Search

Pain intensity remains a primary focus clinically for sickle cell disease pain assessment despite the fact that pain quality and pain location and distribution are critical for clinical diagnosis and treatment of its etiology. However, in part because of measurement issues, scant evidence is available about pain location or its relationship to intensity and quality in adults with SCD.Our study aim was to examine sickle cell disease pain location for relationships with pain quality and intensity measured in outpatient and inpatient settings.We used an existing longitudinal dataset prospectively collected with the valid and reliable tablet-based PAINReportItThe mean pain-affected body surface area was 14.4% ± 15.0% of the total body surface area for outpatient visits (min-max: 0.0%-90.2%) and 13.5% ± 14.7% (min-max: 0.0%-73.0%) for inpatient stay. Pain-affected body surface area was positively correlated with pain quality scores for both visits but not significantly correlated with pain intensity at either visit. Compared with the outpatient visit, mean pain intensity for inpatient stay was higher (p.001); pain quality (p = .12) and pain-affected body surface area (p = .60) did not differ significantly between visits.Unknown is the explanation for pain-affected body surface area association with SCD pain quality but not pain intensity at outpatient and inpatient visits. Additional research is warranted to explore these findings and examine the clinical utility of pain-affected body surface area for chronic sickle cell disease pain and acute sickle cell disease crisis pain.

A previous exploratory analysis of a COMT gene single-nucleotide polymorphism (SNP) and a DRD3 SNP by our group suggested possible contributions to pain-related acute care utilization in people with sickle cell disease (SCD). Our aim was to extend the analysis to gene-spanning haplotypes of COMT SNPs and DRD3 SNPs to investigate possible associations with pain intensity and pain-related acute care utilization in an SCD cohort. Genotyping was conducted, and clinical data were collected, including self-reported pain intensity using PAINReportIt® (average of current pain and least and worst in past 24 hours, average pain intensity [API]) and medical record-extracted, pain-related acute care utilization data of 130 adults with SCD. Haplotype blocks were identified based on linkage disequilibria (COMT = 7 haploblocks; DRD3 = 8 haploblocks). Regression analyses were tested for association between haplotypes and API and utilization, yielding several significant findings. For COMT block 1 (rs2075507, rs4646310, rs737865), the A-G-G haplotype was associated with higher API compared to the reference A-G-A ( p = 0.02), whereas the A-A-A haplotype was associated with higher utilization ( p = 0.02). For DRD3 block 2 (rs9817063, rs2134655, rs963468, and rs3773679), relative to reference T-C-G-C, the T-T-G-C haplotype was associated with higher utilization ( p = 0.01). For DRD3 block 4 (rs167770, rs324029, and rs324023), the A-G-T haplotype was associated with higher API ( p = 0.04) and utilization ( p < 0.001) relative to reference G-A-T, whereas the A-A-T haplotype was associated with higher utilization ( p = 0.01). We found COMT and DRD3 haplotypes associated with pain-related SCD features, suggesting that in future studies more emphasis be placed on cis effects of SNP alleles in evaluating genetic contributions to SCD pain and acute care utilization for pain.

A previous exploratory analysis of a COMT gene single-nucleotide polymorphism (SNP) and a DRD3 SNP by our group suggested possible contributions to pain-related acute care utilization in people with sickle cell disease (SCD). Our aim was to extend the analysis to gene-spanning haplotypes of COMT SNPs and DRD3 SNPs to investigate possible associations with pain intensity and pain-related acute care utilization in an SCD cohort. Genotyping was conducted, and clinical data were collected, including self-reported pain intensity using PAINReportIt(®) (average of current pain and least and worst in past 24 hours, average pain intensity [API]) and medical record-extracted, pain-related acute care utilization data of 130 adults with SCD. Haplotype blocks were identified based on linkage disequilibria (COMT = 7 haploblocks; DRD3 = 8 haploblocks). Regression analyses were tested for association between haplotypes and API and utilization, yielding several significant findings. For COMT block 1 (rs2075507, rs4646310, rs737865), the A-G-G haplotype was associated with higher API compared to the reference A-G-A (p = 0.02), whereas the A-A-A haplotype was associated with higher utilization (p = 0.02). For DRD3 block 2 (rs9817063, rs2134655, rs963468, and rs3773679), relative to reference T-C-G-C, the T-T-G-C haplotype was associated with higher utilization (p = 0.01). For DRD3 block 4 (rs167770, rs324029, and rs324023), the A-G-T haplotype was associated with higher API (p = 0.04) and utilization (p < 0.001) relative to reference G-A-T, whereas the A-A-T haplotype was associated with higher utilization (p = 0.01). We found COMT and DRD3 haplotypes associated with pain-related SCD features, suggesting that in future studies more emphasis be placed on cis effects of SNP alleles in evaluating genetic contributions to SCD pain and acute care utilization for pain.

