scispace - formally typeset
Search or ask a question

Showing papers by "John Radcliffe Hospital published in 2022"


Journal ArticleDOI
Tracy Hussell1, Ramsey Sabit2, Rachel Upthegrove3, Daniel M. Forton4  +524 moreInstitutions (270)
TL;DR: The Post-hospitalisation COVID-19 study (PHOSP-COVID) as mentioned in this paper is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID19 across the UK.

118 citations


Journal ArticleDOI
TL;DR: In this article, the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort was investigated.
Abstract: Background and Objective To investigate the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort. Methods In this multicenter cohort study, paired serum-CSF samples from 474 patients with suspected inflammatory demyelinating disease (IDD) from 11 referral hospitals were included. After serum screening, patients were grouped into seropositive myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD, 31), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD, 60), other IDDs (217), multiple sclerosis (MS, 45), and non-IDDs (121). We then screened CSF for MOG-IgG and compared the clinical and serologic characteristics of patients uniquely positive for MOG-IgG in the CSF to seropositive patients with MOGAD. Results Nineteen patients with seropositive MOGAD (61.3%), 9 with other IDDs (CSF MOG + IDD, 4.1%), 4 with MS (8.9%), but none with AQP4-IgG + NMOSD nor with non-IDDs tested positive in the CSF for MOG-IgG. The clinical, pathologic, and prognostic features of patients uniquely positive for CSF MOG-IgG, with a non-MS phenotype, were comparable with those of seropositive MOGAD. Intrathecal MOG-IgG synthesis, observed from the onset of disease, was shown in 12 patients: 4 of 28 who were seropositive and 8 who were uniquely CSF positive, all of whom had involvement of either brain or spinal cord. Both CSF MOG-IgG titer and corrected CSF/serum MOG-IgG index, but not serum MOG-IgG titer, were associated with disability, CSF pleocytosis, and level of CSF proteins. Discussion CSF MOG-IgG is found in IDD other than MS and also in MS. In IDD other than MS, the CSF MOG-IgG positivity can support the diagnosis of MOGAD. The synthesis of MOG-IgG in the CNS of patients with MOGAD can be detected from the onset of the disease and is associated with the severity of the disease. Classification of Evidence This study provides Class II evidence that the presence of CSF MOG-IgG can improve the diagnosis of MOGAD in the absence of an MS phenotype, and intrathecal synthesis of MOG-IgG was associated with increased disability.

20 citations


Journal ArticleDOI
TL;DR: The retinal phenotype was key to suspecting mitochondrial disease in 11 patients, whereas 12 patients were diagnosed before retinal examination as mentioned in this paper , which may facilitate the often challenging and delayed diagnosis of mitochondrial disease, in particular in patients with mild or nebulous multisystem disease.

