RESUMEN
The RecQ DNA helicase WRN is a synthetic lethal target for cancer cells with microsatellite instability (MSI), a form of genetic hypermutability that arises from impaired mismatch repair1-4. Depletion of WRN induces widespread DNA double-strand breaks in MSI cells, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which WRN protects MSI-associated cancers from double-strand breaks remains unclear. Here we show that TA-dinucleotide repeats are highly unstable in MSI cells and undergo large-scale expansions, distinct from previously described insertion or deletion mutations of a few nucleotides5. Expanded TA repeats form non-B DNA secondary structures that stall replication forks, activate the ATR checkpoint kinase, and require unwinding by the WRN helicase. In the absence of WRN, the expanded TA-dinucleotide repeats are susceptible to cleavage by the MUS81 nuclease, leading to massive chromosome shattering. These findings identify a distinct biomarker that underlies the synthetic lethal dependence on WRN, and support the development of therapeutic agents that target WRN for MSI-associated cancers.
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Roturas del ADN de Doble Cadena , Expansión de las Repeticiones de ADN/genética , Repeticiones de Dinucleótido/genética , Neoplasias/genética , Helicasa del Síndrome de Werner/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Cromosomas Humanos/genética , Cromosomas Humanos/metabolismo , Cromotripsis , División del ADN , Replicación del ADN , Proteínas de Unión al ADN/metabolismo , Endodesoxirribonucleasas/metabolismo , Endonucleasas/metabolismo , Inestabilidad Genómica , Humanos , Recombinasas/metabolismoRESUMEN
Chronic kidney disease (CKD) is a global health burden, with ineffective therapies leading to increasing morbidity and mortality. Renal interstitial fibrosis is a common pathway in advanced CKD, resulting in kidney function and structure deterioration. In this study, we investigate the role of FTO-mediated N6-methyladenosine (m6A) and its downstream targets in the pathogenesis of renal fibrosis. M6A modification, a prevalent mRNA internal modification, has been implicated in various organ fibrosis processes. We use a mouse model of unilateral ureteral obstruction (UUO) as an in vivo model and treated tubular epithelial cells (TECs) with transforming growth factor (TGF)-ß1 as in vitro models. Our findings revealed increased FTO expression in UUO mouse model and TGF-ß1-treated TECs. By modulating FTO expression through FTO heterozygous mutation mice (FTO+/- ) in vivo and small interfering RNA (siRNA) in vitro, we observed attenuation of UUO and TGF-ß1-induced epithelial-mesenchymal transition (EMT), as evidenced by decreased fibronectin and N-cadherin accumulation and increased E-cadherin levels. Silencing FTO significantly improved UUO and TGF-ß1-induced inflammation, apoptosis, and inhibition of autophagy. Further transcriptomic assays identified RUNX1 as a downstream candidate target of FTO. Inhibiting FTO was shown to counteract UUO/TGF-ß1-induced RUNX1 elevation in vivo and in vitro. We demonstrated that FTO signaling contributes to the elevation of RUNX1 by demethylating RUNX1 mRNA and improving its stability. Finally, we revealed that the PI3K/AKT pathway may be activated downstream of the FTO/RUNX1 axis in the pathogenesis of renal fibrosis. In conclusion, identifying small-molecule compounds that target this axis could offer promising therapeutic strategies for treating renal fibrosis.
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Adenina/análogos & derivados , Insuficiencia Renal Crónica , Obstrucción Ureteral , Ratones , Animales , Riñón/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Obstrucción Ureteral/metabolismo , Insuficiencia Renal Crónica/metabolismo , Fibrosis , Desmetilación , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/metabolismoRESUMEN
BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or the bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 41.4-60.3) for NVX-CoV2373. All formulations were similarly well tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT05372588).
