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Carbamazepine, an anticonvulsant also used as a mood stabilizer and for trigeminal neuralgia, is associated with serious, sometimes fatal cutaneous adverse drug reactions, including Stevens Johnson Syndrome and toxic epidermal necrolysis1. Current literature demonstrates a genetic predisposition linked to specific class I and II human leukocyte antigen (HLA) types in various ethnic populations2. HLA-A*31:01 is one such HLA type, and is routinely identified by the tag SNP rs1061235. However, rs1061235 has poor specificity for HLA*31:01 due to interference of HLA-A*33 types3. We investigated the false positive rate in our population and developed a novel real-time PCR assay that distinguishes HLA-A*31:01 from other HLA-A types including HLA-A*33.
120 unique samples were tested in triplicate during the validation of this assay and were sent to a reference lab for HLA next generation sequencing (NGS) typing, including 89 in-house samples and 31 Coriell samples with documented HLA typing results. The results from our real-time PCR assay were compared to the HLA typing results. HLA typing results were also compared to the tag SNP rs1061235 results to calculate the false positive rate.
There was 100% concordance between our real-time PCR results and expected results based on HLA typing. 89 sample results for tag SNP rs1061235 were compared to HLA typing results. 75/89 samples had a rs1061235 variant, but 31/75 (41%) samples did not have the HLA-A*31:01 type, thus defining the false positive rate of the tag SNP for our population. We theorized there would be a small subset of rare HLA-A types that would interfere with the assay and we tested the three types available to us. We confirmed that 3 of the HLA types (HLA-A*31:04, 31:12, and 31:16) result falsely positive due to sequence homology with 31:01. There is no known literature indicating whether these rare HLA-A*31 subtypes are associated with cutaneous adverse reactions. These 3 HLA types and the other suspected interfering HLA types have limited frequency data sets and are expected to occur rarely in our patient population; we expect these HLA types make up less than 0.003% of the our population. Our assay specificity for the validation is >99%.
Our custom real-time PCR assay for detection of HLA-A*31:01 is significantly more specific than the commonly used tag SNP rs1061235. Clinicians considering carbamazepine therapy for their patients will have a better understanding of cutaneous adverse reaction risk and can make improved personalized treatment decisions. This quick, cost effective assay allows more patients in need of carbamazepine treatment to benefit from its use.
Subglacial sediments have the potential to reveal information about the controls on glacier flow, changes in ice-sheet history and characterise life in those environments. Retrieving sediments from beneath the ice, through hot water drilled access holes at remote field locations, present many challenges. Motivated by the need to minimise weight, corer diameter and simplify assembly and operation, British Antarctic Survey, in collaboration with UWITEC, developed a simple mechanical percussion corer. At depths over 1000 m however, manual operation of the percussion hammer is compromised by the lack of clear operator feedback at the surface. To address this, we present a new auto-release-recovery percussion hammer mechanism that makes coring operations depth independent and improves hammer efficiency. Using a single rope tether for both the corer and hammer operation, this modified percussion corer is relatively simple to operate, easy to maintain, and has successfully operated at a depth of >2130 m.
Sink drains in healthcare facilities may provide an environment for antimicrobial-resistant microorganisms, including carbapenemase-producing Klebsiella pneumoniae (CPKP).
We investigated the colonization of a biofilm consortia by CPKP in a model system simulating a sink-drain P-trap. Centers for Disease Control (CDC) biofilm reactors (CBRs) were inoculated with microbial consortia originally recovered from 2 P-traps collected from separate patient rooms (designated rooms A and B) in a hospital. Biofilms were grown on stainless steel (SS) or polyvinyl chloride (PVC) coupons in autoclaved municipal drinking water (ATW) for 7 or 28 days.
Microbial communities in model systems (designated CBR-A or CBR-B) were less diverse than communities in respective P-traps A and B, and they were primarily composed of β and γ Proteobacteria, as determined using 16S rRNA community analysis. Following biofilm development CBRs were inoculated with either K. pneumoniae ST45 (ie, strain CAV1016) or K. pneumoniae ST258 KPC+ (ie, strain 258), and samples were collected over 21 days. Under most conditions tested (CBR-A: SS, 7-day biofilm; CBR-A: PVC, 28-day biofilm; CBR-B: SS, 7-day and 28-day biofilm; CBR-B: PVC, 28-day biofilm) significantly higher numbers of CAV1016 were observed compared to 258. CAV1016 showed no significant difference in quantity or persistence based on biofilm age (7 days vs 28 days) or substratum type (SS vs PVC). However, counts of 258 were significantly higher on 28-day biofilms and on SS.
