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The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

ObjectiveTo evaluate the effect of presenting positively attribute-framed side effect information on COVID-19 booster vaccine intention relative to standard negatively-framed wording and a no-intervention control.Design setting and participantsA representative sample of Australian adults (N=1,204) were randomised to one of six conditions within a factorial design: Framing (Positive; Negative; Control) * Vaccine (Familiar (Pfizer); Unfamiliar (Moderna)).InterventionNegative Framing involved presenting the likelihood of experiencing side effects (e.g., heart inflammation is very rare, 1 in every 80,000 will be affected), whereas Positive Framing involved presenting the same information but as the likelihood of not experiencing side effects (e.g., 79,999 in every 80,000 will not be affected).Primary OutcomeBooster vaccine intention measured pre- and post-intervention.ResultsPositive Framing (M=75.7, SE=0.9, 95% CI[73.9, 77.4]) increased vaccine intention relative to Negative Framing (M=70.7, SE=0.9, 95% CI[68.9, 72.4]) overall (F(1, 1192)=4.68, p=.031, ηp2=.004). Framing interacted with Vaccine and Baseline Intention (F(2, 1192)=6.18, p=.002, ηp2=.01). Positive Framing was superior, or at least equal, to Negative Framing and Control at increasing Booster Intention, irrespective of the participants pre-intervention level of intent. Side effect worry and perceived severity mediated the effect of Positive vs. Negative Framing across vaccines.ConclusionPositive framing of side effect information appears superior for increasing vaccine intent relative to the standard negative wording currently used.Pre-registrationSee: aspredicted.org/LDX_2ZL

BackgroundSkin complaints are common in primary care, and poor outcomes in long-term conditions are often due to low adherence to treatment. Shared decision making and self-management support may help, yet there is little understanding of patient involvement or the support provided by GPs.AimTo describe the content of primary care consultations for skin problems, including shared decision making practice, delivery of self-management advice, and follow-up.Design and settingCross-sectional study of video-recorded UK adult GP consultations and linked data.MethodA coding tool was developed and applied to all consultations with skin problems. Shared decision making was assessed using the observer OPTION5 scale.ResultsA total of 45/318 consultations (14.2%) related to one or more skin problems, which were discussed alongside other problems in 71.1% (32/45) of consultations. Of the 100 different problems discussed in these consultations, 51 were dermatological. The mean amount of time spent on skin problems in the consultations was 4 minutes 16 seconds. Medication was recommended for 66.7% (34/51) of skin problems, with low shared decision making (mean OPTION5 score = 10.7). Self-management advice (verbal only) was given for 47.1% (24/51) of skin problems. Most skin problems (84.3%; 43/51) were not referred to secondary care; 32.6% (14/43) of the skin problems not referred were seen again in primary care within 12 weeks, of which 35.7% (5/14) follow-up appointments were not planned.ConclusionIn this study, skin problems were usually presented alongside other complaints and resulted in a medication recommendation. Shared decision making was uncommon and self-management advice not consistently given, with re-attendance for the same problem common. GPs’ training should reflect how frequently skin problems are seen and seek to improve patient involvement in decision making and support self-management.

Society needs to improve the care of children with complex needs. Guidelines recommend integrating care across health and educational settings, however, there is little research on whether this is achieved or how this can be done in practice. Our aim was to address this gap by examining how the care of children (aged 5–11 years) with Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is shared across home, education and health settings, in order to generate recommendations for integrating care. We undertook semi‐structured interviews with families (22 participants), teachers (11 participants) and healthcare providers (9 participants), analysing the data thematically and comparatively. Our analysis of the data was informed by a socio‐ecological perspective as we sought to understand the complexity of the relationships and systems around the child. The first theme focuses on the child (“individual level”); child‐centred care is seen as essential whilst acknowledging that the child has limited capacity to manage their own care. The second theme presents the distinct roles of parents, teachers and clinicians (“interpersonal and organisational levels”). The third describes how these three levels interact in the management of the child's care, in the context of the health and education systems and policies (“policy levels”). The fourth explores optimal ways to integrate care across home, school and clinical settings. In conclusion, there is opportunity to support a child with complex health needs by targeting the systems around the child; parents, teachers and clinicians, as well as education and health policy that can enable shared‐care. Involving schools in assessment, communicating diagnosis across settings and using a stepped‐care approach to integrated care may be beneficial. Further work is needed to explore these recommendations, with attention to the policy factors that may act as barriers and enablers.

