bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRAF inhibitor resistance confers increased sensitivity to mitotic inhibitors
Authors: Misek SA , Dexheimer TS , Akram M , Conrad SE , Schmidt JC , Neubig RR , Gallo KA 
Published: April 2021

AbstractSingle agent and combination therapy with BRAFV600E/Kand MEK inhibitors have remarkable efficacy against melanoma tumors with activating BRAF mutations, but in most cases resistance eventually develops. The purpose of this study is to uncover pharmacological vulnerabilities of BRAFi-resistant melanoma cells, with the goal of identifying new therapeutic options for patients whose tumors have developed resistance to BRAFi/MEKi therapy. We screened a well-annotated compound library against a panel of isogenic pairs of parental and BRAFi-resistant melanoma cell lines to identify classes of compounds that selectively target BRAFi-resistant cells over their BRAFi-sensitive counterparts. Two distinct patterns of increased sensitivity to classes of pharmacological inhibitors emerged. In two cell line pairs, BRAFi resistance conferred increased sensitivity to compounds that share the property of cell cycle arrest at M-phase, including inhibitors of aurora kinase (AURK), polo-like kinase (PLK), tubulin, and kinesin. Live cell microscopy used to track mitosis in real time revealed that parental, but not BRAFi-resistant, melanoma cells were able to exit from compound-induced mitotic arrest through mitotic slippage, thus escaping death. Consistent with the key role of Cyclin B1 levels in regulating mitosis at the spindle checkpoint, in arrested cells we found higher Cyclin B1 levels in parental over BRAFi-resistant melanoma cells, suggesting that altered Cyclin B1 expression levels may explain why these BRAFi resistant cells have gained increased vulnerability to mitotic inhibitors. Another BRAFi-resistant cell line showed increased sensitivity to Chk1/2 inhibitors, possibly due to an accumulation of DNA damage, resulting in mitotic failure. This study shows that BRAFi-resistance in melanoma cells confers vulnerability to pharmacological disruption of mitosis and suggests a targeted synthetic lethal approach to treat BRAF-mutant melanomas that have become resistant to BRAF/MEK-directed therapies.
Microbiota depletion promotes human rotavirus replication in an adult mouse model
Authors: Gozalbo-Rovira Roberto , Santiso-Bellón Cristina , Buesa Javier , del Campo Antonio Rubio , Vila-Vicent Susana , Muñoz Carlos , Yebra María J. , Monedero Vicente , Rodríguez-Díaz Jesús 
Published: April 2021

SummaryThe study of human rotavirus (RV) infectivityin vivohas been limited by the lack of small animal models able to efficiently replicate the principal human RV genotypes. In recent years, intestinal microbiota-virus-host interaction has emerged as a key factor in mediating enteric virus pathogenicity. With the aim of developing an adult mouse infection model for RV we performed faecal microbiota transplant (FMT) with healthy infants as donors in antibiotic-treated mice. Contrarily to control mice, in the FMT group, but also in antibiotic-treated mice without FMT, challenge with the human RV G1P[8] genotype, Wa strain (RVwa), resulted in viral shedding in the faeces for 6 days. RV titres in faeces were also significantly higher in antibiotic-treated animals with or without FMT. This excluded the hypothesis that donor’s microbiota promoted infection. Antibiotic treatment followed by self-FMT resulted in incomplete re-establishment of mouse microbiota which partially restored suppression of RVwainfection. Microbial composition analysis revealed profound changes in the intestinal microbiota of antibiotic-treated animals, whereas some bacterial groups, including members ofLactobacillus, Bilophila, MucispirillumandOscillospira, reappeared after self-FMT. In antibiotic-treated and FMT animals, differences were observed in gene expression of immune mediators such as IL10, TNF-α and IFNγ and the fucosyltransferase FUT2, responsible for H-type antigen synthesis in the small intestine. Collectively, our results suggest that antibiotic-induced microbiota depletion eradicates the microbial taxa that restrict human RV infectivity in mice. Viral permissiveness could involve changes in the innate immune system at the small intestine and alterations in the bacteria population that potentially interact with RV, creating a favourable environment for human RV replication in mice.
Vigilance for carcinoid heart disease is still required in the era of somatostatin analogues: Lessons from a case series
Authors: Chan David L. , Pavlakis Nick , Crumbaker Megan , Lawrence Ben , Barber Camilla , Price Timothy J. , Michael Michael , Oberg Kjell 
Published: April 2021