17 citations


Journal ArticleDOI
TL;DR: Woodhall et al. as discussed by the authors described four adults who developed clinical features of MOGAD along with serum MOG-IgG1 antibodies between 2 weeks after the initial assay.
Abstract: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a rare condition, with an estimated incidence of up to 3·4 per million per year (as measured in Oxfordshire, UK).1O'Connell K Hamilton-Shield A Woodhall M et al.Prevalence and incidence of neuromyelitis optica spectrum disorder, aquaporin-4 antibody-positive NMOSD and MOG antibody-positive disease in Oxfordshire, UK.J Neurol Neurosurg Psychiatry. 2020; 91: 1126-1128Google Scholar It is most frequently associated with optic neuritis in adults and acute disseminated encephalomyelitis in children, which often encompasses longitudinally extensive transverse myelitis and brainstem encephalitis.2Jurynczyk M Messina S Woodhall MR et al.Clinical presentation and prognosis in MOG-antibody disease: a UK study.Brain. 2017; 140: 3128-3138Google Scholar Here, we describe four adults who developed clinical features of MOGAD along with serum MOG-IgG1 antibodies3Waters P Woodhall M O'Connor KC et al.MOG cell-based assay detects non-MS patients with inflammatory neurologic disease.Neurol Neuroimmunol Neuroinflamm. 2015; 2: e89Google Scholar within 21 days of receiving the first dose of the ChAdOx1 nCoV-19 vaccine (Oxford–AstraZeneca) against SARS-CoV-2 (appendix p 1). These patients were reviewed by the specialised neuromyelitis optica service at the John Radcliffe Hospital (Oxford, UK) between April and September, 2021. A 58-year-old man (patient 1) developed lower limb sensory impairment and right-sided spastic hemiplegia 14 days after vaccination. MRI showed multiple brain and short spinal cord lesions. He was treated for 3 days with 1 g intravenous methylprednisolone per day followed by a 12-month tapering course of oral prednisolone, starting at 15 mg daily. 83 days after symptom onset, he had recovered almost completely. A 28-year-old woman (patient 2) developed lower limb weakness and sensory disturbance with faecal incontinence and urinary retention 14 days after vaccination. MRI showed longitudinally extensive transverse myelitis from C2 to the conus and an occipital white matter lesion (figure). She received five cycles of plasma exchange and 1 g intravenous methylprednisolone daily for 5 days followed by 60 mg oral prednisolone daily, reduced in 10 mg increments each month. She was discharged with a urinary catheter in situ. 135 days after symptom onset, she had ongoing urinary incontinence. Repeat MRI at 3 months showed resolution of the left occipital lesion but persistent spinal cord lesions. A 32-year-old man (patient 3) developed urinary retention and spastic paraplegia 21 days after vaccination. MRI revealed diffuse spinal cord lesions. He was treated with 1 g intravenous methylprednisolone daily for 5 days followed by 40 mg oral prednisolone daily, reducing gradually over 12 months. By 135 days after symptom onset he had recovered almost completely. A 38-year-old woman (patient 4) developed altered sensation in the left upper limb 7 days after vaccination. Over the next 4 days, she developed pyrexia, confusion, headache, paraplegia, and urinary retention. MRI revealed multiple spinal cord and infratentorial lesions (figure). She received 1 g intravenous methylprednisolone daily for 3 days followed by 2 g/kg intravenous immunoglobulin daily for 5 days and 60 mg oral prednisolone per day, tapered in 10 mg increments each month. 118 days after symptom onset, she had ongoing sensory impairment in the lower limbs. Patients 1, 3, and 4 had additional serum samples taken and tested for MOG antibodies between 2 and 12 weeks after the initial assay. Despite receiving steroids, these patients remained strongly MOG-antibody positive (appendix p 1). Longer-term follow-up will determine whether or not these patients will be at risk of relapse. These cases highlight some of the typical features of MOGAD. For example, all patients made good recoveries from a mobility point of view, but all presented with bladder dysfunction that persisted long into the recovery phase. However, atypical for adult MOGAD,2Jurynczyk M Messina S Woodhall MR et al.Clinical presentation and prognosis in MOG-antibody disease: a UK study.Brain. 2017; 140: 3128-3138Google Scholar none of the patients presented with optic neuritis, all had myelitis, and three had cerebral or brainstem involvement. The close temporal association between vaccination with ChAdOx1 nCoV-19 and MOGAD onset meets WHO causality criteria for possible causation.4The Uppsala Monitoring CentreThe use of the WHO-UMC system for standardised case causality assessment.https://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdfDate accessed: January 21, 2022Google Scholar Another feature that supports causality between vaccination and these symptoms is the atypical presentation: instead of presenting with optic neuritis, the patients presented with disease that resembles acute disseminated encephalomyelitis with frequent brainstem involvement, which is more often seen in children with MOGAD after infection or vaccination.5Hennes E-M Baumann M Schanda K et al.Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome.Neurology. 2017; 89: 900-908Google Scholar Taken together, these features suggest the vaccine could be inducing MOGAD with a predilection for the brain and spinal cord. However, we do not know the incidence of MOGAD after other vaccinations and the annual incidence of MOGAD is low, making it difficult to be certain of a causal relationship between this vaccine and MOGAD. Two other diseases have been reported as rare side-effects of both the ChAdOx1 nCoV-19 and Ad26.COV2.S (Johnson & Johnson) vaccines: vaccine-induced thrombocytopaenia and thrombosis, which is associated with autoantibodies against platelet factor 4,6Greinacher A Thiele T Warkentin TE Weisser K Kyrle PA Eichinger S Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination.N Engl J Med. 2021; 384: 2092-2101Google Scholar and Guillain-Barré syndrome, which is associated with autoantibodies against gangliosides.7Maramattom BV Krishnan P Paul R et al.Guillain-Barré syndrome following ChAdOx1-S/nCoV-19 vaccine.Ann Neurol. 2021; 90: 312-314Google Scholar Regulatory warnings regarding the rare occurrence of these adverse effects are now included in the summary of product characteristics for these vaccines.8UK GovernmentInformation for UK recipients on COVID-19 vaccine AstraZeneca (regulation 174).https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-astrazeneca/information-for-uk-recipients-on-covid-19-vaccine-astrazenecaDate accessed: November 24, 2021Google Scholar Together, these observations suggest that adenoviral-vectored COVID-19 vaccines might rarely trigger serious autoimmune disease but the pathophysiology underlying a potential association is uncertain. Possible mechanisms include that the adenovirus vector or the SARS-CoV-2 spike protein might activate pre-existing autoantibody-producing B lymphocytes. Alternatively, simultaneous binding of vaccine component and self-antigen by B cells could lead to autoantibody synthesis,9Prüss H Autoantibodies in neurological disease.Nat Rev Immunol. 2021; 21: 798-813Google Scholar particularly if inflammation caused by the vaccine impairs the integrity of the blood–brain barrier, allowing antigen-presenting cells and B cells to interact with MOG epitopes. Finally, sequence homology between an element of the ChAdOx1 nCoV-19 vaccine and MOG protein could trigger autoreactive B cell expansion and activation (molecular mimicry). Further study is essential to help understand development of MOGAD irrespective of vaccine status. JP has received grants or contracts from Merck-Serono, Roche, and MedImmune; has served on advisory panels for UCB, Mitsubishi, Amplo Roche, Alexion, Chugai, and Merck-Serono; has received payment or honoraria for academic work from Alexion, Roche, MedImmune, and Chugail; serves on the steering committee of MAGNIMS; is on the board of the European Charcot Foundation; is the co-lead of International Women in MS; and has stock or stock options in AstraZeneca. AF and LF declare no competing interests. Download .pdf (.06 MB) Help with pdf files Supplementary appendix