Few estuaries remain unaffected by water management and altered freshwater deliveries. The Caloosahatchee River Estuary is a perfect case study for assessing the impact of altered hydrology on natural oyster reef (Crassostrea virginica) populations. The watershed has been highly modified and greatly enlarged by an artificial connection to Lake Okeechobee. Accordingly, to generate data to support water management recommendations, this study monitored various oyster biometrics over 15 years along the primary salinity gradient. Oyster reef densities were significantly affected by both prolonged high volume freshwater releases creating hyposaline conditions at upstream sites and by a lack of freshwater input creating hypersaline conditions at downstream sites. Low freshwater input led to an increase in disease caused by Perkinsus marinus and predation. Moderate (< 2000 cfs) and properly timed (winter/spring) freshets benefited oysters with increased gametogenesis, good larval mixing, and a reprieve from disease. If high volume freshets occurred in the late summer, extensive mortality occurred at the upstream site due to low salinity. These findings suggest freshwater releases in the late summer, when reproductive stress is at its peak and pelagic larvae are most vulnerable, should be limited to < 2000 cfs, but that longer freshets (1-3 weeks) in the winter and early spring (e.g., December-April) benefit oysters by reducing salinity and lessening disease intensity. Similar strategies can be employed in other managed systems, and patterns regarding the timing of high volume flows are applicable to all estuaries where the management of healthy oyster reefs is a priority.

Virginia’s Readjuster Party was the most successful interracial political coalition in the post-Reconstruction South. Initially arising from a conflict over the payment of Virginia’s massive public debt, the new party became a force of liberal reform and democracy in the Old Dominion. It represented an alternative path before Jim Crow segregation and disfranchisement became the norm. While the Readjusters have long interested historians, the significant work performed by Black Readjusters in building and sustaining the always-tenuous coalition has gone understudied. Knowing their white counterparts were anxious about interracial political alliances, Black Readjusters eased these anxieties by using the Lost Cause. Black Readjusters condemned carpetbaggers as corrupt and repurposed the myth of the faithful slave to strengthen the interracial coalition, press for their own demands, and demonstrate their status as true southerners. The strategy and its seeming contradictions succeeded in some cases and failed in others, and its ultimate effects remain unclear. By shifting focus to Black Readjusters’ coalition-building labors, this article centers Black political activism and challenges the presumptions scholars make about interracial politics and white supremacy.

The internet provides access to a huge variety of information, including health information. There is, however, a dearth of evidence as to how, and to what ends, patients raise prior use of the internet during medical visits. Analysis is based on the Harnessing Resources from the Internet study. Drawing on data from 281 video-recorded primary care consultations, we use conversation analysis (CA) to systematically inspect the data for instances in which patients reveal that they have accessed publicly available online resources regarding their illness, symptoms, or treatment concerns. Patients invoke the internet to support three types of action: to (i) justify concerns about a serious illness; (ii) provide a warrant for treatment where they have been unable to find a solution; and (iii) advocate in relation to treatment. Although invoking the internet risks potential encroachment into the doctor's domain of authority, patients carefully design their turns when raising the internet so as to orientate to the final decision about treatment as residing firmly within the doctor's domain of authority. The work demonstrates how detailed interactional analysis can be used to illuminate the local work that patients and doctors engage in to manage the rise in availability of information from the internet.

In this study, 2 previously described surgical techniques for performing an orchiectomy in the adult male degu (Octodon degus) were evaluated: (1) prescrotal open technique and (2) scrotal open technique. Additionally, an ovariectomy procedure was assessed in female degus using the bilateral (dorsolateral) technique similar to that performed in related species. Twenty two animals (n = 14 males; 8 females) from a local small mammal shelter group, that were presented for routine surgical castration for population control measures, were included in this study. There was a significant difference in mean surgical time for the prescrotal and scrotal approach of 16.46 ± 4.28 and 23.83 ± 2.09 minutes, respectively. No significant differences were noted on anesthesia and recovery times for the orchiectomy procedures. Overall, the prescrotal approach was a faster procedure and required less anesthesia time. One male degu undergoing the scrotal open technique died during surgery, this was believed to be related to anesthesia complications (increased saliva secretions). No other complications were reported perioperatively in any other animals. All animals were observed to have sufficient pain management using an in-house visual analogue scale. The bilateral flank (dorsolateral) ovariectomy approach in female degus yielded a short total procedure time with no adverse events. No over grooming and or self-injurious behaviors were reported during both the 24 hours and 14 days recheck examinations.

Electrical distribution systems are often vulnerable to severe weather. Upgrades, such as microgrids, system hardening, and line redundancy, can greatly reduce the number of electrical outages during such extreme events. More recently, the networking of microgrids has received attention as a solution to further improve the resilience of distribution feeders. Although these upgrades have the potential to improve resilience, a barrier to their execution is a lack of tools and approaches that support systematic exploration of the underlying parameters of these upgrades and their cost vs. resilience tradeoffs.To address this gap, we develop a method for designing resilient distribution grids, including networked microgrids, by posing the problem as a two-stage stochastic program. When resilience is defined as the ability of a network to supply load immediately following a storm event, we show that a decomposition-based heuristic algorithm scales to a 1200-node distribution system. We also vary the study parameters, i.e., the cost of microgrids relative to system hardening and target resilience metrics. In this study, we find regions in this parametric space that correspond to different resilient distribution system architectures, such as individual microgrids, hardened networks, and a transition region that suggests the benefits of microgrids networked via hardened circuit segments.

