University of Illinois Hospital & Health Sciences System

Ark E.D., Gelaye B.K., Redleaf M.

Dember L.M., Hsu J.Y., Mehrotra R., Cavanaugh K.L., Kalim S., Charytan D.M., Fischer M.J., Jhamb M., Johansen K.L., Becker W.C., Pellegrino B., Eneanya N.D., Schrauben S.J., Pun P.H., Unruh M.L., et. al.

ImportanceChronic pain is common among individuals with dialysis-dependent kidney failure.ObjectiveTo evaluate the effectiveness of pain coping skills training (PCST), a cognitive behavioral intervention, on pain interference.Design, Setting, and ParticipantsThis multicenter randomized clinical trial of PCST vs usual care was conducted across 16 academic centers and 103 outpatient dialysis facilities in the US. Adults undergoing maintenance hemodialysis and experiencing chronic pain were randomly assigned to PCST or usual care in a 1:1 ratio. Participants were followed in the trial for 36 weeks. Enrollment began on January 4, 2021, and follow-up ended on December 21, 2023.InterventionsPCST consisting of 12 weekly coach-led sessions via video or telephone conferencing, followed by 12 weeks of daily interactive voice response sessions. Usual care had no trial-driven pain intervention.Main OutcomesThe primary outcome was pain interference measured with the Brief Pain Inventory (BPI) Interference subscale (score range of 0-10, with higher scores indicating more pain interference). Secondary outcomes included pain intensity, pain catastrophizing, quality of life, depression, and anxiety.ResultsA total of 643 participants (mean [SD] age, 60.3 [12.6] years; 288 [44.8%] female) were randomized, with 319 assigned to PCST and 324 assigned to usual care. At week 12 (primary end point), the PCST group had a larger reduction in the BPI Interference score than the usual care group (between-group difference, −0.49; 95% CI, −0.85 to −0.12; P = .009). The effect persisted at week 24 (between-group difference in BPI Interference score, −0.48; 95% CI, −0.86 to −0.11) but was diminished at week 36 (between-group difference in BPI Interference score, −0.34; 95% CI, −0.72 to 0.04). A decrease in BPI Interference score greater than 1 point (minimal clinically important difference) occurred in 143 of 281 participants (50.9%) in the PCST group vs 108 of 295 participants (36.6%) in the usual care group at 12 weeks (odds ratio, 1.79; 95% CI, 1.28-2.49) and 142 of 258 participants (55.0%) in the PCST group vs 113 of 264 participants (42.8%) in the usual care group at 24 weeks (odds ratio, 1.59; 95% CI, 1.13-2.24). Favorable changes with PCST were also apparent for secondary outcomes of pain intensity, quality of life, depression, and anxiety at weeks 12 and/or 24, as well as for pain catastrophizing at weeks 24 and 36.Conclusions and RelevanceIn this randomized clinical trial of patients undergoing maintenance hemodialysis, PCST had benefits on pain interference and other pain-associated outcomes. While the effect on the overall cohort was of modest magnitude, the intervention resulted in a clinically meaningful improvement in pain interference for a substantial proportion of participants.Trial RegistrationClinicalTrials.gov Identifier: NCT04571619

Callahan N.F., Weyh A.M., Ghunaim D., Miloro M.

Dental implant therapy has developed over the past half century to have documented successful outcomes in most patients who receive treatment. The long-term survival of dental implants depends upon a variety of factors including patient, surgeon, restorative dentist, and materials-related factors. The impact of patient-associated factors may impact significantly on the success of dental implants including diabetes mellitus, medications, smoking, parafunctional habits, oral hygiene, head and neck radiation, and the use of bisphosphonates, antiangiogenic, and antiresorptive medications.

Jayaseelan D., Post A., Sault J., Mischke J.

