A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis.

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

Persistent albuminuria and chronic kidney disease in adults with sickle cell anaemia: Results from a multicenter natural history study.

Clinical and laboratory correlates of chronic kidney disease (CKD) in sickle cell anaemia remain incompletely defined. In a multicenter cohort study, we evaluated the prevalence of persistent albuminuria (PA) and characteristics associated with PA, albumin-creatinine ratio (ACR) and decreased estimated glomerular filtration rate (eGFR) using logistic, linear and multinomial regression models, respectively. Of 269 participants (median age: 30 years; 57.2% females), the prevalence of PA was 35.7%. Using baseline ACR values of <100 and ≥100 mg/g, the probabilities of PA were 30.0% and 94.6%, respectively. In multivariable logistic regression analyses, male sex (ß = 0.80 [SE = 0.36], p = 0.024) and ACE inhibitors/ARBs use (ß = 1.54 [SE = 0.43], p < 0.001) were associated with higher likelihoods of PA, while higher haemoglobin (ß = -0.33 [SE = 0.13], p = 0.009) and HbF (ß = -0.04 [SE = 0.02], p = 0.041) were associated with lower likelihoods of PA. In multivariable multinomial regression analyses, older age (ß = 0.06 [SE = 0.02], p = 0.004) and higher alkaline phosphatase (ß = 0.01 [SE = 0.00], p = 0.004) were associated with higher odds of having eGFR 60-90 versus eGFR>90 mL/min/1.73 m2 using the cystatin C-based CKD-EPI-2012 equation. Additionally, higher systolic blood pressure (ß = 0.11 [SE = 0.03], p = 0.001) and blood urea nitrogen (ß = 0.45 [SE = 0.12], p < 0.001) were associated with higher odds, while higher haemoglobin (ß = -1.22 [SE = 0.43], p = 0.004) was associated with lower odds of having eGFR<60 versus eGFR>90 mL/min/1.73 m2. PA and decreased eGFR are associated with measures of disease severity and comorbid conditions (Clinicaltrials.gov Identifier: NCT03277547).

Four-factor prothrombin complex concentrate versus andexanet alfa for direct oral anticoagulant reversal.

BACKGROUND: Optimal reversal agent for direct oral anticoagulant (DOAC)-associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents. OBJECTIVE: This study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings. METHODS: A multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events. RESULTS: There were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group. CONCLUSIONS: There were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA.

Reprint of: Four-factor prothrombin complex concentrate versus andexanet alfa for direct oral anticoagulant reversal.

BACKGROUND: Optimal reversal agent for direct oral anticoagulant (DOAC)-associated major bleeding has not been described. Before the approval of andexanet alfa (AA) in 2018, 4-factor prothrombin complex concentrate (4F-PCC) was recommended by major guidelines. Currently, AA is recommended as the first-line agent by most guidelines. With a paucity of literature comparing the 2 agents, there is clinical value in assessing hemostatic efficacy and safety of the 2 agents. OBJECTIVE: This study aimed to evaluate hemostatic efficacy and safety of AA and 4F-PCC in all DOAC-associated major bleedings. METHODS: A multicenter, retrospective chart review was performed of adult subjects who were admitted for a DOAC-associated major bleeding and received 4F-PCC from February 2018 to May 2019 or AA from May 2019 to September 2021. Some of the exclusion criteria included not receiving a DOAC, receiving multiple reversal agents during the same hospitalization, receiving reversal for any nonmajor bleeding indication, and not receiving the full dose of a reversal agent. The primary outcome was hemostatic efficacy 24 hours after the end of the reversal agent administration. Secondary outcomes included time to administration, hospital mortality, length of stay, need for surgery, and need for additional blood product. Safety outcome was incidence of thrombotic events. RESULTS: There were 99 subjects included in the 4F-PCC group and 84 subjects in the AA group. Hemostatic efficacy was achieved in 69 subjects (69.7%) in the 4F-PCC group and 63 subjects (75%) in the AA group (P = 0.927). In-hospital mortality was seen in 20 subjects (20.2%) in the 4F-PCC group and 10 subjects (11.9%) in the AA group. Thrombotic events were seen in 7 subjects (7.1%) in the 4F-PCC group and 6 subjects (7.1%) in the AA group. CONCLUSIONS: There were no significant differences in hemostatic efficacy, in-hospital mortality, and number of thrombotic events between 4F-PCC and AA.

Current Evidence and Rationale to Guide Perioperative Management, Including Transfusion Decisions, in Patients With Sickle Cell Disease.

