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PURPOSE: Identify urinary catheter (UC)-associated urinary tract infections (CAUTI) incidence and risk factors (RF) in Latin American Countries. METHODS: From 01/01/2014 to 02/10/2022, we conducted a prospective cohort study in 145 ICUs of 67 hospitals in 35 cities in nine Latin American countries: Argentina, Brazil, Colombia, Costa Rica, Dominican Republic, Ecuador, Mexico, Panama, and Peru. To estimate CAUTI incidence, we used the number of UC-days as the denominator, and the number of CAUTIs as numerator. To estimate CAUTI RFs, we analyzed the following 10 variables using multiple logistic regression: gender, age, length of stay (LOS) before CAUTI acquisition, UC-days before CAUTI acquisition, UC-device utilization (DU) ratio, UC-type, hospitalizationtype, ICU type, facility ownership, and time period. RESULTS: 31,631 patients, hospitalized for 214,669 patient-days, acquired 305 CAUTIs. The pooled CAUTI rate per 1000 UC-days was 2.58, for those using suprapubic catheters, it was 2.99, and for those with indwelling catheters, it was 2.21. The following variables were independently associated with CAUTI: age, rising risk 1% yearly (aOR = 1.01; 95% CI 1.01-1.02; p < 0.0001 female gender (aOR = 1.28; 95% CI 1.01-1.61; p = 0.04), LOS before CAUTI acquisition, rising risk 7% daily (aOR = 1.07; 95% CI 1.06-1.08; p < 0.0001, UC/DU ratio (aOR = 1.14; 95% CI 1.08-1.21; p < 0.0001, public facilities (aOR = 2.89; 95% CI 1.75-4.49; p < 0.0001. The periods 2014-2016 and 2017-2019 had significantly higher risks than the period 2020-2022. Suprapubic catheters showed similar risks as indwelling catheters. CONCLUSION: The following CAUTI RFs are unlikely to change: age, gender, hospitalization type, and facility ownership. Based on these findings, it is suggested to focus on reducing LOS, UC/DU ratio, and implementing evidence-based CAUTI prevention recommendations.
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Infecções Relacionadas a Cateter , Infecção Hospitalar , Infecções Urinárias , Humanos , Feminino , Infecção Hospitalar/epidemiologia , Infecções Relacionadas a Cateter/complicações , Estudos Prospectivos , Incidência , América Latina/epidemiologia , Infecções Urinárias/etiologia , Unidades de Terapia Intensiva , Cateteres de Demora/efeitos adversos , Fatores de RiscoRESUMO
In Arabidopsis, multisubunit RNA polymerases IV and V orchestrate RNA-directed DNA methylation (RdDM) and transcriptional silencing, but what identifies the loci to be silenced is unclear. We show that heritable silent locus identity at a specific subset of RdDM targets requires HISTONE DEACETYLASE 6 (HDA6) acting upstream of Pol IV recruitment and siRNA biogenesis. At these loci, epigenetic memory conferring silent locus identity is erased in hda6 mutants such that restoration of HDA6 activity cannot restore siRNA biogenesis or silencing. Silent locus identity is similarly lost in mutants for the cytosine maintenance methyltransferase, MET1. By contrast, pol IV or pol V mutants disrupt silencing without erasing silent locus identity, allowing restoration of Pol IV or Pol V function to restore silencing. Collectively, these observations indicate that silent locus specification and silencing are separable steps that together account for epigenetic inheritance of the silenced state.
