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Machiavelli can be read as a plebeian thinker supportive of plebeian institutions that, as such, differentiate the few from the many and aim to regulate and burden the few. Yet, like numerous contemporary plebeian thinkers, Machiavelli is mostly silent about the moral transgressiveness required by the advocacy of plebeian institutions and ideas. The theses offered here argue that advocates of plebeianism will need, like the Machiavellian prince, to learn how not to be good. In explaining what this means in practice, the theses also defend the propriety of anachronistic readings, caution again plebeian violence, and explain other dynamics of plebeian leftism.

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Addressing this bottleneck, we established T-FINDER (T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors), a platform that rapidly deconvolutes CD4 and CD8 TCR reactivities to targets physiologically processed and presented by an individual’s unmanipulated, complete HLA haplotype. By using a highly sensitive TCR signaling reporter capable of detecting even low-affinity TCR:ligand interactions, T-FINDER not only robustly identifies unknown peptide:HLA ligands from complex antigen libraries, but also rapidly screens and functionally validates the specificity of complex TCR libraries against known or predicted targets. To demonstrate its pan-HLA presentation capacity, we apply the platform to multiple TCR-based applications, including glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER’s potency and versatility.

Assessing a dizzy patient in primary care can be challenging. The richness of human vocabulary and use of terms such as ‘wobbly’, ‘woozy’ or ‘lightheaded’ often present the first challenge of identifying true vertigo. This can make eliciting which of a wide variety of disease processes may be causing symptoms a confusing process. True vertigo is considered a perception of movement in the absence of said movement – this is often, but not exclusively a rotating or swaying sensation. In this article we will cover how to approach a patient with suspected vertigo, including key discriminators in the history and examination that can help make a diagnosis. We will also cover treatment of the conditions causing vertigo, while considering other conditions that may cause other forms of dizziness.

Aggregations abound in nature, from cell formations to locust swarms. One method of modelling these aggregations is the non-local aggregation equation with the addition of degenerate diffusion. In this article we develop a finite volume based numerical scheme for this style of equation and perform an error, computation time, and convergence analysis. In addition we investigate two methods for approximating the non-local component. References A. J. Bernoff and C. M. Topaz. Nonlocal aggregation models: A primer of swarm equilibria. SIAM Rev. 55.4 (2013), pp. 709–747. doi: 10.1137/130925669 R. Bürger, D. Inzunza, P. Mulet, and L. M. Villada. Implicit-explicit methods for a class of nonlinear nonlocal gradient flow equations modelling collective behaviour. Appl. Numer. Math. 144 (2019), pp. 234–252. doi: 10.1016/j.apnum.2019.04.018 J. A. Carrillo, A. Chertock, and Y. Huang. A finite-volume method for nonlinear nonlocal equations with a gradient flow structure. In: Commun. Comput. Phys. 17.1 (2015), pp. 233–258. doi: 10.4208/cicp.160214.010814a J. R. Dormand and P. J. Prince. A family of embedded Runge–Kutta formulae. J. Comput. Appl. Math. 6.1 (1980), pp. 19–26. doi: 10.1016/0771-050X(80)90013-3 J. von zur Gathen and J. Gerhard. Modern computer algebra. 3rd ed. Cambridge University Press, 2013. doi: 10.1017/CBO9781139856065 F. Georgiou, J. Buhl, J. E. F. Green, B. Lamichhane, and N. Thamwattana. Modelling locust foraging: How and why food affects group formation. PLOS Comput. Biol. 17.7 (2021), e1008353. doi: 10.1371/journal.pcbi.1008353 F. Georgiou, B. P. Lamichhane, and N. Thamwattana. An adaptive numerical scheme for a partial integro-differential equation. Proceedings of the 18th Biennial Computational Techniques and Applications Conference, CTAC-2018. Ed. by B. Lamichhane, T. Tran, and J. Bunder. Vol. 60. ANZIAM J. 2019, pp. C187–C200. doi: 10.21914/anziamj.v60i0.14066 F. Georgiou, N. Thamwattana, and B. P. Lamichhane. Modelling cell aggregation using a modified swarm model. Proceedings of the 23rd International Congress on Modelling and Simulation, MODSIM2019. Vol. 6. 2019, pp. 22–27. doi: 10.36334/modsim.2019.a1.georgiou J. E. F. Green, S. L. Waters, J. P. Whiteley, L. Edelstein-Keshet, K. M. Shakesheff, and H. M. Byrne. Non-local models for the formation of hepatocyte–stellate cell aggregates. J. Theor. Bio. 267.1 (2010), pp. 106–120. doi: 10.1016/j.jtbi.2010.08.013 R. J. LeVeque. Finite-volume methods for hyperbolic Pproblems. Cambridge Texts in Applied Mathematics. Cambridge University Press, 2002. doi: 10.1017/CBO9780511791253 C. F. Van Loan. Introduction to Scientific Computing: A Matrix Vector Approach Using MATLAB. 1997. url: https://www.pearson.com/us/higher-education/program/Van- Loan-Introduction-to-Scientific-Computing-A-Matrix-Vector- Approach-Using-MATLAB-2nd-Edition/PGM215520.html A. Mogilner and L. Edelstein-Keshet. A non-local model for a swarm. J. Math. Bio. 38.6 (1999), pp. 534–570. doi: 10.1007/s002850050158 C. M. Topaz, A. L. Bertozzi, and M. A. Lewis. A nonlocal continuum model for biological aggregation. Bull. Math. Biol. 68 (2006), p. 1601. doi: 10.1007/s11538-006-9088-6 C. M. Topaz, M. R. D’Orsogna, L. Edelstein-Keshet, and A. J. Bernoff. Locust dynamics: Behavioral phase change and swarming. PLOS Comput. Bio. 8.8 (2012), e1002642. doi: 10.1371/journal.pcbi.1002642

