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Fms-like tyrosine kinase 3 (FLT3) is the most frequently mutated gene in acute myeloid leukemia (AML). Modern targeting of FLT3 with inhibitors has improved clinical outcomes and FLT3 inhibitors have been incorporated into the treatment of AML in all phases of the disease, including the upfront, relapsed/refractory and maintenance settings. This review will discuss the current understanding of FLT3 biology, the clinical use of FLT3 inhibitors, resistance mechanisms and emerging combination treatment strategies.

Although the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML aged ≥60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-, 11% intermediate-, and 78% had adverse-risk AML. ELN risk was prognostic for overall survival (OS) (P < .001) but did not stratify favorable- from intermediate-risk (P = .71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (n = 316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P < .05). A mutation score was calculated for each combination of these mutations, assigning adverse-risk patients to 2 risk groups: -1 to 0 points (Beat-AML intermediate) vs 1+ points (Beat-AML adverse). In the final refined risk classification, ELN favorable- and intermediate-risk were combined into a newly defined Beat-AML favorable-risk group, in addition to mutation scoring within the ELN adverse-risk group. This approach redefines risk for older patients with ND AML and proposes refined Beat-AML risk groups with improved discrimination for OS (2-year OS, 48% vs 33% vs 11%, respectively; P < .001), providing patients and providers additional information for treatment decision-making.

Despite recent work linking mixed phenotype acute leukemia (MPAL) to certain genetic lesions, specific driver mutations remain undefined for a significant proportion of patients and no genetic subtype is predictive of clinical outcomes. Moreover, therapeutic strategy for MPAL remains unclear, and prognosis is overall poor. We performed multiomic single cell profiling of 14 newly diagnosed adult MPAL patients to characterize the inter- and intra-tumoral transcriptional, immunophenotypic, and genetic landscapes of MPAL. We show that neither genetic profile nor transcriptome reliably correlate with specific MPAL immunophenotypes. Despite this, we find that MPAL blasts express a shared stem cell-like transcriptional profile indicative of high differentiation potential. Patients with the highest differentiation potential demonstrate inferior survival in our dataset. A gene set score, MPAL95, derived from genes highly enriched in the most stem-like MPAL cells, is applicable to bulk RNA sequencing data and is predictive of survival in an independent patient cohort, suggesting a potential strategy for clinical risk stratification.

FLT3 tyrosine kinase inhibitors (TKIs) have clinical efficacy for patients with FLT3-mutated AML (acute myeloid leukemia), but their impact is limited by resistance in the setting of monotherapy and by tolerability problems when used in combination therapies. FF-10101 is a novel compound that covalently binds to a cysteine residue near the active site of FLT3, irreversibly inhibiting receptor signaling. It is effective against most FLT3 activating mutations, and, unlike other inhibitors, is minimally vulnerable to resistance induced by FLT3 ligand. We conducted a phase 1 dose escalation study of oral FF-10101 in patients with relapsed and/or refractory AML, the majority of whom harbored FLT3-activating mutations and/or had prior exposure to FLT3 inhibitors. Fifty-four participants enrolled in cohorts receiving doses ranging from 10 to 225 mg per day and 50 to 100 mg twice daily (BID). The dose limiting toxicities were diarrhea and QT prolongation. Among 40 response-evaluable participants, the composite complete response rate was 10%, and the overall response rate (including partial responses) was 12.5%, including patients who had progressed on gilteritinib. Overall, 56% of participants had prior exposure to FLT3 inhibitors. The recommended phase 2 dose was 75 mg BID. FF-10101 potentially represents a next-generation advance in the management of FLT3-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03194685.

Monosomy 7 and del(7q) are among the most common and poorly understood genetic alterations in myelodysplastic neoplasms and acute myeloid leukemia. Chromosome band 7q22 is a minimally deleted segment in myeloid malignancies with a del(7q). However, the rarity of second hit mutations supports the idea that del(7q22) represents a contiguous gene syndrome. We generated mice harboring a 1.5 Mb germline deletion of chromosome band 5G2 syntenic to human 7q22 that removes Cux1 and 27 additional genes. Hematopoiesis is perturbed in 5G2+/del mice but they do not spontaneously develop hematologic disease. Whereas alkylator exposure modestly accelerated tumor development, the 5G2 deletion did not cooperate with KrasG12D, NrasG12D, or the MOL4070LTR retrovirus in leukemogenesis. 5G2+/del mice are a novel platform for interrogating the role of hemopoietic stem cell attrition/stress, cooperating mutations, genotoxins, and inflammation in myeloid malignancies characterized by monosomy 7/del(7q).

The precise identities of bone marrow resident cells contributing to AML relapse are not fully known. Hollands et al. report early evidence to support the existence of an aberrant monocytic cell population that appears to promote LSC expansion after cytarabine treatment.

OBJECTIVE: Acute promyelocytic leukemia (APL) is associated with an elevated risk of developing disseminated intravascular coagulation (DIC). The purpose of this study was to assess the outcomes of hospitalizations related to DIC in APL and their impact on healthcare. MATERIALS AND METHODS: This study entailed a cross-sectional and retrospective analysis of the US National Inpatient Sample database. We identified adults with APL and categorized them into groups of patients with and without DIC. Our focus areas included in-hospital mortality, length of stay, charges, and complications associated with DIC. Unadjusted odds ratios/coefficients were computed in univariate analysis, followed by adjusted odds ratios (aOR)/coefficients from multivariate analysis that accounted for confounding factors. RESULTS: Our analysis revealed that APL patients with DIC had a substantially higher aOR for mortality (aOR: 6.68, 95% confidence interval [CI]: 4.76-9.37, p

BACKGROUND: Adult patients with cholecystitis who do not undergo cholecystectomy on index admission have worse outcomes, however, there is a paucity of data of the role of cholecystectomy during index hospitalization in the pediatric population. Our aim was to determine outcomes and readmission rates among pediatric patients with cholecystitis who underwent index cholecystectomy versus those who did not. METHODS: We performed a retrospective study of pediatric (

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3 or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

BackgroundTobacco smoke adversely affects the prognosis of adult cancers including myeloid leukemia, but less is known in children.MethodsWe evaluated whether pre- and postnatal exposures to tobacco smoke decrease 5-year survival of 1,235 childhood acute lymphoblastic leukemia (ALL) and 188 childhood acute myeloid leukemia (AML) cases derived from a population-based case-control study in California. Cases were diagnosed between 1995 and 2015 (median follow-up time of 13.2 years overall). We obtained data on tobacco smoking (before conception, during pregnancy, after birth), parental education and income, clinical features, and vital status through 2020. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality associated with smoking, adjusting for sociodemographic characteristics and risk group (ALL only).ResultsAbout 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared with nonsmoking fathers [HR = 1.41; 95% confidence interval (CI), 0.95-3.44 and 3.47; 95% CI, 1.37-8.81, respectively for

Acute generalized exanthematous pustulosis is a severe adverse skin reaction, usually caused by drugs, but in rare cases it can be associated with infections. Several cases related to COVID-19 have been reported, however, almost all were drug-related. Here we report a case of acute generalized exanthematous pustulosis associated with COVID-19 in a previously healthy 64-year-old woman, with no culprit drugs.

DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

Acute myeloid leukemia (AML) is prevalent in both adult and pediatric patients. Despite advances in patient categorization, the heterogeneity of AML remains a challenge. Recent studies have explored the use of gene expression data to enhance AML diagnosis and prognosis, however, alternative approaches rooted in physics and chemistry may provide another level of insight into AML transformation. Utilizing publicly available databases, we analyze 884 human and mouse blood and bone marrow samples. We employ a personalized medicine strategy, combining state-transition theory and surprisal analysis, to assess the RNA transcriptome of individual patients. The transcriptome is transformed into physical parameters that represent each sample's steady state and the free energy change (FEC) from that steady state, which is the state with the lowest free energy.We found the transcriptome steady state was invariant across normal and AML samples. FEC, representing active molecular processes, varied significantly between samples and was used to create patient-specific barcodes to characterize the biology of the disease. We discovered that AML samples that were in a transition state had the highest FEC. This disease state may be characterized as the most unstable and hence the most therapeutically targetable since a change in free energy is a thermodynamic requirement for disease progression. We also found that distinct sets of ongoing processes may be at the root of otherwise similar clinical phenotypes, implying that our integrated analysis of transcriptome profiles may facilitate a personalized medicine approach to cure AML and restore a steady state in each patient.

T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.

Background Aims Methods Results Discussion Conclusion Despite the bidirectional relationship between alcohol use and STB, the two issues are often treated separately in adolescent inpatient psychiatric hospitals, highlighting the need for brief interventions that address both alcohol use and STB in an integrated fashion.This study tested the feasibility, acceptability, and preliminary effectiveness of a brief integrated Alcohol and Suicide Intervention for Suicidal Teens (iASIST) with a post‐discharge mHealth booster for adolescents in inpatient psychiatric treatment.We conducted an RCT of iASIST relative to an attention‐matched comparison condition with adolescents hospitalized following STB (N = 40).iASIST demonstrated feasibility and acceptability and mixed models indicated that both groups had significant decreases in substance use over the 3‐month follow‐up, but post‐intervention group differences were not significant. In terms of cannabis use, however, iASIST participants significantly improved over time. Intervention group participants showed a significant decrease in suicide plans from baseline to follow‐up, which was not the case for control group participants.Study findings suggest a larger RCT is warranted to test the effectiveness of the iASIST intervention.iASIST shows promise in its ability to target the public health problems of alcohol use and STB in an integrated fashion with a high‐risk adolescent population receiving acute psychiatric care. [ABSTRACT FROM AUTHOR]

Objectives We sought to characterize the immunophenotype of acute myeloid leukemia (AML) with CBFB rearrangement and correlate the results with cytogenetic and molecular data. Methods Sixty-one cases of AML with CBFB rearrangement were evaluated. Results The sample population consisted of 33 men and 28 women, with a median age of 49 years. Flow cytometry immunophenotypic analysis showed that myeloblasts were positive for CD34 and CD117 in all cases, and myeloperoxidase was positive in 52 of 55 (95%) cases. The most common abnormalities included decreased CD38 in 90%, increased CD13 in 85%, increased CD123 in 84%, and decreased HLA-DR in 84% of cases. Monocytes were increased, with a mature immunophenotype, and accounted for 23.7% of total cells. Among 60 cases with available karyotype, inv(16)(p13.1q22) was most common in 50 (83%) cases, followed by t(16;16) (p13.1;q22) in 6 (10%). Type A CBFB::MYH11 transcript was most common, detected in 84% of cases. Mutational analysis showed mutations of NRAS in 37%, FLT3 in 25%, and KIT in 24% of cases. Comparing cases with type A vs non–type A transcripts, blasts in type A cases more frequently exhibited CD64 positivity and increased CD13 levels while showing a lower frequency of CD7 and CD56 expression. Trisomy 22 and mutations in KIT, NF1, and TET2 were identified only in cases with type A transcript. Conclusions Myeloblasts of AML with CBFB rearrangement are positive for CD34, CD117, and myeloperoxidase. These neoplasms most frequently carry inv(16)(p13.1q22) and type A fusion transcript. NRAS mutation was the most common mutation. Some immunophenotypic and genetic correlations occurred with different types of transcripts. [ABSTRACT FROM AUTHOR]

Objective We report a rare case of acute hemolytic reactions caused by immunoglobulin (Ig)M anti-M antibody and present a literature review. Case Report A 61-year-old male patient who underwent blood transfusion developed fever, chills, soy sauce–colored urine, and changes in laboratory test results, including persistently decreased hemoglobin levels, neutrophilia, elevated lactate dehydrogenase level, acute kidney injury, mild acute liver injury, and activation of the coagulation system, indicating acute hemolytic transfusion reaction (AHTR). Antibody screening and major crossmatching results indicated weak positive at 37°C for both posttransfusion and pretransfusion sample. Subsequent serological examinations indicated the presence of IgM anti-M antibodies in plasma but the direct antiglobulin and elution tests were negative. Antibody hemolytic activity assay confirmed AHTR caused by anti-M. The transfused red blood cells were MM and the patient is NN. These signs and symptoms disappeared rapidly and required no additional interventions before discharge. Conclusion The accurate diagnosis of anti-M antibody–mediated acute hemolysis is essential for guiding treatment decisions. [ABSTRACT FROM AUTHOR]

