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Four medications with neuroprotective disease-modifying effects are now in use for motor neuron disease (MND). With FDA approvals for tofersen, relyvrio and edaravone in just the past year, 2022 ended a quarter of a century when riluzole was the sole such drug to offer to patients. The acceleration of approvals may mean we are witnessing the beginning of a step-change in how MND can be treated. Improvements in understanding underlying disease biology has led to more therapies being developed to target specific and multiple disease mechanisms. Consideration for how the pipeline of new therapeutic agents coming through in clinical and preclinical development can be more effectively evaluated with biomarkers, advances in patient stratification and clinical trial design pave the way for more successful translation for this archetypal complex neurodegenerative disease. While it must be cautioned that only slowed rates of progression have so far been demonstrated, pre-empting rapid neurodegeneration by using neurofilament biomarkers to signal when to treat, as is currently being trialled with tofersen, may be more effective for patients with known genetic predisposition to MND. Early intervention with personalized medicines could mean that for some patients at least, in future we may be able to substantially treat what is considered by many to be one of the most distressing diseases in medicine.
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Enfermedad de la Neurona Motora , Fármacos Neuroprotectores , Humanos , Enfermedad de la Neurona Motora/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/farmacología , AnimalesRESUMEN
The majority of amyotrophic lateral sclerosis (ALS) is caused by a complex gene-environment interaction. Despite high estimates of heritability, the genetic basis of disease in the majority of ALS patients are unknown. This limits the development of targeted genetic therapies which require an understanding of patient-specific genetic drivers. There is good evidence that the majority of these missing genetic risk factors are likely to be found within the non-coding genome. However, a major challenge in the discovery of non-coding risk variants is determining which variants are functional in which specific CNS cell type. We summarise current discoveries of ALS-associated genetic drivers within the non-coding genome and we make the case that improved cell-specific annotation of genomic function is required to advance this field, particularly via single-cell epigenetic profiling and spatial transcriptomics. We highlight the example of TBK1 where an apparent paradox exists between pathogenic coding variants which cause loss of protein function, and protective non-coding variants which cause reduced gene expression; the paradox is resolved when it is understood that the non-coding variants are acting primarily via change in gene expression within microglia, and the effect of coding variants is most prominent in neurons. We propose that cell-specific functional annotation of ALS-associated genetic variants will accelerate discovery of the genetic architecture underpinning disease in the vast majority of patients.
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Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/genética , Humanos , Animales , Predisposición Genética a la Enfermedad/genéticaRESUMEN
Here, we establish a CT-radiomics based method for application in invasive, orthotopic rodent brain tumour models. Twenty four NOD/SCID mice were implanted with U87R-Luc2 GBM cells and longitudinally imaged via contrast enhanced (CE-CT) imaging. Pyradiomics was employed to extract CT-radiomic features from the tumour-implanted hemisphere and non-tumour-implanted hemisphere of acquired CT-scans. Inter-correlated features were removed (Spearman correlation > 0.85) and remaining features underwent predictive analysis (recursive feature elimination or Boruta algorithm). An area under the curve of the receiver operating characteristic curve was implemented to evaluate radiomic features for their capacity to predict defined outcomes. Firstly, we identified a subset of radiomic features which distinguish the tumour-implanted hemisphere and non- tumour-implanted hemisphere (i.e, tumour presence from normal tissue). Secondly, we successfully translate preclinical CT-radiomic pipelines to GBM patient CT scans (n = 10), identifying similar trends in tumour-specific feature intensities (E.g. 'glszm Zone Entropy'), thereby suggesting a mouse-to-human species conservation (a conservation of radiomic features across species). Thirdly, comparison of features across timepoints identify features which support preclinical tumour detection earlier than is possible by visual assessment of CT scans. This work establishes robust, preclinical CT-radiomic pipelines and describes the application of CE-CT for in-depth orthotopic brain tumour monitoring. Overall we provide evidence for the role of pre-clinical 'discovery' radiomics in the neuro-oncology space.
