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We present an approach for studying the primary, secondary, and tertiary flow transitions in sheared annular electroconvection. In particular, we describe a Newton-Krylov method based on time integration for the computation of rotating waves and amplitude-modulated rotating waves, and for the continuation of these flows as a parameter of the system is varied. The method exploits the rotational nature of the flows and requires only a time-stepping code of the model differential equations, i.e., it does not require an explicit code for the discretization of the linearized equations. The linear stability of the solutions is computed to identify the parameter values at which the transitions occur. We apply the method to a model of electroconvection that simulates the flow of a liquid crystal film in the smectic A phase suspended between two annular electrodes and subjected to an electric potential difference and a radial shear. Due to the layered structure of the smectic A phase, the fluid can be treated as two-dimensional (2D) and is modeled using the 2D incompressible Navier-Stokes equations coupled with an equation for charge continuity. The system is a close analog to laboratory-scale geophysical fluid experiments and thus represents an ideal system in which to apply the method before its application to these other systems that exhibit similar flow transitions. In the model for electroconvection, we identify the parameter values at which the primary transition from steady axisymmetric flow to rotating waves occurs, as well as at which the secondary transition from the rotating waves to amplitude-modulated rotating waves occurs. In addition, we locate the tertiary transition, which corresponds to a transition from the amplitude-modulated waves to a three-frequency flow. Of particular interest is that the method also finds a period-doubling bifurcation from the amplitude-modulated rotating waves and a subsequent transition from the flow resulting from this bifurcation.
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PURPOSE: The importance of the DNA damage response in mediating effects of radiotherapy (RT) has galvanized efforts to target this pathway with radiosensitizers. Yet early clinical trials of this approach have failed to yield a benefit in unselected populations. We hypothesized that ataxia-telangiectasia mutated (Atm)-null tumors would demonstrate genotype-specific synergy between RT and an inhibitor of the DNA damage response protein ataxia-telangiectasia and Rad3-related (ATR) kinase. EXPERIMENTAL DESIGN: We investigated the synergistic potential of the ATR inhibitor (ATRi) RP-3500 and RT in two Atm-null and isogenic murine models, both in vitro and in vivo. Staining of γ-H2AX foci, characterization of the immune response via flow cytometry, and tumor rechallenge experiments were performed to elucidate the mechanism of interaction. To examine genotype specificity, we tested the interaction of ATRi and RT in a Brca1-null model. Finally, patients with advanced cancer with ATM alterations were enrolled in a phase I/II clinical trial to validate preclinical findings. RESULTS: Synergy between RP-3500 and RT was confirmed in Atm-null lines in vitro, characterized by an accumulation of DNA double-strand breaks. In vivo, Atm-null tumor models had higher rates of durable control with RT and ATRi than controls. In contrast, there was no synergy in tumors lacking Brca1. Analysis of the immunologic response indicated that efficacy is largely mediated by cell-intrinsic mechanisms. Lastly, early results from our clinical trial showed complete responses in patients. CONCLUSIONS: Genotype-directed radiosensitization with ATRi and RT can unleash significant therapeutic benefit and could represent a novel approach to develop more effective combinatorial synthetic cytotoxic RT-based treatments.
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BACKGROUND: Remote home monitoring services emerged as critical components of health care delivery from NHS England during the COVID-19 pandemic, aiming to provide timely interventions and reduce health care system burden. Two types of service were offered: referral by community health services to home-based care to ensure the right people were admitted to the hospital at the right time (called COVID Oximetry@home, CO@h); and referral by hospital to support patients' transition from hospital to home (called COVID-19 Virtual Ward, CVW). The information collected for the oxygen levels and other symptoms was provided via digital means (technology-enabled) or over the phone (analogue-only submission mode). This study aimed to evaluate the costs of implementing remote home monitoring for COVID-19 patients across 26 sites in England during wave 2 of the pandemic. Understanding the operational and financial implications of these services from the NHS perspective is essential for effective resource allocation and service planning. METHODS: We used a bottom-up costing approach at the intervention level to describe the costs of setting up and running the services. Twenty-six implementation sites reported the numbers of patients and staff involved in the service and other resources used. Descriptive statistics and multivariable regression analysis were used to assess cost variations and quantify the relationship between the number of users and costs while adjusting for other service characteristics. RESULTS: The mean cost per patient monitored was lower in the CO@h service compared with the CVW service (£527 vs £599). The mean cost per patient was lower for implementation sites using technology-enabled and analogue data submission modes compared with implementation sites using analogue-only modes for both CO@h (£515 vs £561) and CVW (£584 vs £612) services. The number of patients enrolled in the services and the service type significantly affected the mean cost per patient. CONCLUSIONS: Our analysis provides a framework for evaluating the costs of similar services in the future and shows that the implementation of these services benefit from the employment of tech-enabled data submission modes.