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Adulto , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Masculino , Femenino , COVID-19/prevención & control , COVID-19/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Adulto Joven , Persona de Mediana Edad , Adolescente , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversosRESUMEN
Human lifestyles vary enormously over time and space and so understanding the origins of this diversity has always been a central focus of anthropology. A major source of this cultural variation is the variation in institutional complexity: the cultural packages of rules, norms, ontologies and expectations passed down through societies across generations. In this article, we study the emergence of institutions in small-scale societies. There are two primary schools of thought. The first is that institutions emerge top-down as rules are imposed by elites on their societies in order to gain asymmetrical access to power, resources and influence over others through coercion. The second is that institutions emerge bottom-up to facilitate interactions within populations as they seek collective solutions to adaptive problems. Here, we use Bayesian networks to infer the causal structure of institutional complexity in 172 small-scale societies across ethnohistoric western North America reflecting the wide diversity of indigenous lifestyles across this vast region immediately prior to European colonization. Our results suggest that institutional complexity emerges from underlying socioecological complexity because institutions are solutions to coordination problems in more complex environments where human-environment interactions require increased management.
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Teorema de Bayes , Humanos , América del Norte , Diversidad CulturalRESUMEN
Fundamental frequency ( fo) is the most perceptually salient vocal acoustic parameter, yet little is known about how its perceptual influence varies across societies. We examined how fo affects key social perceptions and how socioecological variables modulate these effects in 2,647 adult listeners sampled from 44 locations across 22 nations. Low male fo increased men's perceptions of formidability and prestige, especially in societies with higher homicide rates and greater relational mobility in which male intrasexual competition may be more intense and rapid identification of high-status competitors may be exigent. High female fo increased women's perceptions of flirtatiousness where relational mobility was lower and threats to mating relationships may be greater. These results indicate that the influence of fo on social perceptions depends on socioecological variables, including those related to competition for status and mates.
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Voz , Adulto , Humanos , Masculino , Femenino , Homicidio , Percepción Social , Parejas SexualesRESUMEN
BACKGROUND: Randomised, cluster-based study designs in schools are commonly used to evaluate children's physical activity interventions. Sample size estimation relies on accurate estimation of the intra-cluster correlation coefficient (ICC), but published estimates, especially using accelerometry-measured physical activity, are few and vary depending on physical activity outcome and participant age. Less commonly-used cluster-based designs, such as stepped wedge designs, also need to account for correlations over time, e.g. cluster autocorrelation (CAC) and individual autocorrelation (IAC), but no estimates are currently available. This paper estimates the school-level ICC, CAC and IAC for England children's accelerometer-measured physical activity outcomes by age group and gender, to inform the design of future school-based cluster trials. METHODS: Data were pooled from seven large English datasets of accelerometer-measured physical activity data between 2002-18 (> 13,500 pupils, 540 primary and secondary schools). Linear mixed effect models estimated ICCs for weekday and whole week for minutes spent in moderate-to-vigorous physical activity (MVPA) and being sedentary for different age groups, stratified by gender. The CAC (1,252 schools) and IAC (34,923 pupils) were estimated by length of follow-up from pooled longitudinal data. RESULTS: School-level ICCs for weekday MVPA were higher in primary schools (from 0.07 (95% CI: 0.05, 0.10) to 0.08 (95% CI: 0.06, 0.11)) compared to secondary (from 0.04 (95% CI: 0.03, 0.07) to (95% CI: 0.04, 0.10)). Girls' ICCs were similar for primary and secondary schools, but boys' were lower in secondary. For all ages, combined the CAC was 0.60 (95% CI: 0.44-0.72), and the IAC was 0.46 (95% CI: 0.42-0.49), irrespective of follow-up time. Estimates were higher for MVPA vs sedentary time, and for weekdays vs the whole week. CONCLUSIONS: Adequately powered studies are important to evidence effective physical activity strategies. Our estimates of the ICC, CAC and IAC may be used to plan future school-based physical activity evaluations and were fairly consistent across a range of ages and settings, suggesting that results may be applied to other high income countries with similar school physical activity provision. It is important to use estimates appropriate to the study design, and that match the intended study population as closely as possible.
