Music Listening in Stem Cell Transplantation and Acute Myeloid Leukemia: A Randomized Clinical Trial.

CONTEXT: Music listening (ML) has been shown to have a beneficial effect on patients with cancer. However, novel intervention approaches are needed. OBJECTIVES: We aimed to determine whether ML based on the iso-principle, conducted using a mobile application (GloMus), improves symptom burden, quality of life (QoL), anxiety, and depression in patients undergoing stem cell transplantation (SCT) and intensive induction chemotherapy for acute myeloid leukemia (AML). METHODS: In this randomized controlled clinical trial, we assigned 71 patients to the ML or standard care (SC) groups, stratified by the reason for admission (AML, allogeneic-SCT, or inpatient/outpatient autologous-SCT). Upon admission, participants in the ML groups were invited to undergo daily ML sessions designed to change negative moods into positive ones (iso-principle). The intervention consisted of listening to pre-recorded classical music ordered by beats per minute and tonality. Symptom burden (Edmonton Symptom Assessment System-Revised) was assessed in the ML groups before and after each session. Anxiety, depression (Hospital Anxiety and Depression Scale), and QoL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation/Leukemia) were measured weekly in the ML and SC groups. RESULTS: Symptom burden in both allogeneic- and inpatient autologous-SCT ML groups reduced after the intervention. In all experimental groups, clinically important improvements were observed after ML sessions. No differences were found between the groups (ML vs. SC) at different weeks of admission regarding anxiety, depression, and QoL. CONCLUSIONS: ML based on our innovative iso-principle strategy, conducted using GloMus, reduced the symptom burden in patients undergoing allogeneic- and inpatient autologous-SCT (ClinicalTrials.gov number, NCT05696457).

First-in-human study of JNJ-67571244, a CD33 × CD3 bispecific antibody, in relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome.

Relapsed/refractory (r/r) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) outcomes remain poor. A targeted cluster of differentiation (CD)33 × CD3 bispecific antibody, JNJ-67571244, was assessed to identify the maximum tolerated dose (MTD), recommended phase II dose (RP2D), safety and tolerability, and preliminary clinical activity in patients with r/rAML or r/rMDS. This first-in-human, open-label, phase I, dose-escalation/dose-expansion study included patients with r/rAML or r/rMDS who were ineligible for or had exhausted standard therapeutic options. JNJ-67571244 was administered intravenously or subcutaneously using step-up dosing until ≥1 discontinuation condition was met. Outcomes included safety/tolerability, preliminary clinical activity, and systemic pharmacokinetics and pharmacodynamics. The study was terminated after evaluating 10 dose-escalation cohorts (n = 68) and before starting dose-expansion. Overall, 11 (16.2%) patients experienced ≥1 dose-limiting toxicity; all experienced ≥1 treatment-emergent adverse event (TEAE; treatment related: 60 [88.2%]); and 64 (94.1%) experienced ≥1 TEAE of Grade ≥3 toxicity (treatment related: 28 [41.2%]). Although some patients had temporary disease burden reductions, no responses were seen. JNJ-67571244 administration increased multiple cytokines, which coincided with incidence of cytokine release syndrome, infusion-related reactions, and elevated liver function tests. A prolonged step-up strategy was tested to improve tolerability, though this approach did not prevent hepatotoxicity. T-cell activation following treatment suggested target engagement but did not correlate with clinical activity. Safely reaching the projected exposure level for JNJ-67571244 efficacy was not achieved, thus MTD and RP2D were not determined.

