Hematologic Outcomes Research Articles

The efficacy of partial versus total splenectomy in the treatment of hereditary spherocytosis in children: a systematic review and meta-analysis.

To explore the comparative postoperative efficacy of partial splenectomy (PS) and total splenectomy (TS) in the treatment of children with hereditary spherocytosis (HS). The relevant HS studies from databases were searched and screened, comparing the differences in hemoglobin concentration, reticulocyte percentage, bilirubin concentration before and after TS and PS surgery, and during the follow-up period, as well as the incidence of postoperative adverse events. Statistical analysis was performed using Review Manager 5.4. A total of 5 studies were included in this meta-analysis, with a cumulative enrollment of 312 children, 130 in the PS group and 182 in the TS group. The meta-analysis results showed that both PS and TS groups had statistically significant differences in postoperative hematological outcomes compared to before surgery, with TS showing better improvement than PS. In the postoperative follow-up, the changes in hematological outcomes between PS and TS were statistically significant for hemoglobin concentration: within 1year [MD = 1.85, 95%CI(1.09,2.60)], 1-2years [MD = 1.74, 95%CI(0.25,3.24)], not statistically significant for 4-6years [MD = 1.28, 95%CI(-1.75,4.32)]; for reticulocyte percentage: within 1year [MD = 2.23, 95%CI(0.80,3.66)] was statistically significant, not statistically significant for 4-6years [MD = 1.77, 95%CI(-2.04,5.59)]; for serum bilirubin concentration: within 1year [MD = 1.55, 95%CI(0.91,2.18)] was statistically significant, not statistically significant for 1-2years [MD = 1.77, 95%CI(-2.04,5.99)]. In the incidence of postoperative adverse events, the incidence of cholelithiasis [MD = 1.77, 95%CI(-2.04,5.99)] showed a statistically significant difference between PS and TS, while there were no statistically significant differences in other included events, such as postoperative infection rate, secondary surgery rate, thrombosis rate, postoperative hemorrhage rate, and transfusion therapy rate. Splenectomy is a beneficial surgical strategy for children with moderate-to-severe HS, reducing; early hematological outcomes of TS are more robust than PS in the follow-up period, and there is no difference between the two in the later period; for postoperative adverse events, the incidence of cholelithiasis in children after PS is higher than after TS, and there is a risk of requiring a second surgery for total splenectomy due to hemolytic recurrences.

Distinct clinical profiles and patient outcomes in aCML and CNL.

The classification of atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) as a single disease entity remains a topic of debate. To elucidate the characteristics of both entities, this retrospective cohort study was conducted, encompassing 36 cases of aCML and 18 cases of CNL. We discovered that aCML and CNL presented distinct blood counts, genetics, molecular profiles and outcomes. Specifically, hemoglobin levels (P < 0.001) and platelet counts (P < 0.001) were significantly lower in aCML cases than in CNL cases, with no significant difference in mean white blood cells (P = 0.637). The proportion of abnormal karyotypes was higher in aCML cases compared with CNL cases (P = 0.010). Notably, we found that aCML and CNL showed distinct gene expression profiles by transcriptome sequencing technology. The median follow-up duration for the entire cohort was 8months (rang 0.4 to 36.6months), and the median overall survival (OS) was significantly shorter in aCML cases (7.3months, 95%CI 5.4 to 20.5months) than in CNL cases (median OS not reached). The one-year OS rate for aCML patients was 31.0% (9/29), compared to 92.9% (13/14) for CNL patients. In conclusion, our study supports the notion that aCML and CNL are indeed distinct disease entities characterized by unique hematological features and clinical outcomes.

Chimeric antigen receptor-T-cell therapies going viral: latent and incidental viral infections.