In 1892, H. Seb Doyle, an African American preacher, learned that Democrats sought to lynch him due to his support of Populist Congressman Tom Watson. Was the threat real? This question became the center of a campaign discussion of race, politics, and corruption. Democratic and Populist newspapers’ accounts of this issue reveal the role of the “rhetoric of corruption” in the Georgia Populist Party's campaigns in the 1890s. Ironically, Populists used the same rhetoric Democrats had used against Republicans during Reconstruction. Populists linked Democratic political and economic malfeasance with the racial “corruptions” of miscegenation and “Negro Domination.” Although the Populists attempted to make this link, their insistence on black and white political equality undermined their white supremacist rhetoric, thereby weakening their case. Despite the Populists’ failure, the ultimate result was the same: the Populists came to abandon biracial politics and called for greater disfranchisement, all in the name of reform.

The rapid increase of distributed energy resources has led to the widespread deployment of microgrids. These flexible and efficient local energy grids are able to operate in both grid-connected mode and islanded mode; they are interfaced to the main power system by a fast semiconductor switch and commonly make use of inverter-interfaced generation. This paper focuses on inverter interfaced microgrids, which present a challenge for protection as they do not provide the high short-circuit current necessary for conventional time-overcurrent protection. The application of admittance relaying for the protection of inverter-interfaced microgrids is investigated as a potential solution. The comparison of analytical and simulated results of performed four experiments prove the suitability of admittance relaying for microgrids protection., 9 pages. 21 figures. 4 tables

Protecting inverter-interfaced microgrids is challenging as conventional time-overcurrent protection becomes unusable due to the lack of fault current. There is a great need for novel protective relaying methods that enable the application of protection coordination on microgrids, thereby allowing for microgrids with larger areas and numbers of loads while not compromising reliable power delivery. Tools for modeling and analyzing such microgrids under fault conditions are necessary in order to help design such protective relaying and operate microgrids in a configuration that can be protected, though there is currently a lack of tools applicable to inverter-interfaced microgrids. This paper introduces the concept of applying an optimization problem formulation to the topic of inverter-interfaced microgrid fault modeling, and discusses how it can be employed both for simulating short-circuits and as a set of constraints for optimal microgrid operation to ensure protective device coordination.

ObjectivesTo examine patients’ accounts of their use of the internet before seeing a general practitioner (GP) using thematic analysis of semistructured interviews.DesignQualitative semistructured interview study with transcripts analysed thematically.SettingPrimary care patients consulting with 10 GPs working at 7 GP practices of varying sizes and at a range of locations around London and the Southeast of England.Participants28 adult patients: 16 women and 12 men ranging in age from 18 to 75 from a range of self-defined ethnic backgrounds. Participants were selected based on instances when the patients reported having used the internet before the consultation, when patients referred to the internet in the consultation or when the physician used the internet or made reference to it during the consultation.ResultsPatients report that they can find health information online that they believe is reliable and helpful for both themselves and their GP. However, they report uncertainty about how to share internet-based findings and reluctance to disclose their efforts at researching health issues online for fear of appearing disrespectful or interfering with the flow of the consultation.ConclusionsDespite the democratisation of access to information about health due via the internet, patients continue to experience their use of the internet for health information as a sensitive and potentially problematic topic. The onus may well be on GPs to raise the likelihood (without judgement) that patients will have looked things up before consulting and invite them to talk about what they found.

Despite widespread acknowledgement of internet use for information about health, patients report not disclosing use of online health information in consultations. This paper compares patients' reported use of the internet with matched video recordings of consultations. The concepts of doctorability and epistemics are employed to consider similarities and differences between patients’ reports in interviews and actions in the consultation. Data are drawn from the Harnessing Resources from the Internet study conducted in the UK. The data set consists of 281 video-recorded general practice consultations, with pre-consultation questionnaires completed by all patients, interviews with all 10 participating doctors and 28 selected patients. We focus on the 28 patient interviews and associated consultation recordings. A conversation analytic (CA) approach is used to systematically inspect both the interview and consultation data. In interviews patients presented use of the internet as associated with appropriate self-management and help-seeking. In consultations patients skilfully translated what they had found on the internet in order to provide grounds for the actions they sought. We conclude that patients translate and utilise what they have found on the internet to assert the doctorability of their presenting problems. Furthermore, patients design their talk in both interviews and consultations to accord with their understanding of the epistemic rights of both doctors and patients. Patients search the internet so they are informed about their medical problem, however they carefully manage disclosure of information to avoid disrupting the smooth running of medical interactions., Highlights • Patients seek information from the internet to support decisions to consult. • Patients seek information from the internet to support appropriate self-management. • Patients skilfully translate what they find on the internet to support requests. • Patients skilfully use the internet to invite action from their doctors. • Patients do not openly challenge the epistemic authority of the doctor.

