Adenosine increases PD-L1 expression in mesenchymal stromal cells derived from cervical cancer through its interaction with A2AR/A2BR and the production of TGF-ß1.

Mesenchymal stromal cells (MSCs) together with malignant cells present in the tumor microenvironment (TME), participate in the suppression of the antitumor immune response through the production of immunosuppressive factors, such as transforming growth factor beta 1 (TGF-ß1). In previous studies, we reported that adenosine (Ado), generated by the adenosinergic activity of cervical cancer (CeCa) cells, induces the production of TGF-ß1 by interacting with A2AR/A2BR. In the present study, we provide evidence that Ado induces the production of TGF-ß1 in MSCs derived from CeCa tumors (CeCa-MSCs) by interacting with both receptors and that TGF-ß1 acts in an autocrine manner to induce the expression of programmed death ligand 1 (PD-L1) in CeCa-MSCs, resulting in an increase in their immunosuppressive capacity on activated CD8+ T lymphocytes. The addition of the antagonists ZM241385 and MRS1754, specific for A2AR and A2BR, respectively, or SB-505124, a selective TGF-ß1 receptor inhibitor, in CeCa-MSC cultures significantly inhibited the expression of PD-L1. Compared with CeCa-MSCs, MSCs derived from normal cervical tissue (NCx-MSCs), used as a control and induced with Ado to express PD-L1, showed a lower response to TGF-ß1 to increase PD-L1 expression. Those results strongly suggest the presence of a feedback mechanism among the adenosinergic pathway, the production of TGF-ß1, and the induction of PD-L1 in CeCa-MSCs to suppress the antitumor response of CD8+ T lymphocytes. The findings of this study suggest that this pathway may have clinical importance as a therapeutic target.

Dexamethasone treatment for COVID-19 is related to increased mortality in hematologic malignancy patients: results from the EPICOVIDEHA Registry.

Not available.

SARS-CoV-2 mutant spectra as variant of concern nurseries: endless variation?

Introduction: SARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade. Methods: Here we use high resolution ultra-deep sequencing to analyze SARS-CoV-2 mutant spectra. Results: In 6 out of 11 SARS-CoV-2 isolates from COVID-19 patients, the mutant spectrum of the spike (S)-coding region included two or more amino acids or deletions, that correspond to discordant viral clades. A similar observation is reported for laboratory populations of SARS-CoV-2 USA-WA1/2020, following a cell culture infection in the presence of remdesivir, ribavirin or their combinations. Moreover, some of the clade-discordant genome residues are found in the same haplotype within an amplicon. Discussion: We evaluate possible interpretations of these findings, and reviewed precedents for rapid selection of genomes with multiple mutations in RNA viruses. These considerations suggest that intra-host evolution may be sufficient to generate minority sequences which are closely related to sequences typical of other clades. The results provide a model for the origin of variants of concern during epidemic spread─in particular Omicron lineages─that does not require prolonged infection, involvement of immunocompromised individuals, or participation of intermediate, non-human hosts.

Characterising information gains and losses when collecting multiple epidemic model outputs.

BACKGROUND: Collaborative comparisons and combinations of epidemic models are used as policy-relevant evidence during epidemic outbreaks. In the process of collecting multiple model projections, such collaborations may gain or lose relevant information. Typically, modellers contribute a probabilistic summary at each time-step. We compared this to directly collecting simulated trajectories. We aimed to explore information on key epidemic quantities; ensemble uncertainty; and performance against data, investigating potential to continuously gain information from a single cross-sectional collection of model results. METHODS: We compared projections from the European COVID-19 Scenario Modelling Hub. Five teams modelled incidence in Belgium, the Netherlands, and Spain. We compared July 2022 projections by incidence, peaks, and cumulative totals. We created a probabilistic ensemble drawn from all trajectories, and compared to ensembles from a median across each model's quantiles, or a linear opinion pool. We measured the predictive accuracy of individual trajectories against observations, using this in a weighted ensemble. We repeated this sequentially against increasing weeks of observed data. We evaluated these ensembles to reflect performance with varying observed data. RESULTS: By collecting modelled trajectories, we showed policy-relevant epidemic characteristics. Trajectories contained a right-skewed distribution well represented by an ensemble of trajectories or a linear opinion pool, but not models' quantile intervals. Ensembles weighted by performance typically retained the range of plausible incidence over time, and in some cases narrowed this by excluding some epidemic shapes. CONCLUSIONS: We observed several information gains from collecting modelled trajectories rather than quantile distributions, including potential for continuously updated information from a single model collection. The value of information gains and losses may vary with each collaborative effort's aims, depending on the needs of projection users. Understanding the differing information potential of methods to collect model projections can support the accuracy, sustainability, and communication of collaborative infectious disease modelling efforts.

