Lower Neutrophil Research Articles

P-1015. Cellular Composition of Bronchoalveolar Lavage Fluid in Patients with Hematologic Malignancies and Invasive Pulmonary Aspergillosis: Significant Associations with Peripheral Blood Cell Counts

Abstract Background Bronchoalveolar lavage (BAL) is frequently performed to diagnose invasive pulmonary aspergillosis (IPA) in patients (pts) with hematologic malignancies (HM). Given the critical role of the pulmonary immune environment for fungal control, BAL might be leveraged for diagnostic and prognostic immune biomarkers in IPA pts. However, data on the concordance of cell counts in peripheral blood (PB) and BAL fluid (BALF) of IPA pts is lacking.Figure 1.Heatmap summarizing Spearman’s rank correlation coefficients between peripheral blood white blood cell counts and differentials and those from bronchoalveolar lavage fluid at diagnosis of invasive pulmonary aspergillosis. * p<0.05, ** p<0.01, *** p<0.001. Methods We retrospectively reviewed 63 culture-positive proven/probable IPA cases in adult pts who underwent bronchoscopy at MD Anderson Cancer Center in 2011–2022. BALF cell counts, microbiology data, PB white blood cell (WBC) differentials on the day of bronchoscopy, and IPA outcomes were analyzed.Figure 2.Comparison of bronchoalveolar lavage fluid cell composition according to neutropenia status (A) and 42-day outcomes (B) in invasive aspergillosis patients with hematologic malignancies. Mann-Whitney U test. ** p<0.01, *** p<0.001. Results The median BALF WBC count at IPA diagnosis was 129/µL (interquartile range [IQR] 54–272/µL) and median neutrophil percentage was 11% (IQR 2–46%). PB total WBC counts significantly correlated with BALF WBC (r=0.55, p< 0.001), neutrophil (r=0.59, p< 0.001), and lymphocyte (r=0.48, p< 0.001) counts. Likewise, PB WBC differentials, i.e., absolute neutrophil and lymphocyte counts, significantly correlated with those in BALF (Fig. 1). Neutropenic pts (< 500/µL) had lower median BALF WBC (66 vs. 140/µL, p=0.005) and neutrophil counts (1 vs. 41/µL, p< 0.001) than non-neutropenic pts (Fig. 2A). BALF neutrophil counts were significantly higher in pts with bacterial coinfections than in those without coinfection (143 vs. 8/µL, p=0.005), while both neutrophil (37 vs. 5/µL, p=0.005) and lymphocyte (20 vs. 8/µL, p=0.021) counts were higher in pts with respiratory viral coinfection. Notably, cellular composition of BALF was not significantly associated with BALF galactomannan positivity or 42-day mortality after IPA diagnosis (Fig. 2B). Conclusion Unlike the well-known association between PB cytopenias and IPA outcome, severity of IPA was not significantly influenced by quantitative BAL cell composition, underscoring the unmet need for reliable qualitative/functional BAL biomarkers to prognosticate fungal control in HM pts. Both PB cytopenias and coinfections significantly affected immune cell mobilization into BALF. Thus, clinical context will be critical for normalization and validation of BAL-based host biomarkers. Disclosures Sebastian Wurster, MD, MSc, Astellas Pharma: Grant/Research Support|Gilead Sciences: Grant/Research Support Dimitrios P. Kontoyiannis, MD, AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Knight: Advisor/Consultant|Merck: Advisor/Consultant|Scynexis: Advisor/Consultant

Association of Circulating Basophil Count with Gastric Cancer Prognosis.

Basophils play a crucial role in immunoglobulin E-mediated allergic reactions and parasitic infections. Recently, a low basophil count was reported to be a poor prognostic indicator in patients with malignant tumors. This study aimed to investigate the cut-off value to evaluate the clinicopathological and prognostic significance of the basophil count in patients with gastric cancer. This study enrolled 1192 gastric cancer patient who underwent surgery without preoperative chemotherapy between 2001 and 2020. The cutoff value was 26/μl based on the receiver of characteristics curves for overall survival, and 606 patients were classified as the low basophil group. The clinicopathological and prognostic significance of the low basophil count was assessed by univariate and multivariate analyses. Elderly age (p < 0.001), high C-reactive protein level (p < 0.001), low lymphocyte count (p = 0.044), and low neutrophil count (p < 0.001) are independently associated with low basophil count. The low basophil group demonstrated a significantly worse overall survival than the high basophil group (p = 0.005). Although there was no significant difference in stage I, the low basophil group demonstrated poor overall survival in stage II/III/IV. In stage II, low basophil count was independently associated with poor OS. In stage III/IV, low basophil group tended to have poor overall survival rate. Including all stages, low basophil count was an independent risk factor for poor overall survival (hazard ratio (HR) = 1.29, 95% CI: 1.03-1.61, p = 0.027). Low basophil count was significantly associated with elderly age, high C-reactive protein level, and low neutrophil count (<26/μl). In addition, low basophil count was an independent poor prognostic factor in patients with gastric cancer. Thus, preoperative circulating basophil count assessment may be useful for predicting the postoperative survival of patients with gastric cancer.

