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Objectives: Inflammatory disorders including periodontitis have been investigated for their impact on systemic inflammation and bone health. The present study was conducted with an aim to evaluate impact of control of periodontal inflammation through subgingival instrumentation on serum interleukin 6 and serum C-terminal telopeptide of type I collagen (CTX) in premenopausal females with stage II and III periodontitis. Method and materials: In this single-arm prospective study, periodontal parameters, serum interleukin 6, serum CTX, and hematologic parameters (total leukocyte count, differential leukocyte count, platelet count, mean platelet volume, and platelet distribution width) were assessed at baseline. Subgingival instrumentation was done, and oral hygiene instructions were given. At week 4, professional plaque control was performed, and oral hygiene instructions were reinforced. Serum and hematologic parameters were reassessed at 8 weeks after subgingival instrumentation, in individuals meeting the clinical endpoints (ie, bleeding on probing < 10%). Results: There was significant reduction in serum interleukin 6 of 0.168 ± 0.164 pg/mL (P = .000), and serum CTX of 17.459 ± 4.363 pg/mL (P = .000) at 8 weeks after subgingival instrumentation. There was significant decrease in eosinophil count (P = .018) and mean platelet volume (P = .016) at 8 weeks after subgingival instrumentation; however, no significant change was found in other hematologic parameters. Conclusion: Following subgingival instrumentation, biomarkers of both systemic inflammation (interleukin 6) and bone turnover (CTX) were observed to reduce significantly. This finding hints towards a positive impact of periodontal intervention on bone health. [ABSTRACT FROM AUTHOR]

Background: The systemic immune-inflammation index (SII) is a novel inflammatory marker used to assess the immune-inflammatory status of the human body. The systemic immune inflammation has an interplay and mutual relationship with neurological disorders. Serum neurofilament light chain (sNfL) is widely regarded as a potential biomarker for various neurological diseases. The study aimed to examine the association between SII and sNfL. Methods: This cross-sectional investigation was conducted in a population with complete data on SII and sNfL from the 2013-2014 National Health and Nutrition Examination Survey (NHANES). The SII was calculated by dividing the product of platelet count and neutrophil count by the lymphocyte count. Multivariate linear regression models and smooth curves were used to explore the linear connection between SII and sNfL. Sensitivity analyses, interaction tests, and diabetes subgroup smoothing curve fitting were also performed. Results: A total of 2,025 participants were included in our present research. SII showed a significant positive association with the natural logarithm-transformed sNfL (ln-sNfL) in crude model [0.17 (0.07, 0.28)], partially adjusted model [0.13 (0.03, 0.22)], and fully adjusted model [0.12 (0.02, 0.22)]. In all participants, the positive association between SII and ln-sNfL served as a linear relationship, as indicated by a smooth curve. Interaction tests showed that age, gender, BMI, hypertension, and diabetes did not have a significant impact on this positive association (p for interaction >0.05). The subgroup analysis of diabetes was conducted using smooth curve fitting. It was found that compared to the group without diabetes and the group in a pre-diabetic state, the effect was more pronounced in the group with diabetes. Conclusion: Our findings suggest that there is a positive association between SII and sNfL. Furthermore, in comparison to individuals without diabetes and those in a pre-diabetic state, the positive association between SII and sNfL was more pronounced in individuals with diabetes. Further large-scale prospective studies are needed to confirm the association between SII and sNfL. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion Hematopoietic stem cell transplantation (HCST) is a widely used therapy in the management of hematological malignancies, leading to cytopenias that require transient transfusions. Platelet recovery (PR) following HSCT is assessed by monitoring platelet count (PC). Immature platelet fraction (IPF) is a research parameter offered by Sysmex® on XN series analyzers, enabling rapid diagnostic orientation in the event of thrombocytopenia. It has also been described as a predictive factor for PR after chemotherapy or HSCT, and thresholds have been proposed.The objective of this study was to assess the predictive capability of IPF for PR in a prospective cohort of patients undergoing HSCT and to evaluate its utility in guiding platelet transfusion decision.An optimized A‐IPF (absolute number of IPF) threshold of 2.5 × 109/L was predictive of a PC greater than 50 × 109/L at day 30 with a sensitivity of 78.9%, specificity of 78.6%, positive predictive value (PPV) of 83.3% and negative predictive value (NPV) of 73.3%. We were able to distinguish patients recovering PC before day 15 with an earlier %IPF peak, greater IPF recovery kinetics and faster neutrophil recovery.A‐IPF shows promise as a predictor of PR following HSCT. A multicenter study could help confirm both A‐IPF and %IPF (IPF) clinical utility before it is made available to clinicians. [ABSTRACT FROM AUTHOR]

Background: After a 920-day hiatus, COVID-19 resurged in the Tibet Autonomous Region of China in August 2022. This study compares the characteristics of COVID-19 between high-altitude residents and newcomers, as well as between newcomers and lowlanders. Methods: This multi-center cohort study conducted at the Third People's Hospital of Tibet Autonomous Region and Beijing University Shenzhen Hospital, included 520 high-altitude resident patients, 53 high-altitude newcomer patients, and 265 lowlander patients infected with the Omicron variant. Initially, we documented epidemiological, clinical, and treatment data across varying residency at admission. We compared the severity of COVID-19 and various laboratory indicators, including hemoglobin concentration and SpO2%, over a 14-day period from the date of the first positive nucleic acid test, as well as the differences in treatment methods and disease outcomes between highlanders and high-altitude newcomers. We also compared several characteristics of COVID-19 between high-altitude newcomers and lowlanders. Univariate analysis, multivariable logistic regression, and the generalized linear mixed model were utilized for the analysis. Results: No fatalities were observed. The study found no significant differences in COVID-19 severity or in the physiological measures of hemoglobin concentration and SpO2% between high-altitude and lowland residents. Similarly, there were no statistically significant differences in the values or trends of hemoglobin and SpO2% between high-altitude residents and newcomers throughout the 14-day observation period. However, compared to age- and sex-matched lowlander patients (1:5 ratio), high-altitude newcomers exhibited higher heart rates, respiratory rates, and average hemoglobin concentrations, along with lower platelet counts. There were no significant differences in hospital stays between the two groups. Conclusions: High-altitude residents and newcomer patients exhibit clinical similarities. However, the clinical characteristics of high-altitude newcomers and lowlander patients differ due to the impact of the high-altitude environment. These results highlight potential considerations for public health strategies in high-altitude regions such as Tibet. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions Immature platelet fraction (IPF) for differentiating bacteremia has been explored, whereas its prognostic correlation remains uncertain. This study aims to confirm the predictive capability of IPF for bacteremia and investigate its association with prognosis.Patients with complete blood count (CBC) on the blood culture day (D1) and the preceding day (D0) were retrospectively recruited and categorized into bacteremia and nonbacteremia groups. Immature platelet (IP) analysis, alongside CBC, was conducted. Delta IPF, defined by the absolute values of D1 minus D0 results was calculated. The ability to distinguish bacteremia from nonbacteremia patients, and the correlation with mortality were analyzed.From February to December 2020, a total of 150 patients were enrolled, with 75 having bacteremia. The specificity for delta IPF ≥3.4% to predict bacteremia was 97.3% (95% confidence interval [CI]: 90.7–99.7). When delta IPF ≥3.4% combined with procalcitonin ≥0.5 (ng/mL), the sensitivity was 90.5% (95% CI: 69.6%–98.8%). Within the bacteremia group, delta IPF and the proportion of patients with delta IPF ≥1.5% were significantly higher in nonsurvival, while delta platelet levels did not. Furthermore, delta IPF ≥1.5% was independently associated with 30‐day mortality (adjusted odds ratio: 3.88, 95% CI: 1.2%–11.4%; p = 0.020). The 30‐day survival curve demonstrated a significant difference between patients with delta IPF ≥1.5% and those without (p < 0.001).Delta IPF correlates with mortality in bacteremia patients. Our findings suggest IPF not only helps detect bacteremia but also predicts prognosis in the early stage. [ABSTRACT FROM AUTHOR]

Summary There are variations in individual eltrombopag concentrations that may impact efficacy and adverse drug reactions (ADRs) in paediatric immune thrombocytopaenia (ITP). To solve this problem, we tailored the eltrombopag dosage refer to concentration, then followed up to assess concentration value in paediatric ITP. This is a single‐centre, prospective, observational study. The eltrombopag dosage was adjusted, and children were divided into three groups: the maintenance, discontinuation, and increase groups. Concentration and other data were compared to explore concentration value in guiding the individualized treatment of paediatric ITP. Thirty‐nine patients were enrolled, including 23 in the maintenance group, 3 in the discontinued group and 13 in the increase group. 3 patients discontinued eltrombopag due to ADRs, which was significantly higher than patients in the maintenance group (t = 3.606, p = 0.001). In all, 13 patients increased their dosage due to poor response, whose concentration and platelet count were significantly lower than patients in the maintenance group (t = 2.461, p = 0.019; t = 4.633, p < 0.001). Two months after the increase, the number of patients reaching CR and R respectively increased by 2 and 3, while the median platelet count was significantly raised (Z = −2.411, p = 0.016). Concentration could be used as a reference index for the individualized treatment of eltrombopag in paediatric ITP. [ABSTRACT FROM AUTHOR]