Infections are the leading cause of non-relapse mortality following chimeric antigen receptor (CAR)-T-cell therapy, with viral infections being frequent both in the early and late phases post-infusion. We review the epidemiology of viral infections and discuss critical approaches to prevention and management strategies in this setting. Herpesviruses dominate the early period. herpes simplex virus and varicella zoster virus infections are rare due to widespread antiviral prophylaxis, but cytomegalovirus (CMV) reactivation is increasingly observed, particularly in high-risk groups including B cell maturation antigen (BCMA)-CAR-T-cell therapy recipients and patients receiving corticosteroids. While CMV end-organ disease is rare, CMV is associated with increased mortality, emphasizing the need to evaluate the broader impact of CMV on long-term hematological, infection, and survival outcomes. Human herpesvirus-6 (HHV-6) has also emerged as a concern, with its diagnosis complicated by overlapping symptoms with neurotoxicity, underscoring the importance of considering viral encephalitis in differential diagnoses. Respiratory viruses are the most common late infections with a higher incidence after BCMA CAR-T-cell therapy. Vaccination remains a critical preventive measure against respiratory viruses but may be less immunogenic following CAR-T-cell therapy. The optimal timing, type of vaccine, and dosing schedule require further investigation. A better understanding of viral epidemiology and preventive trials are needed to improve infection prevention practices and outcomes following CAR-T-cell therapies.

A Study on the Effect of Umbilical Cord Milking Along With Delayed Cord Clamping on Hematological Parameters in Comparison to Delayed Cord Clamping Alone in Moderate-to-Late Preterm Newborns.

Background Anemia, particularly iron deficiency anemia (IDA), is a global public health issue with serious implications for infant cognitive and developmental outcomes. Preterm infants are especially vulnerable to IDA due to reduced placental blood transfer at birth. Delayed cord clamping (DCC) and umbilical cord milking (UCM) are interventions aimed at enhancing this blood transfer, thereby improving neonatal iron status. While DCC allows passive blood transfer by delaying cord clamping, UCM actively expedites the process. However, there remains a lack of consensus on the comparative benefits of these methods, particularly in preterm infants. This study aims to clarify the efficacy of UCM combined with DCC versus DCC alone in improving hematological outcomes in moderate-to-late preterm newborns. Methodology This comparative study was conducted at Maharaja Agrasen Medical College, Agroha, Hisar, Haryana, over a 12-month period. The study included 200 moderate-to-late preterm infants (32-36+6 weeks of gestation), divided into two groups: Group A (DCC alone) and Group B (DCC combined with UCM). The study aimed to compare the effects of these two interventions on hematological outcomes. Data were collected on baseline characteristics, birth weight, hemoglobin (Hb) levels at birth and at six weeks, serum ferritin levels at six weeks, and any complications. Statistical analyses included independent t-tests for continuous variables and chi-squared tests for categorical variables to assess the differences between the two groups. Results There were no significant differences in the baseline characteristics, birth weight, or clamping time between the two groups. Mean Hb levels at birth were 15.46 g/dL in the DCC group and 15.72 g/dL in the DCC+UCM group (p = 0.429). At six weeks, the mean Hb levels were 13.10 g/dL for the DCC and 13.24 g/dL for the DCC+UCM (p = 0.541). Serum ferritin levels at six weeks were 239.26 ng/mL for the DCC and 258.06 ng/mL for DCC+UCM (p = 0.146). Complications were similar between the groups, with no significant differences in the rates of intraventricular hemorrhage (IVH), jaundice, or polycythemia. Conclusion In this study, the combination of UCM with DCC did not show significant differences in hematological outcomes compared to DCC alone in moderate-to-late preterm infants. Both interventions demonstrated similar results for hemoglobin and ferritin levels, and there were no notable differences in adverse outcomes. Further research with larger sample sizes and longer follow-ups is necessary to better understand the potential benefits of UCM in preterm neonates.

Relationship between morphologic remission with or without hematologic recovery and outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia.

Outcomes of adults with AML after allografting vary widely. While numerous covariates have been associated with relapse, non-relapse mortality (NRM), and/or shorter survival, the impact of incomplete blood count recovery before transplantation has remained unclear. To address this uncertainty, we examined all adults with AML or MDS/AML who received an allograft in first or second remission between 2006 and 2023 at a single institution. Of 1264 patients, 891 (70%) met criteria for CR, whereas 291 (23%), 24 (2%), and 58 (5%) were classified as CRh, CRi, and morphologic leukemia-free state (MLFS), respectively. CR, CRh, CRi, and MLFS patients differed significantly regarding demographics, disease biology, pre-transplant measurable residual disease, and types of transplants. After multivariable adjustment, outcomes for CRh and CRi patients were not significantly different from each other or from those of CR patients. In contrast, outcomes of MLFS patients were substantially worse than those of CR and CRh patients, with significantly higher risk of NRM and relapse, and significantly shorter relapse-free and overall survival. Similar results were obtained in several distinct subsets. Together, our analysis provides empiric evidence for the importance of distinguishing MLFS from CR and CRh patients for optimized risk assessment and, possibly, individualized treatment decision making.