Rethinking alcoholic foamy degeneration of the liver: a study of nine cases highlighting complex pathological findings

AimsTo reveal clinicopathological characteristics of alcoholic foamy degeneration (AFD)―an uncommon form of alcoholic liver injury.MethodsClinicopathological features of AFD (n=9) were examined in comparison to those of severe alcoholic hepatitis (SAH;...

Prevalence of neutropenia in the U.S. among reproductive-aged women: a population-based analysis of NHANES 2013–2020

BackgroundInfertility is one of the prominent public health concerns nationwide. Neutrophils, despite their established significance as vital players in both inflammatory and immune processes, have been studied scarcely in terms of their effect on female infertility. The present study aimed to determine the prevalence of neutropenia among women of reproductive age in the U.S. to contribute valuable insights to the broader context of reproductive health.MethodsThe present study was designed as a cross-sectional investigation. The data of 5,250 female participants aged 18–45 years were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between the years 2013 and 2020. The representativeness of the population was ensured by conducting statistical assessments based on NHANES weights. A logistic regression model was established to assess the hematologic parameters across the distinct populations stratified according to age, ethnicity, smoking status, and infertility. Multivariate logistic regression was performed next, and weighted odds ratios along with the 95% confidence interval values were calculated, which assisted in predicting the prevalence of neutropenia among the female participants.ResultsThe data of a total of 5,250 female participants, representing a multiracial population of 51.17 million in the United States, were analyzed in the present study. Meanwhile, the estimated neutropenia incidence was 7.09% (95% CI: 6.16−8.01%), which indicated a prevalence among approximately 36.2 million U.S. citizens. In comparison to white subjects, black subjects exhibited a significantly lower average leukocyte count, with a mean difference (MD) of 1.16 × 109/L (P < 0.001), along with a lower neutrophil count (MD: 1.09 × 109/L; P < 0.001). It is noteworthy that a substantial decrease was noted in the distribution graphs of both neutrophil and leukocyte counts among the black subjects. Moreover, compared to non-smokers in the racial populations, including white, Mexican American, and black people, the smokers exhibited significantly elevated mean leukocyte count and mean neutrophil count. The logistic regression analysis indicated an elevated risk of neutropenia among black individuals and females with infertility.ConclusionsNeutropenia appears to have a higher prevalence in the general population compared to that acknowledged previously. The findings of the present study indicated association between neutropenia and infertility. This highlighted the importance of directing increased attention toward neutropenia in the context of both research and clinical practice.

IL-6 and PD-1 antibody blockade combination therapy regulate inflammation and T lymphocyte apoptosis in murine model of sepsis

BackgroundInterleukin-6 (IL-6) plays a central role in sepsis-induced cytokine storm involving immune hyperactivation and early neutrophil activation. Programmed death protein-1 (PD-1) is associated with sepsis-induced immunosuppression and lymphocyte apoptosis. However, the effects of simultaneous blockade of IL-6 and PD-1 in a murine sepsis model are not well understood.ResultsIn this study, sepsis was induced in male C57BL/6 mice through cecal ligation and puncture (CLP). IL-6 blockade, PD-1 blockade, or combination of both was administered 24 h after CLP. Peripheral blood count, cytokine level, lymphocyte apoptosis in the spleen, neutrophil infiltration in the lungs and liver, and survival rate were measured. The mortality rate of the IL-6/PD-1 group was lower, though not statistically significant (p = 0.164), than that of CLP mice (75.0% vs. 91.7%). The IL-6/PD-1 group had lower neutrophil percentage and platelet count compared with the CLP group; no significant difference was observed in other cytokine levels. The IL-6/PD-1 group also showed reduced T lymphocyte apoptosis in the spleen and decreased neutrophil infiltration in the liver and lungs.ConclusionsIL-6/PD-1 dual blockade reduces neutrophil infiltration, lymphocyte apoptosis, and bacterial burden while preserving tissue integrity in sepsis. Although the improvement in survival was not statistically significant, these findings highlight its potential as a therapeutic approach in sepsis.

The modern use of hydroxyurea for children with sickle cell anemia.

