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Current guidelines recommend a target international normalized ratio (INR) range of 2.5 to 3.5 in patients with a mechanical mitral prosthesis. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) Mitral randomized controlled noninferiority trial assessed safety and efficacy of warfarin at doses lower than currently recommended, in patients with an On-X mechanical mitral valve.After On-X mechanical mitral valve replacement followed by at least 3 months of standard anticoagulation, 401 patients at 44 North American centers were randomized to low-dose warfarin (target INR 2.0 to 2.5) or standard-dose warfarin (target INR 2.5 to 3.5). All patients were prescribed aspirin 81 mg daily and encouraged to use home INR testing. The primary endpoint was the sum of the linearized rates of thromboembolism, valve thrombosis, and bleeding events. The design was based on an expected 7.3% event rate and 1.5% noninferiority margin.Mean patient follow-up was 4.1 years. Mean INR was 2.47 and 2.92 (P.001) in the low-dose and standard-dose warfarin groups, respectively. Primary endpoint rates were 11.9%/patient-year in the low-dose group and 12.0%/patient-year in the standard-dose group (difference -0.07, 95% confidence intervals: -3.40, 3.26). The confidence interval exceeded 1.5%, thus noninferiority was not achieved. Rates (%/patient-year) of the individual components of the primary endpoint were 2.3% vs 2.5% for thromboembolism, 0.5% vs 0.5% for valve thrombosis, and 9.13% vs 9.04% for bleeding.Compared to standard-dose warfarin, low-dose warfarin did not achieve noninferiority for the composite primary endpoint. (PROACT Clinicaltrials.gov number, NCT00291525).

In recent years, particularly in Europe, increasing attention is being paid to managing Intellectual Property (IP) competitive effects. Europe achieves greater innovation output with IP overall whilst also implementing the globally harmonised IP laws. The performance differences in innovation output are due to many variables. However, the EU has focussed on three policy goals: “open innovation”, “open science”, and “open to the world”, aiming to foster access to knowledge for advancement as well as overcoming innovation barriers while retaining alignment with harmonised international IP frameworks. Whilst it is still premature to draw conclusions about the effectiveness of the EU approach, it is possible to hypothesise whether such an approach is a viable option in Asia. In this case, the focus will be on the eleven countries of the Southeast Asia region with their various levels of development, from least developed (Cambodia, Laos, Myanmar and Timor-Leste) to highly developed (Singapore). The paper describes the concept of the EU “open innovation” policy, its drivers and its legal basis. From these examples, a framework will be developed against which to test its viability in Southeast Asia. Analysis shows that each of the ten ASEAN member states, including Singapore, is a net importer of patents rather than a developer. Nonetheless, it is considered that the IP ecosystems in Malaysia, Singapore, Thailand and Vietnam are sufficiently robust to at least consider a trial of the Open Innovation, Open Science and Open to the World concepts as being tested in the European Union. Keywords: “Open Innovation”; European Union; Association of Southeast Asian Nations; Intellectual Property legislation

After a long period of instability, Nepal adopted a new Constitution in 2015, creating a multiparty federal republic. Previously Nepal had been a unitary state, albeit with a long period of political instability and insurgencies. In 2017 the two competing communist parties merged to form the ruling Nepal Communist Party (NCP), which operated with a 2/3rd majority in the House of Representatives. The implementation of federalism has been slow and uneven. Despite assurances to the contrary, the government’s response to the COVID-19 pandemic has been lacking, with Constitutional obligations ignored. The machinations of the then Prime Minister have exacerbated this, apparently supported by the President to overcome constitutional norms to keep the Prime Minister in power. The paper analyses the devolution of powers to the provincial and local levels described in the constitution. There have been successes and failures. There appeared to be a concerted effort from the federal parliament and some in the bureaucracy to continue to centralize power. This early inaction has hindered its response to the pandemic. Of even more concern is the then prime minister's role as he sought to maintain his hold on power by ignoring the provisions of the Constitution.

Surgical root canal re-treatment (SRCReT), or root-end surgery, is the most commonly undertaken surgical endodontic technique. Approaches to SRCReT differ, with a variety of different protocols described and varied success rates reported. In the second part of this two-part series, the current scientific literature is examined and clinical examples are given to offer guidance for the optimal protocol for SRCReT. CPD/Clinical Relevance: SRCReT is a procedure which may facilitate the treatment of disease of endodontic origin which is not amenable to management with orthograde non-surgical root canal treatment.