Prevalence, clinical and haematological profile and outcome of BCR-ABL1-like acute lymphoblastic leukaemia in Indian children: A prospective observational study

BackgroundBCR-ABL1-like acute lymphoblastic leukaemia (ALL) represents a perplexing subclass of ALL mainly due to genomic heterogeneity and non-availability of standardized diagnostic tests. The data on prevalence, clinical–haematological profile and outcome are limited, more so from low-middle income countries. MethodsThis prospective observational study enrolled children<14 years with B-ALL. Recurrent genetic/chromosomal aberrations were excluded. BCR-ABL1-like aberrations were analysed using Polymerized Chain Reaction (PCR) or Next-Generation Sequencing (NGS). Two groups with/without BCR-ABL1-like ALL (Mut+/Mut-) were compared. ResultsOut of 214 eligible children; 75 with “B-other ALL” were analysed for BCR-ABL1-like aberrations. Their prevalence was 34/214 (15.8%) in B-ALL and 34/75 (45.3%) in “B-other” ALL (PCR:33.3% and NGS:53.3%). Majority of the aberrations were JAK2E16 and ILR7e5/ILR7e6 with PCR and RAS pathway and PAX5 fusion with NGS. Baseline demographic, clinical and laboratory parameters including aberrant flowcytometry were comparable in Mut+ and Mut-groups. Children with day-8 absolute blast count (ABC) were higher in Mut+ group. High end-induction minimal residual disease (MRD) was comparable in two groups. Number of NCI-standard risk (SR) at diagnosis with high D-8 ABC or high MRD was higher in Mut+ group. Similar results were found when aberrations were analysed by NGS alone. In all 56 children are alive, 19 had an event (relapse/death). The outcomes were comparable in two groups with median follow-up of 1075 days (IQR: 660–1527); when analysis was based on combined as well as NGS-based methodology alone. ConclusionsWe report 15.8% prevalence of BCR-ABL1-like ALL in children by PCR or NGS. High D-8 ABC was associated with BCR-ABL1-like ALL with no impact on outcomes.

Long-term outcomes after cardiac transplantation in AL amyloidosis.

7572 Background: Systemic AL amyloidosis can lead to progressive multi-organ dysfunction including advanced heart failure which may require orthotopic heart transplantation (OHT). Hematologic outcomes of AL amyloidosis post-OHT are not well described. Methods: We report outcomes for patients with AL amyloidosis with cardiac involvement post-OHT from Nov 2008 - Jun 2023 at Vanderbilt University Medical Center. Hematologic response was graded per the ISA guidelines. Results: Fourteen pts underwent OHT of whom 13 had lambda light chain disease. Three (21%) pts had isolated AL amyloidosis (AL) without myeloma (MM), while 11 (79%) also had MM: 6 with bone marrow plasma cells (BMPCs) 10-19% (AL-PCMM-10) and 5 with BMPC ≥20% (AL-PCMM-20). One each with AL-PCMM-10 and AL-PCMM-20 had lytic lesions (AL-CRAB). Median age at OHT was 55.5 yrs (range 37-74). Median time from diagnosis to OHT was 18 mo (range 3-62). Five (35%) pts had biopsy-proven extracardiac amyloid involvement. Median difference in serum free light chains at first evaluation was 70 mg/dL (range 9-289). Three pts were Mayo 2012 stage II, 4 stage III, and 7 stage IV. Four pts had t(11;14) and 1 had 1q gain. Ten (71%) pts received triplet therapy (VCd or VRd) and 3 (21%) received quadruplet therapy (Dara-VCd or Isa-VCd) pre-OHT. Six (43%) pts had autologous stem cell transplantation (ASCT); 1 pre-OHT and 5 post-OHT. Of ASCT pts, 1 pt achieved CHR, 1 VGPR, 2 PR, and 1 had PD pre-ASCT. Pre-OHT, 4 pts achieved CHR, 6 VGPR, 3 PR, and 1 had PD. Eleven pts (79%) received maintenance therapy post-OHT (5 proteosome inhibitors, 6 anti-CD38). At last follow-up, 8 pts were in CHR, 3 in VGPR, 1 in PR, and 2 had PD. Four (29%) pts died post-OHT: 2 from AL recurrence (1 each with AL and AL-PCMM-10), 1 from cardiac allograft vasculopathy (AL-CRAB), and 1 from renal failure (AL-CRAB). Three (21%) pts had hematologic relapse 5, 21 and 48 mo post-OHT, and of those, 2 had recurrent cardiac amyloid in graft 37 and 71 mo post-OHT. Of those with hematologic relapse, 2 had AL-PCMM-10 and 1 had AL. One pt had post-transplant lymphoproliferative disorder 126 mo post-OHT, requiring treatment. Median follow-up and survival of the cohort post-OHT was 2.25 yrs (range 0.5-13.8). Conclusions: In this single-center analysis of pts undergoing OHT for cardiac AL amyloidosis, we demonstrate feasibility of excellent long-term outcomes, in predominantly high-risk AL pts where majority harbored high-risk disease with MM overlap, either by AL-CRAB or AL-BMPC. Induction alone led to ≥VGPR response in 10 (71%) pts pre-OHT and further therapy deepened this to 11 (79%) pts. Both AL-CRAB pts died during follow-up, highlighting the overall poor prognosis in this specific subgroup. In our cohort, non-relapse related mortality was seen in only 2 (14%) pts, demonstrating acceptable post-OHT risk and overall ability to achieve far improved outcomes in the high-risk cardiac AL amyloidosis patient population that otherwise suffers from rapid and universal mortality.

