RESUMEN
OBJECTIVE: To provide the first international comparison of oesophageal and gastric cancer survival by stage at diagnosis and histological subtype across high-income countries with similar access to healthcare. METHODS: As part of the ICBP SURVMARK-2 project, data from 28 923 patients with oesophageal cancer and 25 946 patients with gastric cancer diagnosed during 2012-2014 from 14 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were included. 1-year and 3-year age-standardised net survival were estimated by stage at diagnosis, histological subtype (oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC)) and country. RESULTS: Oesophageal cancer survival was highest in Ireland and lowest in Canada at 1 (50.3% vs 41.3%, respectively) and 3 years (27.0% vs 19.2%) postdiagnosis. Survival from gastric cancer was highest in Australia and lowest in the UK, for both 1-year (55.2% vs 44.8%, respectively) and 3-year survival (33.7% vs 22.3%). Most patients with oesophageal and gastric cancer had regional or distant disease, with proportions ranging between 56% and 90% across countries. Stage-specific analyses showed that variation between countries was greatest for localised disease, where survival ranged between 66.6% in Australia and 83.2% in the UK for oesophageal cancer and between 75.5% in Australia and 94.3% in New Zealand for gastric cancer at 1-year postdiagnosis. While survival for OAC was generally higher than that for OSCC, disparities across countries were similar for both histological subtypes. CONCLUSION: Survival from oesophageal and gastric cancer varies across high-income countries including within stage groups, particularly for localised disease. Disparities can partly be explained by earlier diagnosis resulting in more favourable stage distributions, and distributions of histological subtypes of oesophageal cancer across countries. Yet, differences in treatment, and also in cancer registration practice and the use of different staging methods and systems, across countries may have impacted the comparisons. While primary prevention remains key, advancements in early detection research are promising and will likely allow for additional risk stratification and survival improvements in the future.
Asunto(s)
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiología , Australia/epidemiología , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patología , Humanos , Sistema de Registros , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patologíaRESUMEN
Interactions between ions and water at hydrophobic interfaces within ion channels and nanopores are suggested to play a key role in the movement of ions across biological membranes. Previous molecular-dynamics simulations have shown that anion affinity for aqueous/hydrophobic interfaces can be markedly influenced by including polarization effects through an electronic continuum correction. Here, we designed a model biomimetic nanopore to imitate the polar pore openings and hydrophobic gating regions found in pentameric ligand-gated ion channels. Molecular-dynamics simulations were then performed using both a non-polarizable force field and the electronic-continuum-correction method to investigate the behavior of water, Na+, and Cl- ions confined within the hydrophobic region of the nanopore. Number-density distributions revealed preferential Cl- adsorption to the hydrophobic pore walls, with this interfacial layer largely devoid of Na+. Free-energy profiles for Na+ and Cl- permeating the pore also display an energy-barrier reduction associated with the localization of Cl- to this hydrophobic interface, and the hydration-number profiles reflect a corresponding reduction in the first hydration shell of Cl-. Crucially, these ion effects were only observed through inclusion of effective polarization, which therefore suggests that polarizability may be essential for an accurate description for the behavior of ions and water within hydrophobic nanoscale pores, especially those that conduct Cl-.
Asunto(s)
Nanoporos , Biomimética , Interacciones Hidrofóbicas e Hidrofílicas , Iones , Sodio , Agua/químicaRESUMEN
BACKGROUND: International Cancer Benchmarking Partnership Module 4 reports the first international comparison of ovarian cancer (OC) diagnosis routes and intervals (symptom onset to treatment start), which may inform previously reported variations in survival and stage. METHODS: Data were collated from 1110 newly diagnosed OC patients aged >40 surveyed between 2013 and 2015 across five countries (51-272 per jurisdiction), their primary-care physicians (PCPs) and cancer treatment specialists, supplement by treatment records or clinical databases. Diagnosis routes and time interval differences using quantile regression with reference to Denmark (largest survey response) were calculated. RESULTS: There were no significant jurisdictional differences in the proportion diagnosed with symptoms on the Goff Symptom Index (53%; P = 0.179) or National Institute for Health and Care Excellence NG12 guidelines (62%; P = 0.946). Though the main diagnosis route consistently involved primary-care presentation (63-86%; P = 0.068), onward urgent referral rates varied significantly (29-79%; P < 0.001). In most jurisdictions, diagnostic intervals were generally shorter and other intervals, in particular, treatment longer compared to Denmark. CONCLUSION: This study highlights key intervals in the diagnostic pathway where improvements could be made. It provides the opportunity to consider the systems and approaches across different jurisdictions that might allow for more timely ovarian cancer diagnosis and treatment.