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Neoplasias Encefálicas , Radiómica , Humanos , Animales , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Encefálicas/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Transfer of all severe TBI patients to a neurosurgical unit (NSU) has been advocated irrespective of levels of complexity and prognostic factors. Previous publications have suggested that only 50% of severe TBI patients in Ireland were managed in NSUs. AIMS: This study aims to audit severe TBI referrals to the National Neurosurgical Centre, to evaluate reasons for nonacceptance, assess for differences in the transferred and not transferred cohorts and to analyse observed and expected mortality rates. METHODS: Data on all patients with TBI referred in 2021 were prospectively collected using an electronic referral system. Patients with severe TBI (GCS ≤ 8 and AIS ≥ 3) were included and dichotomised into transferred and not transferred cohorts. RESULTS: Of 118 patients referred with severe TBI, 45 patients (38.1%) were transferred to the neurosurgical centre. Patients in the transferred cohort were significantly younger (p < 0.001), had a higher GCS score (p < 0.001) and a lower proportion of bilaterally unreactive pupils (p < 0.001) compared to the not transferred cohort. 93% (68/73) of those not transferred were either >65 years old, or had bilaterally unreactive pupils, or both. Based on the IMPACT model, the observed to expected mortality ratios in the transferred and not transferred cohorts were 0.65 (95% CI 0.25-1.05) and 0.88 (95% CI 0.65-1.11) respectively. CONCLUSION: The observed mortality rate for severe TBI in Ireland was similar to or better than expected mortality rates when adjusted for important prognostic factors. 93% of severe TBI patients not transferred to a neurosurgical centre were either elderly or had bilaterally unreactive pupils or both. These patients have an extremely poor prognosis and recommendation for transfer cannot be made based on current available evidence.
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Lesiones Traumáticas del Encéfalo , Humanos , Anciano , Irlanda/epidemiología , Escala de Coma de Glasgow , Lesiones Traumáticas del Encéfalo/diagnóstico , Lesiones Traumáticas del Encéfalo/cirugía , Pronóstico , Derivación y ConsultaRESUMEN
Post-assessments psychometric reports are a vital component of the assessment cycle to ensure that assessments are reliable, valid and fair to make appropriate pass-fail decisions. Students' scores can be summarised by examination of frequency distributions, central tendency measures and dispersion measures. Item discrimination indicies to assess the quality of items, and distractors that differentiate between students achieving or not achieving the learning outcomes are key. Estimating individual item reliability and item validity indices can maximise test-score reliability and validity. Test accuracy can be evaluated by assessing test reliability, consistency and validity and standard error of measurement can be used to measure the variation. Standard setting, even by experts, may be unreliable and reality checks such as the Hofstee method, P values and correlation analysis can improve validity. The Rasch model of student ability and item difficulty assists in modifying assessment questions, pinpointing areas for additional instruction. We propose 12 tips to support test developers in interpreting structured psychometric reports, including analysis and refinement of flawed items and ensuring fair assessments with accurate and defensible marks.
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Evaluación Educacional , Estudiantes de Medicina , Humanos , Psicometría , Reproducibilidad de los Resultados , Evaluación Educacional/métodos , AprendizajeRESUMEN
BACKGROUND: Since the COVID-19 pandemic, post-COVID syndrome (persistent symptoms/complications lasting >12 weeks) continues to pose medical and economic challenges. In military personnel, where optimal fitness is crucial, prolonged limitations affecting their ability to perform duties has occupational and psychological implications, impacting deployability and retention. Research investigating post-COVID syndrome exercise capacity and cardiopulmonary effects in military personnel is limited. METHODS: UK military personnel were recruited from the Defence Medical Services COVID-19 Recovery Service. Participants were separated into healthy controls without prior SARS-CoV-2 infection (group one), and participants with prolonged symptoms (>12 weeks) after mild-moderate (community-treated) and severe (hospitalised) COVID-19 illness (group 2 and 3, respectively). Participants underwent cardiac magnetic resonance imaging (CMR) and spectroscopy, echocardiography, pulmonary function testing and cardiopulmonary exercise testing (CPET). RESULTS: 113 participants were recruited. When compared in ordered groups (one to three), CPET showed stepwise decreases in peak work, work at VT1 and VO2 max (all p < 0.01). There were stepwise decreases in FVC (p = 0.002), FEV1 (p = 0.005), TLC (p = 0.002), VA (p < 0.001), and DLCO (p < 0.002), and a stepwise increase in A-a gradient (p < 0.001). CMR showed stepwise decreases in LV/RV volumes, stroke volumes and LV mass (LVEDVi/RVEDVi p < 0.001; LVSV p = 0.003; RVSV p = 0.001; LV mass index p = 0.049). CONCLUSION: In an active military population, post-COVID syndrome is linked to subclinical changes in maximal exercise capacity. Alongside disease specific changes, many of these findings share the phenotype of deconditioning following prolonged illness or bedrest. Partitioning of the relative contribution of pathological changes from COVID-19 and deconditioning is challenging in post-COVID syndrome recovery.