Patient-reported pain locations are critical for comprehensive pain assessment. Our study aim was to introduce an automated process for measuring the location and distribution of pain collected during a routine outpatient clinic visit. In a cross-sectional study, 116 adults with sickle cell disease-associated pain completed PAINReportItⓇ. This computer-based instrument includes a two-dimensional, digital body outline on which patients mark their pain location. Using the ImageJ software, we calculated the percentage of the body surface area marked as painful and summarized data with descriptive statistics and a pain frequency map. The painful body areas most frequently marked were the left leg-front (73%), right leg-front (72%), upper back (72%), and lower back (70%). The frequency of pain marks in each of the 48 body segments ranged from 3 to 79 (mean, 33.2 ± 21.9). The mean percentage of painful body surface area per segment was 10.8% ± 7.5% (ranging from 1.3% to 33.1%). Patient-reported pain locations can be easily analyzed from digital drawings using an algorithm created via the free ImageJ software. This method may enhance comprehensive pain assessment, facilitating research and personalized care over time for patients with various pain conditions.

Objective: Chronic pain is a common symptom experienced among patients with sickle cell disease (SCD). Our aims were to assess the feasibility and acceptability of performing acupuncture for the treatment of chronic pain in adults with SCD. Methods: This was a single-arm, prospective pilot study of six adults with SCD. Participants reported ⩾ 3 months of chronic pain and were > 18 years of age. Per protocol, acupuncture was to be administered twice per week for 5 weeks, for 30 min per session. All treatments were performed in the acupuncture treatment laboratory at the University of Illinois Chicago College of Nursing. Pain intensity, pain interference, and other symptoms were measured at baseline and after the intervention. Participants completed a semi-structured interview and a protocol acceptability questionnaire after the acupuncture intervention. Results: Six participants (mean age 52.5 years, six Black) were enrolled. Although the study was suspended due to COVID-19 and not all participants completed the 10-session protocol, completion rates were high with no missed appointments. One participant did not complete the study due to hospitalization unrelated to acupuncture. No adverse events were reported. At completion of the intervention at 4–5 weeks post-baseline, all participants had reduced pain intensity and pain interference. The mean acceptability score on the protocol acceptability questionnaire was 82%. Conclusion: It was feasible and acceptable to implement acupuncture in adults with SCD. This study can be used to guide a larger randomized controlled trial to evaluate the effect of acupuncture on reducing chronic pain in adults with SCD. Trial registration number: NCT04156399 (ClinicalTrials.gov)

Not available.

Background Guidelines recommend systematic evaluation of distress screening and referral for cancer patients. Implementation remains a notable gap for cancer centers serving disadvantaged communities. We present the implementation of a distress screening program within a Veterans Affairs hospital oncology clinic, serving a majority African American (AA) male population of low socioeconomic status (SES). Methods The Coleman Foundation funded this program supporting a palliative care physician and psychologist to implement screening in a phased approach as follows: (1) Organizing key stakeholders, (2) educating clinical staff, (3) delivering distress screening, (4) generating documentation, and (5) implementing clinical action and referral pathways. We utilized validated measures in the "Patient Screening Questions for Supportive Care" screening tool. Results This program was unsuccessful in screening all veterans with cancer; however, we were able to implement 3 years of longitudinal screening. In distress screens from the initial program period (n = 253), patients were primarily males (95.6%) of older age (m = 70, standard deviation = 9.45), AA (76.4%), with various cancers of advanced disease (69%). Males reported moderate psychosocial distress and elevated financial needs. For males with elevated psychosocial distress (n = 63, PHQ-4 ≥3), 36% were previously connected with psychosocial services. Following screening, engagement increased as the majority (77%) established psychosocial care. Conclusions This screening program had mixed success. Centralized program staff and available supportive care referrals were critical for program implementation. Screening may have increased engagement in social work/mental health services for males of low SES. Screening programs should be tailored to the needs of underserved communities with accessible housing/food subsidies.

Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

Context Unrelieved cancer pain at the end of life interferes with achieving patient-centered goals. Objective To compare effects of usual hospice care and PAINRelieveIt® on pain outcomes in patients and their lay caregivers. Methods In a five-step, stepped-wedge randomized, controlled study, 234 patients (49% male, 18% Hispanic, 51% racial minorities) and 231 lay caregivers (26% male, 20% Hispanic, 54% racial minorities) completed pre-pain/post-pain measures. They received usual hospice care with intervention components that included a summary of the patient's pain data, decision support for hospice nurses, and multimedia education tailored to the patient's and lay caregiver's misconceptions about pain. Results The intervention effect on analgesic adherence (primary outcome) was not significant. Post-test worst pain intensity was significantly higher for the experimental group, but the difference (0.70; CI = [0.12, 1.27]) was not clinically meaningful. There was nearly universal availability of prescriptions for strong opioids and adjuvant analgesics for neuropathic pain in both groups. Lay caregivers' pain misconceptions (0-5 scale) were significantly lower in the experimental group than the usual care group (mean difference controlling for baseline is 0.38; CI = [0.08, 0.67]; P = 0.01). Conclusion This randomized controlled trial was a negative trial for the primary study outcomes but positive for a secondary outcome. The trial is important for clearly demonstrating the feasibility of implementing the innovative set of interventions.