Characteristics and risk factors associated with mortality during the first cycle of prone secondary to ARDS due to SARS-CoV-2 pneumonia / Características y factores de riesgo asociados a mortalidad durante el primer ciclo de prono por SDRA secundario a neumonía por SARS-CoV-2

Objective To analyze characteristics, changes in oxygenation, and pulmonary mechanics, in mechanically ventilated patients with ARDS due to SARS-CoV-2 treated with prone position and evaluate the response to this maneuver.Design Cohort study including patients with PaO2/FiO2 <150mmHg requiring prone position over 18 months. We classified patients according to PaO2/FiO2 changes from basal to 24h after the first prone cycle as: 1) no increase 2) increase <25%, 3) 25%–50% increase 4) increase >50%. Setting 33-bed medical-surgical Intensive Care Unit (ICU) in Argentina. Patients 273 patients. Interventions None. Main variables of interest Epidemiological characteristics, respiratory mechanics and oxygenation were compared between survivors and non-survivors. Independent factors associated with in-hospital mortality were identified. Results Baseline PaO2/FiO2 was 116 [97–135]mmHg (115 [94–136] in survivors vs. 117 [98–134] in non-survivors; p=0.50). After prone positioning, 22 patients (8%) had similar PaO2/FiO2 values; 46(16%) increased PaO2/FiO2 ≤25%; 55 (21%) increased it 25%–50%; and 150 (55%), >50%. Mortality was 86%, 87%, 72% and 50% respectively (p<0.001). Baseline PaO2/FiO2, <100mmHg did not imply that patients were refractory to prone position. Factors independently associated with mortality were age, percentage increase in PaO2/FiO2 after 24h being in prone, and number of prone cycles. Conclusions Older patients unable to improve PaO2/FiO2 after 24h in prone position and who require >1 cycle might early receive additional treatments for refractory hypoxemia. After the first 24h in the prone position, a low percentage of PaO2/FiO2 increase over baseline, beyond the initial value, was independently associated with higher mortality. (AU)

Objetivo Analizar las características, cambios en la oxigenación y mecánica pulmonar, en pacientes ventilados mecánicamente con SDRA por SARS-CoV-2 tratados con posición prona, y evaluar la respuesta a esta maniobra. Diseño Estudio de cohorte que incluyó pacientes con PaO2/FiO2 <150mmHg que requirieron posición prona durante 18 meses. Se clasificaron los pacientes según los cambios de PaO2/FiO2 desde el basal y 24horas después del primer ciclo prono como: 1) Sin aumento 2) Aumento <25%, 3) 25–50% de aumento 4) Aumento >50%. Ambito Unidad de Cuidados Intensivos (UCI) médico-quirúrgica de 33 camas en Argentina. Pacientes 273 pacientes. Intervenciones Ninguna. Principales variables de interés Se compararon características epidemiológicas, mecánica respiratoria y oxigenación entre sobrevivientes y no sobrevivientes. Se identificaron factores independientes asociados a la mortalidad hospitalaria. Resultados La PaO2/FiO2 basal fue de 116 [97–135]mmHg (115 [94–136] en sobrevivientes vs. 117 [98–134] en no sobrevivientes; p=0,50). Después de la posición prona, 22 pacientes (8%) tenían valores similares de PaO2/FiO2; 46 (16%) aumentaron PaO2/FiO2 ≤25%; 55 (21%) lo aumentaron 25%–50%; y 150 (55%), >50%. La mortalidad fue de 86%, 87%, 72% y 50% respectivamente (p<0,001). La PaO2/FiO2 basal, <100mmHg no implicó que los pacientes fueran refractarios a la posición prona. Los factores asociados independientemente con la mortalidad fueron la edad, el aumento porcentual de PaO2/FiO2 después de 24horas en prona, y el número de ciclos prono. Conclusiones Los pacientes mayores que no pueden mejorar PaO2/FiO2 después de 24 horas en posición prona y que requieren más de 1 ciclo podrían recibir tratamientos adicionales para la hipoxemia refractaria. Después de las primeras 24horas en decúbito prono, un bajo porcentaje de aumento de PaO2/FiO2 sobre el valor basal, más allá del valor inicial, se asoció de forma independiente con una mayor mortalidad. (AU)

Characteristics and risk factors associated with mortality during the first cycle of prone secondary to ARDS due to SARS-CoV-2 pneumonia.