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Proteínas de Arabidopsis/genética , Arabidopsis/genética , RNA Polimerases Dirigidas por DNA/genética , Epigênese Genética , Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Histona Desacetilases/genética , Interferência de RNA , Arabidopsis/enzimologia , Proteínas de Arabidopsis/metabolismo , Citosina/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Elementos de DNA Transponíveis , RNA Polimerases Dirigidas por DNA/metabolismo , Loci Gênicos , Genótipo , Hereditariedade , Histona Desacetilases/metabolismo , Mutação , Fenótipo , RNA Interferente Pequeno/biossínteseRESUMO
The endometrium, composed of epithelial and stromal cell compartments, is tightly regulated by the ovarian steroid hormones estrogen (E2) and progesterone (P4) during early pregnancy. Through the progesterone receptor (PGR), steroid receptor coactivators, and other transcriptional coregulators, progesterone inhibits E2-induced cell proliferation and induces the differentiation of stromal cells in a process called decidualization to promote endometrial receptivity. Although interleukin-13 receptor subunit alpha-2 (Il13ra2) is expressed in the human and mouse endometrium, its potential role in the steroid hormone regulation of the endometrium has not been thoroughly examined. In this study, we employed PGR knockout mice and steroid receptor coactivator-1 knockout mice (SRC-1-/-) to profile the expression of Il13ra2 in the murine endometrium and determine the role of these transcriptional regulators in the hormone-responsiveness of Il13ra2 expression. Furthermore, we utilized a well-established decidualization-inducing steroidogenic cocktail and a siRNA-based knockdown of IL13RA2 to determine the importance of IL13RA2 in the decidualization of primary human endometrial stromal cells. Our findings demonstrate that Il13ra2 is expressed in the subepithelial stroma of the murine endometrium in response to ovarian steroid hormones and during early pregnancy in a PGR- and SRC-1-dependent manner. Furthermore, we show that knockdown of IL13RA2 before in vitro decidualization of primary human endometrial stromal cells partially compromises the full decidualization response. We conclude that Il13ra2 is a downstream target of progesterone through PGR and SRC-1 and plays a role in mediating the stromal action of ovarian steroid hormones.
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Regulação da Expressão Gênica/fisiologia , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Útero/metabolismo , Animais , Feminino , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Subunidade alfa2 de Receptor de Interleucina-13/genética , Camundongos , Camundongos Knockout , Coativador 1 de Receptor Nuclear/genética , Interferência de RNA , RNA Mensageiro , RNA Interferente PequenoRESUMO
BACKGROUND: HEARTBiT is a whole blood-based gene profiling assay using the nucleic acid counting NanoString technology for the exclusionary diagnosis of acute cellular rejection in heart transplant patients. The HEARTBiT score measures the risk of acute cellular rejection in the first year following heart transplant, distinguishing patients with stable grafts from those at risk for acute cellular rejection. Here, we provide the analytical performance characteristics of the HEARTBiT assay and the results on pilot clinical validation. METHODS: We used purified RNA collected from PAXgene blood samples to evaluate the characteristics of a 12-gene panel HEARTBiT assay, for its linearity range, quantitative bias, precision, and reproducibility. These parameters were estimated either from serial dilutions of individual samples or from repeated runs on pooled samples. RESULTS: We found that all 12 genes showed linear behavior within the recommended assay input range of 125 ng to 500 ng of purified RNA, with most genes showing 3% or lower quantitative bias and around 5% coefficient of variation. Total variation resulting from unique operators, reagent lots, and runs was less than 0.02 units standard deviation (SD). The performance of the analytically validated assay (AUC = 0.75) was equivalent to what we observed in the signature development dataset. CONCLUSION: The analytical performance of the assay within the specification input range demonstrated reliable quantification of the HEARTBiT score within 0.02 SD units, measured on a 0 to 1 unit scale. This assay may therefore be of high utility in clinical validation of HEARTBiT in future biomarker observational trials.