Over the past 40 years, the introduction and refinement of hydroxyurea therapy has led to remarkable progress for the care of individuals with sickle cell anemia (SCA). From initial small proof-of-principle studies to multi-center Phase 3 controlled clinical trials and then numerous open-label studies, the consistent benefits of once-daily oral hydroxyurea have been demonstrated across the lifespan. Elevated fetal hemoglobin (HbF) serves as the most important treatment response, as HbF delays sickle hemoglobin polymerization and reduces erythrocyte sickling. Increased amounts of HbF, especially when distributed across the majority of erythrocytes, improve clinical outcomes by reducing hemolytic anemia and preventing vasoocclusion, thereby ameliorating both acute and chronic-and overt and covert-complications. Additional benefits of hydroxyurea beyond HbF induction include lower neutrophil and platelet counts, reduced inflammation, and improved rheology. Toxicities of hydroxyurea in SCA are typically mild and predictable; modest cytopenia is expected and actually therapeutic, while occasional gastrointestinal and cutaneous manifestations are well-tolerated. Long-term risks of hydroxyurea for SCA are mainly theoretical but require ongoing surveillance. Accordingly, hydroxyurea should be initiated as part of standard-of-care, ideally in the first year of life. Proper dosing of hydroxyurea is critical, aiming through stepwise dose escalation to achieve modest but safe myelosuppression, with periodic adjustments for weight gain. Precision dosing using pharmacokinetics may facilitate optimal dosing without frequent dose adjustments. Although transformative and even curative therapies for SCA are emerging, hydroxyurea is the only available and accessible disease-modifying treatment that can address the global burden of disease, especially in low-resource settings within sub-Saharan Africa.

Healing Potential of Chromolaena odorata Extract: Modulation of Neutrophil, Macrophage, and Lymphocyte Response in Infected Wounds of Mus musculus

Chromolaena odorata has been reported to possess antimicrobial, antibacterial, and anti-inflammatory properties that aid in wound healing. Previous studies demonstrated the significant effects of a 7.5% concentration of C. odorata extract on non-infected wounds. This study aims to investigate its impact on infected wound healing. An experimental study was conducted on 36 mice, divided into two groups. Partial-thickness wounds were created on the dorsal side of each mouse and contaminated with S. aureus (106 CFU/ml). Group 1 was treated with normal saline, while Group 2 was treated with C. odorata aqueous extract at 7.5%. Histopathological analysis was performed on days 3 and 5 to count neutrophils, macrophages, and lymphocytes. Results showed a significantly lower neutrophil, macrophage, and lymphocyte count in Group 2 compared to Group 1 (p &lt; 0.05). On day 3 and 5, Group 2 had lower neutrophil counts (5.6 ± 1.8, 5.8 ± 0.6) compared to Group 1 (9.2 ± 5.2, 15.1 ± 3.9). Macrophage counts were also lower in Group 2 (6.9 ± 1.7, 1.9 ± 0.7) compared to Group 1 (3.7 ± 1.4, 4.3 ± 0.9). Lymphocyte counts followed a similar trend, with Group 2 having fewer lymphocytes on both days (p &lt; 0.05). In conclusion, C. odorata aqueous extract at a 7.5% concentration demonstrates potential as a wound healing agent by reducing inflammatory cells in infected wounds.

Incidence of patient-reported fatigue developing on palbociclib and endocrine therapy for advanced HR+ HER2- breast cancer.

Fatigue is a common nonhematologic toxicity of the CDK4/6 inhibitor palbociclib in metastatic breast cancer (MBC) patients with prevalence rates of clinician-rated all-grade and grade 3/4 fatigue of 39.2% and 2.5%, respectively. We prospectively assessed the incidence of fatigue emerging on palbociclib using patient-reported measures and explored potential predictors. Eighty-eight patients with HR+ HER2- MBC without fatigue initiating palbociclib with endocrine therapy were assessed before and monthly across the initial 6 cycles. Clinically meaningful levels of patient-reported fatigue (Functional Assessment of Chronic Illness Therapy Fatigue Scale, FACIT-F < 34), severity of, and functional interference due to fatigue (NCI Patient-Reported Outcomes for CTCAE, PRO-CTCAE) were assessed. Hematologic and nonhematologic predictors were examined pretreatment and concurrent with fatigue assessments. Patient-reported fatigue emerged in 21/88 patients [incidence rate 23.9% (95%CI, 15.4%-34.1%)] within 2.8 ± 1.7 treatment cycles. PRO-CTCAE-rated incidence rate of severe fatigue and fatigue interference was 14.8% (95%CI, 8.1%-23.9%) and 10.2% (95%CI, 4.8%-18.5%), respectively. Lower pretreatment absolute neutrophil count (ANC) levels predicted treatment-emergent fatigue (P =.01), but ANC levels on treatment did not (P =.78). Other pretreatment predictors were long sleep duration (P =.02) and low physical activity (trend, P =.07). Treatment-emergent fatigue was associated with objectively measured long sleep duration on treatment (P =.02), but not other measures (P ≥.35). One-quarter of patients with HR+ HER2- MBC initiating palbociclib report rapidly emergent clinically meaningful fatigue, often with severe symptoms and functional interference. Treatment-emergent fatigue is associated with both pretreatment (lower ANC levels, longer sleep duration) and on-treatment (long sleep duration) hematologic and nonhematologic profiles.