These results suggest that CPKP persistence in P-trap biofilms may be strain specific or may be related to the type of P-trap material or age of the biofilm.
Research shows that healthy ageing is defined differently by older adults and researchers, who may put more or less weight on the physiological, psychological, societal and personal aspects of ageing. Although there is growing interest in the research literature on lay models of healthy ageing in socio-cultural context, little work has been done to determine how important or feasible the various components of healthy ageing are viewed to be by older adults. This study asked a convenience sample of 54 older adults in the circumpolar North to rate the importance and feasibility of 36 previously identified components of healthy ageing in their community. Results indicate that seniors in the sample place the most importance on aspects of the social and physical environment, while least important concepts included psychological and individual behaviours. However, most feasible aspects were individual behaviours and least feasible were aspects of the social and physical environment. Although older adults are able to construct a model of what healthy ageing should look like in their community, they do not always view the most important aspects of healthy ageing to be the most feasible to achieve, providing ample opportunity for public and social policy change.
Background: Central-line–associated bloodstream infection (CLABSI) rates have steadily decreased as evidence-based prevention bundles were implemented. Bone marrow transplant (BMT) patients are at increased risk for CLABSI due to immunosuppression, prolonged central-line utilization, and frequent central-line accesses. We assessed the impact of an enhanced prevention bundle on BMT nonmucosal barrier injury CLABSI rates. Methods: The University of Iowa Hospitals & Clinics is an 811-bed academic medical center that houses the only BMT program in Iowa. During October 2018, we added 3 interventions to the ongoing CLABSI prevention bundle in our BMT inpatient unit: (1) a standardized 2-person dressing change team, (2) enhanced quality daily chlorhexidine treatments, and (3) staff and patient line-care stewardship. The bundle included training of nurse champions to execute a team approach to changing central-line dressings. Standard process description and supplies are contained in a cart. In addition, 2 sets of sterile hands and a second person to monitor for breaches in sterile procedure are available. Site disinfection with chlorhexidine scrub and dry time are monitored. Training on quality chlorhexidine bathing includes evaluation of preferred product, application per product instructions for use and protection of the central-line site with a waterproof shoulder length glove. In addition to routine BMT education, staff and patients are instructed on device stewardship during dressing changes. CLABSIs are monitored using NHSN definitions. We performed an interrupted time-series analysis to determine the impact of our enhanced prevention bundle on CLABSI rates in the BMT unit. We used monthly CLABSI rates since January 2017 until the intervention (October 2018) as baseline. Because the BMT changed locations in December 2018, we included both time points in our analysis. For a sensitivity analysis, we assessed the impact of the enhanced prevention bundle in a hematology-oncology unit (March 2019) that did not change locations. Results: During the period preceding bundle implementation, the CLABSI rate was 2.2 per 1,000 central-line days. After the intervention, the rate decreased to 0.6 CLABSI per 1,000 central-line days (P = .03). The move in unit location did not have a significant impact on CLABSI rates (P = .85). CLABSI rates also decreased from 1.6 per 1,000 central-line days to 0 per 1,000 central-line days (P < .01) in the hematology-oncology unit. Conclusions: An enhanced CLABSI prevention bundle was associated with significant decreases in CLABSI rates in 2 high-risk units. Novel infection prevention bundle elements should be considered for special populations when all other evidence-based recommendations have been implemented.