Utilizing RBC or PLT-related parameters to establish rules for the PLT-O reflex test can assist laboratories in quickly identifying specimens with interfered PLT-I that require PLT-O retesting.Prospective PLT-I and PLT-O testing was performed on 6857 EDTA-anticoagulated whole blood samples, split randomly into training and validation cohorts at a 2:3 ratio. Reflex and non-reflex groups were distinguished based on the differences between PLT-I and PLT-O results. By comparing RBC and PLT parameter differences and flags in the training set, we pinpointed factors linked to PLT-O reflex testing. Utilizing Lasso regression, then refining through univariate and multivariate logistic regression, candidate parameters were selected. A predictive nomogram was constructed from these parameters and subsequently validated using the validation set. ROC curves were also plotted.Significant differences were observed between the reflex and non-reflex groups for 19 parameters including RBC, MCV, MCH, MCHC, RDW-CV, RDW-SD, Micro-RBC#, Micro-RBC%, Macro-RBC#, Macro-RBC%, MPV, PCT, P-LCC, P-LCR, PLR,“PLT clumps?” flag, “PLT abnormal histogram” flag, “IDA Anemia?” flag, and “RBC abnormal histogram” flag. After further analysis, Micro-RBC#, Macro-RBC%,“PLT clumps?”, and “PLT abnormal histogram” flag were identified as candidate parameters to develop a nomogram with an AUC of 0.636 (95 %CI: 0.622–0.650), sensitivity of 42.9 % (95 %CI: 37.8–48.1 %), and specificity of 90.5 % (95 %C1: 89.6–91.3 %).The established rules may help laboratories improve efficiency and increase accuracy in determining platelet counts as a supplement to ICSH41 guidelines. [ABSTRACT FROM AUTHOR]

Objective Design Setting Animals Methods Results Conclusion To compare the accuracy of a point‐of‐care coagulation analyzer (POCCA) with a reference laboratory coagulation analyzer (LabCA) and to evaluate for confounding factors that could alter the performance of the POCCA.Prospective, observational study.Two university veterinary teaching hospitals.Forty‐three client‐owned dogs undergoing coagulation testing between April 2020 and June 2021.Samples were obtained from dogs undergoing coagulation testing as part of a diagnostic workup. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured on the POCCA and on the LabCA. PCV, platelet count, total plasma protein, hyperbilirubinemia, hemolysis, lipemia, and autoagglutination were recorded.Moderate correlation was seen for PT and strong correlation was seen for aPTT between the POCCA and the LabCA (PT: 0.59, P < 0.0001; aPTT: 0.71, P < 0.0001). The POCCA results were consistent with normal or hypocoagulable samples for 30 of 38 PT and 33 of 37 aPTT results, as identified by the LabCA. Samples with PCV of 30%–55% were moderately correlated (PT: 0.63, P = 0.0004; aPTT: 0.63, P = 0.0003), but those outside that range were more likely to register an error message on the POCCA or provide disparate results. When hemolysis was present, there was a weak correlation between the POCCA and the LabCA for PT (rho: 0.38 [95% confidence interval: 0.19–0.76], P = 0.18) and a strong correlation for aPTT (rho: 0.86 [95% confidence interval: 0.62–0.95], P < 0.0001). Samples with hyperbilirubinemia were strongly correlated for PT (0.97, P = 0.002) but not for aPTT. Lipemia and autoagglutination were not observed.There was an acceptable correlation in patients with PCV within the manufacturer's recommended reference range; however, measurements on samples with PCV outside the reference range were inconsistent with the LabCA. Caution should be used when using the POCCA in patients with coagulopathy and anemia or other potential confounders. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD), usually caused by long-term tobacco smoking, is independently associated with systemic inflammation. However, little is known about the systemic inflammatory status of patients with early-stage COPD (classified as GOLD 1) and long-term smokers with normal lung function (LF). Here, we characterised the early changes in the associated inflammatory state in patients with GOLD 1 and in long-term smokers with normal LF. Methods: Fresh blood samples from 27 patients with GOLD 1, 27 long-term smokers and 14 non-smokers were analysed. Results: Ex vivo blood analysis revealed greater leucocyte-platelet adhesion to TNFα-stimulated pulmonary endothelium in patients with GOLD 1 than in smokers and non-smokers. In addition, platelet reactivity (platelet count and activation, and fibrinogen levels) and the frequency of leucocyte-platelet aggregates were higher in the GOLD 1 group than in the other groups. Some of these findings correlated with the severity of lung dysfunction, while platelet hyperactivity correlated positively with leucocyte-platelet adhesion. The GOLD 1 group also had a higher Th17/Treg ratio and higher circulating levels of IL-17C and C-reactive protein than the other groups. However, long-term smokers also had higher leucocyte counts and activation, and higher plasma levels of TNFα and IL-6 than non-smokers. Conclusion: Our data suggest that the altered inflammatory parameters in longterm smokers may represent early biomarkers of COPD. Accordingly, peripheral immune monitoring based on the above parameters may be useful to prevent disease progression in long-term smokers with normal LF and early COPD. [ABSTRACT FROM AUTHOR]

Introduction: Traditionally and empirically, Hibiscus sabdariffa L. has been used in treating diabetes mellitus due to its antioxidant activity. This study aimed to investigate the effect of administering the ethyl acetate fraction of hibiscus calyxes (EAFHCs) on malondialdehyde (MDA) levels, tumor necrosis factor-α (TNF-α) levels, bleeding time, and platelet count in male white rats induced with streptozotocin-induced diabetes. Method: Thirty-six Wistar Kyoto rats were induced with intraperitoneal streptozotocin at 55 mg/kg BW and stabilized for 5 days to obtain diabetic conditions. Diabetic animals were divided into four groups; the diabetic group was given vehicle, the glibenclamide group was given 0.45 mg/kg BW of glibenclamide, and two groups were administered the EAFHCs at doses of 100 mg/kg BW and 200 mg/kg BW for 5 days. Subsequently, the MDA, TNF-α, bleeding time and platelet count levels were examined on days 1, 3, and 5, respectively. All data were analyzed using two-way ANOVA followed by the Duncan Multiple Range Test (DMRT). Results: EAFHC significantly reduced MDA and TNF-α levels (p < 0.05). Additionally, this fraction appeared to shorten bleeding time and decrease platelet count in diabetic rats. Administration of the EAFHC for 5 days effectively lowered MDA and TNF-α levels significantly, decreased platelet counts and prolonged coagulation (p < 0.05) in diabetic rats. Conclusion: This study demonstrates that EAFHC effectively reduces MDA and TNF-α levels and reduces the risk of hypercoagulability in diabetic model. [ABSTRACT FROM AUTHOR]

Introduction: Patients with schizophrenia have a higher lifetime prevalence of suicidal behavior (SB) compared to the general population. Therefore, understanding the possible neurobiology of suicide and predicting the risk of suicide in schizophrenia is a solemnly critical issue. Methods: 31 drug-naïve first episode schizophrenia (FES) patients with current SB (FES-S), 69 drug-naive patients with first episode schizophrenia without SB (FES-NS), and 69 drug-naïve non-psychotic patients with current SB (NPS) who were diagnosed according to The Diagnostic and Statistical Manual of Mental Disorders - 5 (DSM-5) participated the study. The control group (HC) consisted of 127 individuals matched with the patients. Symptoms at the time of evaluation were assessed using The Positive and Negative Syndrome Scale (PANSS) and Columbia Suicide Severity Rating Scale (CSSRS). Blood samples were collected from all participants to determine White blood cell (WBC), neutrophil, monocyte, albumin, C-reactive protein (CRP), Lymphocyte, and Platelet levels and to measure this protein ratio. Results: The blood levels of WBC, neutrophil, monocyte, albumin, CRP, and Neutrophil/Albumin Ratio (NAR) were higher in all patient groups compared to HC. CRP/Albumin Ratio (CAR) value was observed to be highest in the NPS group. Monocyte/Lymphocyte Ratio (MLR) value was significantly higher in patients with FES compared to HC. There were no significant differences between the FES-S group and the FES-NS and NPS groups. Conclusion: It can be suggested that although inflammation is not a predictor for suicide attempts in schizophrenia, it is associated with the degree of suicide risk in schizophrenia. In addition, the strong relationship between suicide and psychiatric disorders can be the main reason for high peripheral inflammation levels in suicidal patients. [ABSTRACT FROM AUTHOR]

Objective: Primary immune thrombocytopenia (ITP) is an acquired disorder of platelets with a complex and unclear mechanism of increased immune destruction or impaired production of platelets. While the management of ITP is evolving, there is still a need for guidance, particularly in certain circumstances such as pregnancy, emergencies, or patients requiring co-medications. We aimed to determine the tendencies of hematologists in Türkiye in the event of such special considerations. Materials and Methods: Applying a modified Delphi method, the Turkish National ITP Working Group, founded under the auspices of the Turkish Society of Hematology, developed a questionnaire consisting of statements regarding pregnancy, emergencies, and circumstances requiring co-treatment with antiaggregants or anticoagulants. A total of 107 hematologists working in university or state hospitals voted for their agreement or disagreement with the statements for two sequential rounds. Results: The participating hematologists reached an agreement on starting treatment for pregnant patients with platelets of less than 30x109/L and delivery either vaginally or by cesarean section being safe at platelet counts above 50x109/L. For emergencies and the rescue management of ITP, the panel agreed against the use of high-dose corticosteroids alone, preferring combinations with transfusions or intravenous immunoglobulin. For patients who require interventions, platelet counts of >50x109/L were regarded as safe for low-risk procedures as well as co-treatment with antiplatelets or anticoagulants. Conclusion: As the National ITP Study Group, we have observed the need to increase the practice guidance regarding patients with primary ITP requiring additional treatments including invasive interventions and co-treatments for coagulation. Decisions on the management of ITP during pregnancy should be individualized. There is a lack of consensus on the thresholds of platelet counts as well as co-morbidities and co-medications. This lack of consensus may be due to variations in practices. [ABSTRACT FROM AUTHOR]