Cardiovascular and hematologic complications of Hodgkin vs non-Hodgkin lymphoma and readmission trends: A National Readmission Database analysis from years 2016-2020.

e19034 Background: Cardiovascular complications are a leading cause of non-malignant death in lymphoma survivors. We sought to analyze the national readmission trends and evaluate the in-hospital mortality as well as the cardiovascular and hematological complications in lymphoma patients using the National Readmission Database (NRD). Methods: We selected patients aged &gt;=18 years of age, from the NRD between the years 2016-2020 to generate a cohort of Hodgkin's Lymphoma (HL) and Non-Hodgkin's Lymphoma (NHL) patients using ICD-10 codes. The primary outcome was in-hospital mortality, and the secondary outcome was cardiovascular and hematologic complications of HL vs NHL after adjusting for demographic confounders. We used multivariate logistic regression and propensity score matching (PSM) using STATA v.18. We also analyzed the 30-day readmission trends in these patients. Results: A total of 1,016,338 NHL and 83,036 HL patients were included in the analysis. After matching for demographics confounders, on PSM analysis we found that in-hospital mortality was higher in NHL vs HL (5.9% vs 4.42%; p-value 0.001). The cardiovascular complications that were studied included cardiac tamponade (0.69% in NHL vs 0.4% in HL; p-value 0.001), pericarditis (0.13% in NHL vs 0.14% in HL; p-value 0.717) and anthracycline cardiomyopathy (0.47% in HL vs 0.85% in NHL; p-value 0.001). The hematological outcomes studied included myelodysplastic syndrome (0.71% in NHL vs 0.64% in HL; p-value 0.210), acute leukemia (0.48% in NHL vs 0.44% in HL; p-value 0.43), and myelosuppression (18.59% vs 13.73%; p-value 0.001). A 30-day readmission trend analysis showed a longer length of stay in NHL vs HL (5.34 days vs 4.77 days) while the total inflation-adjusted cost was higher in HL vs NHL (20,989 dollars vs 17176 dollars). Conclusions: An NRD analysis of NHL and HL patient populations from 2016-2020 reflected a slightly increased mortality rate, higher incidence of cardiovascular complications and a longer length of stay in NHL patients. [Table: see text]