Sickle cell disease (SCD) is a collection of inherited hemoglobin disorders that results in chronic hemolytic anemia, vaso-occlusion, pain, and end organ damage. Surgery in the SCD population requires careful planning, as perioperative stressors can lead to increased sickling and risk of inducing or further exacerbating vaso-occlusive episodes (VOEs). Additionally, the underlying hypercoagulability and immunocompromised state due to SCD places patients at increased risk of both venous thromboembolism and infection. Judicious fluid administration, temperature regulation, thorough preoperative and postoperative analgesic planning, and preoperative transfusion are all crucial components of decreasing risks of surgery in patients with SCD.

Youth Top Problems in an Acute Psychiatric Sample: Describing Consumer-Nominated Treatment Needs in an Adolescent Partial Hospital Setting.

Given the wide range of diagnostic presentations treated in partial hospital programs, finding efficient ways to identify and measure progress on the chief concerns of consumers in these settings is important. The current study uses a self-administered version of the Top Problems Assessment to describe treatment targets identified by youth and their caregivers presenting for care at an adolescent partial hospital setting. Caregiver-youth agreement on these chief concerns upon admission and predictors of agreement were explored. About one-third (34.65%) of caregiver-youth pairs did not match on any target problems. Although anxiety and depression were the most commonly cited top problems in this sample, caregivers and youth exhibited disagreement on these domains. Treatment teams in acute care settings such as a partial hospital program can benefit from careful assessment surrounding the initial goals of treatment as youth and their caregivers may not agree on the referral problems upon entering a program.

The Effect of Use of Individualized Pain Plans in Sickle Cell Patients Presenting to the Emergency Department.

STUDY OBJECTIVE: Sickle cell disease (SCD) is an inherited hematologic disorder that affects approximately 100,000 US individuals and results in greater than 200,000 emergency department (ED) visits annually in the United States, with pain being the most common complaint. The objective of this retrospective study is to determine the effect of implementing individualized pain plans in the treatment of patients with SCD in the ED on time to first opioid, length of stay, and disposition. METHODS: At The Ohio State University Wexner Medical Center, a multidisciplinary group including hematologists and ED physicians was formed and enacted a protocol for using individualized pain plans, with the goal of decreasing time to treatment for patients with SCD who presented to the ED with chief complaint of pain. In this retrospective study, data from the year before through the year of implementation were gathered. Generalized linear models were fit to compare time to first opioid, length of stay, and disposition before and after protocol implementation. RESULTS: Data showed a 48% decrease in time to first opioid and a 22% decrease in length of ED stay after protocol implementation. No significant change was found in disposition or length of inpatient admission before and after protocol initiation. CONCLUSION: The use of individualized pain plans in the treatment of patients with SCD in the ED is a useful method of not only ensuring rapid and adequate treatment but also decreasing use of health care resources.

Association between diffuse myocardial fibrosis and diastolic dysfunction in sickle cell anemia.

Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, P < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, P = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, P = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, P = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction (P = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m2, P = .04) compared with those with ECV <0.4. ECV correlated with hemoglobin (r = -0.46, P = .03) and NT-proBNP (r = 0.62, P = .001). In conclusion, diffuse myocardial fibrosis, determined by ECV, is a common and previously underappreciated feature of SCA that is associated with diastolic dysfunction, anemia, and high NT-proBNP. Diffuse myocardial fibrosis is a novel mechanism that appears to underlie diastolic dysfunction in SCA.

From Care to Cure: Demonstrating a Model of Clinical Patient Navigation for Hepatitis C Care and Treatment in High-Need Patients.

The NYC Department of Health implemented a patient navigation program, Check Hep C, to address patient and provider barriers to HCV care and potentially lifesaving treatment. Services were delivered at two clinical care sites and two sites that linked patients to off-site care. Working with a multidisciplinary care team, patient navigators provided risk assessment, health education, treatment readiness and medication adherence counseling, and medication coordination. Between March 2014 and January 2015, 388 participants enrolled in Check Hep C, 129 (33%) initiated treatment, and 119 (91% of initiators) had sustained virologic response (SVR). Participants receiving on-site clinical care had higher odds of initiating treatment than those linked to off-site care. Check Hep C successfully supported high-need participants through HCV care and treatment, and SVR rates demonstrate the real-world ability of achieving high cure rates using patient navigation care models.

Geographic epidemiology of hepatocellular carcinoma, viral hepatitis, and socioeconomic position in New York City.

