Early Life and Childhood Environmental Exposures, More Than Genetic Predisposition, Influence Age of Diagnosis in a Diverse Cohort of 2952 Patients With IBD.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) develops from a combination of genetic and environmental factors. The aim of this study was to determine the contribution of established environmental risk factors and genetic risk on age of IBD diagnosis in a diverse cohort. METHODS: IBD patients in clinic completed detailed questionnaires. Blood was drawn for genetic analysis. Environmental risk factors and age of diagnosis were analyzed by ethnicity (Hispanic/Latinx or non-Hispanic White [NHW] individuals) and IBD subtype (ulcerative colitis or Crohn's disease [CD]). Weighted genetic risk scores and environmental risk scores were developed. We examined the relationship between environmental risk scores, genetic risk scores, and age of diagnosis. RESULTS: A total of 2952 patients were included: 58.9% had CD. A total of 46.83% were of Hispanic background. Early life exposures like cesarean delivery and being born in a developed country were associated with a younger age of IBD diagnosis. Childhood exposures such as frequent plastic water bottle use and having more than 1 bathroom at home were associated with a younger age of IBD. Hispanic and NHW individuals shared similar susceptibilities to environmental exposures. Environmental factors explained 21% of the variance in age of CD diagnosis and 39% in ulcerative colitis. In models incorporating genetic risk score and environmental risk score, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups. CONCLUSIONS: Early life and childhood exposures impact IBD diagnosis and influence Hispanic and NHW individuals similarly. A cumulative environmental risk score contributes more to age of IBD diagnosis than genetic risk.

Evaluating the effects of counterconditioning, novelty-facilitated, and standard extinction on the spontaneous recovery of threat expectancy and conditioned stimulus valence.

Extinction training has proved effective to diminish the expectancy of the aversive unconditioned stimulus (US). However, the negative valence of the conditioned stimulus (CS) may still stay intact. In fact, several studies have suggested that the CS negative valence may be a factor that promotes the return of fear. Our study focuses on the role of changes in the CS valence as a potential mechanism to reduce the spontaneous recovery of threat expectancies. To do that, we evaluated counterconditioning (CC), a technique aimed to reduce the CS negative valence by paring it with a positive stimulus and compared its efficacy to that of a novelty-facilitated extinction (NFE) and a standard extinction interventions. Using a 2-day protocol, participants first learned the relationship between a figure and an aversive sound, using a differential conditioning paradigm, and were then randomly assigned to one of three different groups. For the CC group, CS+ or cue A was paired with a positive US. The standard extinction group was exposed to cue A alone. For a third NFE group, cue A was followed by a neutral US. Finally, on the second day, spontaneous recovery was tested. Our findings did not provide evidence to suggest that CC could be more effective to prevent or reduce the return of threat expectancies or influence valence ratings when compared with NFE and standard extinction.

Role of Mitochondria in Inflammatory Bowel Diseases: A Systematic Review.

Mitochondria are key cellular organelles whose main function is maintaining cell bioenergetics by producing ATP through oxidative phosphorylation. However, mitochondria are involved in a much higher number of cellular processes. Mitochondria are the home of key metabolic pathways like the tricarboxylic acid cycle and ß-oxidation of fatty acids, as well as biosynthetic pathways of key products like nucleotides and amino acids, the control of the redox balance of the cell and detoxifying the cell from H2S and NH3. This plethora of critical functions within the cell is the reason mitochondrial function is involved in several complex disorders (apart from pure mitochondrial disorders), among them inflammatory bowel diseases (IBD). IBD are a group of chronic, inflammatory disorders of the gut, mainly composed of ulcerative colitis and Crohn's disease. In this review, we present the current knowledge regarding the impact of mitochondrial dysfunction in the context of IBD. The role of mitochondria in both intestinal mucosa and immune cell populations are discussed, as well as the role of mitochondrial function in mechanisms like mucosal repair, the microbiota- and brain-gut axes and the development of colitis-associated colorectal cancer.