AbstractAimCarcinoid heart disease (CHD) is a well‐documented complication of neuroendocrine tumors (NETs) due to secreted hormones causing fibrosis. Somatostatin analogues (SSAs) can decrease hormonal secretion and inhibit tumor growth. The reported incidence of CHD has decreased as SSA use has increased. We describe a series of patients who have developed CHD even though they were treated with SSA therapy.MethodsNine patients were seen in four centers in Australia and New Zealand. The average duration of follow‐up from diagnosis was 39 months.ResultsThree patients had Grade 1 and six Grade 2 disease by World Health Organization 2010 criteria. All patients had no CHD symptoms at baseline and started SSA therapy soon after diagnosis, yet developed significant, symptomatic cardiac dysfunction in their disease course. The median time from NET diagnosis to SSA initiation was 1 month, and median time from NET diagnosis to CHD diagnosis was 23 months (range 4–52). All patients who were tested had persistently increased hormonal levels (chromogranin A, urinary 5‐hydroxyindolacetic acid).ConclusionsThe good symptomatic control afforded by SSAs should not lead to reduced vigilance in screening for CHD, especially in patients with persistently elevated hormonal assays. Clinicians should consider regular echocardiographic screening in patients with a secretory syndrome.
Acute ketosis inhibits appetite and decreases plasma concentrations of acyl ghrelin in healthy young men
Authors: Vestergaard Esben Thyssen , Zubanovic Natasa Brkovic , Rittig Nikolaj , Møller Niels , Kuhre Rune Ehrenreich , Holst Jens J. , Rehfeld Jens F. , Thomsen Henrik Holm 
Published: April 2021

AbstractAimTo investigate the acute effect of ketone ester (KE) ingestion on appetite and plasma concentrations of acyl ghrelin (AG), unacylated ghrelin (UAG) and glucagon‐like peptide‐1 (GLP‐1) secretion, and to compare responses with those elicited by isocaloric glucose (GLU) administration.MethodsWe examined 10 healthy young men on three separate occasions using a placebo (PBO)‐controlled crossover design. A KE versus taste‐matched isovolumetric and isocaloric 50% GLU and taste‐matched isovolumetric PBO vehicle was orally administered. Our main outcome measures were plasma concentrations of AG, UAG, glucose‐dependent insulinotropic polypeptide (GIP) and GLP‐1 along with appetite sensation scores assessed by visual analogue scale.ResultsKE ingestion resulted in an average peak beta‐hydroxybutyrate concentration of 5.5 mM. AG and UAG were lowered by approximately 25% following both KE and GLU intake compared with PBO. In the case of AG, the differences were −52.1 (−79.4, –24.8) for KE and −48.4 (−75.4, −21.5) pg/mL for GLU intake (P < .01). Concentrations of AG remained lower with KE but returned to baseline and were comparable with PBO levels after GLU intake. GLP‐1, GIP, gastrin and cholecystokinin were not affected by KE ingestion.ConclusionOur results suggest that the suppressive effects on appetite sensation scores associated with hyperketonaemia are more probable to be mediated through reduced ghrelin concentrations than by increased activity of cholecystokinin, gastrin, GIP or GLP‐1.
Pressure ulcer prevention—Results of a multicentre cross‐sectional survey on hospital infrastructures and processes in acute hospitals and accident and emergency departments
Authors: Strube‐Lahmann Sandra , Lahmann Nils A. 
Published: April 2021