Promoters of lettuce cis-prenyltransferase 3 (LsCPT3) and CPT-binding protein 2 (LsCBP2) specify gene expression in laticifers, as supported by in situ β-glucuronidase stains and microsection analysis. Lettuce (Lactuca sativa) has articulated laticifers alongside vascular bundles. In the cytoplasm of laticifers, natural rubber (cis-1,4-polyisoprene) is synthesized by cis-prenyltransferase (LsCPT3) and CPT-binding protein (LsCBP2), both of which form an enzyme complex. Here we determined the gene structures of LsCPT3 and LsCBP2 and characterized their promoter activities using β-glucuronidase (GUS) reporter assays in stable transgenic lines of lettuce. LsCPT3 has a single 7.4-kb intron while LsCBP2 has seven introns including a 940-bp intron in the 5′-untranslated region (UTR). Serially truncated LsCPT3 promoters (2.3 kb, 1.6 kb, and 1.1 kb) and the LsCBP2 promoter with (1.7 kb) or without (0.8 kb) the 940-bp introns were fused to GUS to examine their promoter activities. In situ GUS stains of the transgenic plants revealed that the 1.1-kb LsCPT3 and 0.8-kb LsCBP2 promoter without the 5′-UTR intron are sufficient to express GUS exclusively in laticifers. Fluorometric assays showed that the LsCBP2 promoter was several-fold stronger than the CaMV35S promoter and was ~ 400 times stronger than the LsCPT3 promoter in latex. Histochemical analyses confirmed that both promoters express GUS exclusively in laticifers, recognized by characteristic fused multicellular structures. We concluded that both the LsCPT3 and LsCBP2 promoters specify gene expression in laticifers, and the LsCBP2 promoter displays stronger expression than the CaMV35S promoter in laticifers. For the LsCPT3 promoter, it appears that unknown cis-elements outside of the currently examined LsCPT3 promoter are required to enhance LsCPT3 expression.

Conversation Analysis (CA hereafter) is a method for analysing communication whose foundations lie in the work of sociologists Harvey Sacks, Emanuel Schegloff and Gail Jefferson. A CA approach offers both theory and method. Its theoretical concern is with identifying and characterising the ‘machinery’ (Sacks 1984: 27) underlying talk and social relations. Its methodological principles involve making and working with recordings of conversations—‘details of actual occurrences’—rather than using interview methods or direct observation where researchers have ‘an active and ongoing part in soliciting reports’ or are present and taking notes ‘as the observed activity unfolds’ (Potter and Shaw 2018: 189). In CA, talk is therefore treated as the topic rather than an ‘unanalysed and unexplicated methodological resource’, for research (Jefferson and Lee 1980: iii). Recordings are transcribed in preparation for analysis using standard conventions developed by Jefferson (2004) that require close attention to both what was said and how it was said.

In geophysics, the slant stack transform is a method used to align signals from different sensors. We focus on the use of the transform within passive refraction microtremor (ReMi) surveys, in order to produce high resolution slowness-frequency plots for use as samples in a machine learning model. Running on a single central processing unit (CPU) thread, this process takes approximately 45 min, 99.5% of which consists of the slant stack transform. In order to reduce the time taken to perform the transform, we use NVIDIA CUDA programming model. Using the same CPU, augmented with a GeForce RTX 2080 Ti we were able to reduce this time down to as little as 0.5 s.

Microgrids are localized electrical grids with control capability that are able to disconnect from the traditional grid to operate autonomously. They strengthen grid resilience, help mitigate grid disturbances, and support a flexible grid by enabling the integration of distributed energy resources. Given the likely presence of critical loads, the proper protection of microgrids is of vital importance; however, this is complicated in the case of inverter-interfaced microgrids where low fault currents preclude the use of conventional time-overcurrent protection. This paper introduces and investigates the application of dynamic state estimation, a generalization of differential protection, for the protection of radial portions of microgrids (or distribution networks); both phasor-based and dynamic approaches are investigated for protection. It is demonstrated through experiments on three case-study systems that dynamic state estimation is capable of correctly identifying model parameters for both normal and faulted operation., Comment: 9 pages. 4 figures. 5 tables

People with dementia are often marginalised in health care due to the effects of the condition on short term memory and communication. The problem presentation is a key area of primary care consultations where patients 'have the floor', and hence are able to direct the trajectory of the consultation to achieve certain ends. An exploration of how patients with advanced dementia participate in this stage of the consultation can thus demonstrate their participation and subsequent engagement. We used conversation analysis to describe how healthcare professionals (HCPs), people with dementia, and their carers establish the presenting problem in 17 out-of-hours primary care home visit consultations. In all cases, the carer had called the out of hours service on behalf of the patient. Rather than traditional "what can I help you with?" problem solicits, HCPs instead stated their reason-for-visit using information provided by the carer. All the patients showed some misalignment with this presented reason-for-visit, by denying the existence of current symptoms and/or their involvement in the decision to call the doctor. Carers appeared to show respect for the patient's ownership of their experience, only providing input on invitation from doctors or patients. Patient acknowledgement and willingness to engage in examination were needed for progressivity, but agreement with the reason-for-visit was not. In two consultations, the reason-for-visit was not explained to patients, and in both cases this resulted in the person with dementia showing frustration and resistance to examination. People with dementia may resist doctor home visits for many reasons, such as embarrassment for not remembering symptoms, or stoicism in the face of medical ailments. These findings show how the balance of progressivity and intersubjectivity tips towards progressivity in consultations with people with dementia, but this is reversed when the patient is not engaged in the reason-for-visit.