Comparación entre la morbilidad y la mortalidad por COVID-19, asociada a factores de riesgo metabólicos en población no indígena e indígena de México / Comparison between morbidity and mortality from COVID-19, associated with metabolic risk factors in non-indigenous and indigenous populations of Mexico

Introducción. La investigación sobre la pandemia de COVID-19, se ha estudiado en tiempo real, ha sido y sigue siendo reveladora. Objetivo. Analizar la morbilidad y la mortalidad por COVID-19, asociadas a factores de riesgo metabólicos en población no indígena e indígena de México. Materiales y métodos. Utilizamos la Base Nacional de Datos COVID-19, durante los años críticos 2020-2021- 2022. Se trabajó con 5.380.247 casos que representaron la población total de positivos al SARS-CoV-2. Se analizaron las discrepancias entre las prevalencias de población no indígena, población indígena, defunción y no defunción. Se definió población indígena, con la clasificación oficial de auto-identificación. Se aplicó el modelo de regresión logística para determinar el riesgo de morir para cada variable: enfermedades cardiovasculares, hipertensión, diabetes, obesidad, sexo, edad y condición indígena. El análisis de multicolinealidad se analizó a través de la prueba de asociación Phi para variables dicotómicas y a través del ajuste de Nagelkerke. Resultados. En los positivos totales 99,2% fue población no indígena y 0,8% indígenas, mientras su porcentaje de letalidad fue de 5,8% y 11,1% respectivamente. En ambos grupos, murieron más hombres (61,5%) que mujeres (38,5%) y las edades de mayor defunción fueron 60 a 79 años. La mortalidad por enfermedades cardiovasculares fue la de mayor incidencia, 26,6% en población general y 32,3% en indígena; por diabetes 22,1% y 27,9%; hipertensión 20,0% y 26,7%y la obesidad 11, 3% y 17,4% respectivamente. Los análisis de regresión logística se ajustaron por sexo, edad y condición indígena. El condicionante de mayor riesgo de muerte, fueron las comorbilidades metabólicas y el de menor riesgo, la condición indígena. Conclusiones. El impacto de la pandemia por COVID-19 fue más grave cuando hubo padecimientos metabólicos tanto en la población no indígena como en la indígena(AU)

Introduction. Research on the COVID-19 pandemic, studied in real time, has been and continues to be revealing. Objective. To analyze morbidity and mortality from COVID-19, associated with metabolic risk factors in non-indigenous and indigenous populations of Mexico. Materials and methods. We use the National COVID-19 Database, during the critical years 2020-2021-2022. We worked with 5,380,247 cases that represented the total population of SARS-CoV-2 positives. The discrepancies between the prevalence of non-indigenous population, indigenous population, death and non-death were analyzed. The indigenous population was defined, with the official self-identification classification. The logistic regression model was applied to determine the risk of dying for each variable: cardiovascular diseases, hypertension, diabetes, obesity, sex, age and indigenous status. The multicollinearity analysis was analyzed through the Phi association test for dichotomous variables and through the Nagelkerke adjustment. Results. Of the total positives, 99.2% were non-indigenous people and 0.8% were indigenous, while their fatality percentage was 5.8% and 11.1% respectively. In both groups, more men (61.5%) than women (38.5%) died and the ages of greatest death were 60 to 79 years. Mortality from cardiovascular diseases was the one with the highest incidence, 26.6% in the general population and 32.3% in the indigenous population; due to diabetes 22.1% and 27.9%; hypertension 20.0% and 26.7% and obesity 11.3% and 17.4% respectively. Logistic regression analyzes were adjusted for sex, age, and indigenous status. The condition with the highest risk of death was metabolic comorbidities and the lowest risk was indigenous status. Conclusions. The impact of the COVID-19 pandemic was more serious when there were metabolic disorders in both the non-indigenous and indigenous populations(AU)

Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila.

Most epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types ensures precise regulation of stem cell behavior and cell fate decisions. These cell-cell interactions are often disrupted during tumorigenesis, but mechanisms by which they are co-opted to support tumor growth in different genetic contexts are poorly understood. Here, we introduce PromoterSwitch, a genetic platform we established to generate large, transformed clones derived from individual adult Drosophila intestinal stem/progenitor cells. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes disrupt cell fate decisions within transformed tissue and result in the emergence of abnormal cell fates. We also show that transformed enteroendocrine cells, a differentiated, hormone-secreting cell lineage, support tumor growth by regulating intestinal stem cell proliferation through multiple genotype-dependent mechanisms, which represent potential vulnerabilities that could be exploited for therapy.

