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Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high-value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterized. Protein-protein interactions elevate solution viscosity in high-concentration formulations, impacting physicochemical stability, manufacturability, and the injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterized. A computational and experimental framework was applied to measure molecular descriptors impacting their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high-concentration mAb formulations. While poorer conformational and colloidal stability and elevated solution viscosity were observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability.
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Sleep research and sleep medicine have benefited from the use of polysomnography but have also suffered from an overreliance on the conventional, polysomnography-defined sleep stages. For example, reports of sleep-specific brain activity patterns have, with few exceptions, been constrained by assessing brain function as it relates to the conventional sleep stages. This limits the variety of sleep states and underlying activity patterns that one can discover. If undiscovered brain activity patterns exist during sleep, then removing the constraint of a stage-specific analysis may uncover them. The current study used all-night functional magnetic resonance imaging sleep data and defined sleep behaviorally with auditory arousal threshold (AAT) to begin to search for new brain states. It was hypothesized that, during sleep compared to wakefulness, corticocortical functional correlations would decrease. Functional correlation values calculated in a window immediately before the determination of AAT were entered into a linear mixed effects model, allowing multiple arousals across the night per subject into the analysis. The hypothesis was supported using both correlation matrices of brain networks and single seed-region analyses showing whole-brain maps. This represents a novel approach to studying the neuroanatomical correlates of sleep with high spatial resolution by defining sleep in a way that was independent from the conventional sleep stages. This work provides initial evidence to justify searching for sleep stages that are more neuroanatomically localized and unrelated to the conventional sleep stages.
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INTRODUCTION: Timely identification of dying in motor neurone disease enables optimal care, yet we know that healthcare professionals can fail to recognise when death is approaching. Clinical factors help predict the end of life in other terminal conditions. Examining these principles in motor neurone disease would help guide more accurate recognition of this critical phase. AIM: To examine and map out what is known about dying in patients with motor neurone disease, and the recognition of dying by healthcare professionals. DESIGN: A scoping review was conducted following the Arksey and O'Malley methodological framework. DATA SOURCES: Four electronic databases (MEDLINE, Scopus, PsycINFO and CINAHL) and grey literature were searched on the 10th May 2023. Reference lists and citations were also reviewed. RESULTS: From 1512 articles, 13 studies were included. Dyspnoea, anxiety and pain were the most common symptoms associated with the dying phase. Worsening respiratory function, the development of specific new symptoms and deteriorating symptom control suggested approaching death. No studies reported changes in vital signs or biomarkers associated with dying. Barriers to the recognition of dying by healthcare professionals included a rapid and unpredictable terminal decline. CONCLUSIONS: Dying in motor neurone disease is associated with patterns of symptoms and signs, however evidence is limited compared with other terminal conditions and requires further exploration. The characteristic sudden and unpredictable terminal decline is a key barrier to recognition of dying by healthcare professionals. Optimising advance care planning is one approach to navigate these complex, unpredictable clinical situations.
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BACKGROUND: Preconception or antenatal lifestyle interventions in women with obesity may prevent adverse cardiovascular outcomes in the child, including cardiac remodelling. We undertook a systematic review of the existing data to examine the impact of randomised controlled trials of lifestyle interventions in pregnant women with obesity on offspring cardiac remodelling and related parameters of cardiovascular health. METHODS: This review was registered with PROSPERO (CRD42023454762) and aligns with PRISMA guidelines. PubMed, Embase, and previous reviews were systematically searched. Follow-up studies from randomised trials of lifestyle interventions in pregnant women with obesity, which included offspring cardiac remodelling or related cardiovascular parameters as outcome measures, were included based on pre-defined inclusion criteria. RESULTS: Eight studies from five randomised controlled trials were included after screening 3252 articles. Interventions included antenatal exercise (n = 2), diet and physical activity (n = 2), and preconception diet and physical activity (n = 1). Children were <2-months to 3-7-years-old, with sample sizes ranging between n = 18-404. Reduced cardiac remodelling, with reduced interventricular septal wall thickness, was consistently reported. Some studies identified improved systolic and diastolic function and a reduced resting heart rate. Risk of bias analyses rated all studies as 'fair' (some risk of bias). A high loss-to-follow-up was a common limitation. CONCLUSION: Although there is some evidence to suggest that lifestyle interventions in women with obesity may limit offspring cardiac remodelling, further high-quality longitudinal studies with larger sample sizes are required to confirm these observations and to determine whether these changes persist to adulthood. Child offspring cardiovascular health benefits of preconception and antenatal lifestyle interventions in women with obesity.
