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Although many factors have been associated with mobility among older adults, there is paucity of research that explores the complexity of factors that influence mobility. This review aims to synthesise the available evidence for factors comprising the cognitive, psychological, and social mobility determinants and their associations with mobility self-reported and performance-based outcomes in older adults (60 years). We followed Arksey and O'Malley's five stages of a scoping review and searched PubMed, EMBASE, PsychINFO, Web of Science, AgeLine, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature and Sociological Abstract databases. Reviewers in pairs independently conducted title, abstract, full-text screening and data extraction. We reported associations by analyses rather than articles because articles reported multiple associations for factors and several mobility outcomes. Associations were categorised as significantly positive, negative, or not significant. We included 183 peer-reviewed articles published in 27 countries, most of which were cross-sectional studies and conducted among community-dwelling older adults. The 183 articles reported 630 analyses, of which 381 (60.5%) were significantly associated with mobility outcomes in the expected direction. For example, older adults with higher cognitive functioning such as better executive functioning had better mobility outcomes (e.g., faster gait speed), and those with poor psychological outcomes, such as depressive symptoms, or social outcomes such as reduced social network, had poorer mobility outcomes (e.g., slower gait speed) compared to their counterparts. Studies exploring the association between cognitive factors, personality (a psychological factor) and self-reported mobility outcomes (e.g., walking for transportation or driving), and social factors and performance-based mobility outcomes in older adults are limited. Understanding the additive relationships between cognitive, psychological, and social factors highlights the complexity of older adults' mobility across different forms of mobility, including independence, use of assistive devices, transportation, and driving.

To synthesise the available evidence on physical factors, such as muscle strength and power, body mass index and their association with older adults’ self-reported and performance-based mobility outcomes. This review followed the Askey and O'Malley framework. We systematically searched PubMed, EMBASE, PsychINFO, Web of Science, AgeLine, Allied and Complementary Medicine Database, and Cumulative Index to Nursing and Allied Health Literature databases, from Jan. 2000 to Jan. 2022. Teams of two reviewers independently conducted title, abstract, full-text screening, and data extraction using predefined inclusion and exclusion criteria. A total of 239 quantitative articles, mostly cross-sectional design, conducted in 32 countries were included in this review. We identified 18 physical factors significantly associated with mobility outcomes in the expected direction. Muscle strength, body composition, falls (number and history of), and chronic conditions (number of and type) were the most studied physical factors. Older adults with muscle weakness, weight concerns, history of falls, and chronic conditions had poorer mobility outcomes, such as slower gait speed, poor balance, limited community mobility and poor driving outcomes compared to their counterparts. Studies exploring the role of physical factors on the use of an assisted device, transportation, or driving, are limited.

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.

Squamous cell lung cancer (SqCLC) is a type of non-small cell lung cancer strongly associated with cigarette smoking and with known targetable mutations, however some patients do not have matching targeted drugs. The S1400I Phase III randomized LungMap sub-study of nivo+ipi versus nivo accrued 275 (252 eligible) previously-treated patients with stage IV SqCLC and absence of matched mutations (NCT02154490).Here, to investigate the longitudinal (baseline, C2 week 3, C4 week 7, C5 week 9) serum protein changes associated with treatment or response, we performed Olink proximity extension assay in 160 patients (561 samples) using an immuno-oncology panel of 92 analytes. We utilized mixed linear and joint models to identify differentially expressed proteins between treatment arms (nivo vs. nivo+ipi), response and quantify the effect of other potential prognostic factors. This approach quantifies the effect of covariates such as smoking status, demographics, prior radiation therapy, and metastases. We jointly modeled expression and survival to identify changes in proteins over time. The thresholds for significance in differentially expression tests were a log fold change of at least 0.5 and a false discovery rate of under 0.05 (FDR as a multiple testing adjustment method). The joint models used thresholds of log fold change of more than 1 and hazard ratio of more than 1. Results revealed increases in 40 serum proteins after treatment with either nivo alone or combined with ipi, including CXCL9, CXCL10, CXCL11, CXCL13, IL6, IL8, IL10, IFNg, and soluble PD-L1 and PDCD1. nivo+ipi treatment showed greater increases in IL8 and CXCL13 post-treatment compared to nivo alone. In addition, circulating IL6, CXCL13, and MIC-A/B were higher in patients with stable or progressive disease compared to those with objective response after treatment. The joint model revealed a worse hazard ratio with increases in 10 soluble proteins, including IL6, IL8, and CXCL13. Finally, for patients with similar values of IL8, those treated by combination had a better survival outcome than those treated by nivo alone. Using a data-modeling approach, we identified significant longitudinal changes in 40 serum proteins out of 92 tested in patients with SqCLC treated with nivo or nivo+ipi. Increases in serum inflammatory markers IL6 and CXCL13 were associated with worse disease. Although overall survival was not statistically different between arms, our modeling approaches suggested that IL-8 monitoring may help identify patients benefiting more from the combination vs. nivo alone. Citation Format: Edgar Gonzalez-Kozlova, Hsin-Hui Huang, Mary Redman, Roy Herbst, Scott Gettinger, Luda Bazhenova, Hui Xie, Manishkumar Patel, Kai Nie, Jocelyn Harris, Kimberly Argueta, Karen Kelly, Ethan Cerami, James Lindsay, Joyce Yu, Roshni Biswas, Stephen Van Nostrand, Radim Moravec, Diane Marie Del Valle, Seunghee Kim-schulze, Sacha Gnjatic. Dynamic changes in circulating protein levels reveal an association between ipilimumab and nivolumab combination treatment (SWOG Lung-MAP S1400I trial) with outcomes in squamous cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5026.