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Acelerometría , Ejercicio Físico , Instituciones Académicas , Humanos , Niño , Inglaterra , Acelerometría/métodos , Acelerometría/estadística & datos numéricos , Femenino , Masculino , Ejercicio Físico/fisiología , Instituciones Académicas/estadística & datos numéricos , Análisis por Conglomerados , Adolescente , Factores Sexuales , Factores de EdadRESUMEN
Calcium-sensing receptors (CaSRs) are G protein-coupled receptors that help maintain Ca2+ concentrations, modulating calciotropic hormone release (parathyroid hormone (PTH), calcitonin and 1,25-dihydroxyvitamin D) by direct actions in the kidneys, gastrointestinal tract and bone. Variability in population calcium levels has been attributed to single nucleotide polymorphisms in CaSR genes, and several conditions affecting calcium and phosphate homeostasis have been attributed to gain- or loss-of-function mutations. An example is autosomal dominant hypercalciuric hypocalcaemia, because of a missense mutation at codon 128 of chromosome 3, as reported in our specific case and her family. As a consequence of treating symptomatic hypocalcaemia as a child, this female subject slowly developed progressive end-stage kidney failure because of nephrocalcinosis and nephrolithiasis. After kidney transplantation, she remains asymptomatic, with decreased vitamin D and elemental calcium requirements, stable fluid and electrolyte homeostasis during intercurrent illnesses and has normalised urinary calcium and phosphate excretion, reducing the likelihood of hypercalciuria-induced graft impairment. We review the actions of the CaSR, its role in regulating renal Ca2+ homeostasis along with the impact of a proven gain-of-function mutation in the CaSR gene resulting in autosomal dominant hypercalciuric hypocalcaemia before and after kidney transplantation.
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Calcio , Homeostasis , Trasplante de Riñón , Receptores Sensibles al Calcio , Humanos , Receptores Sensibles al Calcio/genética , Femenino , Calcio/metabolismo , Hipocalcemia/genética , Hipocalcemia/etiología , Hipercalciuria/genética , Hipercalcemia/genética , Riñón/metabolismo , Mutación Missense , Nefrocalcinosis/genética , Fallo Renal Crónico/cirugía , Hipoparatiroidismo/congénitoRESUMEN
Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.
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Supresores de la Gota , Gota , Oxipurinol , Diálisis Peritoneal , Ácido Úrico , Humanos , Ácido Úrico/sangre , Gota/tratamiento farmacológico , Gota/sangre , Masculino , Oxipurinol/farmacocinética , Supresores de la Gota/farmacocinética , Supresores de la Gota/uso terapéutico , Persona de Mediana Edad , Femenino , Anciano , Alopurinol/uso terapéutico , Alopurinol/farmacocinética , Eliminación Renal , Semivida , Soluciones para Diálisis/farmacocinéticaRESUMEN
AIM: People with chronic kidney disease experience high rates of cardiovascular disease. Cholesterol-lowering therapy is a mainstay in the management but there is uncertainty in the treatment effects on patient-important outcomes, such as fatigue and rhabdomyolysis. Here, we summarise the updated CARI Australian and New Zealand Living Guidelines on cholesterol-lowering therapy in chronic kidney disease. METHODS: We updated a Cochrane review and monitored newly published studies weekly to inform guideline development according to international standards. The Working Group included expertise from nephrology, cardiology, Indigenous Health, guideline development and people with lived experience of chronic kidney disease. RESULTS: The guideline recommends people with chronic kidney disease (eGFR ≥15 mL/min/1.73 m2) and an absolute cardiovascular risk of 10% or higher should receive statin therapy (with or without ezetimibe) to reduce the risk of cardiovascular events and death (strong recommendation, moderate certainty evidence). The guidelines also recommends a lower absolute cardiovascular risk threshold (≥5%) for Aboriginal and Torres Strait Islander Peoples and Maori with chronic kidney disease to receive statin therapy (with or without ezetimibe) (strong recommendation, low certainty evidence). The evidence was actively surveyed from 2020-2023 and updated as required. No changes to guideline recommendations were made, with no new data on the balance and benefits of harms. CONCLUSIONS: The development of living guidelines was feasible and provided the opportunity to update recommendations to improve clinical decision-making in real-time. Living guidelines provide the opportunity to transform chronic kidney disease guidelines.