Objectives: Severe thrombotic antiphospholipid syndrome (APS) frequently affects the kidney, heart, and central nervous system. The precise frequency, clinical picture, differential diagnoses, and outcome of APS-related hematological involvement are lacking, especially in patients requiring ICU admission. This study aimed to describe the hematological manifestations associated with critically ill thrombotic APS patients and catastrophic antiphospholipid syndrome. Methods: This French, national, multicenter, retrospective study, conducted, from January 2000 to September 2018, included all APS patients admitted to 24 participating centers' ICUs with any new thrombotic manifestation. The prevalence of hematological manifestations and their associated outcomes were studied. Results: One hundred and thirty-four patients, female 72%, median [IQR] age 45 [34–56] years, with 152 episodes were included. Anemia was present in 95% of episodes and thrombocytopenia in 93%. The lowest values for hemoglobin and platelets were 7.1 [6.3–8.8] g/dL and 38 [21–60] g/L, respectively. The lowest platelet count below 20 g/L was significantly associated with a higher in-ICU mortality rate (50%, p < 0.0001). A thrombotic microangiopathy syndrome (TMA) syndrome was seen in 16 patients (12%) and was associated with higher in-hospital mortality (p = 0.05). Median ADAMTS-13 levels were 44% [27–74]. Anti-ADAMTS13 antibodies were tested in 11 patients and found negative in all. A suspicion of heparin-induced thrombocytopenia (HIT) was raised in 66 patients but only four patients were classified as definite HIT. Disseminated intravascular coagulation (DIC) was seen in 51% of patients. Conclusion: Thrombocytopenia is very frequent in severe APS patients and may be related to TMA, HIT, or DIC. Deciphering the mechanisms of thrombocytopenia is decisive in CAPS patients. Key Points • Thrombocytopenia is the hallmark laboratory finding in CAPS. • A complete thrombotic microangiopathy pattern is infrequent in CAPS patients. • Alternate diagnoses of CAPS, especially heparin-induced thrombocytopenia, need to be adequately investigated. [ABSTRACT FROM AUTHOR]

A recent article in Global Medical Genetics discusses the use of mesenchymal stem cells (MSCs) in clinical trials for immune disorders. MSCs have unique properties, including regeneration and immunomodulation, which make them a promising therapeutic approach. The article highlights a phase I trial that used human umbilical cord-derived MSCs (UC-MSCs) to treat refractory immune thrombocytopenia (ITP), a hemorrhagic disease resulting from an immune imbalance. The trial showed that UC-MSCs increased platelet counts and improved bleeding symptoms in patients with refractory ITP. MSCs have the potential to treat various immune-related conditions, and further research is needed to understand their distribution and metabolism in organ tissues. [Extracted from the article]

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5–43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs. [ABSTRACT FROM AUTHOR]

Trastuzumab deruxtecan has shown encouraging activity in patients with treatment-refractory HER2-positive, RAS wild-type and BRAF wild-type metastatic colorectal cancer. Dose optimisation and further antitumour assessments in patients with RAS mutations and those with previous anti-HER2 therapy are warranted. We aimed to evaluate two doses of trastuzumab deruxtecan (5·4 mg/kg and 6·4 mg/kg) to establish the recommended dose in patients with pretreated HER2-positive, RAS wild-type or mutant metastatic colorectal cancer. DESTINY-CRC02 was a multicentre, randomised, two-stage, two-arm, phase 2 study done in 53 research hospitals and medical centres in Australia, Belgium, France, Italy, Japan, South Korea, Spain, Taiwan, the UK, and the USA. Eligible patients were aged 18 years and older or 20 years and older (depending on region) with pretreated pathologically documented, unresectable, recurrent, or metastatic HER2-positive, and RAS wild-type or mutant colorectal cancer. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and have received previous chemotherapy, and anti-EGFR, anti-VEGF, or anti-PD-L1 therapy, if clinically indicated. In stage 1, patients were randomly assigned (1:1), via a secure interactive response technology system, to receive 5·4 mg/kg or 6·4 mg/kg trastuzumab deruxtecan administered intravenously every 21 days. Stratification factors were ECOG performance status, HER2 status, and RAS status. In stage 2, patients were assigned into the 5·4 mg/kg treatment group only. The primary endpoint was confirmed objective response rate by blinded independent central review, assessed in all patients for whom treatment was assigned (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04744831 , and is ongoing (not recruiting). Between March 5, 2021, and March 29, 2022, 135 patients were centrally screened, 122 of whom were enrolled. In stage 1, 40 patients each were randomly assigned to receive trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg. In stage 2, an additional 42 patients were enrolled in the 5·4 mg/kg group. 64 (52%) participants were male and 58 (48%) were female. The median duration of follow-up was 8·9 months (IQR 6·7–10·5) in the 5·4 mg/kg group and 10·3 months (5·9–12·7) in the 6·4 mg/kg group. The confirmed objective response rate by blinded independent central review was 37·8% (31/82 [95% CI 27·3–49·2]) in the 5·4 mg/kg group and 27·5% (11/40 [14·6–43·9]) in the 6·4 mg/kg group. 34 (41%) of 83 patients in the 5·4 mg/kg group and 19 (49%) of 39 in the 6·4 mg/kg group had grade 3 or worse drug-related treatment-emergent adverse events. The most common grade 3 or worse drug-related treatment-emergent adverse events were neutrophil count decreased (13 [16%] of 83 patients), anaemia (six [7%]), nausea (six [7%]), and white blood cell count decreased (five [6%]) in the 5·4 mg/kg group; and were neutrophil count decreased (10 [26%] of 39 patients), anaemia (eight [21%]), platelet count decreased (four [10%]), and white blood cell count decreased (four [10%]) in the 6·4 mg/kg group. Drug-related serious adverse events occurred in 11 (13%) of 83 patients in the 5·4 mg/kg group and six (15%) of 39 patients in the 6·4 mg/kg group; the most common in the 5·4 mg/kg group was nausea (three [4%] patients) and the most common in the 6·4 mg/kg group were fatigue (two [5%] patients), neutropenia (two [5%]), and thrombocytopenia (two [5%]). A drug-related treatment-emergent adverse event related to death occurred in one (1%) patient in the 5·4 mg/kg group (due to hepatic failure). Adjudicated drug-related interstitial lung disease or pneumonitis events were observed in seven (8%) patients in the 5·4 mg/kg group (all grade 1 or 2) and in five (13%) patients in the 6·4 mg/kg group (four grade 1 or 2; one grade 5). The promising antitumour activity and favourable safety profile support trastuzumab deruxtecan 5·4 mg/kg as the optimal single-agent dose for patients with pretreated HER2-positive metastatic colorectal cancer, including those with RAS mutations, previous anti-HER2 therapy, or both. Daiichi Sankyo and AstraZeneca. [ABSTRACT FROM AUTHOR]

Platelets are essential component of circulation that plays a major role in hemostasis and thrombosis. During activation and its demise, platelets release platelet‐derived microvesicles, with lysophosphatidylcholine (LPC) being a prominent component in their lipid composition. LPC, an oxidized low‐density lipoprotein, is involved in cellular metabolism, but its higher level is implicated in pathologies like atherosclerosis, diabetes, and inflammatory disorders. Despite this, its impact on platelet function remains relatively unexplored. To address this, we studied LPC's effects on washed human platelets. A multimode plate reader was employed to measure reactive oxygen species and intracellular calcium using H2DCF‐DA and Fluo‐4‐AM, respectively. Flow cytometry was utilized to measure phosphatidylserine expression, mitochondrial membrane potential (ΔΨm), and mitochondrial permeability transition pore (mPTP) formation using FITC‐Annexin V, JC‐1, and CoCl2/calcein‐AM, respectively. Additionally, platelet morphology and its ultrastructure were observed via phase contrast and electron microscopy. Sonoclot and light transmission aggregometry were employed to examine fibrin formation and platelet aggregation, respectively. The findings demonstrate that LPC induced oxidative stress and increased intracellular calcium in platelets, resulting in increased phosphatidylserine expression and reduced ΔΨm. LPC triggered caspase‐independent platelet death and mPTP opening via cytosolic and mitochondrial calcium, along with microvesiculation and reduced platelet counts. LPC increased the platelet's size, adopting a balloon‐shaped morphology, causing membrane fragmentation and releasing its cellular contents, while inducing a pro‐coagulant phenotype with increased fibrin formation and reduced integrin αIIbβ3 activation. Conclusively, this study reveals LPC‐induced oxidative stress and calcium‐mediated platelet death, necrotic in nature with pro‐coagulant properties, potentially impacting inflammation and repair mechanisms during vascular injury. [ABSTRACT FROM AUTHOR]

