Connecting Clinical Capacity and Intervention Sustainability in Resource-Variable Pediatric Oncology Centers in Latin America.

Clinical capacity for sustainability, or the clinical resources needed to sustain an evidence-based practice, represent proximal determinants that contribute to intervention sustainment. We examine the relationship between clinical capacity for sustainability and sustainment of PEWS, an evidence-based intervention to improve outcomes for pediatric oncology patients in resource-variable hospitals. We conducted a cross-sectional survey among Latin American pediatric oncology centers participating in Proyecto Escala de Valoración de Alerta Temprana (EVAT), an improvement collaborative to implement Pediatric Early Warning Systems (PEWS). Hospitals were eligible if they had completed PEWS implementation. Clinicians were eligible to participate if they were involved in PEWS implementation or used PEWS in clinical work. The Spanish language survey consisted of 56 close and open-ended questions about the respondent, hospital, participants' assessment of clinical capacity to sustain PEWS using the clinical sustainability assessment tool (CSAT), and perceptions about PEWS and its use as an intervention. Results were analyzed using a multi-level modeling approach to examine the relationship between individual, hospital, intervention, and clinical capacity determinants to PEWS sustainment. A total of 797 responses from 37 centers in 13 countries were included in the analysis. Eighty-seven percent of participants reported PEWS sustainment. After controlling for individual, hospital, and intervention factors, clinical capacity was significantly associated with PEWS sustainment (OR 3.27, p < .01). Marginal effects from the final model indicate that an increasing capacity score has a positive influence (11% for every additional CSAT point) of predicting PEWS sustainment. PEWS is a sustainable intervention and clinical capacity to sustain PEWS contributes meaningfully to PEWS sustainment.

Urolithin A production drives the effects of pomegranate on the gut microbial metabolism of bile acids and cholesterol in mild dyslipidaemic overweight and obese individuals.

The metabolism of (poly)phenols and some host metabolites, including bile acids (BAs) and cholesterol, varies among individuals depending on their gut microbiota. The gut microbial metabolism of ellagitannins (ETs) and ellagic acid (EA) produces urolithins (Uros), yielding three metabotypes with quantitative and qualitative differences based on dissimilar Uro-producing profiles (UM-A, UM-B, and UM-0, i.e., non-producers). Previous animal studies demonstrated that polyphenols impact BAs and cholesterol microbial metabolism, but data on their effects in humans and data regarding the inter-individual variability of these metabolic conversions are scant. We evaluated whether UMs, as distinctive functional gut-microbiome signatures, could determine the potential effect of a pomegranate extract (PE) rich in ET-EA on the metabolism of BAs and cholesterol in mild dyslipidaemic overweight-obese individuals, with possible consequences on host-lipid homeostasis and gut health. At the baseline, UM-B presented the highest levels of faecal total and secondary BAs and coprostanol, suggesting that the lipid absorption capacity and gut cytotoxic risk could be augmented in UM-B. PE intake significantly reduced faecal coprostanol and BA production, especially secondary BAs, and modulated the gut microbiome, reducing the gut cytotoxic risk, especially in UM-B individuals. The lowering of faecal microbial coprostanol and BAs and some BA-metabolising bacteria was quantitatively correlated with Uro concentrations, mainly faecal Uro-A. This suggests that PE consumption could exert cardiovascular and gut protection through Uro-A production as a direct driver of the effects and indirectly by reducing the Coriobacteriaceae family and BA pool, known factors involved in the gut absorption of lipids.

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-ß driven Alzheimer's disease in mice.

The "gut-brain axis" is emerging as an important target in Alzheimer's disease (AD). However, immunological mechanisms underlying this axis remain poorly understood. Using single-cell RNA sequencing of the colon immune compartment in the 5XFAD amyloid-ß (Aß) mouse model, we uncovered AD-associated changes in ribosomal activity, oxidative stress, and BCR/plasma cell activity. Strikingly, levels of colon CXCR4 + antibody secreting cells (ASCs) were significantly reduced. This corresponded with accumulating CXCR4 + B cells and gut-specific IgA + cells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, was expressed at higher levels in 5XFAD glial cells and in in silico analyzed human brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet attenuated AD markers including Aß plaques and overall frailty. These changes corresponded to an expansion of gut IgA + cells and rescued peripheral T regs levels. Our study points to a key glia-gut axis and potential targets against AD. Study Highlights: AD is associated with altered immune parameters in the gut of 5XFAD mice. 5 XFAD colon has reduced ASCs, including CXCR4 + cells with a migratory gene signature. 5XFAD brain gliosis includes increased CXCL12 expression. CXCR4 + B cells and gut-specific IgA + ASCs accumulate in the 5XFAD brain and/or dura mater. Inulin diet attenuates AD disease parameters while boosting IgA + cell and T reg levels.

Inpatient thrombophilia workup; does hematology consult prevent unnecessary testing?