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CONTEXT: Risk stratification has been suggested as a strategy for improving cancer screening. Any changes to existing programmes must be acceptable to the public. OBJECTIVE: This study aimed to explore the preferences and considerations of individuals relating to the introduction of different risk-based strategies to determine eligibility for colorectal cancer (CRC) screening. STUDY DESIGN: Participants completed a discrete choice experiment (DCE) within online interviews. Nine conjoint-analysis tasks were created, each with two potential CRC screening programmes. The attributes included personal risk of CRC, screening invitation strategy and impact. Participants chose between programmes while thinking aloud and sharing their thoughts. Transcripts were analysed using codebook thematic analysis. PARTICIPANTS: Twenty participants based in England aged 40-79 years without previous cancer history or medical expertise. RESULTS: When choosing between programmes, participants first and primarily looked to prioritise saving lives. The harms associated with screening were viewed as a surprise but also felt by most to be inevitable; the benefits frequently outweighed, therefore, harms were considered less important. Risk stratification using individual characteristics was considered a nuanced approach to healthcare, which tended to be preferred over the age-alone model. Detailed personal risk information could be taken more seriously than non-personalised information to motivate behaviour change. Although it had minimal impact on decision-making, not diverting resources for screening from elsewhere was valued. Individuals who chose not to provide health information were considered irresponsible, while it was important that those with no information to provide should not lose out. CONCLUSION: Risk-stratified CRC screening is generally aligned with public preferences, with decisions between possible stratification strategies dominated by saving lives. Even if attributes including risk factors, risk stratification strategy and risk communication contributed less to the overall decision to select certain programmes, some levels more clearly fulfilled public values; therefore, all these factors should be taken into consideration when redesigning and communicating CRC screening programmes. PATIENT OR PUBLIC CONTRIBUTION: The primary data source for this study is interviews with 20 members of the public (current, past or future CRC screening invitees). Two public representatives contributed to planning this study, particularly the DCE.
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Conducta de Elección , Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Persona de Mediana Edad , Masculino , Femenino , Anciano , Detección Precoz del Cáncer/psicología , Adulto , Medición de Riesgo , Inglaterra , Entrevistas como Asunto , Tamizaje Masivo/métodos , Prioridad del PacienteRESUMEN
Despite the importance of intramuscular fat (IMF) to eating quality, as yet no methodology has been widely adopted by the whole of industry in Australia to measure it routinely. Thus, a study was conducted to investigate the potential for a Near Infra-Red (NIR) device to predict the IMF content of the loin from spectra collected on the topside which is externally located on a hanging carcase and therefore easily accessible. To this end, NIR spectra were collected from topsides (m. semimembranosus) of 258 lamb carcases over 5 data collections and a sample of muscle was collected from the loin and the topside for IMF determination using a wet chemistry method. Subsequent Partial Least Square (PLS) models suggested the ability to predict the absolute IMF content of loins was poor (R2 = 0.28, RMSE = 1.26), yet there was a moderate ability to predict the IMF content of the topside (R2 = 0.56, RMSE = 0.82). Partial Least Square Discrimination Analysis (PLS-DA) models to classify cuts based on the IMF eating quality threshold of 4.5% yielded better predictive outcomes with accuracies of 66.7% and 76.7% for loin and topside respectively. However, further research to assess the relationship between the IMF of the loin and topside and reduce the impact of differences in overall absorbance between data collections will improve predictive outcomes.