Study Objectives Brain-derived neurotrophic factor (BDNF) expression and homeostatic regulation of rapid eye movement (REM) sleep are critical for neurogenesis and behavioral plasticity. Accumulating clinical and experimental evidence suggests that decreased BDNF expression is causally linked with the development of REM sleep-associated neuropsychiatric disorders. Therefore, we hypothesize that BDNF plays a role in sleep–wake (S–W) activity and homeostatic regulation of REM sleep. Methods Male and female wild-type (WT; BDNF +/+) and heterozygous BDNF (KD; BDNF +/−) rats were chronically implanted with S–W recording electrodes to quantify baseline S–W activity and REM sleep homeostatic regulatory processes during the light phase. Results Molecular analyses revealed that KD BDNF rats had a 50% decrease in BDNF protein levels. During baseline S–W activity, KD rats exhibited fewer REM sleep episodes that were shorter in duration and took longer to initiate. Also, the baseline S–W activity did not reveal any sex difference. During the 3-hour selective REM sleep deprivation, KD rats failed to exhibit a homeostatic drive for REM sleep and did not exhibit rebound REM sleep during the recovery S–W period. Conclusion Interestingly, both genotypes did not reveal any sex difference in the quality and/or quantity of REM sleep. Collectively, these results, for the first time, unequivocally demonstrate that an intact BDNF system in both sexes is a critical modulator for baseline and homeostatic regulation of REM sleep. This study further suggests that heterozygous BDNF knockdown rats are a useful animal model for the study of the cellular and molecular mechanisms of sleep regulation and cognitive functions of sleep.

Background We have previously demonstrated that key components of the regional PGME paediatric teaching programme can be shared with the Advanced Clinical Practice (ACP) Paediatric MSc Programme. Both share archived material online and live streamed teaching sessions. This allows students geographically distant from the teaching location to access the MSc Programme. A recent survey of our paediatric trainees returning to training (RTT) revealed a similar need for accessing the regional training programme from more distant locations. We investigated whether the same learning outcomes can be achieved with remote online access by comparing how ACP trainees access the learning resources and their summative assessment results based on their distance from the teaching location. Methods We stratified ACP trainees according to distance between workplace and teaching location with those in the upper quartile classified as distance learners. Using student’s access data, we calculated the number and length of sessions accessed online. The amount of sessions where online resources were used instead of face to face teaching was compared between the distance learning group and the remaining trainees, alongside their mean exam performance across the MSc programme. Results 77 trainees’ data was analysed with a range in distance of 0–264 miles from the teaching location (median 8.5 miles, IQR 0–28 miles). 475 hours of access data was analysed from all 4 modules of the course over 3 years. Distance learners attended more live streamed sessions online than those who lived closer (median 84% vs 32% p=0.00001) yet the amount of archived material accessed was similar (14.4 vs 15.4 hr, p=0.9442). This suggests it is convenience rather than a predisposition that encourages students to choose online access methods. Despite this we did not demonstrate any difference between their summative exam result (70% vs 67% p=0.169) or within individual modules, years or pathways. Conclusion ACP MSc students prefer online methods of learning if they are based a greater distance from teaching locations and this does not impact their performance in summative assessments. This indicates paediatricians RTT with similar distance learning needs may also benefit from accessing online training opportunities in this way.

Promoters of lettuce cis-prenyltransferase 3 (LsCPT3) and CPT-binding protein 2 (LsCBP2) specify gene expression in laticifers, as supported by in situ β-glucuronidase stains and microsection analysis. Lettuce (Lactuca sativa) has articulated laticifers alongside vascular bundles. In the cytoplasm of laticifers, natural rubber (cis-1,4-polyisoprene) is synthesized by cis-prenyltransferase (LsCPT3) and CPT-binding protein (LsCBP2), both of which form an enzyme complex. Here we determined the gene structures of LsCPT3 and LsCBP2 and characterized their promoter activities using β-glucuronidase (GUS) reporter assays in stable transgenic lines of lettuce. LsCPT3 has a single 7.4-kb intron while LsCBP2 has seven introns including a 940-bp intron in the 5'-untranslated region (UTR). Serially truncated LsCPT3 promoters (2.3 kb, 1.6 kb, and 1.1 kb) and the LsCBP2 promoter with (1.7 kb) or without (0.8 kb) the 940-bp introns were fused to GUS to examine their promoter activities. In situ GUS stains of the transgenic plants revealed that the 1.1-kb LsCPT3 and 0.8-kb LsCBP2 promoter without the 5'-UTR intron are sufficient to express GUS exclusively in laticifers. Fluorometric assays showed that the LsCBP2 promoter was several-fold stronger than the CaMV35S promoter and was ~ 400 times stronger than the LsCPT3 promoter in latex. Histochemical analyses confirmed that both promoters express GUS exclusively in laticifers, recognized by characteristic fused multicellular structures. We concluded that both the LsCPT3 and LsCBP2 promoters specify gene expression in laticifers, and the LsCBP2 promoter displays stronger expression than the CaMV35S promoter in laticifers. For the LsCPT3 promoter, it appears that unknown cis-elements outside of the currently examined LsCPT3 promoter are required to enhance LsCPT3 expression.