13 citations




Journal ArticleDOI
TL;DR: 3D functional HHS models are created by preformed cellular aggregates (PCA) bioprinting and exhibit characteristics of early-stage HHS in gene and protein expression, which significantly activated signaling pathway related to inflammation and cell proliferation, and recapitulate in vivo tissue dynamics of scar forming.

6 citations


Journal ArticleDOI
TL;DR: In this article , the molybdenum diselenide (MoSe2) nanosheets dispersed in the cationic polymer chitosan (CS) exhibit exceptional antifungal activity.
Abstract: Antifungal drug resistance is an increasingly significant threat to humans, livestock, and crops. Recent studies have shown nanomaterials as promising alternatives in combating drug-resistant pathogens. Here, we show that molybdenum diselenide (MoSe2) nanosheets dispersed in the cationic polymer chitosan (CS) exhibit exceptional antifungal activity. The MoSe2/CS nanosheets provide minimum inhibitory concentrations (MICs) between 0.78 and 37.5 μg ml–1 against a variety of unicellular fungal strains and demonstrate minimum fungicidal concentrations (MFCs) from 0.5 to 75 μg ml–1 for diverse unicellular and filamentous strains. Furthermore, we demonstrate the ability of MoSe2/CS to eradicate increasingly prevalent and highly multi-drug-resistant (MDR) fungi Candida auris strains with MICs of 25 to 50 μm ml–1 and MFCs of 37.5 to 150 μm ml–1. The effective antifungal activity of MoSe2/CS was observed after an incubation time of 3 h, which is faster than the time needed for other nanomaterial-based antifungal agents incorporating graphene, two-dimensional (2D) nanomaterials, or silver nanoparticles. MoSe2/CS also showed high biocompatibility and was benign toward human red blood cells and human embryonic kidney cells. Electron microscopy and confocal optical microscopy show that fungal cells treated with MoSe2/CS nanosheets exhibit morphological deformities, ruptured cell walls and interior voids, and metabolic inactivation. Mechanistic investigations revealed that treatment with MoSe2/CS triggers complete membrane depolarization and membrane disintegration within 3 h. Hence, this work demonstrates that the biocompatible nanomaterial MoSe2/CS is a highly effective alternative antifungal agent against many kinds of pathogenic fungi including MDR strains.