Objectives: Sickle cell disease (SCD) is a serious illness with disabling acute and chronic pain that needs better therapies, but insufficient patient participation in research is a major impediment to advancing SCD pain management. The purpose of this article is to discuss the challenges of conducting an SCD study and approaches to successfully overcoming those challenges. Design: In a repeated-measures, longitudinal study designed to characterize SCD pain phenotypes, we recruited 311 adults of African ancestry. Adults with SCD completed 4 study visits 6 months apart, and age- and gender-matched healthy controls completed 1 visit. Results: We recruited and completed measures on 186 patients with SCD and 125 healthy controls. We retained 151 patients with SCD with data at 4 time points over 18 months and 125 healthy controls (1 time point) but encountered many challenges in recruitment and study visit completion. Enrollment delays often arose from patients’ difficulty in taking time from their complicated lives and frequent pain episodes. Once scheduled, participants with SCD cancelled 49% of visits often because of pain; controls canceled 30% of their scheduled visits. To facilitate recruitment and retention, we implemented a number of strategies that were invaluable in our success. Conclusion: Patients’ struggles with illness, chronic pain, and their life situations resulted in many challenges to recruitment and completion of study visits. Important to overcoming challenges was gaining the trust of patients with SCD and a participant-centered approach. Early identification of potential problems allowed strategies to be instituted proactively, leading to success.

Purpose Only a few studies have reported quantitative sensory testing (QST) reference values for healthy African Americans, and those studies are limited in sample size and age of participants. The study purpose was to characterize QST values in healthy, pain-free African American adults and older adults whose prior pain experiences and psychological status were also measured. We examined the QST values for differences by sex, age, and body test site. Patients and methods A cross-sectional sample of 124 pain-free African American adults (age 18-69 years, 49% female) completed demographic and self-reported pain, fatigue and psychosocial measures. QST was performed to obtain thermal and mechanical responses and associated pain intensity levels. Results We found thermal detection values at the anterior forearm were (29.2 °C±1.6) for cool detection (CD) and (34.5 °C±1.2) for warm detection (WD). At that site the sample had cold pain threshold (CPTh) (26.3 °C±5.0), heat pain threshold (HPTh) (37.8 °C±3.6), and mechanical pain thresholds (MPTH) (16.7±22.2 grams of force, gF). There was a significant between sex difference for WD, with women being more sensitive (q=0.027). Lower body sites were less sensitive than upper body sites across all thermal modalities (q

Background Chronic pain in adults with sickle cell disease (SCD) may be the result of altered processing in the central nervous system, as indicated by quantitative sensory testing (QST). Sensory pain quality descriptors on the McGill Pain Questionnaire (MPQ) are indicators of typical or altered pain mechanisms but have not been validated with QST-derived classifications. Objectives The specific aim of this study was to identify the sensory pain quality descriptors that are associated with the QST-derived normal or sensitized classifications. We expected to find that sets of sensory pain quality descriptors would discriminate the classifications. Methods A cross-sectional quantitative study of existing data from 186 adults of African ancestry with SCD. Variables included MPQ descriptors, patient demographic data, and QST-derived classifications. Results The participants were classified as central sensitization (n = 33), mixed sensitization (n = 23), and normal sensation. Sensory pain quality descriptors that differed statistically between mixed sensitization and central sensation compared to normal sensitization included cold (p = .01) and spreading (p = .01). Aching (p = .01) and throbbing (p = .01) differed statistically between central sensitization compared with mixed sensitization and normal sensation. Beating (p = .01) differed statistically between mixed sensitization compared with central sensitization and normal sensation. No set of sensory pain quality descriptors differed statistically between QST classifications. Discussion Our study is the first to examine the association between MPQ sensory pain quality descriptors and QST-derived classifications in adults with SCD. Our findings provide the basis for the development of a MPQ subscale with potential as a mechanism-based screening tool for neuropathic pain.

Detection of circulating tumor cells (CTCs) relying on their expression of epithelial cell markers, such as epithelial cell adhesion molecule (EpCAM), has been commonly used. However, this approach unlikely captures CTCs that have undergone the process of epithelial-mesenchymal transition (EMT). In this study, we have induced EMT of in vitro prostate (PCa) and breast cancer (BCa) cell lines by treatment of transforming growth factor β 1 (TGFβ1), a pleiotropic cytokine with transition-regulating activities. We found that the TGFβ1-treated, post-EMT cells exhibited up to a 45% reduction in binding affinity to antibodies against EpCAM (aEpCAM). To overcome this limitation, we designed our capture platform that integrates a unique combination of biomimetic cell rolling, dendrimer-mediated multivalent binding, and antibody cocktails of aEpCAM/aEGFR/aHER-2. Our capture surfaces resulted in up to 98% capture efficiency of post-EMT cells from mixtures of TGFβ1-treated and untreated cancer cells spiked in culture media and human blood. In a clinical pilot study, our CTC device was also able to capture rare CTCs from PCa patients with significantly enhanced capture sensitivity and purity compared to the control surface with aEpCAM only, demonstrating its potential to provide a reliable detection solution for CTCs regardless of their EMT status.