Alterations in executive functions in inmates convicted for violent behavior: a systematic review.

Background: The growth of the prison population and the high recidivism rates of inmates represent a major public safety problem. Objective: This systematic review explored executive functions in inmates convicted of violent behavior compared with inmates convicted of non-violent behavior and healthy controls (HCs). Methods: Systematic searches were carried out using five databases (PubMed, Scopus, Web of Science, EBSCO, and Embase) until March 6th, 2023. Following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, two reviewers independently performed the screening, data extraction, and risk of bias assessment of the 8 studies included. The protocol of this study was registered in Prospective Register of Systematic Reviews (PROSPERO), under registration number CRD42021252043. Results: Consistently, inmates convicted of violent behavior exhibited a greater alteration in inhibition than inmates convicted of non-violent behavior (four out of four studies) and HCs (two out of two studies). In addition, inmates convicted of violent behavior showed greater impairments in cognitive flexibility (two out of three studies) and working memory (two out of three studies) than HCs. Although with limited evidence (only one study), they also showed worse performance in set shifting and planning than HCs. Conclusion: This study provides evidence of alterations in inhibition in inmates convicted of violent behavior compared to inmates convicted of non-violent behavior and HCs. Even though inmates convicted of violent behavior showed greater impairments in planning and set shifting than HCs, these findings were supported in only one study. In general, more robust evidence is needed to confirm alterations in inmates convicted due to violent behavior. These findings highlight the importance of designing and promoting specific cognitive interventions that contribute to the reintegration of inmates into society. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021252043, identifier CRD42021252043.

Steps to improve umbilical vein catheterization in neonatal care.

INTRODUCTION: In neonatal units, umbilical vessel catheterization is the preferred method to gain vascular access in the initial management of the newborn because it is quick and easy. The failure rate ranges from to 50%, as the catheter can be found in the portal system in up to 40% of cases, leading to complications. This failure rate warrants the investigation of different methods to reduce the frequency of catheter malposition. We describe different techniques to improve the success rate in umbilical vein catheterization, such as the double catheter technique, positioning the newborn in right lateral decubitus for insertion, liver compression, and ultrasound-guided catheter insertion. The primary objective of the study was to assess the impact of new techniques on the success rate of central umbilical venous catheterization. MATERIAL AND METHODS: Pre- and post-intervention quasi-experimental study in a level B NICU conducted in January-June 2022 (pre-intervention) and July-December 2022 (post-intervention). RESULTS: Prior to the introduction of these new catheterization techniques, the failure rate of blind umbilical catheter insertion was 52%. Since the introduction of these measures, the overall failure rate has decreased to 27%. CONCLUSIONS: After the introduction of the new catheterization and recanalization methods, our success rate in umbilical vein catheterization has increased, and we believe it is necessary to implement them in units with similar failure rates to ours.

Multi-Omics Approach Reveals Prebiotic and Potential Antioxidant Effects of Essential Oils from the Mediterranean Diet on Cardiometabolic Disorder Using Humanized Gnotobiotic Mice.

Essential oils sourced from herbs commonly used in the Mediterranean diet have demonstrated advantageous attributes as nutraceuticals and prebiotics within a model of severe cardiometabolic disorder. The primary objective of this study was to assess the influences exerted by essential oils derived from thyme (Thymus vulgaris) and oregano (Origanum vulgare) via a comprehensive multi-omics approach within a gnotobiotic murine model featuring colonic microbiota acquired from patients diagnosed with coronary artery disease (CAD) and type-2 diabetes mellitus (T2DM). Our findings demonstrated prebiotic and potential antioxidant effects elicited by these essential oils. We observed a substantial increase in the relative abundance of the Lactobacillus genus in the gut microbiota, accompanied by higher levels of short-chain fatty acids and a reduction in trimethylamine N-oxide levels and protein oxidation in the plasma. Moreover, functional enrichment analysis of the cardiac tissue proteome unveiled an over-representation of pathways related to mitochondrial function, oxidative stress, and cardiac contraction. These findings provide compelling evidence of the prebiotic and antioxidant actions of thyme- and oregano-derived essential oils, which extend to cardiac function. These results encourage further investigation into the promising utility of essential oils derived from herbs commonly used in the Mediterranean diet as potential nutraceutical interventions for mitigating chronic diseases linked to CAD and T2DM.

