RÉSUMÉ
BACKGROUND: Palliative treatment options for painful hepatic cancer can be restricted due to patients eventually becoming refractory to standard treatment. The aim of this study was to determine whether radiotherapy improves hepatic pain from cancer. METHODS: In this open-label, randomised, controlled, phase 3 trial (CCTG HE1) done in nine cancer centres across Canada, we included patients aged 18 years or older with hepatocellular carcinoma or liver metastases, who were refractory to standard treatment, with an Eastern Cooperative Oncology Group performance status of 0-3, with life expectancy of more than 3 months, and pain or discomfort at its worst in the past 24 hours on the Brief Pain Inventory (BPI) of at least 4 out of 10, which was stable for up to 7 days before randomisation. Patients were randomly assigned (1:1), via a minimisation method after stratification by centre and type of cancer (hepatocellular carcinoma vs liver metastases), to single-fraction radiotherapy (8 Gy) to the liver with 8 mg ondansetron (or equivalent) orally and 4 mg dexamethasone orally given 1-2 h before radiotherapy plus best supportive care (including non-opioid or opioid analgesia, or dexamethasone, or a combination of these) or best supportive care alone. The primary endpoint was improvement in patient-reported liver cancer pain or discomfort of at least 2 points on worst pain intensity on the BPI at 1 month after randomisation. All patients with both baseline and 1-month assessments were included in the primary endpoint analysis. Safety was assessed in all patients randomly assigned to treatment. This trial is registered with ClinicalTrials.gov, NCT02511522, and is complete. FINDINGS: Between July 25, 2015, and June 2, 2022, 66 patients were screened and randomly assigned to radiotherapy plus best supportive care (n=33) or best supportive care (n=33). Median age was 65 years (IQR 57-72), 37 (56%) of 66 patients were male, 29 (44%) were female, 43 (65%) had liver metastases, and 23 (35%) had hepatocellular carcinoma (data on race and ethnicity were not collected). As of data cutoff (Sept 8, 2022), median follow-up was 3·2 months (95% CI 3·0-3·4). 24 (73%) of 33 in the radiotherapy plus best supportive care group and 18 (55%) of 33 in the best supportive care only group completed baseline and 1-month assessments. An improvement in hepatic pain of at least 2 points in worst pain intensity on the BPI at 1 month was seen in 16 (67%) of 24 patients in the radiotherapy plus best supportive care group versus four (22%) of 18 patients in the best supportive care group (p=0·0042). The most common grade 3-4 adverse events within 1 month after randomisation were abdominal pain (three [9%] of 33 in the radiotherapy group vs one [3%] of 33 in best supportive care group) and ascites (two [6%] vs one [3%]). No serious adverse events or treatment-related deaths were observed. INTERPRETATION: Single-fraction radiotherapy plus best supportive care improved pain compared with best supportive care alone in patients with liver cancer, and could be considered a standard palliative treatment. FUNDING: Canadian Cancer Society.
RÉSUMÉ
Background Current terms used to describe the MRI findings for musculoskeletal infections are nonspecific and inconsistent. Purpose To develop and validate an MRI-based musculoskeletal infection classification and scoring system. Materials and Methods In this retrospective cross-sectional internal validation study, a Musculoskeletal Infection Reporting and Data System (MSKI-RADS) was designed. Adult patients with radiographs and MRI scans of suspected extremity infections with a known reference standard obtained between June 2015 and May 2019 were included. The scoring categories were as follows: 0, incomplete imaging; I, negative for infection; II, superficial soft-tissue infection; III, deeper soft-tissue infection; IV, possible osteomyelitis (OM); V, highly suggestive of OM and/or septic arthritis; VI, known OM; and NOS (not otherwise specified), nonspecific bone lesions. Interreader agreement for 20 radiologists from 13 institutions (intraclass correlation coefficient [ICC]) and true-positive rates of MSKI-RADS were calculated and the accuracy of final diagnoses rendered by the readers was compared using generalized estimating equations for clustered data. Results Among paired radiographs and MRI scans from 208 patients (133 male, 75 female; mean age, 55 years ± 13 [SD]), 20 were category I; 34, II; 35, III; 30, IV; 35, V; 18, VI; and 36, NOS. Moderate interreader agreement was observed among the 20 readers (ICC, 0.70; 95% CI: 0.66, 0.75). There was no evidence of correlation between reader experience and overall accuracy (P = .94). The highest true-positive rate was for MSKI-RADS I and NOS at 88.7% (95% CI: 84.6, 91.7). The true-positive rate was 73% (95% CI: 63, 80) for MSKI-RADS V. Overall reader accuracy using MSKI-RADS across all patients was 65% ± 5, higher than final reader diagnoses at 55% ± 7 (P < .001). Conclusion MSKI-RADS is a valid system for standardized terminology and recommended management of imaging findings of peripheral extremity infections across various musculoskeletal-fellowship-trained reader experience levels. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Schweitzer in this issue.
