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Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Colorrectales , Neoplasias Pulmonares , Síndrome Debilitante , Animales , Humanos , Ratones , Quinasas de la Proteína-Quinasa Activada por el AMP , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Colorrectales/genética , Neoplasias Pulmonares/patología , Mutación , Proteínas Serina-Treonina Quinasas/metabolismo , Microambiente Tumoral , Pérdida de PesoRESUMEN
INTRODUCTION: The average length of stay of a fast-track area of a large urban hospital was excessively long, which affected the patient experience and the rate at which patients left without being seen. One approach to reducing average length of stay is to create nurse standard work. Nurse standard work was a defined set of process and procedures that reduce variability within a nurse's workflow. METHODS: Nurse standard work was created by a team of nurses assisted by management engineering using lean methodology and A3 problem solving. Data were gathered about average length of stay and left without being seen for patients in the emergency department fast-track area of an urban emergency department from October 2018 to June 2020. This period includes 5 months before the intervention start, 4 months during nurse standard work implementation, 9 months using nurse standard work before the unit was repurposed during COVID-19, and 3 months during COVID-19. RESULTS: Nurse standard work helped reduce average length of stay in the emergency department fast-track area from 205 minutes before project initiation to 150.4 minutes in the 7 months after implementing nurse standard work. The time spent walking for supplies was reduced from 422 and 272 seconds before nurse standard work to 25 and 30 seconds for the nurse technician and nurse, respectively, after nurse standard work. Left without being seen was decreased from 4.7% in October of 2018 to 0.7% by March of 2020. DISCUSSION: Nurse standard work reduced the amount of time that nurses spent performing support tasks and reduced delays in providing patient care, which then allowed more time for nurses to interact directly with patients. Nurse standard work provides a clear task sequence that eliminates delays in treating patients, but it also allows for fast identification of delays that do occur and simplifies problem solving to eliminate reoccurrence of delays. Therefore, nurse standard work is an essential component of efforts to reduce patient average length of stay in health care processes and reduce left without being seen to the national standard of less than 2%.
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COVID-19 , Mejoramiento de la Calidad , Humanos , Tiempo de Internación , Servicio de Urgencia en Hospital , Flujo de TrabajoRESUMEN
BACKGROUND: Cachexia, a syndrome of muscle atrophy, adipose loss, and anorexia, is associated with reduced survival in cancer patients. The colon adenocarcinoma C26c20 cell line secretes the cytokine leukemia inhibitory factor (LIF) which induces cachexia. We characterized how LIF promotes cachexia-associated weight loss and anorexia in mice through JAK-dependent changes in adipose and hypothalamic tissues. METHODS: Cachexia was induced in vivo with the heterotopic allotransplanted administration of C26c20 colon adenocarcinoma cells or the intraperitoneal administration of recombinant LIF in the absence or presence of JAK inhibitors. Blood, adipose, and hypothalamic tissues were collected and processed for cyto/adipokine ELISAs, immunoblot analysis, and quantitative RT-PCR. Cachexia-associated lipolysis was induced in vitro by stimulating differentiated adipocytes with recombinant LIF or IL-6 in the absence or presence of lipase or JAK inhibitors. These adipocytes were processed for glycerol release into the media, immunoblot analysis, and RT-PCR. RESULTS: Tumor-secreted LIF induced changes in adipose tissue expression and serum levels of IL-6 and leptin in a JAK-dependent manner influencing cachexia-associated adipose wasting and anorexia. We identified two JAK inhibitors that block IL-6 family-mediated adipocyte lipolysis and IL-6 induction using an in vitro cachexia lipolysis assay. JAK inhibitors administered to the in vivo C26c20 cancer cachexia mouse models led to 1) a decrease in STAT3 phosphorylation in hypothalamic and adipose tissues, 2) a reverse in the cachexia serum cyto/adipokine signature, 3) a delay in cancer cachexia-associated anorexia and adipose loss, and 4) an improvement in overall survival. CONCLUSIONS: JAK inhibitors suppress LIF-associated adipose loss and anorexia in both in vitro and in vivo models of cancer cachexia.
