Specialization of amygdala subregions in emotion processing.

The amygdala is important for human fear processing. However, recent research has failed to reveal specificity, with evidence that the amygdala also responds to other emotions. A more nuanced understanding of the amygdala's role in emotion processing, particularly relating to fear, is needed given the importance of effective emotional functioning for everyday function and mental health. We studied 86 healthy participants (44 females), aged 18-49 (mean 26.12 ± 6.6) years, who underwent multiband functional magnetic resonance imaging. We specifically examined the reactivity of four amygdala subregions (using regions of interest analysis) and related brain connectivity networks (using generalized psycho-physiological interaction) to fear, angry, and happy facial stimuli using an emotional face-matching task. All amygdala subregions responded to all stimuli (p-FDR < .05), with this reactivity strongly driven by the superficial and centromedial amygdala (p-FDR < .001). Yet amygdala subregions selectively showed strong functional connectivity with other occipitotemporal and inferior frontal brain regions with particular sensitivity to fear recognition and strongly driven by the basolateral amygdala (p-FDR < .05). These findings suggest that amygdala specialization to fear may not be reflected in its local activity but in its connectivity with other brain regions within a specific face-processing network.

Extended septal myectomy versus Alcohol septal ablation. Clinical results in a national referral center.

OBJECTIVES: Extended septal myectomy and alcohol septal ablation are two invasive treatments for hypertrophic obstructive cardiomyopathy. We aim to compare which of these techniques achieves a higher reduction in gradients, improvement in NYHA class and reduction in medical treatment. METHODS: This is a single-center observational and retrospective analysis. This is a single-center observational and retrospective analysis. We have used multivariable regression analyses to assess the association of ablation/myectomy with different outcomes. Odds ratio or coefficient along with the 95% confidence interval were estimated according to the group, and adjusting for the corresponding pre procedural variables and Euroscore II. RESULTS: 78 patients underwent septal myectomy and 25 patients underwent alcohol septal ablation. Basal and Valsalva gradients after myectomy were reduced in a higher degree in comparison to ablation, 21.0 mmHg (p < 0.001, 95%CI -30.7; -11.3), and 34.3 mmHg (p < 0.001, -49.1; -19.5) respectively. Those patients who received myectomy had lower probability of presenting moderate mitral regurgitation (OR = 0.18, p = 0.054). Patients after septal myectomy were more likely to be in NYHA I (80.4%); whilst patients after ablation were more likely to be NYHA III (48%). Both groups continued with betablocker therapy, but disopyramide could be discontinued after myectomy in more cases (20% - 36% vs. 59% - 1.3%; p < 0.001) and there is a tendency in the discontinuation of calcium channel blockers (48% - 16% vs. 15.4-3.8%; p = 0.054). CONCLUSIONS: After adjustment by pre procedural gradients and Euroscore II, myectomy achieves greater reduction in left ventricular outflow tract gradients compared to septal ablation.

Cyborg islets: implanted flexible electronics reveal principles of human islet electrical maturation.

Flexible electronics implanted during tissue formation enable chronic studies of tissue-wide electrophysiology. Here, we integrate tissue-like stretchable electronics during organogenesis of human stem cell-derived pancreatic islets, stably tracing single-cell extracellular spike bursting dynamics over months of functional maturation. Adapting spike sorting methods from neural studies reveals maturation-dependent electrical patterns of α and ß-like (SC-α and ß) cells, and their stimulus-coupled dynamics. We identified two major electrical states for both SC-α and ß cells, distinguished by their glucose threshold for action potential firing. We find that improved hormone stimulation capacity during extended culture reflects increasing numbers of SC-α/ß cells in low basal firing states, linked to energy and hormone metabolism gene upregulation. Continuous recording during further maturation by entrainment to daily feeding cycles reveals that circadian islet-level hormone secretion rhythms reflect sustained and coordinate oscillation of cell-level SC-α and ß electrical activities. We find that this correlates with cell-cell communication and exocytic network induction, indicating a role for circadian rhythms in coordinating system-level stimulus-coupled responses. Cyborg islets thus reveal principles of electrical maturation that will be useful to build fully functional in vitro islets for research and therapeutic applications.