Adenosine Increases the Immunosuppressive Capacity of Cervical Cancer Cells by Increasing PD-L1 Expression and TGF-ß Production through Its Interaction with A2AR/A2BR.

The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-ß1 acts in an autocrine manner to induce PD-L1 expression, enhancing the immunosuppressive effects of CeCa cells on activated T lymphocytes (ATLs) and CD8+ cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from E6 and E7 proteins of HPV-16. Interestingly, the addition of the antagonists ZM241385 and MRS1754, which are specific for A2AR and A2BR, respectively, or SB-505124, which is a selective TGF-ß1 receptor inhibitor, to CeCa cell cultures significantly inhibited PD-L1 expression. In addition, supernatants from CeCa cells that were treated with Ado (CeCa-Ado Sup) increased the expression of PD-1, TGF-ß1, and IL-10 and decreased the expression of IFN-γ in ATLs. Interestingly, the addition of an anti-TGF-ß neutralizing antibody strongly reversed the effect of CeCa-Ado Sup on PD-1 expression in ATLs. These results strongly suggest the presence of a feedback mechanism that involves the adenosinergic pathway, the production of TGF-ß1, and the upregulation of PD-L1 expression in CeCa cells that suppresses the antitumor response of CTLs. The findings of this study suggest that this pathway may be clinically important and may be a therapeutic target.

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).

Decoding the historical tale: COVID-19 impact on haematological malignancy patients-EPICOVIDEHA insights from 2020 to 2022.

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020-2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Utilizing supply-demand bundles in Nature-based Recreation offers insights into specific strategies for sustainable tourism management.

Balancing supply and demand in Nature-based Recreation (NbR) has the potential to yield co-benefits across multiple Ecosystem Services (ES), helping to make tourism activities more sustainable. However, a comprehensive understanding of supply-demand mismatches in NbR is challenging due to the complex interaction among various social, economic and ecological factors. This paper investigates mismatches in NbR supply and demand to provide insights for informing spatial and regional planning to achieve sustainable tourism. To this end, the paper uses a wide range of indicators such as biophysical attributes, accessibility and social indicators to map and assess NbR supply and demand, followed by the application of spatial statistics to analyse supply-demand mismatches. Cluster analysis was performed based on the supply-demand relationship to identify a typology of NbR ES across the study area in the north of Iran. The paper proposes an innovative application of recreation ES bundles with potential implications for sustainable tourism in a region marked as a hot spot for tourism. The analysis generated a typology of five bundles of NbR ES with differing recreational opportunities. Bundles 1 and 2, characterized by a supply surplus and substantial ecological value, are suitable for NbR activities such as camping, hiking, climbing, and birdwatching. In contrast, bundle 4 and 5 associated with urban centres, experience a supply deficit, making them less suitable for NbR. Bundle 3, characterized by a mixture of natural and productive lands, plays an important role in maintaining a balanced supply-demand state. This region holds potential for diverse forms of tourism, including rural and agricultural recreation such as farm tours and farm life experiences. Based on findings, the paper provides valuable insights for spatial and regional planning by proposing targeted strategies to sustainably manage tourism activities.

