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Background: SWAY was a cross-sectional survey that assessed the global impact and treatment of sickle cell disease (SCD) (James et al. ASH 2019). SCD puts patients at risk of multiple complications driven by vaso-occlusion and hemolytic anemia. Vaso-occlusive crises (VOCs) are the hallmark of SCD and can require healthcare attention. VOC frequency may be reduced by HU (Charache et al. N Engl J Med 1995). Aims: We assessed self-reported symptoms and quality of life (QoL) indicators for patients who reported using HU at the time of SWAY versus patients who did not, and we collected data on all treatments reported by SCD patients, by geographical region. Data were also collected regarding historical patient-reported use of HU prior to SWAY but these are not included here. Methods: SWAY was completed between April and October 2019 by SCD patients from 16 countries across 6 regions. A limitation is that Asia and South America were represented by single countries (India and Brazil, respectively). SWAY was completed by proxy (parent/guardian/caregiver) for patients aged 6-11 years and could be optionally self-completed by patients aged ≥12 years. Opinions were captured using a 1-7 Likert scale for some questions (5-7 indicated high satisfaction/impact/agreement). SWAY did not assess treatment outcomes. Results: Of 2145 patients, 652 (30%) reported receiving HU at the time of SWAY (56% female; 50% aged 6-25 years); 1493 patients reported not receiving HU at the time of SWAY (51% female; 59% aged 6-25 years). The number of patients reporting HU use varied regionally (Table). Patients who reported using HU also reported a lower VOC burden than patients who did not report using HU at the time of SWAY (median: 3 vs 4 VOCs in the 12 months before SWAY, respectively). However, considering other symptoms commonly experienced in the month prior to SWAY, a greater proportion of patients who reported using HU experienced these symptoms than patients who did not report using HU, except for headache and poor appetite, which were experienced by a lower proportion of patients who reported HU use (Figure). Similar proportions of patients reported that SCD had a high impact (Likert scale 5-7) on emotional wellbeing (61% [reported HU use at time of SWAY] vs 59% [did not report HU use at time of SWAY]) and daily activities (39% vs 40%, respectively). Overall, when including dietary supplements, the most common treatment reported at the time of SWAY in all regions except the Middle East was folic acid. Common treatments varied regionally when excluding supplements (Table). Top treatment goals for patients in all regions were to improve QoL and prevent SCD worsening. Treatment satisfaction (range: 57-92%) was highest in Asia (Table). Over 70% of patients wanted alternatives to their ongoing pain medications in all regions, except Asia (44%). Discussion: The proportion of patients reporting HU use at the time of SWAY was variable, but relatively low; HU was not in the top 3 treatments for Africa, Europe or North America. HU use was lowest in Africa, where no patients reported receiving HU at the time of the survey, which probably reflects high relative cost and poor access. Our regional analysis showed that many patients take supplements, such as folic acid, rather than HU. This may be indicative of limited alternatives to HU and reflects the differing global costs and availability of both medication and monitoring blood tests. Low reported use of HU may also reflect patients' concerns about side effects or reluctance to take daily medication. It should be noted that some patients may be familiar with 'hydroxycarbamide' as a name for HU and might not have recognized the term 'hydroxyurea' on the survey. Data from SWAY were not validated by medical records and depended on patients' recall. Patients reporting HU use at the time of SWAY had a lower VOC burden than patients not reporting HU use. QoL indicators were similar for the 2 groups, but the overall symptom burden was higher for patients who reported HU use compared with those who did not. However, the 2 groups were not matched for pre-treatment disease burden and no information was collected regarding adherence or duration of previous HU use. Overall, although many patients reported treatment satisfaction, many wanted alternative pain management therapies. A wider range of treatment options are needed to reduce SCD symptoms and improve QoL, ultimately helping patients achieve their treatment goals. Disclosures El Rassi: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclerion: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Membership on an entity's Board of Directors or advisory committees. James:Sickle Cell Society: Current Employment; Novartis: Honoraria. Andemariam:Terumo BCT: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Guidepoint: Honoraria; Accordant: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Hemanext: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CHNCT: Consultancy; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria; bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; CRISPR/Vertex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Inusa:Bluebird bio: Research Funding; AstraZeneca: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Vertex: Research Funding; Novartis: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau. Francis-Gibson:Sickle Cell Disease Association of America: Current Employment. Nero:Novartis: Consultancy; Bluebird bio: Consultancy. Minniti:Global Blood Therapeutics: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; CLS Bering: Consultancy. Trimnell:Novartis: Consultancy; Cyclerion: Consultancy; Global Blood Therapeutics: Consultancy. Abboud:Eli Lilly: Research Funding; Modus Pharmaceuticals: Research Funding; Crispr Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Novartis: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding. Arlet:Novartis: Consultancy, Honoraria. Colombatti:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees. de Montalembert:Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:Thalassemia and Sickle Cell Society: Other: Chief Medical Research Officer and Secretary. Jastaniah:Novartis: Consultancy, Honoraria. Nur:Novartis: Consultancy. Ramscar:Novartis Pharma AG: Current Employment. Bailey:Novartis: Other: Employee of Adelphi Real World, which has received consultancy fees from Novartis; Adelphi Real World: Current Employment. Rajkovic-Hooley:Adelphi Real World: Current Employment; Novartis: Other: Employee of Adelphi Real World, which has received consultancy fees from Novartis. Osunkwo:Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; Data and Safety Monitoring Board (DSMB) membership for Micella Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Health Resources and Services Administration (HRSA): Research Funding; Patient Centered Outcomes Research Institute (PCORI): Research Funding; Terumo: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: Sickle cell disease (SCD) is associated with many clinical complications, with vaso-occlusive crises (VOCs) being a hallmark of the disease. SCD-related complications are largely driven by vaso-occlusion and hemolytic anemia, and can lead to end-organ damage and early death. Analyses of SWAY, a cross-sectional survey, highlighted a substantial global impact of SCD on patients' quality of life (QoL) (James et al. ASH 2019; Osunkwo et al. ASH 2019). However, understanding how the burden of disease differs for pts of different ages could help improve management of SCD over a pt's lifespan. Aim: To assess, using data from SWAY, whether symptoms (excluding VOCs, as previously analyzed by Osunkwo et al. EHA 2020), treatment goals and the perceived impact of SCD were different for pts of different ages. Methods: Between April and October 2019, 2145 SCD pts aged ≥6 years participated in SWAY. The survey was completed by proxy (parent/caregiver/guardian) for pts aged 6-11 years and could be optionally self-completed by pts aged ≥12 years. Opinions were captured using a 1-7 Likert scale for some questions (5-7 indicated high satisfaction/impact/agreement). SWAY was not designed to assess treatment outcomes; all analyses are descriptive. Age groups were not matched and pts were not followed over time. Results: To understand how the most dominant symptoms of SCD differ for pts of different ages, the top 5 most commonly reported symptoms, stratified by age, were analyzed (Figure 1). Fatigue and bone aches were consistently reported, and the proportion of pts reporting them trended towards increasing with age. Furthermore, when asked which symptoms they most wanted to be resolved, fatigue was ranked in the top 3 by 40.7% of pts. Anxiety was a dominant symptom for pts aged 19-25, 36-45 and 46-50 years, whereas low mood was a dominant symptom for pts aged 19-50 and ≥60 years. Poor appetite was a dominant symptom for pts aged 6-16 years. Breathing issues were a dominant symptom for pts aged 6-18, 46-50 and ≥60 years, whereas vision issues were a dominant symptom for pts aged 51-59 years only. Insomnia was dominant for pts aged 46-50. The treatment goals that pts ranked as the most important were similar across age groups. Pts consistently included improving QoL, preventing worsening of SCD, reducing the number of VOCs and improving overall symptoms in their top 3, although the proportions of pts reporting these varied across age groups (Figure 2). Unsurprisingly, 23.0% of pts aged 12-16 years ranked increasing the ability to attend school in their top 3 goals. For pts aged 46-50 and 51-59 years, 27.5% and 20.7%, respectively, ranked reducing fatigue in their top 3 treatment goals. The highest proportions of pts reporting a high impact of SCD on their emotional wellbeing were aged 46-50 years (74.5%) and ≥60 years (73.9%), compared with 59.6% of all pts. Similarly, the highest proportions of pts reporting a high impact of SCD on daily activities were aged 46-50 years (51.0%) and ≥60 years (60.9%), compared with 38.1% of all pts. Limitations: These findings are based on pt and proxy reports, with potential parental bias being introduced for pediatric patients. There were variations in sample sizes, which was most noticeable for patients aged ≥46 years. Discussion: Fatigue and bone aches were consistently reported as dominant symptoms for all ages. Other dominant symptoms that were not consistent across age groups were anxiety, low mood, poor appetite, breathing issues and vision issues. In addition to the 36-45 years and 46-50 years groups, anxiety was a dominant symptom for pts aged 19-25 years. Along with other changes that could occur at this age, a recent transition from pediatric to adult care may contribute to anxiety being a dominant symptom; however, any direct relationship between anxiety and transitioning between care systems requires further investigation. The consistent reporting of low mood among adults, but not pediatrics, may reflect the increasing burden of disease that occurs with age. This is supported by higher proportions of pts aged ≥46 years versus Improving QoL was consistently ranked the most important treatment goal for pts. This emphasizes, from the pt's perspective, the need for further improvements in the management of SCD. Disclosures Colombatti: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees. James:Sickle Cell Society: Current Employment; Novartis: Honoraria. Andemariam:Hemanext: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CHNCT: Consultancy; CRISPR/Vertex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cyclerion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Accordant: Membership on an entity's Board of Directors or advisory committees; Guidepoint: Honoraria; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Vertex: Honoraria; Emmaus: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Inusa:Vertex: Research Funding; Bluebird bio: Research Funding; AstraZeneca: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Global Blood Therapeutics: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau; Novartis: Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau. El Rassi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclerion: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Membership on an entity's Board of Directors or advisory committees. Francis-Gibson:Sickle Cell Disease Association of America: Current Employment. Nero:Bluebird bio: Consultancy; Novartis: Consultancy. Minniti:Global Blood Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TauTona: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Emmaus: Consultancy, Research Funding; CLS Bering: Consultancy. Trimnell:Novartis: Consultancy; Cyclerion: Consultancy; Global Blood Therapeutics: Consultancy. Abboud:Amgen: Other: Travel support; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Crispr Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Modus Pharmaceuticals: Research Funding. Arlet:Novartis: Consultancy, Honoraria. de Montalembert:Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vertex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:Thalassemia and Sickle Cell Society: Other: Chief Medical Research Officer and Secretary. Jastaniah:Novartis: Consultancy, Honoraria. Nur:Novartis: Consultancy. Ramscar:Novartis Pharma AG: Current Employment. Bailey:Novartis: Other: Employee of Adelphi Real World, which has received consultancy fees from Novartis; Adelphi Real World: Current Employment. Rajkovic-Hooley:Adelphi Real World: Current Employment; Novartis: Other: Employee of Adelphi Real World, which has received consultancy fees from Novartis. Osunkwo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Terumo: Consultancy; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acceleron: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Health Resources and Services Administration (HRSA): Research Funding; Patient Centered Outcomes Research Institute (PCORI): Research Funding; Data and Safety Monitoring Board (DSMB) membership for Micella Biopharma: Membership on an entity's Board of Directors or advisory committees.