9044 Background: While Immune checkpoint blockade (ICB) is standard treatment for lung cancer there are limited biomarkers that predict benefit, pharmacokinetic on-treatment activity or explain progression. S1400I was a randomized Phase III trial of nivolumab(N)+ipilimumab(I) versus N (NCT02154490, PMID 34264316) for ICB naïve, previously treated stage IV or recurrent squamous cell lung cancer. We performed circulating serum protein analysis of serial blood specimens from patients enrolled in S1400I to evaluate if serum proteins levels changed over time, changes differed by treatment arm, and if they were associated with overall survival. Methods: 561 serial blood specimens (baseline, weeks (wk) 3, 7, 9, and progression [PD]) from 160 of 252 eligible patients enrolled to S1400I were analyzed for 92 immuno-oncology analytes with the Olink proximity extension assay. Protein levels were normalized with use of internal controls and quantified as log2 protein expression (denoted as NPX). Linear mixed models evaluated change in expression from baseline at each time point (wks 3,7,9 and PD), and NPX differences at baseline, wk3, and PD depending on best objective response. A Cox model was used to evaluate the association between baseline NPX and survival. Overall survival and longitudinal cytokine expression were jointly modeled using a linear mixed model to estimate dynamic biomarker changes in NPX and a Cox model for survival. The joint models for time-varying NPX values included a random intercept and modeled time using a natural spline with three knots. Significance was defined as P < 0.05. Results: Serum proteins PCDC1, CXCL9, and CXCL10 were increased from baseline at wks 3,7,9 and at PD. CCL19 was increased at wks 3 and 7 but not at wk 9 and PD. IL10 and IFNγ were increased at wk 3 but subsequently returned to baseline. Change in CXCL13 from baseline to PD was larger for N+I versus N. Baseline CCL23, CSF-1, IL6, and MUC-16 were associated with shorter survival (HR > 1). Joint modeling of survival with cytokines showed an increased risk of death (HR > 1) with higher longitudinal serum levels of CXCL13, MMP12, CSF-1, and IL8. Patients achieving objective response had higher IL4 and LAMP3 and lower IL6 and IL8 at baseline and wk 3 compared to non-responders. Conclusions: Measurements of blood circulating soluble proteins represent easily accessible biomarkers that may be useful as indicators of outcome, and that will need to be prospectively confirmed. Clinical trial information: NCT02154490.

