unknown. A common noxious fish species, Gambusia holbrooki, was targeted. Individuals (n = 180) from nine wetlands were analyzed. Uptake pathway, size, weight and gender were examined in relation to microplastic uptake in the body (presumed uptake via gut) and head (presumed uptake via gills). On average, 19.4% of fish had microplastics present in their bodies with an abundance of 0.6 items per individual (items/ind) and 7.2% of fish had microplastics in their heads with an abundance of 0.1 items/ind. Polyester was the dominant plastic type and fibers were the most common shape. The amount of microplastics in Gambusia holbrooki in current study is relatively low in a global comparison. The bodies of fish contained more microplastics on average than heads, and the size of microplastics detected in heads were smaller than those found in bodies. Microplastic uptake was directly proportional to size and weight. Furthermore, female individuals showed a tendency to ingest more microplastics than males. Laboratory experiments under controlled conditions are suggested to further explore such relationships. Our findings are important to understanding the potential ecological risks posed by microplastics to organisms in freshwater environments and provide suitable methodologies to conduct biomonitoring in future investigations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We conducted a multicenter pilot investigation of the safety and feasibility of bone marrow transplantation (BMT) in adults with severe sickle cell disease (SCD) (NCT 01565616) using a reduced toxicity preparative regimen of busulfan (13.2 mg/kg), fludarabine (175 mg/m 2 ) and thymoglobulin (6 mg/kg) and cyclosporine or tacrolimus and methotrexate for graft-vs-host disease (GVHD) prophylaxis. Twenty-two patients (median age 22 years; range 17-36) were enrolled at eight centers. Seventeen patients received marrow from an HLA-identical sibling donor and five patients received marrow from an 8/8 HLA-allele matched unrelated donor. Before BMT, patients had stroke, acute chest syndrome, recurrent pain events, were receiving regular red blood cell transfusions, or had an elevated tricuspid regurgitant jet (TRJ) velocity, which fulfilled eligibility criteria. Four patients developed grades II-III acute GVHD (18%) and six developed chronic GVHD (27%) that was moderate in two and severe in one patient. One patient died of intracranial hemorrhage and one of GVHD. Nineteen patients had stable donor chimerism, 1-year post-transplant. One patient who developed secondary graft failure survives disease-free after a second BMT. The one-year overall survival and event-free survival (EFS) are 91% (95% CI 68%-98%) and 86% (95% CI, 63%-95%), respectively, and 3-year EFS is 82%. Statistically significant improvements in the pain interference and physical function domains of health-related quality of life were observed. The study satisfied the primary endpoint of 1-year EFS ≥70%. This regimen is being studied in a prospective clinical trial comparing HLA-matched donor BMT with standard of care in adults with severe SCD (NCT02766465)., (© 2019 Wiley Periodicals, Inc.)

Background: Although sickle cell trait (SCT) is largely a benign carrier state, it may increase risk for certain clinical outcomes., Purpose: To evaluate associations between SCT and clinical outcomes in children and adults., Data Sources: English-language searches of PubMed, CINAHL, the Cochrane Library, Current Contents Connect, Scopus, and Embase (1 January 1970 to 30 June 2018) and bibliographies of review articles., Study Selection: Observational controlled studies (published in English) in children or adults that examined an association between SCT and any of 24 clinical outcomes specified a priori in the following 6 categories: exertion-related injury; renal, vascular, pediatric, and surgery- or trauma-related outcomes; and overall mortality., Data Extraction: A single reviewer extracted study data, which was checked by another; 2 reviewers independently assessed study quality; and strength of evidence was assessed by consensus., Data Synthesis: Of 7083 screened studies, 41 met inclusion criteria. High-strength evidence supported a positive association between SCT and risk for pulmonary embolism, proteinuria, and chronic kidney disease. Moderate-strength evidence supported a positive association between SCT and exertional rhabdomyolysis and a null association between SCT and deep venous thrombosis, heart failure or cardiomyopathy, stroke, and pediatric height or weight. Absolute risks for thromboembolism and rhabdomyolysis were small. For the remaining 15 clinical outcomes, data were insufficient or strength of evidence was low., Limitation: Publication bias was possible, and high-quality evidence was scant., Conclusion: Sickle cell trait is a risk factor for a few adverse health outcomes, such as pulmonary embolism, kidney disease, and exertional rhabdomyolysis, but does not seem to be associated with such complications as heart failure and stroke. Insufficient data or low-strength evidence exists for most speculated complications of SCT., Primary Funding Source: National Human Genome Research Institute.

