959 research outputs found
TRIO gene segregation in a family with cerebellar ataxia
Get PDFAim of the study: To report a family with a novel TRIO gene mutation associated withphenotype of cerebellar ataxia.
Materials and methods: Seven family members of Caribbean descent were recruited through our ataxia research protocol; of the family members, the mother and all 3 children were found to be affected with severe young-onset and rapidly progressive truncal and appendicular ataxia leading to early disability. Array comparative genomic hybridization, mitochondrial DNA analysis, and whole-exome sequencing were performed on 3 of the family members (mother and 2 daughters).
Results: While the maternal grandmother, great uncle and great aunt were unaffected, the mother and 3 children displayed cognitive dysfunction, severe ataxia, spasticity, and speech disturbances. Age of onset ranged between 3 and 17 years, with average current disease duration of 21 years. Whole-exome sequencing showed a variant p.A1214V in exon 22 of the TRIO gene in 3 of the family members. Array comparative genomic hybridization and mitochondrial DNA analysis were normal. The same variant was later discovered in all but one family member.
Conclusions and clinical implications: The TRIO p.A1214V variant is associated with cerebellar ataxia in the studied family; it was present in all affected and unaffected family members. Phenotype is severe and broad. Anticipation seems to be present (based on 2 affected generations). It is warranted to screen additional familial early-onset and rapidly progressive ataxia cases for this genotype. TRIO gene mutations may well represent a novel spinocerebellar ataxia subtype
Real-Time Studies of Iron Oxalate-Mediated Oxidation of Glycolaldehyde as a Model for Photochemical Aging of Aqueous Tropospheric Aerosols
Get PDFThe complexation of iron (III) with oxalic acid in aqueous solution yields a strongly absorbing chromophore that undergoes efficient photodissociation to give iron (II) and the carbon dioxide anion radical. Importantly, iron (III) oxalate complexes absorb near-UV radiation (λ > 350 nm), providing a potentially powerful source of oxidants in aqueous tropospheric chemistry. Although this photochemical system has been studied extensively, the mechanistic details associated with its role in the oxidation of dissolved organic matter within aqueous aerosol remain largely unknown. This study utilizes glycolaldehyde as a model organic species to examine the oxidation pathways and evolution of organic aerosol initiated by the photodissociation of aqueous iron (III) oxalate complexes. Hanging droplets (radius 1 mm) containing iron (III), oxalic acid, glycolaldehyde, and ammonium sulfate (pH ~ 3) are exposed to irradiation at 365 nm and sampled at discrete time points utilizing field-induced droplet ionization mass spectrometry (FIDI-MS). Glycolaldehyde is found to undergo rapid oxidation to form glyoxal, glycolic acid, and glyoxylic acid, but the formation of high molecular weight oligomers is not observed. For comparison, particle-phase experiments conducted in a laboratory chamber explore the reactive uptake of gas-phase glycolaldehyde onto aqueous seed aerosol containing iron and oxalic acid. The presence of iron oxalate in seed aerosol is found to inhibit aerosol growth. These results suggest that photodissociation of iron (III) oxalate can lead to the formation of volatile oxidation products in tropospheric aqueous aerosols
Outcome of everolimus-based therapy in hormone-receptor-positive metastatic breast cancer patients after progression on palbociclib
Get PDFVirchow: A Million-Slide Digital Pathology Foundation Model
Full text linkComputational pathology uses artificial intelligence to enable precision
medicine and decision support systems through the analysis of whole slide
images. It has the potential to revolutionize the diagnosis and treatment of
cancer. However, a major challenge to this objective is that for many specific
computational pathology tasks the amount of data is inadequate for development.
To address this challenge, we created Virchow, a 632 million parameter deep
neural network foundation model for computational pathology. Using
self-supervised learning, Virchow is trained on 1.5 million hematoxylin and
eosin stained whole slide images from diverse tissue groups, which is orders of
magnitude more data than previous works. When evaluated on downstream tasks
including tile-level pan-cancer detection and subtyping and slide-level
biomarker prediction, Virchow outperforms state-of-the-art systems both on
internal datasets drawn from the same population as the pretraining data as
well as external public datasets. Virchow achieves 93% balanced accuracy for
pancancer tile classification, and AUCs of 0.983 for colon microsatellite
instability status prediction and 0.967 for breast CDH1 status prediction. The
gains in performance highlight the importance of pretraining on massive
pathology image datasets, suggesting pretraining on even larger datasets could
continue improving performance for many high-impact applications where limited
amounts of training data are available, such as drug outcome prediction
PRISM: A Multi-Modal Generative Foundation Model for Slide-Level Histopathology
Full text linkFoundation models in computational pathology promise to unlock the
development of new clinical decision support systems and models for precision
medicine. However, there is a mismatch between most clinical analysis, which is
defined at the level of one or more whole slide images, and foundation models
to date, which process the thousands of image tiles contained in a whole slide
image separately. The requirement to train a network to aggregate information
across a large number of tiles in multiple whole slide images limits these
models' impact. In this work, we present a slide-level foundation model for
H&E-stained histopathology, PRISM, that builds on Virchow tile embeddings and
leverages clinical report text for pre-training. Using the tile embeddings,
PRISM produces slide-level embeddings with the ability to generate clinical
reports, resulting in several modes of use. Using text prompts, PRISM achieves
zero-shot cancer detection and sub-typing performance approaching and
surpassing that of a supervised aggregator model. Using the slide embeddings
with linear classifiers, PRISM surpasses supervised aggregator models.