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Obesidad Materna , Humanos , Femenino , Embarazo , Atención Preconceptiva/métodos , Estilo de Vida , Niño , Enfermedades Cardiovasculares/prevención & control , Remodelación Ventricular/fisiología , Atención Prenatal/métodos , Ejercicio Físico/fisiología , Complicaciones del Embarazo/prevención & control , Preescolar , Efectos Tardíos de la Exposición Prenatal , Adulto , Lactante , Obesidad/complicaciones , Obesidad/fisiopatologíaRESUMEN
BACKGROUND: Fetal alcohol spectrum disorders (FASD) include a range of neurocognitive and behavioral impairments resulting from prenatal alcohol exposure (PAE). Among the PAE-related cognitive deficits, number processing is particularly affected. This study examines alterations in number processing networks and whether changes in functional connectivity mediate the adverse effects of PAE on arithmetic performance. METHODS: Magnetic resonance imaging (MRI) was acquired in 57 children (mean (SD) age = 11.3 (+0.9) yr), 38 with FASD (19 fetal alcohol syndrome (FAS) or partial FAS (PFAS), 19 heavily exposed (HE)) and 19 controls. Whole-brain correlation analyses were performed from five seeds located in regions involved in number processing. RESULTS: Children with FAS/PFAS showed dose-dependent reductions in resting state functional connectivity between the seed in the right (R) posterior superior parietal lobule and a cluster in the left (L) inferior frontal gyrus, and between a seed in the R horizontal intraparietal sulcus and clusters in the R precentral gyrus and L cerebellar lobule VI. HE children showed lower resting state functional connectivity in a subset of these regions. Lower functional connectivity in the two fronto-parietal connections partially mediated the adverse effects of PAE on arithmetic performance. CONCLUSION: This study demonstrates PAE-related functional connectivity impairments in functional networks involved in number processing. The weaker connectivity between the R posterior superior parietal lobule and the L inferior frontal gyrus suggests that impaired verbal processing and visuospatial working memory may play a role in number processing deficits, while weaker connectivity between the R intraparietal sulcus and the R precentral gyrus points to poorer finger-based numerical representation, which has been linked to arithmetic computational skills.
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The Stroop task is a well-established tool to investigate the influence of competing visual categories on decision making. Neuroimaging as well as rTMS studies have demonstrated the involvement of parietal structures, particularly the intraparietal sulcus (IPS), in this task. Given its reliability, the numerical Stroop task was used to compare the effects of different TMS targeting approaches by Sack and colleagues (Sack AT 2009), who elegantly demonstrated the superiority of individualized fMRI targeting. We performed the present study to test whether fMRI-guided rTMS effects on numerical Stroop task performance could still be observed while using more advanced techniques that have emerged in the last decade (e.g., electrical sham, robotic coil holder system, etc.). To do so we used a traditional reaction time analysis and we performed, post-hoc, a more advanced comprehensive drift diffusion modeling approach. Fifteen participants performed the numerical Stroop task while active or sham 10 Hz rTMS was applied over the region of the right intraparietal sulcus (IPS) showing the strongest functional activation in the Incongruent > Congruent contrast. This target was determined based on individualized fMRI data collected during a separate session. Contrary to our assumption, the classical reaction time analysis did not show any superiority of active rTMS over sham, probably due to confounds such as potential cumulative rTMS effects, and the effect of practice. However, the modeling approach revealed a robust effect of rTMS on the drift rate variable, suggesting differential processing of congruent and incongruent properties in perceptual decision-making, and more generally, illustrating that more advanced computational analysis of performance can elucidate the effects of rTMS on the brain where simpler methods may not.