Summary Background The Gambia introduced seven-valent pneumococcal conjugate vaccine (PCV7) in August 2009, followed by PCV13 in May, 2011, using a schedule of three primary doses without a booster dose or catch-up immunisation. We aimed to assess the long-term impact of PCV on disease incidence. Methods We did 10 years of population-based surveillance for invasive pneumococcal disease (IPD) and WHO defined radiological pneumonia with consolidation in rural Gambia. The surveillance population included all Basse Health and Demographic Surveillance System residents aged 2 months or older. Nurses screened all outpatients and inpatients at all health facilities using standardised criteria for referral. Clinicians then applied criteria for patient investigation. We defined IPD as a compatible illness with isolation of Streptococcus pneumoniae from a normally sterile site (cerebrospinal fluid, blood, or pleural fluid). We compared disease incidence between baseline (May 12, 2008–May 11, 2010) and post-vaccine years (2016–2017), in children aged 2 months to 14 years, adjusting for changes in case ascertainment over time. Findings We identified 22 728 patients for investigation and detected 342 cases of IPD and 2623 cases of radiological pneumonia. Among children aged 2–59 months, IPD incidence declined from 184 cases per 100 000 person-years to 38 cases per 100 000 person-years, an 80% reduction (95% CI 69–87). Non-pneumococcal bacteraemia incidence did not change significantly over time (incidence rate ratio 0·88; 95% CI, 0·64–1·21). We detected zero cases of vaccine-type IPD in the 2–11 month age group in 2016–17. Incidence of radiological pneumonia decreased by 33% (95% CI 24–40), from 10·5 to 7·0 per 1000 person-years in the 2–59 month age group, while pneumonia hospitalisations declined by 27% (95% CI 22–31). In the 5–14 year age group, IPD incidence declined by 69% (95% CI −28 to 91) and radiological pneumonia by 27% (95% CI −5 to 49). Interpretation Routine introduction of PCV13 substantially reduced the incidence of childhood IPD and pneumonia in rural Gambia, including elimination of vaccine-type IPD in infants. Other low-income countries can expect substantial impact from the introduction of PCV13 using a schedule of three primary doses. Funding Gavi, The Vaccine Alliance; Bill & Melinda Gates Foundation; UK Medical Research Council; Pfizer Ltd.