Household Water Lead and Hematologic Toxic Effects in Chronic Kidney Disease

The consequences of low levels of environmental lead exposure, as found commonly in US household water, have not been established. To examine whether commonly encountered levels of lead in household water are associated with hematologic toxicity among individuals with advanced kidney disease, a group known to have disproportionate susceptibility to environmental toxicants. Cross-sectional analysis of household water lead concentrations and hematologic outcomes was performed among patients beginning dialysis at a Fresenius Medical Care outpatient facility between January 1, 2017, and December 20, 2021. Data analysis was performed from April 1 to August 15, 2023. Concentrations of lead in household water were examined in categorical proportions of the Environmental Protection Agency's allowable threshold (15 μg/L) and continuously. Hematologic toxic effects were defined by monthly erythropoiesis-stimulating agent (ESA) dosing during the first 90 days of incident kidney failure care and examined as 3 primary outcomes: a proportion receiving maximum or higher dosing, continuously, and by a resistance index that normalized to body weight and hemoglobin concentrations. Secondarily, hemoglobin concentrations for patients with data prior to kidney failure onset were examined, overall and among those with concurrent iron deficiency, thought to increase gastrointestinal absorption of ingested lead. Among 6404 patients with incident kidney failure (male, 4182 [65%]; mean [SD] age, 57 [14] years) followed up for the first 90 days of dialysis therapy, 12% (n = 742) had measurable lead in household drinking water. A higher category of household lead contamination was associated with 15% (odds ratio [OR], 1.15 [95% CI, 1.04-1.27]) higher risk of maximum monthly ESA dosing, 4.5 (95% CI, 0.8-8.2) μg higher monthly ESA dose, and a 0.48% (95% CI, 0.002%-0.96%) higher monthly resistance index. Among patients with pre-kidney failure hemoglobin measures (n = 2648), a higher household lead categorization was associated with a 0.12 (95% CI, -0.23 to -0.002) g/dL lower hemoglobin concentration, particularly among those with concurrent iron deficiency (multiplicative interaction, P = .07), among whom hemoglobin concentrations were 0.25 (95% CI, -0.47 to -0.04) g/dL lower. The findings of this study suggest that levels of lead found commonly in US drinking water may be associated with lead poisoning among susceptible individuals.

Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine, and chloroquine in Rhesus macaques.

Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding Anopheles, resulting in reduced transmission. Tafenoquine (TQ) is used to clear the liver reservoir of Plasmodium vivax and as a prophylactic treatment in high-risk populations. It has been suggested to use ivermectin and tafenoquine in combination, but the safety of these drugs in combination has not been evaluated. Early derivatives of 8-aminoquinolones (8-AQ) were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein (P-gp) blood brain barrier (BBB) transporter. Thus, there is concern that co-administration of these drugs could be neurotoxic. This study aimed to evaluate the safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine (CQ) in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine and ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3''-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques; therefore, this combination could be considered for evaluation in human trials.

Obstetric and haematological management and outcomes of women with placenta accreta spectrum by planned or urgent delivery: Secondary data analysis of a public referral hospital in Lebanon.

Lebanon has a high caesarean section use and consequently, placenta accreta spectrum (PAS) is becoming more common. To compare maternal characteristics, management, and outcomes of women with PAS by planned or urgent delivery at a major public referral hospital in Lebanon. Secondary data analysis of prospectively collected data. Rafik Hariri University Hospital (public referral hospital), Beirut, Lebanon. 159 pregnant and postpartum women with confirmed PAS between 2007-2020. Maternal characteristics, management, and maternal and neonatal outcomes. Out of the 159 women with PAS included, 107 (67.3%) underwent planned caesarean delivery and 52 (32.7%) had urgent delivery. Women who underwent urgent delivery for PAS management were more likely to experience antenatal vaginal bleeding compared to those in the planned group (55.8% vs 28.0%, p<0.001). Median gestational age at delivery was significantly lower for the urgent group compared to the planned (34 vs. 36 weeks, p<0.001). There were no significant differences in terms of blood transfusion rates and major maternal morbidity between the two groups; however, median estimated blood loss was significantly higher for women with urgent delivery (1500ml vs. 1200ml, p = 0.011). Furthermore, the urgent delivery group had a significantly lower birth weight (2177.5g vs. 2560g, p<0.001) with higher rates of neonatal intensive care unit (NICU) admission (53.7% vs 23.8%, p<0.001) and perinatal mortality (18.5% vs 3.8%, p = 0.005). Urgent delivery among women with PAS is associated with worse maternal and neonatal outcomes compared to the planned approach. Therefore, early referral of women with known or suspected PAS to specialized centres is highly desirable to maximise optimal outcomes for both women and infants.

