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JMIR AI Mar 2024Central collection of distributed medical patient data is problematic due to strict privacy regulations. Especially in clinical environments, such as clinical...
BACKGROUND
Central collection of distributed medical patient data is problematic due to strict privacy regulations. Especially in clinical environments, such as clinical time-to-event studies, large sample sizes are critical but usually not available at a single institution. It has been shown recently that federated learning, combined with privacy-enhancing technologies, is an excellent and privacy-preserving alternative to data sharing.
OBJECTIVE
This study aims to develop and validate a privacy-preserving, federated survival support vector machine (SVM) and make it accessible for researchers to perform cross-institutional time-to-event analyses.
METHODS
We extended the survival SVM algorithm to be applicable in federated environments. We further implemented it as a FeatureCloud app, enabling it to run in the federated infrastructure provided by the FeatureCloud platform. Finally, we evaluated our algorithm on 3 benchmark data sets, a large sample size synthetic data set, and a real-world microbiome data set and compared the results to the corresponding central method.
RESULTS
Our federated survival SVM produces highly similar results to the centralized model on all data sets. The maximal difference between the model weights of the central model and the federated model was only 0.001, and the mean difference over all data sets was 0.0002. We further show that by including more data in the analysis through federated learning, predictions are more accurate even in the presence of site-dependent batch effects.
CONCLUSIONS
The federated survival SVM extends the palette of federated time-to-event analysis methods by a robust machine learning approach. To our knowledge, the implemented FeatureCloud app is the first publicly available implementation of a federated survival SVM, is freely accessible for all kinds of researchers, and can be directly used within the FeatureCloud platform.
PubMed: 38875678
DOI: 10.2196/47652 -
Modern Rheumatology Case Reports Jun 2024A 53-year-old woman with recurrent stomatitis, genital ulcers, and folliculitis was admitted to our hospital after experiencing visual disturbances for the past two...
A 53-year-old woman with recurrent stomatitis, genital ulcers, and folliculitis was admitted to our hospital after experiencing visual disturbances for the past two weeks, and a non-throbbing headache for the past three days. She had also developed numbness in her left extremities. An ophthalmological examination revealed inflammatory changes in the eye. Cerebrospinal fluid analysis showed increased cell counts, protein, and interleukin-6 levels. Brain magnetic resonance imaging revealed multiple high signal intensities on T2-weighted (T2W)/fluid-attenuated inversion recovery (FLAIR) images of the pons and occipital and parietal lobes. The T2W/FLAIR high-signal-intensity lesion in the pons was hyperintense on diffusion-weighted imaging (DWI) and hypointense on apparent diffusion coefficient mapping (ADC), suggesting cytotoxic edema. Another high-signal-intensity lesion on T2W/FLAIR was isointense to hyperintense on DWI and hyperintense on ADC, indicating vasogenic edema. The vasogenic edema in the left occipital lobe contained a small core that was hyperintense on DWI and hypointense on ADC, suggesting cytotoxic edema. The patient was diagnosed with acute neuro-Behçet's disease (neuro-BD) and responded well to high-dose glucocorticoid and colchicine treatment. The present report emphasizes that patients with acute neuro-BD may present with cytotoxic edema in the pons and cerebral spheres. Further reports of similar cases would contribute to a better understanding of the role of cytotoxic edema in the pathophysiology of neuro-BD and help elucidate the mechanisms underlying a unique presentation characterized by a central cytotoxic edema core within vasogenic edema. (233 words).
PubMed: 38874595
DOI: 10.1093/mrcr/rxae032 -
Molecular Cell Jun 2024Ribosome assembly requires precise coordination between the production and assembly of ribosomal components. Mutations in ribosomal proteins that inhibit the assembly...
