Host Microbiome Regulation of Hyperthermia Mediated by 3,4-Methylenedioxymethamphetamine (MDMA, Molly)

Hyperthermia is one of the most acute and life-threatening consequences of 3,4-methylenedioxymethamphetamine (MDMA) use. The hyperthermia induced by MDMA involves a complex interaction between heat generation and loss of heat dissipation. Recent studies have demonstrated a role for gut microbiome in the regulation of body weight and temperature. Here, we investigated the potential role of the gut microbiome in MDMA-mediated hyperthermia. For fourteen days prior to treatment with MDMA (20 mg/kg, sc) male, Sprague-Dawley rats were provided regular drinking water or drinking water laced with the non-absorbable antibiotics, bacitracin (0.5 mg/mL), neomycin (2mg/mL), and vancomycin (0.2mg/mL). Antibiotic (ABX) treatment reduced gut bacteria and increased cecal size. MDMA-induced a hyperthermic response that resulted in a maximal temperature change (ΔTmax ) of 4.6 ± 0.1 °C and only a 50% survival rate 60 minutes after treatment. Conversely, ABX treatment prior to MDMA attenuated the hyperthermic response with a ΔTmax of 3.4 ± 0.6 °C and a 100% survival rate 60 minutes after treatment. An acute intraperitoneal injection of ABX 30 minutes before MDMA had no effect on the hyperthermic response, eliminating the possibility of a pharmacodynamics interaction between ABX and MDMA. Overall, these findings demonstrate that the gut microbiome contributes to the hyperthermia mediated by MDMA

From House to Case of Fiction: A Study of Modernist Literary Luggage

This thesis presents the first full-length study of modernist literary luggage. It explores all facets of imaginative engagement with luggage, both material and metaphorical, in modernism, as this builds upon and develops a long-standing and overlooked symbolic and analogic tradition. The study approaches luggage in two ways; as thematic motif and as model for modernist form. Drawing on an extensive range of primary sources spanning from the mid-nineteenth through to the mid-twentieth century, it identifies the proliferating appeal of luggage imagery over the course of this period as defined against the diminishing appeal of governing sedentary paradigms for apprehending and framing experience, exemplified in the symbolic form of the house. It contends that the 'case' overtakes the 'house of fiction' in the early-twentieth-century literary imagination as the central structural model for modern fiction in line with the emergence of what E.M. Forster disparagingly refers to as the 'civilisation of luggage' in Howards End in 1910. As Forster's disparagement suggests, the very idea of a civilisation of luggage provoked conflicting responses and contentious readings. Correspondingly, the case of fiction model was characterised by its very paradoxical nature; most conspicuously, it enacted a break from old forms while also demonstrating an inability to entirely leave the past behind. Yet it was precisely because, and not in spite of, this paradoxical quality, this semantic instability, this capacity to inspire divergent responses, that modernist literary luggage became such an appropriate means of encapsulating the experience of modernity in all its complexity. A central focus is the special significance of luggage for women. The thesis will consider the recurrent use of the woman's bag as a pivotal motif and sticking point in portrayals of shifting gender relations around the turn of the twentieth century in order to demonstrate that the woman's struggle for a bag of her own was a necessary precursor to the struggle surrounding the room, feeding into a wider modernist preoccupation with the nature of the relationship between freedom and property. Following this preoccupation more generally into the interwar period, the thesis charts the impact of the politicization of forms of mobility in late modernist work as this is manifested in the problematization of an earlier modernist luggage paradigm. Taking account of luggage conceptions of refugee and evacuee writers caught in the political crossfire on mainland Europe - that other civilization of luggage compelled by force, rather than by choice, to travel light - the study will conclude with a detailed discussion of the widespread reappraisal of the case of fiction model in the late 1930s in light of complicating political factors. Overall, the thesis contends that luggage - signalling obstruction as much as mobility, adventure as much as dispossession, the exhilaration of travel as much as the terror of flight, the material attachment to a familiar past as much as the immaterial projection forward into an unfamiliar future - proposes an innovative re-description of modernist fiction which offers illuminating new perspectives on the contradictory forces, interests and imperatives of modernism with wide-reaching implications

Bone Fractures With and Without Sickle Cell Disease in the Pediatric Population

Background: Individuals with sickle cell disease are restricted from certain physical activities due to the increased risk of complications including fractures secondary to osteopenia. However the exact incidence and outcomes of fractures amongst these patients is unknown. Objectives: (1) describe the incidence, epidemiology, and outcomes of fractures in patients with SCD. (2) to compare fracture patterns and outcomes in patients with and without SCD. Methods: This is a retrospective, cohort study of patients aged 0-25 years old with HbSS, HbSC, or HbS-β-thalassemia with a fracture evaluated at a pediatric emergency department from April 2009-April 2022. Eligible patients were identified using a combination of ICD billing codes and a preexisting hematology clinic database. Patients were age/gender matched with non-SCD patients with fractures. Data on demographics, number and types of fractures and outcomes were collected. Results: 753 patients with SCD were identified during the study period. SCD patients with fractures were more likely to have multiple comorbidities, lower mean vitamin D levels and were less likely to be on vitamin D supplementation compared to those without fractures. The most common etiology was fall and carpal bones were most commonly fractured. Non-SCD patients with fractures were more likely to be obese and require surgical repair compared to their SCD peers. Conclusions: Fracture incidence among SCD patients is low. Male gender, multiple comorbidities, and lack of vitamin D supplementation are associated with increased risk of fracture. SCD patients with a fracture were less likely to require surgical treatment compared to their non-SCD counterparts