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Tejido Adiposo , Músculo Esquelético , Carne Roja , Oveja Doméstica , Espectroscopía Infrarroja Corta , Animales , Músculo Esquelético/química , Espectroscopía Infrarroja Corta/métodos , Australia , Tejido Adiposo/química , Carne Roja/análisis , Análisis de los Mínimos CuadradosRESUMEN
Prochlorperazine is a commonly used medicine to treat nausea and vomiting. The only liquid formulation in the UK was discontinued in November 2022 due to safety concerns. One alternative option available is to use crushed tablets instead. Crushing and mixing tablets in water to produce a liquid is a widespread practice in paediatrics. However, there is often little evidence to support this practice.In this case report, a patient established on liquid prochlorperazine mesilate who was switched to crushed prochlorperazine maleate tablets experienced significant harm. The child's vomiting became uncontrolled and led to multiple healthcare attendances and a prolonged hospital admission. Control was re-established by increasing the prochlorperazine dose to accommodate for loss of drug during preparation. Care should be taken when converting prochlorperazine mesilate liquid doses to crushed prochlorperazine maleate tablets, and the doses used should not be treated as equivalent.
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BACKGROUND: A risk-stratified breast screening program could offer low-risk women less screening than is currently offered by the National Health Service. The acceptability of this approach may be enhanced if it corresponds to UK women's screening preferences and values. OBJECTIVES: To elicit and quantify preferences for low-risk screening options. METHODS: Women aged 40 to 70 y with no history of breast cancer took part in an online discrete choice experiment. We generated 32 hypothetical low-risk screening programs defined by 5 attributes (start age, end age, screening interval, risk of dying from breast cancer, and risk of overdiagnosis), the levels of which were systematically varied between the programs. Respondents were presented with 8 choice sets and asked to choose between 2 screening alternatives or no screening. Preference data were analyzed using conditional logit regression models. The relative importance of attributes and the mean predicted probability of choosing each program were estimated. RESULTS: Participants (N = 502) preferred all screening programs over no screening. An older starting age of screening, younger end age of screening, longer intervals between screening, and increased risk of dying had a negative impact on support for screening programs (P < 0.01). Although the risk of overdiagnosis was of low relative importance, a decreased risk of this harm had a small positive impact on screening choices. The mean predicted probabilities that risk-adapted screening programs would be supported relative to current guidelines were low (range, 0.18 to 0.52). CONCLUSIONS: A deintensified screening pathway for women at low risk of breast cancer, especially one that recommends a later screening start age, would run counter to women's breast screening preferences. Further research is needed to enhance the acceptability of offering less screening to those at low risk of breast cancer. HIGHLIGHTS: Risk-based breast screening may involve the deintensification of screening for women at low risk of breast cancer.Low-risk screening pathways run counter to women's screening preferences and values.Longer screening intervals may be preferable to a later start age.Work is needed to enhance the acceptability of a low-risk screening pathway.
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Neoplasias de la Mama , Conducta de Elección , Detección Precoz del Cáncer , Humanos , Femenino , Neoplasias de la Mama/diagnóstico , Persona de Mediana Edad , Anciano , Adulto , Detección Precoz del Cáncer/métodos , Detección Precoz del Cáncer/psicología , Medición de Riesgo/métodos , Prioridad del Paciente/psicología , Prioridad del Paciente/estadística & datos numéricos , Reino Unido , Factores de Edad , Tamizaje Masivo/métodosRESUMEN
OBJECTIVE: To systematically map evidence to answer the research question: What is the relationship between the characteristics of children and young people (CYP) or their caregivers and primary care service use in the UK, taking into account underlying healthcare needs? DESIGN: Scoping review. SETTING: Primary care. ELIGIBILITY CRITERIA: English-language quantitative or mixed-methods studies published between 2012 and 2022. DATA SOURCES: Medline, Embase, Scopus and Web of Science Social Sciences Citation Index, and grey literature. RESULTS: 22 eligible studies were identified, covering general practice (n=14), dental health (n=4), child mental health (MN) services (n=3) and immunisation (n=1). Only eight studies (36%) controlled for variables associated with healthcare need (eg, age, birth weight and long-term conditions). In these, evidence of horizontal inequity in primary care use was reported for CYP living in deprived areas in England, with and without complex needs. Horizontal inequity was also identified in primary care MN referrals for CYP in England identifying as mixed-race, Asian or black ethnicity, compared with their white British peers. No evidence of horizontal inequity was observed, however, in primary care use for CYP in England exposed to parental depression, or for CYP children from low-income households in Scotland. Increasing CYP's age was associated with decreasing primary care use across included studies. No studies were found regarding CYP from Gypsy or Traveller communities, children in care, or those with disabilities or special educational needs. CONCLUSIONS: There is evidence that socioeconomic factors impact on CYP's primary care use, in particular age, ethnicity and deprivation. However, better quality evidence is required to evaluate horizontal inequity in use and address knowledge gaps regarding primary care use for vulnerable CYP populations and the impact of policy and practice related 'supply side' of primary care.