There is an immediate need to address long-standing questions about the reproductive health of girls and women with sickle cell disease (SCD). There are many SCD-related reproductive risks and uncertainties across girls' and women's reproductive life span, with particularly outstanding concerns about menstruation, contraception, fertility and pregnancy. Extant literature addressing women's reproductive health topics is mostly descriptive; there are few high-quality interventional studies. In 2020, the Centers for Disease Control and Prevention and the Foundation for Women and Girls with Blood Disorders convened an expert panel to assess the knowledge gaps in women's reproductive health in SCD. The panel identified significant limitations to clinical care due to the need for research. The panel also identified prominent barriers to research and care. In this report, we frame these issues, providing a roadmap for investigators, funding agencies, and policy makers to advance care for girls and women with SCD.

Sickle cell disease (SCD) is a genetic disorder, characterized by hemolytic anemia and vaso‐occlusive crises (VOCs). Data on the global SCD impact on quality of life (QoL) from the patient viewpoint are limited. The international Sickle Cell World Assessment Survey (SWAY) aimed to provide insights into patient‐reported impact of SCD on QoL. This cross‐sectional survey of SCD patients enrolled by healthcare professionals and advocacy groups assessed disease impact on daily life, education and work, symptoms, treatment goals, and disease management. Opinions were captured using a Likert scale of 1‐7 for some questions; 5‐7 indicated “high severity/impact.” Two thousand one hundred and forty five patients (mean age 24.7 years [standard deviation (SD) = 13.1], 39% ≤18 years, 52% female) were surveyed from 16 countries (six geographical regions). A substantial proportion of patients reported that SCD caused a high negative impact on emotions (60%) and school achievement (51%) and a reduction in work hours (53%). A mean of 5.3 VOCs (SD = 6.8) was reported over the 12 months prior to survey (median 3.0 [interquartile range 2.0‐6.0]); 24% were managed at home and 76% required healthcare services. Other than VOCs, fatigue was the most commonly reported symptom in the month before survey (65%), graded “high severity” by 67% of patients. Depression and anxiety were reported by 39% and 38% of patients, respectively. The most common patient treatment goal was improving QoL (55%). Findings from SWAY reaffirm that SCD confers a significant burden on patients, epitomized by the high impact on patientsʼ QoL and emotional wellbeing, and the high prevalence of self‐reported VOCs and other symptoms.

Background: SCD is an inherited blood disorder that for many patients (pts) has a high clinical burden, results in poor quality of life (QoL), and reduces life expectancy. Gaining a deeper understanding of pt and HCP experiences of SCD is important to improve pt management. Aims: SWAY was a cross-sectional survey that assessed pt and HCP experiences of SCD. Here we focus on the experiences of HCPs from various regions on SCD symptoms and complications, impact of SCD on QoL, treatment goals and treatment satisfaction. Methods: SWAY was developed by international SCD expert physicians, pt advocates and Novartis. HCPs completed the survey between Apr and Oct 2019. Eligible HCPs had qualified in their primary specialty by 2014 and were managing ≥10 SCD pts at the time of survey (≥5 pts per HCP in Canada; ≥2 pts in the Netherlands). Responses to questions on how much SCD impacts pt QoL, and on HCP treatment satisfaction, were ranked on a Likert scale (1-7, where 1=not at all/strongly dissatisfied, 7=a great deal/strongly satisfied; 5-7 indicated high impact/satisfaction). The data reflect only the experiences of the surveyed HCPs in each region (recruited by Adelphi Real World fieldwork). A limitation is that Asia and South America (SA) were represented by single countries (India and Brazil, respectively). Results: SWAY was completed by 365 HCPs from 6 regions (Table). In all regions HCPs recognized the prevalence of acute and chronic pain, however acute pain was reported less frequently by HCPs in Africa than in other regions (Table). Acute chest syndrome and joint issues were among the top 5 most frequently mentioned complications by HCPs in all regions. Globally, HCPs recognized the high impact of SCD symptoms and complications on pt QoL and the high negative impact of SCD on pt emotional wellbeing (Likert score 5-7 reported by 79-100% and 71-97%, respectively). Fewer HCPs in the Middle East (ME) reported a high impact of SCD on physical and sexual activity, compared with HCPs in other regions. Around 40% of HCPs in the ME and Asia thought SCD has a high impact on daily activities, compared with 79-90% of HCPs in other regions. In Asia, fewer HCPs reported that SCD has a high impact on pts' education and ability to maintain a job compared with HCPs in other regions (Figure). Hydroxyurea (HU) was among the top 3 most common therapies ever initiated and was the therapy most likely to be initiated in any age group by HCPs in almost all regions. In Africa, the most common therapy ever initiated and the therapy most likely to be initiated in any age group was opioids (Table). Fewer HCPs in North America (NA; 32%) and SA (27%) were highly satisfied with current SCD treatments, compared with HCPs in other regions (46-72%). The main reason for dissatisfaction was limited treatment options in all regions except Asia, where HCPs said they were unable to reach their treatment goals with current therapies. Improving pts' QoL was among the top 3 treatment goals for 51-84% of HCPs across all regions. For HCPs in NA and the ME, the most important goal when treating vaso-occlusive crises was to improve QoL; in SA, Europe and Asia it was to avoid organ damage; and in Africa it was to eliminate pain completely. Discussion: The top 5 most frequent SCD symptoms and complications that HCPs reported were similar across all regions. There were regional differences in HCP experiences of how SCD impacts aspects of pts' daily life, with fewer HCPs in the ME reporting a high impact on physical and sexual activity, and fewer HCPs in Asia and the ME reporting a high impact on daily activities compared with other regions. This may be due to cultural variations, with pts in these regions being less comfortable discussing these topics with HCPs. There was a difference in the reported impact of SCD on school and work between HCPs in Asia and other regions, which could be due to varying expectations regarding school/work productivity. HU was one of the top 3 most common treatments ever initiated by HCPs for pts of any age, except in Africa, which may be due to an educational knowledge gap about HU, high cost, or poor access in this region. HCPs in almost all regions, except Asia, were dissatisfied with current SCD treatments because of limited therapeutic options, indicating a global unmet need for additional treatment choices. Improving QoL was the most important treatment goal for HCPs in all regions, demonstrating the high negative impact that SCD has on pt QoL and the ongoing need for methods to address this. Figure 1 Figure 1. Disclosures Osunkwo: Novartis Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; FORMA Therapeutics: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; Chiesi: Consultancy; Acceleron: Consultancy; Cyclerion: Consultancy; Emmaus: Consultancy. Minniti: Roche: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; GBT: Consultancy, Research Funding. Nur: Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Nero: Global Blood Therapeutics: Consultancy; Editas Medicine: Consultancy; bluebird bio: Consultancy; Novartis: Consultancy. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding. de Montalembert: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Addmedica: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Vertex: Membership on an entity's Board of Directors or advisory committees. Abboud: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Support and Advisory Board, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Reserach support and advisory board , Research Funding; GBT: Other: Research Support, Research Funding; Vertex Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB. Arlet: Addmedica: Research Funding; Pfizer: Honoraria; Novartis company: Consultancy, Honoraria, Research Funding. Jastaniah: Novartis: Consultancy, Honoraria, Research Funding. Pita: GLOBAL ALLIANCE OF SCD: Membership on an entity's Board of Directors or advisory committees; LUA VERMELHA SCD ASSOCIATION: Membership on an entity's Board of Directors or advisory committees. Francis-Gibson: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of America: Current Employment; ASH: Membership on an entity's Board of Directors or advisory committees; Alliance for Regenerative Medicine Foundation for Cell and Gene Medicine: Membership on an entity's Board of Directors or advisory committees; Global Alliance of SCD Organizations: Membership on an entity's Board of Directors or advisory committees. Trimnell: Novartis: Consultancy; Cyclerion: Consultancy; Global Blood Therapeutics: Consultancy. DeBonnett: Novartis Pharmaceuticals Corporation: Current Employment. Bailey: Novartis Pharmaceuticals: Other: I am an employee of Adelphi Real World, which received payment from Novartis Pharmaceuticals for this research. Rajkovic-Hooley: Novartis Pharmaceuticals: Other: I am an employee of Adelphi Real World, which received payment from Novartis Pharmaceuticals for this research. James: GBT: Honoraria; Novartis: Honoraria.