Introduction: A growing population of adults living with severe, chronic childhood-onset health conditions has created a need for specialized health care delivered by providers who have expertise both in adult medicine and in those conditions. Optimal care of these patients requires systematic approaches to healthcare transition (HCT). Guidelines for HCT exist, but gaps in care occur, and there are limited data on outcomes of HCT processes., Methods: The Single Disease Workgroup of the Lifespan Domain Task Force of the National Center for Advancing Translational Sciences Clinical and Translational Science Award programs convened a group to review the current state of HCT and to identify gaps in research and practice. Using cystic fibrosis and sickle cell disease as models, key themes were developed. A literature search identified general and disease-specific articles. We summarized key findings., Results: We identified literature characterizing patient, parent and healthcare provider perspectives, recommendations for transition care, and barriers to effective transition., Conclusions: With increased survival of patients with severe childhood onset diseases, ongoing study of effective transition practices is essential as survival increases for severe childhood onset diseases. We propose pragmatic methods to enhance transition research to improve health and key outcomes.

This is the first report of intersex in a lutjanid species, the goldband snapper Pristipomoides multidens, in which the gonads of a male fish contain multifocal oocytes scattered among testicular tissue. The incidence rate of intersex was low (<1.0%), with oocytes observed in the testes of only two of 206 male fish examined. The capacity for P. multidens to develop an intersex condition suggests that future monitoring of this species should include histological analysis of gonads., (© 2018 The Fisheries Society of the British Isles.)

Standard measures and common data elements for sickle cell disease (SCD) will improve the data quality and comparability necessary for cross-study analyses and the development of guidelines that support effective treatments and interventions. In 2014, the National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) funded an Administrative Supplement to the PhenX Toolkit (consensus measures for Phenotypes and eXposures; https://www.phenxtoolkit.org/) to identify common measures to promote data comparability across SCD research. An 11-member Sickle Cell Disease Research and Scientific Panel provided guidance to the project, establishing a core collection of SCD-related measures and defining the scope of 2 specialty collections: (1) cardiovascular, pulmonary, and renal complications, and (2) neurology, quality-of-life, and health services. For each specialty collection, a working group of SCD experts selected high-priority measures using a consensus process that included scientific community input. The SCD measures were released into the Toolkit in August 2015. The 25 measures included in the core collection are recommended for use by all NHLBI-funded investigators performing human-subject SCD research. The 10 neurology, quality-of-life, and health services measures and 14 cardiovascular, pulmonary, and renal measures are recommended for use within these specialized research areas. For SCD and other researchers, PhenX measures will promote collaborations with clinicians and patients, facilitate cross-study analysis, accelerate translational research, and lead to greater understanding of SCD phenotypes and epigenetics. For clinicians, using PhenX measures will help elucidate the etiology, progression, and treatment of SCD, leading to improved patient care and quality of life., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

Approximately 100,000 Americans have sickle cell disease (SCD), a group of recessively inherited red blood cell disorders characterized by abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in the red blood cells. Persons with hemoglobin SS or hemoglobin Sß 0 thalassemia, also known as sickle cell anemia (SCA), have the most severe form of SCD. Hemoglobin SC disease and hemoglobin Sß + thalassemia are other common forms of SCD. Red blood cells that contain sickle hemoglobin are inflexible and can stick to vessel walls, causing a blockage that slows or stops blood flow. When this happens, oxygen cannot reach nearby tissues, leading to attacks of sudden, severe pain, called pain crises, which are the clinical hallmark of SCD. The red cell sickling and poor oxygen delivery can also cause damage to the brain, spleen, eyes, lungs, liver, and multiple other organs and organ systems. These chronic complications can lead to increased morbidity, early mortality, or both. Tremendous strides in treating and preventing the complications of SCD have extended life expectancy. Now, nearly 95% of persons born with SCD in the United States reach age 18 years (1); however, adults with the most severe forms of SCD have a life span that is 20-30 years shorter than that of persons without SCD (2).