Ribosome assembly requires precise coordination between the production and assembly of ribosomal components. Mutations in ribosomal proteins that inhibit the assembly process or ribosome function are often associated with ribosomopathies, some of which are linked to defects in proteostasis. In this study, we examine the interplay between several yeast proteostasis enzymes, including deubiquitylases (DUBs) Ubp2 and Ubp14, and E3 ligases Ufd4 and Hul5, and we explore their roles in the regulation of the cellular levels of K29-linked unanchored polyubiquitin (polyUb) chains. Accumulating K29-linked unanchored polyUb chains associate with maturing ribosomes to disrupt their assembly, activate the ribosome assembly stress response (RASTR), and lead to the sequestration of ribosomal proteins at the intranuclear quality control compartment (INQ). These findings reveal the physiological relevance of INQ and provide insights into mechanisms of cellular toxicity associated with ribosomopathies.
Topics: Ribosomal Proteins; Ribosomes; Saccharomyces cerevisiae Proteins; Saccharomyces cerevisiae; Polyubiquitin; Ubiquitin-Protein Ligases; Ubiquitination; Proteostasis; Cell Nucleus
PubMed: 38870935
DOI: 10.1016/j.molcel.2024.05.018 -
Neuroscience Bulletin Jun 2024This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been...
This study aimed to identify possible pathogenic genes in a 90-member family with a rare combination of multiple neurodegenerative disease phenotypes, which has not been depicted by the known neurodegenerative disease. We performed physical and neurological examinations with International Rating Scales to assess signs of ataxia, Parkinsonism, and cognitive function, as well as brain magnetic resonance imaging scans with seven sequences. We searched for co-segregations of abnormal repeat-expansion loci, pathogenic variants in known spinocerebellar ataxia-related genes, and novel rare mutations via whole-genome sequencing and linkage analysis. A rare co-segregating missense mutation in the CARS gene was validated by Sanger sequencing and the aminoacylation activity of mutant CARS was measured by spectrophotometric assay. This pedigree presented novel late-onset core characteristics including cerebellar ataxia, Parkinsonism, and pyramidal signs in all nine affected members. Brain magnetic resonance imaging showed cerebellar/pons atrophy, pontine-midline linear hyperintensity, decreased rCBF in the bilateral basal ganglia and cerebellar dentate nucleus, and hypo-intensities of the cerebellar dentate nuclei, basal ganglia, mesencephalic red nuclei, and substantia nigra, all of which suggested neurodegeneration. Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, meanwhile, exhibited none of the known repeat-expansions or point mutations in pathogenic genes. Remarkably, this CARS mutation causes a 20% decrease in aminoacylation activity to charge tRNA with L-cysteine in protein synthesis compared with that of the wild type. All family members carrying a heterozygous mutation CARS (E795V) had the same clinical manifestations and neuropathological changes of Parkinsonism and spinocerebellar-ataxia. These findings identify novel pathogenesis of Parkinsonism-spinocerebellar ataxia and provide insights into its genetic architecture.
PubMed: 38869703
DOI: 10.1007/s12264-024-01231-0 -
European Journal of Nuclear Medicine... Jun 2024A hypometabolic profile involving the limbic areas, brainstem and cerebellum has been identified in long COVID patients using [F]fluorodeoxyglucose (FDG)-PET. This study...
PURPOSE
A hypometabolic profile involving the limbic areas, brainstem and cerebellum has been identified in long COVID patients using [F]fluorodeoxyglucose (FDG)-PET. This study was conducted to evaluate possible recovery of brain metabolism during the follow-up of patients with prolonged symptoms.
METHODS
Fifty-six adults with long COVID who underwent two brain [F]FDG-PET scans in our department between May 2020 and October 2022 were retrospectively analysed, and compared to 51 healthy subjects. On average, PET1 was performed 7 months (range 3-17) after acute COVID-19 infection, and PET2 was performed 16 months (range 8-32) after acute infection, because of persistent severe or disabling symptoms, without significant clinical recovery. Whole-brain voxel-based analysis compared PET1 and PET2 from long COVID patients to scans from healthy subjects (p-voxel < 0.001 uncorrected, p-cluster < 0.05 FWE-corrected) and PET1 to PET2 (with the same threshold, and secondarily with a less constrained threshold of p-voxel < 0.005 uncorrected, p-cluster < 0.05 uncorrected). Additionally, a region-of-interest (ROI) semiquantitative anatomical approach was performed for the same comparisons (p < 0.05, corrected).