Background/Aims Most transcatheter aortic valve implantation procedures are now performed under conscious sedation, rather than general anaesthetic. This study evaluated nurse-led conscious sedation, compared with anaesthetist-led sedation, to determine the feasibility of the former. Methods Consecutive patients undergoing transcatheter aortic valve implantation under either nurse-led or anaesthetist-led sedation between July 2018 and September 2021 were reviewed. Assessed outcomes were analysed and compared, including 30-day mortality rate, major vascular access site bleeding, moderate or severe aortic regurgitation, stroke, new pacemaker implantation, duration of procedure and length of stay. Results A total of 212 patients who underwent nurse-led sedation and 412 who underwent anaesthetist-led sedation were identified. There were no significant differences in risk scores between the two groups. In both groups, incidence of conversion to general anaesthetic was low, with nurse sedatitionists seeking anaesthetist support in 13 (6.2%) cases. Cases with nurse-led sedation had a significantly lower average duration of the procedure (90 minutes vs 111 minutes; P=0.001) and length of stay (2 days vs 3 days, P=0.0002). Conclusions Nurse-led sedation can be safely incorporated into transcatheter aortic valve implantation practice. Nurse-led sedation delivered similar outcomes to anaesthetist-led sedation, but with shorter procedural times and legnth of stay. This could allow more flexible scheduling, increased capacity and improved access for patients.

Secondary mitral regurgitation (SMR) is frequent in patients with heart failure with reduced ejection fraction (HFrEF) and portends detrimental prognosis. Despite interventions addressing the mitral valve (MV) have been proven effective to improve survival, an important knowledge gap exists regarding the role of medical therapy (MT) in this context. Thus, we aimed at investigating the role of MT optimization in patients with SMR and HFrEF.A total of 435 patients with SMR and HFrEF were retrospectively evaluated. Of those, 158 with severe SMR were finally included, with 63 (40%) managed with MT alone and 96 (60%) with MV intervention plus MT. Echocardiography was performed after 30 days of MT optimization or MV intervention. Responders were patients with a final mitral regurgitation (MR) grade of ≤2+. Survival data were gathered through the National Database Index and patient chart review. MR severity improved in 131 patients (100% MV intervention; 57% MT) but stayed the same or worsened in 27 patients. Responders and non-responders were similar for baseline characteristics. Overall, long-term survival of responders was significantly higher than non-responders [hazard ratio (HR) 0.55, 95% confidence interval (CI) (0.32-0.96), P = 0.032]. No difference in survival was observed when evaluated by intervention type in the overall population (MT alone, n = 63; MV intervention plus MT, n = 95) [HR 0.77, 95% CI (0.48-1.26), P = 0.3], nor within responder group (MT alone, n = 36; MV intervention plus MT, n = 95) [HR 1.03, 95% CI (0.56-1.89), P = 0.94].MT reduces SMR severity in 57% of the patients with severe SMR. A final SMR grade of ≤2+ is linked to improved survival, independently of the type of treatment they receive.

PurposeDespite the healthy growth in studies and publications in recent years in relation to the expanding paradigm of gender and entrepreneurship, and notwithstanding the success of this very journal, from the perspective of the author, the field remains overly dominated by a focus on female and women's entrepreneurship. Conversely, there are few studies on masculinity and entrepreneurship and the role of men in shaping gendered entrepreneurship. In addition, few male entrepreneurship scholars choose to write in this niche and specialised field. Indeed, there is a discernible imbalance in the literature in relation to what can be termed as “silent” and “silenced” masculinities. In this reflection, the study aims to look back at his career as an entrepreneurship and gender scholar, considering why this situation exists.Design/methodology/approachThis is an invited, reflective essay written in an auto-ethnographic style containing personal viewpoints.FindingsIn the feminist-inspired gender and entrepreneurship literature, “Patriarchy” and the entrepreneurial “strawman” are blamed for the problems associated with the “silent” and silenced female entrepreneur. Much of the gendered literature concentrates on gendered female stereotypes and in particular on negative elements of these. The main finding is that the common assumption of the female as proxy for gender has, to date, prevented the consideration of the full spectrum of gendered identities. These issues are explored, and a call is made for more in-depth research into masculinity and entrepreneurship.Originality/valueThis reflection presents some novel thoughts on how to advance the debate on gender scholarship and in particular masculinity.