Biallelic mutations of the CEBPA gene (CEBPAbi) are generally associated with favorable prognosis in patients with acute myeloid leukemia (AML). Monoallelic mutations of the CEBPA gene in carboxy-terminal DNA-binding region (CEBPAsmbZIP) and amino-terminal transactivation domains (CEBPAsmTAD) indicate distinct clinical characteristics and therapeutic outcomes. However, further investigation is required to fully understand these differences. In this retrospective study, we enrolled 77 AML patients with CEBPA mutations, including 53 with CEBPAbi, 12 with CEBPAsmbZIP and 12 with CEBPAsmTAD. The clinical characteristics of the three CEBPAmut groups presented significant differences in age, FAB classification, hemoglobin level and platelet count at diagnosis. The CEBPAsmTAD group exhibited shorter 2-year overall survival (OS) and relapse-free survival (RFS) compared to the CEBPAbi group and CEBPAsmbZIP group in AML patients. The most common co-mutations observed in CEBPAmut AML patients were TET2 and GATA2, which had no effect on prognosis. 2-year RFS of 27 CEBPAmut AML patients who underwent allo-HSCT was better than those who did not. MRD3 positive was identified as an influencing factor for 2-year OS and RFS. Allo-HSCT was found to improve the prognosis of CEPBAmut AML patients with positive MRD3 and adverse co-mutations. [ABSTRACT FROM AUTHOR]

The pathophysiology of immune thrombocytopenia (ITP) involves immune-mediated platelet destruction. The presence of adipose tissue in obese individuals creates an inflammatory environment that could potentially impact the clinical course and outcomes of ITP. However the relationship between obesity and ITP outcomes has not been well described. We evaluated ITP outcomes in 275 patients diagnosed with primary ITP from 2012 to 2022. Patients were categorized into four groups based on their body mass index (BMI) at diagnosis. Female gender was associated with a lower platelet count at the time of diagnosis at any BMI. Patients with high BMI had lower platelet counts at diagnosis and at platelet nadir (p < 0.001), an increased likelihood of requiring therapy (p < 0.001) and requiring multiple lines of therapy (p = 0.032). Non-obese patients who required corticosteroid treatment experienced a longer remission duration compared to obese patients (p = 0.009) and were less likely to be steroid-dependent (p = 0.048). Our findings suggest that obesity may be a significant risk factor for developing ITP and for ITP prognosis. Future studies are needed to evaluate the role of weight loss intervention in improving ITP outcomes. [ABSTRACT FROM AUTHOR]

Background: Immune thrombocytopenia (ITP) is an immune-mediated disease that results in low platelet counts. Despite appropriate treatment, many patients continue to experience refractory disease. Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, has emerged as a promising option for refractory ITP. Objective: This meta-analysis aims to evaluate the efficacy and safety of fostamatinib compared to conventional therapy in adults aged ≥ 18 years with refractory ITP. Materials and methods: Literature search was conducted in PubMed, Scopus, Embase, and clinicaltrials.gov databases from inception to March 31, 2024. Randomized controlled trials (RCTs) assessing the safety and efficacy of fostamatinib in adults with refractory ITP were included. Data extraction, risk of bias assessment, and statistical analysis were performed following PRISMA guideline. Results: A total of 495 articles were screened, with three RCTs meeting the inclusion criteria. Fostamatinib therapy demonstrated superior efficacy in achieving stable platelet response by week 24 (ORR 0.80; 95%CI 0.72–0.88), platelet count ≥ 50,000/µL at weeks 12 (ORR 0.80; 95%CI 0.72–0.90) and week 24 (ORR 0.82; 95%CI 0.72–0.90). Additionally, fostamatinib improves platelet counts in subjects with a baseline count of < 15,000/µL. The Number Needed to Treat (NNT) was calculated as 10. Adverse effects include diarrhea (RR 2.32; 95%CI 1.11–4.84), hypertension (RR 2.33; 95%CI 1.00-5.43), and abnormal liver function tests (RR 4.18; 95% CI 1.00-17.48). Interestingly, the occurrences of nausea (RR 1.77; 95% CI 0.33–9.67) and rash (RR 2.28; 95% CI 0.50-10.29) did not achieve statistical significance. Conclusion: This meta-analysis provides robust evidence supporting the efficacy of fostamatinib in improving platelet counts and achieving therapeutic goals in adults with refractory ITP. However, fostamatinib's safety profile warrants consideration due to higher rates of diarrhea, hypertension, and abnormal liver function tests. [ABSTRACT FROM AUTHOR]

Although transcatheter aortic valve replacement (TAVR) is safe and effective, mortality and bleeding events post procedure are important. The present study investigated the changes in hematologic parameters to evaluate whether they predict mortality or major bleeding. We enrolled 248 consecutive patients (44.8% male; mean age 79.0 ± 6.4 years) undergoing TAVR. In addition to demographic and clinical examination, blood parameters were recorded before TAVR, at discharge, 1 month and 1 year. Hemoglobin levels before TAVR 12.1 ± 1.8 g/dL, 10.8 ± 1.7 g/dL at discharge, 11.7 ± 1.7 g/dL at first month, 11.8 ± 1.4 g/dL at first year (Hemoglobin values compared with pre-TAVR, P <.001, P =.019, P =.047, respectively). Mean platelet volume (MPV) before TAVR 8.72 ± 1.71 fL, 8.16 ± 1.46 fL at discharge, 8.09 ± 1.44 fL at first month, 7.94 ± 1.18 fL at first year (MPV values compared with pre-TAVR, P <.001, P <.001, P <.001, respectively). Other hematologic parameters were also evaluated. Hemoglobin, platelet count, MPV, and red cell distribution width before the procedure, at discharge, and at the first year did not predict mortality and major bleeding in receiver operating characteristic analysis. After multivariate Cox regression analysis, hematologic parameters were not independent predictors of in-hospital mortality, major bleeding, and death at 1 year after TAVR. [ABSTRACT FROM AUTHOR]

Context.--In the Sysmex DI-60 digital morphology system, a platelet estimate factor (PEF) is used to calculate the estimated platelet count (PLT). Objective.--To determine the most accurate PEF by analyzing various specimens, including those with abnormal flag alerts, using both impedance (PLT-I) and optical fluorescent (PLT-F) PLT methods. A validation study was then conducted using random specimens to evaluate the accuracy of the PEF. Design.--This study included 120 blood specimens with- out flag alerts, and 120 blood specimens with flag alerts related to platelet abnormalities to determine the PEF. Each group was equally divided into thrombocytopenia, normal count, and thrombocytosis specimens. The PEF values obtained from the PLT-I and PLT-F methods were analyzed. An additional 120 specimens were used to compare the estimated PLT from PEF with the PLT-F count. Unadjusted PEF disregarded platelet ranges and flag alerts, whereas adjusted PEF incorporated them. Results.--The mean PEF values ranged within 9.95 to 12.99 for PLT-I-obtained values (PEF-I) and within 10.32 to 11.69 for PLT-F-obtained values (PEF-F) across different PLT ranges. The mean PEF values were significantly higher in specimens with flags compared with those without flags. The values were 12.43 compared with 10.19 for PEF-I and 11.45 compared with 10.4 for PEF-F. A significant difference was found between PEF-I and PEF-F in flagged specimens, with respective values of 12.43 and 11.45. There was excellent agreement between estimated PLTs using adjusted PEF and PLT-F. However, proportional biases were observed between estimated PLT using unadjusted PEF and PLT-F. Conclusions.--Adjustment of PEF values according to specific platelet ranges and flag alert presence was shown to enhance the accuracy of PLT estimation using the Sysmex DI-60 system. [ABSTRACT FROM AUTHOR]

Background: Platelet transfusions are frequently used in the intensive care unit (ICU), but current practices including used product types, volumes, doses and effects are unknown. Study design and methods: Sub‐study of the inception cohort study 'Thrombocytopenia and Platelet Transfusions in the ICU (PLOT‐ICU)', including acutely admitted, adult ICU patients with thrombocytopenia (platelet count <150 × 109/L). The primary outcome was the number of patients receiving platelet transfusion in ICU by product type. Secondary outcomes included platelet transfusion details, platelet increments, bleeding, other transfusions and mortality. Results: Amongst 504 patients with thrombocytopenia from 43 hospitals in 10 countries in Europe and the United States, 20.8% received 565 platelet transfusions; 61.0% received pooled products, 21.9% received apheresis products and 17.1% received both with a median of 2 (interquartile range 1–4) days from admission to first transfusion. The median volume per transfusion was 253 mL (180–308 mL) and pooled products accounted for 59.1% of transfusions, however, this varied across countries. Most centres (73.8%) used fixed dosing (medians ranging from 2.0 to 3.5 × 1011 platelets/transfusion) whilst some (mainly in France) used weight‐based dosing (ranging from 0.5 to 0.7 × 1011 platelets per 10 kg body weight). The median platelet count increment for a single prophylactic platelet transfusion was 2 (−1 to 8) × 109/L. Outcomes of patients with thrombocytopenia who did and did not receive platelet transfusions varied. Conclusions: Among acutely admitted, adult ICU patients with thrombocytopenia, 20.8% received platelet transfusions in ICU of whom most received pooled products, but considerable variation was observed in product type, volumes and doses across countries. Prophylactic platelet transfusions were associated with limited increases in platelet counts. [ABSTRACT FROM AUTHOR]

