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BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.
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Neoplasias Colorrectales , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Adulto , Femenino , Humanos , Masculino , Edad de Inicio , Estudios de Casos y Controles , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/epidemiología , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
BACKGROUND: Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. METHODS: Concentrations of C-peptide-a marker for insulin secretion-were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2 , or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2 , or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14-2.19) and WC (OR = 1.51, 95% CI = 1.09-2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94-1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. CONCLUSION: These findings suggest that being overweight or obese and metabolically unhealthy raises risk of postmenopausal breast cancer while overweight or obese women with normal insulin levels are not at higher risk. Additional research should consider the combined utility of anthropometric measures with metabolic parameters in predicting breast cancer risk.
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Neoplasias , Sobrepeso , Femenino , Humanos , Factores de Riesgo , Sobrepeso/complicaciones , Somatotipos , Posmenopausia , Péptido C , Estudios de Casos y Controles , Estudios Prospectivos , Obesidad/complicaciones , Fenotipo , Tamaño Corporal , Índice de Masa CorporalRESUMEN
BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.
Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.
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Trasplante de Hígado , Supervivencia de Injerto , Humanos , Hígado , Preservación de Órganos , PerfusiónRESUMEN
Pneumothoraces may occur rarely in coronavirus (COVID-19) patients, often resulting from a combination of fibrotic parenchymal changes and prolonged high-pressure ventilation. Very few studies have been published describing the management of pneumothorax in the novel COVID-19 pneumonia patients. Although chest drain insertion represents the first line of treatment, a persistent pneumothorax and air leak requiring intervention could be managed by a thoracoscopic procedure or, as is the case here, by endobronchial valve insertion. Endobronchial valve insertion is a minimally invasive technique that provides a treatment option in patients with severe parenchymal COVID-19 related lung disease. As far as the authors are aware this is the first report of the use of endobronchial valves in a COVID-19 patient.
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COVID-19 , Neumotórax , Broncoscopía/métodos , COVID-19/complicaciones , Tubos Torácicos , Humanos , Neumotórax/etiología , Neumotórax/cirugía , Prótesis e ImplantesRESUMEN
BACKGROUND: Local neuromuscular deficits have been reported in people with patellofemoral pain. We synthesised the neuromuscular characteristics associated with patellofemoral pain to help identify interventional targets and potential mechanisms. METHODS: Five databases were searched for local neuromuscular characteristics in case-control studies. Electromyography, flexibility, muscle performance and cross-sectional area data were derived from functional or isolated task investigations and synthesised accordingly. An evidence gap map was constructed. FINDINGS: Sixty-seven studies were included. In functional tasks, electromyographic investigations showed moderate evidence of small effect for vastus medialis onset-delays relative to vastus lateralis (0.44 [0.03, 0.85]) during stepping/stair negotiation tasks, and higher biceps femoris mean excitation amplitudes (0.55 [0.06, 1.04]) in single-leg triple-hop test. In isolated tasks, we found moderate evidence of medium effect for lower Hoffman-reflex amplitude of vastus medialis (-1.12 [-1.56, -0.67]). Muscle performance investigations showed; strong evidence with medium and small effects for lower extensors concentric (-0.61 [-0.81, -0.40]) and eccentric (-0.56 [-0.79, -0.33]) strength, and moderate evidence of medium effect of lower isometric (-0.64 [-0.87, -0.41]) strength, moderate evidence with small effect for rate of force development to 30% (-0.55[-0.89, -0.21]), 60% (-0.57[-0.90, -0.25]) and medium effect to 90% (-0.76[-1.43, -0.10]) of maximum voluntary contraction, and small effect for lower flexors concentric strength (-0.46 [-0.74, -0.19]) and extensors total work (-0.48 [-0.90, -0.07]). Flexibility investigations showed tighter hamstrings (-0.57 [-0.99, -0.14]). INTERPRETATION: Differences within quadriceps and hamstrings motor-control, hamstrings tightness, and quadriceps and hamstrings weakness are associated with patellofemoral pain, and can be used to guide investigations of treatment effects.