Differential systemic immune-inflammation index levels in people with and without HIV infection.

HIV infection is linked to persistent inflammation despite effective antiretroviral therapy (ART). The Systemic Immune-Inflammation Index (SII) is a marker of inflammation in various conditions. We compared SII values between PWH and PWoH. Clinical blood laboratory data were used to calculate the SII for each participant using the formula [(Platelet count × Neutrophil count) / Lymphocyte count]. Differences in SII values between the groups were analyzed using the Wilcoxon test, and the impact potential confounders was assessed with multivariable regression models. The study included 343 PWH and 199 PWoH. Age and race did not significantly differ, but sex distribution did (83.1% male in PWH vs. 55.8% in PWoH, P < 0.0001). Among PWH, median [IQR] nadir and current CD4 counts were 199 cells/μL [50, 350] and 650 [461,858], respectively. Nearly all PWH were on ART, with 97.2% achieving viral suppression. PWH had lower SII values than PWoH (327 [224, 444] vs. 484 [335,657], P = 1.35e-14). PWH also had lower neutrophils and platelets (ps < 0.001) and higher lymphocyte counts (P = 0.001). These differences remained significant after adjusting for age, sex, and other potential confounders. Contrary to expectations, PWH had lower SII levels, likely due to altered hematologic parameters influenced by HIV and ART. These findings suggest that SII interpretation in PWH requires consideration of unique hematologic profiles and underscore the need for further research to understand the mechanisms and clinical implications of SII in HIV management.

Peripheral Circulating Blood Cells Deviation Based on Tumor Inflammatory Microenvironment Activity in Resected Upstaged Lung Adenocarcinomas.

Background: The tumour inflammatory microenvironment (TIME) reflects a selective activation of the central immune system (IS), particularly T-cells expansion, which leads to immune cells migrating to the target, such as lung cancer, via the bloodstream and lymphatic vessels. In this study, the aim is to investigate whether the distribution of peripheral blood cells varies based on the immune status of patients with lung adenocarcinoma. Methods: This is a single-center retrospective study conducted in the Thoracic Surgery Unit of the University of Padua (Italy) between 1 January 2016 and 1 April 2024. It included patients (>18 years old) with lung adenocarcinoma deemed resectable (cT2bN0M0 or lower) who experienced pathological upstaging (IIB or higher). Patients were classified as TIME-active (with tumour-infiltrating lymphocytes-TILs and/or PD-L1 expression) or TIME-silent (without TILs or PD-L1). According to the TIME status, peripheral blood cell counts with clinical and pathological data were compared between groups using the Fisher's, Pearson's or Wilcoxon's test when appropriate. A Kaplan-Meier estimator investigated overall survival (OS) and recurrence-free survival (RFS) adopting the log-rank test. Results: Preoperatively, the TIME-a group demonstrated a significantly higher lymphocyte count (p = 0.02) and a lower absolute neutrophil rate (p = 0.01) than TIME-s. These differences persisted after resection (p = 0.06 and p = 0.02) while they became similar one month after surgery (p = 1 and p = 0.32). The neutrophil-to-lymphocyte ratio-NLR showed similar trends (p = 0.01 and p = 1). Better OS and RFS were shown in the TIME-a group (p = 0.02 and 0.03, respectively). Conclusions: Resected upstaged lung adenocarcinomas show distinct peripheral blood cell profiles based on immune status. TIME-active patients had a significantly lower NLR, which normalized post-surgery. Surgical resection may help restore native immune surveillance.

In patients with follicular lymphoma, delayed-onset neutropenia induced by anti-CD20 monoclonal antibodies frequently occurs during maintenance therapy and is preferentially associated with obinutuzumab.

The prevalence of anti-CD20 monoclonal antibody (MoAb)-associated delayed-onset neutropenia (DON) varies between 8 and 27%. Despite the wide use of MoAbs as maintenance in follicular lymphoma (FL), data regarding DON occurrence and clinical consequences are limited. This study assessed DON prevalence, severity and risk factors in FL patients during maintenance. Data were retrieved from electronic medical records of FL patients treated at Rambam between 2006 and 2021. The maintenance cohort included 155 patients receiving 165 treatment courses; the non-maintenance cohort included 58 patients receiving 67 courses. Median time on maintenance was 1.81 ± 0.28 years. During maintenance, 23.2% of patients developed DON, with 13.8% experiencing at least one recurrent event. In the non-maintenance cohort, 29.3% developed DON, with 38.8% recurrence. Median time from maintenance initiation to the first neutropenic episode was 5 (1.25-12) months, whereas in the non-maintenance cohort, DON occurred earlier [1.9 (0.97-3.71) months; p = 0.06]. The only DON risk factors in patients on maintenance were induction with the obinutuzumab/bendamustine combination [odds ratio (OR): 4.546 (95%CI = 1.419-14.563); p = 0.011] or obinutuzumab maintenance [OR: 3.138 (95%CI = 1.23-7.94); p = 0.016]. In the non-maintenance cohort, such factors included ≥ 1 line of therapy [OR: 3.93 (95%CI = 1.00-15.38); p = 0.04] and a lower absolute neutrophil count at induction completion. Differences in the likelihood of DON development between patients receiving maintenance with obinutuzumab or rituximab possibly reflect mechanistic dissimilarities between type I and type II MoAbs. Regardless, prolonged MoAb use bears a mitigatory effect, reducing recurrence of DON. The findings obtained could assist in predicting the risk of DON in individual FL patients, optimizing informed treatment choices.