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Imagen por Resonancia Magnética , Tiempo de Reacción , Test de Stroop , Estimulación Magnética Transcraneal , Humanos , Imagen por Resonancia Magnética/métodos , Estimulación Magnética Transcraneal/métodos , Masculino , Femenino , Adulto , Tiempo de Reacción/fisiología , Adulto Joven , Lóbulo Parietal/fisiología , Lóbulo Parietal/diagnóstico por imagen , Toma de Decisiones/fisiología , Mapeo Encefálico/métodosRESUMEN
BACKGROUND: Extended pleurectomy decortication for complete macroscopic resection for pleural mesothelioma has never been evaluated in a randomised trial. The aim of this study was to compare outcomes after extended pleurectomy decortication plus chemotherapy versus chemotherapy alone. METHODS: MARS 2 was a phase 3, national, multicentre, open-label, parallel two-group, pragmatic, superiority randomised controlled trial conducted in the UK. The trial took place across 26 hospitals (21 recruiting only, one surgical only, and four recruiting and surgical). Following two cycles of chemotherapy, eligible participants with pleural mesothelioma were randomly assigned (1:1) to surgery and chemotherapy or chemotherapy alone using a secure web-based system. Individuals aged 16 years or older with resectable pleural mesothelioma and adequate organ and lung function were eligible for inclusion. Participants in the chemotherapy only group received two to four further cycles of chemotherapy, and participants in the surgery and chemotherapy group received pleurectomy decortication or extended pleurectomy decortication, followed by two to four further cycles of chemotherapy. It was not possible to mask allocation because the intervention was a major surgical procedure. The primary outcome was overall survival, defined as time from randomisation to death from any cause. Analyses were done on the intention-to-treat population for all outcomes, unless specified. This study is registered with ClinicalTrials.gov, NCT02040272, and is closed to new participants. FINDINGS: Between June 19, 2015, and Jan 21, 2021, of 1030 assessed for eligibility, 335 participants were randomly assigned (169 to surgery and chemotherapy, and 166 to chemotherapy alone). 291 (87%) participants were men and 44 (13%) women, and 288 (86%) were diagnosed with epithelioid mesothelioma. At a median follow-up of 22·4 months (IQR 11·3-30·8), median survival was shorter in the surgery and chemotherapy group (19·3 months [IQR 10·0-33·7]) than in the chemotherapy alone group (24·8 months [IQR 12·6-37·4]), and the difference in restricted mean survival time at 2 years was -1·9 months (95% CI -3·4 to -0·3, p=0·019). There were 318 serious adverse events (grade ≥3) in the surgery group and 169 in the chemotherapy group (incidence rate ratio 3·6 [95% CI 2·3 to 5·5], p<0·0001), with increased incidence of cardiac (30 vs 12; 3·01 [1·13 to 8·02]) and respiratory (84 vs 34; 2·62 [1·58 to 4·33]) disorders, infection (124 vs 53; 2·13 [1·36 to 3·33]), and additional surgical or medical procedures (15 vs eight; 2·41 [1·04 to 5·57]) in the surgery group. INTERPRETATION: Extended pleurectomy decortication was associated with worse survival to 2 years, and more serious adverse events for individuals with resectable pleural mesothelioma, compared with chemotherapy alone. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (15/188/31), Cancer Research UK Feasibility Studies Project Grant (A15895).