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COVID-19 , Personal Militar , Humanos , Tolerancia al Ejercicio , Pandemias , SARS-CoV-2 , Pulmón , Prueba de EsfuerzoRESUMEN
Objectives: To measure intra-standard-setter variability and assess the variations between the pass marks obtained from Angoff ratings, guided by the latent trait theory as the theoretical model. Methods: A non-experimental cross-sectional study was conducted to achieve the purpose of the study. Two knowledge-based tests were administered to 358 final-year medical students (223 females and 135 males) as part of their normal summative programme of assessments. The results of judgmental standard-setting using the Angoff method, which is widely used in medical schools, were used to determine intra-standard-setter inconsistency using the three-parameter item response theory (IRT). Permission for this study was granted by the local Research Ethics Committee of the University of Nottingham. To ensure anonymity and confidentiality, all identifiers at the student level were removed before the data were analysed. Results: The results of this study confirm that the three-parameter IRT can be used to analyse the results of individual judgmental standard setters. Overall, standard-setters behaved fairly consistently in both tests. The mean Angoff ratings and conditional probability were strongly positively correlated, which is a matter of inter-standard-setter validity. Conclusions: We recommend that assessment providers adopt the methodology used in this study to help determine inter and intra-judgmental inconsistencies across standard setters to minimise the number of false positive and false negative decisions.
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Rendimiento Académico , Educación Médica , Evaluación de Programas y Proyectos de Salud , Humanos , Masculino , Femenino , Estudiantes de Medicina , Educación Médica/normas , Estudios Transversales , Modelos TeóricosRESUMEN
OBJECTIVE: The IMPACT-ALS survey collected the experiences of people living with ALS (plwALS) across nine European countries. We aimed to better understand the functional burden of ALS to ensure the experiences of plwALS inform the development of person-centered therapies. METHODS: The content was informed by the US IMPACT-ALS survey, with adjustments relevant to the European population. Questionnaires consisted of four modules, each of which was pilot tested in advance of distribution. Data were captured using the Qualtrics software and were analyzed in SPSS. RESULTS: 857 respondents completed the survey, with a participation rate ranging from 0.2% to 6.3% across the nine participating countries. The majority were male and aged 55-74 years old. In the previous 2 weeks, symptoms experienced included weakness (81%), fatigue (61%), speech impairment (38%), pain (27%), and depression and other mood changes (23%). Eighty-two percent of respondents reported fears, of which the most common were leaving family too soon (68%) and death from respiratory failure (50%). Lifestyle changes since diagnosis were reported by 89% of respondents, with less time spent doing most daily activities but more time on the internet (81%), reading (56%) and communicating with family and friends (55%). Stopping progression of ALS was the most desired impact for a new therapy for 68% respondents. CONCLUSIONS: The European IMPACT-ALS survey has generated insights into the complex experiences of plwALS. The data provide unique patient perspectives on common symptoms, fears, functional limitations, lifestyle changes, and wishes for future therapies that will enhance patient-centric care in ALS.
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The Alaska Cancer Registry (ACR) conducted a study to identify and correct the vital status of certain cases in its database. These cases were reported as deceased by the original reporting health care facility but were not identified as being deceased using routine death resources. Cases incorrectly reported as deceased are referred to here as "zombies," as they are the "living dead" in the registry database. Zombie cases are problematic as they contribute toward artificially high mortality rates and artificially low survival rates. They are the opposite of "immortals," a term used in the literature to indicate cases that are alive in the registry database but are actually deceased. To start the study, ACR first linked its registry database to the state mortality database, the Social Security Death Index (SSDI), and the National Death Index (NDI). ACR has 3 non-North American Association of Central Cancer Registries (NAACCR) flag fields indicating the status of the linkage with these 3 data sources. ACR was able to identify zombie candidates by selecting deceased cases that did not successfully link with any of these 3 mortality data sources. After all 3 linkages were completed, ACR identified 20 zombie candidates out of 19,590 deceased cases. ACR researched these patients in several state-specific databases and found that 14 of them were true zombies and changed their vital status to alive. Of the remaining 6 deceased cases, 3 died out of country, 2 died in state, and 1 died out of state. ACR recommends that other state registries consider adding these 3 non-NAACCR mortality database flag fields, as they would make searching for zombie cases fairly routine. It would also serve as a way to perform a quality control check on deceased cases that accidentally become alive again after consolidation with a new facility source record.
