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Ultra‐high temporal resolution 4D angiography using arterial spin labeling with subspace reconstruction
AbstractPurposeTo achieve ultra‐high temporal resolution non‐contrast 4D angiography with improved spatiotemporal fidelity.MethodsContinuous data acquisition using 3D golden‐angle sampling following an arterial spin labeling preparation allows for flexibly reconstructing 4D dynamic angiograms at arbitrary temporal resolutions. However, k‐space data is often temporally “binned” before image reconstruction, negatively affecting spatiotemporal fidelity and limiting temporal resolution. In this work, a subspace was extracted by linearly compressing a dictionary constructed from simulated curves of an angiographic kinetic model. The subspace was used to represent and reconstruct the voxelwise signal timecourse at the same temporal resolution as the data acquisition without temporal binning. Physiological parameters were estimated from the resulting images using a Bayesian fitting approach. A group of eight healthy subjects were scanned and the in vivo results reconstructed by different methods were compared. Because of the difficulty of obtaining ground truth 4D angiograms with ultra‐high temporal resolution, the in vivo results were cross‐validated with numerical simulations.ResultsThe proposed method enables 4D time‐resolved angiography with much higher temporal resolution (14.7 ms) than previously reported (˜50 ms) while maintaining high spatial resolution (1.1 mm isotropic). Blood flow dynamics were depicted in greater detail, thin vessel visibility was improved, and the estimated physiological parameters also exhibited more realistic spatial patterns with the proposed method.ConclusionIncorporating a subspace compressed kinetic model into the reconstruction of 4D ASL angiograms notably improved the temporal resolution and spatiotemporal fidelity, which was subsequently beneficial for accurate physiological modeling.
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.
Implementation of pay for performance in primary care: a qualitative study 8 years after introduction.
BACKGROUND: Pay for performance is now a widely adopted quality improvement initiative in health care. One of the largest schemes in primary care internationally is the English Quality and Outcomes Framework (QOF). AIM: To obtain a longer term perspective on the implementation of the QOF. DESIGN AND SETTING: Qualitative study with 47 health professionals in 23 practices across England. Method Semi-structured interviews. RESULTS: Pay for performance is accepted as a routine part of primary care in England, with previous more individualistic and less structured ways of working seen as poor practice. The size of the QOF and the evidence-based nature of the indicators are regarded as key to its success. However, pay for performance may have had a negative impact on some aspects of medical professionalism, such as clinical autonomy, and led a significant minority of GPs to prioritise their own pay rather than patients' best interests. A small minority of GPs tried to increase their clinical autonomy with further unintended consequences. CONCLUSION: Pay for performance indicators are now welcomed by primary healthcare teams and GPs across generations. Almost all interviewees wanted to see a greater emphasis on involving front line practice teams in developing indicators. However, almost all GPs and practice managers described a sense of decreased clinical autonomy and loss of professionalism. Calibrating the appropriate level of clinical autonomy is critical if pay for performance schemes are to have maximal impact on patient care.
Quantifying axonal features of human superficial white matter from three-dimensional multibeam serial electron microscopy data assisted by deep learning.
Short-range association fibers located in the superficial white matter play an important role in mediating higher-order cognitive function in humans. Detailed morphological characterization of short-range association fibers at the microscopic level promises to yield important insights into the axonal features driving cortico-cortical connectivity in the human brain yet has been difficult to achieve to date due to the challenges of imaging at nanometer-scale resolution over large tissue volumes. This work presents results from multi-beam scanning electron microscopy (EM) data acquired at 4 × 4 × 33 nm3 resolution in a volume of human superficial white matter measuring 200 × 200 × 112 μm (Braitenberg and Schüz, 2013), leveraging automated analysis methods. Myelin and myelinated axons were automatically segmented using deep convolutional neural networks (CNNs), assisted by transfer learning and dropout regularization techniques. A total of 128,285 myelinated axons were segmented, of which 70,321 and 2,102 were longer than 10 and 100 μm, respectively. Marked local variations in diameter (i.e., beading) and direction (i.e., undulation) were observed along the length of individual axons. Myelinated axons longer than 10 μm had inner diameters around 0.5 µm, outer diameters around 1 µm, and g-ratios around 0.5. This work fills a gap in knowledge of axonal morphometry in the superficial white matter and provides a large 3D human EM dataset and accurate segmentation results for a variety of future studies in different fields.
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.
Advancing atmospheric solids analysis probe mass spectrometry applications: a multifaceted approach to optimising clinical data set generation.
The use of rapid mass spectrometry techniques, such as atmospheric-solids-analysis-probe mass spectrometry (ASAP-MS), in the analysis of metabolite patterns in clinical samples holds significant promise for developing new diagnostic tools and enabling rapid disease screening. The rapid measurement times, ease of use, and relatively low cost of ASAP-MS makes it an appealing option for use in clinical settings. However, despite the potential of such approaches, a number of important experimental considerations are often overlooked. As well as instrument-specific choices and settings, these include the treatment of background noise and/or contaminant peaks in the mass spectra, and the influence of consumables, different users, and batch effects more generally. The present study assesses the impact of these various factors on measurement accuracy and reproducibility, using human brain and cerebrospinal fluid samples as examples. Based on our results, we make a series of recommendations relating to optimisation of measurement and cleaning protocols, consumable selection, and batch effect detection and correction, in order to optimise the reliability and reproducibility of ASAP-MS measurements in clinical settings.