Background: Sickle cell disease (SCD) is an inherited systemic disorder in which sickle hemoglobin (HbS) polymerization triggers red blood cell sickling, chronic hemolytic anemia, and recurrent episodes of vaso-occlusion. SCD-related complications lead to acute and chronic life-threatening events, cumulative organ damage, disability, and early mortality. Voxelotor (Oxbryta ®) tablets are approved in the United States for treatment of SCD in adults and adolescents aged ≥12 years, based on the efficacy and safety data from the randomized, placebo-controlled, multicenter HOPE trial. Voxelotor is an oral, once-daily HbS-polymerization inhibitor that has been shown to increase hemoglobin (Hb) levels and reduce markers of hemolysis. The Retrospective Study to Evaluate Outcomes in Patients with Sickle Cell Disease Treated with Oxbryta (RETRO) is designed to collect, aggregate, and characterize real-world, retrospective laboratory and clinical data on adults and adolescents with SCD treated with voxelotor as part of their usual care at multiple clinical centers in the United States. Methods: RETRO is a multicenter, post-marketing, retrospective study of approximately 300 patients (aged ≥12 years) with SCD from 10 US study sites. Independent SCD expertise is provided by a steering committee to inform the design and conduct of the voxelotor registry. Clinical and laboratory data have been collected and aggregated 12 months before initiation of voxelotor treatment and compared with post-treatment data outcomes. Patients with documented SCD (all genotypes) who received voxelotor treatment for ≥2 consecutive weeks were included in this analysis. Only data available from patients' medical records (and other secondary data sources) 1 year before and up to 1 year after the first voxelotor dose were documented in de-identified case report forms via an electronic data capture system. Results: Forty-nine patients whose data were entered at 5 sites at the time of data cutoff (June 25, 2021) were included (mean age [SD]: 34.3 [12.91] years; 57.1% female; 85.7% HbSS and 6.1% HbSβ 0 genotype). Mean (SD) duration of voxelotor treatment was 48.1 (23.0) weeks. The initial prescribed voxelotor dose strengths (n, %) were 500 mg (4, 8.2%), 1000 mg (7, 14.3%), and 1500 mg (38, 77.6%). Rationale for prescription (n, %) included reduction of anemia (36, 73.5%), reduction in frequency of vaso-occlusive crises (23, 46.9%), reduction in pain (34, 69.4%), reduction in the need for blood transfusion (8, 16.3%) and other (5, 10.2%); more than 1 reason may have been selected. In 35 patients with recorded baseline and post-treatment Hb values, the peak observed post-treatment Hb (mean [SD]) was 9.4 (2.44) g/dL, an increase of 1.6 (1.5) g/dL from baseline (7.8 [2.02] g/dL). Fifty percent (11/22) of patients had a clinical response (Hb increase of >1.0 g/dL from baseline) within 12 months of voxelotor treatment. Per-patient peak changes in Hb during the study period showed that 62.9% of patients experienced a response at some time up to 12 months during treatment (Figure). Change in hemolytic markers was also evaluated. In patients with recorded baseline and post-treatment reticulocyte percentage (N=19) and indirect bilirubin (N=24), the mean (SD) absolute post-treatment value was 7.4% (4.65%) for reticulocyte percentage, a decrease of 4.9% (6.63%) compared with baseline (12.4% [8.32%]), and 1.9 (1.66) mg/dL for indirect bilirubin, a decrease of 17.7 (81.83) mg/dL compared with baseline (19.6 [81.82] mg/dL). The most common non-SCD-related treatment-emergent adverse events (AEs) were diarrhea, headache, and rash (Table); 19 (38.8%) patients reported ≥1 AE, and most non-SCD-related AEs were mild in severity. Conclusions: RETRO is the first multicenter, retrospective study to examine the real-world effectiveness of voxelotor and describe the observed changes in laboratory and clinical outcomes after ≥2 weeks of therapy. This study shows that voxelotor treatment was associated with increased Hb levels and decreased hemolytic markers. The safety data are consistent with those from the HOPE trial. Further evaluation is needed, with additional data from all 10 sites, and will be presented later. Funding: This study was supported by Global Blood Therapeutics. Figure 1 Figure 1. Disclosures Achebe: Fulcrum Therapeutics: Consultancy; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Clay: GBT: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Nero: Global Blood Therapeutics: Consultancy; Editas Medicine: Consultancy; bluebird bio: Consultancy; Novartis: Consultancy. Osunkwo: Terumo: Consultancy; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; Forma Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Health and Services Administration: Research Funding; Patient Centered Outcomes Research Instituted: Research Funding; Micella Biopharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chiesi: Consultancy; Cyclerion: Consultancy; Emmaus: Consultancy. Idowu: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ironwood: Research Funding; Forma Therapeutics, Inc.: Research Funding; Pfizer: Research Funding. Shah: Novartis: Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Emmaus: Consultancy; GBT: Consultancy, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; CSL Behring: Consultancy; GLG: Consultancy; Bluebird Bio: Consultancy. Curtis: GBT: Consultancy. Minniti: Bluebird Bio: Other: Endpoint adjudicator ; F. Hoffmann-La Roche Ltd: Consultancy; Chiesi: Consultancy; Novo Nordisk: Consultancy; Forma: Consultancy; Novartis: Consultancy; GBT: Consultancy; CSL Behring: Other: Endpoint adjudicator .

Sickle cell disease (SCD) and β-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5-7% of the world's population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and β-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for β-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities.

