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3.
Dev Cell ; 50(4): 494-508.e11, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430451

RESUMO

Clathrin-mediated endocytosis (CME) is key to maintaining the transmembrane protein composition of cells' limiting membranes. During mammalian CME, a reversible phosphorylation event occurs on Thr156 of the µ2 subunit of the main endocytic clathrin adaptor, AP2. We show that this phosphorylation event starts during clathrin-coated pit (CCP) initiation and increases throughout CCP lifetime. µ2Thr156 phosphorylation favors a new, cargo-bound conformation of AP2 and simultaneously creates a binding platform for the endocytic NECAP proteins but without significantly altering AP2's cargo affinity in vitro. We describe the structural bases of both. NECAP arrival at CCPs parallels that of clathrin and increases with µ2Thr156 phosphorylation. In turn, NECAP recruits drivers of late stages of CCP formation, including SNX9, via a site distinct from where NECAP binds AP2. Disruption of the different modules of this phosphorylation-based temporal regulatory system results in CCP maturation being delayed and/or stalled, hence impairing global rates of CME.

4.
Br J Gen Pract ; 69(682): e356-e362, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30803982

RESUMO

BACKGROUND: Despite patient preference and many known benefits, continuity of care is in decline in general practice. The most common method of measuring continuity is the Usual Provider of Care (UPC) index. This requires a number of appointments per patient and a relatively long timeframe for accuracy, reducing its applicability for day-to-day performance management. AIM: To describe the St Leonard's Index of Continuity of Care (SLICC) for measuring GP continuity regularly, and demonstrate how it has been used in service in general practice. DESIGN AND SETTING: Analysis of appointment audit data from 2016-2017 in a general practice with 8823-9409 patients and seven part-time partners, in Exeter, UK. METHOD: The percentage of face-to-face appointments for patients on each doctor's list, with the patient's personal doctor (the SLICC), was calculated monthly. The SLICC for different demographic groupings of patients (for example, sex and frequency of attendance) was compared. The UPC index over the 2 years was also calculated, allowing comparisons between indices. RESULTS: In the 2-year study period, there were 35 622 GP face-to-face appointments; 1.96 per patient per year. Overall, 51.7% (95% confidence interval = 51.2 to 52.2) of GP appointments were with the patients' personal doctor. Patients aged ≥65 years had a higher level of continuity with 64.9% of appointments being with their personal doctor. The mean whole-practice UPC score was 0.61 (standard deviation 0.23), with 'usual provider' being the personal GP for 52.8% and a trainee or locum for 8.1% of patients. CONCLUSION: This method could provide working GPs with a simple way to track continuity of care and inform practice management and decision making.


Assuntos
Agendamento de Consultas , Continuidade da Assistência ao Paciente/estatística & dados numéricos , Medicina de Família e Comunidade , Medicina Geral , Adulto , Idoso , Demografia , Medicina de Família e Comunidade/normas , Medicina de Família e Comunidade/estatística & dados numéricos , Feminino , Medicina Geral/normas , Medicina Geral/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente , Indicadores de Qualidade em Assistência à Saúde , Reino Unido
5.
Phys Med Biol ; 64(8): 08NT01, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30808011

RESUMO

Radiotherapy treatment plans using dynamic couch rotation during volumetric modulated arc therapy (DCR-VMAT) reduce the dose to organs at risk (OARs) compared to coplanar VMAT, while maintaining the dose to the planning target volume (PTV). This paper seeks to validate this finding with measurements. DCR-VMAT treatment plans were produced for five patients with primary brain tumours and delivered using a commercial linear accelerator (linac). Dosimetric accuracy was assessed using point dose and radiochromic film measurements. Linac-recorded mechanical errors were assessed by extracting deviations from log files for multi-leaf collimator (MLC), couch, and gantry positions every 20 ms. Dose distributions, reconstructed from every fifth log file sample, were calculated and used to determine deviations from the treatment plans. Median (range) treatment delivery times were 125 s (123-133 s) for DCR-VMAT, compared to 78 s (64-130 s) for coplanar VMAT. Absolute point doses were 0.8% (0.6%-1.7%) higher than prediction. For coronal and sagittal films, respectively, 99.2% (96.7%-100%) and 98.1% (92.9%-99.0%) of pixels above a 20% low dose threshold reported gamma <1 for 3% and 3 mm criteria. Log file analysis showed similar gantry rotation root-mean-square error (RMSE) for VMAT and DCR-VMAT. Couch rotation RMSE for DCR-VMAT was 0.091° (0.086-0.102°). For delivered dose reconstructions, 100% of pixels above a 5% low dose threshold reported gamma <1 for 2% and 2 mm criteria in all cases. DCR-VMAT, for the primary brain tumour cases studied, can be delivered accurately using a commercial linac.