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Neoplasias , Humanos , Sistema de Registros , Tasa de Supervivencia , Alaska , Bases de Datos Factuales , Neoplasias/epidemiologíaRESUMEN
Cities can host significant biological diversity. Yet, urbanisation leads to the loss of habitats, species, and functional groups. Understanding how multiple taxa respond to urbanisation globally is essential to promote and conserve biodiversity in cities. Using a dataset encompassing six terrestrial faunal taxa (amphibians, bats, bees, birds, carabid beetles and reptiles) across 379 cities on 6 continents, we show that urbanisation produces taxon-specific changes in trait composition, with traits related to reproductive strategy showing the strongest response. Our findings suggest that urbanisation results in four trait syndromes (mobile generalists, site specialists, central place foragers, and mobile specialists), with resources associated with reproduction and diet likely driving patterns in traits associated with mobility and body size. Functional diversity measures showed varied responses, leading to shifts in trait space likely driven by critical resource distribution and abundance, and taxon-specific trait syndromes. Maximising opportunities to support taxa with different urban trait syndromes should be pivotal in conservation and management programmes within and among cities. This will reduce the likelihood of biotic homogenisation and helps ensure that urban environments have the capacity to respond to future challenges. These actions are critical to reframe the role of cities in global biodiversity loss.
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Quirópteros , Urbanización , Animales , Abejas , Síndrome , Ecosistema , Biodiversidad , AvesRESUMEN
Objective: Noninvasive ventilation (NIV) improves survival and quality of life in motor neuron disease (MND), but many patients fail to receive effective ventilation. This study aimed to map the respiratory clinical care for MND patients at a service and individual healthcare professional (HCP) level to understand where attention may be needed to ensure all patients receive optimal care. Methods: Two online surveys of HCPs working with MND patients in the UK were conducted. Survey 1 targeted HCPs providing specialist MND care. Survey 2 targeted HCPs working in respiratory/ventilation services and community teams. Data were analysed using descriptive and inferential statistics. Results: Responses from 55 HCPs providing specialist MND care who worked at 21 MND care centres and networks and 13 Scotland Health Boards were analysed from Survey 1. Responses from 85 HCPs from respiratory/ventilation services and 73 HCPs from community teams, representing 97 services, were analysed from Survey 2. Significant differences in practice were identified at each stage of the respiratory care pathway as well as evidence of the need for improvement. This included when patients were referred to respiratory services, the time taken waiting to commence NIV, the availability of sufficient NIV equipment and provision of services, particularly out of hours. Conclusion: We have highlighted significant disparity in MND respiratory care practices. Increased awareness of the factors that influence NIV success and the performance of individuals and services is important for optimal practice.
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BACKGROUND: Fractional flow reserve-computed tomography (FFR-CT) is endorsed by UK and U.S. chest pain guidelines, but its clinical effectiveness and cost benefit in real-world practice are unknown. OBJECTIVES: The purpose of this study was to audit the use of FFR-CT in clinical practice against England's National Institute for Health and Care Excellence guidance and assess its diagnostic accuracy and cost. METHODS: A multicenter audit was undertaken covering the 3 years when FFR-CT was centrally funded in England. For coronary computed tomographic angiograms (CCTAs) submitted for FFR-CT analysis, centers provided data on symptoms, CCTA and FFR-CT findings, and subsequent management. Audit standards included using FFR-CT only in patients with stable chest pain and equivocal stenosis (50%-69%). Diagnostic accuracy was evaluated against invasive FFR, when performed. Follow-up for nonfatal myocardial infarction and all-cause mortality was undertaken. The cost of an FFR-CT strategy was compared to alternative stress imaging pathways using cost analysis modeling. RESULTS: A total of 2,298 CCTAs from 12 centers underwent FFR-CT analysis. Stable chest pain was the main symptom in 77%, and 40% had equivocal stenosis. Positive and negative predictive values of FFR-CT were 49% and 76%, respectively. A total of 46 events (2%) occurred over a mean follow-up period of 17 months; FFR-CT (cutoff: 0.80) was not predictive. The FFR-CT strategy costs £2,102 per patient compared with an average of £1,411 for stress imaging. CONCLUSIONS: In clinical practice, the National Institute for Health and Care Excellence criteria for using FFR-CT were met in three-fourths of patients for symptoms and 40% for stenosis. FFR-CT had a low positive predictive value, making its use potentially more expensive than conventional stress imaging strategies.
