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In two parallel randomized trials in patients with MS, ublituximab resulted in lower relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not affect disability.

BackgroundTay-Sachs disease is a rare, and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in ß-Hexosaminidase A (HEX A) leads to accumulation of GM ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterised by a more indolent presentation, typically encompassing features of cer- ebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms.Case SummariesWe present four adult patients with known LOTS from four unrelated non-consanguineous families. Each had neurophysiological evidence of chronic motor axonal loss in the limbs, accompanied in 2 cases by peripheral sensory axonal loss. Cerebellar atrophy, reported to be a ubiquitous feature on MRI in LOTS, was absent in all cases.DiscussionOur case series supports the existence of a pure neuromuscular phenotype in LOTS. This condition should be considered in the differential diagnosis of anterior horn cell disorders.

Respiratory syncytial virus (RSV) is the major cause of viral lower respiratory tract illness in children. In contrast to the RSV prototypic strain A2, clinical isolate RSV 2-20 induces airway mucin expression in mice, a clinically relevant phenotype dependent on the fusion (F) protein of the RSV strain. Epidermal growth factor receptor (EGFR) plays a role in airway mucin expression in other systems; therefore, we hypothesized that the RSV 2-20 F protein stimulates EGFR signaling. Infection of cells with chimeric strains RSV A2-2-20F and A2-2-20GF or over-expression of 2-20 F protein resulted in greater phosphorylation of EGFR than infection with RSV A2 or over-expression of A2 F, respectively. Chemical inhibition of EGFR signaling or knockdown of EGFR resulted in diminished infectivity of RSV A2-2-20F but not RSV A2. Over-expression of EGFR enhanced the fusion activity of 2-20 F protein in trans. EGFR co-immunoprecipitated most efficiently with RSV F proteins derived from \"mucogenic\" strains. RSV 2-20 F and EGFR co-localized in H292 cells, and A2-2-20GF-induced MUC5AC expression was ablated by EGFR inhibitors in these cells. Treatment of BALB/c mice with the EGFR inhibitor erlotinib significantly reduced the amount of RSV A2-2-20F-induced airway mucin expression. Our results demonstrate that RSV F interacts with EGFR in a strain-specific manner, EGFR is a co-factor for infection, and EGFR plays a role in RSV-induced mucin expression, suggesting EGFR is a potential target for RSV disease.

PurposeAnnual general meetings have been variously described as dull rituals for accountability versus entertaining theatre at the expense of accountability. The research analyses director and shareholder participation and dialogic interactions at annual and extraordinary general meetings of Cecil Rhodes' British South Africa Company (BSAC). The BSAC was incorporated under a royal charter in 1889 in return for power to exploit a huge territory, Rhodesia/now Zimbabwe. The BSAC's administration ceased in 1924/25. Thus, the BSAC had a dual mandate as a private for-profit listed company and to occupy and develop the territories on behalf of the British government.Design/methodology/approachThe article analyses 29 BSAC general meeting minutes, comprising 25 full sets of verbatim minutes between 1895 and 1925. The study adopts manual content analysis. First, the research adopts conversational analysis to analyse director and shareholder turn-taking and moves by approving and dissenting shareholders. Second, the study identifies and analyses incidents of shareholder sentiment from the shareholder turns/moves. Finally, the article assesses how shareholder sentiment changed throughout the period and whether the BSAC's share price reflected the shareholder sentiment.FindingsThe BSAC's general meetings were associated with the greater colonial project of building the British Empire. The authors find almost 1,500 incidents of shareholder sentiment. Directors and shareholders take roughly an equal number of turns (excluding shareholder sentiment). Ritual and ceremony dominate director and shareholder turns and moves, while accountability to shareholders was minimal. The BSAC share price spiked in the early years of the project, waning after that. Shareholder sentiment, both positive and negative, reflect the share price behaviour.Originality/valueA unique database of verbatim general meeting minutes records shareholders' reactions to what they heard in the form of sounding off through cheering, “hear, hears,” laughter and applause (i.e. shareholder sentiment).

Nearshore (littoral) habitats of clear lakes with high water quality are increasingly experiencing unexplained proliferations of filamentous algae that grow on submerged surfaces. These filamentous algal blooms (FABs) are sometimes associated with nutrient pollution in groundwater, but complex changes in climate, nutrient transport, lake hydrodynamics, and food web structure may also facilitate this emerging threat to clear lakes. A coordinated effort among members of the public, managers, and scientists is needed to document the occurrence of FABs, to standardize methods for measuring their severity, to adapt existing data collection networks to include nearshore habitats, and to mitigate and reverse this profound structural change in lake ecosystems. Current models of lake eutrophication do not explain this littoral greening. However, a cohesive response to it is essential for protecting some of the world’s most valued lakes and the flora, fauna, and ecosystem services they sustain.