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Cuidadores , Atención Primaria de Salud , Humanos , Atención Primaria de Salud/estadística & datos numéricos , Niño , Reino Unido , Cuidadores/psicología , Cuidadores/estadística & datos numéricos , Adolescente , Disparidades en Atención de Salud/estadística & datos numéricos , Preescolar , Necesidades y Demandas de Servicios de Salud , Servicios de Salud del Niño/estadística & datos numéricosRESUMEN
OBJECTIVES: To examine children and young people's (CYP), caregivers' and healthcare professionals' (HCPs) views or experiences of facilitators and barriers to CYP access to UK primary care services to better understand healthcare inequity. To explore differences across CYP subpopulations with greater health needs from deprived areas, identifying as ethnic minorities, with experiences of state care, special educational needs or disabilities, chronic conditions or mental health problems. DESIGN: Scoping review. ELIGIBILITY CRITERIA: Included studies were in English, published 2012-2022 and reported: the views/experiences of CYP (0-25 years), caregivers or HCPs about accessing UK primary care; using quantitative or qualitative empirical methods. DATA SOURCES: PubMed, CINAHL, Web of Science, PsycINFO and Scopus. RESULTS: We included 47 reports (46 studies). CYP/caregivers' decision to access care was facilitated by CYP/caregivers' or their family/friends' ability to identify a health issue as warranting healthcare attention. Barriers to accessing care included perceived stigma (eg, being seen as a bad parent), embarrassment and discrimination experiences. CYP and caregivers believed longer opening hours could facilitate more timely access to care. Caregivers and HCPs reported that delayed or rejected referrals to secondary or adult care were a barrier to having needs met, especially for CYP with poor mental health. CYP and caregivers in numerous studies emphasised the importance of communication and trust with HCPs, including taking their concerns seriously, being knowledgeable and providing continuity of care for CYP. Common barriers reported across high-need subpopulations were caregivers needing knowledge and confidence to advocate for their child, gaps in HCP's knowledge and a lack of connectedness between primary and secondary care. CONCLUSIONS: Connecting general practices and community health workers/services, improving CYP/caregivers' understanding of common childhood conditions, addressing HCP's knowledge gaps in paediatric care and integrated approaches between primary and secondary care may reduce inequity in access.
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Cuidadores , Accesibilidad a los Servicios de Salud , Atención Primaria de Salud , Humanos , Niño , Adolescente , Reino Unido , Cuidadores/psicología , Personal de Salud/psicología , Actitud del Personal de Salud , Preescolar , Adulto Joven , Lactante , Acceso a Atención PrimariaRESUMEN
BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
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Antagonistas de Andrógenos , Anilidas , Nitrilos , Prostatectomía , Neoplasias de la Próstata , Compuestos de Tosilo , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/cirugía , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Andrógenos/administración & dosificación , Anciano , Compuestos de Tosilo/uso terapéutico , Compuestos de Tosilo/administración & dosificación , Persona de Mediana Edad , Anilidas/uso terapéutico , Anilidas/administración & dosificación , Nitrilos/uso terapéutico , Nitrilos/administración & dosificación , Oligopéptidos/administración & dosificación , Oligopéptidos/uso terapéutico , Hormona Liberadora de Gonadotropina/agonistas , Antígeno Prostático Específico/sangre , Terapia Combinada , Esquema de MedicaciónRESUMEN
BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.