Clinical application value of simultaneous plasma and bronchoalveolar lavage fluid metagenomic next generation sequencing in patients with pneumonia-derived sepsis

BackgroundDespite the increasing use of metagenomic next-generation sequencing (mNGS) in sepsis, identifying clinically relevant pathogens remains challenging. This study was aimed to evaluate the clinical utility of simultaneous plasma and bronchoalveolar lavage fluid (BALF) detection using mNGS.MethodsThis retrospective study enrolled 95 patients with pneumonia-derived sepsis (PDS) admitted to the intensive care unit (ICU) between October 2021 and January 2023. Patients were divided into two groups: mNGS group (n = 60) and the non-mNGS group (n = 35), based on whether simultaneous plasma and BALF mNGS were conducted. All patients underwent conventional microbiological tests (CMT), including bacterial/fungal culture of peripheral blood and BALF, as well as sputum culture, detection of 1, 3-beta-D- glucan in BALF and RT-PCR testing. The clinical data of the enrolled patients were collected, and the detection performance and prognosis of plasma mNGS, BALF mNGS and CMT were compared.ResultsThe mNGS group exhibited a lower mortality rate than the non-mNGS group (35.0% vs. 57.1%, P = 0.034). Simultaneous detection in dual-sample resulted in a higher proportion of microorganisms identified as definite causes of sepsis alert compared to detection in either plasma or BALF alone (55.6% vs. 20.8% vs. 18.8%, P<0.001). Acinetobacter baumannii, Stenotrophomonas maltophilia, Candida albicans, and human mastadenovirus B were the primary strains responsible for infections in PDS patients. Patients with lower white blood cells and neutrophil indices had a greater consistency in dual-sample mNGS. Patients in the mNGS group had more antibiotic adjustments compared to the non-mNGS group (85.71% vs. 33.33%, P<0.001). The percentage of neutrophils was a risk factor for mortality in PDS patients (P = 0.002).ConclusionDual sample mNGS has the advantage of detecting and determining the pathogenicity of more pathogens and has the potential to improve the prognosis of patients with PDS.

Investigating the effects of remdesivir on corrected QT interval in patients with severe COVID-19 disease: a historical cohort study

BackgroundThere is little information about the risk of drug-induced QT prolongation by remdesivir as the most important FDA approved anti COVID-19 drug. Prolongation of corrected QT interval (QTc) is considered as an indicator of an unfavorable outcome which may ultimately induce torsade de pointes and provoke ventricular fibrillation. The aim of this study was to determine the effects of remdesivir on QTc in patients with severe COVID 19 disease.MethodsA historical cohort study was conducted on 249 patients who experienced severe COVID-19 disease and were candidate for treatment by intravenous remdesivir. We obtained a 12 lead electrocardiogram at the admission time and five days later to find any significant change in QTc and QT interval following therapy. We took blood samples at the time of hospitalization and then every day to determine the serum levels of electrolytes, complete blood count, fasting blood sugar (FBS), creatinine (Cr), and complete blood count.ResultsThe results of this analysis showed blood pressure and heart rate (HR) were lower and total white blood cells and neutrophil counts, FBS and Cr levels were higher at fifth day than first day of study (P value < 0.001). Furthermore, QT interval was more prolonged at fifth day compared with beginning of remdesivir therapy (379.51 ± 34.90ms vs. 366.72 ± 30.97ms, P value < 0.001). However, QTc was not significantly increased at fifth day in comparison with first day (402.37 ± 33.62ms vs. 400.76 ± 30.18ms, P value = 0.524 by Bazett’s formula and 402.81 ± 36.33 vs. 400.78 ± 32.49, P value = 0.459 by Fridericia’s formula).ConclusionsThe current study found no evidence linking the administration of remdesivir with prolongation of the QTc interval.

Diagnostic accuracy of gasdermin D as a biomarker for necrotizing enterocolitis: a single-center diagnostic test study.