6.
Br J Radiol ; 92(1097): 20180908, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30694086

RESUMO

This paper gives an overview of recent developments in non-coplanar intensity modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT). Modern linear accelerators are capable of automating motion around multiple axes, allowing efficient delivery of highly non-coplanar radiotherapy techniques. Novel techniques developed for C-arm and non-standard linac geometries, methods of optimization, and clinical applications are reviewed. The additional degrees of freedom are shown to increase the therapeutic ratio, either through dose escalation to the target or dose reduction to functionally important organs at risk, by multiple research groups. Although significant work is still needed to translate these new non-coplanar radiotherapy techniques into the clinic, clinical implementation should be prioritized. Recent developments in non-coplanar radiotherapy demonstrate that it continues to have a place in modern cancer treatment.


Assuntos
Neoplasias/radioterapia , Radioterapia Conformacional , Radioterapia de Intensidade Modulada , Humanos , Órgãos em Risco , Aceleradores de Partículas , Radiocirurgia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos
7.
J Chromatogr A ; : 460775, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31959455

RESUMO

The international trade in illegally logged and environmentally endangered timber has spurred enforcement agencies to seek additional technical procedures for the identification of wood species. All Dalbergia species are listed under the Convention on International Trade in Endangered Species (CITES) which is the reason this genus was chosen for study. Multiple sources of the heartwood from different Dalbergia species were extracted and chromatographic profiles collected by gas chromatography with high resolution quadrupole Time of Flight mass spectrometry (GC/QToF). The collected data was mined to select peaks and mass ions representative of the investigated Dalbergia species, and used to develop a Microsoft Excel® template offering immediate graphical representation of the results. Using wood specimens sourced from different xylaria, this graphical fingerprint proved adept at definitive identification of Dalbergia species. The CITES Appendix I species, D. nigra, was easily distinguished from D. melanoxylon and look-alike species of other genera. Similarly, a number of other Dalbergia species were differentiated using this current approach. Kernel discrimination analysis (KDA) was applied to increase the confidence of the species identification. The mislabeling of specimens appears to be common, and the emerging technique of GC/QToF in combination with other techniques, offers improved confidence in identification. GC/QToF further provides automation, the dimension of chromatography to avoid interferences, and production of reproducible electron impact positive (EI+) spectra. The prospect of building an EI+ spectral database for future wood identification is an important feature considering the limited accessibility of authenticated wood species specimens.

8.
Phys Med ; 55: 149-154, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30420271

RESUMO

PURPOSE: Proton CT is widely recognised as a beneficial alternative to conventional X-ray CT for treatment planning in proton beam radiotherapy. A novel proton CT imaging system, based entirely on solid-state detector technology, is presented. Compared to conventional scintillator-based calorimeters, positional sensitive detectors allow for multiple protons to be tracked per read out cycle, leading to a potential reduction in proton CT scan time. Design and characterisation of its components are discussed. An early proton CT image obtained with a fully solid-state imaging system is shown and accuracy (as defined in Section IV) in Relative Stopping Power to water (RSP) quantified. METHOD: A solid-state imaging system for proton CT, based on silicon strip detectors, has been developed by the PRaVDA collaboration. The system comprises a tracking system that infers individual proton trajectories through an imaging phantom, and a Range Telescope (RT) which records the corresponding residual energy (range) for each proton. A back-projection-then-filtering algorithm is used for CT reconstruction of an experimentally acquired proton CT scan. RESULTS: An initial experimental result for proton CT imaging with a fully solid-state system is shown for an imaging phantom, namely a 75 mm diameter PMMA sphere containing tissue substitute inserts, imaged with a passively-scattered 125 MeV beam. Accuracy in RSP is measured to be ⩽1.6% for all the inserts shown. CONCLUSIONS: A fully solid-state imaging system for proton CT has been shown capable of imaging a phantom with protons and successfully improving RSP accuracy. These promising results, together with system the capability to cope with high proton fluences (2×108 protons/s), suggests that this research platform could improve current standards in treatment planning for proton beam radiotherapy.