Hypercoagulable disorders are best described as a group of acquired and hereditary conditions that increase the risk for the development of thrombi within veins or arteries. In the setting of an unprovoked venous thromboembolism, common practice in the inpatient setting has been further investigation via a thrombophilia workup to establish an underlying cause. Current Hematology-Oncology guidelines argue against inpatient workup as the results rarely influence inpatient management. Following American Society of Hematology guidelines (Middledorp), the current study found that only 15% (11/72) of patients met appropriate criteria for thrombophilia testing. There was no relationship between appropriate thrombophilia testing and diagnosis of thrombophilia or initiation of anticoagulation. There was a relationship between appropriate thrombophilia testing and Hematology-Oncology consultation. This demonstrates the need for expert consultation if thrombophilia testing is being considered. The current study provides more evidence that a strong recommendation against inpatient testing should be made as testing does not aid in diagnosis or change management and is an overutilization of healthcare resources.

Proteomic analysis of X-linked dystonia parkinsonism disease striatal neurons reveals altered RNA metabolism and splicing.

X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP is an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within intron 32 of TATA-binding protein associated factor 1 (TAF1) that causes an alteration of TAF1 splicing, partial intron retention, and decreased transcription. Although TAF1 is expressed in all organs, medium spiny neurons (MSNs) within the striatum are one of the cell types most affected in XDP. To define how mutations in the TAF1 gene lead to MSN vulnerability, we carried out a proteomic analysis of human XDP patient-derived neural stem cells (NSCs) and MSNs derived from induced pluripotent stem cells. NSCs and MSNs were grown in parallel and subjected to quantitative proteomic analysis in data-independent acquisition mode on the Orbitrap Eclipse Tribrid mass spectrometer. Subsequent functional enrichment analysis demonstrated that neurodegenerative disease-related pathways, such as Huntington's disease, spinocerebellar ataxia, cellular senescence, mitochondrial function and RNA binding metabolism, were highly represented. We used weighted coexpression network analysis (WGCNA) of the NSC and MSN proteomic data set to uncover disease-driving network modules. Three of the modules significantly correlated with XDP genotype when compared to the non-affected control and were enriched for DNA helicase and nuclear chromatin assembly, mitochondrial disassembly, RNA location and mRNA processing. Consistent with aberrant mRNA processing, we found splicing and intron retention of TAF1 intron 32 in XDP MSN. We also identified TAF1 as one of the top enriched transcription factors, along with YY1, ATF2, USF1 and MYC. Notably, YY1 has been implicated in genetic forms of dystonia. Overall, our proteomic data set constitutes a valuable resource to understand mechanisms relevant to TAF1 dysregulation and to identify new therapeutic targets for XDP.

A ketogenic diet reduces age-induced chronic neuroinflammation in mice Running title: ketogenic diet and brain inflammaging.

Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionally in vitro. Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demonstrate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.

[Experience in COVID-19 in hospitalized patients in pediatric critical units during pandemic period]. / Experiencia en COVID-19 en pacientes hospitalizados en unidades de paciente crítico pediátrico durante el periodo pandémico.

OBJECTIVES: To characterize the COVID-19 disease profile in Chilean children hospitalized in pediatric intensive care units (PICU) and to evaluate risk factors associated with severe COVID-19. PATIENTS AND METHOD: A multicenter prospective cohort study with patients 0-18 years of age with confirmed SARS-CoV-2 hospitalized in PICU. Clinical, laboratory, imaging, and therapeutic variables were recorded. We compared "mild/moderate COVID-19" with ''severe COVID-19" using median with interquartile range (IQR), Mann-Whitney U test, two-tailed Fisher's test, and forward binary multivariate analysis to adjust variables for "severe COVID-19". A p < 0.05 was considered significant. RESULTS: From 16 PICUs, 219 patients were recruited, 55.3% were male, with a median age of 86 months (IQR: 13.5-156). The most frequent comorbidities were obesity and respiratory diseases. Overall mortality was 3.6%. "Severe COVID-19" (26.5%) showed more leukopenia, lymphopenia, increased inflammatory parameters, and altered organ function (p < 0.05). It also developed more sepsis/shock, ARDS, and organ dysfunction, requiring more hemodynamic, anti-inflammatory, anticoagulation, and antibiotic therapy, with a longer stay in the PICU/hospital (p < 0.05), and 13.8% of mortality. Risk factors associated with "severe COVID-19" were shock on admission to the PICU [aOR 28.44 (95%CI 10.45-77.4)], obesity [aOR 3.55 (95%CI 1.3-9.6)], consolidation [aOR 3.1 (95%CI 1.1 -8.7)], atelectasis [aOR: 8.7 (95%CI 1.17-64.3)], stress dose of corticosteroids [aOR 7.7 (95%CI 1.9-30.6)], early antibiotic therapy [aOR: 12.02 (95%CI 1.11-130.02)], acquired/congenital immunodeficiency [aOR: 19.2 (95%CI: 1.19-321)], and oncological pathology [aOR 10.7 (95%CI 2.14-47.8)]. CONCLUSION: In this Chilean pediatric cohort, most patients with COVID-19 admitted to de PICU were male, of school age, with associated comorbidity. Risk factors for developing severe COVID-19 were the presence of comorbidities such as acquired/congenital immunodeficiency, oncological pathology, and obesity, in addition to shock on admission and consolidations on X-rays.

