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Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly.
\n \n\n \n \nObjective: To generate a Korean version of the Oxford Cognitive Screen (K-OCS) and obtain cutoff scores that determine the impairment of each subdomain. Post-stroke cognitive impairment (PSCI) negatively impacts the rehabilitation process and independence in daily life. Its obscure manifestations require effective screening for appropriate rehabilitation. However, in most rehabilitation clinics, psychological evaluation tools for Alzheimer\u2019s dementia have been used without such considerations. The OCS is a screening assessment tool for PSCI and vascular dementia that can evaluate the cognitive domains most often affected by stroke, including language, attention, memory, praxis, and numerical cognition. It comprises 10 subtasks and enables quick and effective cognitive evaluation. Methods: The K-OCS, which considers Korea\u2019s unique cultural and linguistic characteristics, was developed with the approval and cooperation of the original author. Enrollment of participants without disabilities was announced at Duksung Women\u2019s University, Yongin Sevrance Hospital, CHA Bundang Medical Center. The study was conducted between September 2020 and March 2022 on 97 male and female participants aged \u226530 years.Results: All the 97 participants completed the task. In this study, the 5th percentile score was presumed to be the cutoff value for each score, and the values are provided here. The cutoff score for each OCS subtask was similar to that of the original British version.Conclusion: We suggest the usability of the K-OCS as a screening tool for PSCI by providing the cutoff value of each subtask.
\n \n\n \n \nOBJECTIVE: The purpose of this study was to develop and evaluate the performance of RPC-Net (Recursive Prosthetic Control Network), a novel method using simple neural network architectures to translate electromyographic activity into hand position with high accuracy and computational efficiency. METHODS: RPC-Net uses a regression-based approach to convert forearm electromyographic signals into hand kinematics. We tested the adaptability of the algorithm to different conditions and compared its performance with that of solutions from the academic literature. RESULTS: RPC-Net demonstrated a high degree of accuracy in predicting hand position from electromyographic activity, outperforming other solutions with the same computational cost. Including previous position data consistently improved results across subjects and conditions. RPC-Net showed robustness against a reduction in the number of electromyography electrodes used and shorter input signals, indicating potential for further reduction in computational cost. CONCLUSION: The results demonstrate that RPC-Net is capable of accurately translating forearm electromyographic activity into hand position, offering a practical and adaptable tool that may be accessible in clinical settings. SIGNIFICANCE: The development of RPC-Net represents a significant advancement. In clinical settings, its application could enable prosthetic devices to be controlled in a way that feels more natural, improving the quality of life for individuals with limb loss.
\n \n\n \n \nThe inspired sinewave technique (IST) is a non-invasive method to measure lung heterogeneity indices (including both uneven ventilation and perfusion or heterogeneity), which reveal multiple conditions of the lung and lung injury. To evaluate the reproducibility and predicted clinical outcomes of IST heterogeneity values, a comparison with a quantitative lung computed tomography (CT) scan is performed. Six anaesthetised pigs were studied after surfactant depletion by saline-lavage. Paired measurements of lung heterogeneity were then taken with both the IST and CT. Lung heterogeneity measured by the IST was calculated by (a) the ratio of tracer gas outputs measured at oscillation periods of 180\u00a0s and 60\u00a0s, and (b) by the standard deviation of the modelled log-normal distribution of ventilations and perfusions in the simulation lung. In the CT images, lungs were manually segmented and divided into different regions according to voxel density. A quantitative CT method to calculate the heterogeneity (the Cressoni method) was applied. The IST and CT show good Pearson correlation coefficients in lung heterogeneity measurements (ventilation: 0.71, and perfusion, 0.60, p\u2009
\n \n\n \n \nBACKGROUND AND AIM: Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. METHODS: Relevant services were identified by literature search and contacted. Three years of monthly data were requested - a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. RESULTS: Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI -1.8 to 7.6, p =\u20090.24), as did ischemic stroke (2.9, 95% CI -7.8 to 1.9, p =\u20090.25), IVT (-14.3, 95% CI -36.7, 6.1, p
