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Question Answering (QA), the process of computing valid answers to questions formulated in natural language, has recently gained attention in both industry and academia. Translating this idea to the realm of geographic information systems (GIS) may open new opportunities for data scientists. In theory, analysts may simply ask spatial questions to exploit diverse geographic information resources, without a need to know how GIS tools and geodata sets interoperate. In this outlook article, we investigate the scientific challenges of geo-analytical question answering, introducing the problems of unknown answers and indirect QA. Furthermore, we argue why core concepts of spatial information play an important role in addressing this challenge, enabling us to describe analytic potentials, and to compose spatial questions and workflows for generating answers.

Aims: Local anaesthetics, which act as neurolytics and Na+ channel blockers, have been used for disrupting the neural firings in certain neuropathic pain conditions. This study was undertaken to investigate the clinical outcome of trigeminal nerve block with 10% lidocaine in the management of trigeminal neuralgia (TN). Methods: Thirty-five patients with primary TN received trigeminal nerve blocks with 10% lidocaine. Success was defined as complete pain relief or mild pain without medication 1 day after the treatment. We followed the patients up every 2 months assessing for pain recurrence, sensory changes and other complications for a total of 37-45 months (median 43 months). Results: Twelve of the 35 patients (34.3%) responded favourably to the treatment and were considered as success. Eleven patients experienced complete pain relief and one could tolerate pain without medication 1 day after the blocks, which lasted for 3-172 weeks. Four patients experienced mildly decreased sensation in the region of the face supplied by the nerve 1 day after the blocks; however, all recovered normal skin sensation in 6 months. There was neither allodynia nor other sensory discomfort. The pain intensity and current pain duration before treatment were significantly different between the two groups. Conclusion: Trigeminal nerve block with high concentration lidocaine (10%) is capable of achieving an intermediate period of pain relief, particularly in patients with lower pain intensity and shorter pain duration prior to the procedure. [ABSTRACT FROM AUTHOR]

Cotesia ruficrus presents a promising local natural enemy for controlling the invasive fall armyworm Spodoptera frugiperda in China. However, the mechanisms underlying how C. ruficrus locates its target pest remain unclear. In this study, we analyzed the expression patterns of 18 CrufOBPs across different developmental stages of C. ruficrus, and found that CrufOBP1 exhibited consistent and high expression levels in female adults. CrufOBP1 transcript was predominantly localized in sensilla placodea and sensilla trichodea on the antennae. Additionally, we confirmed the binding properties of CrufOBP1 protein to various cuticular compounds of S. frugiperda larvae. Subsequent electroantennogram and behavioral assays revealed that 1-(2-hydroxy-5-methylphenyl)-ethanone attracted female C. ruficrus, consequently increased the parasitism rate. However, upon silencing CrufOBP1, females exhibited reduced attraction towards 1-(2-hydroxy-5-methylphenyl)-ethanone, indicating the crucial role of CrufOBP1 in the chemoreception of C. ruficrus. These findings shed light on the kairomone-based mechanism employed by C. ruficrus to locate S. frugiperda larvae and hold a promise for the development of environmentally friendly pest management strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: There is growing evidence within the healthcare sector that employee investigations can harm individuals involved in the process, an organization's culture and the delivery of its services., Methods: This paper details an intervention developed by an NHS Wales organization to reduce the number of its employee investigations through an organization-wide focus that promoted a 'last resort' approach and introduced the concept of 'avoidable employee harm'. A range of associated improvement initiatives were developed to support behavior change among those responsible for determining whether an employee investigation should be initiated., Results: Over a 13-month period, organizational records showed an annual reduction of 71% in investigation cases post-intervention, resulting in an estimated 3,308 sickness days averted annually and total estimated annual savings of £738,133 (based on direct savings and costs averted). This indicates that the organization has started to embrace the "last resort" approach to using employee investigations to address work place issues. The programme was supported with training for those responsible for commissioning and leading the organization's employee investigations. Analysis of survey data from those who attended training workshops to support the programme indicated that participants showed an increased awareness of the employee investigation process post-workshop and an understanding of the concept of avoidable employee harm., Discussion: The programme is congruent with the Healthy Healthcare concept, as the study illustrates how its practices and processes have a beneficial impact on staff, as well as potentially on patients. This study highlights wider issues for consideration, including the: (1) the role of Human Resources (HR), (2) taking a multi-disciplinary approach, (3) culture and practice, (4) the responsibility of the wider HR profession., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cooper, Teoh, Madine, Neal, Jones, Hussain, Behrens.)