ObjectivesPeople with dementia are more vulnerable to complications in urgent health situations due to older age, increased comorbidity, higher dependency on others and cognitive impairment. This review explored the factors associated with urgent care use in dementia and the experiences of people with dementia, informal carers and professionals.DesignScoping review. The search strategy and data synthesis were informed by people with dementia and carers.Data sourcesSearches of CINAHL, Embase, Medline, PsycINFO, PubMed were conducted alongside handsearches of relevant journals and the grey literature through 15 January 2019.Eligibility criteriaEmpirical studies including all research designs, and other published literature exploring factors associated with urgent care use in prehospital and emergency room settings for people with dementia were included. Two authors independently screened studies for inclusion.Data extraction and synthesisData were extracted using charting techniques and findings were synthesised according to content and themes.ResultsOf 2967 records identified, 54 studies were included in the review. Specific factors that influenced use of urgent care included: (1) common age-related conditions occurring alongside dementia, (2) dementia as a diagnosis increasing or decreasing urgent care use, (3) informal and professional carers, (4) patient characteristics such as older age or behavioural symptoms and (5) the presence or absence of community support services. Included studies reported three crucial components of urgent care situations: (1) knowledge of the patient and dementia as a condition, (2) inadequate non-emergency health and social care support and (3) informal carer education and stress.ConclusionsThe scoping review highlighted a wider variety of sometimes competing factors that were associated with urgent care situations. Improved and increased community support for non-urgent situations, such as integrated care, caregiver education and dementia specialists, will both mitigate avoidable urgent care use and improve the experience of those in crisis.

Orkney and Shetland, the population isolates that make up the Northern Isles of Scotland, are of particular interest to multiple sclerosis (MS) research. While MS prevalence is high in Scotland, Orkney has the highest global prevalence, higher than more northerly Shetland. Many hypotheses for the excess of MS cases in Orkney have been investigated, including vitamin D deficiency and homozygosity: neither was found to cause the high prevalence of MS. It is possible that this excess prevalence may be explained through unique genetics. We used polygenic risk scores (PRS) to look at the contribution of common risk variants to MS. Analyses were conducted using ORCADES (97/2118 cases/controls), VIKING (15/2000 cases/controls) and Generation Scotland (30/8708 cases/controls) data sets. However, no evidence of a difference in MS-associated common variant frequencies was found between the three control populations, aside fromHLA-DRB1*15:01tag SNP rs9271069. This SNP had a significantly higher risk allele frequency in Orkney (0.23,pvalue = 8 × 10–13) and Shetland (0.21,pvalue = 2.3 × 10–6) than mainland Scotland (0.17). This difference in frequency is estimated to account for 6 (95% CI 3, 8) out of 150 observed excess cases per 100,000 individuals in Shetland and 9 (95% CI 8, 11) of the observed 257 excess cases per 100,000 individuals in Orkney, compared with mainland Scotland. Common variants therefore appear to account for little of the excess burden of MS in the Northern Isles of Scotland.

We introduce a novel algorithm - ConvNEAT - that evolves a convolutional neural network (CNN) from a minimal architecture. Convolutional and dense nodes are evolved without restriction to the number of nodes or connections between nodes. The proposed work advances the field with ConvNEAT's ability to evolve arbitrary minimal architectures with multi-dimensional inputs using GPU processing.

BackgroundAwareness of the importance of shared decision making (SDM) is widespread; however, little research has focused on discussions surrounding investigations, despite increasing laboratory testing in primary care.AimTo explore the discussion of blood tests in routine primary care consultations.Design and settingA secondary analysis of 50 video-recorded routine primary care consultations, linked surveys, and records data (all from the One in a Million [OiaM] archive). The consultations were taken by 22 GPs across 12 practices.MethodA coding scheme was developed, using qualitative content analysis, to explore discussion of blood tests in transcripts of recorded consultations. Codes focused on instigating testing, the extent of SDM, and how results were explained. Survey data were used to compare patients’ pre-visit expectations with consultation content. Medical records were reviewed to compare tests discussed with those ordered.ResultsIn 36 out of 50 consultations that discussed ordering blood tests, 11 patients (31%) hinted that they wanted a blood test; however, none asked explicitly. Only four patients (11%) were offered alternative options. In 29 cases (81%) the GP gave some explanation of the indication, but only in six cases (17%) were the limitations of testing explained. Only 10 out of 31 patients (32%) were informed about all blood tests ordered. Of the 23 out of 50 consultations in which results were conveyed, the GP gave no explanation of the results in six cases (26%). Thirteen patients (57%) were only informed of an assessment of the results (for example, ‘normal’), rather than the actual results.ConclusionA lack of information dissemination and SDM exists around ordering tests and conveying results. Promoting SDM could reduce unnecessary testing and improve patient-centred care.

