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BACKGROUND: Polypharmacy and anticholinergic medications are associated with cognitive decline in elderly populations. Although several medications have been associated with HE, associations between medication burden, anticholinergics, and HE have not been explored. We examined medication burden and anticholinergics in patients with cirrhosis and their associations with HE-related hospitalization. METHODS: We conducted a retrospective cohort study of patients aged 18-80 with cirrhosis seen in hepatology clinics during 2019. The number of chronic medications (medication burden) and anticholinergic use were recorded. The primary outcome was HE-related hospitalization. RESULTS: A total of 1039 patients were followed for a median of 840 days. Thirty-seven percent had a history of HE, and 9.8% had an HE-related hospitalization during follow-up. The mean number of chronic medications was 6.1 ± 4.3. Increasing medication burden was associated with HE-related hospitalizations in univariable (HR: 1.09, 95% CI: 1.05-1.12) and multivariable (HR: 1.07, 95% CI: 1.03-1.11) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. Twenty-one percent were taking an anticholinergic medication. Anticholinergic exposure was associated with increased HE-related hospitalizations in both univariable (HR: 1.68, 95% CI: 1.09-2.57) and multivariable (HR: 1.71, 95% CI: 1.11-2.63) models. This relationship was maintained in those with baseline HE but not in those without baseline HE. CONCLUSIONS: Anticholinergic use and medication burden are both associated with HE-related hospitalizations, particularly in those with a history of HE. Special considerations to limit anticholinergics and minimize overall medication burden should be tested for potential benefit in this population.
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Antagonistas Colinérgicos , Encefalopatía Hepática , Hospitalización , Cirrosis Hepática , Polifarmacia , Humanos , Antagonistas Colinérgicos/efectos adversos , Antagonistas Colinérgicos/uso terapéutico , Masculino , Cirrosis Hepática/tratamiento farmacológico , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Anciano , Hospitalización/estadística & datos numéricos , Encefalopatía Hepática/tratamiento farmacológico , Adulto , Anciano de 80 o más Años , Adolescente , Adulto JovenRESUMEN
Targeted agents and immunotherapies have revolutionized cancer treatment, offering promising options for various cancer types. Unlike traditional therapies the principle of "more is better" is not always applicable to these new therapies due to their unique biomedical mechanisms. As a result, various phase I-II clinical trial designs have been proposed to identify the optimal biological dose that maximizes the therapeutic effect of targeted therapies and immunotherapies by jointly monitoring both efficacy and toxicity outcomes. This review article examines several innovative phase I-II clinical trial designs that utilize accumulated efficacy and toxicity outcomes to adaptively determine doses for subsequent patients and identify the optimal biological dose, maximizing the overall therapeutic effect. Specifically, we highlight three categories of phase I-II designs: efficacy-driven, utility-based, and designs incorporating multiple efficacy endpoints. For each design, we review the dose-outcome model, the definition of the optimal biological dose, the dose-finding algorithm, and the software for trial implementation. To illustrate the concepts, we also present two real phase I-II trial examples utilizing the EffTox and ISO designs. Finally, we provide a classification tree to summarize the designs discussed in this article.
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Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Inmunoterapia , Neoplasias , Proyectos de Investigación , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Inmunoterapia/métodos , Ensayos Clínicos Fase I como Asunto/métodos , Ensayos Clínicos Fase II como Asunto/métodos , Relación Dosis-Respuesta a Droga , Terapia Molecular Dirigida/métodos , Algoritmos , Ensayos Clínicos Adaptativos como Asunto/métodosRESUMEN
Background: Pneumonia is the most common reason for pediatric hospitalizations. The impact of penicillin allergy labels among children with pneumonia has not been well studied. Objective: This study assessed the prevalence and impact of penicillin allergy labels among children admitted with pneumonia over a 3-year period at a large academic children's center. Methods: Inpatient charts of pneumonia admissions with a documented allergy to a type of penicillin from January to March in 2017, 2018, and 2019 were reviewed and compared with pneumonia admissions without the label over the same time with regard to days of antimicrobial treatment, route of antimicrobial therapy, and days of hospitalization. Results: There were 470 admissions for pneumonia during this time period, of which 48 patients (10.2%) carried a penicillin allergy label. Hives and/or swelling comprised 20.8% of the allergy labels. Other labels included nonpruritic rashes, gastrointestinal GI symptoms, unknown/undocumented reactions, or other reasons. There were no significant differences between those with a penicillin allergy label to those without regarding days of antimicrobial treatment (inpatient and outpatient), route of antimicrobial therapy, and days of hospitalization. Those with a penicillin allergy label were less likely to be prescribed a penicillin product (p < 0.002). Of the 48 patients who were allergy labeled, 23% (11/48) were given a penicillin medication without adverse reaction. Conclusion: Ten percent of pediatric admissions for pneumonia had a label of penicillin allergy, similar to the overall population. The hospital course and clinical outcome were not significantly affected by the penicillin allergy label. The majority of documented reactions were of low risk for immediate allergic reactions.