Background: Sickle cell disease (SCD) is a multi-system disease affecting millions of people. The disease is characterized by vaso-occlusive crises (VOCs), resulting in acute and chronic pain, end-organ damage and life-threatening complications. The symptoms experienced by patients, caused largely by multi-cellular adhesion leading to vaso-occlusion and vasculopathy, significantly affect their quality of life (QoL) and ability to work/study. Understanding the effect of SCD on patients' daily lives can inform management of the disease and improve patients' QoL. Aims: To assess the impact of SCD on patients' daily lives, including physical symptoms, emotional wellbeing and economic burden, based on the worldwide SWAY survey. Methods: SWAY is an ongoing multi-country, cross-sectional survey of SCD patients, caregivers and treating physicians. Data are collected using self-completed or proxy surveys and categories include demographics, symptoms and impact of disease (physical, emotional and financial) and need for a caregiver. Where relevant, questions include a 7-point severity scale for each statement, with a score of 5 to 7 indicating 'high severity/impact'. Patient enrollment is via treating physicians and patient association groups. The enrollment target is approximately 2000 patients. Results: To date, 1513 SCD patients (48% male, mean age 24.1 years, 63% HbSS and 30% SC disease) have been surveyed from countries across the world, including the USA (365), UK (299), Nigeria (264), Ghana (255), Brazil (160) and Germany (91). The most commonly experienced symptoms of SCD were bone aches (63%), difficulty concentrating (49%), difficulty gaining weight (49%) and joint stiffness (41%). For these symptoms, 67%, 53%, 70% and 59% of patients rated them as 'high severity' on the 7-point scale, respectively. Background pain was present on an average of 2.9 days per week (standard deviation [SD]=2.2). Commonly experienced complications of SCD include fever (65%), joint issues (55%) and infections (55%). Patients reported a total of 7829 VOCs, with a mean of 5.2 VOCs per patient (SD=5.07) in the 12 months before survey completion; 38% of these VOCs resulted in overnight hospitalization, 24% were managed at home, 19% were treated in the emergency room and 19% of patients sought medical assistance in the community. A high impact on emotional wellbeing was reported by 61% of patients. The highest impact was caused by frustration with symptoms (60%), worry about disease worsening (59%) and worry about family/friends/children who care for them (54%). Only 42% of patients have received professional emotional support (eg psychiatrist, psychologist, counseling), but 67% reported a desire to receive this support. A high impact on household daily activities (eg food preparation, housework, childcare) and on family or social life was reported by 39% and 43% of patients, respectively, with 34% stating a high impact in terms of sexual desire/activity and 35% a high impact on relationships with spouse/partner. Physical activity was also affected in patients with SCD, with 60% reporting they avoid intense physical activity and 30% avoiding even mild physical activity, most commonly because of concerns about pain, exhaustion and dehydration (58%, 57% and 50%, respectively). Of the patients surveyed, 32% were employed, 8% not working but seeking employment, 6% not working and not seeking employment, 36% students, 1% retired, 13% on disability pay and 1% long-term sick leave. Employed patients reported SCD had a high impact on their ability to work, with 57% reducing their hours and 47% considering leaving their job. An average of 6.3 hours missed from work was reported in the 7 days prior to survey completion due to SCD. Half of patients believe that their income would be higher if they did not have SCD, 60% reported often missing school in the past and 52% felt that their disease has had a negative impact on their academic achievements. Conclusions: The acute and chronic symptoms associated with SCD have a substantial impact on patients' daily lives, including emotional and physical wellbeing, relationships and school/work. In addition, the acute symptoms associated with VOCs occur several times a year, resulting in frequent hospitalizations. Improved management of SCD would enhance patients' quality of life both at home and at school/work, likely leading to improved emotional wellbeing and a positive economic effect. Disclosures Osunkwo: Micella Biopharma: Other: DSMB Member ; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Terumo: Speakers Bureau. Andemariam:Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: DSMB Member; Imara: Research Funding; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Community Health Network of Connecticut: Consultancy. El-Rassi:Novartis Pharmaceuticals: Research Funding. Francis-Gibson:Sickle Cell Disease Association of America: Employment. Nero:Novartis: Consultancy. Minniti:Doris Duke Foundation: Research Funding. Trimnell:Global Blood Therapeutics: Consultancy; Novartis: Consultancy; Cyclerion: Consultancy. Abboud:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Modus: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other: Travel support; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Colombatti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jastaniah:Novartis Pharmaceuticals: Consultancy, Honoraria. Nur:Novartis Pharmaceuticals: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. James:Sickle Cell Society: Employment; Novartis: Honoraria.

Background: Sickle cell disease (SCD) is a complex genetic disorder affecting mainly people of African origin. A hallmark of SCD is vaso-occlusive crisis (VOC) - this event is acutely painful and the primary cause of hospitalization in SCD patients. VOC can lead to life-threatening complications such as acute chest syndrome. SCD is also associated with chronic complications including pulmonary hypertension, damage to organs and shortened life expectancy. Therefore, effective management and treatment strategies are essential to reduce burden of illness and ensure high quality of life for the patient. Aim: To survey the treatment and management strategies used by patients with SCD, and to determine patient satisfaction levels. Methods: SWAY is an ongoing multi-country, cross-sectional survey of SCD patients, caregivers and treating physicians. The survey, conducted online and in print, includes 6 categories: demographics, symptoms, impact of disease and use of a caregiver, impact on work and finances, disease management/treatment approaches, and patient-physician relationship. Where relevant, questions include a 7-point severity scale for each statement; a score of 5−7 indicates 'high severity/impact'. Patient enrollment is via treating physicians and patient association groups. The enrollment target is approximately 2000 patients. Results: To date, 1513 SCD patients (48% male, mean age 24.1 years, 63% HbSS and 30% HbSC disease) have been surveyed from 11 countries across North and South America, Europe and Africa. When considering the main person responsible for SCD treatment and management, patients primarily reported management by an SCD specialist (59% of patients) or GP/family doctor (20%). Most patients were satisfied with the frequency of interaction with their doctor (78%) and reported they are confident they are being assessed and treated properly (66%; based on high-impact scores 5−7). Accordingly, 60% of patients (scoring 5−7) reported sharing the same goals for SCD management and treatment as their doctor. The most common treatment goals for patients are to improve quality of life (80% of patients), prevent SCD worsening (59%), improve long-term survival (42%) and improve overall symptoms (40%). Patients reported receiving ongoing treatment with folic acid (58%), antibiotics (37%), anti-inflammatories (37%), over-the-counter pain medication (37%), opioids (35%), hydroxyurea (23%), blood transfusions (10%) and L-glutamine (4%). Having surgery or a medical procedure to manage their SCD was reported by 47% of patients, with gall bladder removal (16%), port placement (15%) and splenectomy (11%) being the most frequent. Although 63% of patients (scoring 5−7) indicated satisfaction with their treatment received to manage their SCD, 75% of patients (scoring 5−7) agreed they would like an alternative treatment to their current pain management medication, and 67% of patients would like additional professional emotional support. In the 12 months before survey completion, 7829 VOCs were reported (mean of 5.2 VOCs per patient); 8% of patients experienced 0 VOCs, 51% experienced 1−4 VOCs and 40% experienced ≥5 VOCs. Of these, 38% of VOCs led to overnight hospitalization, 24% were managed at home and 19% were treated in the emergency room. The main reasons that patients chose to manage their VOCs at home include a previous poor experience at hospital (40%), the opinion that medical assistance was not required (28%), the perception that medical professionals do not understand SCD (27%) and the cost of hospital treatment (22%; 41% of patients have no health insurance). Patients who self-managed their VOCs primarily did so with rest/sleep (73%), by drinking fluids (72%) and with opioid-based analgesia (58%). Conclusions: This interim analysis of the SWAY survey suggests that although many patients report satisfaction with their current level of management and treatment, there is still a need for additional healthcare support and alternative treatments. Underlining this, many patients experiencing VOCs do not seek medical assistance despite the potential for life-threatening complications, and >75% of patients surveyed are not receiving hydroxyurea even though the majority are cared for by SCD specialists. Further data collection and analysis will highlight any geographic differences in SCD management strategies and help identify any region-specific unmet patient needs. Disclosures James: Novartis: Honoraria; Sickle Cell Society: Employment. Andemariam:NovoNordisk: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Emmaus: Membership on an entity's Board of Directors or advisory committees; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Imara: Research Funding; Global Blood Therapeutics: Other: DSMB Member; Community Health Network of Connecticut: Consultancy; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Membership on an entity's Board of Directors or advisory committees. El-Rassi:Novartis Pharmaceuticals: Research Funding. Francis-Gibson:Sickle Cell Disease Association of America: Employment. Nero:Novartis: Consultancy. Minniti:Doris Duke Foundation: Research Funding. Trimnell:Novartis: Consultancy; Global Blood Therapeutics: Consultancy; Cyclerion: Consultancy. Abboud:Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Modus: Research Funding; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Eli Lilly: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Colombatti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jastaniah:Novartis: Consultancy, Honoraria. Nur:Novartis: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Osunkwo:Micella Biopharma: Other: DSMB Member ; Terumo: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau.