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Antagonistas de Andrógenos , Anilidas , Nitrilos , Prostatectomía , Neoplasias de la Próstata , Compuestos de Tosilo , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Andrógenos/administración & dosificación , Anciano , Compuestos de Tosilo/uso terapéutico , Compuestos de Tosilo/administración & dosificación , Anilidas/uso terapéutico , Anilidas/administración & dosificación , Persona de Mediana Edad , Nitrilos/uso terapéutico , Nitrilos/administración & dosificación , Oligopéptidos/uso terapéutico , Oligopéptidos/administración & dosificación , Hormona Liberadora de Gonadotropina/agonistas , Terapia Combinada , Antígeno Prostático Específico/sangreRESUMEN
INTRODUCTION: There is a lack of evidence that the benefits of screening for atrial fibrillation (AF) outweigh the harms. Following the completion of the Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) pilot trial, the aim of the main SAFER trial is to establish whether population screening for AF reduces incidence of stroke risk. METHODS AND ANALYSIS: Approximately 82 000 people aged 70 years and over and not on oral anticoagulation are being recruited from general practices in England. Patients on the palliative care register or residents in a nursing home are excluded. Eligible people are identified using electronic patient records from general practices and sent an invitation and consent form to participate by post. Consenting participants are randomised at a ratio of 2:1 (control:intervention) with clustering by household. Those randomised to the intervention arm are sent an information leaflet inviting them to participate in screening, which involves use of a handheld single-lead ECG four times a day for 3 weeks. ECG traces identified by an algorithm as possible AF are reviewed by cardiologists. Participants with AF are seen by a general practitioner for consideration of anticoagulation. The primary outcome is stroke. Major secondary outcomes are: death, major bleeding and cardiovascular events. Follow-up will be via electronic health records for an average of 4 years. The primary analysis will be by intention-to-treat using time-to-event modelling. Results from this trial will be combined with follow-up data from the cluster-randomised pilot trial by fixed-effects meta-analysis. ETHICS AND DISSEMINATION: The London-Central National Health Service Research Ethics Committee (19/LO/1597) provided ethical approval. Dissemination will include public-friendly summaries, reports and engagement with the UK National Screening Committee. TRIAL REGISTRATION NUMBER: ISRCTN72104369.
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Fibrilación Atrial , Tamizaje Masivo , Accidente Cerebrovascular , Humanos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/complicaciones , Anciano , Accidente Cerebrovascular/prevención & control , Tamizaje Masivo/métodos , Electrocardiografía , Inglaterra/epidemiología , Femenino , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Anciano de 80 o más Años , Anticoagulantes/uso terapéuticoAsunto(s)
Brentuximab Vedotina , Micosis Fungoide , Neoplasias Cutáneas , Humanos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/administración & dosificación , Brentuximab Vedotina/uso terapéutico , Inmunoconjugados/administración & dosificación , Inmunoconjugados/uso terapéutico , Micosis Fungoide/tratamiento farmacológico , Retratamiento , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Although research has demonstrated that transport infrastructure development can have positive and negative health-related impacts, most of this research has not considered mental health and wellbeing separately from physical health. There is also limited understanding of whether and how any effects might be experienced differently across population groups, whether this differs according to the stage of development (e.g. planning, construction), and how changes to planned infrastructure may affect mental health and wellbeing. This paper presents a protocol for the Wellbeing Impact Study of HS2 (WISH2), which seeks to address these questions using a high-speed rail development in the UK as an applied example. WISH2 is a 10-year, integrated, longitudinal, mixed-methods project using general practices (primary medical care providers in the UK) as an avenue for participant recruitment and for providing a geographically defined population for which aggregated data on mental health indicators are available. The research comprises: (i) a combined longitudinal and repeated cross-sectional cohort study involving multiple waves of survey data collection and data from medical records; (ii) longitudinal, semi-structured interviews and focus groups with residents and community stakeholders from exposed areas; (iii) analysis of administrative data aggregated at the general practice population level; and (iv) health economic analysis of mental health and wellbeing impacts. The study findings will support the development of strategies to reduce negative impacts and/or enhance positive mental health and wellbeing impacts of high-speed rail developments and other large-scale infrastructure projects.
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Medicina Familiar y Comunitaria , Salud Mental , Humanos , Estudios Transversales , Recolección de Datos , Grupos FocalesRESUMEN
Polarization-independent phase modulators based upon liquid crystals (LCs) with a simple device architecture have long been desired for a range of optical applications. Recently, researchers have demonstrated a novel fabrication procedure using cholesteric LCs as a primer for achieving low polarization dependence coupled with a large phase modulation depth.