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Hipersensibilidad Inmediata , Neumonía , Urticaria , Humanos , Niño , Hospitalización , PenicilinasRESUMEN
Conventional phase I/II clinical trial designs often use complicated parametric models to characterize the dose-response relationships and conduct the trials. However, the parametric models are hard to justify in practice, and the misspecification of parametric models can lead to substantially undesirable performances in phase I/II trials. Moreover, it is difficult for the physicians conducting phase I/II trials to clinically interpret the parameters of these complicated models, and such significant learning costs impede the translation of novel statistical designs into practical trial implementation. To solve these issues, we propose a transparent and efficient phase I/II clinical trial design, referred to as the modified isotonic regression-based design (mISO), to identify the optimal biological doses for molecularly targeted agents and immunotherapy. The mISO design makes no parametric model assumptions on the dose-response relationship and yields desirable performances under any clinically meaningful dose-response curves. The concise, clinically interpretable dose-response models and dose-finding algorithm make the proposed designs highly translational from the statistical community to the clinical community. We further extend the mISO design and develop the mISO-B design to handle the delayed outcomes. Our comprehensive simulation studies show that the mISO and mISO-B designs are highly efficient in optimal biological dose selection and patients allocation and outperform many existing phase I/II clinical trial designs. We also provide a trial example to illustrate the practical implementation of the proposed designs. The software for simulation and trial implementation are available for free download.
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Antineoplásicos , Humanos , Teorema de Bayes , Relación Dosis-Respuesta a Droga , Ensayos Clínicos como Asunto , Simulación por Computador , Proyectos de Investigación , Dosis Máxima ToleradaRESUMEN
Golden pomfret (Trachinotus ovatus) is an important farmed fish in Asia, often consumed following salting and natural microbial fermentation. Flavor development in fermented foods depends on the metabolism of fermenting microbes, especially amino acid metabolism. However, the microbes involved in golden pomfret fermentation and the mechanism by which they regulate flavor development are largely unknown. Accordingly, in this study, we investigated the microbial community and volatile and non-volatile compounds during the traditional fermentation of golden pomfret, focusing on amino acid metabolism. Thirty-five volatile compounds were detected. Glutamate, alanine, and leucine were the main amino acids responsible for the development of the characteristic taste of fermented golden pomfret. Metagenomic analyses were performed, and microbial genes for amino acid metabolism were functionally annotated, revealing the underlying mechanisms of flavor development during fish fermentation. Halobacterium, Clostridium, Natrinema, Alkalibacillus, Natrialba, and Vibrio were the dominant microbial genera with a major contribution to amino acid metabolism during fermentation and were strongly correlated with the majority of volatile compounds. The study provides a theoretical reference for the mechanism of flavor formation and important information on the microbial sources of volatile compounds derived from amino acids.
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Aminoácidos , Alimentos Marinos , Animales , Fermentación , Peces , Ácido GlutámicoRESUMEN
The quality of dried fish products differs based on the drying method employed owing to the different drying principles, with changes in protein affecting the quality of these products. Therefore, we investigated the differences in golden pompano (Trachinotus ovatus) fish tissue structure and protein physicochemical properties under different drying methods. Freeze drying (FD) induced less tissue damage, leaving more intact myofibrils, than that of hot air drying (HAD) and heat pump drying (HPD). The structural stability of myofibrillar protein was retained to a greater extent after FD, while myoglobin oxidation was lower, and fish meat color was well maintained. Our findings not only elucidated the effects of several drying methods on the physicochemical properties of fish protein, but also determined the mechanism underlying quality changes observed during the drying process. This provides a theoretical reference for the study of dried fish filet processing.
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In this paper, glass fiber fabric reinforced polyphenylene sulfide composites were prepared by hot pressing. The effects of glass fibre modification and hot pressing temperature on the properties of the composites were investigated using a scanning electron microscope, infrared spectrometer, universal testing machine, and DIGEYE digital imaging colour measurement system. The results show that after the treatment with a silane coupling agent, the silane coupling agent was more uniformly distributed on the surface of the glass fibres, and the bonding effect between the glass fibre fabric and polyphenylene sulphide was significantly improved. The strength of the composites increased and then decreased with the increase of hot pressing temperature, and the surface colour of the composites became darker and darker. When the hot-pressing temperature is 310 °C, the mechanical properties of glass fabric-reinforced polyphenylene sulfide composites are at their best, the tensile strength reaches 51.9 MPa, and the bending strength reaches 78 MPa.