Sickle cell disease (SCD) and β-thalassemia are among the most common inherited diseases, affecting millions of persons globally. It is estimated that 5–7% of the world’s population is a carrier of a significant hemoglobin variant. Without early diagnosis followed by initiation of preventative and therapeutic care, both SCD and β-thalassemia result in significant morbidity and early mortality. Despite great strides in the understanding of the molecular basis and pathophysiology of these conditions, the burden of disease remains high, particularly in limited resource settings. Current therapy relies heavily upon the availability and safety of erythrocyte transfusions to treat acute and chronic complications of these conditions, but frequent transfusions results in significant iron overload, as well as challenges from acquired infections and alloimmunization. Hydroxyurea is a highly effective treatment for SCD but less so for β-thalassemia, and does not represent curative therapy. As technology and use of cellular and gene therapies expand, SCD and thalassemia should be among the highest disease priorities.

Background and Aim To investigate the impact of hospital-acquired Clostridium difficile infection (CDI) on hospital costs and patient length of stay. Methods Data from the 2007–2008 New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS) database was analyzed using regression analysis and descriptive statistics. Results After analysis of 4 853 800 patient discharges, the incidence rate of hospital-acquired CDI was 0.8 cases per 1000 discharges. The estimated marginal cost associated with each hospital infection was approximately $29 000. The estimated annual cost of CDI in New York State was approximately $55 million with nearly 23 000 additional hospital days. Conclusions The development of hospital-acquired CDI is associated with a significant increase in hospital costs and patient length of stay. Extrapolation of these estimates to all US hospitals suggests this condition represents a major burden to the US healthcare system. Our findings may help hospitals understand the impact of these infections, as well as potential implications if deemed preventable by Centers for Medicare & Medicaid Services and/or private payers. Additionally, this information may benefit hospitals or health care systems transitioning to alternative payment models, such as episode-based payments or accountable care. Healthcare providers and hospitals would benefit from better understanding the impact and frequency of these infections in order to best target preventive strategies.

Understanding how nutrients affect gene expression will help us to understand the mechanisms controlling plant growth and development as a function of nutrient availability. Nitrate has been shown to serve as a signal for the control of gene expression in Arabidopsis . There is also evidence, on a gene-by-gene basis, that downstream products of nitrogen (N) assimilation such as glutamate (Glu) or glutamine (Gln) might serve as signals of organic N status that in turn regulate gene expression. To identify genome-wide responses to such organic N signals, Arabidopsis seedlings were transiently treated with ammonium nitrate in the presence or absence of MSX, an inhibitor of glutamine synthetase, resulting in a block of Glu/Gln synthesis. Genes that responded to organic N were identified as those whose response to ammonium nitrate treatment was blocked in the presence of MSX. We showed that some genes previously identified to be regulated by nitrate are under the control of an organic N-metabolite. Using an integrated network model of molecular interactions, we uncovered a subnetwork regulated by organic N that included CCA1 and target genes involved in N-assimilation. We validated some of the predicted interactions and showed that regulation of the master clock control gene CCA1 by Glu or a Glu-derived metabolite in turn regulates the expression of key N-assimilatory genes. Phase response curve analysis shows that distinct N-metabolites can advance or delay the CCA1 phase. Regulation of CCA1 by organic N signals may represent a novel input mechanism for N-nutrients to affect plant circadian clock function.

Context Sickle cell disease (SCD) confers an increased risk of invasive pneumococcal disease, especially among young children. Pneumococcal vaccination decreases this risk, but the completion rate of age-appropriate vaccinations is not well defined in SCD. Objective The goal of this study was to assess whether pneumococcal vaccines are administered to high-risk children with SCD according to recommended vaccine schedules. Design A case-control design was used to conduct this study. Setting Administrative data were obtained on Michigan Medicaid or Children's Special Health Care Services programs enrollees. In addition, Michigan Newborn Screening and Michigan Care Improvement Registry records were used to confirm diagnosis and vaccine administration. Participants This study compared pneumococcal vaccination rates in a cohort of 179 children with SCD with 537 age-matched non-SCD controls (1:3) enrolled in the Michigan Medicaid Program between 2001 and 2008. Study subjects were born in the state of Michigan between 2001 and 2005. Main outcome measure The main outcome measure was the proportion of children defined as up to date for pneumococcal vaccines at defined milestone ages. Results Children with SCD had significantly higher vaccination rates than controls, yet these values were much lower than state and national immunization survey rates. Conclusion Barriers to completing age-appropriate recommended pneumococcal immunizations should be identified and addressed to further reduce invasive pneumococcal disease in this high-risk patient population.

Proper management of sickle cell anemia (SCA) begins with establishing the correct diagnosis early in life, ideally during the newborn period. The identification of affected infants by neonatal screening programs allows early initiation of prophylactic penicillin and pneumococcal immunizations, which help prevent overwhelming sepsis. Ongoing education of families promotes the early recognition of disease-released complications, which allows prompt and appropriate medical evaluation and therapeutic intervention. Periodic evaluation by trained specialists helps provide comprehensive care, including transcranial Doppler examinations to identify children at risk for primary stroke, plus assessments for other parenchymal organ damage as patients become teens and adults. Treatment approaches that previously highlighted acute vaso-occlusive events are now evolving to the concept of preventive therapy. Liberalized use of blood transfusions and early consideration of hydroxyurea treatment represent a new treatment paradigm for SCA management.

Background: Sickle nephropathy (SN) is a common and progressive manifestation of sickle cell anemia (SCA). Albuminuria indicates glomerular injury and portends renal failure. In a murine model of SCA, we found that increased TGF-Beta signaling underlies SN, and its downregulation by losartan, an angiotensin receptor blocker, reduced albuminuria and SN progression. The effect of losartan in humans with SCA has not been studied. We performed a phase-2, open-label study to inform the design of a phase-3 randomized trial to estimate the effect of losartan on SN. We also explored the effect of losartan on the cardiac phenotype of SCA. Methods: Oral losartan was administered for 6 months to individuals with SCA (HbSS or SBeta0-thalassemia) >6 years of age. Main exclusion criteria: chronic transfusions, GFR 300). The primary endpoint was a >25% reduction UACR from baseline. Sample size was calculated to detect the primary endpoint in >30% of the MicroA group with >80% power. Secondary endpoints: urine osmolality, GFR, UACR classification and toxicity, and cardiac phenotyping by echocardiography and assessment of 6-minute walk distance (6MWD). Results: There were 36 participants (mean age 24.1y; 53% female) in 3 groups (NoA=15; MicroA=13; MacroA=8). Four were not evaluable based on pre-specified criteria (marked non-compliance and/or early termination). The primary endpoint (>25% reduction in UACR) was met in 83% (5/6) of the MacroA group, 58% (7/12) of the MicroA group, and 7% (1/14) of the NoA group (FigureA). The median fold-change in UACR was -0.74, -0.46, and 0.08 for the MacroA, MicroA, and NoA groups, respectively (FigureB). Among MacroA and MicroA participants, 67% (12/18) met the primary endpoint (FigureC). In MacroA and MicroA participants, UACR classification improved (MacroAˆMicroA or MicroAˆNoA) in 50% but worsened in 11%. Mean UACR was 202 mg/g (S.E.M. 59, median 50) before and 137 (S.E.M. 47, median 16) after losartan (P=0.29). Urine osmolality and GFR did not change significantly (393 vs 370 mosm/kg H20, P=0.11; 147 vs 139 mL/min/1.73m2, P=0.43). Losartan was discontinued for leg cramps (N=1); GFR decline >25% (N=1); and serum creatinine rise >50% (N=1). Interestingly, compared to those with NoA, participants with albuminuria (MicroA and MacroA, mean UACR 373±87 mg/g) had worse diastolic function indicated by lower early-to-late ratio of mitral inflow velocities, E/A (1.81±0.1 vs 2.3±0.1, P=0.018), and septal annular velocities ratio, e'/a' (1.5±0.2 vs 2.4±0.2, P Conclusions: Losartan appeared to decrease SCA-related albuminuria in most participants. Those with baseline macroalbuminuria appeared to have the greatest benefit, nearly all of whom showed a response. Albuminuria, a marker of sickle nephropathy, is also associated with evidence of restrictive cardiac physiology, suggesting common underlying mechanisms. However, the short 6-month treatment with losartan had no obvious effects on the cardiac phenotype of SCA. A phase-3, randomized, placebo-controlled trial is being designed to determine the efficacy of losartan in SCA. [This work was supported by NIH R34 HL 108752 (PI: Malik, P)]. Figure Figure. Disclosures Quinn: Silver Lake Research Corporation: Consultancy; Eli Lilly: Research Funding; Amgen: Research Funding. Raj:Novartis: Speakers Bureau.