BackgroundIt is widely reported that the SARS-CoV-2 Omicron variant has resulted in high number of cases, but relatively low incidence of severe disease and deaths, compared to the pre-Omicron variants of concern. We aim to assess the differences in symptom prevalence between Omicron and pre-Omicron infections in a sub-Saharan African population.MethodsIn this cross-sectional observational study, we collected data from children and adult outpatients presenting at two primary healthcare facilities in Blantyre, Malawi. Eligible participants were aged >1month old, with signs suggestive of COVID-19, and those not suspected of COVID-19. Nasopharyngeal swabs were collected for SARS-CoV-2 PCR testing and positive samples whole genome sequenced to identify the infecting variant. The primary outcome was the likelihood of presenting with a given symptom in individuals testing positive during the period in which Omicron-dominated (December 2021 to March 2022) with those infected during the pre-Omicron period (August 2021 to November 2021).FindingsAmong 5176 study participants, the median age was 28 years (IQR 21-38), of which 6.4% were under 5, 9.2% were 6 to 17 years, 77% were 18 to 50 years, and 7.1% were above 50 years old. Prevalence of SARS-CoV-2 infection was 23% (1187/5188), varying over time, with peaks in January 2021, July 2021 and December 2021, driven by the Beta (B.1.351), Delta (B.1.617.2) and Omicron (BA.1/2) variants, respectively. Headache (OR 0.47[CI 0.29 – 0.79]), cough (OR 0.37[CI 0.22 – 0.61]), fatigue (OR 0.20[CI 0.08 – 0.48]) and abdominal pain (OR 0.38[CI 0.18 – 0.78]) were less common in participants infected during the Omicron-dominant period than during pre-Omicron period. Fever was more common in participants infected during the Omicron-dominated period than during pre-Omicron period (OR 2.46[CI 1.29 – 4.97]). COVID-19 vaccination, accounting for number of doses and days since last dose, was not associated with a reduced risk of PCR-confirmed SARS-CoV-2 infection (1 dose, OR 1.10[CI 0.39 – 2.66]; 2 doses, OR 1.11[CI 0.40 – 2.57]; all p=0.8).InterpretationIn this Malawian population, the prevalence of clinical symptoms associated with Omicron infection differ from those of pre-Omicron infections and may be harder to identify clinically with current symptom guidelines. To maintain robust surveillance for COVID-19 and emerging variants, case definitions and testing policies will need to be regularly reviewed to ensure case ascertainment.

Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab’s clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.

Benjamin (Ben) Bagby is one of the world’s distinguished medievalists, and is particularly well-known for his scholarly, yet passionate performances of the music of the medieval epoch — both with the ensemble Sequentia, which he co-founded, and as a soloist. In the fi eld of solo performance he is renowned for bringing to life the important Anglo-Saxon epic Beowulf — presenting it, as far as contemporary scholarship and vivid artistic imagination can allow, in an authentic “bardic” manner. This wide-ranging interview has much discussion of his career in both regards, as well as his experience as a professor at the Sorbonne. Readers who may wish, after reading this interview, to know more about this important musician and scholar can visit these two websites: www.BagbyBeowulf.com / www.Sequentia.org