The infuence of the host microbiome on 3,4- methylenedioxymethamphetamine (MDMA)-induced hyperthermia and vice versa

Hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) can be life-threatening. Here, we investigate the role of the gut microbiome and TGR5 bile acid receptors in MDMA-mediated hyperthermia. Fourteen days prior to treatment with MDMA, male Sprague-Dawley rats were provided water or water treated with antibiotics. Animals that had received antibiotics displayed a reduction in gut bacteria and an attenuated hyperthermic response to MDMA. MDMA treated animals showed increased uncoupling protein 1 (UCP1)and TGR5 expression levels in brown adipose tissue and skeletal muscle while increased expression of UCP3 was observed only in skeletal muscle. Antibiotics prior to MDMA administration significantly blunted these increases in gene expression. Furthermore, inhibition of the TGR5 receptor with triamterene or of deiodinase II downstream of the TGR5 receptor with iopanoic acid also resulted in the attenuation of MDMA-induced hyperthermia. MDMA-treatment enriched the relative proportion of a Proteus mirabilis strain in the ceca of animals not pre-treated with antibiotics. These findings suggest a contributing role for the gut microbiota in MDMA-mediated hyperthermia and that MDMA treatment can trigger a rapid remodeling of the composition of the gut microbiome

A submillimetre survey of the kinematics of the Perseus molecular cloud: I. data

We present submillimetre observations of the J = 3-2 rotational transition of 12CO, 13CO and C18O across over 600 sq arcmin of the Perseus molecular cloud, undertaken with HARP, a new array spectrograph on the James Clerk Maxwell Telescope. The data encompass four regions of the cloud, containing the largest clusters of dust continuum condensations: NGC 1333, IC348, L1448 and L1455. A new procedure to remove striping artefacts from the raw HARP data is introduced. We compare the maps to those of the dust continuum emission mapped with SCUBA (Hatchell et al. 2005) and the positions of starless and protostellar cores (Hatchell et al. 2007a). No straightforward correlation is found between the masses of each region derived from the HARP CO and SCUBA data, underlining the care that must be exercised when comparing masses of the same object derived from different tracers. From the 13CO/C18O line ratio the relative abundance of the two species ([13CO]/[C18O] ~ 7) and their opacities (typically tau is 0.02-0.22 and 0.15-1.52 for the C18O and 13CO gas respectively) are calculated. C18O is optically thin nearly everywhere, increasing in opacity towards star-forming cores but not beyond tau(C18O)~0.9. Assuming the 12CO gas is optically thick we compute its excitation temperature (around 8-30 K), which has little correlation with estimates of the dust temperature.Comment: 20 pages, 15 figures, accepted for publication by MNRA

Intimate physical contact between people from different households during the COVID-19 pandemic: a mixed-methods study from a large, quasi-representative survey (Natsal-COVID)

OBJECTIVES: Physical distancing as a non-pharmaceutical intervention aims to reduce interactions between people to prevent SARS-CoV-2 transmission. Intimate physical contact outside the household (IPCOH) may expand transmission networks by connecting households. We aimed to explore whether intimacy needs impacted adherence to physical distancing following lockdown in Britain in March 2020. METHODS: The Natsal-COVID web-panel survey (July-August 2020) used quota-sampling and weighting to achieve a quasi-representative population sample. We estimate reporting of IPCOH with a romantic/sexual partner in the 4 weeks prior to interview, describe the type of contact, identify demographic and behavioural factors associated with IPCOH and present age-adjusted ORs (aORs). Qualitative interviews (n=18) were conducted to understand the context, reasons and decision making around IPCOH. RESULTS: Of 6654 participants aged 18-59 years, 9.9% (95% CI 9.1% to 10.6%) reported IPCOH. IPCOH was highest in those aged 18-24 (17.7%), identifying as gay or lesbian (19.5%), and in steady non-cohabiting relationships (56.3%). IPCOH was associated with reporting risk behaviours (eg, condomless sex, higher alcohol consumption). IPCOH was less likely among those reporting bad/very bad health (aOR 0.54; 95% CI 0.32 to 0.93) but more likely among those with COVID-19 symptoms and/or diagnosis (aOR 1.34; 95% CI 1.10 to 1.65). Two-thirds (64.4%) of IPCOH was reported as being within a support bubble. Qualitative interviews found that people reporting IPCOH deliberated over, and made efforts to mitigate, the risks. CONCLUSIONS: Given 90% of people did not report IPCOH, this contact may not be a large additional contributor to SARS-CoV-2 transmission, although heterogeneity exists within the population. Public health messages need to recognise how single people and partners living apart balance sexual intimacy and relationship needs with adherence to control measures