The Effectiveness of Clinician-Led Community-Based Group Exercise Interventions on Health Outcomes in Adults with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis evaluated the combined effects of clinician-led and community-based group exercise interventions on a range of health outcomes in adults with type 2 diabetes mellitus. Our literature search spanned Medline, Scopus, PubMed, Embase, and CINAHL databases, focusing on peer-reviewed studies published between January 2003 and January 2023. We included studies involving participants aged 18 years and older and articles published in English, resulting in a dataset of eight studies with 938 participants. Spanning eight peer-reviewed studies with 938 participants, the analysis focused on the interventions' impact on glycemic control, physical fitness, and anthropometric and hematological measurements. Outcomes related to physical fitness, assessed through the six-minute walk test, the 30 s sit-to-stand test, and the chair sit-and-reach test, were extracted from five studies, all of which reported improvements. Anthropometric outcomes from seven studies highlighted positive changes in waist circumference and diastolic blood pressure; however, measures such as body mass index, systolic blood pressure, weight, and resting heart rate did not exhibit significant changes. Hematological outcomes, reviewed in four studies, showed significant improvements in fasting blood glucose, triglycerides, and total cholesterol, with glycemic control evidenced by reductions in HbA1c levels, yet LDL and HDL cholesterol levels remained unaffected. Ten of the fifteen outcome measures assessed showed significant enhancement, indicating that the intervention strategies implemented may offer substantial health benefits for managing key type 2 diabetes mellitus-related health parameters. These findings in combination with further research, could inform the refinement of physical activity guidelines for individuals with type 2 diabetes mellitus, advocating for supervised group exercise in community settings.

Variation in incidence rates of outcomes relevant to vaccine safety monitoring in a US commercially insured population by case identification algorithm

BackgroundLarge health insurance claims databases can be used to estimate rates of rare safety outcomes. We measured incidence rates of rare outcomes that could be used to contextualize adverse events among people receiving pneumococcal vaccines in clinical trials or clinical practice. However, algorithms used to identify outcomes in administrative databases are subject to error. Using two algorithms for each outcome, we assessed the influence of algorithm choice on the rates of the outcomes. MethodsWe used closed administrative medical and pharmacy claims in the Healthcare Integrated Research DatabaseSM (HIRD) to construct a broad cohort of individuals less than 100 years old (i.e., the target cohort) and a trial-similar cohort of individuals resembling those potentially eligible for a vaccine clinical trial (e.g., for a pneumococcal vaccine). We stratified by age and sex and used specific and sensitive algorithms to estimate rates of 39 outcomes including cardiac/cerebrovascular, metabolic, allergic/autoimmune, neurological, and hematologic outcomes. Specific algorithms intended to reduce false positive errors, while sensitive algorithms intended to reduce false negative errors, thereby providing lower and upper bounds for the “true” rates. ResultsWe followed approximately 40 million individuals in the target cohort for an average of 3 years. Of 39 outcomes, 14 (36 %) had a rate from the specific algorithm that was less than half the rate from the sensitive algorithm. Rates of cardiac/cerebrovascular outcomes were most consistent (mean ratio of rates from specific algorithms compared to rates from sensitive algorithms = 0.76), while the rates of neurological and hematologic outcomes were the least consistent (mean ratio of rates = 0.33 and 0.36, respectively). ConclusionsFor many cardiac/cerebrovascular outcomes, rates were similar regardless of the algorithm. For other outcomes, rates varied substantially by algorithm. Using multiple algorithms to ascertain outcomes in claims data can be informative about the extent of uncertainty due to outcome misclassification.

Domestic dogs maintain clinical, nutritional, and hematological health outcomes when fed a commercial plant-based diet for a year.

Domestic dogs can maintain health on complete and well-balanced canine plant-based nutrition (K9PBN). Novel insight on health outcomes in dogs consuming K9PBN is of relevance to veterinary professionals and consumers given a growing interest in non-traditional dog foods with perceived health benefits, while considering potential safety concerns. We aimed to investigate nutritional equivalence by measuring clinical health outcomes in adult dogs fed K9PBN over twelve months compared to a meat-based diet at baseline. We enrolled fifteen clinically healthy adult dogs living in households in Los Angeles County, California in a prospective cohort study and evaluated clinical, hematological, and nutritional parameters in dogs at 0, 6, and 12 months, including complete blood count (CBC), blood chemistry, cardiac biomarkers, plasma amino acids, and serum vitamin concentrations. The study found that clinically healthy, client-owned, adult dogs maintain health, based on physical exams, complete blood count, serum chemistry, plasma amino acids, serum vitamins, and cardiac biomarkers combined with client-reported observations, when fed commercial K9PBN over a twelve-month period. This study is the most comprehensive and longest known K9PBN investigation to date and provides clinically relevant evidence-based nutrition data and new knowledge on outcomes in clinically healthy dogs who thrive without consumption of animal-derived ingredients. These results also provide a valuable foundation for the future study of K9PBN as a potential nutritional intervention for clinically relevant pathologies in canine medicine. Lastly, it is of major relevance to One Health paradigms since ingredients produced independent of industrial food animal production are both more sustainable and help to circumvent ethical dilemmas for maintenance of health in domestic dogs.