Assuntos
Prótons , Tomografia Computadorizada por Raios X/instrumentação , Desenho de Equipamento , Método de Monte Carlo
10.
BMJ Open ; 8(6): e021161, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29959146

RESUMO

OBJECTIVE: Continuity of care is a long-standing feature of healthcare, especially of general practice. It is associated with increased patient satisfaction, increased take-up of health promotion, greater adherence to medical advice and decreased use of hospital services. This review aims to examine whether there is a relationship between the receipt of continuity of doctor care and mortality. DESIGN: Systematic review without meta-analysis. DATA SOURCES: MEDLINE, Embase and the Web of Science, from 1996 to 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Peer-reviewed primary research articles, published in English which reported measured continuity of care received by patients from any kind of doctor, in any setting, in any country, related to measured mortality of those patients. RESULTS: Of the 726 articles identified in searches, 22 fulfilled the eligibility criteria. The studies were all cohort or cross-sectional and most adjusted for multiple potential confounding factors. These studies came from nine countries with very different cultures and health systems. We found such heterogeneity of continuity and mortality measurement methods and time frames that it was not possible to combine the results of studies. However, 18 (81.8%) high-quality studies reported statistically significant reductions in mortality, with increased continuity of care. 16 of these were with all-cause mortality. Three others showed no association and one demonstrated mixed results. These significant protective effects occurred with both generalist and specialist doctors. CONCLUSIONS: This first systematic review reveals that increased continuity of care by doctors is associated with lower mortality rates. Although all the evidence is observational, patients across cultural boundaries appear to benefit from continuity of care with both generalist and specialist doctors. Many of these articles called for continuity to be given a higher priority in healthcare planning. Despite substantial, successive, technical advances in medicine, interpersonal factors remain important. PROSPERO REGISTRATION NUMBER: CRD42016042091.


Assuntos
Continuidade da Assistência ao Paciente/normas , Mortalidade , Relações Médico-Paciente , Médicos/normas , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Satisfação do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Health Technol Assess ; 22(18): 1-64, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29652246