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Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Insuficiencia Renal Crónica , Humanos , Anticolesterolemiantes/uso terapéutico , Anticolesterolemiantes/efectos adversos , Australia/epidemiología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Ezetimiba/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Nueva Zelanda/epidemiología , Guías de Práctica Clínica como Asunto , Brechas de la Práctica Profesional , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/complicacionesRESUMEN
BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX-CoV2373), to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n = 274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.
RESUMEN
Oesophageal adenocarcinoma (OAC) has a relatively poor long-term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumour mutations, presented to cytotoxic T-cells by human leucocyte antigen (HLA) molecules. Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumours from a cohort of seven patients with OAC. We directly identified one HLA-I presented neoantigen from one patient, and report functional T-cell responses from a predicted HLA-II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T-cell responses, emphasizing the need for improved strategies for neoantigen identification.
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Adenocarcinoma , Antígenos de Neoplasias , Humanos , Antígenos de Neoplasias/genética , Antígenos de Histocompatibilidad Clase I , Linfocitos T Citotóxicos , Antígenos HLA , Antígenos de Histocompatibilidad Clase II , InmunoterapiaRESUMEN
OBJECTIVE: The aim of this study was to develop a predictive model for overall survival after esophagectomy using pre/postoperative clinical data and machine learning. SUMMARY BACKGROUND DATA: For patients with esophageal cancer, accurately predicting long-term survival after esophagectomy is challenging. This study investigated survival prediction after esophagectomy using a RandomSurvival Forest (RSF) model derived from routine data from a large, well-curated, national dataset. METHODS: Patients diagnosed with esophageal adenocarcinoma or squamous cell carcinoma between 2012 and 2018 in England and Wales who underwent an esophagectomy were included. Prediction models for overall survival were developed using the RSF method and Cox regression from 41 patient and disease characteristics. Calibration and discrimination (time-dependent area under the curve) were validated internally using bootstrap resampling. RESULTS: The study analyzed 6399 patients, with 2625 deaths during follow-up. Median follow-up was 41 months. Overall survival was 47.1% at 5 years. The final RSF model included 14 variables and had excellent discrimination with a 5-year time-dependent area under the receiver operator curve of 83.9% [95% confidence interval (CI) 82.6%-84.9%], compared to 82.3% (95% CI 81.1%-83.3%) for the Cox model. The most important variables were lymph node involvement, pT stage, circumferential resection margin involvement (tumor at < 1 mm from cut edge) and age. There was a wide range of survival estimates even within TNM staging groups, with quintiles of prediction within Stage 3b ranging from 12.2% to 44.7% survival at 5 years. CONCLUSIONS: An RSF model for long-term survival after esophagectomy exhibited excellent discrimination and well-calibrated predictions. At a patient level, it provides more accuracy than TNM staging alone and could help in the delivery of tailored treatment and follow-up.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Escisión del Ganglio Linfático/métodos , Esofagectomía/métodos , Carcinoma de Células Escamosas/cirugía , Estadificación de NeoplasiasRESUMEN
BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).
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Alopurinol/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Supresores de la Gota/uso terapéutico , Ácido Úrico/sangre , Xantina Oxidasa/antagonistas & inhibidores , Anciano , Alopurinol/efectos adversos , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Nefropatías Diabéticas/fisiopatología , Progresión de la Enfermedad , Método Doble Ciego , Inhibidores Enzimáticos/efectos adversos , Femenino , Supresores de la Gota/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/fisiopatología , Sistema Renina-Angiotensina , Insuficiencia del TratamientoRESUMEN
Minichromosome maintenance proteins (Mcm2-7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3'UTR of the Mcm2 gene (designated Mcm2Cre ) have decreased Mcm2 expression and invariably develop precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL), due to 100-1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre-T LBL would develop non-T-cell malignancies, we used two approaches. Mice engrafted with Mcm2Cre/Cre Lin- Sca-1+ Kit+ hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2Cre allele onto an athymic nu/nu background completely prevented pre-T LBL and extended survival of these mice three-fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2Cre/Cre ;nu/nu mice developed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). We identified recurrent deletions of 100-1000 kb that involved genes known or suspected to be involved in BCP-ALL, including Pax5, Nf1, Ikzf3, and Bcor. Moreover, whole-exome sequencing identified recurrent mutations of genes known to be involved in BCP-ALL progression, such as Jak1/Jak3, Ptpn11, and Kras. These findings demonstrate that an Mcm2Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a "deletor" phenotype affecting known or suspected tumor suppressor genes.