Is REBOA the Last Card to Control a Massive Gastrointestinal Bleeding?

INTRODUCTION: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potential tool for the management of massive gastrointestinal bleeding (MGB). This study aims to describe the experience of the use of REBOA as adjunctive therapy in patients with MGB and to evaluate its effectiveness. METHODS: Serial cases of patients with hemorrhagic shock secondary to MGB in whom REBOA was placed were collected. Patient demographics, bleeding severity, etiology, management, and clinical outcomes were recorded. RESULTS: Between 2017 and 2020, five cases were analyzed. All patients had a severe gastrointestinal bleeding (Glasgow Blatchford Bleeding Score range 12-17; Clinical Rockal Score range 5-9). The etiologies of MGB were perforated gastric or duodenal ulcers, esophageal varices, and vascular lesions. Systolic blood pressure increased after REBOA placement and total occlusion time was 25-60 min. REBOA provided temporary hemorrhage control in all cases and allowed additional hemostatic maneuvers to be performed. Three patients survived more than 24 h. All patients died in index hospitalization. The main cause of death was related to hemorrhagic shock. CONCLUSIONS: Endovascular aortic occlusion can work as a bridge to further resuscitation and attempts at hemostasis in patients with MGB. REBOA provides hemodynamic support and may be used simultaneously with other hemostatic maneuvers, facilitating definitive hemorrhage control.

Uso de la tomografía corporal total en pacientes con heridas de arma de fuego y hemodinámicamente inestables: ¿Rompiendo paradigmas de atención inicial? / Whole-body computed tomography in hemodynamically unstable patients with gunshot wounds: A paradigm shift in trauma management?

Introducción. El objetivo del estudio fue analizar el impacto del uso de la tomografía corporal total en la evaluación de los pacientes con trauma penetrante por proyectil de arma de fuego y hemodinámicamente inestables atendidos en un centro de referencia de trauma. Métodos. Se realizó un estudio analítico, retrospectivo, con base en un subanálisis del registro de la Sociedad Panamericana de Trauma ­ Fundación Valle del Lili. Se incluyeron los pacientes con trauma penetrante por proyectil de arma de fuego atendidos entre 2018 y 2021. Se excluyeron los pacientes con trauma craneoencefálico severo, trauma leve y en condición in extremis. Resultados. Doscientos pacientes cumplieron los criterios de elegibilidad, 115 fueron estudiados con tomografía corporal total y se compararon con 85 controles. La mortalidad intrahospitalaria en el grupo de tomografía fue de 4/115 (3,5 %) vs 10/85 (12 %) en el grupo control. En el análisis multivariado se identificó que la tomografía no tenía asociación significativa con la mortalidad (aOR=0,46; IC95% 0,10-1,94). El grupo de tomografía tuvo una reducción relativa del 39 % en la frecuencia de cirugías mayores, con un efecto asociado en la disminución de la necesidad de cirugía (aOR=0,47; IC95% 0,22-0,98). Conclusiones. La tomografía corporal total fue empleada en el abordaje inicial de los pacientes con trauma penetrante por proyectil de arma de fuego y hemodinámicamente inestables. Su uso no se asoció con una mayor mortalidad, pero sí con una menor frecuencia de cirugías mayores.

Introduction. This study aims to assess the impact of whole-body computed tomography (WBCT) in the evaluation of patients with penetrating gunshot wounds (GSW) who are hemodynamically unstable and treated at a trauma referral center. Methods. An analytical, retrospective study was conducted based on a subanalysis of the Panamerican Trauma Society-FVL registry. Patients with GSW treated between 2018 and 2021 were included. Patients with severe cranioencephalic trauma, minor trauma, and those in extremis were excluded. Patients with and without WBCT were compared. The primary outcome was in-hospital mortality, and the secondary outcome was the frequency of major surgeries (thoracotomy, sternotomy, cervicotomy, and/or laparotomy) during initial care. Results. Two hundred eligible patients were included, with 115 undergoing WBCT and compared to 85 controls. In-hospital mortality in the WBCT group was 4/115 (3.5%) compared to 10/85 (12%) in the control group. Multivariate analysis showed that WBCT was not significantly associated to mortality (aOR: 0.46; 95% CI 0.10-1.94). The WBCT group had a relative reduction of 39% in the frequency of major surgeries, with an associated effect on reducing the need for surgery (aOR: 0.47; 95% CI 0.22-0.98). Conclusions. Whole-body computed tomography was employed in the initial management of patients with penetrating firearm projectile injuries and hemodynamic instability. The use of WBCT was not associated with mortality but rather with a reduction in the frequency of major surgery.