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OBJECTIVES: Medication is a common cause of preventable medical harm in pediatric inpatients. This study aimed to examine the sociotechnical system surrounding pediatric medicines management, to identify potential gaps in this system and how these might contribute to adverse drug events (ADEs). METHODS: An exploratory prospective qualitative study in pediatric wards in three hospitals in the north of England was conducted between October 2020 and May 2022. Analysis included a documentary analysis of 72 policies and procedures and analysis of field notes from 60 hours of participant observation. The cognitive work analysis prompt framework was used to generate a work domain analysis (WDA) and identify potential contributory factors to ADEs. RESULTS: The WDA identified 2 functional purposes, 7 value/priority measures, 6 purpose-related functions, 11 object-related processes and 14 objects. Structured means-ends connections supported identification of 3 potential contributory factors-resource limitations, cognitive demands, and adaptation of processes. The lack of resources (equipment, materials, knowledge, and experience) created an environment where distractions and interruptions were unavoidable. Families helped provide practical support in medicines administration but were largely unacknowledged at an organizational level. There was a lack of teamwork with regards to medication with different professionals responsible for different parts of the system. Mandated safety checks on medicines were frequently omitted because of limited resources and perceived redundancy. Interventions to support adherence to safety policies were also often bypassed because they created more work. CONCLUSIONS: The WDA has provided insights into the complex system of medication safety for children in hospital and has facilitated the identification of potential contributory factors to ADEs. We therefore advocate (in priority order) for processes to involve parents in the care of their children in hospital, development of skill-mix interventions to ensure appropriate expertise is available where it is needed, and modified checking procedures to permit staff to use their skills and judgment effectively and efficiently.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Errores de Medicación , Humanos , Niño , Errores de Medicación/prevención & control , Estudios Prospectivos , Pacientes Internos , Preparaciones FarmacéuticasRESUMEN
Over the past decade, there has been a rising interest in utilizing functionalized porous polymers for sensor applications. By incorporating functional groups into nanostructured materials like hydrogels, nanosheets, and nanopores, exciting new opportunities have emerged for biomarker detection. The ability of functionalized polymers to undergo physical changes and deformations makes them perfect for modulating optical signals. This chemical mechanism enables the creation of biocompatible sensors for in situ biomarker measurement. Here a comprehensive overview of the current publication trends is provided in functionalized polymers, encompassing functional groups that can induce measurable physical deformations. It explores various materials categorized based on their detection targets, which include proteins, carbohydrates, ions, and deoxyribonucleic acid. As such, this work serves as a valuable reference for the development of functionalized polymer-based sensors.
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Nanoporos , Polímeros , Proteínas , Carbohidratos , HidrogelesRESUMEN
CD8 T cells are emerging as important mediators in atherosclerosis and cardiovascular disease (CVD). Immune activation may play a particular role in people with HIV (PWH) who are at an increased risk of CVD, even after controlling for known CVD risk factors. Latent CMV infection is associated with increased CVD risk for both PWH and people without HIV, and human CMV-specific CD4 and CD8 T cells are enriched for an immunosenescent phenotype. We previously showed that CMV coinfection in PWH promotes vascular homing and activation of inflammatory CD4 T cells through the CD2-LFA-3 axis. However, the role of CD2/LFA3 costimulation of CD8 T cells in PWH with CMV has yet to be described. In the present study, we demonstrate that CD2 expression on CX3CR1+CD57+CD28- inflammescent CD8 T cells is increased on cells from CMV-seropositive PWH. In vitro CD2/LFA-3 costimulation enhances TCR-mediated activation of these inflammatory CD8 memory T cells. Finally, we show that LFA-3 is highly expressed in aortas of SIV-infected rhesus macaques and in atherosclerotic plaques of people without HIV. Our findings are consistent with a model in which CMV infection enhances CD2 expression on highly proinflammatory CD8 T cells that can then be stimulated by LFA-3 expressed in the vasculature, even in the absence of CD28 costimulation. This model, in which CMV infection exacerbates toxic cytokine and granzyme production by CD8 T cells within the vasculature, highlights a potential therapeutic target in atherosclerosis development and progression, especially for PWH.