\n \n\n \n \nPURPOSE: Radical prostatectomy (RP) is a common treatment for prostate cancer, but a fraction of patients may experience PSA recurrence after surgery, manifesting as an elevation in prostate specific antigen (PSA). Vast literature has reported different prognostic factors for PSA recurrence without reaching a consensus. This retrospective study investigated the efficacy of a new indicator in predicting PSA recurrence in patients after RP. PATIENTS AND METHODS: From October 2000 to December 2015, 102 PCa patients who underwent laparoscopic prostatectomy in the Urology Department of Peking Union Medical College Hospital were analyzed. We calculated PSApostd3/PSApre, defined as the ratio of the PSA on day 3 postop as the numerator and the pre-operative PSA as the denominator, in these patients to represent PSA decrement after surgery, and investigated its relationship with PSA recurrence during follow-up. RESULTS: The receiver operating characteristic (ROC) curve of PSApostd3/PSApre derived a cut-off at 0.453 (sensitivity=0.704, specificity=0.853, P<0.0001), suggesting an increased risk of PSA recurrence in patients whose PSA on day 3 postop did not decrease to approximately half of their preoperative levels. Among several factors, PSApostd3/PSApre (P<0.0001), pathological T stage (P=0.042) and Gleason Grade (P=0.021) were determined to be significantly associated with PSA recurrence by Fisher's exact test, while only PSApostd3/PSApre (P<0.001) was significantly related to PSA recurrence-free survival (PRFS) by multivariate logistic regression analysis. CONCLUSION: These results imply that PSApostd3/PSApre could provide substantial information for PSA recurrence prediction in patients after RP.
\n \n\n \n \nOBJECTIVE: To characterize the patterns of brain atrophy and perfusion as measured by arterial spin labeling (ASL)-MRI, in amyotrophic lateral sclerosis (ALS) patients with varying levels of cognitive deficit, including ALS with frontotemporal dementia (FTD). METHODS: A total of 55 ALS patients and 20 healthy controls (HCs) were included, and all participants underwent neuropsychological assessments and MRI scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, n\u2009=\u200927), ALS with cognitive impairment (ALS-Ci, n\u2009=\u200917), and ALS-FTD (n\u2009=\u200911). Voxel-based comparisons of gray matter (GM) changes and cerebral blood flow (CBF) were conducted among the subgroups. RESULTS: The whole-brain comparisons of GM changes and CBF among ALS-Ci, ALS-Cn, and HCs were not significantly different. However, the ALS-FTD patients demonstrated a similar pattern of GM loss and hypoperfusion with more significant alterations in the left frontal and temporal lobe compared with the HCs, ALS-Cn, and ALS-Ci patients. Decreased CBF was found in many of the same brain areas wherein structural alterations occurred, although isolated GM loss and hypoperfusion were also observed. In addition, for both GM and CBF abnormalities, a similar pattern of changes was found in the comparisons of ALS-FTD vs. ALS-Ci, ALS-FTD vs. ALS-Cn, and ALS-FTD vs. HCs, with the differences being most significant between ALS-FTD and HCs. CONCLUSION: The cognitive status of ALS patients is associated with different patterns of GM changes and cerebral perfusion. ASL-MRI might be a useful tool with which to investigate the pathological burden of ALS and to disclose the early signature of possible cognitive impairment.
\n \n\n \n \nTo compare the accuracy of magnetic resonance-guided prostate biopsy (MR-GPB) and template-guided transperineal prostate saturation biopsy (TTPSB).A total of 219 patients with elevated prostate-specific antigen, abnormal digital rectal examination or ultrasound findings were enrolled. All patients underwent multiparametric magnetic resonance image (mpMRI). Patients with a Prostate Imaging Reporting and Data System (PI-RADS) score of 3 to 5 underwent MR-GPB using 2 to 5 biopsy cores and then immediately underwent an 11-region TTPSB. Patients with a PI-RADS score of 1 to 2 underwent TTPSB alone. We compared the detection rates for any cancer, clinically significant prostate cancer (csPCA), and the spatial distribution of missed csPCA lesions.Among the 219 cases, 66 (30.1%) had a PI-RADS score of 1 to 2 on mpMRI. The detection rate of TTPSB in these patients was 9.1% (6/66). In total, detection rates for any cancer and csPCA were 48.9% (107/219) and 42.9% (94/219), respectively. Detection rates for any cancer (TTPSB 87/219, 39.7%; MR-GPB76/219, 34.7%, P\u200a=\u200a.161) and csPCA (TTPSB 76/219, 34.7%; MR-GPB 72/219, 32.9%, P\u200a=\u200a.636) did not significantly differ between the 2 groups. The csPCA lesions missed by MR-GPB were most commonly located on the left (8.5%, 8/94) and right (9.6%, 9/94) sides of the urethra.MR-GPB can reduce the rate of unnecessary prostate biopsies by approximately 30% and exhibits an efficacy comparable to TTPSB for the detection of any cancer and csPCA. Nevertheless, approximately 1/4 of csPCAs were missed by MR-GPB and were most commonly located on both sides of the urethra.