The Russian-Ukrainian war (RUW) is responsible for extensive individual suffering and a socio-economic impact on the world and is reshaping global affairs. Many studies have focused on direct exposure to conflict and several public health policies have been devised. Nonetheless, indirect exposure through media has received minimal attention and there is limited evidence that mental health symptoms and disorders may arise as a result. We explored the role of voluntary or involuntary media-based exposure to the RUW on individuals' mental health including stress symptoms, coping strategies, daily functioning, and worries across demographic variables. In our sample, subjects with involuntary and higher amount of exposure seem to have higher stress symptoms. Also, those who had previous ruminations on war issues could be at risk of developing more post-traumatic stress symptoms. Therefore, media appears to be a conduit that spreads negative consequences of community trauma beyond directly affected communities. [ABSTRACT FROM AUTHOR]

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AbstractIntroductionMethodsResultsDiscussionConclusionIn 2015, Australia and New Zealand treatment guidelines recommended a 2 h paracetamol serum concentration for risk assessment of unintentional paracetamol liquid exposures. We assess our experience with this approach.Retrospective case review of children <6 years-old with liquid paracetamol overdoses referred to a regional poisons information centre January 2017 to August 2022. We extracted data on the exposure and management from the poisons information centre and hospital medical records. We identified additional cases with two paracetamol concentrations obtained from September 2022 to June 2024.Of 437 paediatric poisonings, 271 were eligible for inclusion. The median age was 24 months, the median time to presentation was 120 min, and paracetamol was the sole ingestant in 92% of cases. Blood testing was recommended in 131 patients (48.3%), occurring at 2 h post-ingestion in 62 patients (47.3%). Testing at a later time was mostly due to delayed presentation, including to hospitals unable to measure paracetamol concentrations. Eighteen patients (16.7%) had repeat blood testing, and five additional cases were identified in the subsequent period. Overall, the concentration decreased in 19 patients (83%), but in three patients it increased, from 73 mg/L to 81 mg/L (0.49–0.54 mmol/L), from 154 mg/L to 179 mg/L (1.03–1.19 mmol/L), and from 56 mg/L to 115 mg/L (0.37–0.77 mmol/L. Symptomatic patients were more likely to receive a second blood test or acetylcysteine while awaiting investigations. Of 19 patients administered acetylcysteine, it was discontinued in five due to low paracetamol serum concentrations. All patients recovered.Guidelines were followed in >90% of patients and this testing regimen shortened length of stay. Based on these data, Australian treatment guidelines now recommend repeat testing for 2 h paracetamol serum concentrations >100 mg/L (0.67 mmol/L).A paracetamol serum concentration between 2 h and 4 h post-ingestion in children <6 years-old with unintentional poisonings of paracetamol liquid can facilitate medical discharge. [ABSTRACT FROM AUTHOR]

Abstract\nHIGHLIGHTSMesoporous bioactive glass, with its versatile characteristics and morphology, holds significant potential as an ideal hemostatic material. However, limited data is available regarding its toxicity levels. Consequently, this research intends to assess the acute and repeated dose dermal toxicity of Mesoporous antibacterial bioactive glass microsphere impregnated nonwoven surgical cotton gauze (MABGmscg) dressing in albino Wistar rats, following the standards set by the Organization for Economic Cooperation and Development. In the acute dermal toxicity study, the impact of MABG (@2000mg/kg BW) mscg dressing was assessed following a single dermal application in both male and female Wistar rats (n = 10). Mortality, clinical signs, body weight fluctuations and gross observations were consistently monitored over a14 day period following the single dose. The results indicated that, MABG (@2000mg/kg BW) mscg dressing upon dermal exposure did not cause any adverse effect in acute dermal toxicity study in Wistar rats compared to control group. Given that 2000 mg/kg BW of MABG was deemed a nontoxic dose, a repeated dose dermal toxicity study of MABGmscg dressing was subsequently conducted at three dose levels (@200, 500, 1000 mg/kg BW) over 28 consecutive days in Wistar rats. During the study period, no unscheduled deaths occurred, and there were no clinical signs associated with treatment, body weight variations or abnormal gross findings at necropsy in any groups. The analysis concluded that, MABGmscg dressing is safe to be considered as a hemostatic dressing at the various tested dose levels in Wistar rats.A dressing composed of mesoporous antibacterial bioactive glass impregnated into nonwoven surgical cotton gauze (MABGmscg) has been developed to serve as an effective hemostatic material.The acute and repeated dose dermal toxicity study of MABGmscg dressing has been performed in Wistar ratsNo visible changes or systemic effects were observed after applying the MABGmscg dressing at different doses for 28 consecutive days in Wistar rats.Therefore, the MABGmscg dressing is considered safe for use as a hemostatic gauze.A dressing composed of mesoporous antibacterial bioactive glass impregnated into nonwoven surgical cotton gauze (MABGmscg) has been developed to serve as an effective hemostatic material.The acute and repeated dose dermal toxicity study of MABGmscg dressing has been performed in Wistar ratsNo visible changes or systemic effects were observed after applying the MABGmscg dressing at different doses for 28 consecutive days in Wistar rats.Therefore, the MABGmscg dressing is considered safe for use as a hemostatic gauze. [ABSTRACT FROM AUTHOR]

Objective: Quantifying and managing the matches and training loads of players is important for injury prevention. As rugby union is a full-contact sport and frequent contact injuries occur, it might also be important to quantify and manage players' contact loads. This study aimed to clarify the relationship between contact load and injury incidence in elite rugby union players. Methods: Forty-eight elite rugby union players (27.0 ± 3.5 years) in Japan were monitored during one season (8 months). The contact load, an index of training load, was evaluated as collision count and collision load measured using a global positioning system device, and then calculated using the acute: chronic workload ratio (ACWR) based on the exponentially weighted moving average (EWMA). The association between the EWMA-ACWR of contact load and injury incidence was analyzed using generalized estimating equations. Results: Of the 58 injuries during one season, 70.7% were contact injuries. Collision counts and collision load calculated by EWMA-ACWR were associated with the risk of injury (p < 0.01 both), with the odds ratios were 4.20 [95% confidence interval (CI): 1.74-10.11] and 4.44 (95% CI: 1.95-10.13), respectively. Conclusion: Contact load calculated using EWMA-ACWR was associated with injury in elite rugby union players. [ABSTRACT FROM AUTHOR]