OBJECTIVES: Age group differences have been reported for pain and symptom presentations in outpatient and inpatient oncology settings, but it is unknown if these differences occur in hospice. We examined whether there were differences in pain, symptom distress, pain barriers, and comorbidities among three age groups (20–64 years, 65–84 years, and 85+) of hospice patients with cancer. MATERIALS AND METHODS: Participants were recruited from two hospices. Half were women; 49% White and 34% Black. 42% were 20–64 y, 43% 65–84 y, and 15% 85+ y. We analyzed baseline data for 230 hospice patients with cancer (enrolled 2014–2016, mean age 68.2 ±14.0, 20–100 years) from a stepped-wedge randomized controlled trial. Measures were the Average pain intensity (API, 0–10: current, least and worst pain intensity during the past 24 hours), Symptom Distress Scale (SDS, 13–65), Barriers Questionnaire-13 (BQ-13, 0–5), and comorbid conditions. Descriptive, bivariate association, and multiple regression analyses were performed. RESULTS: Mean API scores differed (p

Background Point‐of‐care (POC) International Normalized Ratio (INR) measurement provides efficient monitoring of warfarin therapy; however, its reliability may be affected in patients with anemia, such as those with sickle cell disease (SCD). Objectives To evaluate the correlation of POC‐INR to clinical laboratory INR (CL‐INR) in SCD and use of a correction factor. Patient/Methods In this retrospective study, the accuracy of POC‐INR compared to CL‐INR was evaluated in a cohort of patients with SCD and in a non‐SCD Black cohort. Results Despite the difference in anemia, the SCD cohort showed a similar percentage of in‐range POC‐INR values as observed in the non‐SCD cohort (37% vs 42%). The SCD cohort was randomly divided to form discovery and validation cohorts. In the discovery cohort, 86% of POC‐INRs were in range when the POC‐INRs were ˂4.0, but only 24% were in range if POC‐INRs were ≥4.0. A linear regression of CL‐INR versus POC‐INR for POC‐INR values ≥4.0 yielded a coefficient of 0.72 (95% confidence interval, 0.69‐0.75); Multiplying POC‐INR by this correction factor, rounded to 0.7 for ease of use in clinical practice, improved the proportion of in‐range POC‐INR values ≥4.0 from 24% to 100% in the SCD discovery cohort and from 19% to 95% in the SCD validation cohort. Similar findings applied to analyses of the non‐SCD cohort. Conclusions POC‐INR and CL‐INR in patients with SCD are similar when POC‐INR is

Human hemoglobin switching describes the highly regulated, sequential expression of the five β-like globin genes (HBE, HBG2, HBG1, HBD and HBB) of the human β-globin gene complex. The sequential activation of these β or β-like globin genes during human development from early embryonic through late fetal (‘adult’) stages, and during erythroid maturation, occurs in an order corresponding to their 5’ to 3’ location on chromosome 11. The β-hemoglobinopathies are the most common inherited diseases in humanity, and are diseases of mutated HBB or its altered regulation. Since the other β-like globin genes can potentially substitute for defective HBB, much translational research is directed toward understanding and manipulating sequential activation at the human β-globin gene complex to treat β-hemoglobinopathies. Non-human primates provide a vital contribution to such efforts because of their recapitulation of the developmental/maturational switch in hemoglobin production as observed in humans (mice do not model this switch). Valuable insights into druggable epigenetic forces that mediate the switch have been thereby gained. We review important lessons learned in non-human primates, complemented by other studies, and suggest rational next steps.

Background Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. Methods Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. Results Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. Conclusions S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.

Patients with sickle cell disease (SCD) have access to fewer health care resources and therapies compared to other diseases, which contributes to increased morbidity and health care utilization. We compared health care utilization (inpatient hospital days, emergency care visits) and health care-related costs between SCD adults that underwent hematopoietic stem cell transplantation (HSCT) using a nonmyeloblative conditioning regimen versus those referred for HSCT but did not proceed due to lack of an HLA-matched sibling donor, denial by insurance, red blood cell antibodies to the potential donor, or declining further evaluation. Between 8/2011 and 4/2016, 83 SCD patients were referred for allogeneic HSCT and 16 underwent the procedure. The HSCT and non-HSCT groups were similar by age, sex, prior SCD-related therapy and complications. Compared to pre HSCT, significantly fewer inpatient hospital days (median of 1 versus 22 days, P = 0.003) and emergency care visits (median of 1 versus 4 visits, P = 0.04) were observed by the 2nd year post-HSCT. Similar results were observed in comparison to the standard-of-care group (median of 1 versus 12 hospital days, P = 0.002; median of 1 versus 3 emergency visits, P = 0.03). Lower health care costs were observed by the 2nd year post-HSCT (median of $16,281 versus $64,634 pre-HSCT (P = 0.01) and versus $54,082 in the standard-of-care group (P = 0.05). A median reduction of -$20,833/patient/year (IQR, -$67,078-+$4,442/patient/year) in health care costs compared to pre-HSCT was observed in the 2nd year post-HSCT. In conclusion, allogeneic HSCT leads to improvements in health care utilization and costs compared to standard-of-care therapy in high-risk SCD adults.