Sujet(s)
Imagerie par résonance magnétique , Humains , Imagerie par résonance magnétique/méthodes , Mâle , Femelle , Adulte d'âge moyen , Études rétrospectives , Études transversales , Systèmes d'information de radiologie , Membres/imagerie diagnostique , Adulte , Maladies ostéomusculaires/imagerie diagnostique , Sujet âgé , Reproductibilité des résultatsRÉSUMÉ
The accumulation of amyloid fibrils has been identified in tissues outside the brain, yet little is understood about the formation of extracerebral amyloidosis and its impact on the aging process of these organs. Here, we demonstrate that both transgenic mice modeling Alzheimer's disease (AD) and naturally aging mice exhibit accumulated senescent bone marrow adipocytes (BMAds), accompanied by amyloid deposits surrounding the BMAds. Senescent BMAds acquire a secretory phenotype, resulting in a marked increase in the secretion of serum amyloid P component (SAP), also known as pentraxin 2 (PTX2). SAP/PTX2 colocalizes with amyloid deposits around senescent BMAds in vivo and is sufficient to promote the formation of insoluble amyloid deposits from soluble Aß peptides in in vitro and ex vivo 3D BMAd-based culture experiments. Additionally, Combined treatment with SAP/PTX2 and Aß peptides promotes osteoclastogenesis but inhibits osteoblastogenesis of the precursor cells. Transplantation of senescent BMAds into the bone marrow cavity of healthy young mice is sufficient to induce bone loss. Finally, pharmacological depletion of SAP/PTX2 from aged mice abolishes bone marrow amyloid deposition and effectively rescues the low bone mass phenotype. Thus, senescent BMAds, through the secretion of SAP/PTX2, contribute to the age-associated development of skeletal amyloidosis and resultant bone deficits.
RÉSUMÉ
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis in the world and can lead to severe complications in immunocompromised individuals. HEV is primarily transmitted through eating pork, which has led to an increased in anti-HEV IgG seropositivity in the general population of Europe in particular. However, it can also be transmitted intravenously, such as through transfusions. The growing evidence of HEV contamination of blood products and documented cases of transmission have given rise to practice changes and blood product screening of HEV in many European countries. This review covers the abundant European literature and focuses on the most recent data pertaining to the prevalence of HEV RNA positivity and IgG seropositivity in the North American general population and in blood products from Canada and the United States. Currently, Health Canada and the Food and Drug Administration do not require testing of HEV in blood products. For this reason, awareness among blood product prescribers about the possibility of HEV transmission through blood products is crucial. However, we also demonstrate that the province of Quebec has a prevalence of anti-HEV and HEV RNA positivity similar to some European countries. In light of this, we believe that HEV RNA blood donation screening be reevaluated with the availability of more cost-effective assays.
Sujet(s)
Donneurs de sang , Sélection de donneurs , Virus de l'hépatite E , Hépatite E , Humains , Hépatite E/épidémiologie , Hépatite E/diagnostic , Hépatite E/transmission , Canada/épidémiologie , États-Unis/épidémiologie , Virus de l'hépatite E/isolement et purification , Virus de l'hépatite E/immunologie , Sélection de donneurs/méthodes , ARN viral/sang , Dépistage de masse/méthodes , Prévalence , Anticorps de l'hépatite/sang , Sécurité transfusionnelle , Immunoglobuline G/sang , Don de sangRÉSUMÉ
Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of 6 cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome single nucleotide polymorphism Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through homologous recombination deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, whereas sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma.
RÉSUMÉ
TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer's Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp f/f mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp f/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.
RÉSUMÉ
The consumption value seems to be insufficient to explain consumers' domestic electric vehicle purchase behaviour, especially in a highly competitive global environment. This study aims to investigate how consumer ethnocentrism and perceived interactivity influence consumption value and pro-environmental value, subsequently affecting attitude and intention. A total of 353 valid questionnaires were collected through convenience sampling in Xuzhou, China, and the partial least square (PLS) path modelling approach was performed to test the hypotheses. The results show that consumer ethnocentrism and perceived interactivity positively influence function value, emotional value, and social value; perceived interactivity also positively influences altruistic value, biospheric value, and collectivistic value. Function value, social value, and collectivistic value positively influence attitude; however, emotional value, altruistic value and biospheric value did not find a correlation with attitude. Furthermore, attitude positively influences intention to adopt domestic electric vehicles. Finally, the theoretical and practical implications, as well as limitations were discussed accordingly.