Background Data on the presentation, management, and outcomes of Lassa fever (LF) in children are limited. Methods Description of the clinical and biological features, treatment, and outcomes of reverse transcriptase and polymerase chain reaction (RT-PCR)-confirmed LF in children aged under 15, enrolled in the LASsa fever clinical COurse and Prognostic factors in an Epidemic context (LASCOPE) prospective cohort study in Nigeria between April 2018 and February 2023. Results One hundred twenty-four children (aged under 12 months: 19; over 12 months: 105) were hospitalized with RT-PCR-confirmed LF. All received intravenous ribavirin. During follow-up, 99/124 (80%) had fever; 71/124 (57%) had digestive symptoms, vomiting (n  = 56/122, 46%) and abdominal pain (n  = 34/78 aged ≥5 years, 44%) more often than diarrhea (n  = 19/124, 15%); 17/124 (14%) had hemorrhagic signs; 44/112 (39%) had a hematocrit lower than 25%, of whom 32/44 (73%) received transfusions; 44/88 (50%) developed hypotension; 18/112 (16.1%) developed kidney disease improving global outcome (KDIGO) ≥2 acute kidney injury; 10/112 (8.9%) had KDIGO 3 acute kidney failure; 4/124 (3.2%) underwent renal replacement therapy. Seven children died, including 4 aged under 12 months (case fatality rate: under 12 months—22%, 95% confidence interval (CI): 7%–48%; over 12 months—2.9%, 95% CI: 0.7%–8.7%). In univariable analysis, age (P  = .003), impaired consciousness (P  = .026), and Lassa RT-PCR Ct value (P  = .006) were associated with Day 30 mortality. Conclusions The fatality rate for children over 12 months hospitalized with LF was lower than that previously reported for adults. Hypotension and acute kidney injury were the most frequent organ dysfunctions. Bleeding was relatively infrequent. Anemia and the need for transfusion were common, the relative contribution of ribavirin-induced hemolysis being unknown. [ABSTRACT FROM AUTHOR]

A modified Vesikari severity score (MVSS) is a useful research tool for assessing severity of acute gastroenteritis. We present a MVSS for studies in which a follow-up assessment of symptoms cannot be obtained. The MVSS significantly correlated with other markers of severity, including illness duration and work and school absenteeism. [ABSTRACT FROM AUTHOR]

Objectives Area under the concentration–time curve (AUC)–guided dosing of vancomycin was introduced in a clinical setting; however, the target range of non–steady-state AUCs, such as Day 1 AUC and Day 2 AUC, remains controversial. Therefore, we sought to determine pharmacokinetic parameter thresholds and identify independent risk factors associated with acute kidney injury (AKI) to establish a safe initial dosing design for vancomycin administration. Methods A single-centre, retrospective, cohort study of hospitalized patients treated with vancomycin was conducted to determine the threshold of both non–steady-state AUCs (Day 1 and 2 AUCs) and trough levels at the first blood sampling point (therapeutic drug monitoring, TDM). In addition, independent risk factors associated with AKI were evaluated using univariate and multivariate logistic regression analyses. Results The thresholds for predicting AKI were estimated as 456.6 mg·h/L for AUC0-24h, 554.8 mg·h/L for AUC24-48h, 1080.8 mg·h/L for AUC0-48h and 14.0 μg/mL for measured trough levels, respectively. In a multivariate analysis, Day 2 AUC ≥ 554.8 mg·h/L [adjusted odds ratio (OR), 57.16; 95% confidence interval (CI), 11.95–504.05], piperacillin/tazobactam (adjusted OR, 15.84; 95% CI, 2.73–127.70) and diuretics (adjusted OR, 4.72; 95% CI, 1.13–21.01) were identified as risk factors for AKI. Conclusions We identified thresholds for both AUCs in the non–steady-state and trough levels at the first TDM. Our results highlight the importance of monitoring not only the AUC but also trough levels during vancomycin treatment to reduce the likelihood of AKI. [ABSTRACT FROM AUTHOR]

Objective: Over the past few years, histopathological studies have demonstrated that the ligamentum mucosum (LM) contains neural and vascular structures. These findings suggest that LM can be used for proprioception and revascularization in the repair of anterior cruciate ligament (ACL). The aim of this study was to evaluate the LM structure in knees with ACL injuries. Methods: The data of patients who underwent knee arthroscopy at our clinic between 2017 and 2022 were retrospectively analyzed. Three groups were included in the study; acute ACL tears (n=89), chronic ACL tears (n=111) and intact ACLs (n=101). The arthroscopic video records of all patients were evaluated retrospectively. LM was defined in three different forms: (1) Intact, (2) ruptured, and (3) non-presence. Results: The non-presence of the LM was significantly more common in chronic ACL tears compared to the other groups (p=0.021), while the presence of the LM (either intact or ruptured) was similar between acute ACL tears and intact ACLs. In acute tears, the number of intact LM was significantly lower than that of intact ACLs (p<0.001). However, it was significantly greater than that of chronic tears (p=0.001). Conclusion: According to the present study, the likelihood of intact LM in chronic ACL tears is quite low. In this regard, we suggest that performing surgery in the acute phase of ACL injury will increase the chances of using the LM as a neurovascular source. In addition, because of the possible effect of the LM on proprioception, we recommend preserving the structure during knee arthroscopy procedures if a healthy LM is present. [ABSTRACT FROM AUTHOR]

Background: State-of-the-art stroke treatment significantly reduces lesion size and stroke severity, but it remains unclear whether these therapeutic advances have diminished the burden of post-stroke cognitive impairment (PSCI). Aims: In a cohort of patients receiving modern state-of-the-art stroke care including endovascular therapy, we assessed the frequency of PSCI and the pattern of domain-specific cognitive deficits, identified risk factors for PSCI, and determined the impact of acute PSCI on stroke outcome. Methods: In this prospective monocentric cohort study, we examined patients with first-ever anterior circulation ischemic stroke without pre-stroke cognitive decline, using a comprehensive neuropsychological assessment ⩽10 days after symptom onset. Normative data were stratified by demographic variables. We defined PSCI as at least moderate (<1.5 standard deviation) deficits in ⩾2 cognitive domains. Multivariable regression analysis was applied to define risk factors for PSCI. Results: We analyzed 329 non-aphasic patients admitted from December 2020 to July 2023 (67.2 ± 14.4 years old, 41.3% female, 13.1 ± 2.7 years of education). Although most patients had mild stroke (median National Institutes of Health Stroke Scale (NIHSS) 24 h = 1.00 (0.00; 3.00); 87.5% with NIHSS ⩽ 5), 69.3% of them presented with PSCI 2.7 ± 2.0 days post-stroke. The most severely and often affected cognitive domains were verbal learning, episodic memory, executive functions, selective attention, and constructive abilities (39.1%–51.2% of patients), whereas spatial neglect was less frequent (18.5%). The risk of PSCI was reduced with more years of education (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23–0.99) and right hemisphere lesions (OR = 0.47, 95% CI = 0.26-0.84), and increased with stroke severity (NIHSS 24 h, OR = 4.19, 95% CI = 2.72-6.45), presence of hyperlipidemia (OR = 1.93, 95% CI = 1.01–3.68), but was not influenced by age. After adjusting for stroke severity and depressive symptoms, acute PSCI was associated with poor functional outcome (modified Rankin Scale > 2, F = 13.695, p < 0.001) and worse global cognition (Montreal Cognitive Assessment (MoCA) score, F = 20.069, p < 0.001) at 3 months post-stroke. Conclusion: Despite modern stroke therapy and many strokes having mild severity, PSCI in the acute stroke phase remains frequent and associated with worse outcome. The most prevalent were learning and memory deficits. Cognitive reserve operationalized as years of education independently protects post-stroke cognition. [ABSTRACT FROM AUTHOR]