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Perfilação da Expressão Gênica/métodos , Rejeição de Enxerto/diagnóstico , Transplante de Coração/efeitos adversos , RNA/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Reprodutibilidade dos TestesRESUMO
Botanical carnivory is a novel feeding strategy associated with numerous physiological and morphological adaptations. However, the benefits of these novel carnivorous traits are rarely tested. We used field observations, lab experiments, and a seminatural experiment to test prey capture function of the marginal spikes on snap traps of the Venus flytrap (Dionaea muscipula). Our field and laboratory results suggested inefficient capture success: fewer than one in four prey encounters led to prey capture. Removing the marginal spikes decreased the rate of prey capture success for moderate-sized cricket prey by 90%, but this effect disappeared for larger prey. The nonlinear benefit of spikes suggests that they provide a better cage for capturing more abundant insects of moderate and small sizes, but they may also provide a foothold for rare large prey to escape. Our observations support Darwin's hypothesis that the marginal spikes form a "horrid prison" that increases prey capture success for moderate-sized prey, but the decreasing benefit for larger prey is unexpected and previously undocumented. Thus, we find surprising complexity in the adaptive landscape for one of the most wonderful evolutionary innovations among all plants. These findings enrich understanding of the evolution and diversification of novel trap morphology in carnivorous plants.
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Droseraceae/fisiologia , Animais , Tamanho Corporal , Droseraceae/anatomia & histologia , GryllidaeRESUMO
Medical imaging is an integral part of clinical trial research and it must be managed properly to provide accurate data to the sponsor in a timely manner (Clune in Cancer Inform 4:33-56, 2007; Wang et al. in Proc SPIE Int Soc Opt Eng 7967, 2011). Standardized workflows for site qualification, protocol preparation, data storage, retrieval, de-identification, submission, and query resolution are paramount to achieve quality clinical trial data management such as reducing the number of imaging protocol deviations and avoiding delays in data transfer. Centralization of data management and implementation of relational databases and electronic workflows can help maintain consistency and accuracy of imaging data. This technical note aims at sharing the practical implementation of our centralized clinical trial imaging data management processes to avoid the fragmentation of tasks among various disease centers and research staff, and enable us to provide quality, accurate, and timely imaging data to clinical trial sponsors.
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Ensaios Clínicos como Assunto , Sistemas de Gerenciamento de Base de Dados/organização & administração , Sistemas de Gerenciamento de Base de Dados/estatística & dados numéricos , Armazenamento e Recuperação da Informação/métodos , Neoplasias/diagnóstico por imagem , Bases de Dados Factuais , HumanosRESUMO
Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creating a medical need. In cancer, DCs are indispensable for T cell activation, so there is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3L to expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supporting the notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancer therapeutic regimens.
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Células Dendríticas , Neoplasias , Camundongos , Humanos , Animais , Proteínas de Membrana/metabolismo , Antígenos , Imunoterapia , VacinaçãoRESUMO
BACKGROUND: During acute health deterioration, emergency medicine and palliative care clinicians routinely discuss code status (e.g., shared decision making about mechanical ventilation) with seriously ill patients. Little is known about their approaches. We sought to elucidate how code status conversations are conducted by emergency medicine and palliative care clinicians and why their approaches are different. METHODS: We conducted a sequential-explanatory, mixed-method study in three large academic medical centers in the Northeastern United States. Attending physicians and advanced practice providers working in emergency medicine and palliative care were eligible. Among the survey respondents, we purposefully sampled the participants for follow-up interviews. We collected clinicians' self-reported approaches in code status conversations and their rationales. A survey with a 5-point Likert scale ("very unlikely" to "very likely") was used to assess the likelihood of asking about medical procedures (procedure based) and patients' values (value based) during code status conversations, followed by semistructured interviews. RESULTS: Among 272 clinicians approached, 206 completed the survey (a 76% response rate). The reported approaches differed greatly (e.g., 91% of palliative care clinicians reported asking about a patient's acceptable quality of life compared to 59% of emergency medicine clinicians). Of the 206 respondents, 118 (57%) agreed to subsequent interviews; our final number of semistructured interviews included seven emergency medicine clinicians and nine palliative care clinicians. The palliative care clinicians stated that the value-based questions offer insight into patients' goals, which is necessary for formulating a recommendation. In contrast, emergency medicine clinicians stated that while value-based questions are useful, they are vague and necessitate extended discussions, which are inappropriate during emergencies. CONCLUSIONS: Emergency medicine and palliative care clinicians reported conducting code status conversations differently. The rationales may be shaped by their clinical practices and experiences.