Sujet(s)
Comportement du consommateur , Intention , Humains , Mâle , Femelle , Adulte , Chine , Attitude , Jeune adulte , Valeurs sociales , Enquêtes et questionnaires , Automobiles , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. METHODS: We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. RESULTS: Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. CONCLUSIONS: Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.
Sujet(s)
Protéines de liaison à l'ADN , Exons , Humains , Exons/génétique , Animaux , Protéines de liaison à l'ADN/génétique , Protéines de liaison à l'ADN/métabolisme , Souris , Neurones/métabolisme , Encéphale/métabolisme , Épissage des ARN/génétique , Noyau de la cellule/métabolisme , Protéinopathies TDP-43/génétique , Protéinopathies TDP-43/métabolisme , Protéinopathies TDP-43/anatomopathologieRÉSUMÉ
We describe the first microfluidic device for in vitro testing of brachytherapy (BT), with applications in translational cancer research. Our PDMS-made BT-on-chip system allows highly precise manual insertion of clinical BT seeds, reliable dose calculation using standard clinically-used TG-43 formalism and easy culture of naturally hypoxic spheroids in less than 3 days, thereby increasing the translational potential of the device. As the BT-on-chip platform is designed to be versatile, we showcase three different gold-standard post-irradiation bioassays and recapitulate, for the first time on-chip, key clinical observations such as dose rate effect and hypoxia-induced radioresistance. Our results suggest that BT-on-chip can be used to safely and efficiently integrate BT and radiotherapy to translational research and drug development pipelines, without expensive equipment or complex workflows.
Sujet(s)
Curiethérapie , Curiethérapie/méthodes , Dosimétrie en radiothérapie , BiologieRÉSUMÉ
Nuclear clearance and cytoplasmic aggregation of TDP-43 in neurons, initially identified in ALS-FTD, are hallmark pathological features observed across a spectrum of neurodegenerative diseases. We previously found that TDP-43 loss-of-function leads to the transcriptome-wide inclusion of deleterious cryptic exons in brains and biofluids post-mortem as well as during the presymptomatic stage of ALS-FTD, but upstream mechanisms that lead to TDP-43 dysregulation remain unclear. Here, we developed a web-based resource (SnapMine) to determine the levels of TDP-43 cryptic exon inclusion across hundreds of thousands of publicly available RNA sequencing datasets. We established cryptic exon inclusion across a variety of human cells and tissues to provide ground truth references for future studies on TDP-43 dysregulation. We then explored studies that were entirely unrelated to TDP-43 or neurodegeneration and found that ciclopirox olamine (CPX), an FDA-approved antifungal, can trigger the inclusion of TDP-43-associated cryptic exons in a variety of mouse and human primary cells. CPX induction of cryptic exon occurs via heavy metal toxicity and oxidative stress, suggesting that similar vulnerabilities could play a role in neurodegeneration. Our work demonstrates how diverse datasets can be linked through common biological features and underscores that public archives of sequencing data represent a vastly underutilized resource with tremendous potential for uncovering novel insights into complex biological mechanisms and diseases.
RÉSUMÉ
BACKGROUND: Hypertension guidelines recommend diagnosis and treatment of obstructive sleep apnea (OSA) in patients with hypertension. The mandibular advancement device (MAD) is an oral appliance therapy for patients who decline or cannot tolerate continuous positive airway pressure (CPAP). OBJECTIVES: We compared the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure (BP). METHODS: In an investigator-initiated, randomized, noninferiority trial (prespecified margin 1.5 mm Hg), 321 participants aged ≥40 years with hypertension and increased cardiovascular risk were recruited at 3 public hospitals for polysomnography. Of these, 220 participants with moderate-to-severe OSA (apnea-hypopnea index ≥15 events per hour) were randomized to either MAD or CPAP (1:1). The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. RESULTS: Compared with baseline, the 24-hour mean arterial BP decreased by 2.5 mm Hg (P = 0.003) at 6 months in the MAD group, whereas no change was observed in the CPAP group (P = 0.374). The between-group difference was -1.6 mm Hg (95% CI: -3.51 to 0.24, noninferiority P < 0.001). The MAD group demonstrated a larger between-group reduction in all secondary ambulatory BP parameters compared with the CPAP group, with the most pronounced effects observed in the asleep BP parameters. Both the MAD and CPAP improved daytime sleepiness, with the between-group difference similar (P = 0.384). There were no between-group differences in cardiovascular biomarkers. CONCLUSIONS: MAD is noninferior to CPAP for reducing 24-hour mean arterial BP in participants with hypertension and increased cardiovascular risk. (Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling-Non-inferiority Trial [CRESCENT]; NCT04119999).