Hepatic gene expression and liver histology were examined in sand flathead (Platycephalus bassensis) from six locations in Port Phillip Bay, Victoria, Australia. Four sets of genes including thyroid-related genes (D1, D2, TTR, TRα and TRβ), metal metabolism-related genes (MT, MTF1, TF, Ferritin and FPN1), apoptosis-related genes (Diablo/SMAC1, Diablo/SMAC2 and CYP1A) and an endoplasmic reticulum stress biomarker gene (GRP78) were examined in female flathead using qRT-PCR. TRβ and Diablo/SMAC1 gene expression was significantly up-regulated in fish from all polluted sites compared to those from a reference site. The transcripts of TRα and FPN1 were significantly higher in flathead from Corio Bay, while the hepatic mRNA of TTR and GRP78 were significantly lower in those fish. Positive correlations were observed between Diablo/SMAC1 and CYP1A, D2 and TRβ, TRα and TRβ. This study demonstrates that application of pathway-based biomarker genes and histopathology can provide comprehensive information on the impact of environmental pollutants on fish., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Sickle Cell Disease (SCD) causes profound suffering and decrements in daily functioning. Demand is growing for valid and reliable measures to systematically document these effects, particularly in adults. The Adult Sickle Cell Quality of Life Measurement System, ASCQ-Me℠, was developed for this purpose. ASCQ-Me℠ is one of four measurement systems housed within the Person-Centered Assessment Resource (PCAR), funded by the National Institutes of Health, to support clinical research. To help users select the best of these measures for adults with SCD, we evaluated and compared two PCAR systems: one designed to be "universally applicable" (the Patient-Reported Outcome Measurement Information System, PROMIS®) and one designed specifically for SCD (ASCQ-Me℠)., Methods: Respondents to PROMIS and ASCQ-Me questions were 490 adults with SCD from seven geographically-disbursed clinics within the US. Data were collected for six ASCQ-Me measures (Emotional Impact, Sleep Impact, Social Impact, Stiffness Impact, Pain Impact, SCD Pain Episode Frequency and Severity) and ten PROMIS measures (Pain Impact, Pain Behavior, Physical Functioning, Anxiety, Depression, Fatigue, Satisfaction with Discretionary Social Activities, Satisfaction with Social Roles, Sleep Disturbance, and Sleep-Related Impairment). Statistical analyses, including analysis of variance and multiple linear regression, were conducted to determine the sensitivity of measures to SCD severity. SCD severity was assessed via a checklist of associated treatments and conditions., Results: For those with the most severe SCD, PROMIS scores showed worse health compared to the general population for nine of ten health domains: the magnitude of the difference ranged 0.5 to 1.1 standard deviation units. The PROMIS domains most severely affected were Physical Functioning and Pain (Impact and Behavior). Significant differences by tertile of the SCD-MHC were shown for most PROMIS short forms and all ASCQ-Me short and fixed forms. In most models, ASCQ-Me measures explained statistically significant unique variance in SCD-MHC scores complementary to that explained by corresponding PROMIS measures., Conclusions: Study results supported the validity of both PROMIS and ASCQ-Me measures for use in adults with SCD. Compared to comparable PROMIS scores, most ASCQ-Me scores were better predictors of SCD disease severity, as measured by a medical history checklist. The clinical implications of these results require further investigation.