TO THE EDITOR: The pathophysiologic mechanisms, genetic predictors, and long-term consequences of acute kidney injury (AKI) on kidney function in sickle cell anemia (SCA) are not clear.[1][1][⇓][2][⇓][3][⇓][4]-[5][5] In the general population, AKI is associated with the subsequent development

Background Acute chest syndrome (ACS) is the leading cause of death for patients with sickle cell disease (SCD). Early recognition of ACS improves prognosis. Objective Investigate the use of bedside lung ultrasound (BLU) in identification of early pulmonary findings associated with ACS in SCD patients. Methods Prospective, observational study of a convenience sample of SCD patients presenting to the Emergency Department (ED) for a pain crisis. BLU interpretations were made by an emergency physician blinded to the diagnosis of ACS, and were validated by a second reviewer. The electronic medical record was reviewed at discharge and at 30 days. Results Twenty SCD patients were enrolled. Median age was 31 years, median hemoglobin was 7.7 g/dL. Six patients developed ACS. Five patients in the ACS group had lung consolidations on BLU (83%) compared to 3 patients in the non-ACS group (21%), p = 0.0181, (OR = 12.05, 95% CI 1.24 to 116.73). The ACS group was also more likely to have a pleural effusion and B-lines on BLU than the non-ACS group, p = 0.0175; 0.1657, respectively. In the ACS group, peripheral and frank consolidations on BLU was 83% and 50% sensitive, 79% and 100% specific for ACS, respectively; whereas an infiltrate on initial chest X-ray (CXR) was only 17% sensitive. BLU identified lung abnormalities sooner than CXR (median 3.6 vs. 31.8 h). Conclusions Pulmonary abnormalities on BLU of an adult SCD patient presenting to the ED for a painful crisis appear before CXR, and highly suggest ACS. BLU is a promising predictive tool for ACS.

Background: Pain is the quintessential symptom for individuals suffering from sickle cell disease (SCD). Although the degree of suffering and the cost of treatment are staggering, SCD continues to be grossly understudied, including a lack of data for pain-related genes and prevalence of polymorphisms in this population. This lack of data adds to the inadequacy of pain therapy in this population. Pain genetics investigators have recently examined allele frequencies of single-nucleotide polymorphisms from candidate genes in people who have SCD. One of the genes identified was the arginine vasopressin receptor 1A gene (AVPR1A) and its associated single-nucleotide polymorphism (SNP) rs10877969. Progress in explaining pain-related polymorphisms associated with SCD can be facilitated by understanding the literature. Aim/Design: The purpose of this literature review was to describe mechanisms of the polymorphic gene AVPR1A and the phenotypic variations associated with its SNPs relative to health conditions and pain. Methods: Published studies were included if the research addressed AVPR1A and was a full article in a peer-reviewed journal, in the English language, a human or animal study, and published 2009 to present. Abstracts were included if they were in English and provided information not found in a full article. Results: The results of this review revealed that AVPR1A is associated with behavioral phenotypes, which include pair bonding, autism spectrum disorder, musical aptitude, infidelity, altruism, monogamy, mating, substance abuse, and alcohol preference. In addition, there were associations with pain, stress pain by sex, and sickle cell pain. Conclusion: Summary of this literature could provide insights into future pain research of this SNP in people with SCD.

Aim: Pain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease. Method: Acute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score. Results & conclusion: rs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between 1/2014–3/2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor specific antibodies (DSA) and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells (PBSC). The initial two were conditioned with alemtuzumab/total body irradiation (TBI) 3Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University (Bolaños-Meade J, Blood 2012) with TBI 3Gy. G-CSF was administered from day+12 in those with HbS 0.5 x10(9)/L of 22 days (range, 18–23 days). One patient subsequently lost the graft and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute GVHD ≥ grade 2. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow up of 16 months (range, 11–29 months), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSA and patient declining HSCT, may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter prospective clinical trials.

Vitamin D deficiency (VDD), 25-OHD levels

As high fetal hemoglobin levels ameliorate the underlying pathophysiological defects in sickle cell anemia and beta (β)-thalassemia, understanding the mechanisms that enforce silencing of fetal hemoglobin postnatally offers the promise of effective molecular therapy. Depletion of the Nucleosome Remodeling and Deacetylase complex member MBD2 causes a 10-20-fold increase in γ-globin gene expression in adult β-globin locus yeast artificial chromosome transgenic mice. To determine the effect of MBD2 depletion in human erythroid cells, genome editing technology was utilized to knockout MBD2 in Human Umbilical cord Derived Erythroid Progenitor-2 cells resulting in γ/γ+β mRNA levels of approximately 50% and approximately 40% fetal hemoglobin by high performance liquid chromatography. In contrast, MBD3 knockout had no appreciable effect on γ-globin expression. Knockdown of MBD2 in primary adult erythroid cells consistently increased γ/γ+β mRNA ratios by approximately 10-fold resulting in approximately 30-40% γ/γ+β mRNA levels and a corresponding increase in γ-globin protein. MBD2 exerts its repressive effects through recruitment of the chromatin remodeler CHD4 via a coiled-coil domain, and the histone deacetylase core complex via an intrinsically disordered region. Enforced expression of wild-type MBD2 in MBD2 knockout cells caused a 5-fold decrease in γ-globin mRNA while neither the coiled-coil mutant nor the intrinsically disordered region mutant MBD2 proteins had an inhibitory effect. Co-immunoprecipitation assays showed that the coiled-coil and intrinsically disorder region mutations disrupt complex formation by dissociating the CHD4 and the histone deacetylase core complex components, respectively. These results establish the MBD2 Nucleosome Remodeling and Deacetylase complex as a major silencer of fetal hemoglobin in human erythroid cells and point to the coiled-coil and intrinsically disordered region of MBD2 as potential therapeutic targets.