OBJECTIVE: To analyze characteristics, changes in oxygenation, and pulmonary mechanics, in mechanically ventilated patients with ARDS due to SARS-CoV-2 treated with prone position and evaluate the response to this maneuver. DESIGN: Cohort study including patients with PaO2/FiO2 <150mmHg requiring prone position over 18 months. We classified patients according to PaO2/FiO2 changes from basal to 24h after the first prone cycle as: 1) no increase 2) increase <25%, 3) 25%-50% increase 4) increase >50%. SETTING: 33-bed medical-surgical Intensive Care Unit (ICU) in Argentina. PATIENTS: 273 patients. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Epidemiological characteristics, respiratory mechanics and oxygenation were compared between survivors and non-survivors. Independent factors associated with in-hospital mortality were identified. RESULTS: Baseline PaO2/FiO2 was 116 [97-135]mmHg (115 [94-136] in survivors vs. 117 [98-134] in non-survivors; p=0.50). After prone positioning, 22 patients (8%) had similar PaO2/FiO2 values; 46(16%) increased PaO2/FiO2 ≤25%; 55 (21%) increased it 25%-50%; and 150 (55%), >50%. Mortality was 86%, 87%, 72% and 50% respectively (p<0.001). Baseline PaO2/FiO2, <100mmHg did not imply that patients were refractory to prone position. Factors independently associated with mortality were age, percentage increase in PaO2/FiO2 after 24h being in prone, and number of prone cycles. CONCLUSIONS: Older patients unable to improve PaO2/FiO2 after 24h in prone position and who require >1 cycle might early receive additional treatments for refractory hypoxemia. After the first 24h in the prone position, a low percentage of PaO2/FiO2 increase over baseline, beyond the initial value, was independently associated with higher mortality.

Arthroscopically Assisted Suprapatellar Tibial Nail Removal.

Intramedullary nailing remains the most popular and preferred method of fixation for tibial shaft fractures. The infrapatellar approach through the patellar tendon has long been considered the gold standard. However, the suprapatellar approach has gained popularity because of the advantages of being easier to perform when treating proximal shaft and metaphyseal fractures and there being less postoperative anterior knee pain. Despite increased use of this approach, the removal of the implant from the same suprapatellar approach is tricky, and in most cases, the removal is performed through a new transpatellar tendon approach. This article describes arthroscopically assisted suprapatellar tibial nail removal using the same approach and instrumentation of the nail insertion. The technique has the advantage of preserving the patellar tendon without causing secondary damage to it. Through arthroscopy, direct visualization of the patellofemoral joint aids in preventing possible cartilage injury. Moreover, any associated intra-articular lesions can be diagnosed and addressed.

Proteoglycans in Articular Cartilage and Their Contribution to Chondral Injury and Repair Mechanisms.

Proteoglycans are vital components of the extracellular matrix in articular cartilage, providing biomechanical properties crucial for its proper functioning. They are key players in chondral diseases, specifically in the degradation of the extracellular matrix. Evaluating proteoglycan molecules can serve as a biomarker for joint degradation in osteoarthritis patients, as well as assessing the quality of repaired tissue following different treatment strategies for chondral injuries. Despite ongoing research, understanding osteoarthritis and cartilage repair remains unclear, making the identification of key molecules essential for early diagnosis and effective treatment. This review offers an overview of proteoglycans as primary molecules in articular cartilage. It describes the various types of proteoglycans present in both healthy and damaged cartilage, highlighting their roles. Additionally, the review emphasizes the importance of assessing proteoglycans to evaluate the quality of repaired articular tissue. It concludes by providing a visual and narrative description of aggrecan distribution and presence in healthy cartilage. Proteoglycans, such as aggrecan, biglycan, decorin, perlecan, and versican, significantly contribute to maintaining the health of articular cartilage and the cartilage repair process. Therefore, studying these proteoglycans is vital for early diagnosis, evaluating the quality of repaired cartilage, and assessing treatment effectiveness.