Unveiling metabotype clustering in resveratrol, daidzein, and ellagic acid metabolism: Prevalence, associated gut microbiomes, and their distinctive microbial networks.

The gut microbiota (GM) produces different polyphenol-derived metabolites, yielding high interindividual variability and hampering consistent health effects. GM metabotypes associated with ellagic acid (urolithin metabotypes A (UMA), B (UMB), and 0 (UM0)), resveratrol (lunularin -producers (LP) and non-producers (LNP)), and daidzein (equol-producers (EP) and non-producers (ENP)) are known. However, individual polyphenol-related metabotypes do not occur individually. In contrast, different combinations coexist (i.e., metabotype clusters, MCs). We report here for the first time these MCs, their distribution, and their associated GM in adult humans (n = 127) after consuming for 7 days a nutraceutical (pomegranate, Polygonum cuspidatum, and red clover extracts) containing ellagitannins + ellagic acid, resveratrol, and isoflavones. Urine metabolites (UHPLC-QTOF-MS) and fecal microbiota (16S rRNA sequencing) were analyzed. Ten MCs were identified: LP + UMB + ENP (22.7%), LP + UMA + ENP (21.3%), LP + UMA + EP (16.7%), LP + UMB + EP (16%), LNP + UMA + ENP (11.3%), LNP + UMB + ENP (5.3%), LNP + UMA + EP (3.3%), LNP + UMB + EP (2%), LNP + UM0 + EP (0.7%), and LNP + UM0 + ENP (0.7%). Sex, BMI, and age did not affect the distribution of metabotypes or MCs. Multivariate analysis (MaAslin2) revealed genera differentially present in individual metabotypes and MCs. Network analysis (MENA) showed the taxa acting as module hubs and connectors. Compositional and functional profiling, alpha and beta diversities, topological network features, and GM modulation by the nutraceutical differed depending on whether the entire cohort or each MC was considered. The nutraceutical did not change the composition of LP + UMA + EP (the most robust GM with the most associated functions) but increased its network connectors. This pioneering approach, joining GM's compositional, functional, and network features in polyphenol metabolism, paves the way for identifying personalized GM-targeted strategies to improve polyphenol health benefits.

Factores psicosociales y sociodemográficos asociados con el desgaste profesional en médicos residentes de Sonora (México) / Psychosocial and Sociodemographic Factors Associated with Burnout among Medical Residents of Sonora ­ Mexico / Fatores psicossociais e sociodemográficos associados ao burnout em médicos residentes de Sonora, México

Introducción: la simultaneidad de actividades entre las exigencias académicas y el adiestramiento médico durante las residencias provoca un elevado riesgo de desarrollar un desgaste profesional (o síndrome de burnout [SB]) en los médicos residentes. El objetivo fue identificar los factores psicosociales y socio- demográficos asociados al SB en médicos residentes. Materiales y métodos: estudio transversal y correlacional. Participaron 47 médicos residentes de un hospital público. Se aplicaron la Escala de Desgaste Ocupacional (EDO), el Inventario Multifásico de la Personalidad Minnesota-2 Forma Reestructurada (MMPI2-Rf) y un cuestionario sociodemográfico. Los datos se analizaron mediante la prueba de correlación no paramétrica de Spearman. Resultados: el 25.6 % de los participantes mostró burnout alto, y el 51 %, un agotamiento emocional alto. Respecto a los factores de personalidad y sociodemográficos asociados, solo mostraron relación significativa (p < 0.05) la escala de impulsividad (r = 0.341, p = 0.019) y las horas de ejercicio en la semana (r = −0.414, p = 0.004). Al segmentar por sexo, solo en los hombres del estudio existió una relación entre SB y psicoticismo (r = 0.468, p = 0.018), la disminución de la actividad física (r = −0.620, p = 0.001) y primeros años de residencia (r = −0.396, p = 0.050). Conclusiones: el alto agotamiento emocional de los residentes está asociado con problemas en el manejo de impulsos, distorsiones de la realidad (debido al psicoticismo), pertenecer a los primeros años de residencia y falta de ejercicio físico. Se requiere especial atención a la salud física y mental de estos profesionales