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Mesotelioma , Neoplasias Pleurales , Humanos , Femenino , Masculino , Neoplasias Pleurales/cirugía , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/mortalidad , Persona de Mediana Edad , Anciano , Mesotelioma/cirugía , Mesotelioma/tratamiento farmacológico , Mesotelioma/mortalidad , Resultado del Tratamiento , Reino Unido , Pleura/cirugía , Mesotelioma Maligno/cirugía , Mesotelioma Maligno/tratamiento farmacológico , Terapia Combinada/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patologíaRESUMEN
Introduction: The use of patient-reported outcomes (PROs) has been shown to enhance the accuracy of symptom collection and improve overall survival and quality of life. This is the first study comparing concordance and patient preference for two PRO tools: Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) and the adapted-REQUITE Lung Questionnaire. Materials and Methods: Patients with lung cancer were recruited to the study while attending outpatient clinics at a tertiary cancer centre. Clinician-reported outcomes were generated through initial patient assessment with CTCAE v4.03. Participants then completed the PRO-CTCAE® and adapted-REQUITE questionnaires. Concordance between the 2 questionnaires was assessed by calculating Pearson correlation coefficient. PRO-CTCAE® and CTCAE concordance was demonstrated by calculating Pearson correlation coefficient from the linear predictors of an ordinal logistic regression. P-values were also calculated. Results: Out of 74 patients approached, 65 provided written informed consent to participate in the study. 63 (96.9%) patients completed both PRO-CTCAE® and adapted-REQUITE questionnaires. Pearson correlation coefficient between PRO tools was 0.8-0.83 (p <.001). Correlation between CTCAE and PRO-CTCAE® ranged between 0.66-0.82 (p <.001). Adapted-REQUITE and CTCAE correlation was higher for all symptoms ranging between 0.79-0.91 (p <.001). Acceptable discrepancies within one grade were present in 96.8%-100% of symptom domains for REQUITE and in 92.1%-96.8% for all domains in the PRO-CTCAE®. 54% of the total participant cohort favored the adapted-REQUITE questionnaire due to reduced subjectivity in the questions and ease of use. Conclusion: The adapted-REQUITE questionnaire has shown a superior correlation to clinician-reported outcomes and higher patient preference than the PRO-CTCAE®. The results of this study suggest the use of the REQUITE questionnaire for patients with lung cancer in routine clinical practice.
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A ponto-cerebello-thalamo-cortical network is the pathophysiological correlate of primary orthostatic tremor. Affected patients often do not respond satisfactorily to pharmacological treatment. Consequently, the objective of the current study was to examine the effects of a non-invasive neuromodulation by theta burst repetitive transcranial magnetic stimulation (rTMS) of the left primary motor cortex (M1) and dorsal medial frontal cortex (dMFC) on tremor frequency, intensity, sway path and subjective postural stability in primary orthostatic tremor. In a cross-over design, eight patients (mean age 70.2 ± 5.4 years, 4 female) with a primary orthostatic tremor received either rTMS of the left M1 leg area or the dMFC at the first study session, followed by the other condition (dMFC or M1 respectively) at the second study session 30 days later. Tremor frequency and intensity were quantified by surface electromyography of lower leg muscles and total sway path by posturography (foam rubber with eyes open) before and after each rTMS session. Patients subjectively rated postural stability on the posturography platform following each rTMS treatment. We found that tremor frequency did not change significantly with M1- or dMFC-stimulation. However, tremor intensity was lower after M1- but not dMFC-stimulation (p = 0.033/ p = 0.339). The sway path decreased markedly after M1-stimulation (p = 0.0005) and dMFC-stimulation (p = 0.023) compared to baseline. Accordingly, patients indicated a better subjective feeling of postural stability both with M1-rTMS (p = 0.007) and dMFC-rTMS (p = 0.01). In conclusion, non-invasive neuromodulation particularly of the M1 area can improve postural control and tremor intensity in primary orthostatic tremor by interference with the tremor network.
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Estudios Cruzados , Electromiografía , Corteza Motora , Equilibrio Postural , Estimulación Magnética Transcraneal , Temblor , Humanos , Femenino , Temblor/terapia , Temblor/fisiopatología , Estimulación Magnética Transcraneal/métodos , Masculino , Corteza Motora/fisiopatología , Anciano , Equilibrio Postural/fisiología , Mareo/terapia , Mareo/fisiopatología , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
PURPOSE: Electronic patient-reported outcome measures (ePROMs) are digitalized health questionnaires used to gauge patients' subjective experience of health and disease. They are becoming prevalent in cancer care and have been linked to a host of benefits including improved survival. MyChristie-MyHealth is the ePROM established at the Christie NHS Foundation Trust in 2019. We conducted an evaluation of this service to understand user experiences, as well as strategies to improve its functioning. METHODS: Data collection: Patients who had opted never to complete MyChristie-MyHealth (n = 87), and those who had completed at least one (n = 87) were identified. Demographic data included age, sex, ethnicity, postcode, diagnosis, treatment intent, and trial status. Semistructured interviews were held with noncompleters (n = 30) and completers (n = 31) of MyChristie-MyHealth, as well as clinician users (n = 6), covering themes such as accessibility, acceptability and usefulness, and open discourse on ways in which the service could be improved. RESULTS: Noncompleters of MyChristie-MyHealth were older (median age 72 v 66 years, P = .005), receiving treatment with curative rather than palliative intent (odds ratio [OR], 1.45; P = .045), and less likely to be enrolled on a clinical trial (OR, 0.531; P = .011). They were less likely to own a smartphone (33% v 97%) or have reliable Internet access (45% v 100%). Satisfaction with MyChristie-MyHealth was high in both groups: 93% (n = 29) of completers and 87% (n = 26) noncompleters felt generally happy to complete. Completers of MyChristie-MyHealth wanted their results to be acknowledged by their clinicians. Clinicians wanted results to be displayed in a more user-friendly way. CONCLUSION: We have broadly characterized noncompleters of the Christie ePROM to identify those in need of extra support or encouragement in the clinic. An action plan resulting from this review has been compiled and will inform the future development of MyChristie-MyHealth.