To investigate the impact of hospital-acquired Clostridium difficile infection (CDI) on hospital costs and patient length of stay.Data from the 2007-2008 New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS) database was analyzed using regression analysis and descriptive statistics.After analysis of 4 853 800 patient discharges, the incidence rate of hospital-acquired CDI was 0.8 cases per 1000 discharges. The estimated marginal cost associated with each hospital infection was approximately $29 000. The estimated annual cost of CDI in New York State was approximately $55 million with nearly 23 000 additional hospital days.The development of hospital-acquired CDI is associated with a significant increase in hospital costs and patient length of stay. Extrapolation of these estimates to all US hospitals suggests this condition represents a major burden to the US healthcare system. Our findings may help hospitals understand the impact of these infections, as well as potential implications if deemed preventable by Centers for MedicareMedicaid Services and/or private payers. Additionally, this information may benefit hospitals or health care systems transitioning to alternative payment models, such as episode-based payments or accountable care. Healthcare providers and hospitals would benefit from better understanding the impact and frequency of these infections in order to best target preventive strategies.

This article investigates the financial impact of the Centers for MedicareMedicaid Services' hospital-acquired conditions (HACs).Data from 2007-2008 was analyzed using New York State Department of Health's Statewide Planning and Research Cooperative System (SPARCS), using regression analysis and descriptive statistics for each condition.Of 4,853,800 patient discharges, the development of decubitus ulcers was the most prevalent condition, associated with an annual cost of nearly $680 million and 376,546 hospital days. Mediastinitis after Coronary Artery Bypass Graft (CABG) had the highest marginal impact for both length of stay (LOS) and total costs, but this condition had a relatively low frequency. Extrapolation of the results suggests that HACs represent a major burden to US hospitals.HACs have a significant financial impact on the US health care system. Hospitals would benefit from better understanding the impact and frequency of these conditions in order to best target preventative strategies.

This article reviews the current research-based knowledge on nonpharmacological interventions for students with ADD and highlights findings related to behavior management, academic instruction, home-school collaboration, and comprehensive programming. The literature on educationally relevant interventions is exploratory, not prescriptive; and findings are inconsistent. Investigators have tested relatively few interventions that speak to the day-to-day issues teachers face or to the larger issues related to developing comprehensive educational programs for these students.

Data generation is no longer the limiting factor in advancing biological research. In addition, data integration, analysis, and interpretation have become key bottlenecks and challenges that biologists conducting genomic research face daily. To enable biologists to derive testable hypotheses from the increasing amount of genomic data, we have developed the VirtualPlant software platform. VirtualPlant enables scientists to visualize, integrate, and analyze genomic data from a systems biology perspective. VirtualPlant integrates genome-wide data concerning the known and predicted relationships among genes, proteins, and molecules, as well as genome-scale experimental measurements. VirtualPlant also provides visualization techniques that render multivariate information in visual formats that facilitate the extraction of biological concepts. Importantly, VirtualPlant helps biologists who are not trained in computer science to mine lists of genes, microarray experiments, and gene networks to address questions in plant biology, such as: What are the molecular mechanisms by which internal or external perturbations affect processes controlling growth and development? We illustrate the use of VirtualPlant with three case studies, ranging from querying a gene of interest to the identification of gene networks and regulatory hubs that control seed development. Whereas the VirtualPlant software was developed to mine Arabidopsis (Arabidopsis thaliana) genomic data, its data structures, algorithms, and visualization tools are designed in a species-independent way. VirtualPlant is freely available at www.virtualplant.org.

Background Nitrate-induced reprogramming of the transcriptome has recently been shown to be highly context dependent. Herein, a systems biology approach was developed to identify the components and role of cross-talk between nitrate and hormone signals, likely to be involved in the conditional response of NO3 - signaling. Results Biclustering was used to identify a set of genes that are N-responsive across a range of Nitrogen (N)-treatment backgrounds (i.e. nitrogen treatments under different growth conditions) using a meta-dataset of 76 Affymetrix ATH1 chips from 5 different laboratories. Twenty-one biclusters were found to be N-responsive across subsets of this meta-dataset. N-bicluster 9 (126 genes) was selected for further analysis, as it was shown to be reproducibly responsive to NO3 - as a signal, across a wide-variety of background conditions and datasets. N-bicluster 9 genes were then used as "seed" to identify putative cross-talk mechanisms between nitrate and hormone signaling. For this, the 126 nitrate-regulated genes in N-bicluster 9 were biclustered over a meta-dataset of 278 ATH1 chips spanning a variety of hormone treatments. This analysis divided the bicluster 9 genes into two classes: i) genes controlled by NO3 - only vs. ii) genes controlled by both NO3 - and hormones. The genes in the latter group showed a NO3 - response that is significantly enhanced, compared to the former. In silico analysis identified two Cis-Regulatory Elements candidates (CRE) (E2F, HSE) potentially involved the interplay between NO3 - and hormonal signals. Conclusion This systems analysis enabled us to derive a hypothesis in which hormone signals are proposed to enhance the nitrate response, providing a potential mechanistic explanation for the link between nitrate signaling and the control of plant development.

BackgroundLight and carbon are two important interacting signals affecting plant growth and development. The mechanism(s) and/or genes involved in sensing and/or mediating the signaling pathways involving these interactions are unknown. This study integrates genetic, genomic and systems approaches to identify a genetically perturbed gene network that is regulated by the interaction of carbon and light signaling in Arabidopsis.ResultsCarbon andlightinsensitive (cli) mutants were isolated. Microarray data fromcli186is analyzed to identify the genes, biological processes and gene networks affected by the integration of light and carbon pathways. Analysis of this data reveals 966 genes regulated by light and/or carbon signaling in wild-type. Incli186, 216 of these light/carbon regulated genes are misregulated in response to light and/or carbon treatments where 78% are misregulated in response to light and carbon interactions. Analysis of the gene lists show that genes in the biological processes "energy" and "metabolism" are over-represented among the 966 genes regulated by carbon and/or light in wild-type, and the 216 misregulated genes incli186. To understand connections among carbon and/or light regulated genes in wild-type and the misregulated genes incli186, the microarray data is interpreted in the context of metabolic and regulatory networks. The network created from the 966 light/carbon regulated genes in wild-type, reveals thatcli186is affected in the light and/or carbon regulation of a network of 60 connected genes, including six transcription factors. One transcription factor, HAT22 appears to be a regulatory "hub" in thecli186network as it shows regulatory connections linking a metabolic network of genes involved in "amino acid metabolism", "C-compound/carbohydrate metabolism" and "glycolysis/gluconeogenesis".ConclusionThe global misregulation of gene networks controlled by light and carbon signaling incli186indicates that it represents one of the first Arabidopsis mutants isolated that is specifically disrupted in the integration of both carbon and light signals to control the regulation of metabolic, developmental and regulatory genes. The network analysis of misregulated genes suggests thatCLI186acts to integrate light and carbon signaling interactions and is a master regulator connecting the regulation of a host of downstream metabolic and regulatory processes.