Introduction: The simultaneity of activities between academic demands and medical training during residencies is a high risk of developing burnout syndrome (BS) among resident physicians, which decreases their quality of life. This study aimed to identify the psychosocial and sociodemographic factors associated with BS among resident physicians from a public hospital. Materials and methods: This cross-sectional and correlational study involved 47 resident physicians. The Occupational Burnout Scale (EDO), the Minnesota Multiphasic Personality Inventory-2 Restructured Form, and a sociodemographic questionnaire were applied. The data were analyzed by using nonparametric Spearman's correlation test. Results: We found that 25.6% of the participants had a high level of burnout, while 51% showed a high level of emotional exhaustion. Regarding personality and sociodemographic factors associated with BS, only the impulsivity scale (r = 0.341; p = 0.019) and the hours of exercise performed in a week (r = −0.414; p = 0.004) showed a significant relationship (p < 0.05). When segmented by sex, a relationship between BS and psychoticism (r = 0.468; p = 0.018), decreased physical activity (r = −0.620; p = 0.001), and first years of residence (r = −0.396; p = 0.050) were noted only in men. Conclusions: A high level of emotional exhaustion was evidenced among the medical residents in relation to the development of their activities, which were associated with problems in the management of impulses, distortions of reality (due to psychoticism), belonging to the first years of residency, and the lack of physical exercise. Hence, special attention must be given to the physical and mental health of medical residents

Introdução: a simultaneidade de atividades entre as demandas acadêmicas e ao mesmo tempo a formação médica durante as residências acarreta alto risco de desenvolvimento da Síndrome de Burnout (SB) nos médicos residentes, diminuindo sua qualidade de vida. O objetivo da pesquisa foi identificar os fatores psicossociais e sociodemográficos associados à SB em médicos residentes. Materiais e métodos: estudo transversal e correlacional. Participaram 47 médicos residentes de um hospital público. Aplicou-se a Escala de Desgaste Ocupacional (EDO), o Inventário Multifásico da Personalidade Minnesota-2 Forma Reestruturada (MMPI2-Rf) e adicionalmente um questionário sociodemográfico. Os dados foram analisados por meio do teste de correlação não paramétrica de Spearman. Resultados: 25,6% dos participantes apresentaram alto burnout e 51% alto nível de exaustão emocional. Em relação aos fatores de personalidade e sociodemográficos associados à SB, apenas a escala de impulsividade (r = 0,341; p = 0,019) e as horas de exercício por semana (r = −0,414; p = 0.004) apresentaram relação significativa (p < 0,05). Quando segmentado por sexo, apenas nos homens do estudo houve relação entre SB e psicoticismo (r = 0,468; p = 0,018), diminuição da atividade física (r = −0,620; p = 0,001) e primeiros anos de residência (r = −0,396; p = 0,050). Conclusões: destaca-se o elevado desgaste emocional vivenciado pelos residentes no desenvolvimento das suas atividades, que se associa a problemas na gestão dos impulsos, distorções da realidade (devido ao psicoticismo), estar nos primeiros anos de residência e falta de exercício físico. É necessária atenção especial à saúde física e mental desses profissionais

Effect of paediatric early warning systems (PEWS) implementation on clinical deterioration event mortality among children with cancer in resource-limited hospitals in Latin America: a prospective, multicentre cohort study.

BACKGROUND: Paediatric early warning systems (PEWS) aid in the early identification of clinical deterioration events in children admitted to hospital. We aimed to investigate the effect of PEWS implementation on mortality due to clinical deterioration in children with cancer in 32 resource-limited hospitals across Latin America. METHODS: Proyecto Escala de Valoración de Alerta Temprana (Proyecto EVAT) is a quality improvement collaborative to implement PEWS in hospitals providing childhood cancer care. In this prospective, multicentre cohort study, centres joining Proyecto EVAT and completing PEWS implementation between April 1, 2017, and May 31, 2021, prospectively tracked clinical deterioration events and monthly inpatient-days in children admitted to hospital with cancer. De-identified registry data reported between April 17, 2017, and Nov 30, 2021, from all hospitals were included in analyses; children with limitations on escalation of care were excluded. The primary outcome was clinical deterioration event mortality. Incidence rate ratios (IRRs) were used to compare clinical deterioration event mortality before and after PEWS implementation; multivariable analyses assessed the correlation between clinical deterioration event mortality and centre characteristics. FINDINGS: Between April 1, 2017, and May 31, 2021, 32 paediatric oncology centres from 11 countries in Latin America successfully implemented PEWS through Proyecto EVAT; these centres documented 2020 clinical deterioration events in 1651 patients over 556 400 inpatient-days. Overall clinical deterioration event mortality was 32·9% (664 of 2020 events). The median age of patients with clinical deterioration events was 8·5 years (IQR 3·9-13·2), and 1095 (54·2%) of 2020 clinical deterioration events were reported in male patients; data on race or ethnicity were not collected. Data were reported per centre for a median of 12 months (IQR 10-13) before PEWS implementation and 18 months (16-18) after PEWS implementation. The mortality rate due to a clinical deterioration event was 1·33 events per 1000 patient-days before PEWS implementation and 1·09 events per 1000 patient-days after PEWS implementation (IRR 0·82 [95% CI 0·69-0·97]; p=0·021). In the multivariable analysis of centre characteristics, higher clinical deterioration event mortality rates before PEWS implementation (IRR 1·32 [95% CI 1·22-1·43]; p<0·0001), being a teaching hospital (1·18 [1·09-1·27]; p<0·0001), not having a separate paediatric haematology-oncology unit (1·38 [1·21-1·57]; p<0·0001), and having fewer PEWS omissions (0·95 [0·92-0·99]; p=0·0091) were associated with a greater reduction in clinical deterioration event mortality after PEWS implementation; no association was found with country income level (IRR 0·86 [95% CI 0·68-1·09]; p=0·22) or clinical deterioration event rates before PEWS implementation (1·04 [0·97-1·12]; p=0·29). INTERPRETATION: PEWS implementation was associated with reduced clinical deterioration event mortality in paediatric patients with cancer across 32 resource-limited hospitals in Latin America. These data support the use of PEWS as an effective evidence-based intervention to reduce disparities in global survival for children with cancer. FUNDING: American Lebanese Syrian Associated Charities, US National Institutes of Health, and Conquer Cancer Foundation. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Hospital length of stay throughout bed pathways and factors affecting this time: A non-concurrent cohort study of Colombia COVID-19 patients and an unCoVer network project.