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Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Componente 2 del Complejo de Mantenimiento de Minicromosoma , Animales , Replicación del ADN , Células Madre Hematopoyéticas/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Ratones , Componente 2 del Complejo de Mantenimiento de Minicromosoma/genética , Mutación , Proteínas Represoras/genética , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. METHODS: ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography-tandem mass spectrometry. RESULTS: In a healthy DMHDS subset (n = 376), mean concentrations were: ADMA (0.40 ± 0.06 µmol/L), SDMA (0.42 ± 0.06 µmol/L), L-arginine (93.5 ± 23.1 µmol/L) and L-citrulline (24.0 ± 5.4 µmol/L). In the total cohort (n = 857), SDMA correlated positively with serum creatinine (Pearson's r = 0.55) and pCYSC (r = 0.55), and negatively with eGFR (r = 0.52). A separate cohort of 38 patients with stage 3-4 CKD (eGFR 15-60 mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61 ± 0.11 µmol/L), SDMA (0.65 ± 0.25 µmol/L) and L-citrulline (42.7 ± 11.8 µmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. CONCLUSIONS: Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.
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Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Humanos , Citrulina , Arginina/metabolismo , RiñónRESUMEN
BACKGROUND: Children's physical activity in England is more dependent on active clubs after the COVID-19 pandemic. However, it is unclear how the COVID-19 pandemic and related cost-of-living crisis have impacted on active club participation, costs and provision. This mixed-methods natural experiment explored school-based and community-based active clubs after lockdowns, using a unique combination of data sources to highlight implications for policy and practice post-COVID-19. METHODS: Cross-sectional questionnaire data on school and community active clubs were collected from 10-11-year-old children pre-COVID-19 in 2017-18 (N = 1,296; 50 schools), in 2021 (N = 393; 23 schools), and 2022 (N = 463; 27 schools). Club participation and attendance frequency were modelled using logistic and Poisson mixed effects models, adjusted for child age, gender and household education. In 2021 and 2022, parents reported expenditure on community-based clubs and schools provided data on school-based club provision, with data summarised descriptively. Qualitative data were collected in 2021 and 2022, with one-to-one interviews with school staff (N = 18) and parents (N = 43), and twelve child focus groups (N = 92), and analysed using the framework method. RESULTS: School-based active club participation was higher in 2022 compared to pre-pandemic (50% /43%), while community-based club participation was lower (74%/80%). Children attended 0.3 fewer clubs per week. Those from lower education households were less likely to participate in both types of active clubs, and girls less likely to attend community clubs. In 2022, the median cost of community and school club sessions were £6.67 and £3.88 respectively, with 52% of school-based clubs free to parents. Schools offered an average of 3.4 active clubs per week for 10-11-year-olds in 2022, with 34% partly/wholly subsidised. Qualitative analysis highlighted the impact of the cost-of-living crisis and COVID-19 pandemic on family resources, encouraging a shift to more affordable and convenient school-based active clubs, which negatively impacted the community-based active club environment. However, many schools struggled to meet this increased demand. CONCLUSIONS: Findings emphasise the importance for policymakers to support schools to meet increased demand for clubs and community clubs to increase affordable and convenient physical activity opportunities. Targeted support is needed to prevent socioeconomic and gender inequalities.