Port Phillip Bay, Australia, is a large semi-closed bay with over four million people living in its catchment basin. The Bay receives waters from the Yarra River which drains the city of Melbourne, as well as receiving the discharges of sewage treatment plants and petrochemical and agricultural chemicals. A 1999 study demonstrated that fish inhabiting Port Phillip Bay showed signs of effects related to pollutant exposure despite pollution management practices having been implemented for over a decade. To assess the current health status of the fish inhabiting the Bay, a follow up survey was conducted in 2015. A suite of biomarkers of exposure and effects were measured to determine the health status of Port Phillip Bay sand flathead (Platycephalus bassensis), namely ethoxyresorufin-O-deethylase (EROD) activity, polycyclic aromatic hydrocarbons (PAH) biliary metabolites, carboxylesterase activity (CbE) and DNA damage (8-oxo-dG). The reduction in EROD activity in the present study suggests a decline in the presence of EROD activity-inducing chemicals within the Bay since the 1990s. Fish collected in the most industrialised/urbanised sites did not display higher PAH metabolite levels than those in less developed areas of the Bay. Ratios of PAH biliary metabolite types were used to indicate PAH contaminant origin. Ratios indicated fish collected at Corio Bay and Hobsons Bay were subjected to increased low molecular weight hydrocarbons of petrogenic origin, likely attributed to the close proximity of these sites to oil refineries, compared to PAH biliary metabolites in fish from Geelong Arm and Mordialloc. Quantification of DNA damage indicated a localised effect of exposure to pollutants, with a 10-fold higher DNA damage level in fish sampled from the industrial site of Corio Bay relative to the less developed site of Sorrento. Overall, integration of biomarkers by multivariate analysis indicated that the health of fish collected in industrialised areas was compromised, with biologically significant biomarkers of effects (LSI, CF and DNA damage) discriminating between individuals collected in industrialised areas from observations made in fish collected in less developed areas of the Bay., Competing Interests: The authors have declared that no competing interests exist.

Fish, at all life stages, utilize olfactory information in the decision-making processes essential to survival. Olfaction is a sensitive sensory process, and toxicants within urban aquatic environments can have destructive or depreciating effects. In the present study, the authors exposed Galaxias maculatus, a native fish commonly found in urban waterways throughout southeastern Australia, to 1 of 5 ecologically relevant copper (II) chloride concentrations (<1 μg/L, 1 μg/L, 6 μg/L, 8 μg/L, 18 μg/L) for 16 h. After exposure, the authors tested the response of individual fish to 1 of 3 stimuli: a conspecific skin extract containing a stress-inducing alarm chemical odor, a conspecific odor, and distilled water as a control. Stress responses were quantified through behavioral assays. The authors found evidence for distinct changes in behavioral response with increasing copper concentration and a marked difference in response between control fish and fish exposed to the alarm chemical odor. Copper, even at relatively low concentrations, can have a significant effect on the stress response behavior shown by G. maculatus. Environ Toxicol Chem 2016;35:2209-2214. © 2016 SETAC., (© 2016 SETAC.)

Concentrations of PAHs, OCs, PCBs and trace metals were determined in the white muscle of sand flathead Platycephalus bassensis collected at 6 locations in Port Phillip Bay during 2015. No PAHs, OCs or PCBs were detected in the white muscle of sand flathead at any of the locations, however measurable levels of As, Cu, Hg, Se and Zn were detected at all sites. Only As and Hg exhibited regional difference in white muscle concentrations, with As present only in a non-toxic organic form and Hg measured at levels that are comparable to levels reported in reference sites in other studies. All contaminants detected in the white muscle of sand flathead collected in Port Phillip Bay in 2015 were below Australian Food Standards guideline values, and by world standards, the Port Phillip Bay sand flathead population is considered minimally contaminated. Furthermore, tissue contaminant concentrations appear to be decreasing over time., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Unlabelled: Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems., Significance: Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures., (Published by Elsevier Inc.)

Documented deficiencies in adult sickle cell disease (SCD) care include poor access to knowledgeable providers and inadequate treatment in emergency departments (EDs).The aim of this study was to create patient-reported outcome measures of the quality of ambulatory and ED care for adults with SCD.We developed and pilot tested SCD quality of care questions consistent with Consumer Assessments of Healthcare Providers and Systems surveys. We applied psychometric methods to develop scores and evaluate reliability and validity.The participants of this study were adults with SCD (n = 556)-63% aged 18 to 34 years; 64% female; 64% SCD-SS-at 7 US sites.The measure used was Adult Sickle Cell Quality of Life Measurement information system Quality of Care survey.Most participants (90%) reported at least 1 severe pain episode (pain intensity 7.8 ± 2.3, 0-10 scale) in the past year. Most (81%) chose to manage pain at home rather than the ED, citing negative ED experiences (83%). Using factor analysis, we identified Access, Provider Interaction, and ED Care composites with reliable scores (Cronbach α 0.70-0.83) and construct validity (r = 0.32-0.83 correlations with global care ratings). Compared to general adult Consumer Assessments of Healthcare Providers and Systems scores, adults with SCD had worse care, adjusted for age, education, and general health.Results were consistent with other research reflecting deficiencies in ED care for adults with SCD. The Adult Sickle Cell Quality of Life Measurement Quality of Care measure is a useful self-report measure for documenting and tracking disparities in quality of SCD care., Competing Interests: The authors have no conflicts of interest to disclose.