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Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Reserva del Flujo Fraccional Miocárdico , Humanos , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/terapia , Constricción Patológica , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X , Angiografía Coronaria/métodos , Dolor en el Pecho , Costos y Análisis de Costo , Angiografía por Tomografía Computarizada/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapiaRESUMEN
Genetic diversity among and within populations of all species is necessary for people and nature to survive and thrive in a changing world. Over the past three years, commitments for conserving genetic diversity have become more ambitious and specific under the Convention on Biological Diversity's (CBD) draft post-2020 global biodiversity framework (GBF). This Perspective article comments on how goals and targets of the GBF have evolved, the improvements that are still needed, lessons learned from this process, and connections between goals and targets and the actions and reporting that will be needed to maintain, protect, manage and monitor genetic diversity. It is possible and necessary that the GBF strives to maintain genetic diversity within and among populations of all species, to restore genetic connectivity, and to develop national genetic conservation strategies, and to report on these using proposed, feasible indicators.
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PURPOSE: Little is known about cancer survivors' needs in Alaska. To address this knowledge gap, the Alaska Cancer Partnership conducted a needs assessment survey; our objectives were to identify unmet needs of Alaska's cancer survivors; identify survivor sub-populations that might benefit from targeted interventions or programming; and develop recommendations for public health and community organizations and healthcare providers for addressing cancer survivors' unmet needs. METHODS: Cancer survivors were identified using data from the Alaska Cancer Registry. A random sample of 2,600 individuals was selected to receive the survey, which assessed unmet needs across the following domains: information needs and medical care issues; quality of life; emotional and relationship issues related to cancer diagnoses; and support services. We calculated descriptive statistics for survey responses and assessed demographic predictors of unmet needs using Poisson regression. RESULTS: We received 335 survey responses, for a response of 13.7%. Only 29.9% of cancer survivors expressed that all their needs were met. The most highly ranked unmet needs were as follows: help to reduce stress in life; to know doctors were coordinating care; and managing concerns about cancer coming back. After adjustment, men, adults younger than 65 at diagnosis, Alaska Native people, survivors still receiving or who had recently received care, and people who had to travel 50+ miles for most of their care had significantly greater unmet needs than their comparison groups. CONCLUSION: This assessment provided some of the first information regarding the needs of Alaska's cancer survivors. These results will be used by Alaska Cancer Partnership members across the state to inform healthcare delivery, programs, and public health messaging to support survivors.
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Supervivientes de Cáncer , Neoplasias , Adulto , Masculino , Humanos , Evaluación de Necesidades , Calidad de Vida , Alaska/epidemiología , Estudios Transversales , Encuestas y Cuestionarios , Neoplasias/epidemiología , Neoplasias/terapia , Neoplasias/psicologíaRESUMEN
The longer-term effects of COVID-19 on lung physiology remain poorly understood. Here, a new technique, computed cardiopulmonography (CCP), was used to study two COVID-19 cohorts (MCOVID and C-MORE-LP) at both â¼6 and â¼12 mo after infection. CCP is comprised of two components. The first is collection of highly precise, highly time-resolved measurements of gas exchange with a purpose-built molecular flow sensor based around laser absorption spectroscopy. The second component is estimation of physiological parameters by fitting a cardiopulmonary model to the data set. The measurement protocol involved 7 min of breathing air followed by 5 min of breathing pure O2. One hundred seventy-eight participants were studied, with 97 returning for a repeat assessment. One hundred twenty-six arterial blood gas samples were drawn from MCOVID participants. For participants who had required intensive care and/or invasive mechanical ventilation, there was a significant increase in anatomical dead space of â¼30 mL and a significant increase in alveolar-to-arterial Po2 gradient of â¼0.9 kPa relative to control participants. Those who had been hospitalized had reductions in functional residual capacity of â¼15%. Irrespectively of COVID-19 severity, participants who had had COVID-19 demonstrated a modest increase in ventilation inhomogeneity, broadly equivalent to that associated with 15 yr of aging. This study illustrates the capability of CCP to study aspects of lung function not so easily addressed through standard clinical lung function tests. However, without measurements before infection, it is not possible to conclude whether the findings relate to the effects of COVID-19 or whether they constitute risk factors for more serious disease.NEW & NOTEWORTHY This study used a novel technique, computed cardiopulmonography, to study the lungs of patients who have had COVID-19. Depending on severity of infection, there were increases in anatomical dead space, reductions in absolute lung volumes, and increases in ventilation inhomogeneity broadly equivalent to those associated with 15 yr of aging. However, without measurements taken before infection, it is unclear whether the changes result from COVID-19 infection or are risk factors for more severe disease.