Fracture related infection (FRI) refers to pathogens infecting a fracture site and hence impeding fracture healing. It is a significant complication that carries substantial disease burden and socio-economic costs, but has had limited scientific development. Hence, this paper will review the existing strategies for early detection of FRI, in the form of serum markers, molecular diagnostics and imaging modalities, and further discuss potential future directions for improved detection of FRI. The Anti-infection Global Expert Committee (AIGEC) developed a consensus definition for FRI in 2017, which includes confirmatory and suggestive criteria for diagnosis of FRI. Existing strategies for diagnosis include clinical, laboratory, histopathological, microbiological and radiological investigations. With increasing recognition of FRI, early detection is crucial for early treatment to be enforced. We have identified potential areas for future development in diagnostics for early detection of FRI, which are discussed in this manuscript. They include inflammatory cytokines, serum calcium levels, platelet count, improved management of histopathological and microbiological specimens, metagenomics, wound biomarkers, gut microbiota analysis, and novel imaging technologies. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against complexes of heparin and platelet factor 4 (PF4). The electrostatic interaction between heparin and PF4 is critical for the anti-PF4/heparin antibody response seen in HIT. The binding of metal cations to heparin induces conformational changes and charge neutralization of the heparin molecule, and cation-heparin binding can modulate the specificity and affinity for heparin-binding partners. However, the effects of metal cation binding to heparin in the context of anti-PF4/heparin antibody response have not been determined. Here, we utilized inductively coupled plasma mass spectrometry (ICP-MS) to quantify 16 metal cations in patient plasma and tested for correlation with anti-PF4/heparin IgG levels and platelet count after clinical suspicion of HIT in a cohort of heparin-treated patients. The average age of the cohort (n = 32) was 60.53 (SD = 14.31) years old, had a mean anti-PF4/heparin antibody optical density [OD405] of 0.93 (SD = 1.21) units, and was primarily female (n = 23). Patients with positive anti-PF4/heparin antibody test results (OD405 ≥ 0.5 units) were younger, had increased weight and BMI, and were more likely to have a positive serotonin release assay (SRA) result compared to antibody-negative patients. We observed statistical differences between antibody-positive and -negative groups for sodium and aluminum and significant correlations of anti-PF4/heparin antibody levels with sodium and silver. While differences in sodium concentrations were associated with antibody-positive status and correlated with antibody levels, no replication was performed. Additional studies are warranted to confirm our observed association, including in vitro binding studies and larger observational cohorts. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions The natural history of untreated patients with type 1 Gaucher disease (GD1) is not well documented, and there is controversy over when and how to treat such patients, especially if they are only mildly symptomatic. Treatment of GD1 is inconvenient, very costly, and may result in undesirable side effects. We documented the clinical history of 31 untreated patients with GD1 followed in our clinic for 4–26 (median 15) years.This was a retrospective, observational study of the progress of untreated adult patients with GD1 followed by blood tests (haemoglobin, platelet counts, ferritin and chitotriosidase), organ volumes (spleen and liver), bone manifestations (through magnetic resonance imaging and dual X‐ray absorptiometry scans) and neurological and quality of life issues. Statistical analyses were performed with the use of the Student paired t test and the modified Wald test for 95% confidence intervals.We found that the above parameters remained stable in most patients over a period of 4–26 (median 15) years. Five patients progressed from normal bone density to osteopenia and two from osteopenia to osteofibrosis; six were peri‐ or post‐menopausal females. The DS‐3 was stable over time. Only four of the 31 patients were started on enzyme or substrate reduction therapy.Our results demonstrate that many patients with GD1, provided with close follow‐up by a specialist centre, can be followed for many years without requiring treatment and with no or minimal worsening of their GD1 manifestations. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions The relationship between the combination of platelet count and neutrophil‐lymphocyte ratio (COP‐NLR) and prognosis in patients with advanced non‐small cell lung cancer (NSCLC) treated with immune checkpoint inhibitor (ICI) combination therapy with chemotherapy remains unclear. Thus, we investigated prognostic factors, including the COP‐NLR, to identify patients who could benefit from the therapeutic efficacy of ICI combination therapy for advanced NSCLC. Furthermore, we evaluated the relationship between the COP‐NLR score during ICI combination therapy and treatment response.We conducted a retrospective cohort study of 88 patients with NSCLC who initially received ICI combination therapy. The primary outcome was overall survival (OS). The prognostic factors were extracted using the Cox proportional hazards model. The relationship between COP‐NLR score at 3 weeks after starting ICI combination therapy and a good response (complete response [CR] and partial response [PR]) to treatment was analyzed using the chi‐square test.The median OS was 15.7 months. In the multivariable analysis, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 2, distant metastatic sites ≥2, and baseline COP‐NLR scores of 1, 2 were extracted as significant poor prognostic factors. The proportion of patients with CR and PR in the 3‐week COP‐NLR score of 0 group was significantly higher than that in scores of 1, 2 group.Baseline COP‐NLR, ECOG PS, and number of distant metastatic sites were prognostic factors in patients with NSCLC with ICI combination therapy. A lower 3‐week COP‐NLR was associated with a good response to treatment. [ABSTRACT FROM AUTHOR]

Background: This study aimed to develop a tool for predicting the early occurrence of acute kidney injury (AKI) in ICU hospitalized cirrhotic patients. Methods: Eligible patients with cirrhosis were identified from the Medical Information Mart for Intensive Care database. Demographic data, laboratory examinations, and interventions were obtained. After splitting the population into training and validation cohorts, the least absolute shrinkage and selection operator regression model was used to select factors and construct the dynamic online nomogram. Calibration and discrimination were used to assess nomogram performance, and clinical utility was evaluated by decision curve analysis (DCA). Results: A total of 1254 patients were included in the analysis, and 745 developed AKI. The mean arterial pressure, white blood cell count, total bilirubin level, Glasgow Coma Score, creatinine, heart rate, platelet count and albumin level were identified as predictors of AKI. The developed model had a good ability to differentiate AKI from non-AKI, with AUCs of 0.797 and 0.750 in the training and validation cohorts, respectively. Moreover, the nomogram model showed good calibration. DCA showed that the nomogram had a superior overall net benefit within wide and practical ranges of threshold probabilities. Conclusions: The dynamic online nomogram can be an easy-to-use tool for predicting the early occurrence of AKI in critically ill patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Summary The CYCS gene is highly evolutionarily conserved, with only a few pathogenic variants that cause thrombocytopenia‐4 (THC4). Here, we report a novel CYCS variant NM_018947.6: c.59C>T [NP_061820.1:p.(Thr20Ile)] segregating with thrombocytopenia in three generations of a Czech family. The phenotype of the patients corresponds to THC4 with platelets of normal size and morphology and dominant inheritance. Intriguingly, a gradual decline in platelet counts was observed across generations. CRISPR/Cas9‐mediated gene editing was used to introduce the new CYCS gene variant into a megakaryoblast cell line (MEG‐01). Subsequently, the adhesion, shape, size, ploidy, viability, mitochondrial respiration, cytochrome c protein (CYCS) expression, cell surface antigen expression and caspase activity were analysed in cells carrying the studied variant. Interestingly, the variant decreases the expression of CYCS while increasing mitochondrial respiration and the expression of CD9 cell surface antigen. Surprisingly, the variant abates caspase activation, contrasting with previously known effects of other CYCS variants. Some reports indicate that caspases may be involved in thrombopoiesis; thus, the observed dysregulation of caspase activity might contribute to thrombocytopenia. The findings significantly enhance our understanding of the molecular mechanisms underlying inherited thrombocytopenia and may have implications for diagnosis, prognosis and future targeted therapies. [ABSTRACT FROM AUTHOR]