Background/Objectives: Tendinopathy is a condition associated with pain and limited function. While upper and lower extremity tendinopathies may have different functional implications, there have been a number of reports supporting different patterns of dysfunction in pain processing and inhibition. The purpose of this scoping review was to examine the methods across studies examining pain processing in patients with upper and lower extremity tendinopathy. Methods: Five electronic databases (PubMed, Scopus, CINAHL, the Cochrane Library, and SPORTDiscus) and gray literature sources were searched from inception through 15 April 2024, using appropriate keywords and relevant synonyms. Results: In total, 3219 titles were retrieved from the searches, with 43 studies retained for final inclusion. Of the 43 studies, 22 were specific to upper extremity tendinopathies, 19 were specific to lower extremity tendinopathies, and 2 studies included mixed samples. Physical testing to detect nervous system sensitization was most commonly performed using pressure pain thresholds. Although infrequent, questionnaire instruments were used mostly to include the central sensitization inventory. Substantial variation was noted across studies in mode of testing and instruments used, while patient demographics and inclusion criteria were not clearly reported in many instances. Thirty-one studies (72%) reported nervous system sensitization or dysfunction in tendinopathy, while 13 (28%) did not. Conclusions: While the difference between pain processing in tendinopathy is likely multifactorial, the results of this review identified substantial variability in methodology used and reporting in tendon pain research. As inconsistency in evidence can limit clinical guidance, efforts to standardize tendinopathy pain research appear warranted.

Stauber C.E., Well A., Dawson-Gore C., Mizrahi M., Fraser C.D., Mery C.M., Stromberg D.

Background Aspirin is frequently utilized for antiplatelet therapy in children with congenital heart disease (CHD). Patients who are unresponsive to aspirin, as measured by aspirin reaction units (ARU), are at higher risk for thrombotic events. It is undetermined if dose modification of aspirin results in adequate responsiveness in these patients. This study evaluates the prevalence and risk factors for aspirin nonresponsiveness and the results of dose escalation in this population. Methods This is a retrospective review of patients cared for in the cardiac care unit at a quaternary care academic congenital heart center who received aspirin and had responsiveness evaluated between January 2018 and January 2023. Patient demographics and clinical characteristics were extracted from the medical record. Descriptive, parametric, and nonparametric univariate analysis were employed. Results A total of 142 patients (69 [49%] female, 45 [32%]Non-Hispanic White, and 63 [44%] Hispanic]) were identified. Median age at first aspirin responsiveness assessment was 54 [interquartile range, IQR: 23.3-411.5] days with a median weight of 5.2 [IQR: 3.64-9.29] kg. Of these, 32/142 (22.5%) were nonresponsive on their initial testing. Of these patients, 23/32 (72%) had follow-up testing with 19/23 (83%) subsequently becoming therapeutic. This was achieved with an increased dose in 12/19 (63%) patients and increased duration of therapy in 7/19 (37%) patients. Seventeen of 142 (12%) patients experienced a thrombotic event, 13/17 (77%) of which were therapeutic on initial responsiveness assessment. Conclusions It is common for CHD patients to be aspirin nonresponsive with initial weight-based dosing. If aspirin is used in this population, it is necessary to evaluate ARUs on all patients as underdosing is not uncommon with current weight-based dosing methods.

Souter J., Mehta A.I.

Yu Q., Badar W., Patel M., Kumari D., Ogunlade S., Wang B., Ahmed O.

Research Highlights:1.Large bore aspiration using Lightning FLASH is safe and effective for deep venous thrombosis.2.Short-term post-thrombectomy patency was promising.3.Computer assisted algorithm that fine tunes the power of aspiration based on flow dynamics was associated with acceptable blood loss in the setting of 16-French compatible cannula.AbstractPurposeTo demonstrate the safety and effectiveness of a computer-assisted large bore thrombectomy (CA-LBT) device aspiration thrombectomy device for treatment of deep vein thrombosis (DVT).Materials and methodsA single institutional retrospective review was performed to include 16 consecutive patients (median age 51.1 years, range 19-77; 5 men and 11 women) who underwent percutaneous thrombectomy using a 16 Fr CA-LBT device (Lightning Flash Aspiration System,Penumbra Inc., Alameda, California, USA) for DVT (12 iliofemoral with or without caval extension [75.0%], 3 axillosubclavian [18.8%], and 1 caval [6.3%) between January 2023 and August 2023.ResultsThrombectomy was performed via the popliteal (n=10, 62.5%), femoral (n=3, 18.8%), saphenous (n=1, 6.3%), brachial (n=1, 6.3%), femoral and brachial (n=1, 6.3%) veins, with a median fluoroscopy time of 17 min (range 7.2-61min) and contrast agent volume of 110 ml (30-175 ml). Restoration of anterograde flow was achieved in all cases (100%, 16/16). Thirteen patients (81.2%) received venoplasty after thrombectomy for residual stenosis. Stents were placed in seven patients (43.8%). With a median clinical follow-up of 77 days (range 3-278 days), symptom improvement was achieved among 13/15 (86.7%) patients that initially presented with DVT associated symptoms. In 14 patients with imaging follow-up, patency was confirmed in 12 patients (85.7%). Of the two patients with complete thrombosis on follow-up imaging (14.3%), one patient was successfully treated with repeated thrombectomy using Flash technology, while the other patient was treated with systemic anticoagulation.ConclusionsAspiration thrombectomy with this 16 Fr CA-LBT device may be a feasible option for treatment of proximal or large volume DVT.Graphical abstract