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Background and Objectives: Sarcopenia is a significant concern in stroke rehabilitation, with a high prevalence reported in acute stroke patients. This study examines the effect of sarcopenia on rehabilitation outcomes in acute stroke patients. Materials and Methods: This study was conducted with acute stroke patients admitted within 90 days of onset to the rehabilitation hospital. Participants were divided into a stroke with sarcopenia group and a stroke without sarcopenia group. Evaluations were conducted at baseline, 4 weeks, and 8 weeks, including the following assessments: manual muscle testing (MMT), Berg Balance Scale (BBS), functional ambulation category (FAC), and Modified Barthel Index (MBI). Both groups received an identical rehabilitation program for 8 weeks. Results: Significant within-group improvements were observed in both groups across all measures (p < 0.05). However, the stroke with sarcopenia group showed significantly less improvement in MMT, BBS, FAC, and MBI compared to the stroke without sarcopenia group at both 4 and 8 weeks (p < 0.05). Conclusions: These results underscore the significant impact of sarcopenia on functional recovery in stroke patients, despite both groups receiving identical rehabilitation programs. The presence of sarcopenia was a critical predictor of poorer outcomes in muscle strength, balance, ambulation, and activities of daily living. Given these findings, specific rehabilitation strategies targeting sarcopenia are needed to improve recovery in stroke patients. Future research should include larger sample sizes, longer follow-ups, and sarcopenic patient-specific rehabilitation programs. [ABSTRACT FROM AUTHOR]

Introduction Military members and first responders may, at moment's notice, be asked to assist in incidents that may result in radiation exposure such as Operation Tomadachi in which the U.S. Navy provided significant relief for the Fukushima Daiichi Nuclear Reactor accident in Japan after an earthquake and tsunami in 2011. We are also currently facing potential threats from nuclear power plants in the Ukraine should a power disruption to a nuclear plant interfere with cooling or other safety measures. Exposure to high doses of radiation results in acute radiation syndrome (ARS) characterized by symptoms arising from hematopoietic, gastrointestinal, and neurovascular injuries. Although there are mitigators FDA approved to treat ARS, there are currently no FDA-approved prophylactic medical interventions to help protect persons who may need to respond to radiation emergencies. There is strong evidence that manganese (Mn) has radiation protective efficacy as a promising prophylactic countermeasure. Materials and Methods All animal procedures were approved by the Institutional Animal Care and Use Committee. Male and female B6D2F1J mice, 10 to 11 weeks old, were used for neurotoxicity studies and temporal effects of Mn. Four groups were evaluated: (1) vehicle injection, (2) dose of 4.5 mg/kg for 3 days, (3) dose of 13.5 mg/kg, and (4) sham. Irradiated mice were exposed to 9.5 Gy whole body Co60 γ-radiation. MRI was performed with a high dose of manganese chloride (MnCl2) (150 mg/kg) to assess the distribution of the MnCl2. Results The mice have promising survival curves (highest survival—13.5 mg/kg dose over 3 days of MnCl2 at 80% [87% female, 73% male] P  = 0.0004). The complete blood count (CBC) results demonstrated a typical hematopoietic response in all of the irradiated groups, followed by mildly accelerated recovery by day 28 in the treated groups. No difference between groups was measured by Rota Rod, DigiGait, and Y-maze. Histologic evaluation of the bone marrow sections in the group given 13.5 mg/kg dose over 3 days had the best return to cellularity at 80%. MRI showed a systemic distribution of MnCl2. Discussion The preliminary data suggest that a dose of 13.5 mg/kg of MnCl2 given over 3 days prior to exposure of radiation may have a protective benefit while not exhibiting the neurobehavioral problems. A countermeasure that can prophylactically protect emergency personnel entering an area contaminated with high levels of radiation is needed, especially in light that nuclear accidents are a continued global threat. There is a need for a protective agent with easy long-term storage, easy to transport, easy to administer, and low cost. Histologic evaluation supports the promising effect of MnCl2 in protecting tissue, especially the bone marrow using the dose given over 3 days (4.5 mg/kg per day) of MnCl2. Conclusions Initial experiments show that MnCl2 is a promising safe and effective prophylactic countermeasure against ARS. MRI data support the systemic distribution of MnCl2 which is needed in order to protect multiple tissues in the body. The pathology data in bone marrow and the brain support faster recovery from radiation exposure in the treated animals and decreased organ damage. [ABSTRACT FROM AUTHOR]