Asunto(s)
Benchmarking , Neoplasias Ováricas , Carcinoma Epitelial de Ovario , Femenino , Humanos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Atención Primaria de Salud , Derivación y ConsultaRESUMEN
BACKGROUND: Research from the International Cancer Benchmarking Partnership (ICBP) demonstrates that international variation in lung cancer survival persists, particularly within early stage disease. There is a lack of international consensus on the critical contributing components to variation in lung cancer outcomes and the steps needed to optimise lung cancer services. These are needed to improve the quality of options for and equitable access to treatment, and ultimately improve survival. METHODS: Semi-structured interviews were conducted with 9 key informants from ICBP countries. An international clinical network representing 6 ICBP countries (Australia, Canada, Denmark, England, Ireland, New Zealand, Northern Ireland, Scotland & Wales) was established to share local clinical insights and examples of best practice. Using a modified Delphi consensus model, network members suggested and rated recommendations to optimise the management of lung cancer. Calls to Action were developed via Delphi voting as the most crucial recommendations, with Good Practice Points included to support their implementation. RESULTS: Five Calls to Action and thirteen Good Practice Points applicable to high income, comparable countries were developed and achieved 100% consensus. Calls to Action include (1) Implement cost-effective, clinically efficacious, and equitable lung cancer screening initiatives; (2) Ensure diagnosis of lung cancer within 30 days of referral; (3) Develop Thoracic Centres of Excellence; (4) Undertake an international audit of lung cancer care; and (5) Recognise improvements in lung cancer care and outcomes as a priority in cancer policy. CONCLUSION: The recommendations presented are the voice of an expert international lung cancer clinical network, and signpost key considerations for policymakers in countries within the ICBP but also in other comparable high-income countries. These define a roadmap to help align and focus efforts in improving outcomes and management of lung cancer patients globally.
Asunto(s)
Benchmarking , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Consenso , Detección Precoz del Cáncer , Técnica DelphiRESUMEN
This Review explores the dynamic behavior of water within nanopores and biological channels in lipid bilayer membranes. We focus on molecular simulation studies, alongside selected structural and other experimental investigations. Structures of biological nanopores and channels are reviewed, emphasizing those high-resolution crystal structures, which reveal water molecules within the transmembrane pores, which can be used to aid the interpretation of simulation studies. Different levels of molecular simulations of water within nanopores are described, with a focus on molecular dynamics (MD). In particular, models of water for MD simulations are discussed in detail to provide an evaluation of their use in simulations of water in nanopores. Simulation studies of the behavior of water in idealized models of nanopores have revealed aspects of the organization and dynamics of nanoconfined water, including wetting/dewetting in narrow hydrophobic nanopores. A survey of simulation studies in a range of nonbiological nanopores is presented, including carbon nanotubes, synthetic nanopores, model peptide nanopores, track-etched nanopores in polymer membranes, and hydroxylated and functionalized nanoporous silica. These reveal a complex relationship between pore size/geometry, the nature of the pore lining, and rates of water transport. Wider nanopores with hydrophobic linings favor water flow whereas narrower hydrophobic pores may show dewetting. Simulation studies over the past decade of the behavior of water in a range of biological nanopores are described, including porins and ß-barrel protein nanopores, aquaporins and related polar solute pores, and a number of different classes of ion channels. Water is shown to play a key role in proton transport in biological channels and in hydrophobic gating of ion channels. An overall picture emerges, whereby the behavior of water in a nanopore may be predicted as a function of its hydrophobicity and radius. This informs our understanding of the functions of diverse channel structures and will aid the design of novel nanopores. Thus, our current level of understanding allows for the design of a nanopore which promotes wetting over dewetting or vice versa. However, to design a novel nanopore, which enables fast, selective, and gated flow of water de novo would remain challenging, suggesting a need for further detailed simulations alongside experimental evaluation of more complex nanopore systems.