Hanners E.K., Thambi M., Soni H.P., Jun J., Datta A., Bhaumik D., Stranges P.

Abstract Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Acute pancreatitis (AP) is a common gastrointestinal condition that carries a significant financial and physical burden for patients due to the painful presentation and frequent need for hospitalization. Treatment varies in the type and route of analgesic used. Unmanaged pain can lead to worsening health outcomes and prolonged admissions. Further research is needed to understand current practices for managing AP. Methods This study was a retrospective, exploratory, single-center cohort study. Patients admitted to an internal medicine unit with AP from September 1, 2020, to December 31, 2021, were included. Our primary outcome was the change in pain scores during the first 24-hours after administration of the first pain-relieving medication. Secondary outcomes included change in pain scores within the first 12-hours, time to oral tolerance, characterization of analgesic orders, comparison of median pain scores by home analgesic usage, and specific inpatient opioid use. Results One hundred sixty-nine patients were screened, and 94 were included in the study. Forty-four patients were assigned to the multimodal cohort and 50 patients to the opioid-only cohort. Changes in pain scores per unit of time, assessed by a mixed-effects model, within the first 24 hours were –0.080 (SE, 0.018) in the multimodal cohort and –0.090 (SE, 0.014) in the opioid-only cohort (P = 0.780). Morphine milligram equivalents (MME) administered in the multimodal and opioid-only cohorts were 24.50 (interquartile range [IQR], 51.75) and 52.5 (IQR, 68.5) (P = 0.001), respectively. Conclusion There was no significant difference in the change in pain scores between patients receiving multimodal therapy and those receiving opioids only. Significantly fewer MME were administered in the multimodal group, suggesting that multimodal therapy can be opioid-sparing in AP.

Sowa A., Hu Y., Gladwin M.T., Gordeuk V.R., Nouraie S.M., Zhang Y., Pashankar F.D., Krishnamurti L., Gruen J.

Background: For many patients with sickle cell disease (SCD), episodes of acute pain occur within the context of debilitating persistent or chronic pain. Over half of adult patients report pain on more than half of the days, and almost a third experience pain on 95% of days. No previous GWAS studies have explored the association of genetic polymorphisms with chronic pain in SCD. Methods: We conducted a genome-wide association study (GWAS) involving 405 SCD patients using data from the screening phase of the Walk-PHaSST study (NCT00492531). Participants were age 12 years and older, with a median age of 35 years, and 53% were female; 73% had hemoglobin (Hb) SS, 18% had Hb SC, 4.0% had Hb Sβ + thalassemia, and 4.9% had other subtypes of SCD. Genotypic data were filtered to exclude SNPs with a call rate below 95%, deviations from Hardy-Weinberg equilibrium (P < 0.00001), or a minor allele frequency under 0.05, resulting in 9,874,538 SNPs for analysis. We performed a proportional odds logistic regression to evaluate the association between SNPs and self-reported chronic pain levels, rated on a 0 to 10 scale. Adjustments were made for age, sex, SCD subtype, alpha-thalassemia, hemoglobin concentration, hydroxyurea usage, and the first 10 principal components to control for population stratification. Results: Chronic pain was reported by 146 patients (36%). Three SNPs reached genome-wide significance: rs8026638 (p = 4.16 × 10^-8), rs7180285 (p = 4.64 × 10^-8), and rs10152723 (p = 4.96 × 10^-8). These SNPs, all in high linkage disequilibrium, are located on chromosome 15 within the intronic region of the CHD2 (Chromodomain Helicase DNA Binding Protein 2) gene. Conclusions: To the best of our knowledge, this is the first GWAS to identify a locus for chronic pain in SCD that exceeds genome-wide significance threshold. Analyzing a small but well-phenotyped cohort of individuals with SCD, we found association with three SNPs within the CHD2 gene. The CHD2 gene, part of a family of genes that modify chromatin structure to alter gene expression, has previously been associated with cognitive function, generalized myoclonic and atypical absence seizures, and abnormal pyramidal signs. Further validation in larger cohorts and additional biological studies are needed to confirm these associations and to further explore their potential modulating effects on pain pathophysiology and perception.