A polycistronic transgene design for combinatorial genetic perturbations from a single transcript in Drosophila.

Experimental models that capture the genetic complexity of human disease and allow mechanistic explorations of the underlying cell, tissue, and organ interactions are crucial to furthering our understanding of disease biology. Such models require combinatorial manipulations of multiple genes, often in more than one tissue at once. The ability to perform complex genetic manipulations in vivo is a key strength of Drosophila, where many tools for sophisticated and orthogonal genetic perturbations exist. However, combining the large number of transgenes required to establish more representative disease models and conducting mechanistic studies in these already complex genetic backgrounds is challenging. Here we present a design that pushes the limits of Drosophila genetics by allowing targeted combinatorial ectopic expression and knockdown of multiple genes from a single inducible transgene. The polycistronic transcript encoded by this transgene includes a synthetic short hairpin cluster cloned within an intron placed at the 5' end of the transcript, followed by two protein-coding sequences separated by the T2A sequence that mediates ribosome skipping. This technology is particularly useful for modeling genetically complex diseases like cancer, which typically involve concurrent activation of multiple oncogenes and loss of multiple tumor suppressors. Furthermore, consolidating multiple genetic perturbations into a single transgene further streamlines the ability to perform combinatorial genetic manipulations and makes it readily adaptable to a broad palette of transgenic systems. This flexible design for combinatorial genetic perturbations will also be a valuable tool for functionally exploring multigenic gene signatures identified from omics studies of human disease and creating humanized Drosophila models to characterize disease-associated variants in human genes. It can also be adapted for studying biological processes underlying normal tissue homeostasis and development that require simultaneous manipulation of many genes.

[Differences by socioeconomic and school level in food acquisition of Mexican population]. / Diferencias por nivel socioeconómico y escolar en la adquisición de alimentos de la población mexicana.

Introduction: Introduction: social or school factors influence the acquisition and selection of foods to be consumed. Objective: identifying the socioeconomic or school level that has the greatest weight in the acquisition of food in Mexican households. Methods: cross-sectional, retrospective and comparative study based on the database of the 2018 National Household Expenditure-Income Survey of Mexico. We worked with the national total of 73,274 Mexican households. The variables considered were: expenditure module of food and beverages, school grade of the head of the family and socioeconomic status to which the household belongs. For the statistical analysis, the following tests were used: linear regression analysis, as well as variance analysis, Snedecor's F test, post-hoc test and Schefé's confirmatory test. Results: socioeconomic status has a greater weight (p < .001) for food acquisition. Sugary drinks were the most widely acquired in all social and school levels. The lowest social level is the one who acquires the most cereals, fats, sugars and legumes, while for high school levels animal foods and processed meats are the ones most frequently acquired. Conclusion: the socioeconomic level has a great weight in the acquisition and variety of foods, although this does not mean that foods obtained are the healthiest. Therefore, public policies are urgently required in favor of nutritional education at all school levels, which promote the purchase of healthy foods and compete with commercial advertising strategies.

Introducción: Introducción: los factores sociales o escolares influyen en la adquisición y selección de alimentos a consumir. Objetivo: identificar el nivel socioeconómico o escolar que tenga mayor peso en la adquisición de alimentos en hogares mexicanos. Métodos: estudio transversal, retrospectivo y comparativo a partir de la base de datos de la Encuesta Nacional de Ingreso-Gasto en Hogares de México de 2018. Se trabajó con el total nacional de 73.274 hogares mexicanos. Las variables consideradas fueron: módulo de gasto de alimentos y bebidas, grado escolar del jefe de familia y condición socioeconómica a la que pertenece el hogar. Para el análisis estadístico se utilizó análisis de regresión lineal, así como análisis de varianza, prueba F de Snedecor, prueba post-hoc y confirmatoria de Schefé. Resultados: el nivel socioeconómico tiene un mayor peso (p < ,001) para la adquisición de los alimentos. Las bebidas azucaradas fueron las de mayor adquisición en todos los niveles sociales y escolares. El nivel social más bajo es el que adquiere la mayor cantidad de cereales, grasas, azucares y leguminosas, mientras que en los niveles escolares altos son los alimentos de origen animal y carnes procesadas los más adquiridos. Conclusión: el nivel socioeconómico tiene mayor peso en la adquisición y variedad de los alimentos, aunque esto no quiere decir que por ello se obtengan los más saludables. Por lo tanto, se requiere urgentemente de políticas públicas en favor de una educación nutricional en todos los niveles escolares, que promueva la compra de alimentos saludables y que compita con las estrategias publicitarias comerciales.