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal condition mainly affecting premature infants, and gasdermin D (GSDMD) has emerged as a molecule of interest due to its pivotal role in the inflammatory process called pyroptosis in NEC pathogenesis. The aim of this study is to examine the potential of GSDMD and interleukin-1β (IL-1β) as early diagnostic biomarkers for NEC. We examined 207 infants with clinical symptoms of NEC admitted to our neonatal intensive care unit (NICU) between December 2023 and June 2024. After excluding those with congenital gastrointestinal diseases and other factors, 180 infants were included in the study. Among these, 59 were confirmed to have NEC according to Bell Stage II criteria, and 56 matched controls were selected through propensity score matching (PSM). Blood samples were analyzed for GSDMD expression using quantitative polymerase chain reaction (qPCR) and for IL-1β levels using enzyme-linked immunosorbent assay (ELISA). Patients with NEC exhibited significantly elevated levels of GSDMD (18.46±8.58) and IL-1β (9.05±3.42) compared to controls. Receiver operating characteristic (ROC) curve analysis indicated that GSDMD had a higher predictive value for NEC with an area under the curve (AUC) of 0.83 than IL-1β (AUC 0.77). Clinical symptoms such as fatigue, abdominal distention, and reduced bowel sounds were significantly more common in patients with NEC. Laboratory results showed lower neutrophil and red blood cell counts, higher platelet counts, and increased levels of C-reactive protein (CRP) and procalcitonin (PCT) in patients with NEC. GSDMD and IL-1β can serve as valuable biomarkers for the early diagnosis of NEC, providing insights into the disease's pathogenesis and facilitating improved strategies for early detection and intervention.

Open-lung ventilation versus no ventilation during cardiopulmonary bypass in an innovative animal model of heart transplantation

Open-lung ventilation during cardiopulmonary bypass (CPB) in patients undergoing heart transplantation (HTx) is a potential strategy to mitigate postoperative acute respiratory distress syndrome (ARDS). We utilized an ovine HTx model to investigate whether open-lung ventilation during CPB reduces postoperative lung damage and complications. Eighteen sheep from an ovine HTx model were included, with ventilatory interventions randomly assigned during CPB: the OPENVENT group received low tidal volume (VT) of 3 mL/kg and positive end-expiratory pressure (PEEP) of 8 cm H20, while no ventilation was provided in the NOVENT group as per standard of care. The recipient sheep were monitored for 6 h post-surgery. The primary outcome was histological lung damage, scored at the end of the study. Secondary outcomes included pulmonary shunt, driving pressure, hemodynamics and inflammatory lung infiltration. All animals completed the study. The OPENVENT group showed significantly lower histological lung damage versus the NOVENT group (0.22 vs 0.27, p = 0.042) and lower pulmonary shunt (19.2 vs 32.1%, p = 0.001). In addition, the OPENVENT group exhibited a reduced driving pressure (9.6 cm H2O vs. 12.8 cm H2O, p = 0.039), lower neutrophil (5.25% vs 7.97%, p ≤ 0.001) and macrophage infiltrations (11.1% vs 19.6%, p < 0.001). No significant differences were observed in hemodynamic parameters. In an ovine model of HTx, open-lung ventilation during CPB significantly reduced lung histological injury and inflammatory infiltration. This highlights the value of an open-lung approach during CPB and emphasizes the need for further clinical evidence to decrease risks of lung injury in HTx patients.

Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms.

Background/Objectives: The severity of acute lung injury is significantly impacted by age and sex in patients with hemorrhagic shock. AMP-activated protein kinase (AMPK) is a crucial regulator of energy metabolism but its activity declines with aging. Humanin is a mitochondrial peptide that exerts cytoprotective effects in response to oxidative stressors and is associated with longevity. Using a mouse model of hemorrhagic shock that mimics the clinical condition of adult patients, we investigated whether treatment with a humanin analog, humanin-G, mitigates lung injury and whether its mechanisms of action are dependent on the catalytic AMPKα1 subunit activation. Methods: Male and female AMPKα1 wild-type (WT) and knock-out (KO) mice (8-13 months old) were subjected to hemorrhagic shock by blood withdrawal, followed by resuscitation with shed blood and lactated Ringer's solution. The mice were treated with PEGylated humanin-G or vehicle and euthanized 3 h post-resuscitation. Results: Sex- and genotype-related differences were observed after hemorrhagic shock as lung neutrophil infiltration was more pronounced in the male AMPKα1 WT mice than the female WT mice; also, the male AMPKα1 KO mice experienced a significant decline in mean arterial blood pressure when compared to the male WT mice after resuscitation. The scores of histological lung injury were similarly elevated in all the male and female AMPKα1 WT and KO mice when compared to the control mice. At molecular analysis, acute lung injury was associated with the downregulation of AMPKα1/α2 catalytic subunits in the WT mice, whereas an increased activation of the signal transducer and activator of transcription-3 (STAT3) was observed in all the vehicle-treated groups. The in vivo administration of humanin-G ameliorated histological lung damage in all the groups of animals and ameliorated mean arterial blood pressure in the male AMPKα1 KO mice. The in vivo administration of humanin-G lowered lung neutrophil infiltration in the male and female AMPKα1 WT mice only but not in the KO mice. The beneficial results of humanin-G correlated with the lung cytosolic and nuclear activation of AMPKα in the male and female AMPKα1 WT groups, whereas STAT3 activation was not modified. Conclusions: In adult age, hemorrhage-induced acute lung injury manifests with sex-dependent characteristics. Humanin-G has therapeutic potential and the AMPKα1subunit is an important requisite for its inhibitory effects on lung leucosequestration, but not for the amelioration of lung alveolar structure or the hemodynamic effects of the peptide.