Purpose: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy., Methods: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography., Findings: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study., Implications: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Chemosensory proteins (CSPs) constitute a class of olfactory proteins localized in insect sensory organs that serve a crucial function in decoding external chemical stimuli. This study aims to elucidate the involvement of CrufCSP3 in olfactory perception within the context of Cotesia ruficrus , an indigenous endoparasitoid targeting the invasive pest Spodoptera frugiperda . Through fluorescence-competitive binding assays and site-directed mutagenesis, we pinpointed four amino acids as pivotal residues involved in the interaction between CrufCSP3 and five host-related compounds. Subsequent RNA interference experiments targeting CrufCSP3 unveiled a reduced sensitivity to specific host-related compounds and a decline in the parasitism rate of the FAW larvae. These findings unequivocally indicate the essential role of CrufCSP3 in the chemoreception process of C. ruficrus . Consequently, our study not only sheds light on the functional importance of CSPs in parasitic wasp behavior but also contributes to the development of eco-friendly and efficacious wasp behavior modifiers for effectively mitigating pest population surges.

Early and accurate detection of viruses in children might help prevent transmission and severe diseases. In this study, the severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) detection in children was evaluated using saliva specimens with a Proteinase K (PTK)-based RNA preparation, as saliva collection is a simple and noninvasive procedure, even in young children, with fewer concerns about sample contamination. The saliva-based PTK and the conventional paired nasopharyngeal aspiration (NPA)-based detection methods were compared between COVID-19-positive and -negative children. In addition, the detection rate for SARS-COV-2 and the difference between admission and discharge by the saliva-based PTK method was tested in COVID-19 patients. The diagnostic accuracy of the saliva-based PTK method was 98.8% compared to NP swab-based reverse transcriptase polymerase chain reaction. Saliva samples showed high sensitivity (94.1%) and specificity (100%) when using the PTK method. Furthermore, the saliva-based PTK method significantly reduced the test processing time by 2 h. Notably, C t values at discharge increased in saliva samples compared with those at admission, which might indicate patients' clinical conditions or virus activity. In conclusion, the saliva-based PTK implemented in this study streamlines RNA extraction, making the process faster, safer, and more cost-effective, demonstrating that this method is a rapid and reliable diagnostic tool for SARS-CoV-2 detection in children., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Evidence attests a link between junior doctors' working conditions and psychological distress. Despite increasing concerns around suicidality among junior doctors, little is known about its relationship to their working conditions., Aims: To (a) establish the prevalence of suicidal ideation among junior doctors in the National Health Service; (b) examine the relationships between perceived working conditions and suicidal ideation; and (c) explore whether psychological distress (e.g. symptoms of depression and anxiety) mediates these relationships., Method: Junior doctors were recruited between March 2020 and January 2021, for a cross-sectional online survey. We used the Health and Safety Executive's Management Standards Tool; Depression, Anxiety and Stress Scale 21; and Paykel Suicidality Scale to assess working conditions, psychological distress and suicidality, respectively., Results: Of the 424 participants, 50.2% reported suicidal ideation, including 6.1% who had made an attempt on their own life. Participants who identified as LGBTQ+ (odds ratio 2.18, 95% CI 1.15-4.12) or reported depression symptoms (odds ratio 1.10, 95% CI 1.07-1.14) were more likely to report suicidal ideation. No direct relationships were reported between working conditions (i.e. control, support, role clarity, strained relationships, demand and change) and suicidal ideation. However, depression symptoms mediated all six relationships., Conclusions: This sample of junior doctors reported alarming levels of suicidal ideation. There may be an indirect relationship between working conditions and suicidal ideation via depressive symptoms. Clearer research exploring the experience of suicidality in junior doctors is needed, including those who identify as LGBTQ+. Systematic interventions addressing working environment are needed to support junior doctors' mental health.