Sujet(s)
Pression sanguine , Ventilation en pression positive continue , Hypertension artérielle , Avancement mandibulaire , Syndrome d'apnées obstructives du sommeil , Humains , Syndrome d'apnées obstructives du sommeil/thérapie , Syndrome d'apnées obstructives du sommeil/physiopathologie , Ventilation en pression positive continue/méthodes , Mâle , Femelle , Adulte d'âge moyen , Avancement mandibulaire/instrumentation , Hypertension artérielle/thérapie , Hypertension artérielle/physiopathologie , Hypertension artérielle/complications , Pression sanguine/physiologie , Polysomnographie , Sujet âgé , Surveillance ambulatoire de la pression artérielle/méthodes , Résultat thérapeutiqueRÉSUMÉ
The spread of prion-like protein aggregates is a common driver of pathogenesis in various neurodegenerative diseases, including Alzheimer's disease (AD) and related Tauopathies. Tau pathologies exhibit a clear progressive spreading pattern that correlates with disease severity. Clinical observation combined with complementary experimental studies has shown that Tau preformed fibrils (PFF) are prion-like seeds that propagate pathology by entering cells and templating misfolding and aggregation of endogenous Tau. While several cell surface receptors of Tau are known, they are not specific to the fibrillar form of Tau. Moreover, the underlying cellular mechanisms of Tau PFF spreading remain poorly understood. Here, it is shown that the lymphocyte-activation gene 3 (Lag3) is a cell surface receptor that binds to PFF but not the monomer of Tau. Deletion of Lag3 or inhibition of Lag3 in primary cortical neurons significantly reduces the internalization of Tau PFF and subsequent Tau propagation and neuron-to-neuron transmission. Propagation of Tau pathology and behavioral deficits induced by injection of Tau PFF in the hippocampus and overlying cortex are attenuated in mice lacking Lag3 selectively in neurons. These results identify neuronal Lag3 as a receptor of pathologic Tau in the brainï¼and for AD and related Tauopathies, a therapeutic target.
Sujet(s)
Protéine LAG-3 , Neurones , Tauopathies , Protéines tau , Animaux , Humains , Souris , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/génétique , Maladie d'Alzheimer/anatomopathologie , Antigènes CD/métabolisme , Antigènes CD/génétique , Modèles animaux de maladie humaine , Neurones/métabolisme , Protéines tau/métabolisme , Protéines tau/génétique , Tauopathies/métabolisme , Tauopathies/génétique , Tauopathies/anatomopathologieRÉSUMÉ
Electronic Health Record (EHR) systems increase clerical workload, promote copy-paste and error propagation. Documentation error rate in cancer diagnosis and treatment was examined in 776 patient records. Fifteen percent of the charts contained an error. Modern EHR systems, patient portals and engagement tools may facilitate the maintenance of accurate information.
RÉSUMÉ
OBJECTIVE: To determine the inter-reader reliability and diagnostic performance of classification and severity scales of Neuropathy Score Reporting And Data System (NS-RADS) among readers of differing experience levels after limited teaching of the scoring system. METHODS: This is a multi-institutional, cross-sectional, retrospective study of MRI cases of proven peripheral neuropathy (PN) conditions. Thirty-two radiology readers with varying experience levels were recruited from different institutions. Each reader attended and received a structured presentation that described the NS-RADS classification system containing examples and reviewed published articles on this subject. The readers were then asked to perform NS-RADS scoring with recording of category, subcategory, and most likely diagnosis. Inter-reader agreements were evaluated by Conger's kappa and diagnostic accuracy was calculated for each reader as percent correct diagnosis. A linear mixed model was used to estimate and compare accuracy between trainees and attendings. RESULTS: Across all readers, agreement was good for NS-RADS category and moderate for subcategory. Inter-reader agreement of trainees was comparable to attendings (0.65 vs 0.65). Reader accuracy for attendings was 75% (95% CI 73%, 77%), slightly higher than for trainees (71% (69%, 72%), p = 0.0006) for nerves and comparable for muscles (attendings, 87.5% (95% CI 86.1-88.8%) and trainees, 86.6% (95% CI 85.2-87.9%), p = 0.4). NS-RADS accuracy was also higher than average accuracy for the most plausible diagnosis for attending radiologists at 67% (95% CI 63%, 71%) and for trainees at 65% (95% CI 60%, 69%) (p = 0.036). CONCLUSION: Non-expert radiologists interpreted PN conditions with good accuracy and moderate-to-good inter-reader reliability using the NS-RADS scoring system. CLINICAL RELEVANCE STATEMENT: The Neuropathy Score Reporting And Data System (NS-RADS) is an accurate and reliable MRI-based image scoring system for practical use for the diagnosis and grading of severity of peripheral neuromuscular disorders by both experienced and general radiologists. KEY POINTS: ⢠The Neuropathy Score Reporting And Data System (NS-RADS) can be used effectively by non-expert radiologists to categorize peripheral neuropathy. ⢠Across 32 different experience-level readers, the agreement was good for NS-RADS category and moderate for NS-RADS subcategory. ⢠NS-RADS accuracy was higher than the average accuracy for the most plausible diagnosis for both attending radiologists and trainees (at 75%, 71% and 65%, 65%, respectively).