et al., Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations., Research reported in this publication was supported in part by an ISMMS seed fund to E.G. and a Dean’s office grant to E.G. and I.M. We gratefully acknowledge use of the services and facilities of the Tisch Cancer Institute supported by the National Cancer Institute (NCI) Cancer Center Support grant (no. P30 CA196521), in particular the Hess sequencing core and the BiNGS shared facility. M.S. was supported by an NCI training grant (no. T32CA078207). J.S.Y.H. is supported by the Charles H. Revson Foundation. We acknowledge the technical contribution of D.A. Sánchez, J. Baranda, S. Baztan-Morales, M. Castillo de la Osa, A. Comins-Boo, C. del Álamo Mayo, S. Gil-Manso, B. Gonzalez, S. Hatem, J. Irure-Ventura, I. Miguens, S. Muñoz Martinez, M. Pereira, C. Rodrigues-Guerreiro, M. Rodriguez-Garcia, M.P. Rojo-Portolés and D. San Segundo. We also acknowledge Beckman Coulter for donating the equipment required for the determination of spike-specific IgG antibodies. W.M. was supported by grant no. NCI K00CA212474. This work was supported by ISMMS seed fund to J.O.; Instituto de Salud Carlos III, grant no. COV20-00668 to R.C.R.; Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation (COVID-19 Research Call grant no. COV20/00181) cofinanced by European Development Regional Fund ‘A way to achieve Europe’ to E.P.-A.; Instituto de Salud Carlos III, Spain (grant no. COV20/00170); Government of Cantabria, Spain (grant no. 2020UIC22-PUB-0019) to M.L.H.; Instituto de Salud Carlos III (grant no. PI16CIII/00012) to P.P.; Fondo Social Europeo e Iniciativa de Empleo Juvenil YEI (grant no. PEJ2018-004557-A) to M.P.E. and grant no. REDInREN 016/009/009 ISCIII. This project has received funding from the European Union’s Horizon 2020 research and innovation program VACCELERATE under grant agreement no. 101037867 to J.O. S.G. is supported by grant nos. U24CA224319, U01DK124165 and P30 CA196521.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C., Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

The sixth update of the

The intellectual relationship between Mary Astell, the High Tory Christian Platonist philosopher, and Samuel Richardson, the middle-class epistolary novelist, provides a striking example of the int...

Jane Austen imitated Shakespeare throughout her entire career, from Sense and Sensibility to Sanditon. To make up her characters, she mapped material from Shakespeare and other authors on to family members and celebrities. For Elizabeth Bennet, I argue that she remembered Dorothy Jordan, the most famous comic actress of her day. Jordan was particularly renowned for her roles in Much Ado About Nothing, As You Like It, Measure for Measure, and Twelfth Night, the plays alluded to in Pride and Prejudice. The distinctive set of attributes that marked Jordan's celebrity status reappears in Elizabeth. Austen knew about Jordan, and may have seen her before she starting revising “First Impressions” into Pride and Prejudice. Jordan was considered best at “low” parts, and her unconventional femininity, her energy, her way of exhibiting her legs, and her signature “wild” hair inform Elizabeth's challenge to Miss Bingley about the definition of a truly accomplished woman. Neither musical nor beautiful, Jordan was part...

(2003). EIGHTEENTH–CENTURY STUDIES. Journal of the Australasian Universities Language and Literature Association: Vol. 100, No. 1, pp. 99-107.

Jonathan Edwards, Letters and Personal Writings, reviewed by Linda Munk David Nokes, Jane Austen. A Life, reviewed by Jocelyn Harris Gregory Woods, A History of Gay Literature, reviewed by Linda Hutcheon

An unusual protracted course of calciphylaxis without cutaneous ulcerations has been encountered in 14 cases. Calciphylaxis may include several clinical presentations ranging from an acute, rapidly fatal course to an indolent, more benign variant. Calciphylaxis should be included in the differential diagnosis for patients with kidney disease presenting with a clinical picture of panniculitis. Patients with renal disease with a characteristic clinical presentation with or without cutaneous ulcerations should undergo an urgent biopsy to confirm the diagnosis.

In ‘The Small Personal Voice’, an essay first published in 1957, Doris Lessing argues that the responsible artist should be ‘an architect of the soul’, a humanist working to strengthen good against evil.1 She is, and she has. Born in Persia, raised in colonial Rhodesia, her father embittered and mutilated by the First World War, Doris Lessing came to postwar England and found it wanting. Child of violence and of violent change, she creates unsettingly innocent observers, their perceptions sharpened by unfamiliarity and exile.2 Lessing maps our most urgent concerns: the collapse of empires and idealisms, the shadow of war and the Bomb, urban disaster and environmental ruin. The blueprints that she tests as remedies for these ills include madness, mysticism, apocalypse, Utopia and organic architecture; tests and discards, for she is always moving on.