Chemosensory proteins (CSPs) are a class of soluble proteins that facilitate the recognition of chemical signals in insects. While CSP genes have been identified in many insect species, studies investigating their function remain limited. Cotesia ruficrus (Hymenoptera: Braconidae) holds promise as an indigenous biological control agent for managing the invasive pest Spodoptera frugiperda (Lepidoptera: Noctuidae) in China. This study aimed to shed light on the gene expression, ligand binding, and molecular docking of CrufCSP1 in C. ruficrus . A RT-qPCR analysis revealed that the expression of CrufCSP1 was higher in the wings, with male adults exhibiting significantly higher relative expression levels than other developmental stages. A fluorescence competitive binding analysis further demonstrated that CrufCSP1 has a high binding ability with several host-related volatiles, with trans -2-hexenal, octanal, and benzaldehyde showing the strongest affinity to CrufCSP1. A molecular docking analysis indicated that specific amino acid residues (Phe24, Asp25, Thr53, and Lys81) of CrufCSP1 can bind to these specific ligands. Together, these findings suggest that CrufCSP1 may play a crucial role in the process of C. ruficrus locating hosts. This knowledge can contribute to the development of more efficient and eco-friendly strategies for protecting crops and managing pests.

The authors performed this study to investigate the efficacy and safety of a rosuvastatin (RSV)/amlodipine (AML) polypill compared with those of atorvastatin (ATV)/AML polypill. We included 259 patients from 21 institutions in Korea. Patients were randomly assigned to 1 of 3 treatment groups: RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, or ATV 20 mg /AML 5 mg. The primary endpoint was the efficacy of the RSV 10.20 mg/AML 5 mg via percentage changes in LDL-C after 8 weeks of treatment, compared with the ATV 20 mg /AML 5 mg. There was a significant difference in the mean percentage change of LDL-C at 8 weeks between the RSV 10 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (full analysis set [FAS]: -7.08%, 95% CI: -11.79 to -2.38, p = .0034, per-protocol analysis set [PPS]: -6.97%, 95% CI: -11.76 to -2.19, p = .0046). Also, there was a significant difference in the mean percentage change of LDL-C at 8 weeks between the RSV 20 mg/AML 5 mg and the ATV 20 mg/AML 5 mg (FAS: -10.13%, 95% CI: -15.41 to -4.84, p = .0002, PPS: -10.96%, 95% CI: -15.98 to -5.93, p < .0001). There was no significant difference in the adverse events rates between RSV 10 mg/AML 5 mg, RSV 20 mg/AML 5 mg, and ATV 20 mg/AML 5 mg. In conclusion, while maintaining safety, RSV 10 mg/AML 5 mg and the RSV 20 mg/AML 5 mg more effectively reduced LDL-C compared with the ATV 20 mg /AML 5 mg (Clinical trial: NCT03951207)., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

