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Healthcare professionals' perspectives on assessing selected patient-reported outcome measures in specialist palliative care institutions: a multi-country mixed-methods study.
BACKGROUND: Despite the growing significance of patient-reported outcome measures (PROMs) for various purposes, including economic evaluations, implementing them effectively in palliative and end-of-life care settings remains a challenge. This study aimed to identify barriers and facilitators to PROMs data collection in inpatient specialist palliative care settings and to assess data collectors' applied perspectives on four relevant PROMs. METHODS: We conducted an explanatory sequential mixed-methods study, including an online survey (N = 29) and qualitative interviews (N = 12) with healthcare professionals and researchers from eleven countries. These participants had direct experience with PROMs data collection in specialist palliative care settings, either as part of the international iLIVE project or the Austrian PallPROMS study. The aim was to identify opportunities for optimising clinical care and other assessment purposes in the future. We conducted a descriptive analysis of the survey data and a thematic analysis of the qualitative data. RESULTS: The main reflected factors were patients' very limited ability to self-complete PROMs and the optimal timing and duration of assessments. Opinions on the usefulness of different PROMs varied significantly according to the role of the participants. Overall, setting-specific PROMs assessing symptom burden were preferred to more generic quality-of-life/wellbeing measures. Identified barriers and facilitators related to five themes: patient-related factors, data collection processes, PROM type, staff perceptions and organisational factors. Findings also highlighted better information and training needs. CONCLUSIONS: Prioritising care-relevant tools and carefully planning data collection, with main barriers addressed, can significantly increase the successful implementation of PROMs collection in specialist palliative care institutions. Since the preferred PROMs are not directly suitable for health economic evaluation, it is crucial to explore mapping alternatives for this purpose.
Mapping of validated apathy scales onto the apathy diagnostic criteria for neurocognitive disorders.
BACKGROUND: Diagnostic criteria for apathy in neurocognitive disorders (DCA-NCD) have recently been updated. OBJECTIVES: We investigated whether validated scales measuring apathy severity capture the three dimensions of the DCA-NCD (diminished initiative, diminished interest, diminished emotional expression). MEASUREMENTS: Degree of mapping ("not at all", "weakly", or "strongly") between items on two commonly used apathy scales, the Neuropsychiatric Inventory-Clinician (NPI-C) apathy and Apathy Evaluation Scale (AES), with the DCA-NCD overall and its 3 dimensions was evaluated by survey. DESIGN: Survey participants, either experts (n = 12, DCA-NCD authors) or scientific community members (n = 19), rated mapping for each item and mean scores were calculated. Interrater reliability between expert and scientific community members was assessed using Cohen's kappa. RESULTS: According to experts, 9 of 11 (81.8%) NPI-C apathy items and 6 of 18 (33.3%) AES items mapped strongly onto the DCA-NCD overall. For the scientific community group, 10 of 11 (90.9%) NPI-C apathy items and 7 of 18 (38.8%) AES items mapped strongly onto the DCA-NCD overall. The overall mean mapping scores were higher for the NPI-C apathy compared to the AES for both expert (t (11) = 3.13, p = .01) and scientific community (t (17) = 3.77, p = .002) groups. There was moderate agreement between the two groups on overall mapping for the NPI-C apathy (kappa= 0.74 (0.57, 1.00)) and AES (kappa= 0.63 (0.35, 1.00)). CONCLUSIONS: More NPI-C apathy than AES items mapped strongly and uniquely onto the DCA-NCD and its dimensions. The NPI-C apathy may better capture the DCA-NCD and its dimensions compared with the AES.
Case report on severe myelin oligodendrocyte glycoprotein antibody-associated disease relapse after ectopic pregnancy and laparoscopic medical abortion: relevance of peripheral inflammation for demyelinating disease activity.
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare neurological condition. Tubal ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Regular pregnancy has a disease-modifying effect on MOGAD, with an increased relapse rate postpartum. Still, there are neither case reports nor cohort studies on abortions and ectopic pregnancy as a disease-modifying event for MOGAD. MATERIALS AND METHODS: This is a case report on a severe MOGAD relapse after ectopic pregnancy and laparoscopic abortion. DISCUSSION: For the first time we described that elevated interleukin-1 (IL-1), which was found in cerebrospinal fluid in the current case may be pathogenetically related to ectopic pregnancy. Rituximab (anti-CD20 treatment), downregulated IL-1 and TNF-alfa inflammatory pathways thus is an appropriate drug of choice to treat relapse. Cytokines secreted during ectopic pregnancy could play a disease-modifying role in multiple sclerosis and Guillian-Barré syndrome. CONCLUSION: The first case report of a MOGAD severe relapse after ectopic pregnancy and laparoscopic abortion which resolved with rituximab treatment.
Control of replication and gene expression by ADP-ribosylation of DNA in Mycobacterium tuberculosis.