5 citations


Journal ArticleDOI
TL;DR: In this paper , a review of existing evidence for contemporary therapeutic approaches in auto-immune encephalitis (AE) is presented, highlighting acute and long-term treatments used in specific AE syndromes, exemplifying how understanding disease pathogenesis can inform precision therapy and outlining challenges of defining disability outcomes.
Abstract: Autoimmune encephalitis (AE) refers to immune-mediated neurological syndromes often characterised by the detection of pathogenic autoantibodies in serum and/or cerebrospinal fluid which target extracellular epitopes of neuroglial antigens. There is increasing evidence these autoantibodies directly modulate function of their antigens in vivo. Early treatment with immunotherapy improves outcomes. Yet, these patients commonly exhibit chronic disability. Importantly, optimal therapeutic strategies at onset and during escalation remain poorly understood. In this review of a rapidly emerging field, we evaluate recent studies on larger cohorts, registries, and meta-analyses to highlight existing evidence for contemporary therapeutic approaches in AE.We highlight acute and long-term treatments used in specific AE syndromes, exemplify how understanding disease pathogenesis can inform precision therapy and outline challenges of defining disability outcomes in AE.Early first-line immunotherapies, including corticosteroids and plasma exchange, improve outcomes, with emerging evidence showing second-line immunotherapies (especially rituximab) reduce relapse rates. Optimal timing of immunotherapy escalation remains unclear. Routine reporting of outcome measures which incorporate cognitive impairment, fatigue, pain, and mental health will permit more accurate quantification of residual disability and comprehensive comparisons between international multicentre cohorts, and enable future meta-analyses with the aim of developing evidence-based therapeutic guidelines.

5 citations


Journal ArticleDOI
12 Aug 2022-Brain
TL;DR: In this paper , the authors examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function.
Abstract: Abstract Real-time functional MRI neurofeedback allows individuals to self-modulate their ongoing brain activity. This may be a useful tool in clinical disorders that are associated with altered brain activity patterns. Motor impairment after stroke has previously been associated with decreased laterality of motor cortex activity. Here we examined whether chronic stroke survivors were able to use real-time fMRI neurofeedback to increase laterality of motor cortex activity and assessed effects on motor performance and on brain structure and function. We carried out a randomized, double-blind, sham-controlled trial (ClinicalTrials.gov: NCT03775915) in which 24 chronic stroke survivors with mild to moderate upper limb impairment experienced three training days of either Real (n = 12) or Sham (n = 12) neurofeedback. Assessments of brain structure, brain function and measures of upper-limb function were carried out before and 1 week after neurofeedback training. Additionally, measures of upper-limb function were repeated 1 month after neurofeedback training. Primary outcome measures were (i) changes in lateralization of motor cortex activity during movements of the stroke-affected hand throughout neurofeedback training days; and (ii) changes in motor performance of the affected limb on the Jebsen Taylor Test (JTT). Stroke survivors were able to use Real neurofeedback to increase laterality of motor cortex activity within (P = 0.019), but not across, training days. There was no group effect on the primary behavioural outcome measure, which was average JTT performance across all subtasks (P = 0.116). Secondary analysis found improvements in the performance of the gross motor subtasks of the JTT in the Real neurofeedback group compared to Sham (P = 0.010). However, there were no improvements on the Action Research Arm Test or the Upper Extremity Fugl–Meyer score (both P > 0.5). Additionally, decreased white-matter asymmetry of the corticospinal tracts was detected 1 week after neurofeedback training (P = 0.008), indicating that the tracts become more similar with Real neurofeedback. Changes in the affected corticospinal tract were positively correlated with participants neurofeedback performance (P = 0.002). Therefore, here we demonstrate that chronic stroke survivors are able to use functional MRI neurofeedback to self-modulate motor cortex activity in comparison to a Sham control, and that training is associated with improvements in gross hand motor performance and with white matter structural changes.

4 citations


Journal ArticleDOI
TL;DR: In this paper , the shape and overall intensity of individualised task activations can be modelled separately and explicitly, and training the model on predicting residual differences in brain activity further boosts individualised predictions.

Journal ArticleDOI
TL;DR: In this article , the authors used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1 −/− mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state.
Abstract: Abstract Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout ( Gria1 −/− ) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1 −/− mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1 −/− mice. Furthermore, dopamine signals were initially similar in Gria1 −/− mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1 −/− mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.

