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ABSTRACT IMPACT: The proposed study has the potential to inform new paradigms of type 1 diabetes prevention and therapy with the overall goal of improving β cell health during autoimmunity. OBJECTIVES/GOALS: Type 1 diabetes (T1D) results from immune-mediated destruction of pancreatic βcells. Recent data suggest that activation of senescence and acquisition of a senescence associated secretory phenotype (SASP) by βcells may contribute to T1D pathogenesis. However, the molecular mechanisms responsible for this phenotype are not well understood. METHODS/STUDY POPULATION: We hypothesize that loss of endoplasmic reticulum (ER) Ca2+ induces βcell senescence, SASP as well as mitochondrial dysfunction which drive T1D development. The current study utilizes SERCA2 KO INS-1 βcells (S2KO) exhibiting loss of ER Ca2+ and a SERCA2 haploinsufficient mice on a non-obese diabetic background (NOD-S2+/-) to test the role of ER Ca2+ loss during T1D development. Senescence associated βgalactosidase staining (SA-βgal), expression of senescence markers (RT-qPCR), mitochondrial function (Seahorse, TMRM) and mitochondrial copy number (qPCR) were all measured in S2KO versus WT βcells and are currently being measured in the NOD-S2+/- mouse model at 6, 8, 12, 14, and 16wks of age. RESULTS/ANTICIPATED RESULTS: RT-qPCR assays detecting senescence markers cdkn1a and cdkn2a and mitochondrial specific genes cox1 and nd1 were developed and validated in both INS-1 βcells and mouse islets. Mitochondrial function assay (Seahorse) was optimized for use in INS-1 βcells and is currently under development for use in intact mouse islets. S2KO βcells displayed increased SA- βgal staining as well as increased mitochondrial coupling efficiency (p=0.0146) and baseline mitochondrial copy number (p=0.0053) compared to WT βcells, suggesting a senescence phenotype and altered mitochondrial function. NOD-S2+/- mice exhibited increased expression of the senescence marker cdkn2a in the islet at 12wks (p=0.0117) compared to control mice, whereas cdkn1a remained unchanged across all timepoints tested. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results suggest that loss of SERCA2 and reduced ER Ca2+ alter βcell mitochondrial function and are associated with features of senescence. Future studies will test whether SERCA2 activation and/or senolytic/senomorphic drugs are able to prevent or delay diabetes onset in NOD-S2+/- mice.
Involuntary civil commitment (ICC) to treatment for opioid use disorder (OUD) prevents imminent overdose, but also restricts autonomy and raises other ethical concerns. Using the Kass Public Health Ethics Framework, we identified ICC benefits and harms. Benefits include: protection of vulnerable, underserved patients; reduced legal consequences; resources for families; and “on-demand” treatment access. Harms include: stigmatizing and punitive experiences; heightened family conflict and social isolation; eroded patient self-determination; limited or no provision of OUD medications; and long-term overdose risk. To use ICC ethically, it should be recognized as comprising vulnerable patients worthy of added protections; be a last resort option; utilize consensual, humanizing processes; provide medications and other evidence-based-treatment; integrate with existing healthcare systems; and demonstrate effective outcomes before diffusion. ICC to OUD treatment carries significant potential harms that, if unaddressed, may outweigh its benefits. Findings can inform innovations for ensuring that ICC is used in an ethically responsible way.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
The assayers’ ingots recovered in 2014 from the SS Central America contain geochemical signatures and anomalies which convey information about the culture of miners and assayers in the late 1850s. A significant number of ingots (21%) contain elevated copper and zinc in the same ratio as a common brass alloy of the period, suggesting that adulteration of placer gold dust was a common issue. The ingots with the brass-like signature also have a gold fineness much lower than measured for typical California placer gold. Trace elements like palladium in uniform concentrations in all Kellogg & Humbert ingots suggest the use of quality high-temperature tools, while lead and tin in all ingots suggest specific contamination and industrial hygiene issues common to the whole industry. Other trace constituents such as arsenic, antimony and bismuth are likely to have originated from dense minerals associated with placer gold, or from the natural placer gold alloy itself. Comparison of modern analysis of ingots vs. assay values stamped on the ingots themselves suggests some firms like Kellogg & Humbert did superior assay work, while others like the San Francisco office of Justh & Hunter probably had issues with quality control. The variations in assay ingot alloy chemistry provide a window into this important period in American history.