RESUMO

BACKGROUND: The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e. non-diabetic hyperglycaemia (NDH)]. OBJECTIVE: To assess the feasibility of the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) and to estimate the key parameters to inform the design of the full trial. These parameters include the recruitment strategy, randomisation, electronic data capture, postal drug distribution, retention, study medication adherence, safety monitoring and remote collection of outcome data. DESIGN: A multicentre, individually randomised, double-blind, parallel-group, pragmatic, primary prevention trial. Participants were individually randomised on a 1 : 1 basis, blocked within each site. SETTING: General practices and clinical research facilities in Cambridgeshire, Norfolk and Leicestershire. PARTICIPANTS: Males and females aged ≥ 40 years with NDH who had a high risk of CVD. INTERVENTIONS: Prolonged-release metformin (500 mg) (Glucophage® SR, Merck KGaA, Bedfont Cross, Middlesex, UK) or the matched placebo, up to three tablets per day, distributed by post. MAIN OUTCOME MEASURES: Recruitment rates; adherence to study medication; laboratory results at baseline and 3 and 6 months; reliability and acceptability of study drug delivery; questionnaire return rates; and quality of life. RESULTS: We sent 5251 invitations, with 511 individuals consenting to participate. Of these, 249 were eligible and were randomised between March and November 2015 (125 to the metformin group and 124 to the placebo group). Participants were followed up for 0.99 years [standard deviation (SD) 0.30 years]. The use of electronic medical records to identify potentially eligible individuals in individual practices was resource intensive. Participants were generally elderly [mean age 70 years (SD 6.7 years)], overweight [mean body mass index 30.1 kg/m2 (SD 4.5 kg/m2)] and male (88%), and the mean modelled 10-year CVD risk was 28.8% (SD 8.5%). Randomisation, postal delivery of the study drug and outcome assessment using registers/medical records were feasible and acceptable to participants. Most participants were able to take three tablets per day, but premature discontinuation of the study drug was common (≈30% of participants by 6 months), although there were no differences between the groups. All randomised participants returned questionnaires at baseline and 67% of participants returned questionnaires by the end of the study. There was no between-group difference in Short Form questionnaire-8 items or EuroQol-5 Dimensions scores. Compared with placebo, metformin was associated with small improvements in the mean glycated haemoglobin level [-0.82 mmol/mol, 95% confidence interval (CI) -1.39 to -0.24 mmol/mol], mean estimated glomerular filtration rate (2.31 ml/minute/1.73 m2, 95% CI -0.2 to 4.81 ml/minute/1.73 m2) and mean low-density lipoprotein cholesterol level (-0.11 mmol/l, 95% CI -0.25 to 0.02 mmol/l) and a reduction in mean plasma vitamin B12 level (-16.4 ng/l, 95% CI -32.9 to -0.01 ng/l). There were 35 serious adverse events (13 in the placebo group, 22 in the metformin group), with none deemed to be treatment related. LIMITATIONS: Changes to sponsorship reduced the study duration, the limited availability of information in medical records reduced recruitment efficiency and discontinuation of study medication exceeded forecasts. CONCLUSIONS: A large, pragmatic trial comparing the effects of prolonged-release metformin and placebo on the risk of CVD events is potentially feasible. However, changes to the study design and conduct are recommended to enable an efficient scaling up of the trial. Recommendations include changing the inclusion criteria to recruit people with pre-existing CVD to increase the recruitment and event rates, using large primary/secondary care databases to increase recruitment rates, conducting follow-up remotely to improve efficiency and including a run-in period prior to randomisation to optimise trial adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34875079. FUNDING: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 18. See the NIHR Journals Library website for further project information. Merck KGaA provided metformin and matching placebo.


Assuntos
Doenças Cardiovasculares/epidemiologia , Hiperglicemia/tratamento farmacológico , Hiperglicemia/epidemiologia , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Glicemia , Índice de Massa Corporal , Análise Custo-Benefício , Preparações de Ação Retardada , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Taxa de Filtração Glomerular , Hemoglobina A Glicada , Hemoglobinas , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Lipídeos/sangue , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , Qualidade de Vida , Reprodutibilidade dos Testes , Projetos de Pesquisa , Avaliação da Tecnologia Biomédica
12.
Artigo em Inglês | MEDLINE | ID: mdl-29675258

RESUMO

A 54-year-old woman was admitted to hospital with a presumed allergic reaction to a single dose of amoxicillin given for a suspected upper respiratory tract infection. She complained of chest tightness although there was no wheeze or stridor. On examination, she was pyrexial, tachycardic, hypertensive and had a diffuse mottled rash on her lower limbs. Her initial investigations showed raised inflammatory markers. She was treated in the intensive care for a presumed anaphylactic reaction with an underlying sepsis. Further investigations including CT head and CSF examination were unremarkable; however, a CT abdomen showed a 10 cm heterogeneous right adrenal mass. Based on review by the endocrine team, a diagnosis of pheochromocytoma crisis was made, which was subsequently confirmed on 24-h urinary metanephrine measurement. An emergency adrenalectomy was considered although she was deemed unfit for surgery. Despite intensive medical management, her conditioned deteriorated and she died secondary to multi-organ failure induced by pheochromocytoma crisis. Learning points: Pheochromocytoma have relatively higher prevalence in autopsy series (0.05-1%) suggestive of a diagnosis, which is often missed.Pheochromocytoma crisis is an endocrine emergency characterized by hemodynamic instability induced by surge of catecholamines often precipitated by trauma and medications (ß blockers, general anesthetic agents, ephedrine and steroids).Pheochromocytoma crisis can mimic acute coronary syndrome, cardiogenic or septic shock.Livedo reticularis can be a rare although significant cutaneous marker of underlying pheochromocytoma crisis.