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Background While studies of hospital dermatology have demonstrated diagnostic discordance between primary teams and dermatology consultants, little is known about the impact of biopsy and clinical-pathologic correlation (CPC) in consultation. This study compares biopsy performance based on diagnostic discordance and evaluates the impact of CPC on the diagnosis. Methods This was a retrospective review of 376 dermatologic consultations at a single academic medical center between July 1, 2017, and June 27, 2018. Results Biopsy was significantly less likely to be performed when the diagnosis by the referring primary team was unspecified (p < 0.001). In 24 percent of cases, the diagnosis based on histopathology alone differed from the diagnosis reached by formal CPC consensus review with either potential or significant impact on management. Conclusion Dermatologists who perform inpatient consultations and rely on hospital-based pathology services may consider a consensus review for CPC. Requests to perform a biopsy may be interpreted as a request for diagnostic assistance rather than pressure to perform a procedure.
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BACKGROUND: Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells. RESULTS: Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance. CONCLUSIONS: Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.
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Neoplasias Colorrectales , Complemento C1q , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Complemento C1q/genética , Complemento C1q/uso terapéutico , Humanos , Inestabilidad de Microsatélites , Transcriptoma , Microambiente Tumoral/genéticaRESUMEN
We evaluated maternal pregnancy adaptations and their relationships with circulating hormones in women who conceived with or without in vitro fertilization (IVF). Pregnancies were grouped by corpus luteum (CL) number: 1 CL with physiological plasma relaxin concentration (PRLN; spontaneous pregnancies); 0 CL without circulating RLN (programmed cycles); >1 CL with elevated PRLN (ovarian stimulation). Major findings were that declines in plasma osmolality (Posm) and plasma sodium concentration ([Formula: see text]) were comparable in the 1 CL and 0 CL cohorts, correlated with plasma estradiol and progesterone concentrations but not PRLN; gestational declines in plasma uric acid (UA) concentration (PUA) were attenuated after IVF, especially programmed cycles, partly because of subdued increases of renal UA clearance; and PRLN and cardiac output (CO) were inversely correlated when plasma estradiol concentration was below â¼2.5 ng/mL but positively correlated above â¼2.5 ng/mL. Unexpectedly, PRLN and plasma sFLT1 (PsFLT1) were directly correlated. Although PsFLT1 and CO were not significantly associated, CO was positively correlated with plasma placental growth factor (PLGF) concentration after the first trimester, particularly in women who conceived with 0 CL. Major conclusions are that 1) circulating RLN was unnecessary for gestational falls in Posm and [Formula: see text]; 2) PRLN and CO were inversely correlated during early gestation, suggesting that PRLN in the lower range may have contributed to systemic vasodilation, whereas at higher PRLN RLN influence became self-limiting; 3) evidence for cooperativity between RLN and estradiol on gestational changes in CO was observed; and 4) after the first trimester in women who conceived without a CL, plasma PLGF concentration was associated with recovery of CO, which was impaired during the first trimester in this cohort.
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Fertilización In Vitro , Hormonas Gonadales/sangre , Hemodinámica , Infertilidad/terapia , Adaptación Fisiológica , Adulto , Biomarcadores/sangre , Gasto Cardíaco , Estradiol/sangre , Femenino , Humanos , Infertilidad/sangre , Infertilidad/fisiopatología , Persona de Mediana Edad , Concentración Osmolar , Factor de Crecimiento Placentario/sangre , Embarazo , Primer Trimestre del Embarazo/sangre , Relaxina/sangre , Sodio/sangre , Ácido Úrico/sangre , Vasodilatación , Adulto JovenRESUMEN
In women who conceived with or without assisted reproduction, we evaluated endothelial function by EndoPAT [reactive hyperemia index (RHI)], circulating numbers of endothelial cells (CEC) and endothelial progenitor cells (EPC), and their function before during and after pregnancy. In vitro fertilization (IVF) pregnancies were stratified by method of conception and corpus luteum (CL) number-controlled ovarian stimulation (>1 CL) or programmed (0 CL) cycles and spontaneous singleton pregnancies (1 CL). We observed 1) comparable gestational decline of RHI in the three participant groups secondary to gestational rise of baseline preocclusion pulse-wave amplitude (PWA) incorporated into the RHI calculation by EndoPAT software; 2) progressive rise in "normalized" RHI throughout pregnancy (calculated by substituting prepregnancy baseline preocclusion PWA into the RHI equation), greater in spontaneous conception vs. IVF cohorts; 3) similar gestational increase of maximum PWA and time to maximum PWA after the ischemia stimulus among the three participant groups; 4) modest gestational increase of ischemia response (reactive hyperemia) in the spontaneous conception group and no change or significant decline, respectively, in women who conceived using programmed or controlled ovarian stimulation cycles; 5) enhanced basal nitric oxide production by early (primitive) outgrowth EPC during pregnancy in women who conceived spontaneously, but not through IVF; and 6) gestational increase in CEC in all three participant cohorts, more pronounced in women who conceived by IVF using programmed cycles. On balance, the evidence supported enhanced endothelial function during pregnancy in spontaneous conceptions but less so in IVF pregnancies using either controlled ovarian stimulation or programmed cycles.