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Medicina de Emergência , Cuidados Paliativos , Humanos , Qualidade de Vida , Comunicação , Inquéritos e QuestionáriosRESUMO
Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Using epidemiological and genetic data from FinnGen and Estonian Biobank, we identify two previously known variants and an unknown common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. Using live Borrelia burgdorferi (Bb) we find that recombinant reference SCGB1D2 protein inhibits the growth of Bb in vitro more efficiently than the recombinant protein with SCGB1D2 P53L deleterious missense variant. Finally, using an in vivo murine infection model we show that recombinant SCGB1D2 prevents infection by Borrelia in vivo. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection and opens an exciting therapeutic avenue for Lyme disease.
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Borrelia burgdorferi , Ixodes , Doença de Lyme , Secretoglobinas , Animais , Humanos , Camundongos , Borrelia burgdorferi/genética , Ixodes/microbiologia , Doença de Lyme/microbiologiaRESUMO
Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "don't eat me" signaling axis between CD47 (ligand) and SIRPα (receptor). We identified a protein, P66, on the surface of Borrelia burgdorferi that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRPα. Expression of the gene encoding the protein is required for bacteria to bind SIRPα or a high-affinity CD47 reagent. Genetic deletion of p66 increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by B. burgdorferi inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRPα. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.
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BACKGROUND: Identify urinary catheter (UC)-associated urinary tract infections (CAUTI) incidence and risk factors (RF) in 235 ICUs in 8 Asian countries: India, Malaysia, Mongolia, Nepal, Pakistan, the Philippines, Thailand, and Vietnam. METHODS: From January 1, 2014, to February 12, 2022, we conducted a prospective cohort study. To estimate CAUTI incidence, the number of UC days was the denominator, and CAUTI was the numerator. To estimate CAUTI RFs, we analyzed 11 variables using multiple logistic regression. RESULTS: 84,920 patients hospitalized for 499,272 patient days acquired 869 CAUTIs. The pooled CAUTI rate per 1,000 UC-days was 3.08; for those using suprapubic-catheters (4.11); indwelling-catheters (2.65); trauma-ICU (10.55), neurologic-ICU (7.17), neurosurgical-ICU (5.28); in lower-middle-income countries (3.05); in upper-middle-income countries (1.71); at public-hospitals (5.98), at private-hospitals (3.09), at teaching-hospitals (2.04). The following variables were identified as CAUTI RFs: Age (adjusted odds ratio [aOR] = 1.01; 95% CI = 1.01-1.02; P < .0001); female sex (aOR = 1.39; 95% CI = 1.21-1.59; P < .0001); using suprapubic-catheter (aOR = 4.72; 95% CI = 1.69-13.21; P < .0001); length of stay before CAUTI acquisition (aOR = 1.04; 95% CI = 1.04-1.05; P < .0001); UC and device utilization-ratio (aOR = 1.07; 95% CI = 1.01-1.13; P = .02); hospitalized at trauma-ICU (aOR = 14.12; 95% CI = 4.68-42.67; P < .0001), neurologic-ICU (aOR = 14.13; 95% CI = 6.63-30.11; P < .0001), neurosurgical-ICU (aOR = 13.79; 95% CI = 6.88-27.64; P < .0001); public-facilities (aOR = 3.23; 95% CI = 2.34-4.46; P < .0001). DISCUSSION: CAUTI rate and risk are higher for older patients, women, hospitalized at trauma-ICU, neurologic-ICU, neurosurgical-ICU, and public facilities. All of them are unlikely to change. CONCLUSIONS: It is suggested to focus on reducing the length of stay and the Urinary catheter device utilization ratio, avoiding suprapubic catheters, and implementing evidence-based CAUTI prevention recommendations.
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Infecções Relacionadas a Cateter , Infecção Hospitalar , Infecções Urinárias , Humanos , Feminino , Estudos Prospectivos , Infecção Hospitalar/prevenção & controle , Incidência , Infecções Relacionadas a Cateter/epidemiologia , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Urinárias/prevenção & controle , Unidades de Terapia Intensiva , Cateteres de Demora/efeitos adversos , Fatores de Risco , Paquistão/epidemiologiaRESUMO
OBJECTIVE: To identify urinary catheter (UC)-associated urinary tract infection (CAUTI) incidence and risk factors. DESIGN: A prospective cohort study. SETTING: The study was conducted across 623 ICUs of 224 hospitals in 114 cities in 37 African, Asian, Eastern European, Latin American, and Middle Eastern countries. PARTICIPANTS: The study included 169,036 patients, hospitalized for 1,166,593 patient days. METHODS: Data collection took place from January 1, 2014, to February 12, 2022. We identified CAUTI rates per 1,000 UC days and UC device utilization (DU) ratios stratified by country, by ICU type, by facility ownership type, by World Bank country classification by income level, and by UC type. To estimate CAUTI risk factors, we analyzed 11 variables using multiple logistic regression. RESULTS: Participant patients acquired 2,010 CAUTIs. The pooled CAUTI rate was 2.83 per 1,000 UC days. The highest CAUTI rate was associated with the use of suprapubic catheters (3.93 CAUTIs per 1,000 UC days); with patients hospitalized in Eastern Europe (14.03) and in Asia (6.28); with patients hospitalized in trauma (7.97), neurologic (6.28), and neurosurgical ICUs (4.95); with patients hospitalized in lower-middle-income countries (3.05); and with patients in public hospitals (5.89).The following variables were independently associated with CAUTI: Age (adjusted odds ratio [aOR], 1.01; P < .0001), female sex (aOR, 1.39; P < .0001), length of stay (LOS) before CAUTI-acquisition (aOR, 1.05; P < .0001), UC DU ratio (aOR, 1.09; P < .0001), public facilities (aOR, 2.24; P < .0001), and neurologic ICUs (aOR, 11.49; P < .0001). CONCLUSIONS: CAUTI rates are higher in patients with suprapubic catheters, in middle-income countries, in public hospitals, in trauma and neurologic ICUs, and in Eastern European and Asian facilities.Based on findings regarding risk factors for CAUTI, focus on reducing LOS and UC utilization is warranted, as well as implementing evidence-based CAUTI-prevention recommendations.
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Infecções Relacionadas a Cateter , Infecção Hospitalar , Infecções Urinárias , Humanos , Infecções Relacionadas a Cateter/epidemiologia , Catéteres , Infecção Hospitalar/prevenção & controle , Hospitais Públicos , Incidência , Unidades de Terapia Intensiva , Estudos Prospectivos , Infecções Urinárias/epidemiologiaRESUMO
A 74-year-old lady with lipomatous hypertrophy of the interatrial septum presented with symptomatic anemia. Imaging revealed a new diagnosis of metastatic cancer of presumed lung origin, with a new soft tissue myocardial lesion adjacent to the right atrium within the region of lipomatous hypertrophy. This was favored to represent a myocardial metastasis within concurrent lipomatous hypertrophy of the interatrial septum.
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Mesenchymal stromal cells (MSCs) offer promising potential in biomedical research, clinical therapeutics, and immunomodulatory therapies due to their ease of isolation and multipotent, immunoprivileged, and immunosuppersive properties. Extensive efforts have focused on optimizing the cell isolation and culture methods to generate scalable, therapeutically-relevant MSCs for clinical applications. However, MSC-based therapies are often hindered by cell heterogeneity and inconsistency of therapeutic function caused, in part, by MSC senescence. As such, noninvasive and molecular-based MSC characterizations play an essential role in assuring the consistency of MSC functions. Here, we demonstrated that AI image translation algorithms can effectively predict immunofluorescence images of MSC senescence markers from phase contrast images. We showed that the expression level of senescence markers including senescence-associated beta-galactosidase (SABG), p16, p21, and p38 are accurately predicted by deep-learning models for Doxorubicin-induced MSC senescence, irradiation-induced MSC senescence, and replicative MSC senescence. Our AI model distinguished the non-senescent and senescent MSC populations and simultaneously captured the cell-to-cell variability within a population. Our microscopy-based phenotyping platform can be integrated with cell culture routines making it an easily accessible tool for MSC engineering and manufacturing.
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Following the global spread of COVID-19, scientists and engineers have adapted technologies and developed new tools to aid in the fight against COVID-19. This review discusses various approaches to engineering biomaterials, devices, and therapeutics, especially at micro and nano levels, for the prevention, diagnosis, and treatment of infectious diseases, such as COVID-19, serving as a resource for scientists to identify specific tools that can be applicable for infectious-disease-related research, technology development, and treatment. From the design and production of equipment critical to first responders and patients using three-dimensional (3D) printing technology to point-of-care devices for rapid diagnosis, these technologies and tools have been essential to address current global needs for the prevention and detection of diseases. Moreover, advancements in organ-on-a-chip platforms provide a valuable platform to not only study infections and disease development in humans but also allow for the screening of more effective therapeutics. In addition, vaccines, the repurposing of approved drugs, biomaterials, drug delivery, and cell therapy are promising approaches for the prevention and treatment of infectious diseases. Following a comprehensive review of all these topics, we discuss unsolved problems and future directions.
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3D cancer spheroids represent a highly promising model for study of cancer progression and therapeutic development. Wide-scale adoption of cancer spheroids, however, remains a challenge due to the lack of control over hypoxic gradients that may cloud the assessment of cell morphology and drug response. Here, we present a Microwell Flow Device (MFD) that generates in-well laminar flow around 3D tissues via repetitive tissue sedimentation. Using a prostate cancer cell line, we demonstrate the spheroids in the MFD exhibit improved cell growth, reduced necrotic core formation, enhanced structural integrity, and downregulated expression of cell stress genes. The flow-cultured spheroids also exhibit an improved sensitivity to chemotherapy with greater transcriptional response. These results demonstrate how fluidic stimuli reveal the cellular phenotype previously masked by severe necrosis. Our platform advances 3D cellular models and enables study into hypoxia modulation, cancer metabolism, and drug screening within pathophysiological conditions.
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Neoplasias da Próstata , Esferoides Celulares , Humanos , Masculino , Técnicas de Cultura de Células/métodos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Avaliação Pré-Clínica de MedicamentosRESUMO
Objectives: To identify urinary catheter (UC)-associated urinary tract infections (CAUTI) incidence and risk factors (RF) in nine Middle Eastern countries. Methods: We conducted a prospective cohort study between 1 January 2014 and 2 December 2022 in 212 intensive care units (ICUs) of 67 hospitals in 38 cities in nine Middle Eastern countries (Bahrain, Egypt, Jordan, Kuwait, Lebanon, Morocco, Saudi Arabia, Turkey, and the UAE). To estimate CAUTI incidence, we used the number of UC days as denominator and the number of CAUTIs as numerator. To estimate CAUTI RFs, we analyzed the following 10 variables using multiple logistic regression: patient sex, age, length of stay (LOS) before CAUTI acquisition, UC-days before CAUTI acquisition, UC-device utilization (DU) ratio, hospitalization type, ICU type, facility-ownership, country income level classified by World Bank, and time period. Results: Among 50â 637 patients hospitalized for 434â 523 patient days, there were 580 cases of acquired CAUTIs. The pooled CAUTI rate per 1000 UC days was 1.84. The following variables were independently associated with CAUTI: age, rising risk 1.0% yearly (adjusted odds ratio [aOR] = 1.01, 95% CI: 1.01-1.02; p < 0.0001); female sex (aOR = 1.31, 95% CI: 1.09-1.56; p < 0.0001); LOS before CAUTI acquisition, rising risk 6.0% daily (aOR = 1.06, 95% CI: 1.05-1.06; p < 0.0001); and UC/DU ratio (aOR = 1.11, 95% CI: 1.06-1.14; p < 0.0001). Patients from lower-middle-income countries (aOR = 4.11, 95% CI: 2.49-6.76; p < 0.0001) had a similar CAUTI risk to the upper-middle countries (aOR = 3.75, 95% CI: 1.83-7.68; p < 0.0001). The type of ICU with the highest risk for CAUTI was neurologic ICU (aOR = 27.35, 95% CI: 23.03-33.12; p < 0.0001), followed by medical ICU (aOR = 6.18, 95% CI: 2.07-18.53; p < 0.0001) when compared to cardiothoracic ICU. The periods 2014-2016 (aOR = 7.36, 95% CI: 5.48-23.96; p < 0.001) and 2017-2019 (aOR = 1.15, 95% CI: 3.46-15.61; p < 0.001) had a similar risk to each other, but a higher risk compared to 2020-2022. Conclusions: The following CAUTI RFs are unlikely to change: age, sex, ICU type, and country income level. Based on these findings, it is suggested to focus on reducing LOS, UC/DU ratio, and implementing evidence-based CAUTI prevention recommendations.