Background: The natural history of sickle cell disease (SCD) includes premature death. Advancements in care, such as penicillin prophylaxis, have made death during childhood uncommon. Prior survival estimates for adults with SCD have been limited by survival bias (subjects enrolled as adults) or the limitations of administrative data. No prior study has estimated survival for adults with SCD from a newborn cohort. Herein, we report an continued observation of subjects in the Dallas Newborn Cohort (DNC)1. Methods: The DNC is an inception cohort of patients with SCD defined by: (1) diagnosis by Texas newborn screening after October 31, 1983; (2) evaluation in the pediatric sickle cell program at UT Southwestern (UTSW) / Children’s Medical Center Dallas (CMCD); and (3) confirmation of SS, SC, Sβ0 or Sβ+ genotype. Patients followed at CMCD are transitioned to adult care before the 19th birthday. To identify transitioned patients or those lost to follow-up (LTFU), we reviewed the medical records at Parkland Memorial Hospital (PMH) and UTSW University Hospital (UH), the public and private hospitals affiliated with CMCD and the most common care-sites for transitioned patients. In addition, for patients no longer actively followed at CMCD, we queried the National Death Index (NDI). The NDI is a centralized database of death records obtained from all state vital statistic bureaus in the US and is maintained by the National Center for Health Statistics. As of our query in April 2014, deaths occurring from 1/1/79 - 12/31/11 were available in the NDI. Probabilistic matching is performed by the NDI to identify subjects using identifiers such as name, social security number, birthdate, gender, state of birth, and race. Patients who were LTFU or transitioned to adult care were censored at 12/31/11 or the date of their last clinical encounter, whichever occurred latest. Patients actively followed at CMCD, PMH, or UH were censored at 12/31/13. In addition to descriptive statistics, we constructed survival curves using the Kaplan-Meier method to evaluate overall survival and survival by genotype. Also, Cox Proportional Hazard modeling was used to assess genotype, baseline hemoglobin, baseline reticulocyte count (%), and baseline oxygen saturation as potential predictors of early mortality. To test the sensitivity of the NDI to identify deceased individuals, we submitted 36 known deaths from the cohort. Results: The DNC is now comprised of 1214 patients with 16,636 years of follow-up. The cohort is 49.2% female with a mean age, and duration of follow-up, of 13.2 years (Range 0.1 – 30.0 years). SCD genotypes included 60.5% HbSS, 30.6% HbSC, 6.8% HbSβ+, and 2.1% HbSβ0. Of the 1214 patients in the cohort, 511 were active in the pediatric program, 195 were in the pediatric age range but had moved or were LTFU, 238 were adults with 1 or more visits at PMH or UH, 234 were adults with no subsequent identifiable clinical encounters, and 36 were deceased. Of 36 known deaths submitted to the NDI, 34 were identified by their databases (94.4% sensitivity). Of the 606 patients who were LTFU or aged out of the pediatric program, only 10 were reported to have died by the NDI. One of them was confirmed to be erroneous because the patient had clinical encounters after the NDI-reported date of death. In addition to these 9 deaths in the NDI, 8 additional patients were known to have died as of 12/31/13, bringing the total number of deaths to 53 (4.3%). Of these, 21 (39.6%) have been identified since the last cohort update in 2007. Overall survival in the DNC to age 25 years was 91.4% (95% CI: 88.4%, 93.7%) for all members (Figure), 87.7% (95% CI: 83.3%, 91%) for those with HbSS or HbSβ0, and 98.6% (95% CI: 96.7%, 99.4%) for those with HbSC or HbSβ+. In univariate analysis, early mortality was associated with SS or Sβ0 genotypes (compared to HbSC or HbSβ+), lower baseline hemoglobin, and low baseline SpO2 but not gender or reticulocytes. In multivariate analysis, early mortality was associated with only lower baseline hemoglobin (Hazard Ratio 0.76 [95% CI 0.59, 0.98], P=0.037). Conclusions: These are the first modern estimates of survival into adulthood with an unbiased newborn cohort of SCD patients. Early mortality is associated with low baseline hemoglobin. Survival to age 20 remains excellent at 95% but the mortality rate appears to accelerate in early adulthood. Reference: 1. Quinn et al. Blood. 115(17):3447-52, 2010. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Sickle cell anemia (SCA) is a genetically inherited disorder that can lead to severe sequelae in any organ system. The most clinically devastating complications, e.g. stroke, are managed with chronic red blood cell (RBC) transfusions as curing the underlying SCA is often not an option. Chronic RBC exchange (RBCx), is an effective alternative to simple transfusions and often performed every 4-5 weeks. Isovolemic Hemodilution-Red Blood Cell Exchange (IHD-RBCx) is a modified RBCx method used at UT Southwestern Medical Center (UTSW) and increases the time interval between transfusions, i.e. inter-procedure interval (IPI), up to 9 weeks while maintaining the desired hemoglobin S targets at safe levels. This minimizes the overall lifetime procedures and blood exposures. The standard operating procedure for IHD-RBCx is published (Matevosyan et al, 2012). However, we observed IPI variability between patients in this chronic IHD-RBCx program. We sought to analyze hematologic characteristics in a cohort of adult SCA patients that may be associated with this noted variability. Methods: This IRB approved cross-sectional study evaluated medical and blood bank records of adult patients with SCA, i.e. hemoglobin SS or Sβ0 thalassemia genotypes, undergoing chronic IHD-RBCx at UTSW adult hospital sites between January 1, 2012 and December 31, 2013. Excluded participants were those with autoimmune disease, non-compliance with IHD-RBCx leading to delays > 7 days, or use of hydroxyurea or steroids within four months of the study period. Patients with < 5 exchanges were excluded as several procedures are needed to determine baseline IPIs. The primary indication for IHD-RBCx was secondary stroke prevention. Three subjects had alternative indications (i.e. recurrent severe acute chest syndrome that failed hydroxyurea therapy, intractable pain and severe anemia ineligible for iron chelation due to end-stage renal disease). Median values during the 2 year study were determined for the IPI, laboratory, and RBC properties for use in subsequent analyses. Correlation and multiple regression analyses were performed to determine variables predictive of IPI. Results: Twenty-four SCA patients in this chronic IHD-RBCx transfusion program met inclusion criteria of which 14 (58.3%) were female with age range 18-41 years. Three subjects had incomplete data. The median number of packed RBC (pRBC) units per IHD-RBCx was 8 (range: 6-11 units). The median volume per unit of pRBCs was 304.5 mL (range: 298.8-326.5 mL) with average age of the pRBCs 5.8 days ± 0.7 days. The median IPI was 55.8 days (range: 36.0-65.5 days). The strongest correlation with IPI was the change from the mid to post-procedure hemoglobin and hematocrit values, r=0.56, p=0.005 and r=0.57, p=0.003, respectively. Participants with documented direct antiglobulin test positivity (n=7), compared to those who remained negative (n=16), had 4.9 days increased IPI. This difference was not statistically significant, p=0.19. ABO differences in blood type also did not show statistical significant differences. However, A+ subjects had a 58 day interval compared to 51, 52, 53 days for B+, O+, O- respectively (Figure). In multiple regression models, log blood urea nitrogen (BUN) and post-procedure white blood cell count (WBC) were found to be independent predictors of IPI, beta=-11.3, p=0.04 and -2.1, p=0.03 respectively, with adjusted R2=0.31. Conclusions: Chronic IHD-RBCx effectively treats severe SCA complications. Discontinuing transfusions lead to repeat stroke events or the recurrence of disease manifestations making chronic transfusion programs an indefinite therapy. Outside of the expected correlation between the IPI and hemoglobin/hematocrit, WBC and BUN were found to have negative associations with IPIs. The decrease in WBCs is likely due to the direct clearing effect by the operating system. The association between BUN and IPI may imply relationship with renal function. Interestingly, association with creatinine was not statistically significant. The study is limited by the small sample size. Future studies of similar cohorts should prospectively evaluate target mechanisms which may lead to interventions that can minimize lifetime blood exposures given the growing demands for continued RBCx in severe SCA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract 4753 Introduction For many patients with sickle cell anemia (SCA), jaundice, yellow discoloration of the skin and mucous membranes, may be the most visible manifestation of their disease. The degree to which jaundice impacts the daily lives of patients with SCA has not been previously described. This study aims to assess the effect of jaundice on the health-related quality of life (HRQOL) of adults living with SCA. Methods This study was a cross-sectional survey of patients with SCA. A convenience sample of patients age > 17 years with SCA were approached during routine clinic visits to Parkland Memorial Hospital or UT Southwestern University Hospitals. Consenting patients completed a 15 question survey instrument. The survey was divided into three subscales (personal, relational, and behavioral) where individual items were presented in a 5-point Likert scale. This instrument was reviewed by non-study hematologists, nurses and patients for face validity. No other assessment of reliability or validity was performed. Additional data collected included serum total bilirubin (TB), hemoglobin, reticulocyte count (%) and patient self-report of current treatment for SCA (hydroxyurea [HU], chronic blood transfusions, or other). We tested for associations between survey subscales and TB, reticulocyte count, or hemoglobin using Spearman correlation coefficients. We compared the Spearman correlations of the survey subscales and TB between treatment and non-treatment groups using the Fisher's z transformation. Gender and age adjustments were made using linear regression. TB was transformed by natural log for regression analysis. Results We surveyed 100 subjects (58% female) with SCA. The median age was 25 years (range: 18–63), and the median TB was 2.5 mg/dL (range: 0.4–13.8). Nearly half of patients reported receiving treatment with 28% on HU and 14% on chronic transfusions. The majority of patients reported a history of jaundice, with 79% listing responses of ‘sometimes’, ‘often’, or ‘always’. Summary results for the remainder of the survey are listed in the table. TB was positively correlated with the 3 subscales (personal, r=0.32, p=0.002; relational, r=0.38, p=0.0002; behavioral, r=0.31, p=0.003). We compared these correlations between ‘treatment’ and ‘no treatment’ groups and observed strong correlations in the ‘no treatment’ group (personal, r=0.55, p Conclusion Jaundice negatively impacts the lives of many adults with SCA. The personal and relational subscales suggest more impact on the self-image of respondents, but only a few reported behavioral changes. The impact of jaundice appears to be mitigated by disease-modifying therapy for SCA (HU or chronic transfusions); however, this study was not created to determine the effectiveness of these reported treatments. Despite the fact this instrument was not validated, our study results suggest jaundice should be well-represented in HRQOL assessment tools in adults with SCA. Moreover, prospective studies are needed to clarify potential benefits of disease-modifying therapies, particularly HU, on the burden of jaundice in SCA. Disclosures: Buchanan: HemaQuest Pharmacuetical, Inc.: Research Funding.