13.
Br J Radiol ; 91(1081): 20170267, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28869399

RESUMO

Lung cancer is the leading cause of cancer mortality worldwide. Treatment pathways include regular cross-sectional imaging, generating large data sets which present intriguing possibilities for exploitation beyond standard visual interpretation. This additional data mining has been termed "radiomics" and includes semantic and agnostic approaches. Textural analysis (TA) is an example of the latter, and uses a range of mathematically derived features to describe an image or region of an image. Often TA is used to describe a suspected or known tumour. TA is an attractive tool as large existing image sets can be submitted to diverse techniques for data processing, presentation, interpretation and hypothesis testing with annotated clinical outcomes. There is a growing anthology of published data using different TA techniques to differentiate between benign and malignant lung nodules, differentiate tissue subtypes of lung cancer, prognosticate and predict outcome and treatment response, as well as predict treatment side effects and potentially aid radiotherapy planning. The aim of this systematic review is to summarize the current published data and understand the potential future role of TA in managing lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Humanos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos
14.
Artigo em Inglês | MEDLINE | ID: mdl-29075507

RESUMO

BACKGROUND: Skin tears are common in older adults and those taking steroids and warfarin. They are traumatic, often blunt injuries caused by oblique knocks to the extremities. The epidermis may separate from the dermis or both layers from underlying tissues leaving a skin flap or total loss of tissue, which is painful and prone to infection. 'Dermatuff™' knee-length socks containing Kevlar fibres (used in stab-proof vests and motorcyclists' clothing) aim to prevent skin tears. The acceptability of the socks and the feasibility of a randomised controlled trial (RCT) had not been explored. METHODS: In this pilot parallel group RCT, 90 people at risk of skin-tear injury from Devon care homes and primary care were randomised to receive the socks or treatment as usual (TAU). The pilot aimed to estimate parameters to inform the design of a substantive trial and record professionals' views and participants' acceptability of the intervention and of study participation. RESULTS: Participants were randomised from July 2013 and followed up until February 2015. Community participants were easier to recruit than care homes residents but were 10 years younger on average and more active. To recruit 90 participants, 395 had to be approached overall as 77% were excluded or declined. Seventy-nine participants (88%) completed the trial and 27/44 (61%) wore the socks for 16 weeks. There were 31 skin tear injuries affecting 18 (20%) of the 90 participants. The TAU group received more injuries, more repeated episodes, and larger tears with greater severity. Common daily diary reasons for not wearing the socks included perceived warmth in hot weather or not being available (holiday, in hospital, bed rest). Resource use data were obtainable and indicated that sock wearing gave a reduction in treatment costs whilst well-completed questionnaires showed improvements in secondary outcomes. CONCLUSIONS: This pilot trial has successfully informed the design and conduct of a future definitive cost-effectiveness RCT. It would need to be conducted in primary care with 880 active at-risk, elderly patients (440 per arm). Skin tear incidence and quality of life (from EQ5D5L) over a 4-month period would be the primary and secondary outcomes respectively. TRIAL REGISTRATION: ISRCTN, ISRCTN96565376.