Predictions of hospital beds occupancy depends on hospital admission rates and the length of stay (LoS) according to bed type (general ward -GW- and intensive care unit -ICU- beds). The objective of this study was to describe the LoS of COVID-19 hospital patients in Colombia during 2020-2021. Accelerated failure time models were used to estimate the LoS distribution according to each bed type and throughout each bed pathway. Acceleration factors and 95% confidence intervals were calculated to measure the effect on LoS of the outcome, sex, age, admission period during the epidemic (i.e., epidemic waves, peaks or valleys, and before/after vaccination period), and patients geographic origin. Most of the admitted COVID-19 patients occupied just a GW bed. Recovered patients spent more time in the GW and ICU beds than deceased patients. Men had longer LoS than women. In general, the LoS increased with age. Finally, the LoS varied along epidemic waves. It was lower in epidemic valleys than peaks, and decreased after vaccinations began in Colombia. Our study highlights the necessity of analyzing local data on hospital admission rates and LoS to design strategies to prioritize hospital beds resources during the current and future pandemics.

Socioeconomic disparities associated with mortality in patients hospitalized for COVID-19 in Colombia.

Socioeconomic disparities play an important role in the development of severe clinical outcomes including deaths from COVID-19. However, the current scientific evidence in regard the association between measures of poverty and COVID-19 mortality in hospitalized patients is scant. The objective of this study was to investigate whether there is an association between the Colombian Multidimensional Poverty Index (CMPI) and mortality from COVID-19 in hospitalized patients in Colombia from May 1, 2020 to August 15, 2021. This was an ecological study using individual data on hospitalized patients from the National Institute of Health of Colombia (INS), and municipal level data from the High-Cost Account and the National Administrative Department of Statistics. The main outcome variable was mortality due to COVID-19. The main exposure variable was the CMPI that ranges from 0 to 100% and was categorized into five levels: (i) level I (0%-20%), (ii) level II (20%-40%), (iii) level III (40%-60%), (iv) level IV (60%-80%); and (v) level V (80%-100%). The higher the level, the higher the level of multidimensional poverty. A Bayesian multilevel logistic regression model was applied to estimate Odds Ratio (OR) and their corresponding 95% credible intervals (CI). In addition, a subgroup analysis was performed according to the epidemiological COVID-19 waves using the same model. The odds for dying from COVID-19 was 1.46 (95% CI 1.4-1.53) for level II, 1.41 (95% CI 1.33-1.49) for level III and 1.70 (95% CI 1.54-1.89) for level IV hospitalized COVID-19 patients compared with the least poor patients (CMPI level I). In addition, age and male sex also increased mortality in COVID-19 hospitalized patients. Patients between 26 and 50 years-of-age had 4.17-fold increased odds (95% CI 4.07-4.3) of death compared with younger than 26-years-old patients. The corresponding for 51-75 years-old patients and those above the age of 75 years were 9.17 (95% CI 8.93-9.41) and 17.1 (95% CI 16.63-17.56), respectively. Finally, the odds of death from COVID-19 in hospitalized patients gradually decreased as the pandemic evolved. In conclusion, socioeconomic disparities were a major risk factor for mortality in patients hospitalized for COVID-19 in Colombia.

Proteomic Analysis of Huntington's Disease Medium Spiny Neurons Identifies Alterations in Lipid Droplets.