Validation of mutated CEBPA bZIP as a distinct prognosis entity in acute myeloid leukemia: a study by the Spanish PETHEMA registry.

Not available.

Conventional Versus Traction-Assisted Endoscopic Submucosal Dissection for Esophageal, Gastric, and Colorectal Neoplasms: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Endoscopic submucosal dissection (ESD) is increasingly being utilized for the resection of superficial gastrointestinal neoplasms. However, the long procedure time poses a technical challenge for conventional ESD (C-ESD). Traction-assisted ESD (T-ESD) was developed to facilitate the procedure by reducing its duration. This study compares the efficacy and safety of C-ESD versus T-ESD in the treatment of esophageal, gastric, and colorectal neoplasms. Nine randomized controlled trials (RCTs) were analyzed. Traction-assisted ESD exhibited shorter mean dissection times for the esophagus and colorectal regions and lower perforation rates in colorectal cases. No significant differences were observed in en bloc resection or bleeding rates. Traction-assisted ESD proves to be more efficient in mean procedure time for esophageal and colorectal cases and safer in perforation rates for colorectal cases, but similar rates are noted for en bloc resection or bleeding.

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).

Non-Tuberculous Mycobacterial isolates from Panama: A retrospective 5-year analysis (2017-2021).

BACKGROUND: The genus Mycobacterium includes well-known bacteria such as M. tuberculosis causing tuberculosis and M. leprae causing leprosy. Additionally, various species collectively termed non-tuberculous mycobacteria (NTM) can cause infections in humans and animals, affecting individuals across all age groups and health conditions. However, information on NTM infection prevalence in Panama is limited. METHODS: This study conducted a retrospective analysis of clinical records from 2017 to 2021, specifically focusing on patients with NTM isolates. Data were categorized by variables like sex, age, HIV status, and sample source. RESULTS: Among the 4430 clinical records analyzed, 698 were linked to patients with NTM isolates. Of these patients, 397 were male, and 301 were female. Most female patients with NTM isolates (n = 190) were aged >45 to 85 years, while most male patients (n = 334) fell in the >25 to 75 years age group. A noteworthy proportion of male patients (n = 65) were aged 25-35 years. A significant age difference between male (median [min-max] = 53 years [3-90]) and female (median [61 years [6-94]) patients was observed (p < 0.001). Regarding HIV status, 77 positive individuals were male, and 19 were female (p < 0.001). Most samples (n = 566) were sputum samples, with additional pulmonary-associated samples such as broncho-alveolar lavage, tracheal secretions, and pleural fluid samples. Among extrapulmonary isolates (n = 48), sources included catheter secretions, intracellular fluids, peritoneal fluid, blood cultures, cerebrospinal fluid, bone marrow samples, and capillary transplant lesions. Specifically, the analysis identified the pathogenic microorganisms responsible for mycobacteriosis in Panama during the specific period 2017-2021, as M. fortuitum (34.4%), M. intracellulare (20.06%), and M. abscessus (13.75%), respectively. CONCLUSIONS: This study highlights the growing public health concern of NTM infections in Panama. The research provides valuable insights into the prevalence and distribution of NTM species in the country, offering a foundation for the development and implementation of effective prevention and control strategies for NTM infections in Panama.

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.

Diferencias clínicas entre la amiloidosis cardiaca por transtirretina y la cardiopatía hipertensiva / Clinical differences between transthyretin cardiac amyloidosis and hypertensive heart disease