RESULTS
PET1 and PET2 revealed voxel-based hypometabolisms consistent with the previously reported profile in the literature. This between-group analysis comparing PET1 and PET2 showed minor improvements in the pons and cerebellum (8.4 and 5.2%, respectively, only significant under the less constrained uncorrected p-threshold); for the pons, this improvement was correlated with the PET1-PET2 interval (r = 0.21, p < 0.05). Of the 14,068 hypometabolic voxels identified on PET1, 6,503 were also hypometabolic on PET2 (46%). Of the 7,732 hypometabolic voxels identified on PET2, 6,094 were also hypometabolic on PET1 (78%). The anatomical ROI analysis confirmed the brain hypometabolism involving limbic region, the pons and cerebellum at PET1 and PET2, without significant changes between PET1 and PET2.
CONCLUSION
Subjects with persistent symptoms of long COVID exhibit durable deficits in brain metabolism, without progressive worsening.
PubMed: 38862619
DOI: 10.1007/s00259-024-06775-x -
Animal Models and Experimental Medicine Jun 2024Severe trauma is associated with systemic inflammation and organ dysfunction. Preclinical rodent trauma models are the mainstay of postinjury research but have been...
BACKGROUND
Severe trauma is associated with systemic inflammation and organ dysfunction. Preclinical rodent trauma models are the mainstay of postinjury research but have been criticized for not fully replicating severe human trauma. The aim of this study was to create a rat model of multicompartmental injury which recreates profound traumatic injury.
METHODS
Male Sprague-Dawley rats were subjected to unilateral lung contusion and hemorrhagic shock (LCHS), multicompartmental polytrauma (PT) (unilateral lung contusion, hemorrhagic shock, cecectomy, bifemoral pseudofracture), or naïve controls. Weight, plasma toll-like receptor 4 (TLR4), hemoglobin, spleen to body weight ratio, bone marrow (BM) erythroid progenitor (CFU-GEMM, BFU-E, and CFU-E) growth, plasma granulocyte colony-stimulating factor (G-CSF) and right lung histologic injury were assessed on day 7, with significance defined as p values <0.05 (*).
RESULTS
Polytrauma resulted in markedly more profound inhibition of weight gain compared to LCHS (p = 0.0002) along with elevated plasma TLR4 (p < 0.0001), lower hemoglobin (p < 0.0001), and enlarged spleen to body weight ratios (p = 0.004). Both LCHS and PT demonstrated suppression of CFU-E and BFU-E growth compared to naïve (p < 0.03, p < 0.01). Plasma G-CSF was elevated in PT compared to both naïve and LCHS (p < 0.0001, p = 0.02). LCHS and PT demonstrated significant histologic right lung injury with poor alveolar wall integrity and interstitial edema.
CONCLUSIONS
Multicompartmental injury as described here establishes a reproducible model of multicompartmental injury with worsened anemia, splenic tissue enlargement, weight loss, and increased inflammatory activity compared to a less severe model. This may serve as a more effective model to recreate profound traumatic injury to replicate the human inflammatory response postinjury.
PubMed: 38860566
DOI: 10.1002/ame2.12447 -
Muscle & Nerve Jun 2024Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant...
INTRODUCTION/AIMS
Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage-gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease-causing variants in the CLCN1 gene have been reported. This study provides an MC genotype-phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G.
METHODS
Sanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines.
RESULTS
Sixty-one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in-cis with the c.1649C > G.
DISCUSSION
The large number of patients in whom a diagnosis was established allowed the characterization of genotype-phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.
PubMed: 38855810
DOI: 10.1002/mus.28180 -
Central Pontine Myelinolysis: A Rare and Life-Threatening Adverse Effect of Clobazam and Quetiapine.Cureus May 2024Central pontine myelinolysis (CPM) is a rare neurological disorder characterized by demyelination within the central portion of the pons. While hyponatremia is a...