Background: Vaso-occlusive crisis (VOC) is the hallmark complication of sickle cell disease (SCD) (1), and usually requires intravenous (IV) opioid treatment in emergency room (ER) or acute care center (ACC), a designated observation unit to manage uncomplicated VOC (2). Starting October 2017, there was a critical nationwide drug shortage in parental hydromorphone, a commonly used medication to treat VOC. In April 2018 the University of Illinois Health System (UI Health) adopted a standardized pain management protocol that limited opioids in the ER or ACC to two doses of IV or IM morphine and/or oral opioid. This study evaluates the impact of this standardized pain management protocol on managing VOC in SCD. Methods: A total of 373 SCD adults treated at UI Health from May 2017 to Oct 2018 had at least one ER or ACC visit or hospitalization for VOC. Data on VOC-related patient visits to the ACC, ER, and admissions to the inpatient floors were collected from the electronic medical record and evaluated based on three time periods (prior to shortage: May 2017-Oct 2017; transition: Oct 2017-Apr 2018; and post protocol: Apr 2018-Oct 2018). Descriptive statistics, the Cochrane trend test and Jonckheere-Terpstra trend test were used for data analysis. The study was approved by the Institutional Review Board prior to the initiation of chart review. Results: Between May 2017 and Oct 2018, the 373 SCD adult patients had a total of 1,915 ACC, 2,635 ER and 1,832 inpatient visits. After implementation in April 2018, the compliance rate with the standardized pain protocol was 99.7% in the ACC and 85.1% in the ER. In the ACC, the number of visits decreased after standardized pain protocol implementation, whereas the number of visits increased in the ER (Figure 1). The admission rate to the inpatient service from the ACC increased significantly while the admission rate from the ER remained relatively stable (Table 1). The numbers of opioid doses and the total opioid dose to treat VOC decreased in the ACC, but not in ER. Utilization of oral opioids increased in both settings (Table 1). The number of inpatient hospitalizations increased with implementation of the standardized protocol (542 vs. 626 vs. 664), and the 30-day readmission rate increased (49% vs. 51% vs. 57%, p = 0.003), but the length of hospital stay was reduced (p < 0.001). Summary: Implementation of a standardized pain treatment protocol due to the parenteral hydromorphone shortage decreased the utilization of the ACC compared to the ER and the inpatient service, and resulted in reduced opioid dose but increased admission rates from the ACC. The 30-day readmission rate to inpatient service increased but the length of stay was reduced. A standardized pain protocol that limits opioids to two doses in the acute setting may not be an optimal approach. Reference: F. B. Piel, M. H. Steinberg, D. C. Rees, Sickle Cell Disease. N Engl J Med376, 1561-1573 (2017).J. Han et al., Program expansion of a day hospital dedicated to manage sickle cell pain. Am J Hematol93, E20-E21 (2018). Disclosures Saraf: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Gordeuk:CSL Behring: Consultancy, Honoraria, Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Emmaus: Consultancy, Honoraria.

Introduction: Previous studies have reported that patients with sickle cell disease (SCD) have lower systemic blood pressures when compared with age-, sex-, and race-matched controls. We compared systolic and diastolic blood pressure (SBP and DBP) measurements in an SCD patient cohort followed at our clinical center with values obtained from background population using African Americans from the National Health and Nutrition Examination Survey (NHANES) study. Furthermore, we evaluated the association of SBP and DBP with clinical and laboratory variables in our patient cohort in comparison to NHANES. Methods: We cross-sectionally analyzed 442 adult SCD patients receiving medical care at the University of Illinois at Chicago (UIC) between 2009-2018, categorized as severe (HbSS/Sβ 0-thalassemia; n=342) or mild (HbSC/Sβ +-thalassemia; n=100) genotypes. 884 African American from the NHANES were age-, sex-, and race- matched as control in a 2:1 ratio. We evaluated associations between systolic and diastolic BP and 32 clinical and laboratory variables. Evaluation of medians, interquartile range (IQR), Wilcoxon rank sum and the χ2 test, were performed on covariates. Clinical associations between biomarkers and primary outcomes of SBP, DBP, were determined by first applying single marker regression with covariates. Significant biomarkers were then analyzed by multi-marker regression and model selection to predict the relative strength of outcome association for these biomarkers. All variables included were normally distributed or transformed to normal distribution. Results: The median age of participants ranged from 31-38 years for both SCD cohorts and NHANES control. 16%, 21% and 8% of the mild genotype patients, severe genotype patients and NHANES controls, respectively were on at least one antihypertensive medication for either hypertension or proteinuria. The median (IQR) for systolic and diastolic BP for the patients with mild genotype were 122 mm Hg (112-130) and 78mmHg (70-84); severe genotype 119 mmHg (110-128) and 70 mmHg (64-75); NHANES 118(110-128) and 70 mmHg (62-78). Systolic blood pressures did not differ among the SCD groups versus NHANES, but diastolic blood pressures were higher in the mild SCD genotype patients than severe SCD patients (P Discussion: Our SCD patient cohorts demonstrate a much higher median SBP, and for the mild genotype patients, higher DBP than was described for their age group in the cooperative study of sickle cell disease (Pegelow et al 1997). When compared with a contemporary NHANES cohort, we failed to observe a lower SBP or DBP as was expected. Higher systolic blood pressure has been reported as risk factor for the development of silent cerebral infarct in HbSS children (DeBaun et al 2014). Our study also shows that BP changes in SCD may be less influenced by traditional anthropometric measures and clinical markers. Figure 1 Figure 1. Disclosures Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.