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin (HTT) gene. The resulting polyglutamine (polyQ) tract alters the function of the HTT protein. Although HTT is expressed in different tissues, the medium-spiny projection neurons (MSNs) in the striatum are particularly vulnerable in HD. Thus, we sought to define the proteome of human HD patient-derived MSNs. We differentiated HD72-induced pluripotent stem cells and isogenic controls into MSNs and carried out quantitative proteomic analysis. Using data-dependent acquisitions with FAIMS for label-free quantification on the Orbitrap Lumos mass spectrometer, we identified 6323 proteins with at least two unique peptides. Of these, 901 proteins were altered significantly more in the HD72-MSNs than in isogenic controls. Functional enrichment analysis of upregulated proteins demonstrated extracellular matrix and DNA signaling (DNA replication pathway, double-strand break repair, G1/S transition) with the highest significance. Conversely, processes associated with the downregulated proteins included neurogenesis-axogenesis, the brain-derived neurotrophic factor-signaling pathway, Ephrin-A:EphA pathway, regulation of synaptic plasticity, triglyceride homeostasis cholesterol, plasmid lipoprotein particle immune response, interferon-γ signaling, immune system major histocompatibility complex, lipid metabolism, and cellular response to stimulus. Moreover, proteins involved in the formation and maintenance of axons, dendrites, and synapses (e.g., septin protein members) were dysregulated in HD72-MSNs. Importantly, lipid metabolism pathways were altered, and using quantitative image analysis, we found that lipid droplets accumulated in the HD72-MSN, suggesting a deficit in the turnover of lipids possibly through lipophagy. Our proteomics analysis of HD72-MSNs identified relevant pathways that are altered in MSNs and confirm current and new therapeutic targets for HD.

In vivo administration of gut bacterial consortia replicates urolithin metabotypes A and B in a non-urolithin-producing rat model.

Urolithin (Uro) production capacity and, consequently, at least partly, the health effects attributed to ellagitannin and ellagic acid consumption vary among individuals. The reason is that not all individuals have the gut bacterial ecology needed to produce the different Uro metabolites. Three human urolithin metabotypes (UM-A, UM-B, and UM-0) based on dissimilar Uro production profiles have been described in populations worldwide. Recently, the gut bacterial consortia involved in ellagic acid metabolism to yield the urolithin-producing metabotypes (UM-A and UM-B) in vitro have been identified. However, the ability of these bacterial consortia to customize urolithin production to mimic UM-A and UM-B in vivo is still unknown. In the present study, two bacterial consortia were assessed for their capacity to colonize the intestine of rats and convert UM-0 (Uro non-producers) animals into Uro-producers that mimic UM-A and UM-B, respectively. Two consortia of Uro-producing bacteria were orally administered to non-urolithin-producing Wistar rats for 4 weeks. Uro-producing bacterial strains effectively colonized the rats' gut, and the ability to produce Uros was also effectively transferred. Bacterial strains were well tolerated. No changes in other gut bacteria, except Streptococcus reduction, or adverse effects on haematological and biochemical parameters were observed. Besides, two novel qPCR procedures were designed and successfully optimized to detect and quantify Ellagibacter and Enterocloster genera in faecal samples. These results suggest that the bacterial consortia are safe and could be potential probiotics for human trials, which is especially relevant for UM-0 individuals, who cannot produce bioactive Uros.

Gut Bacteria Involved in Ellagic Acid Metabolism To Yield Human Urolithin Metabotypes Revealed.

We aimed to elucidate the gut bacteria that characterize the human urolithin metabotypes A and B (UM-A and UM-B). We report here a new bacterium isolated from the feces of a healthy woman, capable of producing the final metabolites urolithins A and B and different intermediates. Besides, we describe two gut bacterial co-cultures that reproduced the urolithin formation pathways upon in vitro fermentation of both UM-A and UM-B. This is the first time that the capacity of pure strains to metabolize ellagic acid cooperatively to yield urolithin profiles associated with UM-A and UM-B has been demonstrated. The urolithin-producing bacteria described herein could have potential as novel probiotics and in the industrial manufacture of bioactive urolithins to develop new ingredients, beverages, nutraceuticals, pharmaceuticals, and (or) functional foods. This is especially relevant in UM-0 individuals since they cannot produce bioactive urolithins.

Ellagitannins, urolithins, and neuroprotection: Human evidence and the possible link to the gut microbiota.