AbstractAims and objectivesPressure ulcers (PUs) are a serious health problem. They can be considered as an indicator of the quality of health care and are associated with considerable cost increases for the health care system. The prevention of PUs is a major concern in hospital care. The aim of the study was to reveal the current PU prevention‐related processes and structures with a specific focus on the Accident and Emergency (A&E) Department.MethodIn late 2018/early 2019, all German hospitals were invited to participate in a nationwide cross‐sectional survey. One standardized questionnaire was assigned to a representative of each hospital. The representative was asked to state what PU‐related structures and processes are implemented in their hospital, in general and specific to the A&E department. Besides mostly descriptive analysis, PU‐related processes were analysed on PU incidence in a multivariate linear regression model.ResultsTwo hundred seventy‐six hospitals participated in the survey. 63.4% (n = 175) of the participating hospitals had at least one PU manager. Skin inspection was the most frequently performed procedure. Although not recommended, 1.3% (2.1%) of the facilities still use sheepskins quite often (very often). In the regression model on PU incidence, only the process ‘mobilization in bed’ was statistically significantly associated. Although the risk of developing a PU in the emergency department is high, more than half of the facilities had no PU guidelines.ConclusionEven if recommended procedures (skin inspection, 30° positioning) have been used frequently, regular training could help to bring new scientific findings such as the use of local skin protection dressings into clinical practice. Prevention guidelines should be established in all areas of care even for A&E as well as when patients are transferred inside or out of the hospital, where the risk of PU development was considered low.
The use of interprofessional simulation interventions in medical student education: A scoping review
Authors: Langton Victoria , Dounas Dimitra , Moore Abby , Bacchi Stephen , Thomas Josephine 
Published: April 2021

Introduction: Simulation is commonly used by health and education institutions to facilitate interprofessional learning (IPL). The use of simulation in IPL is resource intensive. Evidence of what works, and with whom, is important to inform practice, policymaking and further research. The aim of this scoping review was to summarise the existing literature on IPL involving medical students, where simulation was the teaching modality. This review examined a variety of simulation-based interventions used to teach IPL to medical students and identified key features and outcomes. Methods: The databases Pubmed, Medline, EMBASE and PsychINFO were searched using the terms related to medical student and simulation combined with interprofessional. Included articles involved medical students alongside a student or practitioner from at least one other health profession taking part in at least one simulation session. Data extraction was performed by two authors using a standardised form. Results: It emerged that simulations of medical emergencies were the most common format to deliver IPL interventions. Most studies evaluated the success of their IPL intervention using the Readiness for Interprofessional Learning Scale (RIPLS). Conclusion: All studies were successful in improving student attitudes towards IPL and interprofessional collaboration when these were measured outcomes. Formal team training prior to simulation is effective in improving teamwork skills. IPL interventions with participants from a greater mix of professions have more positive results.
Development of national physical activity recommendations in 18 EU member states: a comparison of methodologies and the use of evidence
Authors: Tcymbal Antonina , Gelius Peter , Abu-Omar Karim , Foster Charlie , Whiting Stephen , Mendes Romeu , Titze Sylvia , Dorner Thomas Ernst , Halbwachs Christian , Duclos Martine , Toussaint Jean-Francois , Wendel-Vos Wanda , Baxter Beelin , Ferschl Susanne , Breda Joao Joaquim 
Published: April 2021