The polymerization of deoxygenated HbS molecules in the red blood cells (RBCs) of patients with sickle cell disease (SCD) causes RBC destruction resulting in chronic pain, debilitating acute pain crises, strokes, multi-organ damage and a reduced life span. Therapeutic options remain limited. Bone marrow transplantation can be curative but is not an option for the majority of patients. Gene therapy interventions that also offer the promise of a cure are under investigation but are not likely to be available to the vast majority of patients in the near future. Hydroxyurea, the first drug approved for treatment of SCD, increases levels of Fetal Hemoglobin (HbF) that inhibit polymerization of HbS molecules but is not effective in all patients while a more powerful HbF-inducing drug, the DNA methyltransferase inhibitor decitabine has yet to be approved. L-glutamine, another approved therapeutic option, increases NAD redox potential and decreases reactive oxygen species (ROS) in the sickle RBCs to reduce symptoms. In our laboratory we have observed that increased ROS is associated with the retention of mitochondria in the SCD RBCs and have hypothesized that the abnormal presence of mitochondria in these cells is a major source of ROS (Jagadeeswaran et al Exp Hematol 50:46-52, 2017). In this investigation we have tested the hypothesis that chronic oral supplementation with nicotinamide, a direct precursor of NAD synthesis, would improve NAD redox potential, decrease mitochondrial retention and ROS in SCD RBCs, and reduce anemia in the SCD mouse model. The effect of nicotinamide was tested in SCD mice whose drinking water was supplemented for three months with 1% nicotinamide. The percentage of RBCs retaining mitochondria and the levels of ROS were determined by flow cytometric assays using the mitochondrial-specific dye TMRM and the ROS probe CM-H2DCFDA, respectively. In SCD mice receiving nicotinamide the fraction of RBCs retaining mitochondria was reduced 22.1% (p Figure 1 Figure 1. Disclosures Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Chronic kidney disease is observed in up to 50% of adults with sickle cell disease (SCD) and is a consistent predictor for increased morbidity and early mortality. Progression of kidney disease can be manifested by a rapid decline in estimated glomerular filtration rate (eGFR). In retrospective studies, up to 38% of SCD patients have a rapid decline in kidney function, defined from the non-SCD literature as an eGFR slope < -3.0 mL/min/1.73m 2. Clinical and genetic predictors and the appropriate cutoff for rapid eGFR decline in SCD are unclear, but are paramount for guiding intervention studies in sickle cell nephropathy. We investigated 1) genetic, laboratory, and clinical risk factors for eGFR decline and 2) the rate of eGFR decline that best predicted mortality risk in a longitudinal cohort of SCD patients enrolled in a prospective registry at our institution. Between 10/2009 and 2/2018, 439 SCD patients were recruited. Blood samples, clinical and laboratory data were collected after obtaining consent at the time of enrolment during a clinic visit without the patient being in a vaso-occlusive crisis. 352 SCD patients with > 6 months of outpatient eGFR assessments were included in this analysis. The eGFR slope was calculated for each patient by linear regression of eGFR by time. Genotyping for the APOL1 G1 and G2 kidney risk variants and alpha thalassemia were performed by PCR. High-risk APOL1 status was defined as being either homozygous or compound heterozygous for the G1 and/or G2 variants. The statistical analyses for predictors of eGFR decline were conducted using linear regression, adjusting for age, sex, SCD genotype, hydroxyurea use, angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use, and baseline eGFR. Median and interquartile ranges (IQR) are provided. The median age of the cohort was 32 years old (IQR, 24 - 43 years), 60% were female, 76% had Hb SS or Sβ 0-thalassemia genotype, 47% were on hydroxyurea, and 12% were on ACEi or ARB therapy. With a median follow up of 6.7 (IQR, 3.8 - 8.5) years, the median annual eGFR slope was -0.9 (IQR, -3.6 to 1.1) mL/min/1.73m 2. A faster rate of eGFR decline was observed in SCD patients with the Hb SS or Sβ 0-thalassemia genotype, with high-risk APOL1 status, and in those without coinheritance of α-thalassemia (Figure 1A). The urine albumin concentration, based on the average of two consecutive values from the time of enrolment, was significantly associated with a more rapid eGFR decline (β -0.63, P < 0.0001). An albuminuria cutoff of ≥ 100 mg/g creatinine was a stronger predictor for eGFR decline than cutoffs of ≥ 30 or ≥ 300 mg/g (Figure 1B). During the follow up period, we observed 26 deaths (7.4% mortality). An annual eGFR slope of < -6 mL/min/1.73m 2 was independently associated with a greater risk for mortality, after adjusting for age, sex, SCD genotype, hydroxyurea use, ACEi or ARB use, and baseline eGFR (Figure 1C). Using receiver operating curves, this cutoff was also associated with the largest area under the curve for predicting mortality. Our data highlights genetic risk factors and supports albuminuria as an independent predictor of eGFR decline in a longitudinal cohort of SCD patients. We also demonstrate that an annual eGFR slope of < -6 mL/min/1.73m 2 is the strongest predictor for mortality in our cohort. This threshold will need to be validated in other longitudinal SCD cohorts. The association of urine albumin ≥ 100 mg/g creatinine with eGFR decline supports using this cutoff as a clinical biomarker to identify high risk patients for kidney disease progression and for initiating disease modifying and reno-protective therapies. Figure 1 Figure 1. Disclosures Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy.