Introduction Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome. Currently, there is no radiation medical countermeasure approved by the U.S. FDA which can be used before radiation exposure to protect exposed individuals. Here we aimed to evaluate the therapeutic potential of an aqueous suspension of synthetic genistein nanoparticles (BIO 300) as a radioprotectant in a pilot efficacy study using a nonhuman primate model of total body irradiation. Materials and Methods Eight rhesus macaques were divided into two groups; four received vehicle and four received BIO 300 Injectable Suspension 24 h before 5.8 Gy total-body irradiation. Survival, blood cell counts, blood chemistry, and clinical parameters were monitored over the 60 days of the study. Tissues were collected at necropsy 60 days post-irradiation or from animals that met unscheduled euthanasia criteria and subjected to histopathological analysis. Tissues analyzed included the duodenum, jejunum, ileum, sternum, lung, heart, liver, kidney, spleen, gut-associated lymphoid tissue, and urinary bladder. Results In this pilot study, all BIO 300 Injectable Suspension treated animals survived to day 60, while only 50% of the vehicle-treated animals survived. We found that BIO 300 Injectable Suspension did not mediate an improvement in blood cell counts (e.g. neutrophils, platelets, white blood cells). However, BIO 300 Injectable Suspension treated animals had a lower incidence of fever and febrile neutropenia, were able to better maintain their body weight post radiation exposure, and exhibited less anemia and faster recovery from anemia. Histopathological analysis revealed that BIO 300-treated animals had less irradiation-induced damage to the sternum and other tissues compared to vehicle controls. Conclusions BIO 300's mechanism of action is complex and protection against irradiation is attainable without much improvement in the complete blood count (CBC) profile. BIO 300's mechanism for radioprotection involves multiple biological pathways and systems. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) is a potentially life-threatening complication of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). We conducted a systematic review and meta-analyses of studies on acute leukemia in children aged 0–17 years since 2000. Findings were reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We included 24 studies with 3661 ALL patients and 1728 AML patients. IA cumulative incidence varied (0%–10% for ALL and 0%–18% for AML) across the studies. Pooled cumulative IA incidences were estimated at 3.2% (95% CI: 1.8%–5.8%) in ALL and 5.2% (95% CI: 3.1%–8.6%) in AML, with corresponding case fatality rates of 13.3% (95% CI: 6.3%–25.9%), and 7.8% (95% CI: 0.7%–51.2%), respectively. Our analysis highlights the impact of IA in childhood leukemia, underscoring the need to address strategies for prevention, early detection, and treatment of IA in pediatric leukemia. [ABSTRACT FROM AUTHOR]

Background Acute otitis media (AOM) accounts for roughly 25% of antibiotics prescribed to children annually. Despite national guidelines that recommend short (5–7 days) durations of antibiotics for children 2 years and older with AOM, most receive long (10 day) courses. This study aims to evaluate antibiotic durations prescribed for children aged 2–17 years with uncomplicated AOM across two pediatric academic health systems, and to assess the variability in prescribed durations between and within each system. Methods Electronic medical record data from 135 care locations at two health systems were retrospectively analyzed. Outpatient encounters for children aged 2–17 years with a diagnosis of AOM from 2019 to 2022 were included. The primary outcome was the percent of 5-day prescriptions. Secondary outcomes included the proportion of 7-day prescriptions, 10-day prescriptions, prescriptions for nonfirst-line antibiotics, cases associated with treatment failure, AOM recurrence, and adverse drug events. Results Among 73 198 AOM encounters for children 2 years and older, 61 612 (84%) encounters resulted in an antibiotic prescription. Most prescriptions were for 10 days (45 689; 75%), 20% were for 7 days (12 060), and only 5% were for 5 days (3144). Treatment failure, AOM recurrence, adverse drug events, hospitalizations, and office, emergency department or urgent-care visits for AOM within 30 days after the index visit were rare. Conclusions Despite national guidelines that recommend shorter durations for children with uncomplicated AOM, 75% of our cohort received 10-day durations. Shortening durations of therapy for AOM could reduce antibiotic exposure and should be a priority of pediatric antibiotic stewardship programs. [ABSTRACT FROM AUTHOR]

Introduction: Cisplatin is a widely used antineoplastic in the treatment of various types of solid cancers. The objectives of our study were to evaluate the prevalence of acute renal failure (ARF) during cisplatin-based chemotherapy and to determine the factors correlated with renal toxicity. Methods: This is a prospective study that was conducted over a period of 6 months. We included patients followed for histologically confirmed solid cancer and treated with cisplatin-based chemotherapy. Assessment of renal function was made by calculating renal creatinine clearance before starting cisplatin, before every cycle, at 3 months and at 6 months. Results: Forty patients were included. The median age was 54 years (31–71 years). The mean cumulative dose received was 286 mg/m² (100–560 mg/m²). Twelve patients (30%) developed ARF which was grade 1 in 83% of cases. Cisplatin ARF was observed after a mean cumulative dose of 208 mg/m². Digestive toxicity (67%) and obstruction of the excretory tracts of tumoral origin (8%) were aggravating factors. Cisplatin cycle number >3 (p = 0.04) and dose ≥330 mg/m2 (p = 0.04) were the factors associated with cisplatin renal toxicity. Conclusion: This study concluded that ARF is dose-dependent with the predominance of grade 1 toxicity. A cumulative dose exceeding 330 mg/m2 was correlated with an increased risk of occurrence of ARF. [ABSTRACT FROM AUTHOR]

OBJECTIVES Historically, the perfusion-guided sequence suggests to first transplant the side with lowest lung perfusion. This sequence is thought to limit right ventricular afterload and prevent acute heart failure after first pneumonectomy. As a paradigm shift, we adopted the right-first implantation sequence, irrespective of lung perfusion. The right donor lung generally accommodates a larger proportion of the cardiac output. We hypothesized that the right-first sequence reduces the likelihood of oedema formation in the firstly transplanted graft during second-lung implantation. Our objective was to compare the perfusion-guided and right-first sequence for intraoperative extracorporeal membrane oxygenation (ECMO) need and primary graft dysfunction (PGD). METHODS A retrospective single-centre cohort study (2008–2021) including double-lung transplant cases (N  = 696) started without ECMO was performed. Primary end-points were intraoperative ECMO cannulation and PGD grade 3 (PGD3) at 72 h. Secondary end-points were patient and chronic lung allograft dysfunction-free survival. In cases with native left lung perfusion ≤50% propensity score adjusted comparison of the perfusion-guided and right-first sequence was performed. RESULTS When left lung perfusion was ≤50%, right-first implantation was done in 219 and left-first in 189 cases. Intraoperative escalation to ECMO support was observed in 10.96% of right-first versus 19.05% of left-first cases (odds ratio 0.448; 95% confidence interval 0.229–0.0.878; P  = 0.0193). PGD3 at 72 h was observed in 8.02% of right-first versus 15.64% of left-first cases (0.566; 0.263–1.217; P  = 0.1452). Right-first implantation did not affect patient or chronic lung allograft dysfunction-free survival. CONCLUSIONS The right-first implantation sequence in off-pump double-lung transplantation reduces need for intraoperative ECMO cannulation with a trend towards less PGD grade 3. [ABSTRACT FROM AUTHOR]