Oral Iptacopan Monotherapy in Paroxysmal Nocturnal Hemoglobinuria

BackgroundPersistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients.MethodsIn two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5–treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.ResultsIn the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5–treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5–treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan.ConclusionsIptacopan treatment improved hematologic and clinical outcomes in anti-C5–treated patients with persistent anemia — in whom iptacopan showed superiority to anti-C5 therapy — and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.)

Plasma from patients undergoing allogeneic hematopoietic stem cell transplantation promotes NETOSIS in vitro and correlates with inflammatory parameters and clinical severity.

NETosis, the mechanism by which neutrophils release extracellular traps (NETs), is closely related to inflammation. During the allogeneic hematopoietic stem cell transplantation (allo-HSCT), different stimuli can induce NETs formation. Inflammation and endothelial injury have been associated with acute graft-versus-host disease (aGVHD) and complications after allo-HSCT. We focus on the study of NETosis and its relation with cytokines, hematological and biochemical parameters and clinical outcomes before, during and after allo-HSCT. We evaluate the capacity of plasma samples from allo-HSCT patients to induce NETosis, in a cell culture model. Plasma samples from patients undergoing allo-HSCT had a stronger higher NETs induction capacity (NETsIC) than plasma from healthy donors throughout the transplantation process. An optimal cut-off value by ROC analysis was established to discriminate between patients whose plasma triggered NETosis (NETs+IC group) and those who did not (NETs-IC group). Prior to conditioning treatment, the capacity of plasma samples to trigger NETosis was significantly correlated with the Endothelial Activation and Stress Index (EASIX) score. At day 5 after transplant, patients with a positive NETsIC had higher interleukin (IL)-6 and C-reactive protein (CRP) levels and also a higher Modified EASIX score (M-EASIX) than patients with a negative NETsIC. EASIX and M-EASIX scores seek to determine inflammation and endothelium damage, therefore it could indicate a heightened immune response and inflammation in the group of patients with a positive NETsIC. Cytokine levels, specifically IL-8 and IL-6, significantly increased after allo-HSCT with peak levels reached on day 10 after graft infusion. Only, IL-10 and IL-6 levels were significantly higher in patients with a positive NETsIC. In our small cohort, higher IL-6 and IL-8 levels were related to early severe complications (before day 15 after transplant). Although early complications were not related to NETosis by itself, NETosis could predict overall non-specific but clinically significant complications during the full patient admission. In summary, NETosis can be directly induced by plasma from allo-HSCT patients and NETsIC was associated with clinical indicators of disease severity, cytokines levels and inflammatory markers.

COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals

BackgroundThe Global COVID Vaccine Safety (GCoVS) Project, established in 2021 under the multinational Global Vaccine Data Network™ (GVDN®), facilitates comprehensive assessment of vaccine safety. This study aimed to evaluate the risk of adverse events of special interest (AESI) following COVID-19 vaccination from 10 sites across eight countries. MethodsUsing a common protocol, this observational cohort study compared observed with expected rates of 13 selected AESI across neurological, haematological, and cardiac outcomes. Expected rates were obtained by participating sites using pre-COVID-19 vaccination healthcare data stratified by age and sex. Observed rates were reported from the same healthcare datasets since COVID-19 vaccination program rollout. AESI occurring up to 42 days following vaccination with mRNA (BNT162b2 and mRNA-1273) and adenovirus-vector (ChAdOx1) vaccines were included in the primary analysis. Risks were assessed using observed versus expected (OE) ratios with 95 % confidence intervals. Prioritised potential safety signals were those with lower bound of the 95 % confidence interval (LBCI) greater than 1.5. ResultsParticipants included 99,068,901 vaccinated individuals. In total, 183,559,462 doses of BNT162b2, 36,178,442 doses of mRNA-1273, and 23,093,399 doses of ChAdOx1 were administered across participating sites in the study period. Risk periods following homologous vaccination schedules contributed 23,168,335 person-years of follow-up. OE ratios with LBCI > 1.5 were observed for Guillain-Barré syndrome (2.49, 95 % CI: 2.15, 2.87) and cerebral venous sinus thrombosis (3.23, 95 % CI: 2.51, 4.09) following the first dose of ChAdOx1 vaccine. Acute disseminated encephalomyelitis showed an OE ratio of 3.78 (95 % CI: 1.52, 7.78) following the first dose of mRNA-1273 vaccine. The OE ratios for myocarditis and pericarditis following BNT162b2, mRNA-1273, and ChAdOx1 were significantly increased with LBCIs > 1.5. ConclusionThis multi-country analysis confirmed pre-established safety signals for myocarditis, pericarditis, Guillain-Barré syndrome, and cerebral venous sinus thrombosis. Other potential safety signals that require further investigation were identified.