The COVID-19 pandemic forced civil society and business to face a new reality where much greater reliance needed to be placed on networked devices and internet distributed communications, including the provision of services ranging from medical advice to food, entertainment and even the facility to interact with family. The ability to meet in-person with family, friends, colleagues, business associates or customers was severely restricted leaving internationalisation as a utopian dream as borders were closed, students were denied access to a physical classrooms and businesses had to rapidly “pivot” or fail. These alternatives to real life have seemed less appealing to many, with every aspect of life “going online”, whether virtual lectures, exams, meetings, mediations, court appearances, job interviews, shopping for a piece of cheese or starting a new trade relationship. Much innovation over the last two years has been around deploying online business models. There has also been a wider use of artificial intelligence to support “efficient” operations partly stimulated by the falling staffing levels due to the pandemic directly through sickness or forced isolations, or indirectly by a growing sense of the futility of working for a business, known as the Great Resignation (“Over the 12 months ending in January 2022, hires totalled 76.4 million and separations totalled 70.0 million…” indicating a huge refocusing on jobs in the USA) This paper looks at the challenge for legal systems to pivot around the growing trends in deployments of online innovation. Some businesses are now widely deploying software-based analysis systems, such as Airbnb, which is using them to “verify the identity and trustworthiness of a user of an online system” and flag potential guests who may be problematic. Although Airbnb is a multibillion-dollar business, it is a good example of how through using publicly available data, user supplied information, and smart software (artificial intelligence) a business can make predictions on the behaviour of its potential customers. Other AI resources have been creating new gaming scenarios, reporting on the news, and even creating new artworks and music. These kinds of use of AI in the marketplace have challenged the legal frameworks that support individual privacy and also ideas around human creativity.

Sonic and bulk density logs are crucial inputs for many subsurface tasks including formation identification, completion design, and porosity estimation. Economic and operational concerns restrict the acquisition of these logs, meaning the overburden and sometimes entire wells are completely unlogged. In contrast, parameters that monitor drilling operations, such as weight on bit and torque, are recorded for every borehole. Previous studies have applied supervised machine learning approaches to predict these missing logs from the drilling parameters. While the results are promising, they often do not investigate the importance of different features and the corresponding practical implications. Here, we explored the feasibility of predicting compressional slowness and bulk density logs using various combinations of formation markers, gamma-ray logs, and drilling data recorded at the rig. Our tests utilized a temporal convolutional network to allow the model to learn from sequences of input features. Bayesian-based hyperparameter tuning found the optimum set of parameters for each experiment before producing the final log predictions. Finally, a permutation feature importance analysis revealed which input variables contributed most to the outputs. Although drilling parameters contain some insight into the mechanical rock properties, we found that they cannot produce the high-quality log predictions required for many tasks. Supplementing the drilling parameters with a gamma-ray log and formation data produces good-quality log predictions, with the additional inputs helping to constrain the model outputs.

To help health economic modelers respond to demands for greater use of complex systems models in public health. To propose identifiable features of such models and support researchers to plan public health modeling projects using these models. A working group of experts in complex systems modeling and economic evaluation was brought together to develop and jointly write guidance for the use of complex systems models for health economic analysis. The content of workshops was informed by a scoping review. A public health complex systems model for economic evaluation is defined as a quantitative, dynamic, non-linear model that incorporates feedback and interactions among model elements, in order to capture emergent outcomes and estimate health, economic and potentially other consequences to inform public policies. The guidance covers: when complex systems modeling is needed; principles for designing a complex systems model; and how to choose an appropriate modeling technique. This paper provides a definition to identify and characterize complex systems models for economic evaluations and proposes guidance on key aspects of the process for health economics analysis. This document will support the development of complex systems models, with impact on public health systems policy and decision making.