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Much about the role of intestinal microbes at the site of colon cancer development and tumor progression following curative resection remains to be understood. We have recently shown that collagenolytic bacteria such as Enterococcus faecalis predominate within the colon postoperatively, particularly at the site of the colon reconnection (i.e. anastomosis) in the early period of post-surgical recovery. The presence of collagenolytic bacteria at this site correlates with the tumor progression in a mouse model of post-surgical tumor development. In the present study we hypothesized, that collagenolytic bacteria, such as E. faecalis, play an important yet to be discovered role in tumor formation and progression. Therefore the aims of this study were to assess the role of collagenolytic E. faecalis on the migration and invasion of a murine colon cancer cell line. Results demonstrated that both migration and invasion were induced by E. faecalis with collagenolytic activity being required for only invasion. Bidirectional signaling in the E. faecalis-cancer cell interaction was observed by the discovering that the expression of gelE in E. faecalis, the gene required for collagenase production, is expressed in response to exposure to CT26 cells. The mechanism by which migration enhancement via E. faecalis occurs appears to be dependent on its ability to activate pro-uPA, a key element of the urokinase-plasminogen system, a pathway that is well - known to be important in cancer cell invasion and migration. Finally, we demonstrated that collagenase producing microbes preferentially colonize human colon cancer specimens.
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Neoplasias do Colo , Enterococcus faecalis , Animais , Colagenases/metabolismo , Neoplasias do Colo/genética , Enterococcus faecalis/genética , Enterococcus faecalis/metabolismo , Humanos , Camundongos , Fenótipo , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
X-chromosome inactivation is a paradigm of epigenetic transcriptional regulation. Female human embryonic stem cells (hESCs) often undergo erosion of X-inactivation upon prolonged culture. Here, we investigate the sources of X-inactivation instability by deriving new primed pluripotent hESC lines. We find that culture media composition dramatically influenced the expression of XIST lncRNA, a key regulator of X-inactivation. hESCs cultured in a defined xenofree medium stably maintained XIST RNA expression and coating, whereas hESCs cultured in the widely used mTeSR1 medium lost XIST RNA expression. We pinpointed lithium chloride in mTeSR1 as a cause of XIST RNA loss. The addition of lithium chloride or inhibitors of GSK-3 proteins that are targeted by lithium to the defined hESC culture medium impeded XIST RNA expression. GSK-3 inhibition in differentiating female mouse embryonic stem cells and epiblast stem cells also resulted in a loss of XIST RNA expression. Together, these data may reconcile observed variations in X-inactivation in hESCs and inform the faithful culture of pluripotent stem cells.
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Células-Tronco Embrionárias Humanas , RNA Longo não Codificante , Animais , Cromossomos/metabolismo , Feminino , Quinase 3 da Glicogênio Sintase/metabolismo , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Cloreto de Lítio/metabolismo , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Inativação do Cromossomo XRESUMO
Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.