Young people want to be involved in the decisions that impact on them and their health service provision (Royal College of Paediatrics and Child Health [RCPCH], 2017) – a youth forum is one way of enabling this. This chapter will initially focus on the background and development of youth forums/ councils; secondly, an overview of the National Health Service England Youth Forum (NHSEYF) will be provided with the perspectives of Kath Evans (Experience of Care Lead, NHS England (NHSE) – Maternity, Infants, Children and Young People) and NHSEYF members being integrated. Thirdly, an evaluative mixed methods study (undertaken by the University of Hertfordshire (UH)) will be briefly presented. Finally, the chapter will present the Youth Forum Wheel (YFW) that was developed as a direct result of the research; the YFW is offered to health professionals and young people who may be implementing and/or managing youth forums. It aims to provide insight into the underpinning components of success, each of these will be discussed and their practical application considered.
The development of youth forums
A youth forum has been described as being in existence to:
represent the views of young people, giving young people the opportunity to have a voice, discuss issues, engage with decision makers and contribute to improving and developing services for young people. (NHS England, 2015a, p 5)
One of the longest running youth forums that is widely recognised within the UK is the Northern Ireland Youth Forum which was established in 1979 by the Department of Education; this organisation has continued to develop and has a very active membership (Northern Ireland Youth Forum, 2019). In 1999, a youth forum was held in The Hague to enable 132 young people, representing 111 countries, to offer their thoughts and opinions on a range of key organisations (including the United Nations, as well as governmental and non-governmental bodies) about areas such as health, human rights and education (Youth Forum, 1999). In the same year, UNESCO introduced their first youth forum event – this has since been held every two years at the headquarters in Paris; it is open to all young people and aims to provide:
an innovative, ongoing opportunity for youth to work in dialogue with UNESCO, to shape and direct the Organization's approach and to present their concerns and ideas to Member States. (UNESCO, 2019)
Background: Previous work suggests an intermingling of community and hospital transmission networks driving the MRSA epidemic, but how those with CO-HA infections fit into the network remains unclear. We integrated epidemiologic data and whole-genome sequencing (WGS) from existing MRSA clinical isolates to determine whether there were distinguishable features of CO-HA MRSA infections that could guide interventions. Methods: We examined 955 existing clinical MRSA isolates from 2011 to 2013 from patients at Cook County Health, the major public healthcare network in Chicago, Illinois. We performed electronic and manual chart review to ascertain community (eg, illicit drug use, incarceration history) and healthcare exposures and comorbidities. WGS was performed on all sequences, and sequences were typed with multilocus sequence typing (MLST). We assessed the distribution of epidemiological factors and sequence type (ST) across onset type. Results: Infections were more frequent in males (70%); 61% of individuals with infection were African American and 21% were Hispanic. Overall, wound infections were the most common (81%) followed by blood (7%) and respiratory (6%). 82% of infections were ST8 (most USA300), 8% were ST5 (USA100) and 10% were other STs (Fig. 1a). Using standard epidemiologic definitions, we identified 523 CO, 295 CO-HA, and 137 HO infections. USA300 infections were common across CO, CO-HA, and HO categories, whereas USA100 was more frequently observed among CO-HA and HO. Current illicit drug use and history of incarceration—factors typically associated with CO-MRSA—were observed among both CO-HA and HO infections. 38% of CO-HA and 36% of HO had a history of MRSA infection or nasal colonization in the prior 6 months. As expected, 73% of CO-HA had a history of recent hospitalization, but this was also true for 44% of HO cases; points for intervention for both groups, especially CO-HA patients, include outpatient, inpatient, and ER care. Diabetes was common across categories, and HIV was more commonly observed among CO-HA cases (Fig. 1b). Conclusions: We characterized the genomic and epidemiologic features of CO-HA MRSA infections relative to CO and HO. By MLST and epidemiological analysis, CO-HA infections share similarities to both CO and HO. Although USA300 infections were the most common strain type, our findings highlight the need for WGS to discern relationships between individuals to understand the intermixing of healthcare and community networks for CO-HA infections. Higher resolution genomic analysis may help guide whether interventions need to be at hospital discharge or in the community to have the most impact on decreasing CO-HA MRSA infections.