Use of a Bipolar Device (LigaSure) to Seal the Appendiceal Stump in Pediatric Laparoscopic Appendectomy: 10-year Latin-American Experience.

BACKGROUND: Closure of the appendiceal stump is a critical step during an appendectomy. There is a lack of knowledge about the feasibility of using electrosurgical devices for the occlusion of the appendix. This study aims to determine the safety of this technique in pediatric patients. METHODS: We performed a cross-sectional analytical study in patients less than 18 years of age treated at Hospital Militar Central Colombia between 2012 and 2021. Our institution's ethics committee approved the study. We analyzed the data using SPSS 22 statistical program. We present frequencies for qualitative variables and measures of central tendency or dispersion for quantitative variables depending on the distribution measured by the Kolmogorov-Smirnov test. In addition, we measured the association of nominal variables with the Chi-square test or Fisher's exact test. For numerical variables, the difference of means with the Student's t-test or the difference of medians with the Mann-Whitney U test. RESULTS: We treated 209 patients. One hundred sixteen (55.5%) were boys, and the mean age was 9.7 years (SD 3.2). The median intraoperative time was 60 min, and the hospital stay was 2.8 days on average. There were no cases of stump leakage, and only two patients (1%) had an organ-space surgical site infection, which was unrelated to the closure technique. We found no association between procedural complications and appendicular status (p = 0.450). CONCLUSIONS: Our research suggests that using a bipolar sealing device (Ligasure, Medtronic, USA) for appendiceal stump closure in pediatric patients undergoing laparoscopic appendectomy is feasible and should be further studied. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level III.

Bacterial Quorum-Sensing Molecules in Serum: A Potential Tool for Crohn's Disease Management.

Crohn's disease (CD) is an idiopathic inflammatory condition of the gastrointestinal tract with the primary method of diagnosis and follow-up being colonoscopy. A disturbed host-microbiome interaction, including the presence of pathobionts, is implicated in initiation and perpetuation of inflammation. As such, we hypothesized that bacterial quorum-sensing (QS) molecules (QSMs), small molecules bacteria generate to regulate gene expression, would be elevated in patients with CD. We collected serum at the time of colonoscopy from patients with CD and healthy controls, determining through biosensors for QSMs that patients with CD had significantly elevated levels of QSMs in serum. Expansion of these studies may allow for QSM levels in serum to serve as a biomarker for intestinal inflammation in patients with CD.

Beneficial Effects of Essential Oils from the Mediterranean Diet on Gut Microbiota and Their Metabolites in Ischemic Heart Disease and Type-2 Diabetes Mellitus.