Sowa A., Hu Y., Gladwin M.T., Gordeuk V.R., Nouraie S.M., Zhang Y., Pashankar F.D., Krishnamurti L., Gruen J.

Background: Avascular necrosis (AVN) is a debilitating complication of sickle cell disease (SCD). The incidence of AVN in individuals with SCD is markedly higher than in the general population, affecting even young children and up to 30% of those over the age of 45. While candidate gene studies have explored genetic associations with AVN in SCD, no genome-wide association studies (GWAS) have been conducted. Methods: We performed a GWAS on 405 patients with diagnosis of SCD using data from the screening phase Walk-PHaSST study (NCT00492531). Patients were 12 years or older, median age of 35 years, 53% female, 73% had hemoglobin (Hb) SS, 18% had Hb SC, 4.0% had Hb Sβ + thalassemia, and 4.9% had other SCD forms. All samples had a genotype call rate greater than 95%. SNPs deviating from Hardy-Weinberg equilibrium (P < 0.00001) or with a minor allele frequency less than 0.05 were excluded. Following quality control, 9,874,538 SNPs remained for analysis. genomic inflation factor lambda was 1.023, indicating adequate control for population stratification. We performed multivariable logistic regression analysis (PLINK version 1.9) to investigate the association between SNPs and the presence of AVN of the hip and/or shoulder, adjusting for age, sex, SCD type, alpha-thalassemia, hemoglobin level, hydroxyurea use, and the first 10 principal components. Results: There were 88 (21.7%) individuals with AVN of the hip and/or shoulder. Two SNPs on chromosome 1 reached genome-wide significance: rs74436238 (OR=7.43, 95% CI: 3.75-14.70, p=8.11×10^-9) and rs112449951 (OR=6.67, 95% CI: 3.44-12.93, p=1.87×10^-8). These SNPs are in high linkage disequilibrium and located within a long non-coding RNA gene (ENSG00000232537) and an enhancer region (GH01J209266), respectively. The enhancer region is suggested to regulate CAMK1G expression, a gene involved in bone metabolism. Conclusions: To the best of our knowledge, this is the first GWAS of AVN to identify a locus that exceeds genome-wide significance threshold. Analyzing a small but well phenotyped cohort of individuals with SCD, we identified a novel locus for AVN on chromosome 1, potentially involving regulatory elements affecting bone metabolism. Further studies in larger cohorts and functional validation are needed to confirm these findings and explore their clinical implications.

Ren G., Ruiz M.A., Setty S., Gordeuk V.R., Saraf S.L.