Abstract 4136280: Inflammation and Cancer Mortality among CVD Individuals: NHANES-Continuous study

Background: Both cancer and cardiovascular disease (CVD) are the leading causes of death worldwide. While previous research showed a relationship between CVD and cancer incidence, limited evidence is available regarding the relationship between inflammation and cancer mortality in CVD patients. Methods: A prospective cohort study using data from the continuous National Health and Nutrition Examination Survey (NHANES) (1999-2016) merged with Medicare and National Death Index (NDI) mortality data until December 31, 2018. We included CVD individuals with no history of cancer at baseline to investigate the relationship between inflammatory markers, including Neutrophil-to-Lymphocyte ratio (NLR), as the main exposure and cancer mortality as the main outcome. Results: We included 4,089 adult individuals representing 127,809,316 individuals (47% females, 72% non-Hispanic Whites, and 5% Hispanics). The risk factor analysis (Table) using the competing risk modeling showed that while inflammatory markers did not show significant associations with cancer mortality in the overall analysis, upon stratification by race/ethnicity, NH-Blacks showed higher cancer mortality with higher WBC count (aHR 5.61, 95% CI 1.66-18.91, p=0.007) and NLR (aHR 2.97, 95% CI 1.19-7.42, p=0.02), but lower cancer mortality with higher neutrophil (aHR 0.08, 95% CI 0.01-0.60, p=0.02) and lymphocyte (aHR 0.34, 95% CI 0.15-0.80, p=0.02) counts. Notably, our NH-Blacks showed lower neutrophils at baseline than others which could be explained by a phenomenon called “Benign Ethnic Neutropenia -BEN-” that still brings more complexity when interpreting NLR. Conclusions: Our study highlights the close relationship between cardiovascular health, inflammation, and cancer mortality. The findings also suggest that race/ethnicity may play a significant role in the relationship between inflammation and cancer mortality among individuals with CVD. Yet, further research is still needed to underpin the biological pathways influencing this relationship.

Clinical Risk Factors for High-Dose Methotrexate-Induced Oral Mucositis Following Individualized Dosing.

Oral mucositis affects about 20% of children undergoing high-dose methotrexate (HDMTX) for acute lymphoblastic leukemia (ALL), despite existing management strategies. Personalized HDMTX dosing, adjusted by pharmacokinetics and leukemia risk, has reduced mucositis incidence, but variations still occur with similar 24-h methotrexate levels. This retrospective study investigated risk factors for oral mucositis under individualized methotrexate protocols. Data from patients with ≥ Grade 2 oral mucositis (CTCAE v4.0) were analyzed from the St. Jude Children's Research Hospital total 16 trial. A 1:1 case-control matching method considered age, sex, risk classification, immunophenotype, and methotrexate course. McNemar's, Bowker's symmetry, and Wilcoxon signed-rank tests were used for statistical analyses. Risk factors for recurrent mucositis were identified in a case-only analysis. The study found significant associations between methotrexate-induced mucositis and new-onset skin rashes (p = 0.0027), fever (p = 0.0016), neutropenic fever (p = 0.0008), lower absolute neutrophil count (p < 0.0001), acute kidney injury (AKI) (p = 0.0164), delayed methotrexate clearance (p = 0.0133), and higher 42-h methotrexate levels (p = 0.0179). In the standard/high-risk group, mercaptopurine dose was also linked to mucositis (p = 0.0495). Multivariable analysis showed that skin rashes (OR 6.5, p = 0.0016), fever (OR 2.8, p = 0.009), and neutropenia (OR 2.3, p = 0.0106) were independent risk factors for mucositis. Female sex (OR 7.12, p = 0.015) and AKI (OR 3.819, p = 0.037) were associated with recurrent mucositis. Fever, skin rashes, AKI, delayed methotrexate clearance, and higher 42-h methotrexate levels were key risk factors for HDMTX-induced oral mucositis. Skin rashes, fever, and neutropenia were independent predictors, while female sex and AKI were linked to recurrent mucositis.