Evaluation of the averaged parasympathetic tone activity and its dynamic variation to assess intraoperative nociception in relation to hemodynamic changes in dogs.

This study aimed to determine the performance of the averaged parasympathetic tone activity (PTAm) and its dynamic variation (ΔPTA) to assess intraoperative nociception in relation to heart rate (HR) and direct mean arterial pressure (MAP) in dogs undergoing laparoscopic ovariectomy. This prospective, observational, clinical study included 32 bitches. The PTAm, HR, MAP, and bispectral index (BIS) were assessed before (pre-stimulus), as well as 1 min and 2 min after, four surgical stimuli: insufflation, introduction of trocars, and removal of the left and right ovaries. A two-way ANOVA was performed to compare PTAm, HR, MAP, and BIS data across surgical stimuli. A ≥ 20% drop in PTAm or a ≥ 20% increase in HR and/or MAP regarding the pre-stimulus values was considered a PTAm-drop and/or a hemodynamic response, respectively. The performance of PTAm pre-stimulus, PTAm 1 min, and ΔPTA in predicting the hemodynamic response was assessed by calculation of the area under the receiver operating characteristic (ROC) curve. At insufflation, PTAm decreased after 1 (p = 0.010) and 2 (p = 0.045)min, and ΔPTA was different (p = 0.005) between dogs that presented hemodynamic response and dogs that did not. At PTAm-drop, MAP increased after 1 min (p = 0.001) and 2 min (p = 0.001) with respect to pre-stimulus value, whereas HR and BIS did not change. ROC curves showed a threshold value of PTAm pre-stimulus ≤51 to detect hemodynamic response (sensitivity 69%, specificity 52%). The PTAm and ΔPTA only assessed intraoperative nociception during insufflation. The PTAm pre-stimulus association to the hemodynamic response in anaesthetized dogs showed poor sensitivity and no specificity.

Understanding the Wnt Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Feasible Key against Relapses.

Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML.

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors.

(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.

Molecular Landscape and Validation of New Genomic Classification in 2668 Adult AML Patients: Real Life Data from the PETHEMA Registry.

Next-Generation Sequencing (NGS) implementation to perform accurate diagnosis in acute myeloid leukemia (AML) represents a major challenge for molecular laboratories in terms of specialization, standardization, costs and logistical support. In this context, the PETHEMA cooperative group has established the first nationwide diagnostic network of seven reference laboratories to provide standardized NGS studies for AML patients. Cross-validation (CV) rounds are regularly performed to ensure the quality of NGS studies and to keep updated clinically relevant genes recommended for NGS study. The molecular characterization of 2856 samples (1631 derived from the NGS-AML project; NCT03311815) with standardized NGS of consensus genes (ABL1, ASXL1, BRAF, CALR, CBL, CEBPA, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and WT1) showed 97% of patients having at least one mutation. The mutational profile was highly variable according to moment of disease, age and sex, and several co-occurring and exclusion relations were detected. Molecular testing based on NGS allowed accurate diagnosis and reliable prognosis stratification of 954 AML patients according to new genomic classification proposed by Tazi et al. Novel molecular subgroups, such as mutated WT1 and mutations in at least two myelodysplasia-related genes, have been associated with an adverse prognosis in our cohort. In this way, the PETHEMA cooperative group efficiently provides an extensive molecular characterization for AML diagnosis and risk stratification, ensuring technical quality and equity in access to NGS studies.

First-in-human study of JNJ-63709178, a CD123/CD3 targeting antibody, in relapsed/refractory acute myeloid leukemia.