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Few authors have proposed therapeutic protocols to manage retained rectal foreign bodies (RFBs). All patients with retained RFBs in hospitals across Trinidad and Tobago over 5 years were identified. Hospital records were retrieved and manually reviewed to extract the following data: demographics, history, foreign body retrieved, clinical signs at presentation, management strategy, duration of hospitalization, and morbidity and mortality. There were 10 patients with RFBs over the study period. The annual incidence of this phenomenon was 0.15 per 100,000 population. All patients were men at a mean age of 50.6 years (range: 27-83; SD = 15.3) who presented after a voluntary delay of 1.4 days (range: 0.5-2.5; SD = 0.7). Only one patient gave an accurate history on presentation, but all eventually admitted to self-insertion for sexual gratification. At presentation, one patient had a spontaneous rectal perforation (10%). The remaining nine patients had attempts at bedside transanal extraction, which was unsuccessful in 89% (8/9) of cases. The RFB was pushed beyond the grasp of forceps, making removal under anesthesia unsuccessful in 62.5% (5/8) cases. These patients required more invasive extraction methods including transanal minimally invasive surgery (1), laparoscopic-assisted advancement with transanal retrieval (1), and open surgery with transmural extraction and anastomoses (3). A management algorithm is proposed for the management of RFBs. Important points in this algorithm are the importance of clinician-patient rapport, early surgical referral, avoidance of bedside extraction in the emergency room, early examination under anesthesia, and the inclusion of emerging therapies such as transanal minimally invasive surgery.
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Algoritmos , Cuerpos Extraños/epidemiología , Cuerpos Extraños/cirugía , Recto , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sigmoidoscopía , Trinidad y Tobago/epidemiologíaRESUMEN
The search for reliable early indicators of age-related cognitive decline represents a critical avenue for progress in aging research. Chronological age is a commonly used developmental index; however, it offers little insight into the mechanisms underlying cognitive decline. In contrast, biological age (BioAge), reflecting the vitality of essential biological systems, represents a promising operationalization of developmental time. Current BioAge models have successfully predicted age-related cognitive deficits. Research on aging-related cognitive function indicates that the interaction of multiple risk and protective factors across the human lifespan confers individual risk for late-life cognitive decline, implicating a multi-causal explanation. In this review, we explore current BioAge models, describe three broad yet pathologically relevant biological processes linked to cognitive decline, and propose a novel operationalization of BioAge accounting for both moderating and causal mechanisms of cognitive decline and dementia. We argue that a multivariate and mechanistic BioAge approach will lead to a greater understanding of disease pathology as well as more accurate prediction and early identification of late-life cognitive decline.
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Envejecimiento/psicología , Encéfalo/fisiopatología , Trastornos del Conocimiento/etiología , Cognición , Factores de Edad , Envejecimiento/patología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Estado de Salud , Humanos , Inflamación/complicaciones , Estrés Oxidativo , Factores de Riesgo , Enfermedades Vasculares/complicacionesRESUMEN
BACKGROUND: African-American women (AAW) have the highest prevalence of obesity and therefore are at greater risk for obesity-related symptoms and diseases. Obese individuals frequently report poorer sleep quality, more daytime sleepiness, more severe fatigue, and higher physical inactivity than normal weight individuals. The relationships among these variables have not been well-characterized in obese, urban-dwelling, AAW. METHODS: This descriptive, correlational study examined the relationships among sleep quality, daytime sleepiness, fatigue, level of physical activity, and body mass index (BMI) in AAW living in an urban setting. A convenience sample of 69 young adult women with a BMI of greater than 30 kg/m(2) completed measures of sleep quality, sleepiness, fatigue severity, sense of community, and physical activity. Further analysis was done to determine if any of the study variables predicted level of physical activity. FINDINGS: There was a strong and significant correlation between BMI and overall fatigue severity and a significant, negative correlation between BMI and physical activity performance. BMI was significantly correlated with sleep latency but not global sleep quality. There were significant relationships between fatigue severity and poorer global sleep quality and daytime sleepiness. Multiple regression analysis showed BMI and age accounted for a significant amount of the variance in physical activity. CONCLUSIONS: Higher BMI was associated with significant fatigue. Fatigue severity was associated with poorer global sleep quality, daytime sleepiness, and a sense of community. Higher BMI may be a barrier to having an active lifestyle.