Germline Mutations in NFKB2 Implicate the Noncanonical NF-κB Pathway in the Pathogenesis of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by antibody deficiency, poor humoral response to antigens, and recurrent infections. To investigate the molecular cause of CVID, we carried out exome sequence analysis of a family diagnosed with CVID and identified a heterozygous frameshift mutation, c.2564delA (p.Lys855Serfs∗7), in NFKB2 affecting the C terminus of NF-κB2 (also known as p100/p52 or p100/p49). Subsequent screening of NFKB2 in 33 unrelated CVID-affected individuals uncovered a second heterozygous nonsense mutation, c.2557C>T (p.Arg853∗), in one simplex case. Affected individuals in both families presented with an unusual combination of childhood-onset hypogammaglobulinemia with recurrent infections, autoimmune features, and adrenal insufficiency. NF-κB2 is the principal protein involved in the noncanonical NF-κB pathway, is evolutionarily conserved, and functions in peripheral lymphoid organ development, B cell development, and antibody production. In addition, Nfkb2 mouse models demonstrate a CVID-like phenotype with hypogammaglobulinemia and poor humoral response to antigens. Immunoblot analysis and immunofluorescence microscopy of transformed B cells from affected individuals show that the NFKB2 mutations affect phosphorylation and proteasomal processing of p100 and, ultimately, p52 nuclear translocation. These findings describe germline mutations in NFKB2 and establish the noncanonical NF-κB signaling pathway as a genetic etiology for this primary immunodeficiency syndrome

Impacts of COVID-19 on sexual behaviour in Britain: findings from a large, quasi-representative survey (Natsal-COVID).

OBJECTIVES: Physical restrictions imposed to combat COVID-19 dramatically altered sexual lifestyles but the specific impacts on sexual behaviour are still emerging. We investigated physical and virtual sexual activities, sexual frequency and satisfaction in the 4 months following lockdown in Britain in March 2020 and compared with pre-lockdown. METHODS: Weighted analyses of web panel survey data collected July/August 2020 from a quota-based sample of 6654 people aged 18-59 years in Britain. Multivariable regression took account of participants' opportunity for partnered sex, gender and age, to examine their independent associations with perceived changes in sexual frequency and satisfaction. RESULTS: Most participants (86.7%) reported some form of sex following lockdown with physical activities more commonly reported than virtual activities (83.7% vs 52.6%). Altogether, 63.2% reported sex with someone ('partnered sex') since lockdown, three-quarters of whom were in steady cohabiting relationships. With decreasing relationship formality, partnered sex was less frequently reported, while masturbation, sex toy use and virtual activities were more frequently reported. Around half of all participants perceived no change in partnered sex frequency compared with the 3 months pre-lockdown, but this was only one-third among those not cohabiting, who were more likely to report increases in non-partnered activities than those cohabiting. Two-thirds of participants perceived no change in sexual satisfaction; declines were more common among those not cohabiting. Relationship informality and younger age were independently associated with perceiving change, often declines, in sexual frequency and satisfaction. CONCLUSIONS: Our quasi-representative study of the British population found a substantial minority reported significant shifts in sexual repertoires, frequency and satisfaction following the introduction of COVID-19 restrictions. However, these negative changes were perceived by some more than others; predominantly those not cohabiting and the young. As these groups are most likely to experience adverse sexual health, it is important to monitor behaviour as restrictions ease to understand the longer term consequences, including for health services

Reading and Ownership

First paragraph: ‘It is as easy to make sweeping statements about reading tastes as to indict a nation, and as pointless.’ This jocular remark by a librarian made in the Times in 1952 sums up the dangers and difficulties of writing the history of reading. As a field of study in the humanities it is still in its infancy and encompasses a range of different methodologies and theoretical approaches. Historians of reading are not solely interested in what people read, but also turn their attention to the why, where and how of the reading experience. Reading can be solitary, silent, secret, surreptitious; it can be oral, educative, enforced, or assertive of a collective identity. For what purposes are individuals reading? How do they actually use books and other textual material? What are the physical environments and spaces of reading? What social, educational, technological, commercial, legal, or ideological contexts underpin reading practices? Finding answers to these questions is compounded by the difficulty of locating and interpreting evidence. As Mary Hammond points out, ‘most reading acts in history remain unrecorded, unmarked or forgotten’. Available sources are wide but inchoate: diaries, letters and autobiographies; personal and oral testimonies; marginalia; and records of societies and reading groups all lend themselves more to the case-study approach than the historical survey. Statistics offer analysable data but have the effect of producing identikits rather than actual human beings. The twenty-first century affords further possibilities, and challenges, with its traces of digital reader activity, but the map is ever-changing

Schoolbooks and textbook publishing.

In this chapter the author looks at the history of schoolbooks and textbook publishing. The nineteenth century saw a rise in the school book market in Britain due to the rise of formal schooling and public examinations. Although the 1870 Education and 1872 (Scotland) Education Acts made elementary education compulsory for childern between 5-13 years old, it was not until the end of the First World War that some sort form of secondary education became compulsory for all children