ObjectivesThe aim of the study is to compare how member states of the European Union (EU) develop their national physical activity (PA) recommendations and to provide an overview of the methodologies they apply in doing so. Information was collected directly from the physical activity focal points of EU member states in 2018. Five countries were chosen for detailed case study analysis of development processes.DesignCross-sectional survey.ParticipantsThe representatives of the 28 EU member state governments to the EU physical activity Focal Point Network.Outcome measuresFrom national documents we extracted data on (1) the participants of the development process, (2) the different methods used during development, and (3) on which sources national PA recommendations were based. An additional survey for case study countries provided details on (1) anonymised information on the participants of development process, (2) methods employed and rationale for choosing them, (3) development process and timeline, and (4) main source documents used for recommendation development.ResultsEighteen national documents on PA recommendations contained information about development process. The results showed that countries used different approaches to develop national recommendations. The main strategies were (1) adoption of WHO 2010 recommendations or (2) a combination of analysis and adoption of other national and international recommendations and literature review. All of the five case study countries relied on review processes rather than directly adopting WHO recommendations.ConclusionsWhile there are arguments for the use of particular strategies for PA recommendation development, there is currently no evidence for the general superiority of a specific approach. Instead, our findings highlight the broad spectrum of potential development methods, resources utilisation and final recommendations design currently available to national governments. These results may be a source of inspiration for other countries currently planning the development or update of national PA recommendations.
Frailty and driving status associated with disability: a 24-month follow-up longitudinal study
Authors: Doi Takehiko , Tsutsumimoto Kota , Ishii Hideaki , Nakakubo Sho , Kurita Satoshi , Shimada Hiroyuki 
Published: April 2021

ObjectivesTo examine the relationship of driving status and frailty with disability in older adults.DesignA prospective study.Setting and participantsThe study included 8533 participants (mean age: 72.0±6.1 years (range: 60–98 years), women: 54.1%) in a community setting.MeasuresDriving status and frailty were assessed at baseline. The clinical definition of frailty was used according to the Japanese Cardiovascular Health Study index. Disability was prospectively determined using a record of Japanese long-term care insurance (LTCI).ResultsDuring the follow-up period (mean duration: 23.5 months), 58 (0.7%) participants were regarded as moving out of the city, 80 (0.9%) participants had died and 311 (3.6%) participants were certified by LTCI. The proportion of disability was 1.3% among the not-frail group and 5.3% among the frail group. The proportion of disability was 2.5% in participants who were currently driving and 7.5% in those not driving. Based on frailty status and driving, participants were further classified into four groups: not frail and currently driving (n=2945), not frail and not driving (n=642), frail and currently driving (n=3598) and frail and not driving (n=1348). Compared with older adults who are not frail and driving, the combined status of frail and not driving (adjusted HR: 2.28; 95% CI: 1.47 to 3.52) and frail and driving (HR: 1.91; 95% CI: 1.30–2.81) were risk factors for disability.ConclusionsNot driving and frail were associated with a risk of disability in community-dwelling older adults.
Real-world effects of medications for stroke prevention in atrial fibrillation: protocol for a UK population-based non-interventional cohort study with validation against randomised trial results
Authors: Powell Emma Maud , Douglas Ian J , Gungabissoon Usha , Smeeth Liam , Wing Kevin 
Published: April 2021

IntroductionPatients with atrial fibrillation experience an irregular heart rate and have an increased risk of stroke; prophylactic treatment with anticoagulation medication reduces this risk. Direct-acting oral anticoagulants (DOACs) have been approved providing an alternative to vitamin K antagonists such as warfarin. There is interest from regulatory bodies on the effectiveness of medications in routine clinical practice; however, uncertainty remains regarding the suitability of non-interventional data for answering questions on drug effectiveness and on the most suitable methods to be used. In this study, we will use data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)—the pivotal trial for the DOAC apixaban—to validate non-interventional methods for assessing treatment effectiveness of anticoagulants. These methods could then be applied to analyse treatment effectiveness in people excluded from or under-represented in ARISTOTLE.Methods and analysisPatient characteristics from ARISTOTLE will be used to select a cohort of patients with similar baseline characteristics from two UK electronic health record (EHR) databases, Clinical Practice Research Datalink Gold and Aurum (between 1 January 2013 and 31 July 2019). Methods such as propensity score matching and coarsened exact matching will be explored in matching between EHR treatment groups to determine the optimal method of obtaining a balanced cohort.Absolute and relative risk of outcomes in the EHR trial-analogous cohort will be calculated and compared with the ARISTOTLE results; if results are deemed compatible the methods used for matching EHR treatment groups can then be used to examine drug effectiveness over a longer duration of exposure and in special patient groups of interest not studied in the trial.Ethics and disseminationThe study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency. Results will be disseminated in scientific publications and at relevant conferences.
Health insurance awareness and its uptake in India: a systematic review protocol
Authors: Reshmi Bhageerathy , Unnikrishnan Bhaskaran , Parsekar Shradha S , Rajwar Eti , Vijayamma Ratheebhai , Venkatesh Bhumika Tumkur 
Published: April 2021