Ischemic heart disease (IHD) and type-2 diabetes mellitus (T2DM) remain major health problems worldwide and commonly coexist in individuals. Gut microbial metabolites, such as trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), have been linked to cardiovascular and metabolic diseases. Previous studies have reported dysbiosis in the gut microbiota of these patients and the prebiotic effects of some components of the Mediterranean diet. Essential oil emulsions of savory (Satureja hortensis), parsley (Petroselinum crispum) and rosemary (Rosmarinus officinalis) were assessed as nutraceuticals and prebiotics in IHD and T2DM. Humanized mice harboring gut microbiota derived from that of patients with IHD and T2DM were supplemented with L-carnitine and orally treated with essential oil emulsions for 40 days. We assessed the effects on gut microbiota composition and abundance, microbial metabolites and plasma markers of cardiovascular disease, inflammation and oxidative stress. Our results showed that essential oil emulsions in mice supplemented with L-carnitine have prebiotic effects on beneficial commensal bacteria, mainly Lactobacillus genus. There was a decrease in plasma TMAO and an increase in fecal SCFAs levels in mice treated with parsley and rosemary essential oils. Thrombomodulin levels were increased in mice treated with savory and parsley essential oils. While mice treated with parsley and rosemary essential oils showed a decrease in plasma cytokines (INFÉ£, TNFα, IL-12p70 and IL-22); savory essential oil was associated with increased levels of chemokines (CXCL1, CCL2 and CCL11). Finally, there was a decrease in protein carbonyls and pentosidine according to the essential oil emulsion. These results suggest that changes in the gut microbiota induced by essential oils of parsley, savory and rosemary as prebiotics could differentially regulate cardiovascular and metabolic factors, which highlights the potential of these nutraceuticals for reducing IHD risk in patients affected by T2DM.

Lamina Propria Phagocyte Profiling Reveals Targetable Signaling Pathways in Refractory Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Lamina propria phagocytes are key mediators of inflammatory bowel disease (IBD). We aimed to understand the transcriptomic and functional differences in these cells based on location, disease type, inflammation state, and medication use in patients with IBD. METHODS: Phagocytic immune cells in the lamina propria, as defined by the marker CD11b, were isolated from 54 unique patients (n = 111 gut mucosal biopsies). We performed flow cytometry for cell phenotyping (n = 30) and RNA sequencing with differential gene expression analysis (n = 58). We further cultured these cells in vitro and exposed them to janus kinase inhibitors to measure cytokine output (n = 27). Finally, we matched patient genomic data to our RNA sequencing data to perform candidate gene expression quantitative trait locus analysis (n = 34). RESULTS: We found distinct differences in gene expression between CD11b+ cells from the colon vs ileum, as well as in different inflammatory states and, to a lesser degree, IBD types (Crohn's disease or ulcerative colitis). These genes mapped to targetable immune pathways and metabolic and cancer pathways. We further explored the janus kinase-signal transducer and activator of transcription pathway, which was upregulated across many comparisons including in biopsies from anti-tumor necrosis factor refractory patients. We found that isolated CD11b+ cells treated with janus kinase inhibitors had decreased secretion of cytokines tumor necrosis factora and interleukin-8 (P ≤ .05). We also found 3 genetic variants acting as expression quantitative trait loci (P ≤ .1) within our CD11b+ data set. CONCLUSIONS: Lamina propria phagocytes from IBD mucosa provide pathogenetic clues on the nature of treatment refractoriness and inform new targets for therapy.

Morphological and anatomical characterization of yellow diploid potato flower for effective breeding program.

The diploid yellow potato (Solanum tuberosum L. Phureja Group) is an important plant genetic resource. In this study, we report for the first time the characterization of anther development and pollen formation in the cultivar Criolla Colombia. The description of morphological and histological characters of buds and flowers at different developmental stages permitted to identify ten main stages, from the differentiation of the male cells of the sporangium, meiosis, microspores formation and maturation, to the release of mature pollen. In addition, the results provide a graphic guide of the development of the anther, through the sequential and orderly formation of the epidermis, the endothecium, the middle layer and the nutritive layer or tapetum. This microanatomical information will be useful for work focused on androgenesis and identification of gene regulation in floral biology and gamete formation. Therefore, this study determined that to efficiently obtain haploids, flower buds between 5 and 8.9 mm long (stage 6 to 8) should be used, in which tetrads and microspores are in the early uninucleate and binucleate stage.

COVID-19 Secondary Infections in ICU Patients and Prevention Control Measures: A Preliminary Prospective Multicenter Study.