Background: Antibiotic time outs (ABTOs), formal reassessments of all new antimicrobial regimens by the care team, can optimize antimicrobial regimens, reducing antimicrobial overuse and potentially improving outcomes. Implementation of ABTOs is a substantial challenge. We used quality improvement methods to implement robust, meaningful, team-driven ABTOs in general medicine ward services. Methods: We identified and engaged stakeholders to serve as champions for the quality improvement initiative. On October 1, 2018, 2 internal medicine teaching services (services A and B), began conducting ABTOs on all patients admitted to their services receiving systemic antimicrobials for at least 36 hours. Eligible patients were usually identified by the team pharmacist. ABTOs were completed within 72 hours of antibiotic initiation and were documented in the electronic medical record (EMR) by providers using a template. The process was modified as necessary in response to feedback from frontline clinicians using plan-do-study-act (PDSA) methods. We subsequently spread the project to 2 additional internal medicine services (services C and D); 2 family medicine teams (services E and F); and 1 general pediatric service (service G). The project is ongoing. We collected data for the following metrics: (1) proportion of ABTO-eligible patients with an ABTO; (2) proportion of ABTOs conducted within the recommended time frame; (3) documented plan changes as a result of ABTO (eg, change IV antibiotics to PO); (4) proportion of documented plan changes actually completed within 24 hours. Results: Within 12 weeks, services A and B were successfully completing time outs in >80% of their patients. This target was consistently reached by services C, D, E, F, and G almost immediately following launch on those services. As of June 29, 2019, >80% of eligible patients across all participating services have had a time out conducted for 16 consecutive weeks. ABTOs have resulted in a change in management in 35% of cases, including IV-to-PO change in 19% of cases and discontinuation in 5%. Overall, 77% of time outs occurred during the 36–72-hour window. Ultimately, 95% of documented plan changes were completed within 24 hours. Conclusions: ABTOs are effective but implementation is challenging. We achieved high compliance with ABTOs without using electronic reminders. Our results suggest that ABTOs were impactful in the non–critical-care general medicine setting. Next steps include (1) development of EMR-based tools to facilitate identifying eligible patients and ABTO documentation; (2) continued spread through our health care system; and (3) analysis of ABTO impact using ABTO-unexposed patients as a control group.
Cultural representations of pandemics and other apocalyptic scenarios often encourage us to reflect differently on those things we take for granted in our day-to-day lives. Seemingly mundane and dependable items no longer appear so mundane, nor so dependable. ‘Money’ itself is one such entity, which has been the object of various reimaginings within fictional accounts of disaster and subsequent societal breakdown. In ‘Bartertown’, the fictional trading place in the Mad Max film, for example, we witness the total collapse of civilization and, with it, the entire monetary system; swapping and bartering are all that matter in such a place. Money is erased from a society in which violence dictates everyday life.
Thankfully, such fictional accounts appear not to reflect the reality of the COVID-19 pandemic; however, the crisis does still provoke important questions about the future of money and how we pay for things. Cash – our physical coins and banknotes – has moved from being a mundane and dependable thing to something that many view as a threat, another source of spreading the virus. Cash as a medium of ‘exchange’ has taken on a new meaning. As such, many retailers are strongly encouraging customers to pay by card, while the limit on contactless payments has been increased from £30 to £45 per transaction in the UK, with similar moves across Europe. Automated teller machine (ATM) withdrawal figures – which were already on the decline – have plummeted.
What just a few months ago might have seemed like fiction – a seismic shift in the way we pay for things – has now become reality. The future of cash is very much at stake, and in the discussion that follows we begin by exploring why this still matters. We then consider the effect of COVID-19 on access to cash, situating these changes in the broader context of digitization and pre-crisis trends. We conclude by reflecting what the pandemic can teach us about what we can do better moving forward, ensuring that no one is left behind.
Money has been integral to human history for thousands of years. Early coins in circulation across Asia and Europe enabled civilization and economies to evolve from bartering to the generalized system of exchange that continues to exist in modern capitalism.
Life course research embraces the complexity of health and disease development, tackling the extensive interactions between genetics and environment. This interdisciplinary blueprint, or theoretical framework, offers a structure for research ideas and specifies relationships between related factors. Traditionally, methodological approaches attempt to reduce the complexity of these dynamic interactions and decompose health into component parts, ignoring the complex reciprocal interaction of factors that shape health over time. New methods that match the epistemological foundation of the life course framework are needed to fully explore adaptive, multilevel, and reciprocal interactions between individuals and their environment. The focus of this article is to (1) delineate the differences between lifespan and life course research, (2) articulate the importance of complex systems science as a methodological framework in the life course research toolbox to guide our research questions, (3) raise key questions that can be asked within the clinical and translational science domain utilizing this framework, and (4) provide recommendations for life course research implementation, charting the way forward. Recent advances in computational analytics, computer science, and data collection could be used to approximate, measure, and analyze the intertwining and dynamic nature of genetic and environmental factors involved in health development.