Central pontine myelinolysis (CPM) is a rare neurological disorder characterized by demyelination within the central portion of the pons. While hyponatremia is a well-known precipitating factor, other etiologies, including medication use, have been reported. We present a case of a 69-year-old male with a history of obsessive-compulsive disorder, stroke, and type 2 diabetes mellitus who developed confusion, altered sensorium, and weakness in all four limbs. An MRI brain imaging revealed characteristic findings suggestive of CPM. Despite normal serum sodium levels, discontinuation of clobazam and quetiapine, medications taken by the patient, led to clinical improvement. This case underscores the importance of considering medication-induced CPM in the differential diagnosis of patients presenting with neurological symptoms, even in the absence of electrolyte abnormalities.
PubMed: 38854288
DOI: 10.7759/cureus.60007 -
Hand Surgery & Rehabilitation Jun 2024De Quervain's tendinitis is frequently observed after placement of a trapeziometacarpal prosthesis. The aim of this study was to investigate the relationship between De...
OBJECTIVES
De Quervain's tendinitis is frequently observed after placement of a trapeziometacarpal prosthesis. The aim of this study was to investigate the relationship between De Quervain's tendinitis, osteoarthritis of the thumb and placement of a trapeziometacarpal prosthesis. The second aim was a critical analysis of the literature in search of a cause for this postoperative event after arthroplasty or trapeziectomy.
METHODS
We reviewed a series of 331 trapeziometacarpal prostheses.
RESULTS
There were no differences in thumb column length, gender, type of neck (straight or angled), or surgical approach between patients who developed De Quervain's tendinitis and those who did not. However, the frequency of De Quervain's tendinitis was much higher after arthroplasty than trapeziectomy.
CONCLUSIONS
We believe that the preoperative frequency of De Quervain's tendinitis in trapeziometacarpal osteoarthritis is underestimated, being part of a more general pain symptomatology. More precise and specific examination is needed for a better preoperative diagnosis. Trapeziometacarpal osteoarthritis should be considered within a more global framework of peri-trapeziometacarpal pathology, including the trapeziometacarpal and triscaphoid levels, the articular ligaments and the abductor pollicis longus, extensor pollicis brevis, flexor pollicis longus, and flexor carpi radialis tendons.
PubMed: 38851633
DOI: 10.1016/j.hansur.2024.101737 -
Biomedicine & Pharmacotherapy =... Jul 2024Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the...
Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the behavior of 11 CXC chemokines in the blood of 104 mCRC patients undergoing first-line oxaliplatin-based treatment to pinpoint predictive and prognostic markers. Serum samples were collected before treatment, at response evaluation (EVAR), and at disease progression or last follow-up. Chemokines were assessed in all samples using a Luminex® custom panel. CXCL13 levels increased at EVAR in responders, while in non-responders it decreased. Increasing levels of CXCL13 at EVAR, independently correlated with improved progression-free survival (PFS) and overall survival (OS). Nanostring® analysis in primary tumor samples showed CXCL13 gene expression's positive correlation not only with gene profiles related to an immunogenic tumor microenvironment, increased B cells and T cells (mainly CD8+) but also with extended OS. In silico analysis using RNAseq data from liver metastases treated or not with neoadjuvant oxaliplatin-based combinations, and deconvolution analysis using the MCP-counter algorithm, confirmed CXCL13 gene expression's association with increased immune infiltration, improved OS, and Tertiary Lymphoid Structures (TLSs) gene signatures, especially in neoadjuvant-treated patients. CXCL13 analysis in serum from 36 oxaliplatin-treated patients from the METIMMOX study control arm, reported similar findings. In conclusion, the increase of CXCL13 levels in peripheral blood and its association with the formation of TLSs within the metastatic lesions, emerges as a potential biomarker indicative of the therapeutic efficacy in mCRC patients undergoing oxaliplatin-based treatment.
Topics: Humans; Colorectal Neoplasms; Oxaliplatin; Male; Chemokine CXCL13; Female; Aged; Middle Aged; Biomarkers, Tumor; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Adult; Aged, 80 and over; Progression-Free Survival; Tumor Microenvironment; Prognosis
PubMed: 38850664
DOI: 10.1016/j.biopha.2024.116857