Asunto(s)
Canales Iónicos/química , Membrana Dobles de Lípidos/química , Nanoporos , Agua/química , Animales , Humanos , Canales Iónicos/metabolismo , Membrana Dobles de Lípidos/metabolismo , Simulación de Dinámica Molecular , Agua/metabolismoRESUMEN
Water diffusion through membrane proteins is a key aspect of cellular function. Essential processes of cellular metabolism are driven by osmotic pressure, which depends on water channels. Membrane proteins such as aquaporins (AQPs) are responsible for enabling water permeation through the cell membrane. AQPs are highly selective, allowing only water and relatively small polar molecules to cross the membrane. Experimentally, estimation of water flux through membrane proteins is still a challenge, and hence, accurate simulations of water permeation are of particular importance. We present a numerical study of water diffusion through AQP1 comparing three water models: TIP3P, OPC, and TIP4P/2005. Bulk diffusion, diffusion permeability, and osmotic permeability are computed and compared among all models. The results show that there are significant differences between TIP3P (a particularly widespread model for simulations of biological systems) and the more recently developed TIP4P/2005 and OPC models. We demonstrate that OPC and TIP4P/2005 reproduce protein-water interactions and dynamics in very good agreement with experimental data. From this study, we find that the choice of the water model has a significant effect on the computed water dynamics as well as its molecular behavior within a biological nanopore.
Asunto(s)
Acuaporina 1/metabolismo , Modelos Biológicos , Agua/metabolismo , Difusión , Humanos , PermeabilidadRESUMEN
OBJECTIVE: To explore differences in position emission tomography-computed tomography (PET-CT) service provision internationally to further understand the impact variation may have upon cancer services. To identify areas of further exploration for researchers and policymakers to optimize PET-CT services and improve the quality of cancer services. DESIGN: Comparative analysis using data based on pre-defined PET-CT service metrics from PET-CT stakeholders across seven countries. This was further informed via document analysis of clinical indication guidance and expert consensus through round-table discussions of relevant PET-CT stakeholders. Descriptive comparative analyses were produced on use, capacity and indication guidance for PET-CT services between jurisdictions. SETTING: PET-CT services across 21 jurisdictions in seven countries (Australia, Denmark, Canada, Ireland, New Zealand, Norway and the UK). PARTICIPANTS: None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULTS: PET-CT service provision has grown over the period 2006-2017, but scale of increase in capacity and demand is variable. Clinical indication guidance varied across countries, particularly for small-cell lung cancer staging and the specific acknowledgement of gastric cancer within oesophagogastric cancers. There is limited and inconsistent data capture, coding, accessibility and availability of PET-CT activity across countries studied. CONCLUSIONS: Variation in PET-CT scanner quantity, acquisition over time and guidance upon use exists internationally. There is a lack of routinely captured and accessible PET-CT data across the International Cancer Benchmarking Partnership countries due to inconsistent data definitions, data linkage issues, uncertain coverage of data and lack of specific coding. This is a barrier in improving the quality of PET-CT services globally. There needs to be greater, richer data capture of diagnostic and staging tools to facilitate learning of best practice and optimize cancer services.
Asunto(s)
Benchmarking , Neoplasias , Australia , Canadá , Humanos , Irlanda , Neoplasias/diagnóstico por imagen , Nueva Zelanda , Noruega , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
Ion channel proteins form nanopores in biological membranes which allow the passage of ions and water molecules. Hydrophobic constrictions in such pores can form gates, i.e. energetic barriers to water and ion permeation. Molecular dynamics simulations of water in ion channels may be used to assess whether a hydrophobic gate is closed (i.e. impermeable to ions) or open. If there is an energetic barrier to water permeation then it is likely that a gate will also be impermeable to ions. Simulations of water behaviour have been used to probe hydrophobic gates in two recently reported ion channel structures: BEST1 and TMEM175. In each of these channels a narrow region is formed by three consecutive rings of hydrophobic sidechains and in both cases such analysis demonstrates that the crystal structures correspond to a closed state of the channel. In silico mutations of BEST1 have also been used to explore the effect of changes in the hydrophobicity of the gating constriction, demonstrating that substitution of hydrophobic sidechains with more polar sidechains results in an open gate which allows water permeation. A possible open state of the TMEM175 channel was modelled by the in silico expansion of the hydrophobic gate resulting in the wetting of the pore and free permeation of potassium ions through the channel. Finally, a preliminary study suggests that a hydrophobic gate motif can be transplanted in silico from the BEST1 channel into a simple ß-barrel pore template. Overall, these results suggest that simulations of the behaviour of water in hydrophobic gates can reveal important design principles for the engineering of gates in novel biomimetic nanopores.