Chronic kidney disease (CKD) is a common complication that leads to substantial morbidity and early mortality in sickle cell anemia (SCA). Renin-angiotensin-aldosterone system (RAAS) inhibitors, such as losartan, are recommended to treat SCA-related CKD although these guidelines are based on small studies with short follow-up. The pathophysiology of SCA-related CKD is complex with increased hemolysis and hemoglobinuria identified as risk factors for the development and progression of CKD (PMID 24329963). GBT1118, a mouse analogue of voxelotor, reduces intravascular hemolysis and hemoglobinuria thereby protecting the kidneys from damage if started early (12 weeks of age) before CKD has developed in SCA mice (PMID 35759756). We investigated whether concurrent GBT1118 + losartan treatment would improve biomarkers of kidney damage and kidney function in older SCA mice starting at 24 weeks of age when CKD is evident. Transgenic sickle mice (Hb SS; Townes model, Jackson Laboratory) were treated as follows: A) GBT1118 + losartan, B) losartan-only, C) control chow (n = 10; 5 male and 5 female mice in each arm). Losartan treatment was started at 21 weeks (groups A & B), GBT1118 at 24 weeks (group A), and both treatments continued until 36 weeks of age. Urine was collected for 24 hours using metabolic cages. We compared markers of hemolysis (hemoglobin, reticulocyte %, hemoglobinuria), reactive oxygen species (thiobarbituric acid reactive substances [TBARS]), kidney injury (kidney injury molecule-1 [KIM-1], nephrin), and kidney function (albuminuria, proteinuria; serum cystatin C and BUN) using ANOVA adjusting for sex. Mean ± standard error values are provided. At 36 weeks of age, SCA mice treated with GBT1118 + losartan (Group A) had higher hemoglobin concentrations (A: 6.9 ± 0.3 g/dL, B: 5.2 ± 0.4 g/dL, C: 6.5 ± 0.1 g/dL; P = 0.0017), lower reticulocyte % (A: 23 ± 1%, B: 33 ± 1%, C: 38 ± 1%; P < 0.0001), and lower urine hemoglobin concentrations (A: 0.3 ± 0.1 ng/24h, B: 1.7 ± 0.2 ng/24h, C: 1.7 ± 0.3 ng/24h; P = 0.0001) compared to the losartan-only (Group B) and control (Group C) mice. The hemoglobin concentrations and reticulocyte % were significantly lower in the losartan-only versus control mice (P ≤ 0.002). Urinary biomarkers of oxidant injury (TBARS; A: 43.2 ± 4.5 nmol/24h, B: 80.9 ± 8.1 nmol/24h, C: 87.0 ± 5.9 nmol/24h; P = < 0.0001) and tubular injury (KIM-1; A: 163 ± 13 pg/24h, B: 219 ± 21 pg/24h, C: 307 ± 24 pg/24h; P = 0.0002) were lowest in SCA mice receiving GBT1118 + losartan. Urinary nephrin concentrations, a biomarker of glomerular injury, were similar in the GBT1118 + losartan and losartan-only treated mice and trended lower compared to control mice (A: 8.1 ± 0.9 ng/24h, B: 8.0 ± 1.1 ng/24h, C: 9.8 ± 0.9 ng/24h; P = 0.2). We observed significant improvements in albuminuria (A: 22 ± 2 µg/24h, B: 37 ± 6 µg/24h, C: 115 ± 15 µg/24h; P < 0.0001) and proteinuria (A: 1.0 ± 0.2 mg/24h, B: 1.5 ± 0.2 mg/24h, C: 4.2 ± 0.5 mg/24h; P < 0.0001) in the GBT1118 + losartan treated mice. Serum cystatin C and BUN increased in the losartan-only treated mice compared to control mice (P≤ 0.004) while remaining stable in the GBT1118 + losartan treated mice (cystatin C; A: 606 ± 15 ng/mL, B: 667 ± 19 ng/dL, C: 586 ± 14 ng/dL) (BUN; A: 26 ± 1 mg/dL, B: 32 ± 2 mg/dL, C: 24 ± 2 mg/dL). Studies are ongoing to evaluate histopathologic and ultrastructural kidney changes across the three treatment groups. In conclusion, the combination of GBT1118 + losartan improves hemolysis as well as several biomarkers of kidney injury and function in older SCA mice after CKD has developed. Losartan reduces intraglomerular pressure and we observed that losartan-only treated mice had lower urine nephrin, albumin and protein concentrations compared to control SCA mice. RAAS inhibitors have been shown to reduce erythropoietin levels and decrease kidney perfusion pressures in some studies of non-SCA related CKD. Consistent with this, losartan-only treated SCA mice developed more severe anemia and increased serum cystatin C and BUN concentrations compared to control SCA mice. Adding GBT1118 to losartan provided additional protection to the kidney, based upon further improvements in urine TBARS, KIM-1, albumin and protein concentrations, while improving the hemoglobin concentration and maintaining stable serum cystatin C and BUN levels. Our results provide support for developing multimodal strategies, such as the combination of voxelotor + losartan, to treat SCA-related CKD in humans.

Park Y., Mahmud D., Charan G.I., Ganapathy A., Kassis A.R., Tepak E., Rondelli D., Mahmud N.