Journal ArticleDOI
TL;DR: In this article , the authors investigated the genomic profile underlying CRLF2 overexpression in T-cell acute lymphoblastic leukemia (T-ALL) by analyzing RNA-seq, WES, and SNP-array data from 264 T-ALL patients and five cell lines deposited on the TARGET initiative.
Abstract: CRLF2 overexpression has been described as a biomarker of poor prognosis in T-cell acute lymphoblastic leukemia (T-ALL). In the present study, we aimed to unravel the genomic profile underlying CRLF2 overexpression (CRLF2-high) by analyzing RNA-seq, WES, and SNP-array data from 264 T-ALL patients and five cell lines deposited on the TARGET initiative, Cancer Cell Line Encyclopedia and Gene Expression Omnibus. These data allowed us to delineate the genomic landscape of CRLF2-high in T-ALL, which was associated with PTEN, JAK3, PHF6, EZH2, and RUNX1 mutations. We also observed an enrichment of CRLF2-high in early T-precursor (ETP)-ALL (23.08% vs. 4.02%, P = 7.579e-06 ) and a very similar gene upregulation profile between these two entities. The inhibition of BET (iBET) proteins is a strategy previously demonstrated to reverse the gene upregulation pattern of ETP cells through restoration of polycomb repressive complex 2 (PRC2) activity. While CRLF2 expression was rescued by using this strategy in LOUCY (untreated vs. iBET P = 0.0095, DMSO vs. iBET P = 0.0286), a classical ETP-ALL cell line, PRC2 loss was not sufficient to promote CRLF2 upregulation in JURKAT, a more mature T-ALL cell line. Considering the role of IKZF1 in CRLF2 regulation and in recruitment of PCR2, we evaluated IKZF1 status according to CRLF2-expression subgroups. We identified that IKZF1 transcripts with intron retention were upregulated in the CRLF2-high subgroup. Here, we delineated the gene expression profile of CRLF2-high T-ALL samples and unraveled the crucial role of PRC2 in CRLF2 regulation in ETP-ALL.

Posted ContentDOI
25 Jul 2022
TL;DR: In this paper , an inverse modeling framework that couples satellite chemical data assimilation to a chemical transport model and infers satellite-constrained emissions totals using the iterative finite-difference mass-balance method is introduced.
Abstract: Abstract. Satellite observations of tropospheric NO2 columns can provide top-down observational constraints on emissions estimates of nitrogen oxides (NOx). Mass-balance based methods are often applied for this purpose, but do not isolate near-surface emissions from those aloft, such as lightning emissions. Here, we introduce an inverse modeling framework that couples satellite chemical data assimilation to a chemical transport model and infers satellite-constrained emissions totals using the iterative finite-difference mass-balance method. The approach improves the finite-difference mass-balance inversion by isolating the near-surface emissions increment. We apply the framework to estimate lightning and anthropogenic NOx emissions over the Northern Hemisphere. Using overlapping observations from the Ozone Monitoring Instrument (OMI) and the Tropospheric Monitoring Instrument (TROPOMI), we compare NOx emissions inferences from these satellite instruments, as well as the impacts of emissions changes on modeled NO2 and O3. OMI inferences of anthropogenic emissions consistently lead to larger emissions than TROPOMI inferences, attributed to a low bias in TROPOMI NO2 retrievals. Updated lightning NOx emissions from either satellite improve the chemical transport model’s low tropospheric O3 bias. Combined lightning and anthropogenic updates inferred from satellite observations can improve the model’s ability to represent background and ground-level O3 concentrations, an ongoing policy consideration in the U.S. as domestic and international emissions control strategies evolve.

Book ChapterDOI
01 Jan 2022

Journal ArticleDOI
TL;DR: In this paper , the authors report their experience with the combination of radical surgical excision and intestinal transplantation in patients with recurrent Pseudomyxoma Peritonei (PMP) not amenable to further Cytoreductive surgery (CRS).
Abstract: Objective: To report our experience with the combination of radical surgical excision and intestinal transplantation in patients with recurrent Pseudomyxoma Peritonei (PMP) not amenable to further Cytoreductive surgery (CRS). Background: CRS and heated intra-operative peritoneal chemotherapy is an effective treatment for many patients with PMP. In patients with extensive small bowel involvement, or non-resectable recurrence, disease progression results in small bowel obstruction, nutritional failure, fistulation, with resulting abdominal wall failure. Methods: Between 2013-2022, patients with PMP who had nutritional failure and were not suitable for further CRS underwent radical debulking and intestinal transplantation at our centre. Results: 15 patients underwent radical exenteration of affected intra-abdominal organs, and transplantation adapted according to the individual case. Eight patients had isolated small bowel transplantation and seven patients underwent modified multi-visceral transplantation. Additionally, in seven patients with significant abdominal wall tumour involvement, a full thickness vascularized abdominal wall transplant was performed. Two of the 15 patients died within 90 days due to surgically related complications. Actuarial 1-year and 5-year patient survivals were 79% and 55% respectively. The majority of the patients had significant improvement in quality of life after transplantation. Progression/recurrence of disease was detected in 91% of patients followed up for more than six months. Conclusion: Intestinal/multi-visceral transplantation enables a more radical approach to the management of PMP than can be achieved with conventional surgical methods and is suitable for patients for whom there is no conventional surgical option. This complex surgical intervention requires combined skills of both peritoneal malignancy and transplant teams.