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Síndrome de Dolor Patelofemoral , Estudios de Casos y Controles , Electromiografía , Humanos , Articulación de la Rodilla , Músculo CuádricepsRESUMEN
Following accidental releases, gamma spectrometry of impregnated charcoal filters is used to measure gaseous 131I contamination, but is subject to sampling inhomogeneity. In this study two germanium detectors are calibrated using a charcoal multi-gamma standard. Activities in samples spiked with a matrix of 131I aliquots are compared based on measurement, spike known activity, and monte-carlo simulation, and used to test a simple mixing method. Measurement efficiency, and removal of 11% inhomogeneity effect by mixing, was successfully reproduced in GESPECOR calculations.
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Adults who are homeless experience poor health and frequently require hospital in-patient care but the physical functioning ability of this group is rarely considered. The objective of this study was to evaluate a broad range of physical functioning variables to enable better future planning of targeted health and accommodation services for this group. This cross-sectional, observational study was conducted in a large acute hospital in Dublin, Ireland. A comprehensive ward-based test battery evaluated physical functioning in 65 in-patients registered as homeless with an age range of 23-80 years. Less than 10% (n = 5) were > 70 years. 58/65 (83%) of participants had mobility limitations and 35/65 (54%) reported at least one fall in the previous six months. Only 25/66 (35%) were able to walk for 6 min and 20/65 (31%) were able to climb one flight of stairs. 45/63 (70%) of participants were pre-frail or frail. Muscular mass was normal in the majority of participants but grip strength was low. This study revealed hospital in-patients registered as homeless displayed particularly poor physical functioning levels and mobility regardless of age. Health and housing services should address the unmet physical functioning needs of this vulnerable group.
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Hospitalización/estadística & datos numéricos , Personas con Mala Vivienda , Rendimiento Físico Funcional , Autoinforme/estadística & datos numéricos , Poblaciones Vulnerables/estadística & datos numéricos , Accidentes por Caídas/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Prueba de Esfuerzo/estadística & datos numéricos , Femenino , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Clinical data networks that leverage large volumes of data in electronic health records (EHRs) are significant resources for research on coronavirus disease 2019 (COVID-19). Data harmonization is a key challenge in seamless use of multisite EHRs for COVID-19 research. We developed a COVID-19 application ontology in the national Accrual to Clinical Trials (ACT) network that enables harmonization of data elements that that are critical to COVID-19 research. The ontology contains over 50,000 concepts in the domains of diagnosis, procedures, medications, and laboratory tests. In particular, it has computational phenotypes to characterize the course of illness and outcomes, derived terms, and harmonized value sets for SARS-CoV-2 laboratory tests. The ontology was deployed and validated on the ACT COVID-19 network that consists of nine academic health centers with data on 14.5M patients. This ontology, which is freely available to the entire research community on GitHub at https://github.com/shyamvis/ACT-COVID-Ontology, will be useful for harmonizing EHRs for COVID-19 research beyond the ACT network.
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Ventilación no Invasiva , Oxígeno , Femenino , Humanos , Hipoxia/terapia , Intubación Intratraqueal , Pulmón , Terapia por Inhalación de OxígenoRESUMEN
This study analysed the effectiveness of plasma treatment on airborne bacteria and surface counts during a 14-day intervention within a four-bedded bay in an adult respiratory ward at Cork University Hospital, Ireland. One-hundred-litre air samples were collected twice daily every weekday for 4 weeks, with settle plates and surface swabs. The plasma treatment did not have an effect on airborne bacteria and fungi that was detectable by culture. However, the possibility that culture-based sampling may be insufficiently sensitive to detect an effect, or that the duration of the study was insufficient for plasma treatment to affect a complex environment, cannot be excluded.