Satellite imagery presents a number of challenges for object detection such as significant variation in object size (from small cars to airports) and low object resolution. In this work we focus on recognizing objects taken from the xView Satellite Imagery dataset. The xView dataset introduces its own set of challenges, the most prominent being the imbalance between the 60 classes present. xView also contains considerable label noise as well as both semantic and visual overlap between classes. In this work we focus on techniques to improve performance on an imbalanced, noisy dataset through data augmentation and balancing. We show that a very small convolutional neural network (SAT-CNN) with approximately three million parameters can outperform a deep pre-trained classifier, VGG16 - which is used for many state-of-the-art tasks - with over 138 million parameters.

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

Aerial applications of liquid methoprene are used in salt marshes to control mosquitoes by preventing adult emergence. Despite concern about toxicity to non-target organisms, little is known about environmental concentrations after applications, nor methoprene's persistence in salt marsh environments. Aqueous and sediment samples were collected from two marshes receiving weekly applications. Aqueous samples were collected as early as 30 min after applications and as long as nine days afterwards; sediment samples were taken within hours of application and as long as 19 days post-application. Use of time-of-flight liquid chromatography – mass spectral analysis allowed for ultra-low detection limits (0.5 ng/L) in water samples. The data show loss of nearly all methoprene from 1 m deep marsh ditches within 1 day and presence but not accumulation of methoprene in marsh sediments despite repeated applications. Methoprene concentrations observed in salt-marsh mosquito ditches were below those found to be of toxicological significance in other studies.

A 5-year-old female spayed Shetland sheepdog presented for evaluation of bandage sores on the left pelvic limb after a splint was placed to stabilise a digit fracture incurred approximately 2 weeks previously. Multiple areas of necrosis were identified upon bandage removal. After debridement of devitalised tissue, a 4 cm wound on the plantar surface of the metatarsal bones (with exposed bone and tendons) remained. The Papineau technique (which involves removal of infected or necrotic tissue, placement of autogenous cancellous bone graft within a wound, and delayed skin closure) was used to treat this wound. Use of bone graft in this manner aims to promote early granulation tissue formation and reduce the time until wound reconstruction can be performed. Autogenous cancellous bone graft was harvested from the proximal humerus and placed within the metatarsal wound. Once a healthy granulation tissue bed was noted to cover the bone graft, a meshed full thickness skin graft was placed. To our knowledge, this is the first report of the Papineau technique being used for this purpose in a dog.

Providing early childhood professionals with professional development opportunities to enhance their skills and knowledge can improve quality of care. For professional development to be valued by t...

Background Oropharyngeal Squamous Cell Carcinoma (OPSCC) is increasing in incidence despite a decline in traditional risk factors. Human Papilloma Virus (HPV), specifically subtypes 16, 18, 31 and 35, has been implicated as the high-risk etiologic agent. HPV positive cancers have a significantly better prognosis than HPV negative cancers of comparable stage, and may benefit from different treatment regimens. Currently, HPV related carcinogenesis is established indirectly through Immunohistochemistry (IHC) staining for p16, a tumour suppressor gene, or polymerase chain reaction (PCR) that directly tests for HPV DNA in biopsied tissue. Loop mediated isothermal amplification (LAMP) is more accurate than IHC, more rapid than PCR and is significantly less costly. In previous work we showed that a subtype specific HPV LAMP assay performed similar to PCR on purified DNA. In this study we examined the performance of this LAMP assay without DNA purification. Methods We used LAMP assays using established primers for HPV 16 and 18, and new primers for HPV 31 and 35. LAMP reaction conditions were tested on serial dilutions of plasmid HPV DNA to confirm minimum viral copy number detection thresholds. LAMP was then performed directly on different human cell line samples without DNA purification. Results Our LAMP assays could detect 105, 103, 104, and 105 copies of plasmid DNA for HPV 16, 18, 31, and 35, respectively. All primer sets were subtype specific, with no cross-amplification. Our LAMP assays also reliably amplified subtype specific HPV DNA from samples without requiring DNA isolation and purification. Conclusions The high risk OPSCC HPV subtype specific LAMP primer sets demonstrated, excellent clinically relevant, minimum copy number detection thresholds with an easy readout system. Amplification directly from samples without purification illustrated the robust nature of the assay, and the primers used. This lends further support HPV type specific LAMP assays, and these specific primer sets and assays can be further developed to test for HPV in OPSCC in resource and lab limited settings, or even bedside testing.