Interstitial lung disease is a known complication of rheumatoid arthritis, with a lifetime risk of developing the disease in any individual of 7·7%. We aimed to assess the safety, tolerability, and efficacy of pirfenidone for the treatment of patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD).TRAIL1 was a randomised, double-blind, placebo-controlled, phase 2 trial done in 34 academic centres specialising in interstitial lung disease in four countries (the UK, the USA, Australia, and Canada). Adults aged 18-85 years were eligible for inclusion if they met the 2010 American College of Rheumatology and European Alliance of Associations for Rheumatology criteria for rheumatoid arthritis and had interstitial lung disease on a high-resolution CT scan imaging and, when available, lung biopsy. Exclusion criteria include smoking, clinical history of other known causes of interstitial lung disease, and coexistant clinically significant COPD or asthma. Patients were randomly assigned (1:1) to receive 2403 mg oral pirfenidone (pirfenidone group) or placebo (placebo group) daily. The primary endpoint was the incidence of the composite endpoint of a decline from baseline in percent predicted forced vital capacity (FVC%) of 10% or more or death during the 52-week treatment period assessed in the intention-to-treat population. Key secondary endpoints included change in absolute and FVC% over 52 weeks, the proportion of patients with a decline in FVC% of 10% or more, and the frequency of progression as defined by Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02808871.From May 15, 2017, to March 31, 2020, 231 patients were assessed for inclusion, of whom 123 patients were randomly assigned (63 [51%] to the pirfenidone group and 60 [49%] to the placebo group). The trial was stopped early (March 31, 2020) due to slow recruitment and the COVID-19 pandemic. The difference in the proportion of patients who met the composite primary endpoint (decline in FVC% from baseline of 10% or more or death) between the two groups was not significant (seven [11%] of 63 patients in the pirfenidone group vs nine [15%] of 60 patients in the placebo group; OR 0·67 [95% CI 0·22 to 2·03]; p=0·48). Compared with the placebo group, patients in the pirfenidone group had a slower rate of decline in lung function, measured by estimated annual change in absolute FVC (-66 vs -146; p=0·0082) and FVC% (-1·02 vs -3·21; p=0·0028). The groups were similar with regards to the decline in FVC% by 10% or more (five [8%] participants in the pirfenidone group vs seven [12%] in the placebo group; OR 0·52 [95% CI 0·14-1·90]; p=0·32) and the frequency of progression as defined by OMERACT (16 [25%] in the pirfenidone group vs 19 [32%] in the placebo group; OR 0·68 [0·30-1·54]; p=0·35). There was no significant difference in the rate of treatment-emergent serious adverse events between the two groups, and there were no treatment-related deaths.Due to early termination of the study and underpowering, the results should be interpreted with caution. Despite not meeting the composite primary endpoint, pirfenidone slowed the rate of decline of FVC over time in patients with RA-ILD. Safety in patients with RA-ILD was similar to that seen in other pirfenidone trials.Genentech.

ICONI Magazine is proud to present an interview conducted by Dr. Edward Green, professor at the Manhattan School of Music, with Maestro Diego Sánchez Haase, the most distinguished musician yet produced by the nation of Paraguay. First and foremost a composer, with works in many different genres, Haase is likewise a major orchestral conductor, and a powerful advocate for the music of Bach. This interview includes discussion of his operas Pancha y Elisa (2018) and Ñomongeta (2019) — each rooted in the history and culture of Paraguay: the latter opera being the fi rst ever to have its libretto in Guarani — the language of its indigenous population. (It is one of the two offi cial languages of Paraguay; the other being Spanish.) In this interview is also substantial discussion of Haaseʼs study of Bach with Helmut Rilling, and of two operas Maestro Haase is currently creating, including one based on the Bibleʼs “Song of Songs.”

We learn in this interview with the leading Norwegian composer of his generation, Marcus Paus (b. 1979), how critical he is of the “academic tradition” which, in his view, has hurt a good deal of contemporary music over the last several decades: a certain snobbish adherence to non-tonal, non-melodic “abstract modernism.” Paus, on the contrary, asserts the living freshness of traditional values. His own music is grounded in tradition, is steeped in the value of careful craftsmanship, and yet, at the same time, is passionate, surprising, original, deeply lyrical, and fervently humanist in its social and political orientation. We learn, too, of his great esteem for the American composer John Williams, best known for his cinematic scores. Paus sees Williams as a model of nobility: both musically, and as a human being. In this interview there is also substantial discussion of the value of the philosophy of Aesthetic Realism, founded by the great American philosopher Eli Siegel, and his profound ideas concerning Art and Life. During this wide-ranging conversation, Paus speaks likewise of world music, pop music, and his abiding interest in literature and painting. There is also an extended passage where he keenly and generously comments on the composers of his own generation, and points to several of their most outstanding works.

This interview for the journal ICONI, taken by Dr. Edward Green, Professor at the Manhattan School of Music, is with one of the leading composers of the United States, George Tsontakis. A professor at Bard Conservatory of Music, he is the recipient of numerous awards for his work, including the prestigious Grawmeyer Award for his Second Violin Concerto. Professor Tsontakis’ work — nearly all of it commissioned — is wide-ranging in terms of genre, imaginative in its orchestrations, and always strongly emotional. Included in this interview are discussions of some of the biographical background to a number of his major pieces, including The Past, The Passion. Among the subjects discussed is the meaning of “concerto.” Several of his concertos and concerto-like compositions are specifically discussed in this interview, including Man of Sorrows (piano), and Sonnets (English Horn). The interview also touches upon his relations with two important American composers of earlier generation: George Rochberg, and Roger Sessions — who had been Tsontakis’ teacher of composition at Julliard.

The idea of self-reliance is important not only because it is often taken to be definitive of the ethics of democratic individualism, but because its greatest theorists have been uncommonly forthright about a problem that, though familiar to ordinary civic experience, frequently gets ignored: that self-reliant individuality is a basis for not fully supporting otherwise endorsed social justice causes. This article turns to Ralph Waldo Emerson, Henry David Thoreau and Bob Dylan who are unusual for so honestly reflecting upon this problem and who, because of the differences in the way they conceptualize it, are instructive for civic ethics. I demonstrate that Emerson and Thoreau imbue their self-reliant withdrawal from social action with a self-satisfaction that is lacking for Dylan, who is much readier to acknowledge the moral costs of self-reliance. This acknowledgement does not invalidate self-reliance but alters its epistemological, ethical and political features, providing a variant of self-reliance more suitable to contemporary conditions.

Bob Dylan’s performance at the 1963 March on Washington is often interpreted as reflective of the same kind of commitment to social justice manifested by other leading participants at the March. Ho...

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P

Background The frequency of radiological surveillance after curative colorectal cancer resection has long been a controversial issue with the need to balance potential harm from ionizing radiation and the financial burden of intense surveillance against advantages of early detection of recurrent disease. NICE guidelines issued in 2018 suggested having two surveillance computed tomography (CT) scans within three years of surgery without specifying the timing or the interval. Aim To examine whether an evidence-based flexible approach based on individual patients' risk factors can add value to surveillance protocols. Reaching a targeted protocol that can maximize early detection of metastasis without consumption of resources and most important without compromising patient safety. Methodology A retrospective study involving five years of data of patients who underwent curative colorectal cancer resections. Data extracted after patients completed their three-year surveillance CT scans, CT reports retrieved together with post-operative histology reports, and a detailed database was constructed. Results Of 179 patients included, 66 developed recurrence (7 local and 59 distant). Recurrence increased from 23.5% in T1 to 66% in T4 (P=0.0001). The median time to recurrence 23 months in T4 disease compared to 36, 42 and 43 months for stages T1, T2 and T3, respectively (P=0.0001). A similar incremental increase in recurrence noted from 22% in the N0 stage to 73.5% in the N2 stage (P=0.0001); the median time to recurrence of 14 months in N2 patients compared to 45 and 33 months for stages N0 and N1, respectively (P=0.0001). Recurrence correlated well with positive extramural vascular invasion (EMVI) status, (71.7% versus 19.3% P=0.0001) being detected significantly earlier in EMVI positive group at 17 versus 45 months (P=0.0001). Conclusion Flexible protocol for radiological surveillance after curative resection of colorectal cancer, based on known pathological prognostic factors, is likely to be more effective in maximizing resource utilization as well as improving patient outcomes.

Chirally pure (R)-1,3-butanediol ((R)-1,3-BDO) is a valuable intermediate for the production of fragrances, pheromones, insecticides and antibiotics. Biotechnological production results in superior enantiomeric excess over chemical production and is therefore the preferred production route. In this study (R)-1,3-BDO was produced in the industrially important whole cell biocatalyst Clostridium saccharoperbutylacetonicum through expression of the enantio-specific phaB gene from Cupriavidus necator. The heterologous pathway was optimised in three ways: at the transcriptional level choosing strongly expressed promoters and comparing plasmid borne with chromosomal gene expression, at the translational level by optimising the codon usage of the gene to fit the inherent codon adaptation index of C. saccharoperbutylacetonicum, and at the enzyme level by introducing point mutations which led to increased enzymatic activity. The resulting whole cell catalyst produced up to 20 mM (1.8 g/l) (R)-1,3-BDO in non-optimised batch fermentation which is a promising starting position for economical production of this chiral chemical.

This paper examines whether and how the challenging target of 95% decarbonisation can be achieved for the Welsh building stock. First, a critical review of the literature and relevant case studies are presented to understand the effectiveness of different retrofit approaches in practice, and the degree to which these approaches are evidence based, and applicable to the Welsh context. These findings are synthesised into a collection of 14 recurrent dwelling ‘archetypes’, with appropriate retrofit strategies developed for each. The impacts of these strategies are modelled in terms of capital cost, primary energy use, fuel bills and carbon emissions. Conclusions provide an evidence base for future policy and a decarbonisation strategy. Retrofit strategies should include fabric first-measures to minimise increases in household fuel bills and a consequent increase in fuel poverty. Retrofit options for a significant percentage of housing are constrained by character, which would limit changes to the external fabric. Given that decarbonisation of the future energy supply is currently uncertain, all other housing should be retrofitted to perform beyond SAP90. A flexible approach that pushes all housing to achieve stringent standards by 2050 is the only way to achieve targeted reductions in carbon emissions under the assumed energy supply scenarios. 'Policy relevance' The Welsh housing stock, among the oldest and least efficient in Europe, is responsible for 21% of Welsh carbon emissions. In 2019, the UK Committee for Climate Change (CCC) determined that Wales should target a 95% reduction in emissions by 2050. This paper assesses whether this challenging target can be achieved, and potential strategies for doing so. Key recommendations are drawn from the research, which encompass technical, social and organisational issues, and the importance of a holistic approach to decarbonisation is identified. These findings informed the Independent Steering Group recent report 'Better Homes, Better Wales, Better World' (2019), and the report’s recommendations were adopted by the Welsh Government on 24 September 2019. This work should continue to provide an evidence base upon which future policy can be developed through the development of retrofit strategies for recurring dwelling archetypes and a decarbonisation strategy for Wales that is likely to include legislation, regulation, incentives and penalties.

This interview is with the person rightlycalled China’s fi rst “avant-garde” composer,Ge Gan-ru. The honor is due to his 1983 compositionfor solo cello, Yi Feng (Lost Style), whichgrew out of his in-depth analysis of how Westernand Chinese music differ in their core presumptionsabout pitch, rhythm, timbre, and dynamics.A summary of that analysis is an important featureof this interview. Among other works discussedare his Wrong, Wrong, Wrong! for Voice,self-accompanied by a Toy Orchestra (2006), andhis Fifth String Quartet (2007), titled Fall of Baghdad.Interview with Ge Gan-ru for ICONI, conductedby Dr. Edward Green.

Interview with Edward Green.

129 Background: Pathogenic HRR gene mutations may confer sensitivity to PARP inhibitors (PARPi) and/or platinum chemotherapy (chemo). While pts harboring mutations in BRCA1/2 appear to benefit from these DNA damaging therapeutics, outcomes data for those with non- BRCA1/2 mutations are less robust. We evaluated outcomes in men with HRR gene-mutated PC who received treatment with PARPi and/or platinum-based chemo stratified by type of HRR alteration. Methods: Retrospective data from the PROMISE Consortium was utilized (PMID: 34363009). PC pts with pathogenic HRR mutations who received PARPi and/or platinum-based chemo were included. Differences in PSA progression-free survival (PFS), clinical/radiographic PFS (rPFS), and overall survival (OS) between those with BRCA1/ 2 mutations (Cohort A) and those with mutations in HRR genes that do not directly interact with the BRCA complex (Cohort B: ATM, CDK12, CHEK1, CHEK2, FANCL) were evaluated. We also evaluated outcomes in pts with HRR gene mutations known to interact with the BRCA complex aside from BRCA1/2 (Cohort C: RAD51B/C/D, RAD54L2, BARD1, GEN1, PALB2, FANCA, BRIP1). Results: Of 361 pts identified with HRR gene alterations, 89 received PARPi and 70 received platinum-based chemo. Prior therapy and metastatic disease sites were similar between cohorts. PSA PFS, rPFS, and OS were significantly improved in Cohort A vs. Cohort B with PARPi but not platinum-based chemo (Table). Sample size in cohort C was too small to allow for statistical comparison, although PSA PFS, PFS and OS were reasonably long. Conclusions: PC pts with BRCA1/2 mutations had improved outcomes to PARPi compared to those with mutations in HRR genes not directly interacting with the BRCA complex. Platinum-based chemo appeared effective regardless of which HRR gene was affected. [Table: see text]

The growing wealth gap has eroded support for liberal democracy by exposing its unfulfilled egalitarian promises. A renewal of civic obligations could be the best defense against creeping plutocracy.

This essay looks at John Lennon of The Beatles to comment on the great need musicologists have for a method of writing biography that is capable of doing justice to ethical dimension of an artist’s life and work. The author advocates the use of Aesthetic Realism to achieve this. It is the philosophy founded in 1941 by the great American scholar Eli Siegel. In Aesthetic Realism is a new way of understanding the relation of Ethics and Aesthetics. Central to it is Eli Siegel’s comprehension of the on-going debate in every human mind between Contempt and Respect – a debate illustrated in the life and work of Lennon. To give both more immediacy and more dimension to these matters, the author – who, like Lennon, is a composer – quotes from class discussions with him from his study, in the 1970s, with Eli Siegel. Keywords: John Lennon, Eli Siegel, The Beatles, Aesthetic Realism, Ethics.

Summary Background Little information is available about the effect of pneumococcal conjugate vaccines (PCVs) in low-income countries. We measured the effect of these vaccines on invasive pneumococcal disease in The Gambia where the 7-valent vaccine (PCV7) was introduced in August, 2009, followed by the 13-valent vaccine (PCV13) in May, 2011. Methods We conducted population-based surveillance for invasive pneumococcal disease in individuals aged 2 months and older who were residents of the Basse Health and Demographic Surveillance System (BHDSS) in the Upper River Region, The Gambia, using standardised criteria to identify and investigate patients. Surveillance was done between May, 2008, and December, 2014. We compared the incidence of invasive pneumococcal disease between baseline (May 12, 2008–May 11, 2010) and after the introduction of PCV13 (Jan 1, 2013–Dec 31, 2014), adjusting for changes in case ascertainment over time. Findings We investigated 14 650 patients, in whom we identified 320 cases of invasive pneumococcal disease. Compared with baseline, after the introduction of the PCV programme, the incidence of invasive pneumococcal disease decreased by 55% (95% CI 30–71) in the 2–23 months age group, from 253 to 113 per 100 000 population. This decrease was due to an 82% (95% CI 64–91) reduction in serotypes covered by the PCV13 vaccine. In the 2–4 years age group, the incidence of invasive pneumococcal disease decreased by 56% (95% CI 25–75), from 113 to 49 cases per 100 000, with a 68% (95% CI 39–83) reduction in PCV13 serotypes. The incidence of non-PCV13 serotypes in children aged 2–59 months increased by 47% (−21 to 275) from 28 to 41 per 100 000, with a broad range of serotypes. The incidence of non-pneumococcal bacteraemia varied little over time. Interpretation The Gambian PCV programme reduced the incidence of invasive pneumococcal disease in children aged 2–59 months by around 55%. Further surveillance is needed to ascertain the maximum effect of the vaccine in the 2–4 years and older age groups, and to monitor serotype replacement. Low-income and middle-income countries that introduce PCV13 can expect substantial reductions in invasive pneumococcal disease. Funding GAVI's Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP), Bill & Melinda Gates Foundation, and the UK Medical Research Council.