Although a number of published trials exist of HLA-identical sibling hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) that span 2 decades, when and for whom this therapy should be pursued is a subject of debate. Assessments of the risks of transplant-related complications that include infertility and debilitating graft-versus-host disease and long-term quality of life after successful HCT are difficult to perform without prospective trials in transplant and nontransplant cohorts. However, it is possible to assess the risk of mortality and to compare published rates of survival in individuals with SCD treated and not treated by HCT. In this brief review, projections about mortality risk based on recent published reports are reviewed and summarized. The published data show overall survival and event-free survival rates of 95% and 92%, respectively, in children treated by HLA-identical sibling HCT. The overall survival rates in the Center for International Blood and Marrow Transplant Research (N = 412) and European Blood and Marrow Transplant (N = 487) registries were 91% and 95%, respectively. These results provide broad support for the therapeutic value of HLA-identical sibling HCT for children with SCD and serve as the basis for a strong recommendation in favor of the option of HCT when a suitable donor is available. The experience of HLA-identical sibling HCT in adults with SCD is limited but appears to be similar to results in children. These preliminary observations, however, warrant further investigation., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Guidelines are discordant concerning management of patients having thrombocytopenia with cancer-associated thrombosis (CAT)., Methods: Hospitalized adults with CAT and platelets ≤50 × 10(9) cells/L were managed with dalteparin 100 units/kg subcutaneously once daily. Comparator patients with CAT and platelets >50 × 10(9) cells/L were managed with dalteparin 200 units/kg/d., Results: Outcomes of 35 patients with thrombocytopenia (mean platelet count 26 ± 8.3 × 10(9) cells/L) and 58 comparator patients (mean platelet count 155 ± 75 × 10(9) cells/L) were evaluated. In all, 2 (5.7%) patients in the thrombocytopenia group and 1 patient (1.9%) in the comparator group experienced new-onset venous thromboembolism (odds ratio 3.31, 95% confidence interval [CI] 0.29-37.90, P = .556). The incidence of bleeding in patients with thrombocytopenia (8.6%) was similar to that in comparator patients (9.4%; risk ratio 0.94, 95% CI 0.37-2.39, P = .607)., Conclusion: In hospitalized patients having thrombocytopenia with CAT, reduced-dose low-molecular-weight heparin was generally efficacious., (© The Author(s) 2014.)

The target-specific oral anticoagulants (TSOACs), eg, dabigatran, rivaroxaban, and apixaban, are changing the way we manage thromboembolic disease. At the same time, many clinicians wonder how best to manage TSOAC therapy when patients need surgery. An in-depth understanding of these drugs is essential to minimize the risk of bleeding and thrombosis perioperatively., (Copyright© 2014 The Cleveland Clinic Foundation.)

Importance: Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused., Objective: To support and expand the number of health professionals able and willing to provide care for persons with SCD., Evidence Review: Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists., Findings: Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated., Conclusions and Relevance: Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