Sujet(s)
Imagerie par résonance magnétique , Biais de l'observateur , Neuropathies périphériques , Humains , Neuropathies périphériques/imagerie diagnostique , Imagerie par résonance magnétique/méthodes , Études transversales , Études rétrospectives , Reproductibilité des résultats , Femelle , Mâle , Adulte d'âge moyen , Adulte , Sujet âgé , Indice de gravité de la maladie , Radiologues , Compétence clinique , Radiologie/enseignement et éducationRÉSUMÉ
Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS-FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS-FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS-FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials.
Sujet(s)
Sclérose latérale amyotrophique , Démence frontotemporale , Humains , Démence frontotemporale/génétique , Sclérose latérale amyotrophique/génétique , Protéine C9orf72/génétique , Protéines de liaison à l'ADN/génétique , Protéines de liaison à l'ADN/métabolisme , Marqueurs biologiques/liquide cérébrospinalRÉSUMÉ
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.
Sujet(s)
Sclérose latérale amyotrophique , Maladies neurodégénératives , Humains , Sclérose latérale amyotrophique/diagnostic , Marqueurs biologiques , MotoneuronesRÉSUMÉ
The bookings and revenues of youth hostels have significantly decreased because of the multiple effects of the COVID-19 pandemic. It is necessary to investigate young consumers' perceptions of visiting youth hostels aftermath this pandemic. The current study examines the relationship between multi-dimensions of perceived risk, three types of images, willingness to pay and visit intention. A convenience sampling was developed where 534 questionnaires were received, followed by subsequent empirical testing of the proposed hypotheses using SPSS and AMOS-SEM. Results showed that perceived risk negatively influenced cognitive and affective image, respectively. Cognitive and affective image positively influenced overall image and finally influenced willingness to pay and visit intention separately. In addition, cognitive image positively influenced affective image. The theoretical framework satisfactorily accounted for willingness to pay and intention, and our results help youth hostels practitioners invent efficient strategies to boost young consumers' willingness to pay and intention to visit youth hostels.
Sujet(s)
COVID-19 , Humains , Adolescent , COVID-19/épidémiologie , Pandémies , Intention , Enquêtes et questionnaires , Comportement du consommateurRÉSUMÉ
INTRODUCTION: The aim of this systematic review was to summarize the current literature on wearable technologies in oncology patients for the purpose of prognostication, treatment monitoring, and rehabilitation planning. METHODS: A search was conducted in Medline ALL, Cochrane Central Register of Controlled Trials, Embase, Emcare, CINAHL, Scopus, and Web of Science, up until February 2022. Articles were included if they reported on consumer grade and/or non-commercial wearable devices in the setting of either prognostication, treatment monitoring or rehabilitation. RESULTS: We found 199 studies reporting on 18 513 patients suitable for inclusion. One hundred and eleven studies used wearable device data primarily for the purposes of rehabilitation, 68 for treatment monitoring, and 20 for prognostication. The most commonly-reported brands of wearable devices were ActiGraph (71 studies; 36%), Fitbit (37 studies; 19%), Garmin (13 studies; 7%), and ActivPAL (11 studies; 6%). Daily minutes of physical activity were measured in 121 studies (61%), and daily step counts were measured in 93 studies (47%). Adherence was reported in 86 studies, and ranged from 40% to 100%; of these, 63 (74%) reported adherence in excess of 80%. CONCLUSION: Wearable devices may provide valuable data for the purposes of treatment monitoring, prognostication, and rehabilitation. Future studies should investigate live-time monitoring of collected data, which may facilitate directed interventions.