Asunto(s)
Canales Iónicos/química , Nanoporos , Agua/química , Interacciones Hidrofóbicas e Hidrofílicas , Simulación de Dinámica MolecularRESUMEN
Background: Pyrazinamide is one of four first-line antibiotics used to treat tuberculosis; however, antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation in pncA, encoding an enzyme that converts pyrazinamide into its active form. Methods: We curated a dataset of 664 non-redundant, missense amino acid mutations in PncA with associated high-confidence phenotypes from published studies and then trained three different machine-learning models to predict pyrazinamide resistance. All models had access to a range of protein structural-, chemical- and sequence-based features. Results: The best model, a gradient-boosted decision tree, achieved a sensitivity of 80.2% and a specificity of 76.9% on the hold-out test dataset. The clinical performance of the models was then estimated by predicting the binary pyrazinamide resistance phenotype of 4027 samples harbouring 367 unique missense mutations in pncA derived from 24â231 clinical isolates. Conclusions: This work demonstrates how machine learning can enhance the sensitivity/specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs.
RESUMEN
BACKGROUND: International variations in cancer outcomes persist and may be influenced by differences in the accessibility and organisation of cancer patient pathways. More evidence is needed to understand to what extent variations in the structure of primary care referral pathways for cancer investigation contribute to differences in the timeliness of diagnoses and cancer outcomes in different countries. AIM: To explore the variation in primary care referral pathways for the management of suspected cancer across different countries. DESIGN AND SETTING: Descriptive comparative analysis using mixed methods across the International Cancer Benchmarking Partnership (ICBP) countries. METHOD: Schematics of primary care referral pathways were developed across 10 ICBP jurisdictions. The schematics were initially developed using the Aarhus statement (a resource providing greater insight and precision into early cancer diagnosis research) and were further supplemented with expert insights through consulting leading experts in primary care and cancer, existing ICBP data, a focused review of existing evidence on the management of suspected cancer, published primary care cancer guidelines, and evaluations of referral tools and initiatives in primary care. RESULTS: Referral pathway schematics for 10 ICBP jurisdictions were presented alongside a descriptive comparison of the organisation of primary care management of suspected cancer. Several key areas of variation across countries were identified: inflexibility of referral pathways, lack of a managed route for non-specific symptoms, primary care practitioner decision-making autonomy, direct access to investigations, and use of emergency routes. CONCLUSION: Analysing the differences in referral processes can prompt further research to better understand the impact of variation on the timeliness of diagnoses and cancer outcomes. Studying these schematics in local contexts may help to identify opportunities to improve care and facilitate discussions on what may constitute best referral practice.
Asunto(s)
Benchmarking , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Derivación y Consulta , Detección Precoz del Cáncer , Atención Primaria de SaludRESUMEN
Water molecules within biological ion channels are in a nanoconfined environment and therefore exhibit behaviors which differ from that of bulk water. Here, we investigate the phenomenon of hydrophobic gating, the process by which a nanopore may spontaneously dewet to form a "vapor lock" if the pore is sufficiently hydrophobic and/or narrow. This occurs without steric occlusion of the pore. Using molecular dynamics simulations with both rigid fixed-charge and polarizable (AMOEBA) force fields, we investigate this wetting/dewetting behavior in the transmembrane protein 175 ion channel. We examine how a range of rigid fixed-charge and polarizable water models affect wetting/dewetting in both the wild-type structure and in mutants chosen to cover a range of nanopore radii and pore-lining hydrophobicities. Crucially, we find that the rigid fixed-charge water models lead to similar wetting/dewetting behaviors, but that the polarizable water model resulted in an increased wettability of the hydrophobic gating region of the pore. This has significant implications for molecular simulations of nanoconfined water, as it implies that polarizability may need to be included if we are to gain detailed mechanistic insights into wetting/dewetting processes. These findings are of importance for the design of functionalized biomimetic nanopores (e.g., sensing or desalination) as well as for furthering our understanding of the mechanistic processes underlying biological ion channel function.