In the 2019 ASCCP Risk-Based Management Consensus Guidelines, clinical management decisions are based on immediate and 5-year cervical intraepithelial neoplasia (CIN) 3+ risk estimates. However, data for technologies other than human papillomavirus testing and cytology may be limited to clinical trials and observational studies of shorter duration than 5 years. To enable decisions about 1- or 3-year intervals, 3-year CIN 3+ risk equivalents to 5-year CIN 3+ risk thresholds were generated. MATERIALS AND METHODS: We examined screening test result scenarios around the 5-year risk thresholds of 0.15% and 0.55% and calculated the average percent increase in CIN 3+ risk from 3 to 5 years. Using this average increase, we obtained estimates of corresponding risk thresholds at 3 years. We then validated whether use of the 3-year risk threshold would have resulted in equivalent management per the 2019 recommendations. RESULTS: Around the 5-year CIN 3+ risk threshold of 0.55%, the average increase in risk from 3 to 5 years was 0.16%. Therefore, the equivalent threshold for 3-year risk was estimated as 0.39%. We found no difference in recommendations to return in 1 or 3 years using the 3-year or 5-year risk thresholds in 66 of the 67 scenarios (98.5%) in follow-up in 2019 guidelines. CONCLUSIONS: In this methodological addendum, the Enduring Guidelines Committee adopted the use of the 0.39% 3-year CIN 3+ risk threshold as equivalent of the 0.55% 5-year CIN 3+ risk threshold for technologies with fewer than 5 years of follow-up data. This allows evidence-based guidance for surveillance intervals of 1 or 3 years for new technologies with limited longitudinal data.

Myanmar, or Burma as it was previously known, has been under almost most continuous military rule since 1962 except for a brief period from 2016 until 1 February 2021. The military started the transfer of power to a civilian government in 2010 until the military staged a coup on 1 February 2021. The country has essentially been in a state of various civil wars since its independence in 1948. The period from 2010 saw the opening up of the telecommunications sector and a rapid uptake in social media. The spread of smartphones has opened up communication to the masses and provided them with access to information; the Myanmar Military has also used it to spread disinformation. These campaigns are used to uphold the state, people and religion. To the military, this essentially means the Burman (Bamar) majority, the Buddhist religion and the unitary state (with the military as its guardian). In many of these endeavours, they have been supported by non-state actors such as militant Buddhist monks. Since the military takeover in 2021, the resistance has also used social media, particularly young people and the many ethnic armed groups. Keywords: Social-media, disinformation, human rights, military rule, cyber security legislation

A main challenge in Heat-Assisted Magnetic Recording technology is the build-up of contaminants called smear on the near field transducer. In this paper, we investigate the role of optical forces originating from the electric field gradient in the formation of smear. First, based on suitable theoretical approximations, we compare this force with air drag and the thermophoretic force in the head-disk interface for two smear nanoparticle shapes. Then, we evaluate the force field’s sensitivity to the relevant parameter space. We find that the smear nanoparticle’s refractive index, shape, and volume significantly impact the optical force. Further, our simulations reveal that the interface conditions, such as spacing and the presence of other contaminants, also influence the magnitude of the force.

Lanthanide (Ln) based systems in the ZrSiS-type nodal-line semimetals have been subjects of research investigations as grounds for studying the interplay of topology with possible magnetic ordering and electronic correlations that may originate from the presence of Ln 4f electrons. In this study, we carried out a thorough study of a LnSbTe system - NdSbTe - by using angle-resolved photoemission spectroscopy along with first-principles calculations and thermodynamic measurements. We experimentally detect the presence of multiple gapless nodal-line states, which is well supported by first-principles calculations. A dispersive and an almost non-dispersive nodal-line exist along the bulk X-R direction. Another nodal-line is present well below the Fermi level across the G- M direction, which is formed by bands with high Fermi velocity that seem to be sensitive to light polarization. Our study provides an insight into the electronic structure of a new LnSbTe material system that will aid towards understanding the connection of Ln elements with topological electronic structure in these systems., 34 pages, 12 figures; Supplemental Material included

