Divine providence and epidemic cholera : a contribution to the study of secularization of thought in nineteenth century England

The idea of providence was a prominent and pervasive theme in public discourse on subjects of national importance, and upon momentous occasions in nineteenthcentury England. Perceptions of divine involvement and purpose in human affairs embodied in the notion of providence seemed to be at the heart of a religious world view in the Christian tradition, and thus essential elements for study in any historical investigation of religious change. The midcentury years, ostensibly a period of high religious consciousness, provide an opportunity to explore processes which were eventually to lead to the more secular nature of society apparent by the end of the century. The recurring cholera epidemics between 1831 and 1854 were alarming events which provoked reactions throughout society; they provide a means of tracing developments in perceptions of providential involvement in calamitous events during a critical twenty-four year period. Systematic surveys of a broad range of sources, including newspapers, periodicals and sermons were carried out to document the responses of different sections of society, and facilitated investigation of cross-sectional and longitudinal patterns in religious attitudes. It was hypothesised that changing ideas about the nature and extent of providential action in relation to epidemic disease could provide an index of the process of secularization of thought, and thus contribute to the wider debate on secularization. The results vindicated the use of the concept of providence to explore religious consciousness. They have confirmed the mid-nineteenth century to be a critical period for religious change. Analysis of religious perceptions of cholera at three points in time produced a complex picture of changing attitudes, including an unexpected peaking of providential interpretations by some observers during the second epidemic. However, the variation between different sources and social groups did not obscure a significant longer-term trend of decline in providential attitudes, consistent with a secularization of thought during the quarter of a century studied

Role of persistent CMV infection in configuring T cell immunity in the elderly

Ageing is associated with declines in many physiological parameters, including multiple immune system functions. The rate of acceleration of the frequency of death due to cardiovascular disease or cancer seems to increase with age from middle age up to around 80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are often associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. Thus, the manner in which CMV and the host immune system interact is critical in determining the "age" of specific immunity. We may therefore consider immunosenescence in some respects as an infectious state. This implies that interventions aimed at the pathogen may improve the organ system affected. Hence, CMV-directed anti-virals or vaccination may have beneficial effects on immunity in later life

Motor-Skill Learning in Alzheimer’s Disease: A Review with an Eye to the Clinical Practice

Since elderly people suffering from dementia want to go on living independently for as long as possible, they need to be able to maintain familiar and learn new practical skills. Although explicit or declarative learning methods are mostly used to train new skills, it is hypothesized that implicit or procedural techniques may be more effective in this population. The present review discusses 23 experimental studies on implicit motor-skill learning in patients with Alzheimer’s disease (AD). All studies found intact implicit motor-learning capacities. Subsequently, it is elaborated how these intact learning abilities can be exploited in the patients’ rehabilitation with respect to the variables ‘practice’ and ‘feedback.’ Recommendations for future research are provided, and it is concluded that if training programs are adjusted to specific needs and abilities, older people with AD are well able to (re)learn practical motor skills, which may enhance their autonomy

Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Computer-based technology and student engagement: a critical review of the literature

Computer-based technology has infiltrated many aspects of life and industry, yet there is little understanding of how it can be used to promote student engagement, a concept receiving strong attention in higher education due to its association with a number of positive academic outcomes. The purpose of this article is to present a critical review of the literature from the past 5 years related to how web-conferencing software, blogs, wikis, social networking sites (Facebook and Twitter), and digital games influence student engagement. We prefaced the findings with a substantive overview of student engagement definitions and indicators, which revealed three types of engagement (behavioral, emotional, and cognitive) that informed how we classified articles. Our findings suggest that digital games provide the most far-reaching influence across different types of student engagement, followed by web-conferencing and Facebook. Findings regarding wikis, blogs, and Twitter are less conclusive and significantly limited in number of studies conducted within the past 5 years. Overall, the findings provide preliminary support that computer-based technology influences student engagement, however, additional research is needed to confirm and build on these findings. We conclude the article by providing a list of recommendations for practice, with the intent of increasing understanding of how computer-based technology may be purposefully implemented to achieve the greatest gains in student engagement. © 2017, The Author(s)

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [&lt;1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None