Introducción: Un porcentaje importante de pacientes finalmente diagnosticados de amiloidosis cardIaca por transtirretina (ATTR) fueron previamente diagnosticados de cardiopatía hipertensiva (CHTA), ya que ambas enfermedades suelen cursar con insuficiencia cardíaca (IC) con fracción de eyección preservada (ICFEp) e hipertrofia ventricular. Nuestros objetivos fueron evaluar las diferencias clínicas, electrocardiográficas y ecocardiográficas, y analizar si existe un pronóstico diferencial entre ambas entidades nosológicas. Material y métodos: Se incluyeron retrospectivamente todos los pacientes con CHTA a los que se solicitó una gammagrafía cardíaca con 99mTc-Difosfonatos (GDPD) y estudio de cadenas ligeras en sangre y orina para despistaje de ATTR en nuestro centro, en el periodo 2016-2021. Para el análisis, se excluyeron aquellos diagnosticados de otros tipos de amiloidosis. Resultados: Se analizaron un total de 72 pacientes: 33 fueron diagnosticados de ATTR y 39 de CHTA, finalmente. Los pacientes con ATTR presentaron mayores niveles de troponina I ultrasensible (TnI-US) y propéptido natriurético cerebral N-terminal (NT-ProBNP); en electrocardiograma (ECG) presentaron más frecuentemente patrón de seudoinfarto y alteraciones de la conducción; en ecocardiograma transtorácico (ETT) presentaron mayor grado de hipertrofia ventricular, disfunción ventricular izquierda y parámetros de peor función diastólica, con presiones de llenado más elevadas. En el seguimiento a 4 años, el grupo de ATTR mostró mayor necesidad de marcapasos (MCP), sin evidenciarse evidencias en cuanto a mortalidad, desarrollo de fibrilación auricular o más ingresos por IC. Conclusiones: En nuestra serie, los pacientes con ATTR presentaron diferencias clínicas, electrocardiográficas y ecocardiográficas respecto a aquellos con CHTA, con mayor riesgo necesidad de MCP en el seguimiento.(AU)

Introduction: A significant percentage of patients eventually diagnosed with cardiac transthyretin amyloidosis (TTRA) was previously diagnosed with hypertensive heart disease (HHD), since both conditions usually present with heart failure (HF) with preserved ejection fraction (HFpEF) and ventricular hypertrophy. Our objectives were to evaluate the clinical, electrocardiographic and echocardiographic differences, and to analyse whether there exists a differential prognosis between these two nosological entities. Materials and methods: We retrospectively included all patients with HHD for whom a cardiac scintigraphy with 99mTc-diphosphonate (GDPD) and a free light chains test in blood and urine were ordered for ATTR screening in our centre, in the period between 2016 and 2021. Those diagnosed with other types of amyloidosis were excluded from the analysis. Results: A total of 72 patients were analyzed: 33 were finally diagnosed with TTRA and 39 with CHTA. Patients with TTRA had higher levels of ultrasensitive troponin I (TnI-US) and N-terminal brain natriuretic propeptide (NT-ProBNP); in electrocardiography (ECG) they presented a pseudo-infarction pattern more frequently as well as conduction disturbances; in echocardiography (TTE) they presented a higher degree of ventricular hypertrophy, left ventricular dysfunction and worse diastolic function parameters, with elevated filling pressures. In the 4-year follow-up, the ATTR group showed greater need for pacemaker (PCM), with no evidence regarding mortality, development of atrial fibrillation (AF), or more admissions for heart failure (HF). Conclusions: In our series, patients with TTRA showed clinical, electrocardiographic and echocardiographic differences compared to patients with HHD, with increased risk of need for PCM.(AU)

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)

The Fabaceae in Northeastern Mexico (Subfamily Caesalpinioideae, Mimosoideae Clade, Tribes Mimoseae, Acacieae, and Ingeae).

A synoptic compendium of the legumes of the Mimosoideae clade in northeastern Mexico is presented for the first time, including changes in their botanical nomenclature and retypification of genera. Furthermore, based on new information recently published, the taxonomic limits of several new genera segregated from Acacia (Acaciella, Mariosousa, Senegalia, and Vachellia) and Prosopis (Neltuma and Strombocarpa) are clarified and included. Based on field work, collection of botanical samples over the past 30 years, and reviewing botanical materials in national and international herbaria, we have completed the diversity of legumes of the Mimosoideae clade of northeastern Mexico. Three tribes (Acacieae, Ingeae, and Mimosaeae), 22 genera, 92 species, and 19 infraspecific categories were recorded. Only the genus Painteria is endemic to Mexico. Eighty-eight species are native to Mexico, and four are exotic: Acacia salicina, Neptunia prostrata, Neltuma chilensis and Albizia lebbeck. Twenty-eight species are endemic to Mexico, nine species are endemic to northeastern Mexico, and four species are endemic to only one state in Mexico. The 22 registered genera represent 44% and 65% of the generic flora of the Mimosoideae clade for Mexico and the planet, respectively, while the 92 species registered represent 3% and 18% of the species of the clade Mimosoideae for the planet and Mexico, respectively. According to the new nomenclature of legumes, the number of genera in the Mimosoideae clade in northern Mexico has increased from 19 to 24.