Background: Providers and patients have called for improved understanding of the health care requirements of adults with sickle cell disease (SCD) and have identified the need for a systematic, reliable and valid method to document the patient-reported outcomes (PRO) of adult SCD care. To address this need, the Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) was designed to complement the Patient Reported Outcome Measurement Information System (PROMIS®). Here we describe methods and results of the psychometric evaluation of ASCQ-Me item banks (IBs)., Methods: At seven geographically-disbursed clinics within the US, 556 patients responded to questions generated to assess cognitive, emotional, physical and social impacts of SCD. We evaluated the construct validity of the hypothesized domains using exploratory factor analysis (EFA), parallel analysis (PA), and bi-factor analysis (Item Response Theory Graded Response Model, IRT-GRM). We used IRT-GRM and the Wald method to identify bias in responses across gender and age. We used IRT and Cronbach's alpha coefficient to evaluate the reliability of the IBs and then tested the ability of summary scores based on IRT calibrations to discriminate among tertiles of respondents defined by SCD severity., Results: Of the original 140 questions tested, we eliminated 48 that either did not form clean factors or provided biased measurement across subgroups defined by age and gender. Via EFA and PA, we identified three subfactors within physical impact: sleep, pain and stiffness impacts. Analysis of the resulting six item sets (sleep, pain, stiffness, cognitive, emotional and social impacts of SCD) supported their essential unidimensionality. With the exception of the cognitive impact IB, these item sets also were highly reliable across a broad range of values and highly significantly related to SCD disease severity., Conclusion: ASCQ-Me pain, sleep, stiffness, emotional and social SCD impact IBs demonstrated exceptional measurement properties using modern and classical psychometric methods of evaluation. Further development of the cognitive impact IB is required to improve its sensitivity to differences in SCD disease severity. Future research will evaluate the sensitivity of the ASCQ-Me IBs to change in SCD disease severity over time due to health interventions.

Background: The role of pulmonary hypertension as a cause of mortality in sickle cell disease (SCD) is controversial., Methods and Results: We evaluated the relationship between an elevated estimated pulmonary artery systolic pressure and mortality in patients with SCD. We followed patients from the walk-PHaSST screening cohort for a median of 29 months. A tricuspid regurgitation velocity (TRV)≥ 3.0 m/s cuttof, which has a 67-75% positive predictive value for mean pulmonary artery pressure ≥ 25 mm Hg was used. Among 572 subjects, 11.2% had TRV ≥ 3.0 m/sec. Among 582 with a measured NT-proBNP, 24.1% had values ≥ 160 pg/mL. Of 22 deaths during follow-up, 50% had a TRV ≥ 3.0 m/sec. At 24 months the cumulative survival was 83% with TRV ≥ 3.0 m/sec and 98% with TRV < 3.0 m/sec (p < 0.0001). The hazard ratios for death were 11.1 (95% CI 4.1-30.1; p < 0.0001) for TRV ≥ 3.0 m/sec, 4.6 (1.8-11.3; p = 0.001) for NT-proBNP ≥ 160 pg/mL, and 14.9 (5.5-39.9; p < 0.0001) for both TRV ≥ 3.0 m/sec and NT-proBNP ≥ 160 pg/mL. Age > 47 years, male gender, chronic transfusions, WHO class III-IV, increased hemolytic markers, ferritin and creatinine were also associated with increased risk of death., Conclusions: A TRV ≥ 3.0 m/sec occurs in approximately 10% of individuals and has the highest risk for death of any measured variable. The study is registered in ClinicalTrials.gov with identifier: NCT00492531.

Vitellogenin (Vtg) is the major egg-yolk precursor protein in oviparous organisms normally synthesised only in mature females. In males and juveniles, the vtg gene, although present, is silent, but its hepatic expression may be activated by xenoestrogens. Surprisingly, its induction and potential consequences in non-hepatic tissues remain unexplored. Here we test the hepatic and testicular response of vtg expression in adult male rainbowfish Melanotaenia fluviatilis exposed to either 1, 3, 5 μg/L 17β-estradiol or 100, 500 μg/L 4-n-nonylphenol for 24-96 h. Significant increase in the expression level of vtg mRNA in the liver and testes of exposed males was observed. The early (24 h), sensitive and reliable detection of the vtg induction using qPCR demonstrates the assay's robustness to monitor xenobiotic exposure particularly in smaller fish like rainbowfish, an emerging indicator species. Whilst, the ectopic induction of vtg mRNA in testes suggests a more complex Vtg pathway.