Background: There were limited data investigating platelet indices in predicting peritoneal dialysis (PD) outcomes on comorbidities. The aim of this study was to evaluate the association between platelet indices and new-onset comorbidity and all-cause mortality in PD patients. Methods: A single-center, retrospective observational cohort study was conducted in incident PD patients from 28 December 2011 to 24 January 2018, and followed up until 31 December 2022. Time to the first new-onset cardiovascular disease (CVD) and time to the first new-onset infection event after PD were identified as the primary outcomes. All-cause mortality was identified as the secondary endpoint. The correlation between platelet indices and comorbidities and all-cause mortality were assessed by Cox model. Data of liver disease status was not collected and analyzed. Survival curves were performed by Kaplan-Meier method with log-rank tests. Results: A total of 250 incident PD patients with a median follow-up of 6.79 (inter-quarter range 4.05, 8.89) years was included. A total of 81 and 139 patients experienced the first new-onset CVD and infection event respectively during the follow-up period. High mean platelet volume (MPV) was independently associated with high risk of time to the first new-onset CVD (HR 1.895, 95% CI 1.174–3.058, p = 0.009) and all-cause mortality (HR 1.710, 95% CI 1.155–2.531, p = 0.007). Patients with low mean platelet volume to platelet count ratio (MPV/PC) were prone to occur the new-onset infection events (log rank 5.693, p = 0.017). Low MPV/PC (HR 0.652, 95% CI 0.459–0.924, p = 0.016) was significantly associated with the time to the first new-onset infection event on PD. Conclusions: Platelet indices were associated with the new-onset CVD, infectious comorbidities and all-cause mortality on PD. Low MPV/PC was associated with time to the first new-onset infection event in PD patients. Moreover, high MPV was associated with new-onset CVD and all-cause mortality in the incident PD patients. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a severe pregnancy complication characterized by significant alterations in coagulation function. This study aims to analyze the correlation between coagulation function, platelet parameters, and pregnancy outcomes in PE patients. Clinical data, along with blood and urine samples, were collected from 168 PE patients and 128 healthy pregnant women. General demographic and laboratory testing data were recorded, and maternal and fetal outcomes were followed up. Data were analyzed using Kaplan–Meier and logistic regression analyses. In mild PE patients, thrombin time (p = .000), platelet distribution width (PDW) (p = .000), and clot formation time (p = .000) were increased, while prothrombin time (p = .000) and fibrinogen (p = .045) were reduced. With increasing PE severity, prothrombin time (p = .000), platelet count (PLT) (p = .000), mean platelet volume (MPV) (p = .000), plateletcrit (p = .000), maximum amplitude (MA) (p = .000), and coagulation index (p = .001) decreased, whereas activated partial thromboplastin time (APTT) (p = .000), thrombin time (p = .002), D‐dimer (p = .026), and PDW (p = .000) increased. Lower prothrombin time (p = .048), PLT (p = .004), and coagulation index (p = .026) or higher APTT (p = .032), thrombin time (p = .044), D‐dimer (p = .023), and PDW (p = .016) were associated with a higher risk of poor pregnancy outcomes. Thrombin time was identified as an independent risk factor (p = .025, OR = 2.918, 95% CI: 1.145–7.436), whereas gestational age was an independent protective factor (p = .000, OR = 0.244, 95% CI: 0.151–0.395). This study demonstrates that specific coagulation and platelet parameters are significantly associated with PE severity and adverse pregnancy outcomes. These findings highlight the importance of monitoring coagulation function in PE patients to improve clinical management and outcomes. [ABSTRACT FROM AUTHOR]

Background: Echinocandins belong to the fourth generation of antifungals, and there are no systematic studies on their risk in coagulation dysfunction; this study will predict the risk of coagulation dysfunction of echinocandins using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Method: Data from January 2004 to March 2024 were obtained from FAERS. We examined the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare echinocandins with the full database. Results: There were 313 reports of coagulation dysfunction related to echinocandins as the primary suspect (PS) drug. The median time to incident for coagulation dysfunction was 3 (interquartile range [IQR] 1–9) days. Compared to triazoles and polyenes, echinocandins have a stronger signal (ROR 3.18, 95%CI 2.81–3.51, p < 0.01) of coagulation dysfunction. Compared to caspofungin and micafungin, anidulafungin has a stronger signal (ROR 6.84, 95%CI 4.83–9.70, p < 0.01). The strongest signal corresponding to disseminated intravascular coagulation (DIC), platelet count decreased, thrombocytopenia, gastrointestinal haemorrhage, cerebral haemorrhage, pulmonary haemorrhage and thrombotic thrombocytopenic purpura (TTP) is micafungin (ROR 27.19, 95%CI 18.49–39.98), micafungin (ROR 3.50, 95%CI 2.36–5.19), anidulafungin (ROR 9.75, 95%CI 5.22–18.19), micafungin (ROR 3.17, 95%CI 2.02–4.97), micafungin (ROR 4.95, 95%CI 2.81–8.72), caspofungin (ROR 20.76, 95%CI 11.77–36.59), micafungin (ROR 20.43, 95%CI 8.49–49.14), respectively. Conclusions: For coagulation dysfunction, we found stronger signals for echinocandins than triazoles and polyenes, and stronger signals for anidulafungin than micafungin and caspofungin. Coagulation parameters should be closely monitored while using the respective drugs. Highlights: Real world data were used to predict the risk of coagulopathy for three classes of drugs: echinocandins, triazoles, and polyenes. Real-world data were used to compare the risk of coagulopathy between caspofungin, micafungin, and anidulafungin. Different causes of coagulation dysfunction were analyzed by subgroups. [ABSTRACT FROM AUTHOR]

2,3-dimethylquinoxaline (DMQ) is a broad-spectrum antimicrobial phytochemical. This study aims to assess its toxicological profile. In vitro studies conducted in appropriate cell cultures, included assessment of cardiotoxicity, nephrotoxicity, and hepatotoxicity. An in vivo study was conducted in mice to determine acute oral toxicity (AOT), and subacute oral toxicity (SAOT). Acute dermal toxicity (ADT) was conducted in rats. All in-vitro toxicity studies of DMQ had negative results at concentrations ≤100 μM except for a non-significant reduction in the ATP in human hepatocellular carcinoma cell culture. The median lethal dose of DMQ was higher than 2000 mg/kg. All animals survived the scheduled necropsy and none showed any alteration in clinical signs. Biochemistry analysis revealed a significant difference between the satellite and control groups, showing an increase in platelet counts and white blood cell counts by 99.8% and 188.8%, respectively. Histology revealed enlargement of renal corpuscles; hyperplasia of testosterone-secreting cells; and dilatation of coronaries and capillaries. The present data suggests an acceptable safety profile of DMQ in rodents except for thrombocytosis, leukocytosis, and histological changes in high doses that need further investigation. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions Coagulation assessment in traumatic brain injury (TBI) typically relies upon laboratory‐based standard coagulation tests (SCTs), including the activated partial thromboplastin time (aPTT), INR and platelet count. Rotational thromboelastometry (ROTEM) sigma is an alternative point‐of‐care assay; however, its role in isolated TBI is under‐evaluated. The present study aims to assess the prognostic utility of ROTEM sigma in isolated TBI.ROTEM sigma analysis was performed during the initial evaluation of patients presenting to the Royal Adelaide Hospital between February 2022 and 2023 with radiographically demonstrated traumatic intracranial haemorrhage and GCS ≤14. Patients with concomitant severe extracranial injury, or who received blood products or antifibrinolytic therapy prior to sample collection were excluded.Thirty‐six patients had blood samples analysed with ROTEM, 25 of these patients were also evaluated with paired SCTs. Twenty‐two per cent (8/36) of patients with isolated TBI had a hypocoaguable ROTEM profile, and this was associated with an increased incidence of head injury‐related death (50% [4/8] vs 11% [3/28], P = 0.03). Median diagnostic turn‐around‐times were shorter for ROTEM parameters compared to SCT counterparts: EXTEM clotting time (CT) versus INR (20 vs 63 min, P < 0.01), and INTEM CT versus aPTT (21 vs 63 min, P < 0.01). EXTEM CT, FIBTEM CT and INR values had similar performance in predicting head injury‐related death, area under the receiver operator curves were 0.8, 0.8 and 0.7, respectively.ROTEM sigma expedites the detection of clinically significant coagulopathy in isolated TBI. EXTEM and FIBTEM CT values are more rapidly attainable than INR and comparable in predicting head injury‐related death. [ABSTRACT FROM AUTHOR]

Summary Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)‐mediated release of active transforming growth factor beta (TGFβ) from the TGFβ propeptide latency‐associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti‐thrombotic therapy was identified between patients with JAK2‐ and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2‐ and CALRmut patients. [ABSTRACT FROM AUTHOR]

Platelet lysate (PL) is investigated as a potential replacement for fetal bovine serum (FBS) in cell culture. However, there is limited research on its impact on the immune profile of equine mesenchymal stromal cells (eMSCs). This study aimed to evaluate the effects of different PL formulations on the proliferative capacity, multipotentiality, and immune profile of equine adipose tissue-derived MSCs (eAD-MSCs). In vitro growth kinetics and trilineage differentiation of eAD-MSCs (n = 7) were assessed under three culture conditions: mediumconcentration PL (MPL), high-concentration PL (HPL), and FBS as a control. The immune profile was evaluated by studying the expression of immunogenic receptors such as MHC I, MHC II, and immunomodulatory molecules IL-6, IL-10, and TNF-α, determined by gene expression, surface marker expression, and cytokine quantification. Both PL formulations, pooled from 5 donors, exhibited 3.3 and 6.5-fold higher platelet counts than baseline plasma for MPL and HPL, respectively. Higher concentrations of TGF-β and PDGF were found in both PL formulations compared to baseline. Furthermore, MPL and HPL subcultures demonstrated proliferative, clonogenic, and multipotent capacities similar to FBS. The immune profile of PL-cultured cells exhibited gene expression levels related to immunogenicity and immunomodulation similar to the reference condition, and the surface antigen presence of MHC II was also similar. However, HPL media exhibited higher IL-6, IL-10, and TNF-α concentrations in the culture supernatant. In conclusion, both PL media contained higher concentrations of growth factors compared to FBS, supporting the in vitro culture of eAD-MSCs with proliferative, clonogenic, and multipotent capacity similar to the reference medium. Nonetheless, PL usage led to a variation in the immunomodulatory cytokine microenvironment, with higher concentrations of IL-6, IL-10, and TNF-α in HPL media compared to MPL and FBS. [ABSTRACT FROM AUTHOR]