Valve Hemodynamics by Valve Size and 1-Year Survival Following Implantation of the Portico Valve in the Multicenter CONFIDENCE Registry.

Background: The CONtrolled delivery For ImproveD outcomEs with cliNiCal Evidence registry was initiated to characterize the clinical safety and device performance from experienced transcatheter aortic valve implantation (TAVI) centers in Europe and Australia that use the Portico valve to treat patients with severe aortic stenosis. We herein report for the first time the valve performance at 30-day across all implanted valve sizes and the 1-year survival from this registry. Methods: This was a prospective, multicenter, single-arm observational clinical investigation of patients clinically indicated for implantation of a Portico valve in experienced TAVI centers. Patients were treated with a commercially available valve (size 23, 25, 27, or 29 mm) using either the first-generation delivery system (DS) (n = 501) or the second-generation (FlexNav) DS (n = 500). Adverse events were adjudicated by an independent clinical events committee according to Valve Academic Research Consortium-2 criteria. Echocardiographic outcomes were assessed at 30 days by an independent core laboratory, and a survival check was performed at 1 year. Results: We enrolled 1001 patients (82.0 years, 62.5% female, 63.7% New York Heart Association functional class III/IV at baseline) from 27 clinical sites in 8 countries across Europe and one site in Australia. Implantation of a single valve was successful in 97.5% of subjects. Valve hemodynamics at 30 days were substantially improved relative to baseline, with large aortic valve areas and low mean gradients across all implanted valve sizes (aortic valve areas were 1.7 ± 0.4, 1.7 ± 0.5, 1.8 ± 0.5, and 2.0 ± 0.5 cm2, and mean gradients were 7.0 ± 2.7, 7.5 ± 4.7, 7.3 ± 3.3, and 6.4 ± 3.3 mmHg for 23, 25, 27, and 29 mm valve sizes, respectively). Across all implanted valve sizes, most patients (77.1%) had no patient-prosthesis mismatch. Death from any cause within 1 year occurred in 13.7% of the patients in the first-generation DS group as compared with 11.0% in the second-generation DS group (p = 0.2). Conclusions: The Portico valve demonstrated excellent hemodynamic performance across all valve sizes in a large cohort of subjects implanted in experienced TAVI centers. One-year survival rates were favorable when using both the first-generation and second-generation (FlexNav) DSs in this high-risk cohort. ClinicalTrialsgov Identifier: NCT03752866.

Clinical differences between transthyretin cardiac amyloidosis and hypertensive heart disease. / Diferencias clínicas entre la amiloidosis cardiaca por transtirretina y la cardiopatía hipertensiva.

INTRODUCTION: A significant percentage of patients eventually diagnosed with cardiac transthyretin amyloidosis (TTRA) was previously diagnosed with hypertensive heart disease (HHD), since both conditions usually present with heart failure (HF) with preserved ejection fraction (HFpEF) and ventricular hypertrophy. Our objectives were to evaluate the clinical, electrocardiographic and echocardiographic differences, and to analyse whether there exists a differential prognosis between these two nosological entities. MATERIALS AND METHODS: We retrospectively included all patients with HHD for whom a cardiac scintigraphy with 99mTc-diphosphonate (GDPD) and a free light chains test in blood and urine were ordered for ATTR screening in our centre, in the period between 2016 and 2021. Those diagnosed with other types of amyloidosis were excluded from the analysis. RESULTS: A total of 72 patients were analyzed: 33 were finally diagnosed with TTRA and 39 with CHTA. Patients with TTRA had higher levels of ultrasensitive troponin I (TnI-US) and N-terminal brain natriuretic propeptide (NT-ProBNP); in electrocardiography (ECG) they presented a pseudo-infarction pattern more frequently as well as conduction disturbances; in echocardiography (TTE) they presented a higher degree of ventricular hypertrophy, left ventricular dysfunction and worse diastolic function parameters, with elevated filling pressures. In the 4-year follow-up, the ATTR group showed greater need for pacemaker (PCM), with no evidence regarding mortality, development of atrial fibrillation (AF), or more admissions for heart failure (HF). CONCLUSIONS: In our series, patients with TTRA showed clinical, electrocardiographic and echocardiographic differences compared to patients with HHD, with increased risk of need for PCM.