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Neoplasias , Medición de Resultados Informados por el Paciente , Anciano , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Encuestas y CuestionariosRESUMEN
A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.
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Estimulación Transcraneal de Corriente Directa , Estimulación Magnética Transcraneal , Humanos , Investigación Biomédica , Aprobación de Recursos/legislación & jurisprudencia , Europa (Continente) , Unión Europea , Legislación de Dispositivos Médicos , Estimulación Magnética Transcraneal/métodosRESUMEN
In competitive interactions, humans have to flexibly update their beliefs about another person's intentions in order to adjust their own choice strategy, such as when believing that the other may exploit their cooperativeness. Here we investigate both the neural dynamics and the causal neural substrate of belief updating processes in humans. We used an adapted prisoner's dilemma game in which participants explicitly predicted the coplayer's actions, which allowed us to quantify the prediction error between expected and actual behavior. First, in an EEG experiment, we found a stronger medial frontal negativity (MFN) for negative than positive prediction errors, suggesting that this medial frontal ERP component may encode unexpected defection of the coplayer. The MFN also predicted subsequent belief updating after negative prediction errors. In a second experiment, we used transcranial magnetic stimulation (TMS) to investigate whether the dorsomedial prefrontal cortex (dmPFC) causally implements belief updating after unexpected outcomes. Our results show that dmPFC TMS impaired belief updating and strategic behavioral adjustments after negative prediction errors. Taken together, our findings reveal the time course of the use of prediction errors in social decisions and suggest that the dmPFC plays a crucial role in updating mental representations of others' intentions.
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Corteza Prefrontal , Interacción Social , Estimulación Magnética Transcraneal , Humanos , Corteza Prefrontal/fisiología , Masculino , Femenino , Adulto Joven , Adulto , Electroencefalografía , Dilema del Prisionero , Cultura , Potenciales Evocados/fisiologíaRESUMEN
A significant body of research has investigated potential correlates of deception and bodily behavior. The vast majority of these studies consider discrete, subjectively coded bodily movements such as specific hand or head gestures. Such studies fail to consider quantitative aspects of body movement such as the precise movement direction, magnitude and timing. In this paper, we employ an innovative data mining approach to systematically study bodily correlates of deception. We re-analyze motion capture data from a previously published deception study, and experiment with different data coding options. We report how deception detection rates are affected by variables such as body part, the coding of the pose and movement, the length of the observation, and the amount of measurement noise. Our results demonstrate the feasibility of a data mining approach, with detection rates above 65%, significantly outperforming human judgement (52.80%). Owing to the systematic analysis, our analyses allow for an understanding of the importance of various coding factor. Moreover, we can reconcile seemingly discrepant findings in previous research. Our approach highlights the merits of data-driven research to support the validation and development of deception theory.