Mycobacterium tuberculosis maintains long-term infections characterised by the need to regulate growth and adapt to contrasting in vivo environments. Here we show that M. tuberculosis complex bacteria utilise reversible ADP-ribosylation of single-stranded DNA as a mechanism to coordinate stationary phase growth with transcriptional adaptation. The DNA modification is controlled by DarT, an ADP-ribosyltransferase, which adds ADP-ribose to thymidine, and DarG, which enzymatically removes this base modification. Using darG-knockdown M. bovis BCG, we map the first DNA ADP-ribosylome from any organism. We show that inhibition of replication by DarT is reversible and accompanied by extensive ADP-ribosylation at the origin of replication (OriC). In addition, we observe ADP-ribosylation across the genome and demonstrate that ADP-ribose-thymidine alters the transcriptional activity of M. tuberculosis RNA polymerase. Furthermore, we demonstrate that during stationary phase, DarT-dependent ADP-ribosylation of M. tuberculosis DNA is required to optimally induce expression of the Zur regulon, including the ESX-3 secretion system and multiple alternative ribosome proteins. Thus, ADP-ribosylation of DNA can provide a mechanistic link through every aspect of DNA biology from replication to transcription to translation.
ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis
RNA binding proteins (RBP) of the ZFP36 family limit the differentiation and effector functions of CD4 and CD8 T cells, but little is known of their expression or function in regulatory T (Treg) cells. By using Treg cell-restricted deletion of Zfp36 family members we identify the role of Zfp36l1 and Zfp36l2 in Treg cells to maintain immune homeostasis. Mice with Treg cells deficient in these RBP display an inflammatory phenotype with an expansion in the numbers of type-2 conventional dendritic cells, T effector cells, T follicular helper and germinal center B cells and elevated serum cytokines and immunoglobulins. In the absence of Zfp36l1 and Zfp36l2, the pool of cycling CTLA-4 in naïve Treg cells is reduced, Treg cells are less sensitive to IL-2 and IL-7 but are more sensitive to IFNγ. In mice lacking both RBP in Treg cells, the deletion of a single allele of Ifng is sufficient to ameliorate the pathology. Our results indicate that ZFP36L1 and ZFP36L2 regulate the availability of IFNγ and are required for the maintenance of Treg cell stability. Thus, ZFP36L1 and ZFP36L2 regulate multiple pathways that enable Treg cells to enforce immune homeostasis.
RELIGION AND THE SUSCEPTIBILITY TO FALSE BELIEFS
Religion has played a particularly important role in human evolution. It is the one trait that categorically distinguishes us from other animals. Yet it is about belief in a world that does not exist - the spirit world. I shall argue that it arises through two very ancient psychological predispositions. A tendency for the magical to have priority when we cannot see an obvious explanation and a strong tendency to be attracted to charismatic leaders. The first is a derivative of our advanced mentalising capacities, which allow us to imagine worlds that do not exist. The second is seems to be associated with the fact that networks that evolve leaders work more efficiently. Both of these played a central role in our evolution as a species.
Low-Rank Conjugate Gradient-Net for Accelerated Cardiac MR Imaging
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide. Both diagnosis and prognosis of these diseases benefit from high-quality imaging, which cardiac magnetic resonance imaging provides. CMR imaging requires lengthy acquisition times and multiple breath-holds for a complete exam, which can lead to patient discomfort and frequently results in image artifacts. In this work, we present a Low-rank tensor U-Net method (LowRank-CGNet) that rapidly reconstructs highly undersampled data with a variety of anatomy, contrast, and undersampling artifacts. The model uses conjugate gradient data consistency to solve for the spatial and temporal bases and employs a U-Net to further regularize the basis vectors. Currently, model performance is superior to a standard U-Net, but inferior to conventional compressed sensing methods. In the future, we aim to further improve model performance by increasing the U-Net size, extending the training duration, and dynamically updating the tensor rank for different anatomies.
The profile of gastrointestinal dysfunction in prodromal to late-stage Parkinson's disease.
Gastrointestinal dysfunction (GID) may play a key role in Parkinson's disease (PD) but its relationship with disease progression remains unclear. We recruited 404 PD cases, 37 iRBD (isolated REM Sleep Behaviour Disorder) and 105 controls. Participants completed the Gastrointestinal Dysfunction Scale for PD (GIDS-PD) and standardised disease severity assessments. Whole gut transit time (WGTT) was measured by ingestion of blue dye and recorded time to blue stools appearance ('Blue Poop Challenge') in a subset of PD cases. Gastrointestinal symptoms were more common and prevalent in iRBD and PD versus controls, and WGTT was significantly higher in PD versus controls. After adjustment for confounding factors, disease stage was not a significant predictor of GIDS-PD Constipation or Bowel Irritability scores. Longitudinal assessment of GIDS-PD scores and WGTT confirmed stability over a 4 year period. Bowel dysfunction may be a phenotypic feature in a subset of Parkinson's with implications for patient stratification and management.
GPCR signaling via cAMP nanodomains.