Umbral crítico de administración en pacientes con trauma severo y reanimación endovascular: ¿Un concepto útil? / Critical Administration Threshold in severe trauma patients and endovascular resuscitation: A useful concept?

Introducción. Se describe la utilidad del umbral crítico de administración (CAT por su denominación en inglés) como herramienta para la reanimación hemostática en pacientes con trauma severo y oclusión endovascular aórtica. Métodos. Revisión retrospectiva de pacientes adultos con hemorragia por trauma, con o sin oclusión endovascular aórtica (REBOA), atendidos entre enero de 2015 y junio de 2020, en un centro de trauma nivel I en Cali, Colombia. Se registraron variables demográficas, severidad del trauma, estado clínico, requerimiento transfusional, tiempo hasta CAT+ y CAT alcanzado (1, 2 ó 3). Resultados. Se incluyeron 93 pacientes, se utilizó REBOA en 36 y manejo tradicional en 57. El grupo REBOA presentó mayor volumen de sangrado (mediana de 3000 ml, RIC: 1950-3625 ml) frente al grupo control (mediana de1500 ml, RIC: 700-2975ml) (p<0,001) y mayor cantidad de glóbulos rojos transfundidos en las primeras 6 horas (mediana de 5, RIC:4-9); p=0,015 y en las primeras 24 horas (mediana de 6, RIC: 4-11); p=0,005. No hubo diferencias estadísticamente significativas en número de pacientes CAT+ entre grupos o tiempo hasta alcanzarlo. Sin embargo, el estado CAT+ durante los primeros 30 minutos de la cirugía fue mayor en grupo REBOA (24/36, 66,7 %) frente al grupo control (17/57, 29,8 %; p=0,001), teniendo este mayor tasa de mortalidad intrahospitalaria frente a los pacientes CAT-. Conclusión. El umbral crítico de administración es una herramienta útil en la reanimación hemostática de pacientes con trauma y REBOA, que podría predecir mortalidad precoz.

Introduction. The objective is to describe the utility of the Critical Administration Threshold (CAT) as a tool in hemostatic resuscitation in patients with severe trauma and REBOA. Methods. Retrospective review between January 2015 and June 2020 of adult patients with hemorrhage secondary to trauma with or without REBOA in a level I trauma center in Cali, Colombia. Demographic variables, trauma severity, clinical status, transfusion needs, time to CAT+ and number of CAT achieved (1, 2 or 3) were recorded. Results. Ninety-three patients were included, in which REBOA was used in 36 and traditional management in 57. The REBOA group had a higher bleeding volume (3000 ml), IQR: 1950-3625 ml vs the control group (1500 ml, IQR: 700-2975 ml) (p<0.001) and a higher rate of PRBC units transfused in the first 6 hours (median 5, IQR: 4-9); p=0.015 and in the first 24 hours (median 6, IQR: 4-11); p=0.005. There were no statistically significant differences in the number of CAT+ patients between groups or time to CAT+. However, CAT+ status during the first 30 minutes of surgery was higher in the REBOA Group (24/36, 66.7%) vs. the control group (17/57, 29.8%; p=0.001), having this group a higher in-hospital mortality rate vs. CAT- patients. Conclusion. CAT is a useful tool in the hemostatic resuscitation of patients with trauma and REBOA that could predict early mortality.