not change over the study period (trend P 0.47) but neonatal mortality and morbidity increased from 2.5% to 2.7% (trend P32 weeks gestation, 128,562 (22.3%) were planned births before the due date including 72,564 (12.6%) pre-labor cesarean sections and 55,998 (9.7%) labor inductions. Over the study period there were sustained increases in both pre-labor cesarean and labor induction births. By 2007, 25.3% of all births greater than 32 weeks were both planned and before the due date, with 14.3% pre-labor cesarean births, and 11.0% induction births. Neonatal morbidity and mortality was strongly associated with gestational age with a stepwise reduction in frequency with each additional week of gestation from 69.7% at 33 weeks to 2.0% at 39 weeks following pre-labor cesarean and 49.4% to 2.6% respectively following labor induction. CONCLUSION: Planned birth before the due date is increasing. This was associated with increased morbidity for the neonate and has not been accompanied by a reduction in stillbirths. There is a need to review clinical practice regarding the indication, timing and mode of planned birth with the potential to issue stricter guidelines related to early planned delivery.

IntroductionHospitals, as one major cornerstone of contingency planning, are often expected to be fully functional during a major incident. However, the continuous streamlining of todays healthcare system with a constrained economy, lean production principles and increasing complexity together with changing levels of the threats may result in an evacuation, should hospitals themselves be the targets for a disastrous action.ObjectiveThe aims of this study were 1) to evaluate an appropriate risk and vulnerability analysis model as a basis for hospital evacuation plan, 2) to identify hazards triggering an evacuation 3) to evaluate the response needed in an evacuation situation and 4) to clarify the impact of such an evacuation plan on the ordinary emergency medical plan.Material and MethodsA systematic online literature search based on the following keywords; evacuation/closure, hospitals/medical facilities, and disaster/hazards; alone or with planning, and also a risk and vulnerability analysis as a case study at the hospital in Lidkoping, Sweden, were conducted.ResultsOur findings indicate that hospitals are vulnerable to different risks such as technological dysfunctions, climate changes and terror actions, which can result in an evacuation of patients. In such a situation, well functional transport organization and availability of temporary facilities along with good communication are necessities to assure patient safety. Such functional abilities may be assessed by planning, education and continuous training.Discussion and ConclusionThere is a need for an elaborated evacuation planning for hospitals. Such plan should continuously be drilled based on a risk and vulnerability analysis and be integrated in the ordinary medical emergency plan. Simulations of different scenarios are one way to determine risks and identify proper actions before a major incident or disaster strikes.

Nero , L. C. (Illinois Institute of Technology, Chicago), Mae G. Tarver, and L. R. Hedrick . Growth of Acanthamoeba castellani with the yeast Torulopsis famata . J. Bacteriol. 87: 220–225. 1964.— Acanthamoeba castellani and Torulopsis famata cells were cultured together for 10 days at three different temperatures: 18, 25, and 32 C. In the 18- and 25-C series, the yeast population reached a peak within 3 to 5 days and then declined for the next 5 days. This decrease in yeast population corresponded with an increase in the development of amoebae, which first appeared as vegetative cells and later transformed themselves into cysts. The changes in population were determined by counts in a hemocytometer. The vegetative amoeba population seldom exceeded 4 × 10 7 cells per bottle culture, but the encysted population approached 16 × 10 7 cysts per bottle culture within 10 days of incubation. The amoebae actively ingested the yeasts and used these cells as their principal source of energy. At 18 C each amoeba consumed 70 yeast cells per day; at 25 C each amoeba ingested 35 yeast cells per day. In the 32-C series, both the yeast and the amoebae had slow growth rates. The development of cysts corresponded with the growth of the yeast population without the rapid increase in yeast population prior to the growth of the amoebic cells.

Acidification in the toad bladder occurs as a result of electrogenic H+ secretion (JH). When a pH gradient is applied in a stepwise fashion in the absence of exogenous CO2, JH decreases linearly with the mucosal (M) solution pH and is null when pHm is approximately 4.5. When pHm is returned to initial values (7.4) in a stepwise fashion, JH increases linearly with pHm. However, on this return, higher values of JH are initially obtained. To investigate this hysteresis, hemibladders mounted in chambers were used to measure the change in the H+ current before and after acid pulses were applied to the mucosal solution. In the absence of exogenous CO2, the application of graded acid pulses to mucosa for 1, 2, 4, and 8 min resulted in a graded decrease in JH. The restoration of pHm to 7.4 was followed by an immediate transient overshoot of reversed short-circuit current (Irsc), which was related to the time of exposure and the magnitude of the acid pulse. The longer the acid pulse or the larger the pulse, the greater the Irsc overshoot. The addition of protonophores, dinitrophenol, or salicylate, into the mucosal solution enhanced this overshoot. Similar Irsc overshoots could be obtained with the application of pulses of adverse electrical gradients. Introduction of exogenous CO2 into the system (3%) completely inhibited the overshoot in JH after an acid pulse. In conclusion, when pHm is decreased JH is reduced and the cell pH presumably decreases because of continued exit of alkali at the serosal side of the cell and entry of H+ from the mucosal solution. The decrease in cell pH then triggers the pump to produce a sharp overshoot in JH when pHm returns to 7.4.

Background Prediction of transcriptional regulatory mechanisms in Arabidopsis has become increasingly critical with the explosion of genomic data now available for both gene expression and gene sequence composition. We have shown in previous work [1], that a combination of correlation measurements and cis-regulatory element (CRE) detection methods are effective in predicting targets for candidate transcription factors for specific case studies which were validated. However, to date there has been no quantitative assessment as to which correlation measures or CRE detection methods used alone or in combination are most effective in predicting TF→target relationships on a genome-wide scale. Results We tested several widely used methods, based on correlation (Pearson and Spearman Rank correlation) and cis- regulatory element (CRE) detection (≥1 CRE or CRE over-representation), to determine which of these methods individually or in combination is the most effective by various measures for making regulatory predictions. To predict the regulatory targets of a transcription factor (TF) of interest, we applied these methods to microarray expression data for genes that were regulated over treatment and control conditions in wild type (WT) plants. Because the chosen data sets included identical experimental conditions used on TF over-expressor or T-DNA knockout plants, we were able to test the TF→target predictions made using microarray data from WT plants, with microarray data from mutant/transgenic plants. For each method, or combination of methods, we computed sensitivity, specificity, positive and negative predictive value and the F-measure of balance between sensitivity and positive predictive value (precision). This analysis revealed that the ≥1 CRE and Spearman correlation (used alone or in combination) were the most balanced CRE detection and correlation methods, respectively with regard to their power to accurately predict regulatory-target interactions. Conclusion These findings provide an approach and guidance for researchers interested in predicting transcriptional regulatory mechanisms using microarray data that they generate (or microarray data that is publically available) combined with CRE detection in promoter sequence data.