Neonicotinoids have been previously detected in Iowa surface waters, but less is known regarding their occurrence in groundwater. To help fill this research gap, a groundwater study was conducted in eastern Iowa and southeastern Minnesota, a corn and soybean producing area with known heavy neonicotinoid use. Neonicotinoids were studied in alluvial aquifers, a hydrogeologic setting known to be vulnerable to surface-applied contaminants. Groundwater samples were analyzed from 40 wells for six neonicotinoid compounds (acetamiprid, clothianidin, dinotefuran, imidacloprid, thiacloprid, thiamethoxam), and sulfoxaflor. Samples were analyzed using liquid chromatography tandem mass spectrometry (LC/MS/MS) with both direct aqueous injection and solid phase extraction methods. Neonicotinoids were prevalent in the alluvial aquifers with 73% of the wells having at least one neonicotinoid detection. Clothianidin (68%, max: 391.7 ng/L) was the most commonly detected, followed by imidacloprid (43%, max: 6.7 ng/L) and thiamethoxam (3%, max: 0.2 ng/L). Acetamiprid, dinotefuran, sulfoxaflor, and thiacloprid were not detected during the study. The solid phase extraction method was more sensitive than direct aqueous injection, where only clothianidin detected in 23% of samples. SPE is the preferred method for detecting low concentrations of hydrophilic pesticides in water. This study documented that the combination of heavy chemical use overlying a hydrogeologic setting vulnerable to surface applied contaminants leads to transport of neonicotinoids into an important groundwater resource.

In the era of patient participation in health care decision making, we know surprisingly little about the ways in which treatment recommendations are made, the contexts that shape their formulation, and the consequences of these formulations. In this article, we introduce a systematic collective investigation of how recommendations for medications are responded to and made in primary versus secondary care, in the US versus the UK, and in contexts where the medication was over the counter versus by prescription. This article provides an overview of the coding system that was used in this project including describing what constitutes a recommendation, the primary action types clinicians use for recommendations, and the types of responses provided by patients to recommendations.

Rapid eye movement (REM) sleep dysregulation is a symptom of many neuropsychiatric disorders, yet the mechanisms of REM sleep homeostatic regulation are not fully understood. We have shown that, after REM sleep deprivation, the pedunculopontine tegmental nucleus (PPT) plays a critical role in the generation of recovery REM sleep. In this study, we used multidisciplinary techniques to show a causal relationship between brain‐derived neurotrophic factor (BDNF)‐tropomyosin receptor kinase B (TrkB) signaling in the PPT and the development of REM sleep homeostatic drive. Rats were randomly assigned to conditions of unrestricted sleep or selective REM sleep deprivation (RSD) with PPT microinjections of vehicle control or a dose of a TrkB receptor inhibitor (2, 3, or 4 nmol K252a or 4 nmol ANA‐12). On experimental days, rats received PPT microinjections and their sleep‐wake physiological signals were recorded for 3 or 6 h, during which selective RSD was performed in the first 3 h. At the end of all 3 h recordings, rats were killed and the PPT was dissected out for BDNF quantification. Our results show that K252a and ANA‐12 dose‐dependently reduced the homeostatic responses to selective RSD. Specifically, TrkB receptor inhibition reduced REM sleep homeostatic drive and limited REM sleep rebound. There was also a dose‐dependent suppression of PPT BDNF up‐regulation, and regression analysis revealed a significant positive relationship between REM sleep homeostatic drive and the level of PPT BDNF expression. These data provide the first direct evidence that activation of BDNF‐TrkB signaling in the PPT is a critical step for the development of REM sleep homeostatic drive.

Background Despite the clear harm associated with smoking tobacco, many people with smoking-related chronic diseases or serious mental illnesses (SMI) are unwilling or unable to stop smoking. In many cases, these smokers have tried and exhausted all methods to stop smoking and yet clinicians are repeatedly mandated to offer them during routine consultations. Providing nicotine through electronic cigarettes (e-cigarettes) may reduce the adverse health consequences associated with tobacco smoking, but these are not currently offered. The aim of this study is to examine the feasibility, acceptability and effectiveness of general practitioners (GPs) and nurses delivering a brief advice intervention on e-cigarettes and offering an e-cigarette starter pack and patient support resources compared with standard care in smokers with smoking-related chronic diseases or SMI who are unwilling to stop smoking. Methods/design This is an individually randomised, blinded, two-arm trial. Smokers with a smoking-related chronic condition or SMI with no intention of stopping smoking will be recruited through primary care registers. Eligible participants will be randomised to one of two groups if they decline standard care for stopping smoking: a control group who will receive no additional support beyond standard care; or an intervention group who will receive GP or nurse-led brief advice about e-cigarettes, an e-cigarette starter pack with accompanying practical support booklet, and telephone support from experienced vapers and online video tutorials. The primary outcome measures will be smoking reduction, measured through changes in cigarettes per day and 7-day point-prevalence abstinence at 2 months. Secondary outcomes include smoking reduction, 7-day point-prevalence abstinence and prolonged abstinence at 8 months. Other outcomes include patient recruitment and follow-up, patient uptake and use of e-cigarettes, nicotine intake, contamination of randomisation and practitioner adherence to the delivery of the intervention. Qualitative interviews will be conducted in a subsample of practitioners, patients and the vape team to garner their reactions to the programme. Discussion This is the first randomised controlled trial to investigate whether e-cigarette provision alongside a brief intervention delivered by practitioners leads to reduced smoking and abstinence among smokers with smoking-related chronic diseases or SMI. Trial registration ISRCTN registry, ISRCTN59404712. Registered 28/11/17.