Funding: Funding: from CDC Broad Agency Announcement: Genomic Epidemiology of Community-Onset Invasive USA300 MRSA Infections; Contract ID: 75D30118C02923
Background: Long-term acute-care hospitals (LTACHs) are disproportionately burdened by multidrug-resistant organisms (MDROs) like KPC-Kp. Although cohorting KPC-Kp+ patients into rooms with other carriers can be an outbreak-control strategy and may protect negative patients from colonization, it is unclear whether cohorted patients are at unintended increased risk of cross colonization with additional KPC-Kp strains. Methods: Cohorting KPC-Kp+ patients at admission into rooms with other positive patients was part of a bundled intervention that reduced transmission in a high-prevalence LTACH. Rectal surveillance culturing for KPC-Kp was performed at the start of the study, upon admission, and biweekly thereafter, capturing 94% of patients. We evaluated whole-genome sequencing (WGS) evidence of acquisition of distinct KPC-Kp strains in a convenience sample of patients positive for KPC-Kp at study start or admission to identify plausible secondary KPC-Kp acquisitions. Results: WGS multilocus sequence type (MLST) strain variability was observed among the 452 isolates from the 254 patients colonized by KPC-Kp (Fig. 1). Among the 32 patients who were positive at the beginning of the study or admission and had a secondary isolate collected at a later date (median, 89 days apart, range, 2–310 days), 17 (53%) had secondary isolates differing by MLST from their admission isolate. Although 60% of the KPC-Kp in the study was ST258, there was substantial genomic variation within ST258 isolates from the same patient (range, 0–102 genetic variants), suggesting multiple acquisitions of distinct ST258 isolates. Among the 17 patients who imported ST258 and had ST258 isolated again later, 11 (65%) carried secondary isolates genetically closer to isolates from other importing patients than to their own ST258 (Fig. 2). Examination of spatiotemporal exposures among patients with evidence of multiple acquisitions revealed that 11 (65%) patients with multiple MLSTs shared a room with a patient who was colonized with an isolate matching the secondary MLST, and 6 (35%) patients who carried multiple distinct ST258 isolates shared a room with a patient who imported these closely related isolates prior to secondary acquisition. Conclusions: Half of patients who imported KPC-Kp and had multiple isolates available had genomically supported secondary acquisitions linked to roommates who carried the acquired strains. Although cohorting is intended to protect negative patients from acquiring MDROs, this practice may promote multiple strain acquisitions by colonized patients in the cohort, potentially prolonging the period of MDRO carriage and increasing time at risk of infection. Our findings add to the debate about single-patient rooms, which may be preferred to cohorts to minimize potential harms by reducing MDRO transmission.
The scarcity of Romano-British human remains from north-west England has hindered understanding of burial practice in this region. Here, we report on the excavation of human and non-human animal remains1 and material culture from Dog Hole Cave, Haverbrack. Foetal and neonatal infants had been interred alongside a horse burial and puppies, lambs, calves and piglets in the very latest Iron Age to early Romano-British period, while the mid- to late Roman period is characterised by burials of older individuals with copper-alloy jewellery and beads. This material culture is more characteristic of urban sites, while isotope analysis indicates that the later individuals were largely from the local area. We discuss these results in terms of burial ritual in Cumbria and rural acculturation. Supplementary material is available online (https://doi.org/10.1017/S0068113X20000136), and contains further information about the site and excavations, small finds, zooarchaeology, human osteology, site taphonomy, the palaeoenvironment, isotope methods and analysis, and finds listed in Benson and Bland 1963.