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Células Progenitoras Endoteliales/fisiología , Endotelio Vascular/fisiología , Fertilización In Vitro , Adulto , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Adulto JovenRESUMEN
Objectives: In this study, we explored the potential impact of disasters on individuals' fruit and vegetable consumption. Methods: Individual-level data (N = 351,229) from the Behavioral Risk Factor Surveillance System (BRFSS) 2011 survey were merged with county-level disaster declaration data from the Federal Emergency Management Agency (FEMA) based on disaster duration, interview month and residential county. Multilevel mixed-effects generalized linear models were conducted to examine the impact of different types of disasters on self-reported daily fruit, 100% pure fruit juice, beans, green vegetables, orange vegetables, other vegetables and overall vegetables consumption frequencies, adjusting for individual covariates. Results: No associations between disasters and daily fruit and overall vegetable consumption frequency were identified at either national or state levels. Only floods were consistently associated with reduced consumption of orange vegetables. Conclusions: This study did not identify an association between natural disasters and daily overall fruit/vegetable consumption frequency at national or state levels, whereas disasters were found to alter the consumption of certain vegetable subgroup (orange vegetables) slightly. Longitudinal studies with validated and detailed measures on diet and disaster are warranted to advance research in this field.
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Dieta , Desastres Naturales , Sistema de Vigilancia de Factor de Riesgo Conductual , Femenino , Frutas , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , VerdurasRESUMEN
Objectives: Hurricane Katrina was an intense tropical cyclone that made landfall in the United States (US) in August 2005, causing catastrophic damage in several states. This study examined the impact of Hurricane Katrina on mental health status among US adults. Methods: Multilevel regressions based on the difference-in-differences study design were performed on individual-level data (N = 70,267) retrieved from the Behavioral Risk Factor Surveillance System 2004-2006 surveys. Results: Hurricane Katrina was found to be associated with an increase of 0.68 poor mental health days among residents of Katrina-affected states. The negative impact of Hurricane Katrina on mental health status tended to be larger among Louisiana residents, women, young and middle-aged adults, lower income respondents, and those with poor/fair self-rated physical health than among Mississippi residents, men, older adults, higher income respondents, and those with good/excellent self-rated physical health. Conclusion: Hurricane Katrina adversely impacted mental health of residents in Katrina-affected states, and the impact differed across population subgroups. Future studies should investigate other potential risk and protective factors for the mental health consequences of disasters. They should examine long-term impacts on mental health following disasters to better inform population-based mental health interventions for disaster survivors.
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Tormentas Ciclónicas , Desastres , Salud Mental , Adaptación Psicológica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Estado de Salud , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Investigación Cualitativa , Autoinforme , Estados Unidos , Adulto JovenRESUMEN
This study was purposed to investigate the effectiveness of bacterial screening with 24 hours holding in preventing and controlling bacterial contamination of platelets. Bacterial screening of apheresis platelets preserved for 24 hours was performed by using BacT/ALERT automatic bacterial culture system. The samples from 5 bags of platelet were taken in aseptic condition and were merged into 1 bag. The final sample was inoculated into aerobic and anaerobic bottle respectively for testing, meanwhile the screened platelet samples were held for 24 hours. If the platelets were cultured for 24 hours and identification of bacterial strains showed negative, the platelets could be released, and the original platelet samples should be rescreened if initiate positive was found. The results showed that in screening 8017 samples of apheresis platelets the initiate positive results were 16 (0.2%) and confirmed positive were 4 (0.05%). Out of 4 confirmed positive strains, three were Staphylococcus aureus and another was Staphylococcus auricularis. It is concluded that it is necessary for blood center to apply the method of bacterial screening of platelet with 24 hours holding as conventional screening method, which is an effective and feasible way to prevent and control bacterial contamination of platelets.