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Quality control (QC) assessment is a vital part of FMRI processing and analysis, and a typically under-discussed aspect of reproducibility. This includes checking datasets at their very earliest stages (acquisition and conversion) through their processing steps (e.g., alignment and motion correction) to regression modeling (correct stimuli, no collinearity, valid fits, enough degrees of freedom, etc.) for each subject. There are a wide variety of features to verify throughout any single subject processing pipeline, both quantitatively and qualitatively. We present several FMRI preprocessing QC features available in the AFNI toolbox, many of which are automatically generated by the pipeline-creation tool, afni_proc.py. These items include: a modular HTML document that covers full single subject processing from the raw data through statistical modeling; several review scripts in the results directory of processed data; and command line tools for identifying subjects with one or more quantitative properties across a group (such as triaging warnings, making exclusion criteria or creating informational tables). The HTML itself contains several buttons that efficiently facilitate interactive investigations into the data, when deeper checks are needed beyond the systematic images. The pages are linkable, so that users can evaluate individual items across a group, for increased sensitivity to differences (e.g., in alignment or regression modeling images). Finally, the QC document contains rating buttons for each "QC block", as well as comment fields for each, to facilitate both saving and sharing the evaluations. This increases the specificity of QC, as well as its shareability, as these files can be shared with others and potentially uploaded into repositories, promoting transparency and open science. We describe the features and applications of these QC tools for FMRI.
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BACKGROUND: Visualizing edges is critical for neuroimaging. For example, edge maps enable quality assurance for the automatic alignment of an image from one modality (or individual) to another. NEW METHOD: We suggest that using the second derivative (difference of Gaussian, or DoG) provides robust edge detection. This method is tuned by size (which is typically known in neuroimaging) rather than intensity (which is relative). RESULTS: We demonstrate that this method performs well across a broad range of imaging modalities. The edge contours produced consistently form closed surfaces, whereas alternative methods may generate disconnected lines, introducing potential ambiguity in contiguity. COMPARISON WITH EXISTING METHODS: Current methods for computing edges are based on either the first derivative of the image (FSL), or a variation of the Canny Edge detection method (AFNI). These methods suffer from two primary limitations. First, the crucial tuning parameter for each of these methods relates to the image intensity. Unfortunately, image intensity is relative for most neuroimaging modalities making the performance of these methods unreliable. Second, these existing approaches do not necessarily generate a closed edge/surface, which can reduce the ability to determine the correspondence between a represented edge and another image. CONCLUSION: The second derivative is well suited for neuroimaging edge detection. We include this method as part of both the AFNI and FSL software packages, standalone code and online.
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Encéfalo , Imagen por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/normas , Encéfalo/diagnóstico por imagen , Imagenología Tridimensional/métodos , Imagenología Tridimensional/normas , Algoritmos , Procesamiento de Imagen Asistido por Computador/métodos , Procesamiento de Imagen Asistido por Computador/normas , Neuroimagen/métodos , Neuroimagen/normasRESUMEN
BACKGROUND: Social homecare workers provide essential care to those living at home at the end of life. In the context of a service experiencing difficulties in attracting and retaining staff, we have limited knowledge about the training, support needs and experiences of this group. AIM: To gain a timely understanding from the international literature of the experience, training and support needs of homecare workers providing end-of-life care. METHODS: We conducted a rapid review and narrative synthesis using the recommendations of the Cochrane Rapid Reviews Methods Group. Building on a previous review, social homecare worker and end-of-life search terms were used to identify studies. Quality appraisal was conducted using a multimethods tool. DATA SOURCES: CINAHL and Medline databases (2011-2023; English language). RESULTS: 19 papers were included representing 2510 participants (91% women) providing new and deeper insights. Four themes were generated: (1) emotional support; homecare workers need to manage complex and distressing situations, navigating their own, their clients' and clients' family, emotions; (2) interaction with other social and healthcare workers; homecare workers are isolated from, and undervalued and poorly understood by the wider healthcare team; (3) training and support; recognising the deteriorating client, symptom management, practicalities around death, communications skills and supervision; (4) recognising good practice; examples of good practice exist but data regarding effectiveness or implementation of interventions are scant. CONCLUSIONS: Social homecare workers are essential for end-of-life care at home but are inadequately trained, often isolated and underappreciated. Our findings are important for policy-makers addressing this crucial challenge, and service providers in social and healthcare.