15.
BMJ Open ; 7(7): e015972, 2017 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-28698337

RESUMO

INTRODUCTION: A new prognostic model has been developed and externally validated, the aim of which is to assist in the management of the blunt chest wall trauma patient in the emergency department (ED). A definitive randomised controlled trial (impact trial) is required to assess the clinical and cost effectiveness of the new model before it can be accepted in clinical practice. The purpose of this trial is to assess the feasibility and acceptability of such a definitive trial and inform its design. METHODS/ANALYSIS: This feasibility trial is designed to test the methods of a multicentre, cluster-randomised (stepped- wedge) trial, with a substantial qualitative component. Four EDs in England and Wales will collect data for all blunt chest wall trauma patients over a 5-month period; in the initial period acting as the controls (normal care), and in the second period acting as the interventions (in which the new model will be used). Baseline measurements including completion of the SF-12v2 will be obtained on initial assessment in the ED. Patient outcome data will then be collected for any subsequent hospitalisations. Data collection will conclude with a 6-week follow-up completion of two surveys (SF-12v2 and Client Services Receipt Inventory). Analysis of outcomes will focus on feasibility, acceptability and trial processes and will include recruitment and retention rates, attendance at clinician training rates and use of model in the ED. Qualitative feedback will be obtained through clinician interviews and a research nurse focus group. An evaluation of the feasibility of health economics outcomes data will be completed. ETHICS AND DISSEMINATION: Wales Research Ethics Committee 6 granted approval for the trial in September 2016. Patient recruitment will commence in February 2017. Planned dissemination is through publication in a peer-reviewed Emergency Medicine Journal, presentation at appropriate conferences and to stakeholders at professional meetings. TRIAL REGISTRATION NUMBER: ISRCTN95571506; Pre-results.


Assuntos
Gerenciamento Clínico , Serviço Hospitalar de Emergência/estatística & dados numéricos , Traumatismos Torácicos/terapia , Ferimentos não Penetrantes/terapia , Análise Custo-Benefício , Inglaterra , Estudos de Viabilidade , Pessoal de Saúde/educação , Humanos , Prognóstico , Qualidade de Vida , Projetos de Pesquisa , Inquéritos e Questionários , Parede Torácica , País de Gales
16.
Nano Lett ; 17(8): 4881-4885, 2017 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-28731722

RESUMO

Mastering dynamic free-space spectral control and modulation in the near-infrared (NIR) and optical regimes remains a challenging task that is hindered by the available functional materials at high frequencies. In this work, we have realized an efficient metadevice capable of spectral control by minimizing the thermal mass of a vanadium dioxide phase-change material (PCM) and placing the PCM at the feed gap of a bow-tie field antenna. The device has an experimentally measured tuning range of up to 360 nm in the NIR and a modulation depth of 33% at the resonant wavelength. The metadevice is configured for integrated and local heating, leading to faster switching and more precise spatial control compared with devices based on phase-change thin films. We envisage that the combined advantages of this device will open new opportunities for signal processing, memory, security, and holography at optical frequencies.

17.
Phys Med Biol ; 62(13): 5403-5416, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28604371

RESUMO

Several studies have recently reported on the value of CT texture analysis in predicting survival, although the topic remains controversial, with further validation needed in order to consolidate the evidence base. The aim of this study was to investigate the effect of varying the input parameters in the Kaplan-Meier analysis, to determine whether the resulting P-value can be considered to be a robust indicator of the parameter's prognostic potential. A retrospective analysis of the CT-based normalised entropy of 51 patients with lung cancer was performed and overall survival data for these patients were collected. A normalised entropy cut-off was chosen to split the patient cohort into two groups and log-rank testing was performed to assess the survival difference of the two groups. This was repeated for varying normalised entropy cut-offs and varying follow-up periods. Our findings were also compared with previously published results to assess robustness of this parameter in a multi-centre patient cohort. The P-value was found to be highly sensitive to the choice of cut-off value, with small changes in cut-off producing substantial changes in P. The P-value was also sensitive to follow-up period, with particularly noisy results at short follow-up periods. Using matched conditions to previously published results, a P-value of 0.162 was obtained. Survival analysis results can be highly sensitive to the choice in texture cut-off value in dichotomising patients, which should be taken into account when performing such studies to avoid reporting false positive results. Short follow-up periods also produce unstable results and should therefore be avoided to ensure the results produced are reproducible. Previously published findings that indicated the prognostic value of normalised entropy were not replicated here, but further studies with larger patient numbers would be required to determine the cause of the different outcomes.