Cryopreservation of hematopoietic stem/progenitor cell (HSPC) grafts for future infusion into patients is a common practice. However, cryopreservation and long-term storage can influence the post-thaw recovery of target cells retaining functional potency. We analyzed 38 graft aliquots stored in liquid nitrogen (auto 10 yrs = 7, auto 1 yr = 12, allo 10 yrs = 5, allo 5 yrs = 5, allo 1 yr = 9). The viable CD34+ cell frequency in allogeneic (allo) HSPC grafts was higher than in autologous (auto) grafts cryopreserved 10 years ago (auto 10 yrs = 0.39 ± 0.24%, allo 10 yrs = 0.96 ± 0.31%, allo 5 yrs = 0.82 ± 0.3%, p = 0.018). The recovery of viable total nucleated cells was 46.83 ± 4.98% for auto 10 years, 43.11 ± 7.76% for allo 10 years, 48.74 ± 4.94% for allo 5 years, and 87.56 ± 6.93% for allo 1 year. The viable CD34+ cell recovery between the groups was comparable. Auto HSPC grafts stored for 10 years displayed 64.05 ± 16%, while auto grafts stored for less than a year yielded 85.4 ± 15.15% viable CD34+ cell recovery. Surprisingly, autografts, in comparison to allografts stored for 5 to 10 years, displayed higher red fraction (JC-1), indicative of higher mitochondrial membrane potential (MMP) and viability (auto 10 yrs = 72.24 ± 12.45%, allo 10 yrs = 40.6 ± 13.92%, allo 5 yrs = 47.2 ± 15.36%, p = 0.011). The higher fraction of cells with intact MMP (red fraction) within CD34+ cells suggest a likely higher resilience of autografts. Grafts stored up to 10 years displayed positive colony-forming unit (CFU) growth. CFU recovery for HSPC grafts stored for less than 1 year displayed 82.93 ± 25.68% for auto while allo grafts displayed 72.46 ± 34.76%. The viable CD34+ cell recovery for autografts was 85.4 ± 15.15%, and for allografts, recovery was 86.85 ± 18.0% for grafts thawed within one year. Furthermore, to validate the in vivo functional potential of post-thaw HSPC grafts from auto and allo donors stored for longer than 10 years, these grafts were transplanted into NSGS mice in a xenotransplantation assay. Mice were sacrificed after 12 weeks, and bone marrow and spleen were harvested to determine human blood cell chimerism by flow cytometry. Human CD45+ blood cells in mice (n = 7) receiving grafts from auto donors had 12.02 ± 1.61%, and mice (n = 7) receiving grafts from allo donors had 13.97 ± 3.19%, which was not statistically significant. However, in the spleen, mice receiving HSPC grafts from auto donors had 4-fold higher human CD45+ cell chimerism than mice receiving grafts from allo donors (38.41 ± 2.71 vs. 9.04 ± 2.04, p < 0.0001). Notably, post-thaw HSPC grafts, even after 10 years of storage, showed comparable in vivo hematopoietic reconstitution, validating the retention of post-thaw functional potency. Higher MMP displayed by post-thaw auto HSPC grafts in comparison to allo grafts, in conjunction with significantly higher hematopoietic chimerism in the spleen after 10 years of storage, may reflect their metabolically activated state or higher resilience, presumably due to past exposure to chemotherapy, unlike HSPCs from allo donors (normal subjects). Post-thaw auto HSPC grafts also displayed relatively higher mitochondrial content than allo grafts stored for 10 years. Taken together, the post-thaw viable CD34+ cell recovery corresponds well with in vivo hematopoietic reconstitution. Most notably, retention of in vivo reconstitution capacity displayed by both auto and allo grafts in NSGS mice validates the stability of cryopreserved HSPCs. The relatively higher resilience of auto HSPC grafts in contrast to allo grafts stored for 10 years, as demonstrated by significantly higher engraftment in the spleen and relatively greater mitochondrial content, will need to be further validated.

Pendharkar D., Nirmal G., Pande M., Han J., Gordeuk V.R., Saraf S.L.