Estuaries are often the final repositories for aquatic pollutants but how estuarine hydrology influences the availability of marine- and freshwater-derived pollutants is not well understood, particularly for micro-pollutants such as endocrine disrupting chemicals. To address this knowledge gap, this study measured natural and synthetic estrogen concentrations within the Little River, a tidal estuary in close vicinity to the major discharge point of Melbourne's largest waste water treatment plant (WWTP), the Western Treatment Plant. Quantitative enzyme-linked immunosorbent assays (ELISA) were used to determine concentrations of natural estrogens (ES: ∑E1 (estrone), E2 (17β-estradiol), E3 (estriol)) and the synthetic estrogen, 17α-ethinylestradiol (EE2). The highest concentrations were measured in samples taken from the WWTP effluent discharge channel (29.0 ng/L and 0.35 ng/L, respectively). Within the estuary, concentrations of ES (2.25-23.16 ng/L) varied somewhat between locations and sampling periods (p < 0.05), however patterns were not consistent. Significant spatial variation was observed on only one sampling occasion, and likewise temporal variation was only observed once. In the upstream freshwaters, ES (2.95-7.26 ng/L) concentrations were lower than in the estuary, although their presence suggests an additional source of ES to the environment, most likely of agricultural origin. The EE2 concentrations measured in both the estuarine and freshwater areas were all low (mostly below 0.20 ng/L), which created difficulties in interpretation due to problems associated with trying to measure such low concentrations with confidence. However, some patterns did emerge, with EE2 concentrations exhibiting significant temporal and tidal variation (p < 0.05), with concentrations greatest during low and flooding (incoming) tides. Physico-chemical properties explained 30% of the variation in ES concentrations, whereby concentrations increased with decreasing pH and DO and increasing salinity. Given the higher concentrations observed during flooding tides and the association of higher estrogen concentrations with increased salinity and low DO, we suggest that estrogens might accumulate in estuarine bottom waters and upon disturbance from the incoming tidal flows, may be a contributing source of estrogens into the estuary. This study contributes the first comprehensive investigation of estrogen dynamics in an Australian estuary, and provides the foundation for further research aimed at identifying which compounds are present in estuarine waterways, where they are coming from and how their concentrations vary through space and time., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2-9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: NCT00492531).

Leg ulcers are a debilitating complication of patients with sickle cell disease, and their frequency in North America was reported to be 2.5% by the Cooperative Study of Sickle Cell Disease more than 20 years ago. We sought to determine if the frequency of leg ulcers in sickle cell patients in the United States had declined and to assess which treatments providers use most commonly. We sent an e-mail survey to health professionals belonging to the national Sickle Cell Adult Provider Network. Responses were obtained from 31 of them (26.0%). Most of them (96.0%) reported having some patients with leg ulcers. Providers reported a total of 185 patients with active leg ulcers and 224 in the previous 5 years, for a total of 409 patients. Hb SS (homozygous sickle cell anemia) was the most common genotype of affected individuals, followed by Hb SC (double heterozygote for Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] and Hb C [β6(A3)Glu→Lys, GAG>AAG; HBB: c.19G>A]). Males showed a 2:1 predominance. Two-thirds of patients were treated with either hydroxyurea (HU) or transfusion therapy and most used compression stockings and topical therapies as directed by wound care services. We conclude that leg ulcers continue to be a debilitating complication of young adults with sickle cell disease, despite improved supportive care and the widespread use of disease modifying agents such HU and transfusion. While some providers offer office-based ulcer care, the majority prefer specialty consultation including podiatry, plastic surgery and dermatology. Despite their frequency, there is no clear consensus among providers as to the best treatment.

Background: Noninvasively assessed pulmonary pressure elevations and left ventricular (LV) diastolic dysfunction are associated with increased mortality in adults with sickle cell disease, but their relationship to exercise intolerance has not been evaluated prospectively., Methods and Results: Echocardiography, 6-minute walk distance, hemolytic rate, and serum concentrations of ferritin and erythropoietin were evaluated in a cohort of 483 subjects with homozygous hemoglobin S in the U.S. and U.K. Walk-Treatment of Pulmonary Hypertension and Sickle Cell Disease with Sildenafil Therapy (Walk-PHaSST) study. Tricuspid regurgitation velocity, which reflects systolic pulmonary artery pressure, was 2.7 to <3.0 m/s (mean±SD, 2.8±0.1) in 26% of the subjects and ≥3.0 m/s (mean±SD, 3.4±0.4) in 11%. The LV lateral E/e' ratio, which has been shown to reflect LV filling pressure in other conditions but has not been studied in sickle cell disease, was significantly higher in the groups with tricuspid regurgitation velocity ≥2.7 m/s. Increased hemolysis (P<0.0001), LV lateral E/e' ratio (P=0.0001), blood urea nitrogen (P=0.0002), and erythropoietin (P=0.002) were independently associated with an increased tricuspid regurgitation velocity. Furthermore, female sex (P<0.0001), older age (P<0.0001), LV lateral E/e' ratio (P=0.014), and tricuspid regurgitation velocity (P=0.019) were independent predictors of a shorter 6-minute walk distance., Conclusions: Echocardiography-estimated elevated pulmonary artery systolic pressure and LV lateral E/e' ratio were independently associated with poor exercise capacity in a large cohort of patients with sickle cell anemia. Controlled trials investigating whether strategies to prevent or delay pulmonary hypertension and/or LV diastolic dysfunction will improve exercise capacity and long-term outcomes in sickle cell anemia should be considered. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00492531.