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Microbiología del Aire , Contaminación del Aire/prevención & control , Hospitales , Gases em Plasma , Monitoreo del Ambiente , Hongos , IrlandaRESUMEN
We investigate the forces and atmosphere-ionosphere coupling that create atmospheric dynamo currents using two rockets launched nearly simultaneously on 4 July 2013 from Wallops Island (USA), during daytime Sq conditions with ΔH of -30 nT. One rocket released a vapor trail observed from an airplane which showed peak velocities of >160 m/s near 108 km and turbulence coincident with strong unstable shear. Electric and magnetic fields and plasma density were measured on a second rocket. The current density peaked near 110 km exhibiting a spiral pattern with altitude that mirrored that of the winds, suggesting the dynamo is driven by tidal forcing. Such stratified currents are obscured in integrated ground measurements. Large electric fields produced a current opposite to that driven by the wind, believed created to minimize the current divergence. Using the observations, we solve the dynamo equation versus altitude, providing a new perspective on the complex nature of the atmospheric dynamo.
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BACKGROUND: Family-centered care is a valued approach to improving child and family outcomes in early intervention (EI), yet there is need to implement interventions that support information exchange for shared decision-making when planning and monitoring EI care. This study aims at estimating the feasibility, acceptability, and value of implementing the Young Children's Participation and Environment Measure (YC-PEM), a valid electronic patient-reported outcome (e-PRO) that is designed to support family engagement when planning care and monitoring outcomes of care. METHODS: Data were gathered from caregivers (N = 139) that were enrolled in a Phase 1 trial of the YC-PEM e-PRO as implemented within 1 month of their child's next EI evaluation of progress. YC-PEM e-PRO feasibility was estimated according to enrollment and completion rates, and mean completion time. Chi-square tests were used to examine parent perceptions of YC-PEM e-PRO acceptability by caregiver education and family income. Caregiver feedback via open-ended responses were content coded to inform intervention and protocol optimizations. YC-PEM e-PRO value was estimated via composite and item-level scores to capture the extent of participation difficulty in home and community activities, and common areas of need regarding caregivers desired change in their child's participation. RESULTS: Feasibility of implementing the YC-PEM e-PRO in routine EI care was mixed, as evidenced by low enrollment rates (21.0-29.2%), a high completion rate (85.3%), and limited missing data (80.6% of completed cases contained no missing data). More than half of the participants reported that the completion of the YC-PEM e-PRO was at least somewhat helpful, regardless of family income or caregiver education, providing support for its acceptability. As for its value, the YC-PEM e-PRO results were viewed by 64% of caregivers, whose desire for change most often pertained to the child's participation in non-discretionary activities at home and structured activities in the community. CONCLUSIONS: Results may support the implementation of YC-PEM e-PRO as a feasible, acceptable, and valued option for engaging families in planning the child's EI care. Results also inform select intervention and protocol optimizations prior to undertaking a multi-site pragmatic trial of its effectiveness on family engagement and shared decision-making within an EI clinical workflow. TRIAL REGISTRATION: Trial number: NCT03904797 . Trial registered at Clinicaltrials.gov . Registered 22 March 2019. Retrospectively registered.
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Cuidadores , Familia , Medición de Resultados Informados por el Paciente , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Padres , Encuestas y Cuestionarios , Adulto JovenAsunto(s)
Infecciones por Coronavirus , Pandemias , Neumonía Viral , Salud Pública , COVID-19 , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/transmisión , Humanos , Irlanda/epidemiología , Pandemias/prevención & control , Neumonía Viral/diagnóstico , Neumonía Viral/epidemiología , Neumonía Viral/prevención & control , Neumonía Viral/transmisiónRESUMEN
Aims Our aim was to determine the number of cases of aneuploidy which were prenatally diagnosed in our tertiary referral unit from 2005-2015 and to analyse the subsequent outcomes of Trisomies 13, 18 and 21(T13, T18 and T21). Methods This was a retrospective observational study. We firstly determined the total number of prenatally diagnosed aneuploidies. We then analysed their subsequent outcomes including average gestation at miscarriage or IUD, mode of delivery and neonatal outcome. Results 402 cases of T13, T18 or T21 were identified of which 40% opted for expectant management. T18 was the most likely diagnosis to result in miscarriage, IUD or intrapartum death. The highest caesarean delivery rate was in T21. Conclusion With regards to T13 and T18, live birth rates show that some parents may achieve the goal of spending time with their baby in the immediate postpartum period. This information will act as a valuable resource in our counselling.