Journal ArticleDOI
TL;DR: TorMehandru S Colombel JF Peyrin-Biroulet L Crohn's disease. as mentioned in this paper , a multicentre, randomised, double-blind, parallel-group, phase 3b trial.

Posted ContentDOI
26 Aug 2022
TL;DR: Marvel as mentioned in this paper is a package for single-cell splicing analysis applicable to RNA sequencing generated from the plate-and droplet-based methods, which enables systematic and integrated splicing and gene expression analysis of single cells.
Abstract: ABSTRACT Alternative splicing is an important source of heterogeneity in gene expression between individual cells but remains an understudied area due to the paucity of computational tools to analyze splicing dynamics at single-cell resolution. Here, we present MARVEL, a comprehensive R package for single-cell splicing analysis applicable to RNA sequencing generated from the plate- and droplet-based methods. We performed extensive benchmarking of MARVEL against available tools and demonstrated its utility by analyzing iPSC differentiation into endoderm cells and cardiomyocytes. MARVEL enables systematic and integrated splicing and gene expression analysis of single cells to characterize the splicing landscape and reveal biological insights.

Journal ArticleDOI
TL;DR: This article investigated cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF-related craniosynostosis, together with three of their carrier parents.
Abstract: Pathogenic variants of the ERF gene were previously associated with craniosynostosis, craniofacial dysmorphism and Chiari malformation. This study investigates cognitive, behavioural, speech, language, and developmental outcomes in the first 5 children identified at the Oxford Craniofacial Unit as having ERF- related craniosynostosis, together with three of their carrier parents.There were no consistent findings related to overall intelligence. However, a pattern of cognitive difficulties is described, which includes poor attention, impulsivity and difficulties with functional fine motor skills, such as handwriting. A high frequency of speech, language and communication difficulties was evident, which was most often related to early language difficulties, speech sound difficulties, hyponasal resonance and concern regarding social communication skills and emotional immaturity.It was common for these children to have needed input from ear, nose and throat services. Problems with tonsils and/or adenoids and/ or fluctuating conductive hearing loss were found which may be contributors to early speech, language and communication difficulties.The authors make recommendations regarding the need for formal assessment of a range of developmental aspects upon diagnosis of a pathogenic variant in the ERF gene. The aim of this report is to give clinical guidance to anyone who may have care of patients with the ERF -related mutation.

Journal ArticleDOI
TL;DR: In this article , the authors present 12 tips for dynamic and engaging neuroanatomy teaching formulated based on their experiences as medical students and evidence-based techniques, focusing on the anatomical, physiological, and clinical aspects of neurology and their integration.
Abstract: Neuroanatomy is a complex and fascinating subject that is often a daunting prospect for medical students. In fact, the fear of learning neuroanatomy has gained its own name - "neurophobia." This widespread phenomenon among medical students poses a challenge to medical teachers and educators. To tackle "neurophobia" by summarising tips for dynamic and engaging neuroanatomy teaching formulated based on our experiences as medical students and evidence-based techniques.Focusing on the anatomical, physiological, and clinical aspects of neurology and their integration, here we present 12 tips which are [1] Teach the basic structure before fine details, [2] Supplement teaching with annotated diagrams, [3] Use dissections for haptic learning, [4] Teach form and function together, [5] Group anatomy into systems, [6] Familiarise students with neuroimaging, [7] Teach from clinical cases, [8] Let the patient become the teacher, [9] Build from first principles, [10] Try working in reverse, [11] Let the student become the teacher, [12] Let the student become the examiner. These 12 tips can be used by teachers and students alike to provide a high-yield learning experience.