Background and Aim: The Model for End‐Stage Liver Disease (MELD) is a reliable prognostic tool for short‐term outcome prediction in patients with end‐stage liver disease. MELD 3.0 was introduced to enhance the predictive accuracy. This study assessed the performance of MELD 3.0, in comparison to MELD and MELD‐Na, in patients with alcoholic liver cirrhosis. Methods: This multicenter prospective cohort study comprised patients with alcoholic cirrhosis admitted for acute deterioration of liver function in the Republic of Korea between 2015 and 2019. This study compared the predictive abilities of MELD, MELD‐Na, and MELD 3.0, for 30‐day and 90‐day outcomes, specifically death or liver transplantation, and explored the factors influencing these outcomes. Results: A total of 1096 patients were included in the study, with a mean age of 53.3 ± 10.4 years, and 82.0% were male. The mean scores for MELD, MELD‐Na, and MELD 3.0 at the time of admission were 18.7 ± 7.2, 20.6 ± 7.7, and 21.0 ± 7.8, respectively. At 30 and 90 days, 7.2% and 14.1% of patients experienced mortality or liver transplantation. The areas under the receiver operating characteristic curves for MELD, MELD‐Na, and MELD 3.0 at 30 days were 0.823, 0.820, and 0.828; and at 90 days were 0.765, 0.772, and 0.776, respectively. Factors associated with the 90‐day outcome included concomitant chronic viral hepatitis, prolonged prothrombin time, elevated levels of aspartate transaminase, bilirubin, and creatinine, and low albumin levels. Conclusion: MELD 3.0 demonstrated improved performance compared to previous models, although the differences were not statistically significant. [ABSTRACT FROM AUTHOR]

Objectives: Current policies for older patients do not adequately address the barriers to effective implementation of optimal care models in New Zealand, partly due to differences in patient definitions and the in-patient pathway they should follow through hospital. This research aims to: (a) synthesise a definition of a complex older patient; (b) identify and explore primary and secondary health measures; and (c) identify the primary components of a care model suitable for a tertiary hospital in the midland region of the North Island of New Zealand. Method: This mixed-methods study utilised a convergence model, in which qualitative and quantitative data were investigated separately and then combined for interpretation. Semi-structured interviews (n=11) were analysed using a general inductive method of enquiry to develop key codes, categories and themes. Univariate data analysis was employed using six years of routinely collected data of patients admitted to the emergency department and inpatient units (n=261,773) of the tertiary hospital. Results: A definition of a complex older patient was determined that incorporates chronic conditions, comorbidities and iatrogenic complications, functional decline, activities of daily living, case fatality, mortality, hospital length of stay, hospital costs, discharge destination, hospital readmission and emergency department revisit and age – not necessarily over 65 years old. Well-performing geriatric care models were found to include patient-centred care, frequent medical review, early rehabilitation, early discharge planning, a prepared environment and multidisciplinary teams. Conclusions: The findings of this New Zealand study increase understanding of acute geriatric care for complex older patients by filling a gap in policies and strategies, identifying potential components of an optimal care model and defining a complex geriatric patient. Implications for Public Health: The findings of this study present actionable opportunities for clinicians, managers, academics and policymakers to better understand a complex older patient in New Zealand, with significant relevance also for international geriatric care and to establish an effective acute geriatric care model that leads to beneficial health outcomes and provides safeguard mechanisms. [ABSTRACT FROM AUTHOR]

Objective Despite evidence-based guidelines stating that lipase alone should be used in the diagnosis of suspected acute pancreatitis, health care providers continue to order amylase or amylase and lipase together. The purpose of this study was to assess the utilization of appropriate laboratory testing related to the diagnosis of acute pancreatitis. Methods The study used a retrospective cross-sectional design. The timeframe was from January 1, 2020, to December 31, 2020. A retrospective chart review was used to collect data for the following: patient-provider encounter notes, patient demographics, provider demographics, differential and final diagnosis, and laboratory test results. Data analysis include stratification of categorical variables and calculation of cost savings. Results For the 12-month period, this study found 2567 (9.3%) of all amylase and lipase tests to be unnecessary. Amylase tests (1881; 73.2%) made up the most unnecessary tests followed by lipase tests (686; 26.7%). An analysis of test-ordering behavior by providers revealed that 81.5% of all unnecessary tests were ordered by MDs. Finally, this study estimated a total cost savings of $128,350 if all unnecessary tests were eliminated. Conclusion Our study demonstrated that amylase and lipase tests have been overutilized in the diagnosis of acute pancreatitis. [ABSTRACT FROM AUTHOR]

Objectives Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53 -mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC. Methods We retrospectively identified 28 pre- and posttherapy bone marrow biopsy specimens from 9 patients with TP53+ AML/MDS and a p53 overexpressor phenotype by IHC (strong 3+ staining at initial diagnosis). Next-generation sequencing and/or MRD-FC results were collected for each specimen. Results Using a threshold of more than ten 2-3+ cells in any one 400× field, p53 IHC detected residual disease with a sensitivity of 94% and a specificity of 89%. The threshold used in this study showed a high degree of concordance among 6 blinded pathologists (Fleiss κ = 0.97). Conclusions Our study suggests that p53 IHC can be used as a rapid tool (within 24 hours) to aid in the detection of residual disease that may complement MRD-FC or NGS in cases in which the flow cytometry immunophenotype is equivocal and/or the bone marrow aspirate is suboptimal. [ABSTRACT FROM AUTHOR]

B‐cell Acute Lymphoblastic Leukemia (B‐ALL) is the most common pediatric cancer, arising most often in children aged 2–5 years. This distinctive age distribution hints at an association between B‐ALL development and disrupted immune system function during a susceptible period during childhood, possibly triggered by early exposure to infection. While cure rates for childhood B‐ALL surpass 90% in high‐income nations, survivors suffer from diminished quality of life due to the side effects of treatment. Consequently, understanding the origins and evolution of B‐ALL, and how to prevent this prevalent childhood cancer, is paramount to alleviate this substantial health burden. This article provides an overview of our current understanding of the etiology of childhood B‐ALL and explores how this knowledge can inform preventive strategies. [ABSTRACT FROM AUTHOR]