Ellagitannins (ETs) and ellagic acid (EA) are dietary polyphenols poorly absorbed but extensively metabolized by the human gut microbiota to produce different urolithins (Uros). Depending on the individuals' microbial signatures, ETs metabolism can yield the Uro metabotypes A, B, or 0, potentially impacting human health after consuming ETs. Human evidence points to improved brain health after consuming ET-rich foods, mainly pomegranate juices and extracts containing punicalagin, punicalin, and different EA-derivatives. Although ETs and (or) EA are necessary to exert the effects, the precise mechanism, actual metabolites, or final drivers responsible for the observed effects have not been unraveled. The cause-and-effect evidence on Uro-A administration and the improvement of animal brain health is consistent but not addressed in humans. The Uro-A's in vivo anti-inflammatory, mitophagy, autophagy, and mitochondrial biogenesis activities suggest it as a possible final driver in neuroprotection. However, the precise Uro metabolic forms reaching the brain are unknown. In addition to the possible participation of direct effectors in brain tissues, the current evidence points out that improving blood flow, gut microbiota ecology, and gut barrier by ET-rich foods and (or) Uro-A could contribute to the neuroprotective effects. We show here the current human evidence on ETs and brain health, the possible link between the gut microbiota metabolism of ETs and their effects, including the preservation of the gut barrier integrity, and the possible role of Uros. Finally, we propose a roadmap to address what is missing on ETs, Uros, and neuroprotection.

Association between erectile dysfunction and the severity of obstruction to airflow in patients with chronic obstructive pulmonary disease / Asociación entre disfunción eréctil y la severidad de la obstrucción al flujo aéreo en pacientes con enfermedad pulmonar obstructiva crónica

Objectives: The objective of this study was to explore a possible association between ED and the severity of airflow obstruction in patients with COPD. Materials and methods: A cross-sectional study was conducted using the International Index Erectile Function (IIEF), a scale validated and translated to Spanish. Bivariate analyses between subgroups were made for quantitative variables using a t-test for means and Mann­Whitney U for medians; qualitative variables were compared using the χ2 test or Fisher's test, depending on distribution. Confusion bias in the association between ED and airflow obstruction was controlled using a logistic regression model. Results: The Spanish version of the IIEF-15 scale was valid and applicable to the Colombian population. The prevalence of ED in COPD patients living at high altitudes was similar to that found at sea level. Such prevalence is higher than in general population. Beta-blockers increased 7 times the risk of ED, but we found no association between the degree of airflow obstruction and ED. Conclusion: Although the severity of COPD is not associated with ED, the prevalence of ED in COPD is higher than in general population. Therefore, ED screening in COPD patients using the IIEF could be justified. The strong association between beta-blockers and ED had not been previously described in patients with COPD but must be considered in their clinical management.

Objetivos: Explorar una posible asociación entre DE y severidad de la obstrucción al flujo aéreo en pacientes con EPOC. Materiales y métodos: Estudio de corte transversal aplicando el Índice Internacional de Función Eréctil (IIFE), validado y traducido al español. Se realizó análisis bivariado para variables cuantitativas usando prueba-t para medias y U de Mann Whitney para medianas; las variables cualitativas fueron comparadas usando prueba de Chi2 o test de Fisher, según distribución. Los sesgos de confusión en la asociación entre DE y obstrucción al flujo aéreo fueron controlados usando un modelo de regresión logística. Resultados: La versión en español de la escala IIFE-15 fue aplicable en población colombiana. La prevalencia de DE en pacientes con EPOC viviendo a gran altura fue similar a lo encontrado a nivel del mar. Esta prevalencia es mayor que en población general. El uso de beta-bloqueadores aumentó hasta siete veces el riesgo de DE, pero no se encontró asociación entre el grado de obstrucción y la DE. Conclusiones: Aunque la severidad de la EPOC no está asociada con DE, la prevalencia de DE en EPOC es mayor que en población general. Está justificada la realización de tamizaje usando el IIFE. La asociación fuerte entre beta-bloqueadores y DE no se ha descrito previamente en pacientes con EPOC, pero debe considerarse en su manejo.

Postnatal Conditional Deletion of Bcl11b in Striatal Projection Neurons Mimics the Transcriptional Signature of Huntington's Disease.

The dysregulation of striatal gene expression and function is linked to multiple diseases, including Huntington's disease (HD), Parkinson's disease, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neurons in the striatum and are critical to motor control. The transcription factor, Bcl11b (also known as Ctip2), is required for striatal development, but the function of Bcl11b in adult MSNs in vivo has not been investigated. We conditionally deleted Bcl11b specifically in postnatal MSNs and performed a transcriptomic and behavioral analysis on these mice. Multiple enrichment analyses showed that the D9-Cre-Bcl11btm1.1Leid transcriptional profile was similar to the HD gene expression in mouse and human data sets. A Gene Ontology enrichment analysis linked D9-Cre-Bcl11btm1.1Leid to calcium, synapse organization, specifically including the dopaminergic synapse, protein dephosphorylation, and HDAC-signaling, commonly dysregulated pathways in HD. D9-Cre-Bcl11btm1.1Leid mice had decreased DARPP-32/Ppp1r1b in MSNs and behavioral deficits, demonstrating the dysregulation of a subtype of the dopamine D2 receptor expressing MSNs. Finally, in human HD isogenic MSNs, the mislocalization of BCL11B into nuclear aggregates points to a mechanism for BCL11B loss of function in HD. Our results suggest that BCL11B is important for the function and maintenance of mature MSNs and Bcl11b loss of function drives, in part, the transcriptomic and functional changes in HD.