Journal ArticleDOI
TL;DR: In this paper , relative binding free energy (RBFE) calculations were used to predict the effects of M. tuberculosis RNA polymerase and DNA gyrase mutations on rifampicin and moxifloxacin susceptibility respectively.
Abstract: Drug resistant Mycobacterium tuberculosis, which mostly results from single nucleotide polymorphisms in antibiotic target genes, poses a major threat to tuberculosis treatment outcomes. Relative binding free energy (RBFE) calculations can rapidly predict the effects of mutations, but this approach has not been tested on large, complex proteins. We use RBFE calculations to predict the effects of M. tuberculosis RNA polymerase and DNA gyrase mutations on rifampicin and moxifloxacin susceptibility respectively. These mutations encompass a range of amino acid substitutions with known effects and include large steric perturbations and charged moieties. We find that moderate numbers (n = 3-15) of short RBFE calculations can predict resistance in cases where the mutation results in a large change in the binding free energy. We show that the method lacks discrimination in cases with either a small change in energy or that involve charged amino acids, and we investigate how these calculation errors may be decreased.

Posted ContentDOI
06 Jun 2022
TL;DR: In this paper , a machine learning approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with myeloproliferative neoplasms or a reactive / nonneoplastic marrow was developed.
Abstract: Abstract The detection and grading of fibrosis in myeloproliferative neoplasms (MPN) is an important component of disease classification, prognostication and disease monitoring. However, current fibrosis grading systems are only semi-quantitative and fail to capture sample heterogeneity. To improve the detection, quantitation and representation of reticulin fibrosis, we developed a machine learning (ML) approach using bone marrow trephine (BMT) samples (n = 107) from patients diagnosed with MPN or a reactive / nonneoplastic marrow. The resulting Continuous Indexing of Fibrosis (CIF) enhances the detection and monitoring of fibrosis within BMTs, and aids the discrimination of MPN subtypes. When combined with megakaryocyte feature analysis, CIF discriminates between the frequently challenging differential diagnosis of essential thrombocythemia (ET) and pre-fibrotic myelofibrosis (pre-PMF) with high predictive accuracy [area under the curve = 0.94]. CIF also shows significant promise in the identification of MPN patients at risk of disease progression; analysis of samples from 35 patients diagnosed with ET and enrolled in the Primary Thrombocythemia-1 (PT-1) trial identified features predictive of post-ET myelofibrosis (area under the curve = 0.77). In addition to these clinical applications, automated analysis of fibrosis has clear potential to further refine disease classification boundaries and inform future studies of the micro-environmental factors driving disease initiation and progression in MPN and other stem cell disorders. The image analysis methods used to generate CIF can be readily integrated with those of other key morphological features in MPNs, including megakaryocyte morphology, that lie beyond the scope of conventional histological assessment. Key Points Machine learning enables an objective and quantitative description of reticulin fibrosis within the bone marrow of patients with myeloproliferative neoplasms (MPN), Automated analysis and Continuous Indexing of Fibrosis (CIF) captures heterogeneity within MPN samples and has utility in refined classification and disease monitoring Quantitative fibrosis assessment combined with topological data analysis may help to predict patients at increased risk of progression to post-ET myelofibrosis, and assist in the discrimination of ET and pre-fibrotic PMF (pre-PMF)

Journal ArticleDOI
Ying Liu1
28 Jul 2022
TL;DR: In this article , a brief over view of the contents of Michael Wooldridge's book gives an account of my own background in computing and AI, including machine learning's relationship to AI, applications to medical areas, the need to consider probabilistic effects on decisions, the importance of self-reproduction and whether AI can be made moral.
Abstract: Following a brief over view of the contents of Michael Wooldridge's book I give an account of my own background in computing and AI. I then cover a range of topics stimulated by reading the book including machine learning's relationship to AI, applications to medical areas, the need to consider probabilistic effects on decisions, the importance of self-reproduction and whether AI can be made moral. I finish with a discussion of the mind-brain relationship and what makes us human.


Journal ArticleDOI
TL;DR: In this paper , the glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization.
Abstract: Successful subunit vaccination with recombinant proteins requires adjuvants. The glycolipid trehalose-dibehenate (TDB), a synthetic analog of the mycobacterial cord factor, potently induces Th1 and Th17 immune responses and is a candidate adjuvant for human immunization. TDB binds to the C-type lectin receptor Mincle and triggers Syk-Card9-dependent APC activation. In addition, interleukin (IL)-1 receptor/MyD88-dependent signaling is required for TDB adjuvanticity. The role of different innate immune cell types in adjuvant-stimulated Th1/Th17 responses is not well characterized. We investigated cell recruitment to the site of injection (SOI) and to the draining lymph nodes (dLNs) after immunization with the TDB containing adjuvant CAF01 in a protein-based vaccine. Recruitment of monocytes and neutrophils to the SOI and the dramatic increase in lymph node cellularity was partially dependent on both Mincle and MyD88. Despite their large numbers at the SOI, neutrophils were dispensable for the induction of Th1/Th17 responses. In contrast, CCR2-dependent monocyte recruitment was essential for the induction of Th1/Th17 cells. Transport of adjuvant to the dLN did not require Mincle, MyD88, or CCR2. Together, adjuvanticity conferred by monocytes can be separated at the cellular level from potential tissue damage by neutrophils.