Introduction The harmful effects of first and secondhand smoking are well-established. Smoke-free laws aim at protecting nonsmokers. This study aimed to assess the impact of the 2013 total ban on indoor smoking in Chile on hospitalizations and deaths of major cardiovascular events. Aims and Methods The logarithm of the monthly hospitalization and death rates, standardized by age for every 100 000 inhabitants, were estimated for ischemic heart disease, acute myocardial infarction, strokes, and a composite outcome of ischemic heart diseases (which includes acute myocardial infarction) and strokes. In addition, interrupted time series with synthetic control groups were used to assess changes in levels and trends after the intervention. Results The total ban on indoor smoking caused significant reductions in death rates for the three diseases studied for age groups above 20 years old. In addition, there were substantial decreases in the post-intervention hospitalization rates for ischemic heart disease: for the 20–44 age group, the decrease was 8.7% compared to the pre-intervention period (p  < .01). In comparison, such a reduction was 4% (p  < .01) for the ≥65 age group. For acute myocardial infarction, the decrease was 11.5% (p  < .01) for the 20–44 age group, while for stroke, it was a 1.2% (p  < .01) decrease for the total population. It is estimated that the smoking ban averted 15.6% of the deaths compared with the synthetic control groups. Conclusions The implementation of total smoke-free environments in Chile contributed to the reduction of mortality for main cardiovascular diseases. This study provides additional evidence of causality linking the policy to health outcomes. Implications The total indoor smoking ban significantly affected age-standardized hospitalization and deaths. The number of deaths averted by this policy is estimated at approximately 4758 and 5256 for IHD and stroke, respectively, during the 2013–2017 period (15.6% fewer deaths than predicted by the synthetic control groups). The study contributes to the body of evidence that supports total indoor smoking bans. [ABSTRACT FROM AUTHOR]

Introduction: Pediatric acute limb ischemia (PALI) is a consequence of sudden loss of blood flow to an extremity that can progress to irreversible ischemia if not promptly treated. This may unfortunately result in life-changing consequences which include limb loss, limb length discrepancy, emotional trauma, and or financial stress. Due to the rarity of this condition, and the lack of high-quality evidence, treatment strategies have largely been anecdotal or extrapolated from treatment of the adult patient. The article is a guide to improve overall functional outcomes and reduce morbidity of PALI. Methods: The authors retrospectively analysed patient data on the electronic patient record of the hospital between January 2021 and December 2023. The patients with PALI were divided into three broad categories: iatrogenic arterial injury managed with the best medical management, managed surgically; iatrogenic deep vein injury/thrombosis, and trauma. Results: A total of 13 patients were referred during the study period. 9 were male. 8 cases were line related, 2 trauma and 3 acute deep vein thrombosis [DVT]. Two patients succumbed prior to intervention. Eight patients were managed with best medical therapy, two surgically and one by endovascular means. Conclusion: Since experience worldwide is limited with PALI, we decided to share our experience and a propose comprehensive algorithm for the management of PALI emphasizing a multi-disciplinary team approach that we follow at our hospital. Early and decisive involvement of vascular surgeons, hematologists, intervention radiologists, and pediatric intensive care physicians is necessary to achieve the most favorable outcomes.

BACKGROUND: Stroke is a sudden-onset, uncontrollable event; stroke-related stress may impede rehabilitation and recovery. Lifetime stress may sensitize patients to experiencing greater stroke-related stress and indirectly affect outcomes. We examine lifetime stress as predictor of poststroke acute stress and examine lifetime and acute stress as predictors of 3- and 12-month functional status. We also compare acute stress and baseline National Institutes of Health Stroke Scale as predictors of poststroke functional status. METHODS: Between 2016 and 2020 the STRONG Study (Stroke, Stress, Rehabilitation, and Genetics) enrolled adults with new radiologically confirmed stroke 2 to 10 days poststroke onset at 28 acute care US hospitals. Participants were interviewed 3 times: acute admission (acute stress; Acute Stress Disorder Interview), 3 months (Fugl-Meyer Upper Extremity motor impairment [Fugl-Meyer Upper Arm Assessment; N=431], modified Rankin Scale [3 months; N=542], Stroke Impact Scale-Activities of Daily Living [3 months; N=511], Lifetime Stress Exposure Inventory), and 12 months (modified Rankin Scale, N=533; Stroke Impact Scale 3.0 Activities of Daily Living; N=485; Telephone Montreal Cognitive Assessment; N=484) poststroke. Structural equation models examined whether acute stress predicted 3- and 12-month functional outcomes, and mediated an association between lifetime stress and outcomes controlling for demographics and initial National Institutes of Health Stroke Scale. Standardized betas are reported. RESULTS: Sample (N=763) was 19 to 95 years old (mean=63; SD=14.9); 448 (58.7%) were male. Acute stress scores ranged from 0 to 14 (mean, 3.52 [95% CI, 3.31-3.73]). Controlling for age, gender, baseline National Institutes of Health Stroke Scale, and race and ethnicity, higher lifetime stress predicted higher acute stress (β=0.18, P0.18), but Fugl-Meyer scores (χ2[1]=7.01, P=0.008) less strongly than baseline National Institutes of Health Stroke Scale. CONCLUSIONS: Lifetime stress/trauma is associated with more poststroke acute stress, which is associated with greater motor and cognitive impairment and disability 3 and 12 months poststroke. Poststroke interventions for acute stress may help mitigate stroke-related disability.

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

PURPOSE: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR). RESULTS: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively. CONCLUSION: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of IRF1 in leukemia, we explored the potential of IRF1 expression level as a stratification marker for human acute myeloid leukemia. We show that IRF1-based stratification identifies distinct cancer-related signatures in patient subgroups. These findings establish IRF1 as a pivotal HSC controller and provide previously unknown insights into HSC regulation, with potential implications to IRF1 functions in the context of leukemia.

Next-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations among different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this interlaboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed patients with AML enrolled in the Beat AML Master Trial (BAMT) at 2 academic institutions. We analyzed the diagnostic samples from patients with AML for the detection of pathogenic myeloid mutations in 8 genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (site 1) or the GeneTrails Comprehensive Heme Panel (site 2) at the 2 institutions and compared them with the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. The overall percent agreement was over 95% each in all 8 genes, with almost perfect agreement (κ > 0.906) in all but WT1, which had substantial agreement (κ = 0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze samples from patients with AML enrolled in the BAMT show high concordance, a reassuring finding given the wide use of NGS for therapeutic decision-making in AML.