Protein therapeutics are often compromised by sub-optimal biodistribution contributing to poor efficacy and adverse events. Drug delivery mechanisms better able to target protein drugs to the disease site and provide localized, sustained release have the potential to transform therapeutic standards. PODS®crystals (PODS) are natural-mimetic, micron-scale protein co-crystals engineered to incorporate a protein cargo that can be sustainably released under the action of resident proteases. PODS are efficiently taken up by phagocytic cells with the cargo protein subsequently released in a bioactive form. Since blood-circulating phagocytic cells, including monocytes, are actively recruited into diseased and inflamed tissue, such as the tumour microenvironment, we postulated that monocyte/macrophage-mediated PODS delivery could be used as a molecular “Trojan horse” to efficiently deliver therapeutic proteins to target cells. This could improve the pharmacodynamics and pharmacokinetics of protein drug delivery to treat systemic and disseminated diseases. Interleukin-2 (IL-2) is notoriously toxic at the high doses required for therapeutic efficacy. Here, we demonstrate the therapeutic efficacy and tolerability of low doses of PODS containing IL-2 cargo (PODS-IL-2) administered intravenously in a mouse model of melanoma. We further demonstrate the therapeutic benefit of PODS delivering IL-2, interleukin-15 (IL-15) and interferon gamma (IFN-γ) in a mouse model of renal cell carcinoma at two doses. Efficacy was seen in both doses with the higher dose generating rapid and complete rejection of the tumour in some of the mice treated with each cytokine. This study provides proof-of-concept for the utility of intravenously administered PODS to provide a generalised and widely applicable mechanism to effectively deliver protein drugs for the therapy of cancer and potentially other diseases.

A Cognitive Task Force (CTF) was established for the MissionAD program with the aim of reducing the screen failure (SF) rate to ∼30% and thereby reduce unnecessary subject burden, site burden, and excess trial costs.The MissionAD program consisted of 2 global phase 3 studies evaluating the BACE inhibitor elenbecestat in subjects with early Alzheimer disease. The CTF monitored and engaged with MissionAD clinical sites to provide support through collegial discussions to maximize the efficiency of the preconsent recruitment phase.The CTF significantly improved cognitive screening efficiency in the MissionAD program, with a 24% decline in cognitive SF rate for the sites that the CTF contacted. The study-wide 11.5% reduction in cognitive SF rates were likely further driven by wider country-level initiatives in which CTF members held CTF-specific Investigator meetings with the recruitment staff, speaking to all sites on a country level regardless of their recruitment performance.The establishment of a CTF to support efficient cognitive screening is highly recommended for future Alzheimer disease studies. Additional benefits included improved site relationships, increased engagement in MissionAD and access to a group of cognitive experts for consulting, with a focus on achieving more efficient trial recruitment.

Seismic inversion is the process of converting seismic reflectivity data into physical subsurface properties. The most common inversion methods use physics-based forward modeling, but these require time-consuming steps, such as initial model building and wavelet extraction. Coherent noise in the seismic volume also may lead to suboptimal results. Advances in deep learning enable the development of new geophysical workflows that may help overcome these challenges. One example is the temporal convolutional network (TCN), a deep neural network that learns from sequential data, such as seismic traces. Previous research using the TCN architecture has indicated promising inversion results on synthetic data. However, applying the method to field data has several additional challenges that need to be considered, including complex noise and limited well availability. We used a poststack field data set containing coherent noise to evaluate the TCN approach for acoustic impedance inversion under these conditions. Despite the small data set, a TCN trained using traces and logs acquired at well locations produced better results than conventional inversion when supplemented with an additional time feature. While the physics-based inversion created false artifacts related to the noise, the neural network approach learned to ignore the suspected multiple events. Supervised learning using well data also makes semi-automated inversion a possibility. However, obtaining acceptable results using the few locations with logged boreholes may only be possible in relatively simple geological scenarios. To overcome the issue of small data sets, we developed a workflow for generating realistic synthetic data to provide more samples and variation for model training. A TCN trained using synthetic data ultimately produced the best impedance estimates, but care is needed to ensure the synthetic traces contain realistic noise. Overall, we show that a TCN can successfully invert seismic data contaminated with coherent noise, producing superior results compared to model-based inversion.