Background: We aim to develop a new prognostic model that incorporates inflammation, nutritional parameters and clinical-pathological features to predict overall survival (OS) and disease free survival (DFS) of breast cancer (BC) patients. Methods: The study included clinicopathological and follow-up data from a total of 2857 BC patients between 2013 and 2021. Data were randomly divided into two cohorts: training (n=2001) and validation (n=856) cohorts. A nomogram was established based on the results of a multivariate Cox regression analysis from the training cohorts. The predictive accuracy and discriminative ability of the nomogram were evaluated by the concordance index (C-index) and calibration curve. Furthermore, decision curve analysis (DCA) was performed to assess the clinical value of the nomogram. Results: A nomogram was developed for BC, incorporating lymphocyte, platelet count, hemoglobin levels, albumin-to-globulin ratio, prealbumin level and other key variables: subtype and TNM staging. In the prediction of OS and DFS, the concordance index (C-index) of the nomogram is statistically greater than the C-index values obtained using TNM staging alone. Moreover, the time-dependent AUC, exceeding the threshold of 0.7, demonstrated the nomogram's satisfactory discriminative performance over different periods. DCA revealed that the nomogram offered a greater overall net benefit than the TNM staging system. Conclusion: The nomogram incorporating inflammation, nutritional and clinicopathological variables exhibited excellent discrimination. This nomogram is a promising instrument for predicting outcomes and defining personalized treatment strategies for patients with BC. [ABSTRACT FROM AUTHOR]

This study compared the power of the novel inflammatory markers systemic immune inflammation index (SII) and the system inflammation response index (SIRI) versus the classical hematological indices neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and platelet counts in distinguishing between major depressive disorder (MDD) with and without suicide attempts and distinguishing the non-response to selective serotonin reuptake inhibitor (SSRI) treatment. A total of 139 young adult MDD patients and 54 healthy controls (HC) were included. We found that, in comparison to HC, baseline NLR, PLR, SII, and SIRI were significantly higher in MDD patients, but only NLR and SII had area under the ROC curve (AUC) values greater than 0.7. MDD patients with suicide attempts (SA) showed significantly higher baseline MLR and SIRI, and a tendency to increase NLR compared to those without SA. In terms of AUC, sensitivity, and specificity, NLR was better than MLR, SIRI, SII, and PLR in distinguishing SA. Non-responders to SSRI treatment showed a significant increase in baseline platelet count and PLR compared to responders with an AUC greater than 0.7. These findings highlight the potential benefit of combining novel and classical hematological indices in predicting depression, suicide attempts and treatment response. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Donor‐derived dengue infections present significant challenges to organ transplantation, particularly in endemic regions like Singapore. Although primarily transmitted by Aedes mosquitoes, dengue can also be transmitted through organ transplantation, occasionally with fatal outcomes. This study aims to evaluate the outcomes and evolution of dengue screening protocols for potential deceased donors in Singapore from 2006 to 2022.Initially, screening was done via dengue immunoglobulin M (IgM), targeting donors with specific clinical criteria (thrombocytopenia, drop in platelet count, prolonged prothrombin time/partial thromboplastin time, and discretion of the transplant team), later transitioning to blood dengue reverse transcription‐polymerase chain reaction (RT‐PCR) in 2007 with similar criteria, and subsequently universal screening in 2016. In 2021, urine dengue RT‐PCR was added following a case of donor‐derived dengue infection from an aviremic but viruric donor.Out of 431 potential deceased donors, 395 (91.6%) underwent dengue screening, with six (1.5%) testing positive for dengue. In 2006, three positive screens were identified: two through dengue IgM and one via blood dengue RT‐PCR; subsequent years saw one positive screen each in 2007, 2008, and 2019 via blood dengue RT‐PCR. Potential deceased donors with a positive blood dengue screen were rejected as solid organ and tissue donors. Those with negative blood dengue RT‐PCR but positive urine dengue RT‐PCR would be rejected as kidney donors, but the use of other organs and tissues was at the discretion of the transplantation team.The optimal screening protocol remains uncertain, but our findings suggest that a universal screening strategy utilizing both blood and urine dengue RT‐PCR could be considered in dengue‐endemic countries. [ABSTRACT FROM AUTHOR]

Valemetostat is an oral inhibitor of enhancer of zeste homolog (EZH) 2 and EZH1 approved in Japan for the treatment of adult T‐cell leukemia/lymphoma (ATLL). To support the approved daily dose of 200 mg and inform dose adjustments in patients with ATLL, Bayesian exposure–response analyses were conducted using data from two clinical trials. The analyses included two efficacy endpoints, overall response by central and investigator assessments in patients with ATLL (n = 38, 150–200 mg), and six safety endpoints in patients with non‐Hodgkin lymphoma (n = 102, 150–300 mg), which included grade ≥3 laboratory values for anemia, absolute neutrophil count decreased, and platelet count decreased; any grade ≥3 treatment‐emergent adverse event (TEAE); and dose reductions and dose interruptions due to TEAEs. A slightly positive relationship was observed between unbound exposure and efficacy endpoints. A steeper relationship was observed in safety endpoints, compared with efficacy. Candidate covariate effects, except intercepts of the baseline laboratory values, were regularized via spike and slab priors in a Bayesian framework; only the laboratory values for corresponding hematologic TEAEs were shown to be of substantial impact. The target exposure range was established by defining a modified region of practical equivalence (184–887 ng·h/mL), which was expected to provide satisfactory efficacy and acceptable safety within the range of available exposure data. The simulated exposure range considering inter‐individual variability showed that 200 mg could reach target exposure in the overall population and across subpopulations of interest, supporting the use of valemetostat 200 mg in patients with ATLL. [ABSTRACT FROM AUTHOR]

Background and Objective: Klotho is a protein that is closely related to human aging. Soluble Klotho (S-Klotho) is a circulating protein, and its level decreases in response to systemic inflammation. The relationship between the platelet/high-density lipoprotein cholesterol ratio (PHR), an emerging inflammatory index, and S-Klotho concentrations is still unclear. In addition, the mean platelet volume has been confirmed to have a significant negative association with S-Klotho concentrations, but the relationship between the platelet count (PC) and S-Klotho concentrations has not yet been reported. Methods: Data from individuals who participated in the National Health and Nutrition Examination Survey (NHANES) during the five cycles from 2007 to 2016 were retrieved for analysis. Linear regression, two-piecewise linear regression, and restricted cubic spline (RCS) methods were used to analyze the associations of the PHR index and its components with S-Klotho concentrations. In addition, subgroup analysis and effect modification tests were conducted. Results: A total of 11,123 participants (5463 men (48.17%)), with an average age of 56.2 years, were included. After full adjustment, the S-Klotho levels of participants in the highest quartile group of PHR (β: -51.19, 95% CI: -75.41 to -26.97, P < 0.001) and the highest quartile group of PC (β: -72.34, 95% CI: -93.32 to -51.37, P < 0.0001) were significantly lower than those in their respective lowest quartile groups, and a significant downward trend was presented among the four groups (P for trend < 0.05, respectively). However, high-density lipoprotein cholesterol (HDL-C) concentrations were not significantly associated with S-Klotho concentrations. RCS revealed that the PHR and PC were nonlinearly associated with S-Klotho concentrations; two-piecewise linear regression revealed that the inflection points were 175.269 and 152, respectively, and that these associations slightly weakened after the inflection point. According to the subgroup analysis, liver disease status enhanced the association between the PC and S-Klotho concentrations. Conclusions: Both the PHR and PC were significantly negatively associated with S-Klotho concentrations, and these associations were nonlinear. There was no significant association between HDL-C and S-Klotho concentrations. Liver disease status enhances the negative association between the PC and S-Klotho concentrations, and the specific mechanism deserves further exploration. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the role of platelet count (PLT) in the prognosis of patients with acute respiratory distress syndrome (ARDS). Methods: The data were extracted from the Medical Information Mart for Intensive Care database (version 2.2). Patients diagnosed with ARDS according to criteria from Berlin Definition and had the platelet count (PLT) measured within the first day after intensive care unit admission were analyzed. Based on PLT, ARDS patients were divided into four groups: PLT ≤ 100 × 109/L, PLT 101–200 × 109/L, PLT 201–300 × 109/L, and PLT > 300 × 109/L. The primary outcome was 28-day mortality. Survival probabilities were analyzed using Kaplan–Meier. Furthermore, the association between PLT and mortality in ARDS patients was assessed using a univariate and multivariable Cox proportional hazards model. Results: Overall, the final analysis included 3,207 eligible participants with ARDS. According to the Kaplan–Meier curves for 28-day mortality of PLT, PLT ≤ 100 × 109/L was associated with a higher incidence of mortality (P = 0.001), the same trends were observed in the 60-day (P = 0.001) and 90‐day mortality (P = 0.001). In the multivariate model adjusted for the potential factors, the adjusted hazard ratio at PLT 101–200 × 109/L group, PLT 201–300 × 109/L, and PLT > 300 × 109/L was 0.681 [95% confidence interval (CI): 0.576–0.805, P < 0.001], 0.733 (95% CI: 0.604–0.889, P = 0.002), and 0.787 (95% CI: 0.624–0.994, P = 0.044) compared to the reference group (PLT ≤ 100 × 109/L), respectively. Similar relationships between the PLT ≤ 100 × 109/L group and 28-day mortality were obtained in most subgroups. Conclusion: PLT appeared to be an independent predictor of mortality in critically ill patients with ARDS. [ABSTRACT FROM AUTHOR]