Exosome-Containing Extracellular Vesicles Contribute to the Transport of Resveratrol Metabolites in the Bloodstream: A Human Pharmacokinetic Study.

Exosomes are extracellular vesicles (EVs) that regulate intercellular signaling by transferring small RNAs, proteins, nucleic acids, lipids, and other metabolites to local or distant organs, including the brain, by crossing the blood-brain barrier. However, the transport of (poly)phenols in human EVs has not yet been described. Therefore, we aimed here to explore (i) whether resveratrol and (or) its derived metabolites are found in the cargo of human plasma exosome-containing EVs (E-EVs), (ii) when this incorporation occurs, and (iii) whether resveratrol intake stimulates the release of E-EVs. Thus, in a pharmacokinetic study, healthy volunteers (n = 16) consumed 1 capsule (420 mg resveratrol) in the evening before attending the clinic and one more capsule on the day of the pharmacokinetics. The plasma and the isolated E-EVs were analyzed using UPLC-ESI-QTOF-MS. Of 17 metabolites in the plasma, 9 were identified in the E-EVs, but not free resveratrol. The kinetic profiles of resveratrol metabolites were similar in the plasma and the E-EVs, a higher metabolite concentration being detected in the plasma than in the E-EVs. However, the plasma/E-EVs ratio decreased in the gut microbial metabolites, suggesting their better encapsulation efficiency in E-EVs. In addition, glucuronide conjugates of resveratrol, dihydroresveratrol, and lunularin were incorporated into the E-EVs more efficiently than their corresponding sulfates despite glucuronides reaching lower plasma concentrations. Notably, more E-EVs were detected 10 h after resveratrol consumption. This exploratory study provides the first evidence that (i) resveratrol metabolites are transported by E-EVs, with a preference for glucuronide vs. sulfates, (ii) the gut microbial metabolites concentration and kinetic profiles are closely similar in E-EVs and plasma, and (iii) resveratrol intake elicits E-EVs secretion. Overall, these results open new research avenues on the possible role of E-EVs in (poly)phenol health effects.

Model for regional collaboration: Successful strategy to implement a pediatric early warning system in 36 pediatric oncology centers in Latin America.

BACKGROUND: Pediatric early warning systems (PEWS) aid in the early identification of deterioration in hospitalized children with cancer; however, they are under-used in resource-limited settings. The authors use the knowledge-to-action framework to describe the implementation strategy for Proyecto Escala de Valoracion de Alerta Temprana (EVAT), a multicenter quality-improvement collaborative, to scale-up PEWS in pediatric oncology centers in Latin America. METHODS: Proyecto EVAT mentored participating centers through an adaptable implementation strategy to: (1) monitor clinical deterioration in children with cancer, (2) contextually adapt PEWS, (3) assess barriers to using PEWS, (4) pilot and implement PEWS, (5) monitor the use of PEWS, (6) evaluate outcomes, and (7) sustain PEWS. The implementation outcomes assessed included the quality of PEWS use, the time required for implementation, and global program impact. RESULTS: From April 2017 to October 2021, 36 diverse Proyecto EVAT hospitals from 13 countries in Latin America collectively managing more than 4100 annual new pediatric cancer diagnoses successfully implemented PEWS. The time to complete all program phases varied among centers, averaging 7 months (range, 3-13 months) from PEWS pilot to implementation completion. All centers ultimately implemented PEWS and maintained high-quality PEWS use for up to 18 months after implementation. Across the 36 centers, more than 11,100 clinicians were trained in PEWS, and more than 41,000 pediatric hospital admissions had PEWS used in their care. CONCLUSIONS: Evidence-based interventions like PEWS can be successfully scaled-up regionally basis using a systematic approach that includes a collaborative network, an adaptable implementation strategy, and regional mentorship. Lessons learned can guide future programs to promote the widespread adoption of effective interventions and reduce global disparities in childhood cancer outcomes. LAY SUMMARY: Pediatric early warning systems (PEWS) are clinical tools used to identify deterioration in hospitalized children with cancer; however, implementation challenges limit their use in resource-limited settings. Proyecto EVAT is a multicenter quality-improvement collaborative to implement PEWS in 36 pediatric oncology centers in Latin America. This is the first multicenter, multinational study reporting a successful implementation strategy (Proyecto EVAT) to regionally scale-up PEWS. The lessons learned from Proyecto EVAT can inform future programs to promote the adoption of clinical interventions to globally improve childhood cancer outcomes.