Contains fulltext : 252086.pdf (Publisher’s version ) (Open Access) BACKGROUND: Freezing of gait (FOG) is one of the most disabling gait disorders affecting 80% of patients with Parkinson's disease (PD). Clinical guidelines recommend a behavioral approach for gait rehabilitation, but there is a wide diversity of behavioral modalities. OBJECTIVE: The objective of this network meta-analysis was to compare the effectiveness of different behavioral interventions for FOG management in PD patients. METHODS: Six databases were searched for randomized controlled trials of behavioral interventions for FOG management among PD patients from 1990 to December 2021. Bayesian network meta-analysis was used to combine both direct and indirect trial evidence on treatment effectiveness, while the surface under the cumulative ranking (SUCRA) score was used to estimate the ranked probability of intervention effectiveness. RESULTS: Forty-six studies were included in the qualitative synthesis. Among, 36 studies (1454 patients) of 72 interventions or control conditions (12 classes) were included in the network meta-analysis, with a mean intervention period of 10.3 weeks. After adjusting for the moderating effect of baseline FOG severity, obstacle training [SMD -2.1; 95% credible interval (Crl): -3.3, -0.86], gait training with treadmill (SMD -1.2; 95% Crl: -2.0, -0.34), action observation training (SMD -1.0; 95% Crl: -1.9, -0.14), conventional physiotherapy (SMD -0.70; 95% Crl: -1.3, -0.12) and general exercise (SMD -0.64; 95% Crl: -1.2, -0.11) demonstrated significant improvement on immediate FOG severity compared to usual care. The SUCRA rankings suggest that obstacle training, gait training on treadmill and general exercises are most likely to reduce FOG severity. CONCLUSION: Obstacle training, gait training on treadmill, general exercises, action observation training and conventional physiotherapy demonstrated immediate real-life benefits on FOG symptoms among patients with mild-moderate PD. With the promising findings, the sustained effects of high complexity motor training combined with attentional/cognitive strategy should be further explored. Future trials with rigorous research designs using both subjective and objective outcome measures, long-term follow-up and cost-effective analysis are warranted to establish effective behavioral strategies for FOG management.

Studio coursework that focuses on real-world problems and stakeholder collaboration is an integral component of interdisciplinary design education. In the wake of the COVID-19 pandemic and increased interest in flexible models of content delivery, we conceptualize the studio course as central to interdisciplinary undergraduate education. Leveraging the pandemic as an opportunity, we argue that changes to studio coursework have created new modalities for design education. By focusing on adaptive, iterative studio coursework during each year of the undergraduate degree, we allow for hybridization of undergraduate design coursework. We present an example of the studio-centred model in action at a large polytechnic university in the United States. Our results may be beneficial to educators and practitioners interested in anchoring undergraduate curricula within interdisciplinary studio work, and for ensuring that interdisciplinary studios are able to respond to the twenty-first-century life skills essential for producing competitive graduates on the global market. We present studio-centred coursework as a model for hybridizing design education. We emphasize collaboration and discovery as key skills to develop in undergraduates. We develop this model through: (1) collaborating with industry partners to determine problem spaces and mentor students; (2) building interdisciplinary teams of students and faculty and (3) hybridizing lecture-based disciplinary coursework. We anchor our results with three years of programme assessment data. By integrating faculty, students and industry partners within the studio-centred model, this study demonstrates how hybridized design-led education can equip students for interdisciplinary collaboration as they progress towards their career goals. Furthermore, we provide discussion on how these competencies are evaluated by stakeholders as desirable skills. Students’ overall positive responses to the studio-centred coursework are captured in our quantitative data. Stakeholder responses come via focus groups held once per semester. Using studio coursework to centre design curricula allows for increased hybridization of the curriculum, as students use studio courses and capstones to apply knowledge, develop projects and attain professional mentorship. Emphasis on societal impact guides students to emphasize the broader impacts of their designs. Using quantitative and qualitative data, we provide a model that integrates research and education in undergrad curricula using a studio-centred model.

This chapter surveys the changes that have taken place in the science of astronomy over the last two centuries. It looks at the shifting views of astronomers themselves with regard to the scope of astronomy. It looks at the changing composition of the astronomical workforce and surveys the development of challenging new ideas about the nature and scope of the physical universe. It shows how increasingly large telescopes were used to map the heavens and state observatories were instituted. It shows how new techniques such as spectroscopy were deployed to investigate the composition of celestial bodies and how new ideas about the size and age of the universe were developed.