The gasdermins are a family of pore-forming proteins that has recently been suggested to play a central role in pyroptosis. In this study, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell-derived exosomes. In apoptotic human HeLa and HEK293 cells, GSDMA, GSDMC, GSDMD, and GSDME increased the release of apoptotic exosomes. GSDMB and DFNB59, in contrast, negatively affected the release of apoptotic exosomes. GSDME at its full-length and cleaved forms was localized in the exosomes and exosomal membrane. Full-length and cleaved forms of GSDME are suggested to increase Ca2+ influx to the cytosol through endosomal pores and thus increase the biogenesis of apoptotic exosomes. In addition, the GSDME-mediated biogenesis of apoptotic exosomes depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins, that is, annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of apoptotic exosomes begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that GSDME-bearing tumors released apoptotic exosomes to induce inflammatory responses in the in vivo mouse 4T1 orthotropic model of BALB/c breast cancer. The data indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Background: This study evaluated the association of body mass index (BMI) with adverse clinical outcomes during chronic maintenance antiplatelet monotherapy after percutaneous coronary intervention (PCI) with drug-eluting stents (DES)., Methods and results: Overall, 5,112 patients were stratified (in kg/m 2 ) into underweight (BMI ≤18.4), normal weight (18.5-22.9), overweight (23.0-24.9), obesity (25.0-29.9) and severe obesity (≥30.0) categories with randomized antiplatelet monotherapy of aspirin 100 mg or clopidogrel 75 mg once daily for 24 months. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome and major bleeding of Bleeding Academic Research Consortium type ≥3. Compared with normal weight, the risk of primary composite outcomes was higher in the underweight (hazard ratio [HR] 2.183 [1.199-3.974]), but lower in the obesity (HR 0.730 [0.558-0.954]) and severe obesity (HR 0.518 [0.278-0.966]) categories, which is partly driven by the difference in all-cause death. The risk of major bleeding was significantly higher in the underweight (HR 4.140 [1.704-10.059]) than in the normal weight category. A decrease in categorical BMI was independently associated with the increased risk of primary composite outcomes., Conclusions: Lower BMI is associated with a higher risk of primary composite outcomes, which is primarily related to the events of all-cause death or major bleeding during chronic maintenance antiplatelet monotherapy after PCI with DES.

Background: Patients with coronary artery disease and impaired renal function are at higher risk for both bleeding and ischemic adverse events after percutaneous coronary intervention (PCI)., Objectives: This study assessed the efficacy and safety of a prasugrel-based de-escalation strategy in patients with impaired renal function., Methods: We conducted a post hoc analysis of the HOST-REDUCE-POLYTECH-ACS study. Patients with available estimated glomerular filtration rate (eGFR) (n = 2,311) were categorized into 3 groups. (high eGFR: >90 mL/min; intermediate eGFR: 60 to 90 mL/min; and low eGFR: <60 mL/min). The end points were bleeding outcomes (Bleeding Academic Research Consortium type 2 or higher), ischemic outcomes (cardiovascular death, myocardial infarction, stent thrombosis, repeated revascularization, and ischemic stroke), and net adverse clinical event (including any clinical event) at 1-year follow-up., Results: Prasugrel de-escalation was beneficial regardless of baseline renal function ( P for interaction = 0.508). The relative reduction in bleeding risk from prasugrel de-escalation was higher in the low eGFR group than in both the intermediate and high eGFR groups (relative reductions, respectively: 64% (HR: 0.36; 95% CI: 0.15-0.83) vs 50% (HR: 0.50; 95% CI: 0.28-0.90) and 52% (HR: 0.48; 95% CI: 0.21-1.13) ( P for interaction = 0.646). Ischemic risk from prasgurel de-escalation was not significant in all eGFR groups (HR: 1.18 [95% CI: 0.47-2.98], HR: 0.95 [95% CI: 0.53-1.69], and HR: 0.61 [95% CI: 0.26-1.39]) ( P for interaction = 0.119)., Conclusions: In patients with acute coronary syndrome receiving PCI, prasugrel dose de-escalation was beneficial regardless of the baseline renal function., Competing Interests: This post hoc analysis was supported by research grants from the GENESIS registry (research ID: 620102880) and from Seoul National University Hospital (research ID: 03-2021-0030). Dr Kyung Woo Park has received speaker fees from Daiichi Sankyo, Sanofi, Bristol Myers Squibb, Bayer, Pfizer, InnoN Pharmaceutical, DaeWoong Pharmaceutical, and JW Pharmaceutical outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Doctors, including junior doctors, are vulnerable to greater levels of distress and mental health difficulties than the public. This is exacerbated by their working conditions and cultures. While this vulnerability has been known for many years, little action has been taken to protect and support junior doctors working in the NHS. As such, we present a series of recommendations from the perspective of junior doctors and other relevant stakeholders, designed to improve junior doctors' working conditions and, thus, their mental health., Methods: We interviewed 36 junior doctors, asking them for recommendations for improving their working conditions and culture. Additionally, we held an online stakeholder meeting with a variety of healthcare professionals (including junior doctors), undergraduate medical school leads, postgraduate speciality school leads and NHS policymakers where we asked what could be done to improve junior doctors' working conditions. We combined interview data with notes from the stakeholder discussions to produce this set of recommendations., Results: Junior doctor participants and stakeholders made organisational and interpersonal recommendations. Organisational recommendations include the need for more environmental, staff and educational resources as well as changes to rotas. Interpersonal recommendations include changes to communication and recommendations for better support and teamwork., Conclusion: We suggest that NHS policymakers, employers and managers consider and hopefully implement the recommendations set out by the study participants and stakeholders as reported in this paper and that the gold standards of practice which are reported here (such as examples of positive learning environments and supportive supervision) are showcased so that others can learn from them., (© 2022. The Author(s).)