Hepatitis C virus point-of-care microelimination approach in a vulnerable population in the South of Spain.

Background: Since the introduction of direct-acting antivirals, thousands of chronic hepatitis C patients have been successfully treated. However, vulnerable populations have a higher prevalence of hepatitis C virus (HCV) infection and face barriers that impede their access to antivirals. We carried out an HCV microelimination program focused on vulnerable population groups in Malaga. Methods: People in drug addiction treatment centers and homeless shelters in Malaga who participated in the program between October 2020 and October 2021 were included. After providing participants with educational information on HCV, a dry drop test (DDT) was used to collect blood for subsequent screening for HCV infection. The participants who were diagnosed with HCV infection were scheduled for comprehensive healthcare assessments, including blood tests, ultrasonography, elastography, and the prescription of antivirals, all conducted in a single hospital visit. Sustained viral response (SVR) was analysed 12 weeks after end of treatment. Results: Of the 417 persons invited to participate, 271 (65%) agreed to participate in the program. These participants were screened for HCV infection and 28 of them were diagnosed with HCV infection (10%). These hepatitis C-infected patients had a mean age of 53 ± 9 years; 86% were males and 93% were or had been drug users. Among 23 patients with HCV infection, HCV genotype 1a predominated (74%). Medical exams showed that 19% (4/21) had advanced fibrosis (F3-4), and 5% (1/21) had portal hypertension. Finally, 23 infected patients received treatment with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir and SVR was confirmed in 22 patients (96%). Conclusions: Drug users and homeless people have a higher prevalence of HCV infection than the general population. The microelimination program with educational activity and screening tools achieved a high participation rate, easy healthcare access, and a high rate of SVR despite the SARS-CoV-2 pandemic.

Death Anxiety in Caregivers of Chronic Patients.

This study aimed to determine the extent to which caregivers of patients with chronic illnesses experience death anxiety, and which variables from caregivers and patients might potentially be related to their death anxiety. It also aimed to compare the levels of death anxiety between patients and caregivers. Web of Science, Scopus, PubMed, Psychology Database, Cochrane, and Google Scholar were searched for original studies available until December 2022 that quantitatively addressed death anxiety in family and informal caregivers of individuals with chronic illnesses. The methodological quality of the included studies was assessed, and a meta-analysis was conducted using Hedges' g as the effect size index and the DerSimonian-Laird method to analyze differences between patients and caregivers in death anxiety. The results of the 11 included studies showed moderate levels of death anxiety in caregivers, and the meta-analysis (k = 7; 614 patients and 586 caregivers) revealed non-significant differences between the death anxiety experienced by patients and caregivers (pooled Hedges' g = -0.03, 95% CI = -0.29 to 0.25, p = 0.802). Some sociodemographic and psychological factors (e.g., gender, depression, and anxiety) might be related to the death anxiety experienced, but additional research is necessary to validate these findings.

Survival in multiple myeloma and SARS-COV-2 infection through the COVID-19 pandemic: Results from the EPICOVIDEHA registry.

Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and subsequent coronavirus (20)19 disease (COVID-19)-related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID-19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS-CoV-2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow-up was 52 days for the entire cohort and 83 days for survivors. Three-hundred and three patients died (24%) and COVID-19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 109 /L was found to be protective. This data suggests that MM patients remain at risk of SARS-CoV-2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic.

False Positive in [ 99m Tc]Tc-DPD Scintigraphy for Cardiac Amyloidosis Due to Intravenous Iron Administration.

ABSTRACT: [ 99m Tc]Tc-DPD (3,3-diphosphono-1,2-propanodicarboxylic acid) scintigraphy is an essential tool for diagnosing transthyretin amyloid cardiac amyloidosis. An 86-year-old woman suffering from heart failure with preserved ejection fraction underwent [ 99m Tc]Tc-DPD scintigraphy and a SPECT/CT for suspected transthyretin amyloid cardiac amyloidosis. The scan showed intracardiac and liver uptake. As the patient had taken intravenous iron on the morning of the scan, we decided to repeat the scan, but this time, it showed no uptake in the heart or the liver. Accordingly, we concluded the first result was a false positive due to drug interaction.