Patients with sickle cell disease (SCD) are known to require increased dosing of drugs including opioids due to differences in renal and hepatic metabolism. While it is known that SCD patients require higher opioid doses to achieve the same degree of analgesia, it is not clear if this is associated with a similar increase in drug toxicities. A significant risk of opioid use is respiratory depression, and naloxone is used for rapid reversal of this adverse effect. In the setting of a nationwide opioid shortage in 2018, our institution established a policy requiring the use of patient-controlled analgesia (PCA) rather than intravenous push (IVP) for hospitalized SCD patients. This coincided with a mandate for end tidal carbon dioxide (ETCO) monitoring with PCA use, effectively implementing ETCO in the routine care of this population. In this study, we describe our experience using naloxone for opioid reversal in hospitalized SCD patients. We studied naloxone use in patients admitted to the University of Illinois at Chicago for two 24-month time periods (July 31, 2015 - July 31, 2017 and May 1, 2018 - May 1, 2020). These dates were chosen to compare naloxone use before and after implementation of ETCO monitoring. A pharmacy reporting tool was used to identify every dose of naloxone administered within the hospital during these dates. We isolated patients on the inpatient sickle cell service and compared the proportion of SCD patients between study periods using Fisher's exact test. For SCD patients who received naloxone, we obtained baseline patient characteristics and divided doses into episodes when multiple doses were given within a day. For each episode, we studied analgesic regimens, details of the hospitalization, and laboratory values. Given the small data sample, we used descriptive statistics for analysis. Among 931 total naloxone doses given in the two time periods, 35 were given to SCD patients. Out of 580 total distinct patients, there were 14 patients admitted to the sickle cell service. There were 5 out of 279 (1.8%) SCD patients who received 12 out of 443 (2.7%) doses between July 2015 and July 2017. There were 10 out of 309 (3.2%) SCD patients who received 23 out of 488 (4.7%) doses between May 2018 and May 2020. There was no significant difference in naloxone use by SCD patients before and after implementation of ETCO. For the two time periods combined, there were 14 out of 580 (2.4%) SCD patients who received 35 out of 931 (3.8%) doses. We were able to manually confirm 10 SCD patients and 17 episodes of naloxone use by chart review. Among these, 2 patients who only had 1 episode each received naloxone in the absence of opioid overdose. One patient with multiple episodes had an episode of receiving naloxone for opioid overdose not involving hospital-administered medications. Among the remaining 8 SCD patients who appropriately received naloxone for opioid reversal in the hospital, 100% were black or African American race. Seven (87.5%) out of 8 had Hgb SS genotype, and male-to-female ratio was 1:1. Six out of 14 (42.9%) episodes occurred when patients were not receiving their usual pain regimen. Vaso-occlusive crisis was a diagnosis for 13 out of 14 (92.9%) episodes. A median of 2 doses of naloxone were given per episode. Median creatinine clearance was 20.85 mL/min, and several cases coincided with acute kidney injury. Median sedation scale score prior to naloxone dose was 1 (minimally sedated). One patient was treated with a naloxone continuous infusion. Our study highlights the relatively low use of naloxone in patients with SCD despite generally high usage of opioids. Nearly every patient admitted to the sickle cell service utilizes opioid pain medications, but the proportion of naloxone use in SCD patients is small. There was no significant difference in naloxone use after policy changes instituted the use of ETCO, but this may be due to sample size. The low rates of naloxone use in SCD patients may be related to mechanisms of hyperfiltration that necessitate increased opioid dosing. Our results suggest that the higher observed opioid dosages are not associated with worsened toxicities in SCD patients. With techniques such as ETCO, SCD patients can more safely be treated for pain using opioid medications, and providers should be mindful of pertinent pharmacological factors when caring for this population. Disclosures Saraf: Pfizer: Research Funding; 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.