This study aimed to identify a recommended phase II dose and evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary clinical activity of JNJ-63709178, a CD123/CD3 dual-targeting antibody, in patients with relapsed or refractory acute myeloid leukemia. Intravenous (i.v.) and subcutaneous (s.c.) administration of JNJ-63709178 were evaluated. The i.v. infusions were administered once every 2 weeks (cohorts 1-5 [n = 17]) or twice weekly (cohorts 6-11 [n = 36]). A twice-weekly s.c. dosing regimen with step-up dosing was also studied (s.c. cohorts 1-2 [n = 9]). Treatment-emergent adverse events (TEAEs) greater than or equal to grade 3 were observed in 11 (65%) patients in cohorts 1-5 and 33 (92%) patients in cohorts 6-11. At the highest i.v. dose (4.8 µg/kg), 5 (71%) patients discontinued treatment due to TEAEs. For s.c. administration (n = 9), eight (89%) patients experienced TEAEs greater than or equal to grade 3 and injection site reactions (≤ grade 3) emerged in all patients. At 4.8 µg/kg (i.v. and s.c.), the mean maximum serum concentrations were 30.3 and 3.59 ng/ml, respectively. Increases in multiple cytokines were observed following i.v. and s.c. administrations, and step-up dosing strategies did not mitigate cytokine production or improve the safety profile and led to limited duration of treatment. Minimal clinical activity was observed across all cohorts. The i.v. and s.c. dosing of JNJ-63709178 was associated with suboptimal drug exposure, unfavorable safety profiles, limited clinical activity, and inability to identify a recommended phase II dose.

Spontaneous Remission of Acute Myeloid Leukemia: A Case Report.

Spontaneous remissions (SRs) in acute myeloid leukemia (AML) are infrequent, poorly documented and transient. Similarly, morphological and cytogenetic complete remissions (CR) under azacitidine treatment are scarce. We report a 71-year-old man with a secondary AML arising from essential thrombocythemia (ET), who developed an SR after discontinuation of azacitidine following a respiratory infection (four courses were administered). The distinctive feature of our case is the depth of the achieved CR, documented by next-generation sequencing (NGS) techniques. We also detected persistence of molecular lesions that might already have been present in the previous ET clone. Our patient relapsed 5 months after achieving CR. We conclude that our patient showed a spontaneous remission of his AML rather than an exquisite response to azacitidine. We hypothesize that the concurrent respiratory infection, or any other unknown trigger, might have activated his immune system forcing the leukemic stem cell to enter a quiescent state through a yet unexplained mechanism.

Comparison of the efficacy of two alveolar recruitment manoeuvres in improving the lung mechanics and the degree of atelectasis in anaesthetized healthy sheep.

The aim of the present study was to evaluate whether the application of two types of alveolar recruitment manoeuvres (ARMs) followed by a positive end-expiratory pressure (PEEP) improved lung mechanics and the degree of atelectasis caused by general anaesthesia. Twenty-one female Merino sheep were divided into three groups: sustained inflation ARM (ARMsust), stepwise ARM (AMRstep), and control (without ARM). Sheep received detomidine-morphine for premedication, propofol for induction, and isoflurane during general anaesthesia in a volume-controlled mode with 100% oxygen during the first 15 min of anaesthesia and 40% the rest of the study. The right jugular vein and metacarpal artery were catheterised for mixed venous and arterial blood sample collection, respectively. The quasistatic compliance (Cqst), oxygenation parameters, and shunt fraction (Qs/Qt) were monitored before ARM application (TpreARM), and at 10 (T10) and 60 min (T60) after ARM application. A pulmonary histopathological study was conducted on five animals from each group. A significant increase in Cqst was observed in both ARM groups at T10 compared to TpreARM (ARMsust: P = 0.001; ARMstep: P = 0.002), although only the ARMsust group showed significant differences compared to the control group. The ARMstep group presented a significant improvement in oxygenation parameters and Qs/Qt fraction (T10: 4.84 (3.26-16.48)%, P = 0.048; T60: 4.40 (4.31-14.16)%, P = 0.004) compared with TpreARM (21.48 (20.61-28.32)%). The ARMstep group had the highest percentage of alveolar area and the most homogeneous values. In conclusion, the application of a stepwise ARM followed by PEEP improved atelectasis caused by isoflurane anaesthesia in healthy sheep.