The incidence of secondary infections in critically ill coronavirus disease 2019 (COVID-19) patients is worrisome. We investigated whether selective digestive decontamination (SDD) added to infection control measures during an intensive care unit (ICU) stay modified these infection rates. Methods: A retrospective observational cohort study was carried out in four ICUs in Spain. All consecutive ventilated patients with a SARS-CoV-2 infection engaged in national infection control programs between 1 March and 10 December 2020 were investigated. Patients were grouped into two cohorts according to the site of ICU admission. Secondary relevant infections were included. Infection densities corresponding to ventilator-associated pneumonia (VAP), catheter bacteremia, secondary bacteremia, and multi-resistant germs were obtained as the number of events per 1000 days of exposure and were compared between SDD and non-SDD groups using Poisson regression. Factors that had an independent association with mortality were identified using multidimensional logistic analysis. Results: There were 108 patients in the SDD cohort and 157 in the non-SDD cohort. Patients in the SDD cohort showed significantly lower rates (p < 0.001) of VAP (1.9 vs. 9.3 events per 1000 ventilation days) and MDR infections (0.57 vs. 2.28 events per 1000 ICU days) and a non-significant reduction in secondary bacteremia (0.6 vs. 1.41 events per 1000 ICU days) compared with those in the non-SDD cohort. Infections caused by MDR pathogens occurred in 5 patients in the SDD cohort and 21 patients in the non-SDD cohort (p = 0.006). Differences in mortality according to SDD were not found. Conclusion: The implementation of SDD in infection control programs significantly reduced the incidence of VAP and MDR infections in critically ill SARS-CoV-2 infected patients.

Transcriptional Behavior of Regulatory T Cells Predicts IBD Patient Responses to Vedolizumab Therapy.

BACKGROUND: Inflammatory bowel disease (IBD) involves chronic T cell-mediated inflammatory responses. Vedolizumab (VDZ), a monoclonal antibody against α4ß7 integrin, inhibits lymphocyte extravasation into intestinal mucosae and is effective in ulcerative colitis (UC) and Crohn's disease (CD). AIM: We sought to identify immune cell phenotypic and gene expression signatures that related to response to VDZ. METHODS: Peripheral blood (PBMC) and lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry and Cytofkit. Sorted CD4 + memory (Tmem) or regulatory T (Treg) cells from PBMC and LPMC were analyzed by RNA sequencing (RNA-seq). Clinical response (≥2-point drop in partial Mayo scores [UC] or Harvey-Bradshaw index [CD]) was assessed 14 to 22 weeks after VDZ initiation. Machine-learning models were used to infer combinatorial traits that predicted response to VDZ. RESULTS: Seventy-one patients were enrolled: 37 received VDZ and 21 patients remained on VDZ >2 years. Fourteen of 37 patients (38%; 8 UC, 6 CD) responded to VDZ. Immune cell phenotypes and CD4 + Tmem and Treg transcriptional behaviors were most divergent between the ileum and colon, irrespective of IBD subtype or inflammation status. Vedolizumab treatment had the greatest impact on Treg metabolic pathways, and response was associated with increased expression of genes involved in oxidative phosphorylation. The strongest clinical predictor of VDZ efficacy was concurrent use of thiopurines. Mucosal tissues offered the greatest number of response-predictive biomarkers, whereas PBMC Treg-expressed genes were the best predictors in combinatorial models of response. CONCLUSIONS: Mucosal and peripheral blood immune cell phenotypes and transcriptional profiles can inform VDZ efficacy and inform new opportunities for combination therapies.

Vedolizumab (VDZ) is effective in the treatment of IBD. Immunophenotyping and RNAseq of T cells were used to inform its mechanism of action. Changes in T regulatory cells in the periphery and mucosa have the greatest relationship to VDZ response.

Improved Brain Pathology and Progressive Peripheral Neuropathy in a 15 Year Old Survivor of Infantile Krabbe Disease Treated With Umbilical Cord Transplantation.