Journal ArticleDOI
Saritem1
TL;DR: Public reason has been a central topic in the field of political theory for a long time as discussed by the authors , and it has a distinctive subject matter: it applies to the common good of modern political societies and the political institutions that serve that common good, and contrasts with forms of reasoning that apply to less inclusive associations and communities that exist within a modern political society.
Abstract: The publication of John Rawls’s Political Liberalism put public reason squarely on the agenda of contemporary political theory. Ever since, it has been a central topic in the field. Although Rawls developed a distinctive account of public reason, his account is but one among many. Indeed, some commentators have insisted that public reason is a very old notion, one that can be found in the political writings of Hobbes, Locke, Rousseau, and Kant, for example. Public reason has a distinctive subject matter. It applies to the common good of a modern political society and the political institutions that serve that common good, and it contrasts with forms of reasoning that apply to less inclusive associations and communities that exist within a modern political society, such as churches, voluntary clubs, or professional associations. Public reason also contrasts with applications of reason that are not transparent and/or acceptable to adult citizens of modern political societies. The demands of transparency and acceptability have proven to be complex and contentious, and rival articulations of these notions have generated rival accounts of public reason. Public reason informs public political justification, and proponents of public reason often hold that public, political justification of at least the fundamental political arrangements of a political society is necessary for its political order to be legitimate. The reasons for insisting on public reason and the reasons for rejecting it are diverse. Common to all defenses of public reason is the thought that it represents a fitting response to the fact of intractable disagreement in modern political societies.

Book ChapterDOI
01 Jan 2022
TL;DR: In this article, advances and potential applications of novel long-acting delivery systems such as nanoparticles, liposomes, and others are discussed, which led to the successful targeting of organs and a significant reduction in the dosage of the drug administrated, hence limiting systemic side effects.
Abstract: Sexual and reproductive health is a vital field of medicine, which faces with many challenges, including contraception, sexually infectious diseases, infertility, and cancers. The available therapeutic approaches rely mainly on medical rather than surgical approach. However, the medical approach is significantly limited by the short action of the available drugs, thus relying on patient compliance, in addition to the need of repetitive doses that increase the risk of systemic side effects. Therefore novel techniques that provide long-acting drug delivery systems and selective targeting of organs are crucial. In this chapter, advances and potential applications of novel long-acting delivery systems such as nanoparticles, liposomes, and others are discussed. These systems led to the successful targeting of organs and a significant reduction in the dosage of the drug administrated, hence limiting systemic side effects. In the context of sexual and reproductive health, we highlight the significant role of these systems in improving the management of many gynecological cancers, AIDS, and other pathological conditions. We also provide updates for the systems that are already present on the market such as contraceptive methods and AIDS prophylaxis.


Book ChapterDOI
06 Jul 2022

Journal ArticleDOI
23 Apr 2022
TL;DR: In this paper , the authors conducted field research and manuscript analysis in Matang Teupah Village, Aceh Tamiang District, Indonesia to investigate the impact of chicken farming on the environment.
Abstract: This research will answer, how is the implementation of the Matang Teupah Village Regulation No. 12 of 2010 concerning the business license for chicken farming, how is the environment for the poultry farm business in Matang Teupah Village according to Fiqh Siyasah. This research is field research and manuscript analysis and this type of research uses descriptive qualitative methods. The results of the study are: the efforts of the Matang Teupah Village Government and the Aceh Tamiang District Government in controlling environmental pollution caused by the community who have a broiler business have been going quite well because the Village Government has made several efforts in accordance with government regulations in controlling the waste pollution. and set forth in Village Regulations so as to be able to maintain the surrounding environment free from waste pollution. In view of fiqh siyasah environmental pollution carried out by the community in Matang Teupah Village, in not accordance with Islamic law, because humans as caliphs on earth are to be able to prosper the earth in accordance with Islamic law and preserve it. In the view of Islam, the caliph is responsible for himself, he must also bear the responsibility of his fellow living creatures and the whole of nature, including in maintaining the sustainability of the existing environment.