Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Abrocitinib, tralokinumab and upadacitinib for treating moderate-to-severe atopic dermatitis.

Background: Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). Objectives: To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib). Data sources: Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review. Methods: A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources. Results: Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost. Conclusions: The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations. Future work and limitations: The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective. Study registration: This study is registered as PROSPERO CRD42021266219. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in Health Technology Assessment; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.

Atopic dermatitis is one of the most common skin conditions in children but can also develop in adulthood. People with atopic dermatitis have dry, red (inflamed) skin that is also extremely itchy (pruritus). There is no cure for atopic dermatitis. Therapy starts with topical treatments that are applied to the skin, such as emollients. Severe forms of atopic dermatitis are often treated with systemic treatments, which are drugs that are provided as tablets or an injection. Ciclosporin A is often the first systemic therapy given. If atopic dermatitis does not get better with ciclosporin A, options available in the National Health Service are dupilumab and baricitinib. New therapies that have been evaluated in clinical trials for atopic dermatitis but have not been assessed for use in the National Health Service are abrocitinib, tralokinumab and upadacitinib. The aim of this project is to review the medical benefits, risks and value for money for the National Health Service of abrocitinib, tralokinumab and upadacitinib for the treatment of moderate-to-severe atopic dermatitis in a multiple technology appraisal. Our review found that: For children aged between 12 and 18 years, abrocitinib and a low dose of upadacitinib (15 mg) are good value for money for the National Health Service. For adults who need a first systemic treatment, upadacitinib is unlikely to be good value for money for the National Health Service. For adults who are still suffering from their atopic dermatitis after having a systemic treatment and need a different drug, upadacitinib 15 mg and tralokinumab could be good value for money for the National Health Service if they are used on their own. For adults who are still suffering from their atopic dermatitis after having a systemic treatment and need a different drug, but need to take it with steroid cream, abrocitinib 100 mg, upadacitinib 15 mg and tralokinumab could all be good value for money for the National Health Service.

Lipid Metabolism Is Dysregulated in the Motor Cortex White Matter in Amyotrophic Lateral Sclerosis.

Lipid metabolism is profoundly dysregulated in amyotrophic lateral sclerosis (ALS), yet the lipid composition of the white matter, where the myelinated axons of motor neurons are located, remains uncharacterised. We aimed to comprehensively characterise how myelin is altered in ALS by assessing its lipid and protein composition. We isolated white matter from the motor cortex from post-mortem tissue of ALS patients (n = 8 sporadic ALS cases and n = 6 familial ALS cases) and age- and sex-matched controls (n = 8) and conducted targeted lipidomic analyses, qPCR for gene expression of relevant lipid metabolising enzymes and Western blotting for myelin proteins. We also quantified myelin density by using spectral confocal reflectance microscopy (SCoRe). Whilst myelin protein composition was similar in ALS and control tissue, both the lipid levels and the expression of their corresponding enzymes were dysregulated, highlighting altered lipid metabolism in the white matter as well as a likely change in myelin composition. Altered myelin composition could contribute to motor neuron dysfunction, and this highlights how oligodendrocytes may play a critical role in ALS pathogenesis.

α-Amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor and RNA processing gene dysregulation are early determinants of selective motor neuron vulnerability in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a late-onset adult neurodegenerative disease, although there is mounting electrophysiological and pathological evidence from patients and animal models for a protracted preclinical period of motor neuron susceptibility and dysfunction, long before clinical diagnosis. The key molecular mechanisms linked to motor neuron vulnerability in amyotrophic lateral sclerosis have been extensively studied using transcriptional profiling in motor neurons isolated from adult mutant superoxide dismutase 1 mice. However, neonatal and embryonic motor neurons from mutant superoxide dismutase 1 mice show abnormal morphology and hyperexcitability, suggesting preceding transcriptional dysregulation. Here, we used RNA sequencing on motor neurons isolated from embryonic superoxide dismutase 1G93A mice to determine the earliest molecular mechanisms conferring neuronal susceptibility and dysfunction known in a mouse model of amyotrophic lateral sclerosis. Transgenic superoxide dismutase 1G93A mice expressing the spinal motor neuron homeobox HB9:green fluorescent protein reporter allowed unambiguous identification and isolation of motor neurons using fluorescence-activated cell sorting. Gene expression profiling of isolated motor neurons revealed transcriptional dysregulation in superoxide dismutase 1G93A mice as early as embryonic Day 12.5 with the majority of differentially expressed genes involved in RNA processing and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-mediated glutamate receptor signalling. We confirmed dysregulation of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2, at transcript and protein levels, in embryonic superoxide dismutase 1G93A mouse motor neurons and human motor neurons derived from amyotrophic lateral sclerosis patient induced pluripotent stem cells harbouring pathogenic superoxide dismutase 1 mutations. Mutant superoxide dismutase 1 induced pluripotent stem cell-derived motor neurons showed greater vulnerability to α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate-mediated excitotoxicity, consistent with α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2 downregulation. Thus, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor Subunit 2 deficiency leading to enhanced α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor signalling, calcium influx, hyperexcitability, and chronic excitotoxicity is a very early and intrinsic property of spinal motor neurons that may trigger amyotrophic lateral sclerosis pathogenesis later in life. This study reinforces the concept of therapeutic targeting of hyperexcitability and excitotoxicity as potential disease-modifying approaches for amyotrophic lateral sclerosis.