Identification of seasonal variation in the diagnosis of acute myeloid leukaemia: a population-based study.

Until now, the role that seasonal factors play in the aetiology of acute myeloid leukaemia (AML) has been unclear. Demonstration of seasonality in AML diagnosis would provide supportive evidence of an underlying seasonal aetiology. To investigate the potential seasonal and long-term trends in AML diagnosis in an overall population and in subgroups according to sex and age, we used population-based data from a Spanish hospital discharge registry. We conducted a larger study than any to date of 26 472 cases of AML diagnosed in Spain between 2004 and 2015. Using multivariable Poisson generalized linear autoregressive moving average modelling, we found an upward long-term trend, with monthly incidence rates of AML annually increasing by 0.4% [95% confidence interval (CI), 0.2%-0.6%; p = 0.0011]. January displayed the highest incidence rate of AML, with a minimum average difference of 7% when compared to February (95% CI, 2%-12%; p = 0.0143) and a maximum average difference of 16% compared to November (95% CI, 11%-21%; p < 0.0001) and August (95% CI, 10%-21%; p < 0.0001). Such seasonal effect was consistent among subgroups according to sex and age. Our finding that AML diagnosis is seasonal strongly implies that seasonal factors, such as infectious agents or environmental triggers, influence the development and/or proliferation of disease, pointing to prevention opportunities.

Single-cell transcriptomics of the ventral posterolateral nucleus-enriched thalamic regions from HSV-1-infected mice reveal a novel microglia/microglia-like transcriptional response.

BACKGROUND: Microglia participate in the immune response upon central nervous system (CNS) infections. However, the role of these cells during herpes simplex encephalitis (HSE) has not been fully characterized. We sought to identify different microglia/microglia-like cells and describe the potential mechanisms and signaling pathways involved during HSE. METHODS: The transcriptional response of CD11b+ immune cells, including microglia/microglia-like cells, was investigated using single-cell RNA sequencing (scRNA-seq) on cells isolated from the ventral posterolateral nucleus (VPL)-enriched thalamic regions of C57BL/6 N mice intranasally infected with herpes simplex virus-1 (HSV-1) (6 × 105 PFUs/20 µl). We further performed scanning electronic microscopy (SEM) analysis in VPL regions on day 6 post-infection (p.i.) to provide insight into microglial functions. RESULTS: We describe a novel microglia-like transcriptional response associated with a rare cell population (7% of all analyzed cells), named "in transition" microglia/microglia-like cells in HSE. This new microglia-like transcriptional signature, found in the highly infected thalamic regions, was enriched in specific genes (Retnlg, Cxcr2, Il1f9) usually associated with neutrophils. Pathway analysis of this cell-type transcriptome showed increased NLRP3-inflammasome-mediated interleukin IL-1ß production, promoting a pro-inflammatory response. These cells' increased expression of viral transcripts suggests that the distinct "in transition" transcriptome corresponds to the intrinsic antiviral immune signaling of HSV-1-infected microglia/microglia-like cells in the thalamus. In accordance with this phenotype, we observed several TMEM119+/IBA-I+ microglia/microglia-like cells immunostained for HSV-1 in highly infected regions. CONCLUSIONS: A new microglia/microglia-like state may potentially shed light on how microglia could react to HSV-1 infection. Our observations suggest that infected microglia/microglia-like cells contribute to an exacerbated CNS inflammation. Further characterization of this transitory state of the microglia/microglia-like cell transcriptome may allow the development of novel immunomodulatory approaches to improve HSE outcomes by regulating the microglial immune response.