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COVID-19 , Pandemias , Femenino , Humanos , Niño , Estudios Transversales , COVID-19/epidemiología , COVID-19/prevención & control , Control de Enfermedades Transmisibles , Inglaterra , Instituciones Académicas , Encuestas y Cuestionarios , PolíticasRESUMEN
BACKGROUND: The COVID-19 pandemic has resulted in marked impacts on children's physical activity, with large reductions in moderate-to-vigorous physical activity (MVPA) reported during lockdowns. Previous evidence showed children's activity levels were lower and sedentary time higher immediately post-COVID lockdown, while there was little change in parental physical activity. We need to know if these patterns persist. METHODS: Active-6 is a natural experiment using repeated cross-sectional data conducted in two waves. Accelerometer data were collected on 393 children aged 10-11 and their parents from 23 schools in Wave 1 (June 2021-December 2021), and 436 children and parents from 27 schools in Wave 2 (January 2022-July 2022). These were compared to a pre-COVID-19 comparator group (March 2017-May 2018) of 1,296 children and parents in the same schools. Mean minutes of accelerometer-measured MVPA and sedentary time were derived for week- and weekend-days and compared across waves via linear multilevel models. We also analysed the date of data collection as a time series, to explore temporal patterns via generalised additive mixed models. RESULTS: There was no difference in children's mean MVPA in Wave 2 (weekdays: -2.3 min; 95% CI: -5.9, 1.3 and weekends: 0.6 min; 95% CI: -3.5, 4.6) when compared to the pre-COVID-19 data. Sedentary time remained higher than pre-pandemic by 13.2 min (95% CI:5.3, 21.1) on weekdays. Differences compared to pre-COVID-19 changed over time, with children's MVPA decreasing over winter, coinciding with COVID-19 outbreaks, and only returning to pre-pandemic levels towards May/June 2022. Parents' sedentary time and weekday MVPA was similar to pre-COVID-19 levels, with MVPA higher than pre-pandemic by 7.7 min (95% CI: 1.4, 14.0) on weekends. CONCLUSION: After an initial drop, children's MVPA returned to pre-pandemic levels by July 2022, while sedentary time remained higher. Parents' MVPA remained higher, especially at weekends. The recovery in physical activity is precarious and potentially susceptible to future COVID-19 outbreaks or changes in provision, and so robust measures to protect against future disruptions are needed. Furthermore, many children are still inactive, with only 41% meeting UK physical activity guidelines, and so there is still a need to increase children's physical activity.
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COVID-19 , Conducta Sedentaria , Humanos , Niño , Estudios Transversales , Pandemias , Acelerometría , COVID-19/epidemiología , COVID-19/prevención & control , Control de Enfermedades Transmisibles , Ejercicio Físico , PadresRESUMEN
AIM: This study examined whether survival and causes of death differed between participants enrolled from Australia (AUS), Malaysia (MYL), and New Zealand (NZ) in extended follow-up of the Study of Heart and Renal Protection (SHARP), a randomized controlled trial (RCT) of participants with moderate to severe chronic kidney disease comparing placebo to combination therapy with Simvastatin and Ezetimibe. METHODS: All participants alive at final SHARP study visit in participating centres were eligible for inclusion. Consenting participants were re-enrolled following final SHARP Study visit and followed for 5 years. Data collection included: significant medical events, hospital admissions and requirement for kidney replacement therapy. Data linkage was performed to national kidney and mortality registries. The primary outcome was all-cause mortality compared across the three countries. RESULTS: The SHARP trial randomized 2029 participants from AUS (1043/2029, 51%), MYL (701/2029, 35%), and NZ (285/2029, 14%), with 1136 participants alive and eligible for extended follow-up at the end of SHARP. In multivariable analysis, risk of death was increased for participants in MYL (HR 1.37, 95% CI 1.17-1.61, p < .001) and NZ (HR 1.28, 95% CI 1.04-1.57, p = .02) when compared to AUS participants. Adjustment for kidney transplantation as a competing risk did not explain the variation seen between countries. CONCLUSION: This study allows a better understanding of the differences in long-term mortality risk across participants from AUS, MYL, and NZ in extended follow-up of the SHARP study and demonstrates the feasibility and value of extended follow-up of participants enrolled in RCTs.