Ferroptosis mediates selective motor neuron death in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1G93A), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1G93A mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment.

Dysregulation in Subcellular Localization of Myelin Basic Protein mRNA Does Not Result in Altered Myelination in Amyotrophic Lateral Sclerosis.

Pathological hallmarks of amyotrophic lateral sclerosis (ALS), including protein misfolding, are well established in oligodendrocytes. More recently, an RNA trafficking deficit of key myelin proteins has been suggested in oligodendrocytes in ALS but the extent to which this affects myelination and the relative contribution of this to disease pathogenesis is unclear. ALS autopsy research findings showing demyelination contrasts with the routine clinical-pathological workup of ALS cases where it is rare to see white matter abnormalities other than simple Wallerian degeneration secondary to widespread neuronal loss. To begin to address this apparent variance, we undertook a comprehensive evaluation of myelination at an RNA, protein and structural level using human pathological material from sporadic ALS patients, genetic ALS patients (harboring C9orf72 mutation) and age- and sex-matched non-neurological controls. We performed (i) quantitative spatial profiling of the mRNA transcript encoding myelin basic protein (MBP), (ii) quantification of MBP protein and (iii) the first quantitative structural assessment of myelination in ALS post-mortem specimens by electron microscopy. We show no differences in MBP protein levels or ultrastructural myelination, despite a significant dysregulation in the subcellular trafficking of MBP mRNA in ALS patients compared to controls. We therefore confirm that whilst there are cell autonomous mRNA trafficking deficits affecting oligodendrocytes in ALS, this has no effect on myelin structure.

Novel Modification of a Confirmatory SMA Sequencing Assay that Can Be Used to Determine SMN2 Copy Number.

Promising treatments for spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, prompted calls for inclusion in newborn screening (NBS). In January 2018, the New England Newborn Screening Program (NENSP) began statewide screening for SMA using a tiered algorithm looking for the absence of SMN1 Exon 7. When results from the first and second tier needed reconciliation, we developed and validated a third tier DNA sequencing assay to ensure the presence or absence of SMN1 Exon 7. All nine infants referred to specialty centers through NBS showed single base substitution of c.840C>T, and were confirmed to have SMA. Further, a minor sequencing protocol modification allowed the estimation of SMN2 copy number in SMA affected patients; we developed and validated a copy-number assay yielding 100% match with seven previously characterized specimens of SMA patients. All nine SMA-affected infants found through NBS were also assayed for SMN2 copy number. Results were comparable but not 100% matched with those that were reported by independent diagnostic laboratories. In conclusion, a sequencing protocol confirms NBS findings from real-time qPCR, and its modified application allows NBS programs that have sequencing capabilities to provide SMN2 copy numbers without the need for additional instrumentation.

iPSC-derived myelinoids to study myelin biology of humans.

Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids ("myelinoids") and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination-both at the level of individual oligodendrocytes and globally across whole myelinoids-and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination.

Prognostic tools for identification of high risk in people with Crohn's disease: systematic review and cost-effectiveness study.