\n \n\n \n \nThis paper presents a deep learning system applied for detecting anomalies from respiratory sound recordings. Our system initially performs audio feature extraction using Continuous Wavelet transformation. This transformation converts the respiratory sound input into a two-dimensional spectrogram where both spectral and temporal features are presented. Then, our proposed deep learning architecture inspired by the Inception-residual-based backbone performs the spatio-temporal-focusing and multi-head attention mechanism to classify respiratory anomalies. In this work, we evaluate our proposed models on the benchmark SPRSound (The Open-Source SJTU Paediatric Respiratory Sound) database proposed by the IEEE BioCAS 2023 challenge. As regards the Score computed by an average between the average score and harmonic score, our robust system has achieved Top-1 performance with Scores of 0.810, 0.667, 0.744, and 0.608 in Tasks 1-1, 1-2, 2-1, and 2-2, respectively.
\n \n\n \n \nAge-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly in the developed world. Whilst AMD is a multifactorial disease, the involvement of the complement system in its pathology is well documented, with single-nucleotide polymorphisms (SNPs) in different complement genes representing an increased risk factor. With several complement inhibitors explored in clinical trials showing limited success, patients with AMD are still without a reliable treatment option. This indicates that there is still a gap of knowledge in the functional implications and manipulation of the complement system in AMD, hindering the progress towards translational treatments. Since the discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool, the field of molecular biology has been revolutionised. Genetic variants in the complement system have long been associated with an increased risk of AMD, and a variety of haplotypes have been identified to be predisposing/protective, with variation in complement genes believed to be the trigger for dysregulation of the cascade leading to inflammation. AMD-haplotypes (SNPs) alter specific aspects of the activation and regulation of the complement cascade, providing valuable insights into the pathogenic mechanisms of AMD with important diagnostic and therapeutic implications. The effect of targeting these AMD-related SNPs on the regulation of the complement cascade has been poorly explored, and the CRISPR/Cas system provides an ideal tool with which to explore this avenue. Current research concentrates on the association events of specific AMD-related SNPs in complement genes without looking into the effect of targeting these SNPs and therefore influencing the complement system in AMD pathogenesis. This review will explore the current understanding of manipulating the complement system in AMD pathogenesis utilising the genomic manipulation powers of the CRISPR/Cas systems. A number of AMD-related SNPs in different complement factor genes will be explored, with a particular emphasis on factor H (CFH), factor B (CFB), and complement C3 (C3).
\n \n\n \n \nBackground/aimsTo investigate the clinical effectiveness of adjunctive triamcinolone acetonide (TA) given at the time of vitreoretinal surgery following open globe trauma (OGT).MethodsA phase 3, multicentre, double-masked randomised controlled trial of patients undergoing vitrectomy following OGT comparing adjunctive TA (intravitreal and subtenons) against standard care (2014-2020). The primary outcome was the proportion of patients with at least 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letter improvement in corrected visual acuity (VA) at 6 months. Secondary outcomes included: change in ETDRS, retinal detachment (RD) secondary to PVR, retinal reattachment, macular reattachment, tractional RD, number of operations, hypotony, elevated intraocular pressure and quality of life.Results280 patients were randomised over 75 months, of which 259 completed the study. 46.9% (n=61/130) of patients in the treatment group had a 10-letter improvement in VA compared with 43.4% (n=56/129) of the control group (difference 3.5% (95% CI -8.6% to 15.6%), OR=1.03 (95% CI 0.61 to 1.75), p=0.908)). Secondary outcome measures also failed to show any treatment benefit. For two of the secondary outcome measures, stable complete retinal and macular reattachment, outcomes were worse in the treatment group compared with controls, respectively, 51.6% (n=65/126) vs 64.2% (n=79/123), OR=0.59 (95% CI 0.36 to 0.99), and 54.0% (n=68/126) vs 66.7% (n=82/123), OR=0.59 (95% CI 0.35 to 0.98), for TA vs control.ConclusionThe use of combined intraocular and sub-Tenons capsule TA is not recommended as an adjunct to vitrectomy surgery following OGT.Trial registration numberNCT02873026.