High-throughput RNA sequencing transcriptome analysis of ABC-DLBCL reveals several tumor evasion strategies.

Activated B-cell (ABC) lymphoma, a distinct molecular entity within diffuse large B-cell lymphoma (DLBCL), remains highly incurable, showing a worse response to standard immunochemotherapy. The discouraging results obtained in several clinical trials using proteasome inhibitors, tyrosine kinase inhibitors, or immunomodulators, lead to an intense search for new, potentially druggable biomarkers in DLBCL. In this study, we designed an experimental strategy for DLBCL to discover high- and low-abundance RNA-seq-derived transcripts involved in the oncogenic phenotype in patients diagnosed with ABC-DLBCL. Based on the results of a comparative analysis, 79 DE genes and two enriched gene sets related to metabolism and immunity were selected. Genes related to drug resistance, anti-inflammatory response, and tumor-cell dissemination were found to be up-regulated, while tumor suppressor genes were down-regulated. Then, we searched for the perturbagens most suitable for gene expression profiling (GEP) by iLINCS-CMap. Herein, we present a novel experimental approach that connects the omics signature of DLBCL with potential drugs for more accurate treatments.

Parasympathetic Tone Changes in Anesthetized Horses after Surgical Stimulation, and Morphine, Ketamine, and Dobutamine Administration.

Autonomic nervous system (ANS) activity can modify cardiovascular parameters in response to nociceptive stimuli or drugs in anesthetized animals. The aim of this study was to determine if a surgical nociceptive stimulus and morphine, ketamine, and dobutamine administration would modify ANS activity observed as a change in the mean parasympathetic tone activity (PTAm) in anesthetized horses. In 20 anesthetized horses, heart rate (HR), mean arterial pressure (MAP), and PTAm were monitored before and 1, 3, and 5 min after surgical incision, and before and 10 min after the administration of morphine (0.2 mg/kg IV). If nystagmus or spontaneous ventilation was observed, ketamine (0.5 mg/kg IV) was given, and the three variables were registered before and 3 and 5 min afterward. If MAP reached ≤62 mmHg, a dobutamine infusion was administered, and the three variables were recorded before and 5 min after starting/increasing the infusion (0.25 µg/kg/min IV every 5 min). The three variables were registered before and 1, 3, and 5 min after a PTAm decrease of ≥20%, HR increase of ≥10%, or MAP increase of ≥20%. The PTAm decreased 3 min after the administration of ketamine and 1 min after a PTA event. The surgical incision, dobutamine, and morphine did not modify PTAm. The absence of changes in ANS activity after the nociceptive stimulus and lack of correlation between PTAm and HR or MAP suggest that PTAm is a poor indicator of sympathetic activation under the study conditions. Ketamine seems to affect ANS activity by decreasing PTAm.

Understanding the Notch Signaling Pathway in Acute Myeloid Leukemia Stem Cells: From Hematopoiesis to Neoplasia.

The Notch signaling pathway is fundamental to early fetal development, but its role in acute myeloid leukemia is still unclear. It is important to elucidate the function that contains Notch, not only in acute myeloid leukemia, but in leukemic stem cells (LSCs). LSCs seem to be the principal cause of patient relapse. This population is in a quiescent state. Signaling pathways that govern this process must be understood to increase the chemosensitivity of this compartment. In this review, we focus on the conserved Notch signaling pathway, and its repercussions in hematopoiesis and hematological neoplasia. We found in the literature both visions regarding Notch activity in acute myeloid leukemia. On one hand, the activation of Notch leads to cell proliferation, on the other hand, the activation of Notch leads to cell cycle arrest. This dilemma requires further experiments to be answered, in order to understand the role of Notch not only in acute myeloid leukemia, but especially in LSCs.

Effect of Colchicine vs Usual Care Alone on Intubation and 28-Day Mortality in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

Importance: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription-polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04328480.