BACKGROUND: Crohn's disease is a lifelong condition that can affect any segment of the gastrointestinal tract. Some people with Crohn's disease may be at higher risk of following a severe course of disease than others and being able to identify the level of risk a patient has could lead to personalised management. OBJECTIVE: To assess the prognostic test accuracy, clinical impact and cost-effectiveness of two tools for the stratification of people with a diagnosis of Crohn's disease by risk of following a severe course of disease. DATA SOURCES: The data sources MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials were searched to inform the systematic reviews on prognostic accuracy, clinical impact of the prognostic tools, and economic evaluations. Additional data sources to inform the review of economic evaluations were NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database. REVIEW METHODS: Systematic reviews of electronic databases were carried out from inception to June 2019 for studies assessing the prognostic accuracy and clinical impact of the IBDX® (Crohn's disease Prognosis Test; Glycominds Ltd, Lod, Israel) biomarker stratification tool and the PredictSURE-IBD™ (PredictImmune Ltd, Cambridge, UK) tool. Systematic reviews of studies reporting on the cost-effectiveness of treatments for Crohn's disease were run from inception to July 2019. Two reviewers independently agreed on studies for inclusion, assessed the quality of included studies and validated the data extracted from studies. Clinical and methodological heterogeneity across studies precluded the synthesis of data for prognostic accuracy. A de novo economic model was developed to compare the costs and consequences of two treatment approaches - the 'top-down' and 'step-up' strategies, with step-up considered standard care - in people at high risk of following a severe course of Crohn's disease. The model comprised a decision tree and a Markov cohort model. RESULTS: Sixteen publications, including eight original studies (n = 1478), were deemed relevant to the review of prognostic accuracy. Documents supplied by the companies marketing the prognostic tools were also reviewed. No study meeting the eligibility criteria reported on the sensitivity or specificity of the IBDX biomarker stratification tool, whereas one study provided estimates of sensitivity, specificity and negative predictive value for the PredictSURE-IBD tool. All identified studies were observational and were considered to provide weak evidence on the effectiveness of the tools. Owing to the paucity of data on the two tools, in the base-case analysis the accuracy of PredictSURE-IBD was assumed to be 100%. Accuracy of IBDX was assumed to be 100% in a scenario analysis, with the cost of the tests being the only difference between the analyses. The incremental analysis of cost-effectiveness demonstrated that top-down (via the use of PredictSURE-IBD in the model) is more expensive and generates fewer quality-adjusted life-years than step-up (via the standard care arm of the model). LIMITATIONS: Despite extensive systematic searches of the literature, no robust evidence was identified of the prognostic accuracy of the biomarker stratification tools IBDX and PredictSURE-IBD. CONCLUSIONS: Although the model indicates that standard care dominates the tests, the lack of evidence of prognostic accuracy of the two tests and the uncertainty around the benefits of the top-down and step-up treatment approaches mean that the results should be interpreted as indicative rather than definitive. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019138737. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 23. See the NIHR Journals Library website for further project information.

Crohn's disease is a condition in which parts of the digestive system become inflamed (swollen). People of any age can develop Crohn's disease. It is a lifelong condition for which there is no cure. In the UK, Crohn's disease affects about 1 in every 650 people. Any part of the digestive system can be affected, and the severity of the disease can vary from person to person. Symptoms come and go, and there can be times when there are no symptoms at all. Common symptoms of Crohn's disease are diarrhoea, stomach-ache and blood in faeces. Treatment is given to reduce or control symptoms and to try to stop inflammation from coming back. Some people with Crohn's disease are more likely than others to have more relapses and to develop complications of Crohn's disease that might require surgery. This project looked at how well two tools worked at identifying people with Crohn's disease who might develop complications or need surgery. Identifying those who have a higher chance of experiencing complications of Crohn's disease could help them and their doctor to choose their treatment, with the goal of reducing the number of relapses and the risk of surgery in the longer term. In addition, the review assessed whether or not the tools offered value for money. We found limited evidence of how well the tools worked in identifying people who were more likely to develop complications of Crohn's disease. The lack of evidence on the tools meant that the cost-effectiveness analysis could only assess the value for money of the treatment that is given in clinical practice at this time or of more intensive treatments for people who are more likely to develop complications. The analysis found that current standard care offers more value for money than intensive treatments for people with a higher chance of developing complications of Crohn's disease.

Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.

Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the TARDBP gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified. Furthermore, expression analysis for monocarboxylate transporter 1 (a lactate transporter) coupled with a glycolytic stress test showed no deficit in lactate export. However, using confocal microscopy, we report TDP-43 mutation-dependent pathological mis-accumulation of TDP-43. Furthermore, using in vitro patch-clamp recordings, we identified functional Ca2+-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor dysregulation in oligodendrocytes. Together, these findings establish a platform for further interrogation of the role of oligodendrocytes and cellular autonomy in TDP-43 proteinopathy.