PURPOSE: Liver cancer (hepatocellular carcinoma (HCC)) incidence and mortality rates are increasing in the United States. New York City (NYC) has a high burden of liver cancer risk factors, including hepatitis C (HCV) and hepatitis B (HBV) infection, which disproportionately affect persons of low socioeconomic position. Identifying neighborhoods with HCC disparities is essential to effectively define targeted cancer control strategies. METHODS: New York State Cancer Registry data from 1 January 2001 through 31 December 2012 were matched with NYC HCV and HBV surveillance data. HCC data were aggregated to NYC Zip Code Tabulation Areas (ZCTAs). Moran's I cluster analysis, Poisson regression, and geographically weighted Poisson regression were used to identify hotspots in HCC incidence and to examine the spatial associations with viral hepatitis rates, poverty, and uninsured status. RESULTS: Among NYC residents, 8,827 HCC cases were diagnosed during 2001-2012. Significant clustering was detected in the HCC rates (Moran's I = 0.25) with the strongest clustering found in HCC patients with comorbid HCV infection (Moran's I = 0.47). Poverty and uninsured status were associated (p < 0.05) with increased rates of HCC patients with HBV or HCV infection. Neighborhoods with high rates of HCC without viral hepatitis infection had lower rates of poverty and uninsured status. CONCLUSIONS: The geographic variation in HCC highlights the need for neighborhood-targeted interventions to address risk factors and barriers to care. The clusters of HCC by viral hepatitis status may serve as a basis for healthcare policymakers and practitioners to prioritize neighborhoods for cancer screening and control efforts.

Risk factors for mortality in adult patients with sickle cell disease: a meta-analysis of studies in North America and Europe.

Although recent studies show an improved survival of children with sickle cell disease in the US and Europe, for adult patients mortality remains high. This study was conducted to evaluate the factors associated with mortality in adult patients following the approval of hydroxyurea. We first evaluated the association between selected variables and mortality at an academic center (University of North Carolina). Data sources were then searched for publications from 1998 to June 2016, with meta-analysis of eligible studies conducted in North America and Europe to evaluate the associations of selected variables with mortality in adult patients. Nine studies, combined with the UNC cohort (total n=3257 patients) met the eligibility criteria. Mortality was significantly associated with age (per 10-year increase in age) [7 studies, 2306 participants; hazard ratio (HR): 1.28; 95% confidence interval (CI): 1.10-1.50], tricuspid regurgitant jet velocity 2.5 m/s or more (5 studies, 1577 participants; HR: 3.03; 95%CI: 2.0-4.60), reticulocyte count (3 studies, 1050 participants; HR: 1.05; 95%CI: 1.01-1.10), log(N-terminal-pro-brain natriuretic peptide) (3 studies, 800 participants; HR: 1.68; 95%CI: 1.48-1.90), and fetal hemoglobin (7 studies, 2477 participants; HR: 0.97; 95%CI: 0.94-1.0). This study identifies variables associated with mortality in adult patients with sickle cell disease in the hydroxyurea era.

Neighborhood Inequalities in Hepatitis C Mortality: Spatial and Temporal Patterns and Associated Factors.

Deaths attributable to hepatitis C (HCV) infection are increasing in the USA even as highly effective treatments become available. Neighborhood-level inequalities create barriers to care and treatment for many vulnerable populations. We seek to characterize citywide trends in HCV mortality rates over time and identify and describe neighborhoods in New York City (NYC) with disproportionately high rates and associated factors. We used a multiple cause of death (MCOD) definition for HCV mortality. Cases identified between January 1, 2006, and December 31, 2014, were geocoded to NYC census tracts (CT). We calculated age-adjusted HCV mortality rates and identified spatial clustering using a local Moran's I test. Temporal trends were analyzed using joinpoint regression. A multistep global and local Poisson modeling approach was used to test for neighborhood associations with sociodemographic indicators. During the study period, 3697 HCV-related deaths occurred in NYC, with an average annual percent increase of 2.6% (p = 0.02). The HCV mortality rates ranged from 0 to 373.6 per 100,000 by CT, and cluster analysis identified significant clustering of HCV mortality (I = 0.23). Regression identified positive associations between HCV mortality and the proportion of non-Hispanic black or Hispanic residents, neighborhood poverty, education, and non-English-speaking households. Local regression estimates identified spatially varying patterns in these associations. The rates of HCV mortality in NYC are increasing and vary by neighborhood. HCV mortality is associated with many indicators of geographic inequality. Results identified neighborhoods in greatest need for place-based interventions to address social determinants that may perpetuate inequalities in HCV mortality.