Geoffrey Chaucer's Troilus and Criseyde is a narrative of war that disavows any interest in recounting the events of war. Set towards the end of the Trojan War, Chaucer's tale turns its back on valorous deeds and bloody battles in favour of the love affair between a Trojan prince and a beautiful widow, Troilus and Criseyde. This attitude is epitomized by a line from the opening of the poem that Chaucer closely translated from Giovanni Boccaccio's Il Filostrato: ‘The thynges fellen, as they don of werre’ (1.134). Things happened, as they do in war: armies attacked the city, the city fought back; pitched battles occurred, soldiers died; the war of attrition continued. The events of the Trojan War are ‘wel wist’ (1.57), and it is not Chaucer's task or his intention to recapitulate what we already know about the war. This idea is repeated at the end of the poem, where Chaucer states that if he had intended to write ‘The armes of this ilke worthi man, / Than wolde ich of his batailles endite; / But for that I to writen first bigan / Of his love, I have seyd as I kan’ (5.1765–1769). If Chaucer had meant to write about Troilus’ military endeavours, then he would have done so, but his focus has been on Troilus the lover, not Troilus the soldier. For those readers wishing to learn about the ‘worthi dedes’ of Troilus, Chaucer writes, they should turn to Dares, author of a supposedly reliable account of the Trojan War. The echo of the Aeneid's opening line, ‘Of arms and the man I sing’ [arma virumque cano], in Chaucer's reference to ‘The armes of this ilke worthi man’ serves to reinforce the distance between Chaucer and the literary tradition that venerates the deeds of war.3 In place of ‘his batailles’, Chaucer chooses instead ‘his love’.
Yet the gap between Troilus's ‘love’ and his ‘batailles’, between the amorous quest of love and the military quest of war, is not that great.
We present a detailed overview of the cosmological surveys that we aim to carry out with Phase 1 of the Square Kilometre Array (SKA1) and the science that they will enable. We highlight three main surveys: a medium-deep continuum weak lensing and low-redshift spectroscopic HI galaxy survey over 5 000 deg2; a wide and deep continuum galaxy and HI intensity mapping (IM) survey over 20 000 deg2 from
$z = 0.35$
to 3; and a deep, high-redshift HI IM survey over 100 deg2 from
$z = 3$
to 6. Taken together, these surveys will achieve an array of important scientific goals: measuring the equation of state of dark energy out to
$z \sim 3$
with percent-level precision measurements of the cosmic expansion rate; constraining possible deviations from General Relativity on cosmological scales by measuring the growth rate of structure through multiple independent methods; mapping the structure of the Universe on the largest accessible scales, thus constraining fundamental properties such as isotropy, homogeneity, and non-Gaussianity; and measuring the HI density and bias out to
$z = 6$
. These surveys will also provide highly complementary clustering and weak lensing measurements that have independent systematic uncertainties to those of optical and near-infrared (NIR) surveys like Euclid, LSST, and WFIRST leading to a multitude of synergies that can improve constraints significantly beyond what optical or radio surveys can achieve on their own. This document, the 2018 Red Book, provides reference technical specifications, cosmological parameter forecasts, and an overview of relevant systematic effects for the three key surveys and will be regularly updated by the Cosmology Science Working Group in the run up to start of operations and the Key Science Programme of SKA1.
UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.
Describe the development, implementation and results of this questionnaire.
An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.
A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.
The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
Crack initiation in zirconium alloys is an important issue for the safety of water-cooled fission reactors. Zirconium hydrides that precipitate in service are potential crack nucleation sites. In this work, the deformation and cracking of zirconium hydrides was studied during room temperature deformation of a Zircaloy-4 tensile sample up to fracture. The sample contained a hydrogen concentration of 100 ± 20 ppm. The main aims of this study were to better understand the mechanisms behind the hydride fracture in a polycrystalline matrix, and to identify at which point in the deformation of the Zr matrix the first hydrides break. Cracks thus nucleated may coalesce and propagate through the hydrided Zr-alloy. Scanning electron microscopy (SEM) images of a number of hydrides, both intergranular and intragranular, were taken at discrete increments of deformation during an interrupted tensile test. The results show that cracks in hydrides tend to always occur normal to the applied load, signalling the importance of the external stress. However, evidence is also provided to support the hypothesis that internal stresses generated by microstructural constraints may lead to the fracture of some intergranular hydrides.