Furthermore, we demonstrate that fine-tuning of the PRISM slide encoder yields
label-efficient training for biomarker prediction, a task that typically
suffers from low availability of training data; an aggregator initialized with
PRISM and trained on as little as 10% of the training data can outperform a
supervised baseline that uses all of the data
Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial
Get PDFBACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme
Treatment planning comparison in the PROTECT-trial randomising proton versus photon beam therapy in oesophageal cancer:Results from eight European centres
Get PDFPURPOSE
To compare dose distributions and robustness in treatment plans from eight European centres in preparation for the European randomized phase-III PROTECT-trial investigating the effect of proton therapy (PT) versus photon therapy (XT) for oesophageal cancer.
MATERIALS AND METHODS
All centres optimized one PT and one XT nominal plan using delineated 4DCT scans for four patients receiving 50.4 Gy (RBE) in 28 fractions. Target volume receiving 95% of prescribed dose (V95%iCTVtotal) should be >99%. Robustness towards setup, range, and respiration was evaluated. The plans were recalculated on a surveillance 4DCT (sCT) acquired at fraction ten and robustness evaluation was performed to evaluate the effect of respiration and inter-fractional anatomical changes.
RESULTS
All PT and XT plans complied with V95%iCTVtotal >99% for the nominal plan and V95%iCTVtotal >97% for all respiratory and robustness scenarios. Lung and heart dose varied considerably between centres for both modalities. The difference in mean lung dose and mean heart dose between each pair of XT and PT plans was in median [range] 4.8 Gy [1.1;7.6] and 8.4 Gy [1.9;24.5], respectively. Patients B and C showed large inter-fractional anatomical changes on sCT. For patient B, the minimum V95%iCTVtotal in the worst-case robustness scenario was 45% and 94% for XT and PT, respectively. For patient C, the minimum V95%iCTVtotal was 57% and 72% for XT and PT, respectively. Patient A and D showed minor inter-fractional changes and the minimum V95%iCTVtotal was >85%.
CONCLUSION
Large variability in dose to the lungs and heart was observed for both modalities. Inter-fractional anatomical changes led to larger target dose deterioration for XT than PT plans
Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase.
Get PDFDrug-resistant tuberculosis poses a persistent public health threat. The ReSeqTB platform is a collaborative, curated knowledgebase, designed to standardize and aggregate global Mycobacterium tuberculosis complex (MTBC) variant data from whole genome sequencing (WGS) with phenotypic drug susceptibility testing (DST) and clinical data. We developed a unified analysis variant pipeline (UVP) ( https://github.com/CPTR-ReSeqTB/UVP ) to identify variants and assign lineage from MTBC sequence data. Stringent thresholds and quality control measures were incorporated in this open source tool. The pipeline was validated using a well-characterized dataset of 90 diverse MTBC isolates with conventional DST and DNA Sanger sequencing data. The UVP exhibited 98.9% agreement with the variants identified using Sanger sequencing and was 100% concordant with conventional methods of assigning lineage. We analyzed 4636 publicly available MTBC isolates in the ReSeqTB platform representing all seven major MTBC lineages. The variants detected have an above 94% accuracy of predicting drug based on the accompanying DST results in the platform. The aggregation of variants over time in the platform will establish confidence-graded mutations statistically associated with phenotypic drug resistance. These tools serve as critical reference standards for future molecular diagnostic assay developers, researchers, public health agencies and clinicians working towards the control of drug-resistant tuberculosis
Author Correction: Integrating standardized whole genome sequence analysis with a global Mycobacterium tuberculosis antibiotic resistance knowledgebase.
Get PDFAn amendment to this paper has been published and can be accessed via a link at the top of the paper
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