IntroductionHealth insurance is one of the important approaches that can help in boosting universal healthcare coverage through improved healthcare utilisation and financial protection. This objectives of this review are to identify various interventions implemented in India to promote awareness of health insurance, and to provide evidence for the effectiveness of such interventions on the awareness and uptake of health insurance by the resident Indian population.Methods and analysisA systematic review will be carried out based on the Cochrane handbook for systematic reviews of interventions. The review will include experimental and analytical observational studies that have included adult population (>18 years) in India. We will include any intervention, policy or programme that directly or indirectly affects awareness or uptake of health insurance. The following outcomes will be eligible to be included: awareness or health insurance literacy, attitude such as readiness to buy health insurance or decision making, uptake of health insurance, demand-side and supply-side factors for awareness of health insurance, and awareness as a factor for uptake and re-enrolment in health insurance. Databases such as MEDLINE (PubMed), Web of Science, Scopus, 3ie impact evaluation repository and Social Science Research Network will be searched from January 2010 to 15 July 2020. Additionally, important government websites and references of the included studies will be scanned to identify potential records. Three authors, independently, will carry out screening and data extraction. Studies will be categorised into quantitative and qualitative, and mixed-methods synthesis will be employed to analyse the findings.Ethics and disseminationThis review will be based on published studies and will not recruit human participants directly, therefore, ethical clearance is not applicable. We will disseminate the final review findings in a national or international conference and publish in a peer-reviewed journal.
Prehospital stratification in acute chest pain patient into high risk and low risk by emergency medical service: a prospective cohort study
Authors: Wibring Kristoffer , Lingman Markus , Herlitz Johan , Amin Sinan , Bång Angela 
Published: April 2021

ObjectivesTo describe contemporary characteristics and diagnoses in prehospital patients with chest pain and to identify factors suitable for the early recognition of high-risk and low-risk conditions.DesignProspective observational cohort study.SettingTwo centre study in a Swedish county emergency medical services (EMS) organisation.ParticipantsUnselected inclusion of 2917 patients with chest pain contacting the EMS due to chest pain during 2018.Primary outcome measuresLow-risk or high-risk condition, that is, occurrence of time-sensitive diagnosis on hospital discharge.ResultsOf included EMS missions, 68% concerned patients with a low-risk condition without medical need of acute hospital treatment in hindsight. Sixteen per cent concerned patients with a high-risk condition in need of rapid transport to hospital care. Numerous variables with significant association with low-risk or high-risk conditions were found. In total high-risk and low-risk prediction models shared six predictive variables of which ST-depression on ECG and age were most important. Previously known risk factors such as history of acute coronary syndrome, diabetes and hypertension had no predictive value in the multivariate analyses. Some aspects of the symptoms such as pain intensity, pain in the right arm and paleness did on the other hand appear to be helpful. The area under the curve (AUC) for prediction of low-risk candidates was 0.786 and for high-risk candidates 0.796. The addition of troponin in a subset increased the AUC to >0.8 for both.ConclusionsA majority of patients with chest pain cared for by the EMS suffer from a low-risk condition and have no prognostic reason for acute hospital care given their diagnosis on hospital discharge. A smaller proportion has a high-risk condition and is in need of prompt specialist care. Building models with good accuracy for prehospital identification of these groups is possible. The use of risk stratification models could make a more personalised care possible with increased patient safety.