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

Pain is the predominant medical presentation to hospitalists for patients with sickle cell disease (SCD). Dramatic treatment gains of SCD in childhood have resulted in more adults now requiring hospitalization than children. This has created new challenges to improve the quality of hospital care for SCD. The evidence base for pain management in SCD is lacking. We therefore offer some evidence and our informed opinion to answer frequently asked questions (FAQs) about pain management by hospitalists caring for adults with SCD. The most common questions center around defining a crisis; selecting and managing opioids; distinguishing between opioid tolerance, physical dependence, and addiction or misuse; determining appropriateness of discharge; and avoiding lengthy or recurrent hospitalizations., (Copyright © 2011 Society of Hospital Medicine.)

The aim of this study was to evaluate a direct thrombin inhibitor (DTI) titration protocol in patients with suspected HIT. This observational study compared patients treated with argatroban or bivalirudin according to the University of Colorado Hospital DTI titration protocol versus a control group treated prior to protocol implementation. Protocol patients had DTI initial doses based on organ function and fixed dosage adjustments of 10, 25, or 50%. Initial doses and titrations in the control group were made per physician discretion. A total of 130 patients were enrolled: 47 in the protocol group and 83 in the control group (median age 54 years, 63% male, 78% critically ill, and 54% received argatroban). Goal aPTT was achieved with initial DTI dose in 64% of protocol patients and 46% of control patients (P = 0.07). Median (IQR) time to goal aPTT was reduced in the protocol group compared to the control group [5 hr (2-10 hr) vs. 13 hr (6-29 hr); P < 0.0001]. Median time to dose stabilization was 10 hr (6-27 hr) and 22 hr (13-40 hr) in the protocol and control groups, respectively; P < 0.0001. Median number of titrations to goal was 0 (0-1) versus 1 (0-4), respectively; P = 0.02. Median percentage of aPTT values in goal was 67% (41-100%) versus 53% (33-76%), respectively; P = 0.027. The DTI titration protocol shortened time to achieve goal aPTT, reduced time to dose stabilization, decreased the number of titrations required to achieve aPTT goal, and improved the percentage of aPTT values in goal range., (Copyright © 2011 Wiley-Liss, Inc.)

Chronic pulmonary complications, including pulmonary hypertension (PH), are common in sickle cell disease (SCD), especially in adults with sickle cell anemia (SCA). The underlying pathophysiology is complex and variable, involving multiple biological systems. Recent emphasis has been placed on the pleotropic biological factor nitric oxide (NO). An elevated tricuspid regurgitant velocity (TRV) appears to have limitations in specificity in SCA, but may indicate the presence of PH, a diagnosis confirmed by right heart catheterization. TRV has been used in recent clinical trials to identify or define subjects with PH for enrollment into PH-specific interventions; these include sildenafil, which enhances NO-induced vasorelaxation. Results from a controlled trial show no benefit and an unexpected increase in adverse events, emphasizing the biological complexities of SCA. Management remains principally supportive, includes recognition and treatment of comorbidities, and may incorporate individualized PH-specific strategies (despite recent trials) based on appropriate diagnostic testing. Ultimately, therapy is likely to be multimodal and tailored to the processes identified to be the most contributory in a given individual. Based on the relative prevalence of the conditions, routine screening for asthma in children with SCD and by Doppler echocardiography to measure TRV as an initial screen for PH in adults with SCA may be warranted. Data are limited regarding the clinical utility of screening in other forms of SCD and the pediatric population. This article offers an individual perspective on practical and challenging clinical considerations.