Mutant TDP-43 Expression Triggers TDP-43 Pathology and Cell Autonomous Effects on Primary Astrocytes: Implications for Non-cell Autonomous Pathology in ALS.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase 1 (SOD1) is partly non-cell autonomous, involving cellular dysfunction of astrocytes. Whether non-cell autonomous effects occur in other forms of ALS, such as TAR DNA binding protein 43 (TDP-43)-related disease, remains unclear. Here, we characterised the impact of mutant TDP-43 expression on primary astrocytes derived from transgenic TDP-43A315T mice. Mutant TDP-43 astrocytes revealed evidence for TDP-43 pathology, shown by cytoplasmic TDP-43 inclusions and accumulation in insoluble cell fractions which was exacerbated by proteasomal inhibition. L-glutamate uptake, measured using an [3H]D-aspartate assay, was impaired in mutant TDP-43 astrocytes, while ATP accumulation was abnormal, suggesting mutant TDP-43 induced astrocytic dysfunction. Astrocyte activation coupled with spinal and cortical motor neuron loss in transgenic TDP-43A315T mice could imply non-cell autonomous effects of astrocytes in vivo. These data demonstrate mutant TDP-43-mediated cell autonomous effects on astrocytes that may contribute to motor neuron pathology in ALS.

Improved detection of RNA foci in C9orf72 amyotrophic lateral sclerosis post-mortem tissue using BaseScope™ shows a lack of association with cognitive dysfunction.

The C9orf72 hexanucleotide repeat expansion is the commonest known genetic mutation in amyotrophic lateral sclerosis. A neuropathological hallmark is the intracellular accumulation of RNA foci. The role that RNA foci play in the pathogenesis of amyotrophic lateral sclerosis is widely debated. Historically, C9orf72 RNA foci have been identified using in situ hybridization. Here, we have implemented BaseScope™, a high-resolution modified in situ hybridization technique. We demonstrate that previous studies have underestimated the abundance of RNA foci in neurons and glia. This improved detection allowed us to investigate the abundance, regional distribution and cell type specificity of sense C9orf72 RNA foci in post-mortem brain and spinal cord tissue of six deeply clinically phenotyped C9orf72 patients and six age- and sex-matched controls. We find a correlation between RNA foci and the accumulation of transactive response DNA-binding protein of 43 kDa in spinal motor neurons (rs = 0.93; P = 0.008), but not in glia or cortical motor neurons. We also demonstrate that there is no correlation between the presence of RNA foci and the accumulation of transactive response DNA binding protein of 43 kDa in extra-motor brain regions. Furthermore, there is no association between the presence of RNA foci and cognitive indices. These results highlight the utility of BaseScope™ in the clinicopathological assessment of the role of sense RNA foci in C9orf72.

Dysregulation of AMPA receptor subunit expression in sporadic ALS post-mortem brain.

Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there are over 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not genetically determined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanisms converge and diverge between the multiple known familial causes of ALS (fALS) and sporadic forms of ALS (sALS) and furthermore between different neuron types, is poorly understood. One common pathway that is implicated in selective motor neuron death is enhanced α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPAR)-mediated excitoxicity. Specifically, human in vitro and pathological evidence has linked the C9orf72 repeat expansion mutation to a relative increase in the Ca2+ -permeable AMPAR population due to AMPAR subunit dysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPAR subunit transcripts, using BaseScope, in post-mortem lower motor neurons (spinal cord, anterior horn), upper motor neurons (motor cortex) and neurons of the pre-frontal cortex in sALS and fALS due to mutations in SOD1 and C9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases. However, sALS and mutant C9orf72 cases exhibited GluA1 upregulation whereas mutant SOD1 cases displayed GluA2 down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motor and pre-frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brain region. In contrast, AMPAR dysregulation in mutant SOD1 and C9orf72 cases was restricted to lower motor neurons only. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both converging and diverging mechanisms at play between different brain regions and between ALS cohorts. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Effectiveness of topical and ablative therapies in treatment of anogenital warts: a systematic review and network meta-analysis.