Paracrine Wnt signaling both promotes and inhibits human breast tumor growth.

Wnt signaling in mouse mammary development and tumorigenesis has been heavily studied and characterized, but its role in human breast cancer remains elusive. Although Wnt inhibitors are in early clinical development, it is unclear whether they will be of therapeutic benefit to breast cancer patients, and subsequently, to which ones. To address this, we generated a panel of Wnt reporting human breast cancer cell lines and identified a previously unrecognized enrichment for the ability to respond to Wnt in the basal B or claudin-low subtype, which has a poor prognosis and no available targeted therapies. By co-injecting Wnt3A expressing human mammary fibroblasts with human breast cancer cell lines into mouse mammary fat pads, we showed that elevated paracrine Wnt signaling was correlated with accelerated tumor growth. Using this heterotypic system and a dual lentiviral reporter system that enables simultaneous real-time measurement of both Wnt-responsive cells and bulk tumor cells, we analyzed the outcome of elevated Wnt signaling in patient-derived xenograft (PDX) models. Interestingly, the PDX models exhibited responses not observed in the cell lines analyzed. Exogenous WNT3A promoted tumor growth in one human epidermal growth factor receptor 2-overexpressing PDX line but inhibited growth in a second PDX line obtained from a patient with triple-negative breast cancer. Tumor suppression was associated with squamous differentiation in the latter. Thus, our work suggests that paracrine Wnt signaling can either fuel or repress the growth of human breast cancers depending on yet to be determined aspects of the molecular pathways they express.

Open Versus Arthroscopic Ankle Arthrodesis: A Comparison of Subsequent Procedures in a Large Database.

Arthroscopic and open ankle arthrodesis have been compared in very few studies, and no consensus has been reached regarding the incidence of postoperative revision surgery associated with each technique. The purpose of the present study was to compare these 2 approaches for the incidence of postsurgical operations. Patients who had undergone either arthroscopic or open ankle arthrodesis were identified between January 2005 to December 2011 in the PearlDiver(™) database using a predetermined algorithm and searched for the following postsurgical operations: revision ankle arthrodesis, midfoot arthrodesis, and hindfoot arthrodesis. In the current database, 7322 cases were performed with an open technique and 1152 arthroscopically. The incidence of revision arthrodesis was not significantly different statistically between the 2 techniques. However, the incidence of subsequent adjacent joint arthrodesis was greater for the open cohort (5.6% versus 2.6%; odds ratio 2.17, 95% confidence interval 1.49 to 3.16). In the open cohort, the incidence of hindfoot arthrodesis was greater than the incidence of midfoot arthrodesis (3.9% versus 1.6%, odds ratio 2.43, 95% confidence interval 1.95 to 3.01). The results showed that although open ankle arthrodesis is more commonly performed, it is associated with a greater incidence of subsequent adjacent joint arthrodesis specifically in the hindfoot.

Alloimmunization is associated with older age of transfused red blood cells in sickle cell disease.

Red blood cell (RBC) alloimmunization is a significant clinical complication of sickle cell disease (SCD). It can lead to difficulty with cross-matching for future transfusions and may sometimes trigger life-threatening delayed hemolytic transfusion reactions. We conducted a retrospective study to explore the association of clinical complications and age of RBC with alloimmunization in patients with SCD followed at a single institution from 2005 to 2012. One hundred and sixty six patients with a total of 488 RBC transfusions were evaluated. Nineteen patients (11%) developed new alloantibodies following blood transfusions during the period of review. The median age of RBC units was 20 days (interquartile range: 14-27 days). RBC antibody formation was significantly associated with the age of RBC units (P = 0.002), with a hazard ratio of 3.5 (95% CI: 1.71-7.11) for a RBC unit that was 7 days old and 9.8 (95% CI: 2.66-35.97) for a unit that was 35 days old, 28 days after the blood transfusion. No association was observed between RBC alloimmunization and acute vaso-occlusive complications. Although increased echocardiography-derived tricuspid regurgitant jet velocity (TRV) was associated with the presence of RBC alloantibodies (P = 0.02), TRV was not significantly associated with alloimmunization when adjusted for patient age and number of transfused RBC units. Our study suggests that RBC antibody formation is significantly associated with older age of RBCs at the time of transfusion. Prospective studies in patients with SCD are required to confirm this finding.