Objective: Krabbe disease is a fatal leukodystrophy caused by deficiency in galactocerebrosidase enzyme activity. The only currently available therapy is hematopoietic stem cell transplantation with bone marrow or umbilical cord blood (UCBT), which leads to increased lifespan and functional abilities when performed in the preclinical stage. While stabilization of white matter disease has been seen on serial MRI studies, neuropathological changes following transplantation have not been documented so far. Materials and Methods: We report the first postmortem examination of a 15-year-old female patient with infantile Krabbe disease after UCBT in infancy. Results: In contrast to an untreated Krabbe disease brain, which showed severe myelin and oligodendrocyte loss with occasional globoid cells, the transplanted brain displayed markedly improved myelin preservation, but not reaching normal myelination levels. Consistent with the transplanted patient's clinical presentation of pronounced deficits in gross motor skills, corticospinal tracts were most severely affected. No globoid cells or evidence of active demyelination were observed in the central nervous system, indicative of at least partially successful functional restoration. This was corroborated by the identification of male donor-derived cells in the brain by in situ hybridization. Unlike the observed disease stabilization in the central nervous system, the patient experienced progressive peripheral neuropathy. While diminished macrophage infiltration was seen postmortem, peripheral nerves exhibited edema, myelin and axon loss and persistent Schwann cell ultrastructural inclusions. Conclusion: Umbilical cord blood transplantation was able to alter the natural disease progression in the central but less so in the peripheral nervous system, possibly due to limited cross-correction of Schwann cells.

The role of relief, perceived control, and prospective intolerance of uncertainty in excessive avoidance in uncertain-threat environments.

Excessive avoidance is a key feature of pathological anxiety. However, the precise mechanisms underlying the development of excessive avoidance are still unknown. In the present study, we tested the hypothesis that excessive avoidance, especially in individuals with high Intolerance of Uncertainty (IU) is aimed at distress reduction via the enhancement of subjective perceived control in uncertain-threat environments. In our experiment, participants learned to avoid an uncertain aversive sound through a discriminated free operant procedure. In a later test phase in extinction, we manipulated the amount of avoidance responses available per trial by creating a limited and an unrestricted response condition. Nonetheless, the aversive sound could be effectively avoided in both conditions. We measured response frequency, avoidance confidence ratings and anxiety-predisposing traits such as intolerance of uncertainty, trait anxiety and distress tolerance. The degree of distress suffered during trials was inferred from post-trial relief ratings that were requested after trials in which the aversive sound had been omitted. In the avoidance acquisition phase, we found a positive association between prospective intolerance of uncertainty (P-IU) and the decline rate of distress. This relationship was not significant, however, when inhibitory intolerance of uncertainty (I-IU) was controlled for. At test, we found that the increase in avoidance responses led to distress reduction through the enhancement of avoidance confidence. Finally, we found a significant modulating role of P-IU in the effect of response limit on distress reduction that lends further support to our hypothesis. Specifically, P-IU was positively associated with the effect of response limit on distress. However, such modulating role was not significant when controlling for trait anxiety or I-IU.

Combining Pentoxifylline With Vedolizumab for Crohn's Disease: Results of a Randomised, Placebo-controlled Pilot Study.

BACKGROUND AND AIMS: The efficacy of current biologics may be limited by targeting only one pathway. Pentoxifylline [PTX] interferes with tumour necrosis factor [TNF] gene expression. We performed a randomised, placebo-controlled pilot study to determine if PTX plus vedolizumab [VDZ] in patients with Crohn's disease [CD] is safe and improves response compared with VDZ monotherapy. METHODS: Thirty adult patients with active CD were randomised to VDZ/PTX or VDZ/placebo and followed for 24 weeks. Endoscopic activity and inflammatory cytokines were measured at baseline and Week 24. Descriptive statistics were used to determine estimates of effect. RESULTS: Demographics were similar but baseline disease activity was higher in the VDZ/PTX group. There was no difference in clinical remission at Week 14 (60.0% vs 66.67%, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.16, 3.51) or steroid-free clinical remission at Week 24 in patients receiving VDZ/PTX. Improved clinical response was noted in the VDZ/PTX group at Weeks 6, 14, and 24 [Week 6: 20% vs 6.67%, Week 14: 26.67% vs 6.67%, Week 24: 40% vs 20%]. The rate of endoscopic remission was similar between the groups [40% vs 33.33%], with a greater mean decrease in Simple Endoscopic Score-CD [SES-CD] and C-reactive protein [CRP] with VDZ/PTX [SES-CD -3.17 vs -0.15, CRP -5.56 vs 0.46]. An increase in serum TNF-α concentration was observed with VDZ/placebo group; PTX mitigated this effect. No serious adverse events occurred. CONCLUSIONS: VDZ/PTX did not provide benefit over VDZ monotherapy in clinical or endoscopic remission but appeared to improve clinical response and was safe. These data should inform a fully powered study.