PurposeTaking a communication perspective, the paper explores management's rhetoric in profit warnings, whose sole purpose is to disclose unexpected bad news.Design/methodology/approachAdopting a close-reading approach to text analysis, the authors analyse three profit warnings of the now-collapsed Carillion, contrasting the rhetoric with contemporaneous investor conference calls to discuss the profit warnings and board minutes recording boardroom discussions of the case company's precarious financial circumstances. The analysis applies an Aristotelian framework, focussing on logos (appealing to logic and reason), ethos (appealing to authority) and pathos (appealing to emotion) to examine how Carillion's board and management used language to persuade shareholders concerning the company's adverse circumstances.FindingsAs non-routine communications, the language in profit warnings displays and mimics characteristics of routine communications by appealing primarily to logos (logic and reason). The rhetorical profiles of investor conference calls and board meeting minutes differ from profit warnings, suggesting a different version of the story behind the scenes. The authors frame the three profit warnings as representing three stages of communication as follows: denial, defiance and desperation and, for our case company, ultimately, culminating in defeat.Research limitations/implicationsThe research is limited to the study of profit warnings in one case company.Originality/valueThe paper views profit warnings as a communication artefact and examines the rhetoric in these corporate documents to elucidate their key features. The paper provides novel insights into the role of profit warnings as a corporate communication vehicle/genre delivering bad news.

PurposeA royal charter of incorporation imposing public benefit/social responsibilities established the privately owned British South Africa Company (BSAC), in return for power to exploit a huge territory using low-cost local labour. This study explores the dual principal–agent problem of how the BSAC used annual report narratives to report on its conflicting economic responsibilities to investors versus its public benefit charter responsibilities to the British Crown.Design/methodology/approachHaving digitised the dataset, the research analyses narratives from 29 BSAC annual reports spanning a continuous 35-year royal charter period, using computer-aided keyword content analysis to identify economic-orientated versus public benefit-orientated annual report narratives. The research analyses how the annual report narratives shifted according to four key contextual periods by reference to the changing influence of private investors versus the British Crown.FindingsThere are two key findings. First, economic primacy. At no point do public benefit disclosures outweigh economic disclosures. Second, the BSAC's meso-corporate context and macro-social/political context can explain patterns in public benefit disclosures. The motivation for producing public benefit information is not altruism. Rather, commercial interests motivate disclosure. The BSAC used its annual reports to sustain what proved ultimately unsustainable – royal charter-style colonialism.Originality/valueThis accounting history study contributes to an understanding of corporate narrative reporting using one of the earliest known cases of such analysis and shows how accounting plays a central role in facilitating a company in sustaining its interests. This 100-year lookback may be a portend of the future for modern-day annual report corporate social responsibility narratives in, say, mining and oil and gas company corporate reports, especially if these natural resources run out.

Non-typeable Haemophilus influenzae contains an N 6 -adenine DNA-methyltransferase (ModA) that is subject to phase-variable expression (random ON/OFF switching). Five modA alleles, modA2 , modA4, modA5 , modA9 and modA10 , account for over two-thirds of clinical otitis media isolates surveyed. Here, we use single molecule, real-time (SMRT) methylome analysis to identify the DNA-recognition motifs for all five of these modA alleles. Phase variation of these alleles regulates multiple proteins including vaccine candidates, and key virulence phenotypes such as antibiotic resistance ( modA2 , modA5 , modA10 ), biofilm formation ( modA2 ) and immunoevasion ( modA4 ). Analyses of a modA2 strain in the chinchilla model of otitis media show a clear selection for ON switching of modA2 in the middle ear. Our results indicate that a biphasic epigenetic switch can control bacterial virulence, immunoevasion and niche adaptation in an animal model system. Non-typeable Haemophilus influenzae , which causes ear and lung infections, has a DNA methyltransferase encoded by alternative alleles that are subject to random ON/OFF switching. Here, Atack et al. show that this epigenetic switch controls the expression of key proteins involved in virulence.

IntroductionMaintaining cognitive health in later life is a global priority. Encouraging individuals to make health behaviour changes, such as regular physical activity, and providing supportive urban environments can help maintain cognitive health, thereby preventing or delaying the progress of dementia and cognitive decline. However, the mechanistic pathways by which the urban environmental exposome influences cognitive health outcomes are poorly understood. The aim of this study is to use granular measures of the urban environment exposome (encompassing the built, natural and social environment) and physical activity to explore how these interact with a person’s biology to ultimately influence cognitive health outcomes.Methods and analysisThis ongoing study uses a cohort design, recruiting participants from the Northern Ireland Cohort for the Longitudinal study of Ageing and the Harmonised Cognitive Assessment Protocol study. Participants (n=400 at each wave) will be aged ≥65 years and have the capacity to provide written informed consent. Measures include device-measured physical activity (Actigraph wGT3XP-BT), environmental location data (Global Positioning System, Qstarz BT-Q1000XT), linked to a battery of neuropsychological tests, including the Mini Mental State Examination and the Centre for Epidemiological Studies Depression Scale. Blood-derived biochemical, genetic and epigenetic data will be included in multimodal analyses. These data will be integrated with urban environment Geographic Information System data and analysed using causal inference and mediation methods to investigate plausible mechanistic pathways.Ethics and disseminationThis study has been approved by the Queen’s University Belfast, Faculty of Medicine, Health and Life Sciences Research Ethics Committee (MHLS 21_72). Alongside peer-reviewed publications in high-ranking international journals, dissemination activities include conference presentations, project videos, working papers, policy briefing papers, newsletters, summaries and case study stories.

Background and purpose Tay−Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in β‐hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late‐onset Tay−Sachs disease (LOTS) is extremely rare, especially in the non‐Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms. Cases A case series of four unrelated patients of non‐Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients. Conclusion This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders.