Development and Sensory Experience Dependent Regulation of Microglia in Barrel Cortex

The barrel cortex is within the primary somatosensory cortex of the rodent, and processes signals from the vibrissae. Much focus has been devoted to the function of neurons, more recently, the role of glial cells in the processing of sensory input has gained increasing interest. Microglia are the principal immune cells of the nervous system that survey and regulate the cellular constituents of the dynamic nervous system. We investigated the normal and disrupted development of microglia in barrel cortex by chronically depriving sensory signals via whisker trimming for the animals’ first postnatal month. Using immunohistochemistry to label microglia, we performed morphological reconstructions as well as densitometry analyses as a function of developmental age and sensory experience. Findings suggest that both developmental age and sensory experience has profound impact on microglia morphology. Following chronic sensory deprivation, microglia undergo a morphological transition from a monitoring or resting state to an altered morphological state, by exhibiting expanded cell body size and retracted processes. Sensory restoration via whisker regrowth returns these morphological alterations back to agematched control values. Our results indicate that microglia may be recruited to participate in the modulation of neuronal structural remodeling during developmental critical periods and in response to alteration in sensory input

Rebalancing the central-local relationship: Achieving a bottom-up approach to localism

Recent governments have introduced a plethora of reforms seeking to decentralise power to local government in England. Invariably, however, these have fallen short of stated objectives, leaving councils at the mercy of central supervision and with insufficient local autonomy. This article explores the reasons underpinning this concern. It identifies a top-down approach to localism and considers the culture of centralism that persists as a consequence. It then discusses how a bottom-up approach might be achieved, exploring how political and legal mechanisms can protect councils from centralised interference in the future

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The Musical Language of the "Symphonic Pieces" from "Lulu" (Alban Berg).

This dissertation comprises an examination of the musical language in the Symphonic Pieces (1934) from the opera Lulu (1928-35) by Alban Berg. The Pieces offer the advantages of being relatively brief and of including passages that display the most characteristic themes and transformations of material. Thereby, they allow for a self-contained analysis as well as providing an entry into a study of the entire opera. The analysis is directed from three related perspectives: the use of systematic procedures related both to twelve-tone and non-twelve-tone elements, the components of the harmonic language, and the local and larger-level organization of material into formal units. One of the principal characteristics of the musical language is the integration of tonal and twelve-tone elements. Tonal elements are related to the twelve-tone set structure principally by means of triads derived both segmentally and non-segmentally from various sets, the diatonic hexachords in the principal sets, and the general determination of transposition levels by diatonic "white"-note and predominantly "black"-note pitch-class collections. Areas of tonal focus are characterized by the use of extended and delayed resolution of tones and chords in an extension of late nineteenth-century practice, creating an ambiguous language often only implying tonal function. A development of twelve-tone techniques unique to Lulu, where more than one set is used, is the relationship of the derived sets to the Basic Set. Rather than being related by the classical twelve-tone operators, these sets are derived by operations on order position such as cyclic and extended cyclic operations and extraction based on numerical gradations. The nature of the operation defines specific relationships between sets capable of compositional exploitation. The methods of derivation, which may be seen as analogous to operations on pitch-class, constitute a considerable expansion of the twelve-tone system.Ph.D.MusicUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160798/1/8600454.pd

Making the break work : a study of professional women's careers

Even among graduate professionals, men and women continue to have different career patterns. Men typically enjoy uninterrupted careers, while women experience discontinuous employment, with a career break for family responsibilities (Hewitt, 1993). A recent comprehensive study (Hakim, 1996) detected a sharp divide between home-centred women and the minority of career-oriented women for whom employment is just as central to their lives as it is for men. Other research (Michaels et al. 1995) highlights the growing desire of graduate women to return to the workplace once they have completed their families. The University of Lincolnshire and Humberside has run ‘Professional Updating for Women’ (PUW) courses to facilitate this process since 1989, designed in conjunction with the Women Returners’ Network and attracting funding from Objective 3 of the European Social Fun

The z-relation in theory and practice

Includes vita and abstract. --- Thesis (Ph. D.)--University of Rochester, 2012. --- Includes bibliographical references.Though the z-relation--the relationship whereby two sets not related by transposition and/or inversion have the same interval-class content--has been one of the core concepts of pitch-class set theory since its inception, the principles underlying the relationship have to a large extent remained obscure. However, new information is emerging. First, recent work on the Fourier transform for pitch-class-set analysis (in particular, by Ian Quinn, which builds on work by David Lewin) provides new information concerning the subset structure of z-related sets. Second, as recognized by Clifton Callender and Rachel Hall, the z-relation is an instance of what crystallographers call homometry, which has been written about extensively. The aim of this study is to utilize these new means to present a comprehensive description of the z-relation that addresses the criteria upon which the z-relation relies as well as the ways in which z-related sets interrelate. Building upon algebraic formulas suggested by crystallographers, I develop an approach that describes z-related pairs in terms of formulas that correspond to subset properties illustrated by the Fourier transform. In addition to devising my own formulas, I show that the formulas can be extended with a method called 'pumping' (O'Rourke, et alii), which adds pitch-classes to preformed formulas. Together, the formulas and pumping lead to a general theory of the z-relation that not only describes the relationships between the sets of a z-related pair, but also those between z-related pairs of different cardinalities. Since it exposes transformational relationships, the algebraic approach lends itself well to the analysis of music that involves z-related sets, whether twelve-tone music based on rows with discrete hexachords that are z-related, or other non-serial music that prominently features z-related sets as motivic harmonies. In my own work I use the theory to analyze twentieth-century works by composers including Schoenberg, Berg, Carter and Berio. Overall, the theory exposes that transformational networks involving z-related sets are not only possible, but are altogether relevant to the analysis of music that involves such harmonies

On row-class equivalence classes

Includes abstract and vita.This dissertation adds a statistical layer to twelve-tone analysis, and in so doing, broadens the purview from the row class of an individual composition to a larger context of collections of row classes that share features relevant to a composition at hand. Twelve-tone analysis traditionally details the numbers of a row class that appear within a composition and suggests ways to interpret coherence in the combination and succession of row forms. The present study builds upon this approach by evaluating row-form selection in a context that classifies row properties within all row classes. The dissertation creates this context by asking: how many twelve-tone row classes possess the features emphasized in an analysis? Answering the question identifies norms within the collection of twelve-tone row classes; degrees of normativity are expressed via the normalcy / distinctiveness rating, a useful measure for the types of compositional relationships found in row-based works. The dissertation argues that these norms offer one avenue for contextualizing twelve-tone analyses and thereby provide additional opportunities for interpretation. Chapter 1 reviews the relevant scholarship on twelve-tone theory and analysis. It focuses, first, on the origins and development of "classical" twelve-tone analysis and, second, the tradition of enumerating the twelve-tone row classes that possess particular features, creates equivalence classes within the collection of twelve-tone row classes, and formalizes the normalcy / distinctiveness rating. Chapters 3 and 4 explore the interpretive potential for enumerations for twelve-tone analysis. Chapter 3 illustrates the theory with analytical vignettes of Arnold Schoenberg's Violin concerto op. 36/I and Variations for orchestra, op. 31, and Webern's Concerto for nine instruments, op. 24/I. Chapter 4 focuses exclusively on Webern's Variations for orchestra, op. 30. In each discussion, both the potential and composed-out features of the row-class are evaluated within the context of the piece and with reference to larger statistical norms