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Importance: US government personnel stationed internationally have reported anomalous health incidents (AHIs), with some individuals experiencing persistent debilitating symptoms. Objective: To assess the potential presence of magnetic resonance imaging (MRI)-detectable brain lesions in participants with AHIs, with respect to a well-matched control group. Design, Setting, and Participants: This exploratory study was conducted at the National Institutes of Health (NIH) Clinical Center and the NIH MRI Research Facility between June 2018 and November 2022. Eighty-one participants with AHIs and 48 age- and sex-matched control participants, 29 of whom had similar employment as the AHI group, were assessed with clinical, volumetric, and functional MRI. A high-quality diffusion MRI scan and a second volumetric scan were also acquired during a different session. The structural MRI acquisition protocol was optimized to achieve high reproducibility. Forty-nine participants with AHIs had at least 1 additional imaging session approximately 6 to 12 months from the first visit. Exposure: AHIs. Main Outcomes and Measures: Group-level quantitative metrics obtained from multiple modalities: (1) volumetric measurement, voxel-wise and region of interest (ROI)-wise; (2) diffusion MRI-derived metrics, voxel-wise and ROI-wise; and (3) ROI-wise within-network resting-state functional connectivity using functional MRI. Exploratory data analyses used both standard, nonparametric tests and bayesian multilevel modeling. Results: Among the 81 participants with AHIs, the mean (SD) age was 42 (9) years and 49% were female; among the 48 control participants, the mean (SD) age was 43 (11) years and 42% were female. Imaging scans were performed as early as 14 days after experiencing AHIs with a median delay period of 80 (IQR, 36-544) days. After adjustment for multiple comparisons, no significant differences between participants with AHIs and control participants were found for any MRI modality. At an unadjusted threshold (P < .05), compared with control participants, participants with AHIs had lower intranetwork connectivity in the salience networks, a larger corpus callosum, and diffusion MRI differences in the corpus callosum, superior longitudinal fasciculus, cingulum, inferior cerebellar peduncle, and amygdala. The structural MRI measurements were highly reproducible (median coefficient of variation <1% across all global volumetric ROIs and <1.5% for all white matter ROIs for diffusion metrics). Even individuals with large differences from control participants exhibited stable longitudinal results (typically, <±1% across visits), suggesting the absence of evolving lesions. The relationships between the imaging and clinical variables were weak (median Spearman ρ = 0.10). The study did not replicate the results of a previously published investigation of AHIs. Conclusions and Relevance: In this exploratory neuroimaging study, there were no significant differences in imaging measures of brain structure or function between individuals reporting AHIs and matched control participants after adjustment for multiple comparisons.
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Imagen de Difusión Tensora , Sustancia Blanca , Humanos , Femenino , Adulto , Masculino , Imagen de Difusión Tensora/métodos , Reproducibilidad de los Resultados , Teorema de Bayes , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Neuroimagen , Sustancia Blanca/patología , Familia , Gobierno , Medidas de SeguridadRESUMEN
BACKGROUND: Left prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. OBJECTIVE/HYPOTHESIS: In our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. METHODS: Concurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. RESULTS: Concurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. CONCLUSIONS: Full iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.
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Imagen por Resonancia Magnética , Estimulación Magnética Transcraneal , Humanos , Estimulación Magnética Transcraneal/métodos , Imagen por Resonancia Magnética/métodos , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiología , Giro del Cíngulo , Corteza Prefontal DorsolateralRESUMEN
Sweet chestnut, an Asiatic tree introduced in many parts of Europe including the United Kingdom, is planted for nut production, timber, and amenity. Its major threat is the disease called blight, caused by the fungus Cryphonectria parasitica, which infects through wounds by airborne spores. Field trapping using sticky rods rotating traps was performed in an infected area in Devon (between May 2021 and April 2023). An improved dual hydrolysis Taqman probes real-time PCR was used. The number of spores was calculated by comparing the cycle threshold to the Ct of standards with known amounts of conidia or known target fragment copies cloned into a plasmid. Weekly spore counts were in the range of around 60 to approximately 8.5 × 103, with fluctuations of peaks (mainly in late summer-autumn 2021) and troughs. The effects of weather parameters were modelled, finding correlations between spore numbers and temperature, humidity, dewpoint, rainfall, wind speed, and wind duration. Additionally, an insect trapping was performed to confirm the presence/absence and quantity of C. parasitica conidia potentially phoretic on some insects by using the same molecular approach. None of the ten collected insect species harboured spores of this fungus.
RESUMEN
Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.