BACKGROUND: IDH1-mutated gliomas are associated with less abundant and phenotypically skewed innate and adaptive immune cell infiltrates compared to IDH1 wild-type tumors. Despite this, the most frequent mutation, IDHR132H, represents a clonal shared neoantigen and mutations in IDH are associated with a more favorable prognosis. While the tumor cell-intrinsic consequences of the oncometabolite R-2-hydroxyglutarate (R-2-HG) accumulating in IDH1-mutated gliomas as a result of a neomorphic enzymatic function, are well-characterized, potential direct paracrine effects of R-2-HG influencing the glioma immune microenvironment remain incompletely understood. METHODS AND RESULTS: By means of comprehensive analyses of expression datasets from human gliomas and syngeneic murine tumor models as well as transporter studies we demonstrate that R-2-HG is imported by both microglia and macrophages via SLC family transporters and suppresses their function in a paracrine manner. Functional analyses of microglia and macrophages indicate an R-2-HG-driven induction of tolerogenicity as evidenced by accumulation of IL10 and TGFβ and suppression of MHC-II expression, which results in impaired activation of antigen-specific T cells and activation of immune checkpoint molecules. Multi-level signature profiling of human tumor-infiltrating as well as primary immune cells was complemented by reporter gene assays and pathway analyses and revealed that R-2-HG activates the cytosolic transcription factor aryl hydrocarbon receptor (AHR), a key immunomodulatory target of immunosuppressive tryptophan metabolism. Functional relevance of R-2-HG-mediated, AHR-driven impairment of myeloid cell immunity was demonstrated in vivo by pharmacological AHR inhibition, increasing the efficacy of checkpoint blockade. CONCLUSION: R-2-HG impairs antitumor immunity in IDH1-mutated gliomas by activating the AHR in innate immune cells, thus suppressing the innate immune microenvironment by compromising antigen presentation and activation of antigen-specific T cells. This, together with recent findings on inhibitory effects on T cell immunity, represents a novel mechanism of immune evasion of an immunogenic driver mutation and opens a novel therapeutic approach to IDH1-mutated gliomas.

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.

Insofar as no democratic society can fully realize norms of free and equal citizenship, citizens in such regimes are likely to experience some degree of discontent with their political lives. This raises a second purpose for democratic theory beyond the usual focus on improving democratic institutions: the psychological issue of how ordinary citizens might find solace in the face of disappointment. Democratic theory is capable of providing solace because egalitarian commitments – equality, free speech, solidarity, and self-sufficiency – have a double potential: they not only ground efforts to democratize institutions, but when sublimated in apolitical form also have the capacity to generate a transcendence of the political form itself. In this essay, I pursue both ideas – the need for solace and egalitarianism's ability to provide it – through analysis of the way Epicureanism may have functioned for the ordinary, plebeian citizens in late Republican Rome.

This essay defends a broad, eclectic, and inclusive kind of political theory against methodological militants who would restrict political theory's permissible purview. It rejects the idea—frequently voiced by exponents of both analytic-philosophic and historicist methodologies—that philosophical and historical analyses are necessarily two separate enterprises that ought to be kept distinct, not just conceptually but as a matter of scholarly practice. Against the methodological militants, this essay explains the value of those forms of political theory that combine philosophy (the study of what should be done) with history (the study of what past authors thought about politics). It concludes by raising one further objection to the methodological militants: They fail to acknowledge the reality and importance of the “classic” work within the study of political thought.