BackgroundOn a Friday evening in July 2021, Public Health Wales received notification of two cases of salmonella gastroenteritis. Both cases reported attending an Eid al-Adha celebration barbecue in a public park in Cardiff, UK two days earlier. Case finding over the weekend indicated further cases in those who had attended this event and an outbreak investigation was initiated.MethodsCases were defined as an individual with diarrhoea and/or vomiting with date of onset on the day of the barbecue, with an epidemiological link to the Eid-al Adha celebration meal. We undertook a cohort study in 36 people attending the barbecue and an associated lunchtime event, and a nested case-control study using Firth logistic regression. A communication campaign that was sensitive towards cultural practices was developed in collaboration with the community, community liaison staff and the Public Health Wales communications team.ResultsConsumption of a traditional raw liver dish, ‘marrara’, at the barbecue was the most likely vehicle for infection (Firth logistic regression, aOR: 49.99, 95%CI 1.71-1461.54, p=0.02). Meat came from two local butchers with the same supplier and food samples yielded identical whole genome sequences to those from cases. This outbreak highlights the need for appropriate food hygiene advice in communities preparing traditional dishes.ConclusionsThis outbreak identified a new vehicle of interest, a traditional raw offal dish. Future outbreak investigations, particularly where cultural events are associated with particular foods, should consider dishes beyond those on routine questionnaires to those which may be relevant to the community in question.

The rare-earth monopnictide (REM) family, which hosts magnetic ground states with extreme magnetoresistance, has established itself as a fruitful playground for the discovery of interesting topological phases. Here, by using high-resolution angle-resolved photoemission spectroscopy complemented by first-principles density functional-theory based modeling, we examine the evolution of the electronic structure of the candidate REM Dirac semimetal NdSb across the magnetic transition. A complex angel-wing-like band structure near the zone center and three arc-like features at the zone corner have been observed. This dramatic reconstruction of the itinerant bands around the zone center is shown to be driven by the magnetic transition: Specifically,, the Nd 5d electron band backfolds at the Gamma point and hybridizes with the Sb 5p hole bands in the antiferromagnetic phase. Our study indicates that antiferromagnetism plays an intricate role in the electronic structure of the REM family., Comment: 13 pages, 13 figures; Supplemental Materials included

Atomoxetine is mainly metabolized by CYP2D6 while CYP2C19 plays a secondary role. It is known that patients carrying genotypes encoding decreased/absent CYP2D6 metabolism obtain higher atomoxetine concentrations and are at increased risk of adverse effects. Here, we aimed to investigate the added effects of reduced-function CYP2C19 genotype on atomoxetine concentrations in real-world settings. Serum atomoxetine concentrations and CYP2D6/2C19 genotypes were included from a therapeutic drug monitoring service. Patients were first subgrouped according to CYP2D6 encoding normal, reduced or absent CYP2D6 metabolism, referred to as normal (NM), intermediate (IM) or poor metabolizers (PM). Then, the effect of reduced-function CYP2C19 genotypes was investigated. Genotyping of the CYP2D6 nonfuctional or reduced variant alleles comprised CYP2D6*3-*5, *9-*10 and *41. For CYP2C19, the CYP2C19*2 was analysed to define metabolizer phenotype. Dose-adjusted serum atomoxetine concentration was the exposure measure. Using a patient cohort (n=315), it was found that CYP2D6 IM and PM patients had 1.9-fold (95%CI: 1.4-2.7) and 9.6-fold (5.9-16) higher exposure of atomoxetine compared with CYP2D6 NMs. CYP2C19*2 carriers had 1.5-fold (1.1-2.2) higher atomoxetine exposure than non-carriers regardless of CYP2D6 genotype. CYP2D6 genotype has a great impact on atomoxetine exposure, where our real-world data suggest atomoxetine dose requirements to be around half and one-tenth in CYP2D6 IM and PM vs. NM patients, respectively. When adding CYP2C19 genotype as a factor of relevance for personalized atomoxetine dosing, CYP2C19*2 carriers should further reduce the dose by a third. These findings suggest that pre-emptive CYP2D6/CYP2C19 genotyping should be performed to individualize atomoxetine dosing and prevent adverse effects.

The farming Industry and rural locations are increasingly being targeted by predatory environmental criminals but as will be demonstrated there is also an insider element to environmental crimes. Such criminal activities pose an environmental challenge and require creative solutions. Indeed, the notion of the farmer as an environmental criminal is a contentious addition to the typology of rural criminals. Traditionally, environmental crime was an overlooked and under researched category of criminology, primarily because 'farmers' as a genre were treated with an elevated level of societal respect in line with their 'idyllic' portrayal. They do not fit accepted social constructs and stereotypes of the urban based criminal fraternity. Consequentially, we heard little of the stereotype of the 'bad' farmer. Recent years have seen a rise in public interest and concern relating to ethical aspects of farming leading to a raising of public awareness. Farmers are no longer immune from criticism, nor prosecution. Using documentary research methods this study reports on several high-profile cases at the nexus and reveals an updated typology of rural environmental crimes and criminals.