Heparin-induced thrombocytopenia (HIT) is a life- and limb-threatening immune-mediated emergency classically associated with heparin therapy. This review focuses on type II HIT, characterized by the development of antibodies against platelet-factor 4 (PF4) bound to heparin after exposure, causing life-threatening thrombocytopenia, arterial thrombosis, and/or venous thrombosis. The high morbidity and mortality rates emphasize the need for early recognition and urgent intervention with discontinuation of heparin and initiation of non-heparin anticoagulation. We discuss the management of HIT with an emphasis on recent developments: (i) incorporating the phases of HIT (i.e., suspected, acute, subacute A and B, and remote) into its management, categorized according to platelet count, immunoassay, and functional assay results and (ii) direct-acting oral anticoagulants (DOACs), which are increasingly used in appropriate cases of acute HIT (off-label). In comparison to parenteral options (e.g., bivalirudin and danaparoid), they are easier to administer, are more cost-effective, and obviate the need for transition to an oral anticoagulant after platelet recovery. We also identify the knowledge gaps and suggest areas for future research. [ABSTRACT FROM AUTHOR]

Background We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. Methods Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted 12 March 2020–30 December 2021 to the pediatric intensive care unit (PICU) or high-acuity unit for acute COVID-19 were included. Results Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs 4.6%, P =.005) and hospitalization was longer (P =.01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, P =.40). In patients with ICCs, bacterial coinfection was more common in those with life-threatening COVID-19. Conclusions In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities. [ABSTRACT FROM AUTHOR]

Background: In critically ill cases, CRRT is a renal replacement intervention. The most common reason why CRRT terminates prematurely (non-electively) is clotting in the extracorporeal circuit, more especially in the filter. Aim of work: To determine the frequency of thrombotic and hemorrhage complications throughout CRRT, the role of antithrombin III level monitoring, the type of anticoagulation, and the dose and laboratory tests utilized to monitor it. Method: The study was carried out on 58 children who were undergoing CRRT. The children underwent a comprehensive history-taking, assessment, CRRT prescription parameters and alterations, vascular access data, anticoagulation type, dose, and adjustment, as well as monitoring of antithrombin III levels. Furthermore, any extracorporeal circuit clotting or bleeding was documented. Results: Of the 58 sessions that were examined, 25 (43.1%) resulted in filter clotting. The indication was cured in 16 cases (27.6%), 8 cases (13.8%) resulted in the patient's mortality, and 9 cases (15.5%) had life-threatening bleeding. The remaining 33 cases (56.9%) were not terminated with filter clotting. Forty-one (70.7%) of studied sessions used unfractionated heparin as anticoagulation, 22.4% used heparin-protamine, 5.2% was not anticoagulated, and one circuit (1.7%) was anticoagulated using regional citrate. Filter clotting incidence was significantly related to activated partial thromboplastin time (a PTT) value at the end of sessions (P value = 0.000), and platelets count after 4 h of session initiation (P value = 0.048). Antithrombin III levels pre-heparin infusion less than 80 were found in patients who received higher doses of a heparin bolus dose, median dose 35 (IQR 20–35), this relation is statistically significant (P value = 0.042). Conclusion: In the 58 cases that were examined, the incidence of bleeding was 32.8%; however, 19% of the cases were not severe. The incidence of filter clotting was 43.1% in the study group. a PTT value at the end of sessions, and platelets count after 4 h could be predictors of thrombotic complications during CRRT, antithrombin III deficiency before sessions is a predictor of filter clotting. [ABSTRACT FROM AUTHOR]

Introduction Materials and Methods Results Conclusion Elderly acute myeloid leukemia (AML) patients with poor‐risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor‐risk cytogenetics 60–75 years old patients.We included 60–75‐year‐old AML patients eligible to allogenic stem cell transplantation (allo‐SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019.Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0–103) and 26 days (range, 0–63). The median duration of the first hospitalization was 32 days (ranges, 7–79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo‐SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo‐SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro‐intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06).VEN‐based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60–75 with adverse cytogenetics. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) and depression have a bidirectional association, with inflammation and metabolic factors being common important triggers for both conditions. However, as a novel inflammatory and metabolic marker, platelet-to-HDL-C ratio (PHR) has not been established in relation to depression and cardiovascular disease. Materials and methods: Participants aged 20 years and older were included in the 2005-2018 NHANES database. PHR was calculated as the ratio of platelet count (1000 cells/mL) to HDL-C (mmol/L). The Patient Health Questionnaire (PHQ-9) was used to diagnose depression, with a cutoff value of 10. Weighted logistic regression analysis and restricted cubic spline (RCS) analysis were employed to examine the association between PHR and depression-related features. Additionally, weighted COX regression and RCS were used to analyze the association of PHR with CVD mortality in patients with depression. Receiver operating characteristic curves were used to assess whether PHR had an advantage over HDL-C in predicting depression. Finally, the mediating role of PHR in the latest cardiovascular health indicator Life's Essential 8 and depression was explored. Results: A total of 26,970 eligible participants were included, including 2,308 individuals with depression, representing approximately 160 million U.S. adults when weighted. After full adjustment, we estimated that the odds ratio (OR) of depression associated with a per standard deviation (SD) increase in PHR was 1.06 (95% CI: 1.01-1.12, P=0.03). The restricted cubic spline (RCS) analysis indicated a linear association (Nonlinear P=0.113). When PHR was divided into four groups based on quartiles and included in the model after full adjustment for depression risk factors, participants in quartile 2, quartile 3, and quartile 4 of PHR showed a trend of increasing risk of depression compared to the lowest quartile group (P trend=0.01). In addition, weighted COX regression and RCS revealed that a per SD increase in PHR was associated with a higher risk of CVD mortality among patients with depression (HR: 1.38, 95% CI: 1.05-1.81, P=0.02, Nonlinear P=0.400). Subgroup analyses showed that current alcohol consumption enhanced the association between PHR and depression (P for interaction=0.017). Furthermore, the areas under the ROC curves (AUC) were 0.556 (95% CI, 0.544-0.568; P < 0.001) for PHR and 0.536 (95% CI, 0.524-0.549; P < 0.001) for HDL-C (PDeLong = 0.025). Finally, mediation analysis indicated that PHR was an intermediate mechanism between LE8 and depression (mediation proportion=5.02%, P=0.02). Conclusion: In U.S. adults, an increase in PHR linearly increases the risk of depression and CVD mortality among individuals with depression. Additionally, PHR has a better predictive advantage for depression compared to HDL-C. Furthermore, PHR significantly mediates the association between LE8 scores and depression. [ABSTRACT FROM AUTHOR]

Background: Proper control of the lineage bias of megakaryocytic and erythroid progenitor cells (MEPs) is of significant importance, the disorder of which will lead to abnormalities in the number and function of platelets and erythrocytes. Unfortunately, the signaling pathways regulating MEP differentiation largely remain to be elucidated. This study aimed to analyze the role and the underlying molecular mechanism of miR-1915-3p in megakaryocytic and erythroid differentiation. Methods: We utilized miRNA mimics and miRNA sponge to alter the expression of miR-1915-3p in megakaryocytic and/or erythroid potential cells; siRNA and overexpression plasmid to change the expression of SOCS4, a potential target of miR-1915-3p. The expression of relevant surface markers was detected by flow cytometry. We scanned for miR-1915-3p target genes by mRNA expression profiling and bioinformatic analysis, and confirmed the targeting by dual-luciferase reporter assay, western blot and gain- and lost-of-function studies. One-way ANOVA and t-test were used to analyze the statistical significance. Results: In this study, overexpression or knockdown of miR-1915-3p inhibited or promoted erythroid differentiation, respectively. Accordingly, we scanned for miR-1915-3p target genes and confirmed that SOCS4 is one of the direct targets of miR-1915-3p. An attentive examination of the endogenous expression of SOCS4 during megakaryocytic and erythroid differentiation suggested the involvement of SOCS4 in erythroid/megakaryocytic lineage determination. SOCS4 knockdown lessened erythroid surface markers expression, as well as improved megakaryocytic differentiation, similar to the effects of miR-1915-3p overexpression. While SOCS4 overexpression resulted in reversed effects. SOCS4 overexpression in miR-1915-3p upregulated cells rescued the effect of miR-1915-3p. Conclusions: miR-1915-3p acts as a negative regulator of erythropoiesis, and positively in thrombopoiesis. SOCS4 is one of the key mediators of miR-1915-3p during the differentiation of MEPs. [ABSTRACT FROM AUTHOR]

Background: Inflammation is an important causative factor of obesity. This study aimed to explore the possible association between the systemic immune-inflammatory index, a novel indicator of inflammation, and obesity. Methods: Data were collected from 4395 participants of the National Health and Nutrition Examination Survey 2017–2018 aged ≥ 20 years. The systemic immune-inflammatory index was calculated by multiplying the platelet count by the neutrophil-to-lymphocyte ratio. Obesity was defined as a body mass index ≥ 30 kg/m2. Results: A significant positive correlation was observed between the systemic immune-inflammatory index and body mass index following multivariate linear regression analysis (β = 1.75; 95% confidence interval = 1.16–2.33), which was greatest in adults aged < 60 years without hypertension and diabetes. Smoothed curve fitting and threshold effect analysis were used to characterize the nonlinear association between the systemic immune-inflammatory index and body mass index, and the inflection point was found to be 729.3. Conclusions: The systemic immune-inflammatory index is positively associated with body mass index among adults in the United States and has the potential to enhance efforts to prevent adult obesity. [ABSTRACT FROM AUTHOR]

Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel. [ABSTRACT FROM AUTHOR]