The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.

Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.

A gene regulatory network critical for axillary bud dormancy directly controlled by Arabidopsis BRANCHED1.

The Arabidopsis thaliana transcription factor BRANCHED1 (BRC1) plays a pivotal role in the control of shoot branching as it integrates environmental and endogenous signals that influence axillary bud growth. Despite its remarkable activity as a growth inhibitor, the mechanisms by which BRC1 promotes bud dormancy are largely unknown. We determined the genome-wide BRC1 binding sites in vivo and combined these with transcriptomic data and gene co-expression analyses to identify bona fide BRC1 direct targets. Next, we integrated multi-omics data to infer the BRC1 gene regulatory network (GRN) and used graph theory techniques to find network motifs that control the GRN dynamics. We generated an open online tool to interrogate this network. A group of BRC1 target genes encoding transcription factors (BTFs) orchestrate this intricate transcriptional network enriched in abscisic acid-related components. Promoter::ß-GLUCURONIDASE transgenic lines confirmed that BTFs are expressed in axillary buds. Transient co-expression assays and studies in planta using mutant lines validated the role of BTFs in modulating the GRN and promoting bud dormancy. This knowledge provides access to the developmental mechanisms that regulate shoot branching and helps identify candidate genes to use as tools to adapt plant architecture and crop production to ever-changing environmental conditions.

Critical systolic blood pressure threshold for endovascular aortic occlusion-A multinational analysis to determine when to place a REBOA.

BACKGROUND: Systolic blood pressure (SBP) is a potential indicator that could guide when to use a resuscitative endovascular balloon occlusion of the aorta (REBOA) in trauma patients with life-threatening injuries. This study aims to determine the optimal SBP threshold for REBOA placement by analyzing the association between SBP pre-REBOA and 24-hour mortality in severely injured hemodynamically unstable trauma patients. METHODS: We performed a pooled analysis of the aortic balloon occlusion (ABO) trauma and AORTA registries. These databases record the details related to the use of REBOA and include data from 14 countries worldwide. We included patients who had suffered penetrating and/or blunt trauma. Patients who arrived at the hospital with a SBP pre-REBOA of 0 mm Hg and remained at 0 mm Hg after balloon inflation were excluded. We evaluated the impact that SBP pre-REBOA had on the probability of death in the first 24 hours. RESULTS: A total of 1,107 patients underwent endovascular aortic occlusion, of these, 848 met inclusion criteria. The median age was 44 years (interquartile range [IQR], 27-59 years) and 643 (76%) were male. The median injury severity score was 34 (IQR, 25-45). The median SBP pre-REBOA was 65 mm Hg (IQR, 49-88 mm Hg). Mortality at 24 hours was reported in 279 (32%) patients. Math modeling shows that predicted probabilities of the primary outcome increased steadily in SBP pre-REBOA below 100 mm Hg. Multivariable mixed-effects analysis shows that when SBP pre-REBOA was lower than 60 mm Hg, the risk of death was more than 50% (relative risk, 1.5; 95% confidence interval, 1.17-1.92; p = 0.001). DISCUSSION: In patients who do not respond to initial resuscitation, the use of REBOA in SBPs between 60 mm Hg and 80 mm Hg may be a useful tool in resuscitation efforts before further decompensation or complete cardiovascular collapse. The findings from our study are clinically important as a first step in identifying candidates for REBOA. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