Sickle cell anemia (SCA) is among the most common monogenetic diseases affecting approximately 8 million people and 300,000 newborns per year worldwide. In certain regions of India, the hemoglobin (Hb) S mutation is observed in up to 40% of the population with 2% being homozygous (Hb SS). Despite the high prevalence of SCA in India, the characteristics of SCA in this population and the impact of Hb F% on the SCA phenotype are not well understood. We conducted a prospective, observational study to better understand the Hb F% patterns and relationship to complete blood count (CBC) parameters in a tribal region of central India. 575 patients with SCA were recruited between 11/2021 and 4/2024 and blood was collected to determine Hb F%, Hb concentrations, and white blood cell (WBC) counts. We compared our findings to a separate cohort of 240 SCA patients enrolled in a registry from a large urban academic center in the US. The Hb F% from the US cohort were obtained either before initiating hydroxyurea therapy or at the time of recruitment if not on hydroxyurea therapy. The median age of the SCA cohort from India was 16 (interquartile range [IQR], 9 - 25) years old and 284 (49%) were female. The median Hb F% was 26.8% (IQR, 22.3% - 31.2%) and the median Hb concentration was 8.5 g/dL (IQR, 7.3 - 9.6 g/dL). Females had significantly higher Hb F% versus males (25.7% vs. 23.4%, respectively; P = 0.001) while older age was associated with a trend for lower Hb F% (β -0.032 ± 0.027; P = 0.1). A higher Hb F% was associated with improved Hb concentrations (β 0.083 ± 0.012; P < 0.0001) and lower WBC counts (β -0.129 ± 0.035; P < 0.0001). In the US cohort, the median age was 31 (IQR, 23 - 42) years old and 143 (59%) were female. The median Hb F% was 4.4% (IQR, 2.4 - 7.9%) and significantly lower compared to the Hb F% observed in SCA patients from India (age-adjusted P < 0.0001). The median Hb concentration was 8.6 g/dL (IQR, 7.7 - 9.4 g/dL), similar to the Hb concentrations observed in SCA patients from India (P = 0.6). Consistent with the Indian cohort, females had significantly higher Hb F% versus males (5.0% vs. 3.4%, respectively; P = 0.002) while there was no association between age and Hb F% (P = 0.7) in the US SCA cohort. Also similar to the Indian cohort, a higher Hb F% was associated with improved Hb concentrations (β 0.084 ± 0.019; P < 0.0001) and lower WBC counts (β -0.125 ± 0.047; P = 0.008). In conclusion, we demonstrate laboratory phenotyping of a large cohort of patients with SCA from a tribal region in central India. Hb F% were significantly higher in this cohort compared to a cohort of SCA patients from the US. We observed parallel findings between the two cohorts for higher Hb F% in women versus men as well as the protective effects of Hb F% on improved hemoglobin concentrations and reduced WBC counts, a biomarker that predicts vaso-occlusive episodes. Interestingly, although Hb F% were higher in SCA patients from the cohort in India vs. US, the Hb concentrations were similar. This suggests other factors, such as nutritional deficiencies, may be contributing to the anemia in SCA patients from India. Continued research is needed to better understand the phenotype of SCA in India as well as the impact of therapies that augment Hb F%, including gene therapy, in this patient population.

Amaru R., Prchal J.T., Paton D., Carrasco M., Mancilla E., Gordeuk V.R.

Bolivian Andean Aymara highlanders have been living at 4000 meters for 14,000 years, and have developed evolutionary genetic adaptations to hypoxia (PMID:28448578; PMID:29100088; PMID:36980912). These include EGLN1 encoding prolyl hydroxylase 2 (PHD2), a regulator of transferrin transcription. Transferrin increases in hypoxia and iron deficiency (PMID: 9242677); contrasting reports indicate that elevated transferrin associates with thrombosis in mice but decreased thrombosis in a congenital disorder of hypoxia-sensing (PMID: 36040436; PMID: 31310728; PMID: 8281634). We analyzed clinical and laboratory data of Andean Aymara patients with High-Altitude Anemia (n=137, mean age 45 years, female gender 79%,) or High-Altitude Erythrocytosis (n=149, mean age 56 years, female gender 30%) with transferrin results in their medical records. Iron deficiency was present in 57% of anemia and 23% of erythrocytosis patients. Mean (SD) transferrin concentration was 3.08 (1.25) g/L in anemia and 3.34 (0.84) g/L in erythrocytosis patients. Thrombosis history was present in 8% of anemia and 13% of erythrocytosis patients. In logistic regression analysis in High-Altitude Anemia patients with adjustment for age and gender, iron deficiency associated with increased thrombosis history (odds ratio [OR] 6.7, P=0.030) while higher serum transferrin associated with decreased thrombosis history (OR 0.4, P=0.013). In High-Altitude Erythrocytosis patients iron deficiency associated with increased thrombosis history (OR 5.0, P=0.005), but transferrin's association with thrombosis history was not statistically significant (OR 0.8, P=0.52). In anemia and erythrocytosis patients combined, iron deficiency associated with increased thrombosis history (OR 4.6, P=0.0006) while elevated transferrin associated with reduced thrombosis history (OR 0.62, P=0.038). In individuals with extreme environmental hypoxia, we found no evidence that increasing transferrin is associated with increased thrombosis history, but rather observed a trend to decreased thrombosis history.