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.

Expansion of human hematopoietic stem cells by inhibiting translation.

Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ~5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of the BCL11A+58 enhancer, overcoming a major obstacle to ex vivo gene correction for human hemoglobinopathies.

Pre-freezing selection of Holstein bull semen with the BoviPure colloid as double- or single-layer centrifugation improves the post-thawing quality.

Artificial insemination (AI) is critical for breeding in the dairy industry. High-merit bulls can present low freezability, hampering genetic dissemination. Thawed semen can be improved using density gradient centrifugation (DGC) with colloids, but little information deals with the pre-freezing application. Thus, the BoviPure colloid (optimized for bull spermatozoa) was tested for pre-freezing application as the usual double-layer (DLC) versus single-layer (SLC, quick and economical). Semen from twelve Holstein-Friesian bulls was extended with OPTIXcell extender, frozen (Control), or processed by SLC or DLC and frozen. Sperm were assessed pre-freezing for motility and viability and post-thawing (directly and after 4 h 38 °C) for apoptosis, capacitation status, acrosomal damage, mitochondrial activity, cytoplasmic and mitochondrial reactive oxygen species (ROS), and chromatin status (SCSA for DNA fragmentation and chromatin compaction and monobromobimane, mBBr, for disulfide bridges evaluation). The DGC improved parameters post-thawing (e.g., 57.5%±10.1 motility vs. control 53.3% ± 11.2) at the cost of sperm loss (sperm recovery of DGC 14.4% ± 2.5 and SLC 17.4% ± 2.5). DNA fragmentation (%DFI) decreased (0.21% ± 0.53 vs. control 1.30% ± 0.10), and SLC reduced chromatin compaction. A clustering procedure separated lesser (LF) and greater freezability (GF) bulls. LF samples were especially benefited by DGC, with SLC providing better post-thawing results for this group. In conclusion, pre-freezing DGC improved sperm parameters post-thawing, potentially improving the cryopreservation of low-freezability semen from high-merit bulls. SLC, quicker and economical, would be preferable since it showed similar or higher performance than DLC.

Immunohistochemical Analysis of Knee Chondral Defect Repair after Autologous Particulated Cartilage and Platelet-Rich Plasma Treatment in Sheep.

This study performs an analysis that will enable the evaluation of the quality, durability, and structure of repaired cartilaginous extracellular matrix tissue using an autologous-based particulated autograft cartilage and platelet-rich plasma treatment (PACI + PRP). A single-blind controlled experiment was conducted on 28 sheep to evaluate the efficacy of the PACI + PRP treatment for cartilage defects. Full-thickness 8 mm diameter defects were created in the weight-bearing area of both knees. The right knees received PACI + PRP. The left knees were treated with Ringer's lactate solution (RLS) or hyaluronic acid (HA) injections. Sheep were euthanized at 9- or 18-months post-surgery. An extensive immunohistochemical analysis was performed to assess collagen types (I, II, III, V, VI, IX, X, XI) and aggrecan positivity. A semiquantitative scoring system provided a detailed evaluation of immunostaining. Collagens and aggrecan scores in the PACI + PRP groups were similar to healthy cartilage. Significant differences were found in collagens associated with matrix maturity (II and V), degradation (IX), structure and mechanics (VI), and hypertrophy (X) between healthy cartilage and RLS- or HA-repaired cartilage. The PACI + PRP treatment advanced the repair cartilage process in chondral defects with mature hyaline cartilage and enhanced the structural and mechanical qualities with better consistent cartilage, less susceptible to degradation and without hypertrophic formation over time.