Objective: To investigate the effects of rehabilitation either before or after operation for lung cancer on postoperative pulmonary complications and the length of hospital stay. Data sources: MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, CINAHL Plus, SPORTDiscus, PsycInfo and Embase were searched from inception until June 2021. Review methods: Inclusion criteria were patients scheduled to undergo or had undergone operation for lung cancer, randomised controlled trials comparing rehabilitative interventions initiated before hospital discharge to usual care control. Two reviewers independently assessed eligibility, extracted data and risks of bias. Pooled odds ratios (ORs) or standardised mean differences (SMDs) with 95% Confidence Intervals (CI) were estimated using random-effects meta-analyses. Results: Twenty-three studies were included (12 preoperative, 10 postoperative and 1 perioperative), with 2068 participants. The pooled postoperative pulmonary complication risk and length of hospital stay were reduced after preoperative interventions (OR = 0.32; 95% CI = 0.22, 0.47; I2 = 0.0% and SMD = −1.68 days, 95% CI = −2.23, −1.13; I2 = 77.8%, respectively). Interventions delivered during the immediate postoperative period did not have any significant effects on either postoperative pulmonary complication or length of hospital stay (OR = 0.85; 95% CI = 0.56, 1.29; I2 = 0.0% and SMD = −0.23 days, 95% CI = −1.08, 0.63; I2 = 64.6%, respectively). Meta-regression showed an association between a higher number of supervised sessions and shorter hospital length of stay in preoperative studies (β = −0.17, 95% CI = −0.29, −0.05). Conclusion: Preoperative rehabilitation is effective in reducing postoperative pulmonary complications and length of hospital stay associated with lung cancer surgery. Short-term postoperative rehabilitation in inpatient settings is probably ineffective.

All clinicians are ethically obliged to prescribe responsibly and cautiously to diminish the potential for opioid diversion and to help minimize the growth of the current opioid abuse epidemic. Advance nurse practitioners should establish procedures to better control and limit opioid prescription and develop analgesic regimens to treat pain. The main purpose and goal for this review is to present data congruent with clinical, medical, and legal reports for allowing an appreciation of the possibility of the risk assumed when ordering and prescribing opioids within our podiatry profession. First, the concept and process of risk management as illustrated using a root cause analysis approach will be introduced as well as applying these principles specifically to opioid prescribing will be presented. Then, several examples found in both medical and legal literature documenting the reasons for opioid prescription risk will be presented. Finally, mitigating strategies for safe opioid prescribing will be presented so that mitigation of opioid harm can be possible and realized by the advance nurse practitioner

Objectives To examine the effects of qigong interventions on sleep disturbance-related symptom clusters for cancer patients and to explore the possible mediating role of fatigue and depression in affecting sleep. Methods In this systematic review and meta-analysis, a systematic search was conducted through October 2020 by searching multiple English and Chinese databases. Inclusion was limited to randomized controlled trials that measured the effect of qigong on sleep and fatigue/depressive symptoms in cancer patients. Eleven studies involving 907 cancer patients were included in the systematic review, whereas the meta-analysis included ten studies with 851 cancer patients. Results The most commonly investigated form of qigong was Taichi, and the intervention length ranged from 10 days to 6 months. All studies employed self-reported measurements. Overall, qigong significantly improved sleep (SMD = −1.28, 95% CI: −2.01, −0.55) and fatigue (SMD = −0.89, 95% CI: −1.59, −0.19) in cancer patients post-intervention, but not depressive symptoms (SMD = −0.69, 95% CI: −1.81, 0.42). Notably, the benefits on sleep and fatigue became non-significant after 3 months. Qigong's effect on sleep was significantly mediated by its effect on fatigue (β = 1.27, SE = 0.24, p = 0.002), but not depressive symptoms (β = 0.53, SE = 0.26, p = 0.106). Conclusions Qigong can be recommended for improving sleep disturbance-fatigue symptom clusters in the cancer population, while qigong's benefit on sleep is likely based on its effect on reducing fatigue. Future qigong studies should adopt more rigorous design and employ strategies to maintain longevity of intervention benefits.

Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.