Ecosystems across the globe are vulnerable to the effects of climate change, as are the communities that depend on them. However, ecosystems can also protect people from climate change impacts. As the evidence base strengthens, nature-based solutions (NbS) are increasingly prominent in climate change policy, especially in developing nations. Yet intentions rarely translate into measurable, evidence-based targets. As Paris Agreement signatories revise their Nationally Determined Contributions, we argue that NbS are key to meeting global goals for climate and biodiversity, and we urge researchers to work more closely with policy-makers to identify targets that benefit both people and ecosystems.
The ability to make inferences is essential for effective language comprehension. While inferencing training benefits reading comprehension in school-aged children (see Elleman, 2017, for a review), we do not yet know whether it is beneficial to support the development of these skills prior to school entry. In a pre-registered randomised controlled trial, we evaluated the efficacy of a parent-delivered intervention intended to promote four-year-olds’ oral inferencing skills during shared book-reading. One hundred children from socioeconomically diverse backgrounds were randomly assigned to inferencing training or an active control condition of daily maths activities. The training was found to have no effect on inferencing. However, inferencing measures were highly correlated with children's baseline language ability. This suggests that a more effective approach to scaffolding inferencing in the preschool years might be to focus on promoting vocabulary to develop richer and stronger semantic networks.
Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.
We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.
We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.
Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.
Adolescent association with deviant and delinquent friends was examined for its roots in coercive parent–teen interactions and its links to functional difficulties extending beyond delinquent behavior and into adulthood. A community sample of 184 adolescents was followed from age 13 to age 27, with collateral data obtained from close friends, classmates, and parents. Even after accounting for adolescent levels of delinquent and deviant behavior, association with deviant friends was predicted by coercive parent–teen interactions and then linked to declining functioning with peers during adolescence and greater internalizing and externalizing symptoms and poorer overall adjustment in adulthood. Results are interpreted as suggesting that association with deviant friends may disrupt a core developmental task—establishing positive relationships with peers—with implications that extend well beyond deviancy-training effects.
We analyzed antibiotic use data from 29 southeastern US hospitals over a 5-year period to determine changes in antibiotic use after the fluoroquinolone US Food and Drug Administration (FDA) advisory update in 2016. Fluoroquinolone use declined both before and after the FDA announcement, and the use of select, alternative antibiotics increased after the announcement.
Fluoroquinolones are among the 4 most commonly prescribed antibiotic classes.1,2 Postmarketing reports of serious adverse events linked to fluoroquinolones include tendonitis, neuropathy, hypoglycemia, psychiatric side effects, and possible aortic vessel rupture, leading to safety label changes in July 2008 and August 2013.3 In July 2016, the US Food and Drug Administration (FDA) strengthened the “black box” warning following an initial safety announcement in May 2016, recommending avoidance of fluoroquinolones for uncomplicated infections such as acute exacerbation of chronic bronchitis, uncomplicated urinary tract infections, and acute bacterial sinusitis.4 Concerns over safety and the association with Clostridiodes difficile infection have led inpatient antimicrobial stewardship programs (ASPs) to develop initiatives to promote avoidance of quinolones. The objective of this study was to quantify the effect of the 2016 FDA “black box” update on inpatient antibiotic use among a cohort of southeastern US hospitals.
Designing products with a focus on self-explanatory assembly can reduce the use of procedural instructions and the associated problems. This paper describes how different groups of students, in two different design-engineering courses designed or redesigned products in an attempt to make the assembly of the product self-explanatory. The design outcomes are discussed in relation to the design context and linked to existing theory on design for meaning.
Innovation and creativity are a mandatory for companies who wish to stay competitive. In order to promote an inventive dynamic, it implies to set up tools, habits, and an adapted environment to foster creativity. Creativity is the wealth of companies that should be valorized. To promote creativity, companies implement creativity workshops that gather people with various roles and expertise exchange and create knowledge to solve collectively open-ended engineering problems. However, group dynamics or facilitation can make the wrong decision and make the creative problem-solving unfruitful. The aim of our research project is to create a digital system to manage and valorize knowledge during creativity workshops. To design this system, we need to formalize the knowledge domain of creative workshops. The ontologies are used for decades to structure and manage information and knowledge in different domains. However, methodologies to design these ontologies are either hardly reproducible or not oriented to extract knowledge from organization. This article describes a methodology based on an organizational modeling to build ontologies. We will illustrate our approach by designing an ontology that models knowledge of creativity workshops.