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Trasplante de Riñón , Insuficiencia Renal Crónica , Humanos , Ezetimiba/uso terapéutico , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/tratamiento farmacológico , Simvastatina/uso terapéutico , Trasplante de Riñón/efectos adversos , RiñónRESUMEN
BACKGROUND: Restrictions during the COVID-19 pandemic have led to increased screen-viewing among children, especially during strict periods of lockdown. However, the extent to which screen-viewing patterns in UK school children have changed post lockdowns is unclear. The aim of this paper is to examine how screen-viewing changed in 10-11-year-old children over the 2020-21 COVID-19 pandemic, how this compares to before the pandemic, and the influences on screen-viewing behaviour. METHODS: This is a mixed methods study with 10-11-year-olds from 50 schools in the Greater Bristol area, UK. Cross-sectional questionnaire data on minutes of weekday and weekend television (TV) viewing and total leisure screen-viewing were collected pre-COVID-19 in 2017-18 (N = 1,296) and again post-lockdowns in 2021 (N = 393). Data were modelled using Poisson mixed models, adjusted for age, gender, household education and seasonality, with interactions by gender and household education. Qualitative data were drawn from six focus groups (47 children) and 21 one-to-one parent interviews that explored screen-viewing behaviour during the pandemic and analysed using the framework method. RESULTS: Total leisure screen-viewing was 11% (95% CI: 12%-18%) higher post-lockdown compared to pre-COVID-19 on weekdays, and 8% (95% CI: 6%-10%) on weekends, equating to around 12-15 min. TV-viewing (including streaming) was higher by 68% (95% CI: 63%-74%) on weekdays and 80% (95% CI: 75%-85%) on weekend days. Differences in both were higher for girls and children from households with lower educational attainment. Qualitative themes reflected an unavoidable increase in screen-based activities during lockdowns, the resulting habitualisation of screen-viewing post-lockdown, and the role of the parent in reducing post-2020/21 lockdown screen-viewing. CONCLUSIONS: Although screen-viewing was higher post-lockdown compared to pre-COVID-19, the high increases reported during lockdowns were not, on average, sustained post-lockdown. This may be attributed to a combination of short-term fluctuations during periods of strict restrictions, parental support in regulating post-lockdown behaviour and age-related, rather than COVID-19-specific, increases in screen-viewing. However, socio-economic differences in our sample suggest that not all families were able to break the COVID-19-related adoption of screen-viewing, and that some groups may need additional support in managing a healthy balance of screen-viewing and other activities following the lockdowns.
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COVID-19 , Computadores , Femenino , Humanos , Niño , Estudios Transversales , Pandemias/prevención & control , Conducta Sedentaria , COVID-19/epidemiología , COVID-19/prevención & control , Control de Enfermedades Transmisibles , Encuestas y Cuestionarios , Reino Unido/epidemiología , TelevisiónRESUMEN
BACKGROUND: The COVID-19 pandemic significantly impacted children's physical activity. Recent evidence indicated children's accelerometer-measured physical activity levels have, on average, returned to near pre-pandemic levels in 2022, though sedentary behaviour remains higher. However, insufficient physical activity levels among children continues to be a critical public health issue in the UK, with only 41% meeting physical activity guidelines. This study aimed to provide in-depth analysis of how the pandemic has shaped children's physical activity patterns beyond the short-term periods following lockdowns and identify the new challenges to engaging children in physical activity. METHODS: One-to-one interviews with parents (n = 22), school staff (n = 9), and six focus groups with children aged 10-11 years (n = 45) were conducted between February and July 2022. Topics explored changes to children's physical activity and sedentary behaviour patterns, including screen-viewing, and factors influencing any changes. The framework method was used for analysis. RESULTS: Five themes were generated. Theme 1 described residual lockdown habits, including increased screen-viewing within the home, while activities outside the home continued to feel less spontaneous. Theme 2 highlighted an interrupted development of social, emotional, and physical skills among children compared to what would be expected pre-pandemic. This coincided with Theme 3 which reflected increased mental health challenges among families, creating complex barriers to children's physical activity. A new normal for child physical activity was evoked and explored in Theme 4, with greater dependence on structured and organised activities. However, Theme 5 highlighted that girls and children with lower socio-economic position may be especially at risk of decreased physical activity. CONCLUSIONS: There is a new normal for children's physical activity that is characterised by increased dependence on structured and organised physical activities, such as active clubs, and less on unstructured and spontaneous physical activities, such as physical play. While this may suit many children, girls and children from lower socio-economic households face barriers to participating in the new normal. It is important that affordable and equitable opportunities are provided to all children to prevent physical activity and health inequalities.