OBJECTIVE: To generate estimates of comparative clinical effectiveness for interventions used in the treatment of anogenital warts (AGWs) through the systematic review, appraisal and synthesis of data from randomised controlled trials (RCTs). DESIGN: Systematic review and network meta-analysis of RCTs. Search strategies were developed for MEDLINE, Embase, the Cochrane Library and the Web of Science. For electronic databases, searches were run from inception to March 2018. The systematic review was carried out following the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PARTICIPANTS: People aged ≥16 years with clinically diagnosed AGWs (irrespective of biopsy confirmation). INTERVENTIONS: Topical and ablative treatments recommended by the British Association for Sexual Health and HIV for the treatment of AGWs, either as monotherapy or in combination versus each other. OUTCOME MEASURES: Complete clearance of AGWs at the end of treatment and at other scheduled visits, and rate of recurrence. RESULTS: Thirty-seven RCTs met inclusion criteria. Twenty studies were assessed as being at unclear risk of bias, with the remaining studies categorised as high risk of bias. Network meta-analysis indicates that, of the treatment options compared, carbon dioxide laser therapy is the most effective treatment for achieving complete clearance of AGWs at the end of treatment. Of patient-applied topical treatments, podophyllotoxin 0.5% solution was found to be the most effective at achieving complete clearance, and was associated with a statistically significant difference compared with imiquimod 5% cream and polyphenon E 10% ointment (p<0.05). Few data were available on recurrence of AGWs after complete clearance. Of the interventions evaluated, surgical excision was the most effective at minimising risk of recurrence. CONCLUSION: Of the studies assessed, as a collective, the quality of the evidence is low. Few studies are available that evaluate treatment options versus each other. TRIAL REGISTRATION NUMBER: CRD42013005457.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of  white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when  compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

Could an Impairment in Local Translation of mRNAs in Glia be Contributing to Pathogenesis in ALS?

One of the key pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis is abnormal RNA processing. Studies to date have focussed on defects in RNA stability, splicing, and translation, but this review article will focus on the largely overlooked RNA processing mechanism of RNA trafficking, with particular emphasis on the importance of glia. In the central nervous system (CNS), oligodendrocytes can extend processes to myelinate and metabolically support up to 50 axons and astrocytes can extend processes to cover up to 100,000 synapses, all with differing local functional requirements. Furthermore, many of the proteins required in these processes are large, aggregation-prone proteins which would be difficult to transport in their fully translated, terminally-folded state. This, therefore, highlights a critical requirement in these cells for local control of protein translation, which is achieved through specific trafficking of mRNAs to each process and local translation therein. Given that a large number of RNA-binding proteins have been implicated in ALS, and RNA-binding proteins are essential for trafficking mRNAs from the nucleus to glial processes for local translation, RNA misprocessing in glial cells is a likely source of cellular dysfunction in ALS. To date, neurons have been the focus of ALS research, but an intrinsic deficit in glia, namely astrocytes and oligodendrocytes, could have an additive effect on declining neuronal function in ALS. This review article aims to highlight the key evidence that supports the contention that RNA trafficking deficits in astrocytes and oligodendrocytes may contribute to in ALS.

Impact of delivered tidal volume on the occurrence of intraventricular haemorrhage in preterm infants during positive pressure ventilation in the delivery room.

BACKGROUND AND OBJECTIVES: Delivery of inadvertent high tidal volume (VT) during positive pressure ventilation (PPV) in the delivery room is common. High VT delivery during PPV has been associated with haemodynamic brain injury in animal models. We examined if VT delivery during PPV at birth is associated with brain injury in preterm infants <29 weeks' gestation. METHODS: A flow-sensor was placed between the mask and the ventilation device. VT values were compared with recently described reference ranges for VT in spontaneously breathing preterm infants at birth. Infants were divided into two groups: VT<6 mL/kg or VT>6 mL/kg (normal and high VT, respectively). Brain injury (eg, intraventricular haemorrhage (IVH)) was assessed using routine ultrasound imaging within the first days after birth. RESULTS: A total of 165 preterm infants were included, 124 (75%) had high VT and 41 (25%) normal VT. The mean (SD) gestational age and birth weight in high and normal VT group was similar, 26 (2) and 26 (1) weeks, 858 (251) g and 915 (250) g, respectively. IVH in the high VT group was diagnosed in 63 (51%) infants compared with 5 (13%) infants in the normal VT group (P=0.008).Severe IVH (grade III or IV) developed in 33/124 (27%) infants in the high VT group and 2/41 (6%) in the normal VT group (P=0.01). CONCLUSIONS: High VT delivery during mask PPV at birth was associated with brain injury. Strategies to limit VT delivery during mask PPV should be used to prevent high VT delivery.

Dinutuximab Beta for Treating Neuroblastoma: An Evidence Review Group and Decision Support Unit Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company's submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company's original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company's ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG's analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company's ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS.

Dose-dependent exacerbation of ventilation-induced lung injury by erythropoietin in preterm newborn lambs.

Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO1000; n = 5), or 3,000 (EPO3000; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar-arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1ß, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.