Asunto(s)
Aterosclerosis , Enfermedades Cardiovasculares , Infecciones por Citomegalovirus , Infecciones por VIH , Animales , Humanos , Antígenos CD28/metabolismo , Infecciones por VIH/tratamiento farmacológico , Citomegalovirus , Antígenos CD58/metabolismo , Macaca mulatta , Linfocitos T CD8-positivos , Linfocitos T CD4-Positivos , Aterosclerosis/metabolismoRESUMEN
INTRODUCTION: Almost all patients receiving mechanical ventilation (MV) in intensive care units (ICUs) require analgesia and sedation. The most widely used sedative drug is propofol, but there is uncertainty whether alpha2-agonists are superior. The alpha 2 agonists for sedation to produce better outcomes from critical illness (A2B) trial aims to determine whether clonidine or dexmedetomidine (or both) are clinically and cost-effective in MV ICU patients compared with usual care. METHODS AND ANALYSIS: Adult ICU patients within 48 hours of starting MV, expected to require at least 24 hours further MV, are randomised in an open-label three arm trial to receive propofol (usual care) or clonidine or dexmedetomidine as primary sedative, plus analgesia according to local practice. Exclusions include patients with primary brain injury; postcardiac arrest; other neurological conditions; or bradycardia. Unless clinically contraindicated, sedation is titrated using weight-based dosing guidance to achieve a Richmond-Agitation-Sedation score of -2 or greater as early as considered safe by clinicians. The primary outcome is time to successful extubation. Secondary ICU outcomes include delirium and coma incidence/duration, sedation quality, predefined adverse events, mortality and ICU length of stay. Post-ICU outcomes include mortality, anxiety and depression, post-traumatic stress, cognitive function and health-related quality of life at 6-month follow-up. A process evaluation and health economic evaluation are embedded in the trial.The analytic framework uses a hierarchical approach to maximise efficiency and control type I error. Stage 1 tests whether each alpha2-agonist is superior to propofol. If either/both interventions are superior, stages 2 and 3 testing explores which alpha2-agonist is more effective. To detect a mean difference of 2 days in MV duration, we aim to recruit 1437 patients (479 per group) in 40-50 UK ICUs. ETHICS AND DISSEMINATION: The Scotland A REC approved the trial (18/SS/0085). We use a surrogate decision-maker or deferred consent model consistent with UK law. Dissemination will be via publications, presentations and updated guidelines. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03653832.
Asunto(s)
Dexmedetomidina , Propofol , Adulto , Humanos , Propofol/uso terapéutico , Dexmedetomidina/uso terapéutico , Análisis Costo-Beneficio , Clonidina/uso terapéutico , Enfermedad Crítica/terapia , Calidad de Vida , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Dolor/inducido químicamente , Unidades de Cuidados Intensivos , Reino Unido , Respiración Artificial , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
Exposure to child maltreatment (CM), and parental domestic violence and abuse (DVA), impose considerable adverse life outcomes in both the short and long term, yet, the extent and effects of their co-occurrence on outcomes have not been comprehensively quantified. This study describes the analysis of data from the Avon Longitudinal Study of Parents and Children, quantifying the prevalence of CM, parental DVA, co-occurrence rates, and the impact of different combinations of childhood exposures on life outcomes (health, economic, and likelihood of perpetrating intimate partner violence as a young person). Childhood exposure prevalences were estimated at 41.7% for any form of CM, 19.3% for parental DVA, and 49.0% for exposure to at least one form of CM and/or parental DVA. Co-occurring parental DVA was reported in 21%-42% of CM-exposed households. Sexual abuse was reported in 2% of parental DVA-exposed households, whilst co-occurrence of other forms of CM ranged between 19% and 41%. Co-occurring CM and parental DVA exposures were associated with increased risks of drug use, anxiety, depression, smoking, unemployment, social welfare use, and perpetration of intimate partner violence as a young person - highlighting the intergenerational effects of exposure. Increased risks across a wider range of adverse outcomes were associated with child-reported awareness of parental DVA, compared to parent-reported DVA exposure. The high cumulative prevalence of childhood exposure to CM and/or parental DVA, and the scale of the resulting adverse impacts emphasise the need for policies and family interventions sensitive to the possibility of co-occurring forms of abuse.