Cohorting patients who are colonized or infected with multidrug-resistant organisms (MDROs) protects uncolonized patients from acquiring MDROs in healthcare settings. The potential for cross transmission within the cohort and the possibility of colonized patients acquiring secondary isolates with additional antibiotic resistance traits is often neglected. We searched for evidence of cross transmission of KPC+ Klebsiella pneumoniae (KPC-Kp) colonization among cohorted patients in a long-term acute-care hospital (LTACH), and we evaluated the impact of secondary acquisitions on resistance potential.
Genomic epidemiological investigation.
A high-prevalence LTACH during a bundled intervention that included cohorting KPC-Kp–positive patients.
Whole-genome sequencing (WGS) and location data were analyzed to identify potential cases of cross transmission between cohorted patients.
Secondary KPC-Kp isolates from 19 of 28 admission-positive patients were more closely related to another patient’s isolate than to their own admission isolate. Of these 19 cases, 14 showed strong genomic evidence for cross transmission (<10 single nucleotide variants or SNVs), and most of these patients occupied shared cohort floors (12 patients) or rooms (4 patients) at the same time. Of the 14 patients with strong genomic evidence of acquisition, 12 acquired antibiotic resistance genes not found in their primary isolates.
Acquisition of secondary KPC-Kp isolates carrying distinct antibiotic resistance genes was detected in nearly half of cohorted patients. These results highlight the importance of healthcare provider adherence to infection prevention protocols within cohort locations, and they indicate the need for future studies to assess whether multiple-strain acquisition increases risk of adverse patient outcomes.
Early medieval thinkers often conceived of God in legal terms, especially when they interpreted contemporary disasters as God's ‘just judgement’. Modern scholars have emphasized the importance of these ideas for motivating early medieval reform and legislation and for interpreting history itself. This article explores how these ideas were used in Carolingian legislation and history writing and argues that God's judgement was not as straightforward a theme as it first appears. God's judgement, for example, was not nearly as important for Carolingian historians as it had been for their predecessors. Similarly, in both legal and historical texts, there was great variety in how God's judgement or punishment was expressed, both in how that punishment fell and on whom (whether on the audience or on their enemies). Across these works, however, it is clear that God's judgement was almost never referred to apart from his continuing mercy and help towards to the audiences of these texts. This shows the importance of the various aspects of God's character for early medieval churches and their attitudes to law and history.
Propagating inhomogeneous electromagnetic waves called surface plasmon polaritons (SPPs) can be excited by free-space beams on corrugated conducting surfaces at resonance angles determined by corrugation period, permittivity, and optical frequency. SPPs are coupled to and co-propagate with surface charge displacements. Complete electrical isolation of individual conducting corrugations prevents the charge displacement necessary to sustain an SPP, such that excitation resonances of traveling SPPs are absent. However, SPPs can be excited via electric induction if a smooth conducting surface exists below and nearby the isolated conducting corrugations. The dependence of SPP excitation resonances on that separation is experimentally investigated here at long-wave infrared wavelengths. We find that excitation resonances for traveling SPPs broaden and disappear as the dielectric’s physical thickness is increased beyond ~1% of the free-space wavelength. The resonance line width increases with refractive index and optical thickness of the dielectric.
The start of the “Third Wave of science studies” dates to a paper we wrote that was published in April 2002 by the journal Social Studies of Science (Collins & Evans, 2002). The paper challenged the idea, then dominant in science and technology studies (STS), that the problems associated with the role of science in policy making could be solved by reducing the influence of scientific experts and giving more rights in these matters to ordinary citizens. The Third Wave paper (hereafter 3Wave) set out a normative theory of expertise that remains consistent with the sociology of scientific knowledge but which can be used to argue against both an excessive reliance on science and an unrestrained suspicion of expertise. The trick is to turn attention from how truth is made to who is an expert and concentrate on making the “best” decisions rather than the “right” decisions. It can take half a century or more to know what was the right decision, but one can decide on the best decision by taking advice from the best experts and experts can be identified in the short term.