Vascular access complications associated with resuscitative endovascular balloon occlusion of the aorta in adult trauma patients: A systematic review and meta-analysis.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is gaining popularity worldwide for managing hypotensive trauma patients. Vascular access complications related to REBOA placement have been reported, with some cases resulting in permanent morbidity. We aim to capitalize on the increase in literature to further describe and estimate the incidence of REBOA-associated vascular access complications in adult trauma patients. METHODS: We searched Medline, EMBASE, Scopus, and CINAHL for studies reporting vascular access complications of REBOA in adult trauma patients from inception to October 14, 2021. Studies reporting data from adult trauma patients who underwent REBOA insertion were eligible. Exclusion criteria included patients 15 years and younger, nontrauma patients, non-REBOA use, non-vascular access complications and patient duplication. Study data was abstracted using the PRISMA checklist and verified independently by three reviewers. Meta-analysis of proportions was performed using a random effects model with Freeman-Turkey double-arcsine transformation. Post hoc meta-regression by year of publication, sheath-size, and geographic region was also performed. The incidence of vascular access complications from REBOA insertion was the primary outcome of interest. Subgroup analysis was performed by degree of bias, sheath size, technique of vascular access, provider specialty, geographical region, and publication year. RESULTS: Twenty-four articles were included in the systematic review and the meta-analysis, for a total of 675 trauma patients who underwent REBOA insertion. The incidence of vascular access complications was 8% (95% confidence interval, 5%-13%). In post hoc meta-regression adjusting for year of publication and geographic region, the use of a smaller (7-Fr) sheath was associated with a decreased incidence of vascular access complications (odds ratio, 0.87; 95% confidence interval, 0.75-0.99; p = 0.046; R 2 = 35%; I 2 = 48%). CONCLUSION: This study provides a benchmark for quality of care in terms of vascular access complications related to REBOA insertion in adult trauma patients. Smaller sheath size may be associated with a decrease in vascular access complications. LEVEL OF EVIDENCE: Systematic Review and Meta-Analysis; Level III.

Exploring Spoken Discourse and Its Neural Correlates in Women With Alzheimer's Disease With Low Levels of Education and Socioeconomic Status.

PURPOSE: Early impairments in spoken discourse abilities have been identified in Alzheimer's disease (AD). However, the impact of AD on spoken discourse and the associated neuroanatomical correlates have mainly been studied in populations with higher levels of education, although preliminary evidence seems to indicate that socioeconomic status (SES) and level of education have an impact on spoken discourse. The purpose of this study was to analyze microstructural variables in spoken discourse in people with AD with low-to-middle SES and low level of education and to study their association with gray matter (GM) density. METHOD: Nine women with AD and 10 matched (age, SES, and education) women without brain injury (WWBI) underwent a neuropsychological assessment, which included two spoken discourse tasks, and structural magnetic resonance imaging. Microstructural variables were extracted from the discourse samples using NILC-Metrix software. Brain density, measured by voxel-based morphometry, was compared between groups and then correlated with the differentiating microstructural variables. RESULTS: The AD group produced a lower diversity of verbal time moods and fewer words and sentences than WWBI but a greater diversity of pronouns, prepositions, and lexical richness. At the neural level, the AD group presented a lower GM density bilaterally in the hippocampus, the inferior temporal gyrus, and the anterior cingulate gyrus. Number of words and sentences produced were associated with GM density in the left parahippocampal gyrus, whereas the diversity of verbal moods was associated with the basal ganglia and the anterior cingulate gyrus bilaterally. CONCLUSIONS: The present findings are mainly consistent with previous studies conducted in groups with higher levels of SES and education, but they suggest that atrophy in the left inferior temporal gyrus could be critical in AD in populations with lower levels of SES and education. This research provides evidence on the importance of pursuing further studies including people with various SES and education levels. WHAT IS ALREADY KNOWN ON THIS SUBJECT: Spoken discourse has been shown to be affected in Alzheimer disease, but most studies have been conducted on individuals with middle-to-high SES and high educational levels. WHAT THIS STUDY ADDS: The study reports on microstructural measures of spoken discourse in groups of women in the early stage of AD and healthy women, with low-to-middle SES and lower levels of education. CLINICAL IMPLICATIONS OF THIS STUDY: This study highlights the importance of taking into consideration the SES and education level in spoken discourse analysis and in investigating the neural correlates of AD. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24905046.