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.
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.
Dreaming of Better Treatments: Advances in Drug Development for Sleep Medicine and Chronotherapy.
Throughout history, the development of new sleep medicines has been driven by progress in our understanding of the mechanisms underlying sleep. Ancient civilisations used their understanding of the sedative nature of natural herbs and compounds to induce sleep. The discovery of barbiturates and bromides heralded a new era of synthetic sleep medicine in the 19th century. This was followed by the development of benzodiazepines that were used to inhibit signalling throughout the brain by promoting gamma-amino butyric acid release and thereby produce loss of consciousness. As our understanding of sleep has deepened, newer therapies have more specifically targeted the wake-inducing neurotransmitter orexin with fewer side effects. Given the newly highlighted role of kinases in sleep/wake regulation, we predict that the next breakthroughs in sleep medicine will likely target these kinases. Given the fundamental role that sleep plays in maintaining brain health through processes such as glymphatic clearance, sleep medicine has therapeutic potential beyond just sleep. Recent evidence suggests that sleep disruptions directly contribute to the build-up of pathological neuronal proteins in neurodegenerative disorders. Therefore, sleep medicine could improve prognosis in disorders such as these. Great attention must be paid to the mechanism of action of each sleep medicine, however, as sleep medicines which do not fully mimic sleep could actually worsen disease progression.
Positivity Rate of PD-L1 Expression and Its Clinical Significance in Vulvar Cancer: A Systematic Review and Meta-Analysis
The prevalence and prognostic value of programmed death ligand 1 (PD-L1) expression, as a potential biomarker in vulvar squamous cell carcinomas (VSCCs), remain underexplored. We searched the PubMed, Scopus, Embase, and Cochrane Library databases until July 2024 for articles examining PD-L1 expression in VSCCs. Random-effects meta-analyses summarized PD-L1 expression overall and in subgroups by immunohistochemistry antibody type, positivity cutoff, tumor stage, and HPV positivity. Additionally, random-effects meta-analyses summarized the association between PD-L1 positivity and cancer prognosis. We included 26 studies comprising 1912 VSCC cases. The summary PD-L1 positivity rate in tumor cells was 59.9% (95% confidence interval [CI]: 47.7–71.4%; I2 = 96%, n = 26), influenced by the different cutoff thresholds utilized to define PD-L1 positivity. Compared to tumor cells, positivity rates were higher in intratumoral immune cells (75.6%; 95%CI: 52.9–92.5; I2 = 95.4%, n = 6) and peritumoral cells (78.9%; 95%CI: 54.4–95.5%; I2 = 91%, n = 3) but with overlapping 95%CIs. No heterogeneity was observed in the rates by tumor stage or HPV status. Positive PD-L1 expression was associated with worse overall (hazard ratio [HR] = 1.43; 95%CI: 1.06–1.93; I2 = 28.9%, n = 7) and progression-free survival (HR = 1.57; 95%CI: 1.07–2.3; I2 = 38.3%, n = 5). The PD-L1 expression rate in VSCC tumor cells varied across studies, was influenced by differences in immunohistochemical evaluation, and was identified as an unfavorable prognostic factor. Large, prospective, multicenter studies with standardized protocols are crucial to further elucidate the clinical significance of PD-L1 expression in VSCCs.
Thalamic deep brain stimulation for central poststroke pain syndrome: an international multicenter study.
OBJECTIVE: The effectiveness and optimal stimulation site of deep brain stimulation (DBS) for central poststroke pain (CPSP) remain elusive. The objective of this retrospective international multicenter study was to assess clinical as well as neuroimaging-based predictors of long-term outcomes after DBS for CPSP. METHODS: The authors analyzed patient-based clinical and neuroimaging data of previously published and unpublished cohorts from 6 international DBS centers. DBS leads were reconstructed and normalized. A stimulation map was constructed on the basis of individual stimulation settings and associated outcomes. Furthermore, the authors projected the individual segmented stroke lesions and volumes of tissue activated (VTAs) of the stimulating electrode onto a normalized human connectome to obtain the connectivity profiles of the individual lesions and VTAs. RESULTS: The authors analyzed the data of 54 patients, of whom 15 were excluded from the final analysis due to a lack of imaging data. Among the remaining 39 patients from 6 different cohorts, the authors found 14 (35.9%) responders who were defined by pain relief of at least 50% at 12-month follow-up. Stimulation mapping identified areas in the posterior limb of the internal capsule, the sensorimotor thalamus, and the medial and intralaminar thalamus as effective for pain reduction. Baseline characteristics did not differ between responders and nonresponders. The stimulation sites of the responders showed significantly reduced structural connectivity to the sensory areas of the cerebral cortex compared to nonresponders. CONCLUSIONS: This comprehensive, multicenter analysis corroborates the efficacy of DBS in treating CPSP for a relevant number of patients. The posterior limb of the internal capsule and the sensorimotor thalamus emerged as potential stimulation sweet spots. The difference in structural connectivity between responders and nonresponders may constitute a biomarker of effective stimulation that can help guide surgical planning in future well-designed prospective trials.