\n \n\n \n \nINTRODUCTION: Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy. METHODS AND MATERIALS: Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype. RESULTS: A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C\u2009>\u2009G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls. DISCUSSION: Mild choroideremia may result from\u2009+3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.
\n \n\n \n \nABSTRACT\nPatched 1 (PTCH1) is the primary receptor for the sonic hedgehog (SHH) ligand and negatively regulates SHH signalling, an essential pathway in human embryogenesis. Loss-of-function mutations in PTCH1 are associated with altered neuronal development and the malignant brain tumour medulloblastoma. As a result of differences between murine and human development, molecular and cellular perturbations that arise from human PTCH1 mutations remain poorly understood. Here, we used cerebellar organoids differentiated from human induced pluripotent stem cells combined with CRISPR/Cas9 gene editing to investigate the earliest molecular and cellular consequences of PTCH1 mutations on human cerebellar development. Our findings demonstrate that developmental mechanisms in cerebellar organoids reflect in vivo processes of regionalisation and SHH signalling, and offer new insights into early pathophysiological events of medulloblastoma tumorigenesis without the use of animal models.
\n \n\n \n \nSleep restriction therapy is a behavioural component within cognitive behavioural therapy for insomnia and is an effective standalone treatment for insomnia, but its effect on depressive symptoms remains unclear. This review aimed to synthesise and evaluate the impact of single-component sleep restriction therapy on depressive symptoms relative to a control intervention. We searched electronic databases and sleep-related journals for randomised controlled trials and uncontrolled clinical trials, published from 1 January 1986 until 19 August 2023, that delivered sleep restriction therapy to adults with insomnia. Random-effects meta-analysis of standardised mean differences and Cochrane risk of bias assessment were performed on randomised controlled trials, while uncontrolled clinical trials were discussed narratively. The meta-analysis was pre-registered on PROSPERO (ID: CRD42020191803). We identified seven randomised controlled trials (N\u2009=\u20091102) and two uncontrolled clinical trials (N\u2009=\u200922). Findings suggest that sleep restriction therapy is associated with a medium effect for improvement in depressive symptoms at post-treatment (Nc \u2009=\u20096, g\u2009=\u2009-0.45 [95% confidence interval\u2009=\u2009-0.70 to -0.21], p\u2005
\n \n\n \n \nShortages in the physician anaesthesia workforce have led to proposals to introduce new staff groups, notably in the UK\u00a0National Health Service (NHS) Anaesthesia Associates (AAs) who have shorter training periods than doctors and could potentially contribute to workflow efficiencies in several ways. We analysed the economic viability of the most efficient staffing model, previously endorsed by both the UK Royal College of Anaesthetists and the Association of Anaesthetists, wherein one physician supervises two AAs across two operating lists (1:2 model). For this model to be economically rational (something which neither national organisation considered), the employment cost of the two AAs should be equal to or less than that of a single supervisor physician (i.e. AAs should be paid <50% of the supervisor's salary). As the supervisor can be an autonomous specialty and specialist (SAS) doctor, this sets the economically viable AA salary envelope at less than \u00a340,000 per year. However, we report that actual advertised AA salaries greatly exceed this, with even student AAs paid up to \u00a348,472. Economically, one way to justify such salaries is for AAs to become autonomous such that they eventually replace SAS doctors at a lower cost. We discuss some other options that might increase AA productivity to justify these salaries (e.g. \u22651:3 staffing ratios), but the medico-political consequences of each of them are also profound. Alternatively, the AA programme should be terminated as economically nonviable. These results have implications for any country seeking to introduce new models of working in anaesthesia.
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