Asunto(s)
Simulación de Dinámica Molecular , Nanoporos , Interacciones Hidrofóbicas e Hidrofílicas , Canales Iónicos/metabolismo , Agua/metabolismoRESUMEN
Ion channels are proteins which form gated nanopores in biological membranes. Many channels exhibit hydrophobic gating, whereby functional closure of a pore occurs by local dewetting. The pentameric ligand gated ion channels (pLGICs) provide a biologically important example of hydrophobic gating. Molecular simulation studies comparing additive vs polarizable models indicate predictions of hydrophobic gating are robust to the model employed. However, polarizable models suggest favorable interactions of hydrophobic pore-lining regions with chloride ions, of relevance to both synthetic carriers and channel proteins. Electrowetting of a closed pLGIC hydrophobic gate requires too high a voltage to occur physiologically but may inform designs for switchable nanopores. Global analysis of â¼200 channels yields a simple heuristic for structure-based prediction of (closed) hydrophobic gates. Simulation-based analysis is shown to provide an aid to interpretation of functional states of new channel structures. These studies indicate the importance of understanding the behavior of water and ions within the nanoconfined environment presented by ion channels.
RESUMEN
Self-assembling cyclic peptide nanotubes can form nanopores when they are inserted in lipid bilayers, acting as ion and/or water permeable channels. In order to improve the versatility of these systems, it is possible to specifically design cyclic peptides with a combination of natural and non-natural amino acids, enabling the control of the nature of the inner cavity of the channels. Here, the behavior of two types of self-assembling peptide motifs, alternating α-amino acids with γ- or δ-aminocycloalkanecarboxylic acids, is studied via molecular dynamics (MD) simulations. The behavior of water molecules in nanopores is expected to affect the properties of these channels and therefore merits detailed examination. A number of water models commonly used in MD simulations have been validated by how well they reproduce bulk water properties. However, it is less clear how these water models behave in the nanoconfined condition inside a channel. The behavior of four different water models-TIP3P, TIP4P, TIP4P/2005, and OPC-are evaluated in MD simulations of self-assembled cyclic peptide nanotubes of distinct composition and diameter. The dynamic behavior of the water molecules and ions in these designed artificial channels depends subtly on the water model used. TIP3P water molecules move faster than those of TIP4P, TIP4P/2005, and OPC. This demeanor is clearly observed in the filling of the nanotube, in water diffusion within the pore, and in the number and stability of hydrogen bonds of the peptides with water. It was also shown that the water model influences the simulated ion flux through the nanotubes, with TIP3P producing the greatest ion flux. Additionally, the two more recent models, TIP4P/2005 and OPC, which are known to reproduce the experimental self-diffusion coefficient of bulk water quite well, exhibit very similar results under the nanoconfined conditions studied here. Because none of these models have been parametrized specifically for waters confined in peptide nanotubes, this study provides a point of reference for further validation.
Asunto(s)
Nanotubos de Péptidos , Nanotubos , Simulación de Dinámica Molecular , Péptidos Cíclicos , AguaRESUMEN
This study was conducted at 5 Veterans Administration Medical Centers (VAMCs). A cross sectional survey was administered to 134 workers who routinely lift and mobilize patients within their workplaces' safe patient handling and mobility (SPHM) programs, which are mandated in all VAMCs. The survey was used to examine a comprehensive list of SPHM and non-SPHM variables, and their associations with self-reported musculoskeletal injury and pain. Previously unstudied variables distinguished between "bariatric" (≥300 lb or 136 kg) and "non-bariatric" (<300 lb or 136 kg) patient handling. Significant findings from stepwise and logistic regression provide targets for workplace improvements, predicting: lower injury odds with more frequently having sufficient time to use equipment, higher back pain odds with more frequent bariatric handling, lower back pain odds with greater ease in following SPHM policies, and lower odds of upper extremity pain with more bariatric equipment, and with higher safety climate ratings.