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, mediating essential physiological responses through diverse intracellular signaling pathways. When coupled to Gs or Gi proteins, GPCR modulates the synthesis of 3'-5'-cyclic adenosine monophosphate (cAMP), which governs a wide array of processes, ranging from cellular growth and survival to metabolic regulation. Studies have highlighted that cAMP is not uniformly distributed within cells but instead is compartmentalized into highly localized nanodomains. These nanodomains, mostly regulated by phosphodiesterases (PDEs), play a critical role in enabling signal precision and functional effects that are specific to individual stimuli. GPCRs can initiate distinct cAMP responses based on their localization within the cell, with evidence showing that both receptors resident at the plasma membrane and intracellular receptors-including endosomal, Golgi, and nuclear GPCRs-elicit unique cAMP signaling profiles. This review examines the mechanisms underlying GPCR signaling through cAMP nanodomains. We focus on the role of PDE-mediated cAMP degradation in shaping local cAMP signals, the emerging views on mechanisms that may contribute to signal compartmentalization, and the role of intracellular membrane compartments. By exploring these aspects, we aim to highlight the complexity of GPCR signaling networks and illustrate some of the implications for the regulation of cellular function.
Dopamine D2 receptor upregulation in dorsal striatum in the LRRK2-R1441C rat model of early Parkinson's disease revealed by in vivo PET imaging.
We conducted PET imaging with [18F]FDOPA and dopamine D2/3 receptor ligand [18F]fallypride in aged transgenic rats carrying human pathogenic LRRK2 R1441C or G2019S mutations. These rats have mild age-dependent deficits in dopamine release restricted to dorsal striatum despite no overt loss of dopamine neurons or dopamine content and demonstrate L-DOPA-responsive movement deficits.LRRK2 mutant rats displayed no deficit in [18F]FDOPA uptake, consistent with intact dopamine synthesis in striatal axons. However, LRRK2-R1441C rats demonstrated greater binding of [18F]fallypride than LRRK2-G2019S or non-transgenic controls, from a regionally selective increase in dorsal striatum. Immunocytochemical labelling post-mortem confirmed a greater density of D2 receptors in LRRK2-R1441C than other genotypes restricted to dorsal striatum, consistent with upregulation of D2-receptors as a compensatory response to the greater dopamine release deficit previously demonstrated in this genotype.These results show that [18F]fallypride PET imaging is sensitive to dysregulation of dopamine signalling in the LRRK2-R1441C rat, revealing upregulation of D2 receptors that parallels observations in human putamen in early sporadic PD. Future studies of candidate therapies could exploit this non-invasive approach to assess treatment efficacy.
Machine learning-based prediction of anxiety disorders using blood metabolite and social trait data from the UK Biobank
Anxiety disorders are the most prevalent type of mental health disorders and are characterised by excessive fear and worry. Despite affecting one in four individuals within their lifetime, there remains a gap in our understanding regarding the underlying pathophysiology of anxiety disorders, which limits the development of novel treatment options. Exploring blood-based biomarkers of anxiety disorder offers the potential to predict the risk of clinically significant anxiety in the general population, increase our understanding of anxiety pathophysiology, and to reveal options for preventative treatment. Here, using psychosocial variables in combination with blood and urine biomarkers, reported in the UK Biobank, we sought to predict future anxiety onset. Machine learning accurately predicted (ROC AUC: ∼0.83) ICD-10-coded anxiety diagnoses up to 5 years (mean 3.5 years) after blood sampling, against lifetime anxiety-free controls. Analysis of the blood biochemistry measures indicated that anxious individuals were more anaemic and exhibited higher levels of markers of systemic inflammation than controls. However, blood biomarkers alone were not predictive of resilience or susceptibility to anxiety disorders in a subset of individuals rigorously matched for a wide range of psychosocial covariates (ROC AUC: ∼0.50). Overall, we demonstrate that the integration of biological and psychosocial risk factors is an effective tool to screen for and predict anxiety disorder onset in the general population.
Contributed Talks I: The role of fixational drift in the Vernier task.
We develop a simple one-dimensional continuum model of the Vernier discrimination task to study the impact of Gaussian blur, fixational drift, receptor noise, and retinal adaptation on an ideal observer's Vernier performance. Two rectangular stimuli with a prescribed width and relative offset are subjected to a Gaussian blur. Fixational drift shifts the resulting signal with time. The perceived signal is the weighted average over the history of local stimulation encoded by an adaptation kernel. We model this kernel as a difference of two exponentials, introducing two timescales describing initial integration and eventual recovery of a receptor. Ultimately, Gaussian white noise is added to capture random receptor fluctuations. Based on the Bayesian estimation of location and relative offset of both stimuli, we can study Vernier performance through numerical simulation as well as through analytical approximation for different eye movements. Analyzing diffusive motion in particular, we extract the diffusion constant that optimizes stimulus localization for long observation times. This optimal diffusion constant is inversely proportional to an average of the two timescales describing adaptation and proportional to the square of the larger of stimulus size or blurring width, giving rise to two separate regimes. We generalize our analysis to optimize discrimination and extend the class of eye motions considered beyond purely diffusive drift, e.g. with the inclusion of persistence.