The science of studying diamond inclusions for understanding Earth history has developed significantly over the past decades, with new instrumentation and techniques applied to diamond sample archives revealing the stories contained within diamond inclusions. This chapter reviews what diamonds can tell us about the deep carbon cycle over the course of Earth’s history. It reviews how the geochemistry of diamonds and their inclusions inform us about the deep carbon cycle, the origin of the diamonds in Earth’s mantle, and the evolution of diamonds through time.
The authors report on 7Li, 19F, and 1H pulsed field gradient NMR measurements of 26 organosilyl nitrile solvent-based electrolytes of either lithium bis(trifluorosulfonyl)imide (LiTFSI) or lithium hexafluorophosphate. Lithium transport numbers (as high as 0.50) were measured and are highest in the LiTFSI electrolytes. The authors also report on solvent blend electrolytes of fluoroorganosilyl (FOS) nitrile solvent mixed with ethylene carbonate (EC) and diethyl carbonate. Solvent diffusion measurements on an electrolyte with 6% FOS suggest both the FOS and EC solvate the lithium cation. By comparing lithium transport and transference numbers, the authors find less ion pairing in FOS nitrile carbonate blend electrolytes and difluoroorganosilyl nitrile electrolytes.
Certain species of parasites have the apparent ability to alter the behaviour of their host in order to facilitate the completion of their own life cycle. While documented in hairworms (phylum Nematomorpha), the ability for mermithid parasites (from the sister phylum Nematoda) to force hosts to enter water remains more enigmatic. Here, we present the first experimental evidence in a laboratory setting that an insect which normally never enters open water (the European earwig Forficula auricularia) will readily enter the water when infected with a mermithid nematode (Mermis nigrescens). Only adult mermithids appear capable of inducing this polarising shift in behaviour, with mermithid length being a very strong predictor of whether their host enters water. However, mermithid length was only weakly associated with how long it took an earwig to enter water following the beginning of a trial. Considering the evidence presented here and its alignment with a proteomic investigation on the same host–parasite system, this study provides strong evidence for adaptive behavioural manipulation and a foundational system for further behavioural and mechanistic exploration.
Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
This article explores the ways in which histories were used in the moral and doctrinal education of Christian elites in the West from the late Roman to the Carolingian periods. In the sixth century, Cassiodorus wrote that histories, whether Christian or not, were useful for ‘instructing the minds of readers in heavenly matters’. How far was this characteristic of the period? Traditionally, scholars have emphasized either the apologetic purpose or the moral of specific histories, such as Orosius's Historiae or Bede's Historia Ecclesiastica. Few modern scholars, however, have examined the long-term development of history writing as a vehicle for Christian education during the transformation of the Roman world. Those who have done, such as Karl-Ferdinand Werner and Hans-Werner Goetz, have emphasized continuity rather than change. The article sketches some of the changes and continuities across the period. In particular, it demonstrates that there was a shift from the apologetic concerns of the fifth-century historians, writing to educate Christians from pagan backgrounds, to the doctrinal (as much as moral) concerns of Frankish historians, emerging from the Carolingian Renaissance.
This research explores media reporting of Indigenous students’ Programme for International Student Assessment (PISA) results in two national and 11 metropolitan Australian newspapers from 2001 to 2015. Of almost 300 articles on PISA, only 10 focused on reporting of Indigenous PISA results. While general or non-Indigenous PISA results featured in media reports, especially at the time of the publication of PISA results, there was overwhelming neglect of Indigenous results and the performance gap. A thematic analysis of articles showed mainstream PISA reporting had critical commentary which is not found in the Indigenous PISA articles. The three themes identified include: a lack of teacher quality in remote and rural schools; the debate on Gonski funding recommendations and the PISA achievement gap between Indigenous and non-Indigenous students. This study concluded the overwhelming neglect is linked to media bias, which continues to drive mainstream media coverage of Indigenous Australians.