Predictive Modeling of Drug-Related Adverse Events with Real-World Data: A Case Study of Linezolid Hematologic Outcomes.

Electronic health records (EHRs) provide meaningful knowledge of drug-related adverse events (AEs) that are not captured in standard drug development and postmarketing surveillance. Using variables obtained from EHR data in the University of California San Francisco de-identified Clinical Data Warehouse, we aimed to evaluate the potential of machine learning to predict two hematological AEs, thrombocytopenia and anemia, in a cohort of patients treated with linezolid for 3 or more days. Features for model input were extracted at linezolid initiation (index), and outcomes were characterized from index to 14 days post-treatment. Random forest classification (RFC) was used for AE prediction, and reduced feature models were evaluated using cumulative importance (cImp) for feature selection. Grade 3+ thrombocytopenia and anemia occurred in 31% of 2,171 and 56% of 2,170 evaluable patients, respectively. Of the total 53 features, as few as 7 contributed at least 50% cImp, resulting in prediction accuracies of 70% or higher and area under the receiver operating characteristic curves of 0.886 for grade 3+ thrombocytopenia and 0.759 for grade 3+ anemia. Sensitivity analyses in strictly defined patient subgroups revealed similarly high predictive performance in full and reduced feature models. A logistic regression model with the same 50% cImp features showed similar predictive performance as RFC and good concordance with RFC probability predictions after isotonic calibration, adding interpretability. Collectively, this work demonstrates potential for machine learning prediction of AE risk in real-world patients using few variables regularly available in EHRs, which may aid in clinical decision making and/or monitoring.

Thrombocytosis and Transaminitis in Infants Born to Women With Inflammatory Bowel Disease Is Associated With Exposure to Maternal Inflammation In Utero

Abstract Background Despite reassuring clinical safety data, thrombocytosis, anemia, lymphopenia, and liver function derangements have been observed in infants born to women with inflammatory bowel disease (IBD) treated with thiopurines and biologics. We aimed to define the prevalence, course, associations, and clinical impact of hematological and biochemical abnormalities in such infants. Methods This multicenter prospective cohort study assessed clinical, hematologic, and biochemical outcomes of infants exposed to thiopurines or biologics in utero for management of maternal IBD. Liver transaminases, full blood examination, and infant thiopurine metabolites (where exposed) were taken at delivery and 6 weeks of age. Abnormal results were repeated until normalization. Infants were followed clinically by a pediatric gastroenterologist up to 2 years of age. Results A total of 130 infants were included. Thrombocytosis and elevated alanine transaminase (ALT) were seen in over half of infants up to 6 months of age with no significant clinical impact. Elevated ALT was associated with increasing maternal C-reactive protein in second trimester, while thrombocytosis was associated with increasing maternal C-reactive protein and fecal calprotectin in third trimester. Preceding infection and vaccination were associated with an increased risk of elevated alkaline phosphatase at 3 months. In those exposed to thiopurines, increasing maternal 6-methylmercaptopurine at delivery was associated with increased ALT to 6 months. Conclusions Infants born to women with IBD commonly developed thrombocytosis, elevated alkaline phosphatase, and elevated ALT. These findings were associated with exposure to maternal inflammation, elevated 6-methylmercaptopurine at delivery, and infant vaccinations and infections, and had minimal clinical consequence.

Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights.

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd-Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.