Assuntos
Neoplasias Pulmonares/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
18.
Artigo em Inglês | MEDLINE | ID: mdl-28458906

RESUMO

SUMMARY: A 65-year-old woman was admitted to the emergency unit with a 48 h history of generalised weakness and confusion. On examination, she had mild slurring of speech although there was no other focal neurological deficit. She had profound hyponatraemia (serum sodium level of 100 mmol/L) on admission with the rest of her metabolic parameters being within normal range. Subsequent investigations confirmed the diagnosis of small-cell lung cancer with paraneoplastic syndrome of inappropriate antidiuresis (SIAD). She was monitored closely in high-dependency unit with an attempt to cautiously correct her hyponatraemia to prevent sequelae associated with rapid correction. The patient developed prolonged psychosis (lasting over 2 weeks) and displayed delayed dyskinetic movements, even after a gradual increase in serum sodium levels close to 130 mmol/L. To our knowledge, delayed neurological recovery from profound hyponatraemia (without long-term neurological sequelae) has previously not been reported. This case should alert a clinician regarding the possibility of prolonged although reversible psychosis and dyskinetic movements in a patient presenting with profound symptomatic hyponatraemia. LEARNING POINTS: Patients with profound hyponatraemia may develop altered sensorium, dyskinesia and psychotic behaviour.Full recovery from psychotic symptoms and dyskinesia may be delayed despite cautious correction of serum sodium levels.Careful and close monitoring of such patients can help avoid long-term neurological sequelae.

19.
Chemistry ; 23(28): 6811-6828, 2017 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-28261884

RESUMO

Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N1 ,N2 -bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials.


Assuntos
Antimaláricos/química , Quinolinas/química , Aminoquinolinas/química , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Cristalografia por Raios X , Desenho de Drogas , Espectroscopia de Ressonância de Spin Eletrônica , Compostos Férricos/química , Halogenação , Hemina/química , Hemina/metabolismo , Ligações de Hidrogênio , Isomerismo , Locomoção/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Malária/tratamento farmacológico , Malária/parasitologia , Malária/patologia , Camundongos , Conformação Molecular , Oxirredução , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/patogenicidade , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Termodinâmica
20.
BMJ Open ; 7(2): e014045, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28196950

RESUMO

OBJECTIVES: To clarify the relationship between social deprivation and age as two factors associated with emergency admissions to hospital. DESIGN: Emergency admissions for 12 months were analysed for patients in the NHS NEW Devon CCG. Social deprivation was measured by the Index of Multiple Deprivation (IMD). Logistic regression models estimated the separate and combined effects of social deprivation and age on the risk of emergency admissions for people aged under and over 65. SETTING: East Devon, UK-area of the NEW Devon CCG. POPULATION: 765 861 patients in the CCG database. MAIN OUTCOME MEASURE: Emergency admission to any English hospital. RESULTS: Age (p<0.001) and social deprivation (p<0.001) were significantly associated with emergency admission to hospital, but there was a significant interaction between age and social deprivation (p<0.001). From the third quintile of age upwards, age progressively overtakes deprivation and age has a dominant effect on emergency admissions over the age of 65. The effect of age was J-shaped in all deprivation groups, increasing exponentially after age 40. For patients under 65, age and social deprivation had similar risks for emergency admissions, the differences in risk between the top and bottom quintiles of IMD and age being ∼1.5 and 0.9 percentage points. In patients over 65, age had a much greater effect on the risk of admissions than social deprivation, the differences in risk between the top and bottom quintiles of IMD and age being ∼2.8 and 18.7 percentage points. CONCLUSIONS: Risk curves for all social groups have similar shapes, implying a common biological pattern for ageing in any social group. Over age 65, the biological effects of ageing outweigh the social effects of deprivation. Our model enables CCGs to anticipate and plan for emergency admissions to hospital. These findings provide a new logic for allocating resources to different populations.


Assuntos
Fatores Etários , Admissão do Paciente/estatística & dados numéricos , Isolamento Social , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Emergências , Feminino , Alocação de Recursos para a Atenção à Saúde , Nível de Saúde , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Regionalização , Características de Residência , Fatores Socioeconômicos , Reino Unido , Adulto Jovem
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