Impact of neutrophil-to-lymphocyte ratio on clinical outcomes in patients with acute or chronic coronary syndrome undergoing percutaneous coronary intervention

Abstract Background Neutrophil-to-lymphocyte ratio (NLR) has recently emerged as an inflammatory biomarker associated with atherosclerosis and cardiovascular events. However, its role in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains unclear. Purpose We aimed to evaluate the clinical impact of baseline NLR in patients undergoing PCI for acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). Methods We retrospectively evaluated all consecutive patients undergoing PCI between 2012-2022 in a large tertiary US hospital. We excluded patients for whom NLR was not available and those who were deemed to have active hematological or infective diseases, including patients presenting with extremely low or high lymphocyte and neutrophil counts or with hs-CRP above 10 mg/L. Quartiles of NLR were derived in the overall population and patients were stratified according to clinical presentation. Within each group, we estimated the risk of 12-month adverse events using the lowest NLR quartile as reference. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints were MACE individual components and any periprocedural or post-discharge clinically relevant bleeding. Results A total of 7,201 patients were included in the analysis; of these 3,975 (55.2%) had ACS and 3,226 (44.8%) CCS. Patients in the 4th quartile (NLR &amp;gt; 5.0) were more frequently male, older, and presented more often with chronic kidney disease and complex coronary artery disease. Smoking, diabetes and history of CAD, as well as triglycerides, LDL, non-HDL and total cholesterol levels were lower in the 4th NLR quartile. In patients presenting with CCS, the risk of MACE, all-cause death, MI was similar across NLR quartiles, while the risk of bleeding increased stepwise (Figure 1). In patients presenting with ACS, the 4th NLR quartile had the highest adjusted risk of MACE (HRadj 1.82, 95% CI 1.25-2.67; P=0.002), all cause death (HRadj 2.56, 95% CI 1.41-4.66; P&amp;lt;0.001), and bleeding (HRadj 1.82 95% CI 1.25-2.63, P&amp;lt;0.001) at 1 year, as compared to the lowest quartile (Table 1). Conclusions Among patients undergoing PCI, elevated NLR is strongly associated with risk of MACE and all-cause mortality in patients presenting with ACS but not in those with CCS. Conversely, the risk of bleeding was augmented with higher NLR in both ACS and CCS patients undergoing PCI. In this setting, NLR may inform risk stratification at the time of PCI.

Impact of neutrophil-to-lymphocyte ratio on clinical outcomes in patients with or without chronic kidney disease undergoing percutaneous coronary intervention

Abstract Background Neutrophil-to-lymphocyte ratio (NLR) has recently emerged as inexpensive inflammatory biomarker associated with worse cardiovascular outcomes. However, little is known about its role in risk stratification of patients with both chronic kidney disease (CKD) and coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). Purpose We aimed to evaluate the clinical impact of baseline NLR in patients with and without CKD undergoing PCI. Methods We retrospectively evaluated all consecutive patients undergoing PCI between 2012-2022 in a large tertiary US center. We excluded patients without available NLR and those who were deemed to have active hematological or infective diseases, including patients with extremely low or high lymphocyte and neutrophil counts or with hs-CRP above 10 mg/L. Quartiles of NLR were derived in the overall population and patients were stratified according to presence of CKD (eGFR &amp;lt; 60 ml/min). Within each group, we estimated the risk of adverse events using the lowest NLR quartile as reference. The primary endpoint was 12-month incidence of major adverse cardiovascular events (MACE), defined as the composite of all-cause death, myocardial infarction, or stroke. Secondary endpoints included incidence of clinically relevant bleeding and contrast-associated acute kidney injury (CA-AKI), defined as ≥ 0.3 mg/dL or ≥ 50% serum creatinine increase from baseline. Results A total of 7,287 patients were included in the analysis; of these 2,008 (27.6%) had CKD and 5,279 (72.4%) did not. CKD patients (mean eGFR 40.8±16.1 ml/min) were older, had more comorbidities, and presented with higher hs-CRP levels and a greater estimated risk of CA-AKI. Overall, patients with elevated NLR had more severe CAD and underwent more complex PCI. In CKD patients, incidence of adverse events increased stepwise and those in the 4th NLR quartile had the highest adjusted risks of MACE (HRadj 1.86, 95% CI 1.12-3.08; P=0.012), all cause death (HRadj 2.44, 95% CI 1.18-5.05; P=0.003) and bleeding (HRadj 1.74, 95% CI 1.07-2.84; P=0.002) at 1 year, as compared to those in the lowest quartile (Table 1). In patients without CKD, MACE and all-cause death incidences were numerically higher in the 4th quartile but risk estimates were no longer statistically significant after adjustment. The overall incidence of CA-AKI was much greater in the CKD group. When compared to the lowest quartile, patients in the 4th NLR quartile showed a trend for higher risk of CA-AKI in CKD group, while they had a significant increased risk in non-CKD group (Figure 1). Conclusions Elevated NLR is strongly associated with higher risk of MACE and all-cause mortality in CKD patients. Conversely, the risk of bleeding and CA-AKI is increased with elevated NLR in both CKD and non-CKD patients. Thus, NLR may further inform risk stratification of CKD patients undergoing PCI.