An S., Park Y., Mora C., Uzoka C., Sanchez M., Zucchetti E., Sweiss K., Campbell Lee S., Rondelli D., Mahmud N.

This retrospective study compares the effects of body weight-based CD34+ cell dosing with body surface area (BSA) and body mass index (BMI) on the predictability of neutrophil and platelet engraftment after autologous stem cell transplantation (SCT) in multiple myeloma (MM) patients. MM patients (autologous donors, n = 97; 48 males and 49 females) were categorized into two groups based on BMI (<25 and >25) and BSA (<1.9 m² and >1.9 m²). The average age for males was 64.50 ± 9.13 years and for females was 64.89 ± 8.72 years (no statistical significance). Time to hematopoietic engraftment was compared between BMI and BSA groups to establish their correlation with the recovery of neutrophils and platelets following SCT. Time to neutrophil engraftment following autologous SCT was 11.14 ± 0.56 days for patients with BMI greater than 25 (n = 22), while it was 11.1 ± 0.80 days for patients with BMI lower than 25 (n = 75). Thus, neutrophil engraftment time displayed no significant difference between the normal (BMI < 25) and overweight (BMI > 25) groups. Time to platelet engraftment following SCT was 17.05 ± 5.13 days for the high BMI group and 17.79 ± 4.76 days for the low BMI group. There was no statistical significance in neutrophil and platelet engraftment between the two BMI groups (high and low). On average, patients with a BSA lower than 1.9 m² (n = 40) had a BMI of 26.61 ± 5.55, while those with a BSA greater than 1.9 m² (n = 57) had a BMI of 32.09 ± 6.36 (p ≤ 0.001). There was no statistically significant difference in neutrophil engraftment between the higher and lower BSA groups. However, the higher BSA group (>1.9 m²) required a significantly longer time for platelet engraftment 18.55 ± 4.71 days compared to 16.28 ± 4.75 days (p ≤ 0.05) in patients with a BSA less than 1.9 m², following SCT despite receiving comparable CD34+ cells/kg body weight. The CD34+ cells/kg (× 10⁶ per kg of body weight) administered to the two groups, one with a body surface area (BSA) greater than 1.9 m² and the other with a BSA less than 1.9 m², were comparable (7.06 ± 4 vs. 6.66 ± 3.65, no statistical significance). However, when the dose of CD34+ cells infused was calculated based on BSA, patients with a BSA greater than 1.9 m² received a significantly higher dose of CD34+ cells (× 10⁸/m²) (6.07 ± 3.31 vs. 4.78 ± 2.60 in the low BSA group, p < 0.05). Notably, there was a significant delay in platelet engraftment following SCT in male patients with a BSA greater than 1.9 m², compared to those with a lower BSA (19.59 ± 4.9 days vs. 15.47 ± 5.79 days, p < 0.05), despite both groups receiving comparable CD34+ cells per kg of body weight. When CD34+ cells infused were compared as CD34+ cells/kg, CD34/m² BSA, and CD34/BMI unit, there was no statistically significant difference, except for a delay in neutrophil engraftment in males (11.3 ± 0.75 days) compared to female patients (10.89 ± 0.7 days, p ≤ 0.01). Within high BSA group 51% were African American while 39% were non-Hispanic White and remaining 10% were Asian or others. Reducing the time to hematopoietic engraftment following SCT can not only reduce the duration of hospital stay but also have a potentially significant clinical impact by reducing infection, bleeding, and transfusion-related complications. Our current study implies the necessity of adjusting the CD34+ cell dose to be infused based on body weight (kg) in accordance with BSA, especially for donors with higher BSA (>1.9 m²). The observed delay in platelet engraftment with BSA greater than 1.9 m², who are also obese (BMI 32.09) males, and the delay in neutrophil engraftment in males, independent of BSA or BMI, despite comparable CD34+ cell doses (kg body weight) infused, highlight the significance of implementing personalized dosing strategies.