Purpose: Pitavastatin is a unique lipophilic statin with moderate efficacy in lowering LDL-C levels by 30% to 50% with a tolerable safety profile. However, the efficacy of adding ezetimibe to pitavastatin in patients with dyslipidemia has not been well investigated. Therefore, the objective of this double-blind, multicenter, randomized, Phase III study was to compare the efficacy and safety of pitavastatin and ezetimibe combination therapy with those of pitavastatin monotherapy in Korean patients with primary hypercholesterolemia., Methods: Korean men and women aged >19 and <80 years with primary hypercholesterolemia requiring medical treatment were included in this study. During the 8-week screening period, all patients were instructed to make therapeutic lifestyle changes. The screening period consisted of a 4-week washout period and a placebo run-in period (4-8 weeks). During treatment period I, patients were randomly assigned to receive 1 of 4 treatments: pitavastatin 2 mg plus ezetimibe 10 mg, pitavastatin 2 mg, pitavastatin 4 mg plus ezetimibe 10 mg, or pitavastatin 4 mg. The 8-week double-blind treatment period then commenced. Adverse events (AEs), clinical laboratory data, and vital signs were assessed in all patients., Findings: The percentages in LDL-C from baseline after 8 weeks of double-blind treatment decreased significantly in the pooled pitavastatin/ezetimibe (-52.8% [11.2%]) and pooled pitavastatin (-37.1% [14.1%]) groups. Treatment with pitavastatin/ezetimibe resulted in a significantly greater LDL-C-lowering effect than that with pitavastatin (difference, -15.8 mg/dL; 95% CI, -18.7 to -12.9; P < 0.001). The precentages of achieving LDL-C goal in pooled pitavastatin/ezetimibe and pooled pitavastatin groups were 94.2% and 69.1%, respectively (P < 0.001). There were no significant differences in the incidence of overall AEs and adverse drug reactions. Serious AEs were comparable between the groups., Implications: Pitavastatin and ezetimibe combinations effectively and safely decreased LDL-C levels by >50% in patients with dyslipidemia. The safety and tolerability of pitavastatin and ezetimibe combination therapy were comparable with those of pitavastatin monotherapy., Clinicaltrials: gov identifier: NCT04584736., Competing Interests: Declaration of Interest The authors have indicated that they have no conflicts of interest regarding the content of this article. The sponsor supplied the investigational products and funded the laboratory tests and clinical research coordinator expenses. The funding source had no involvement in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication., (Copyright © 2022. Published by Elsevier Inc.)

The COVID-19 pandemic has had a deep impact on people worldwide since late 2019 when SARS-CoV-2 was first identified in Wuhan, China. In addition to its effect on public health, it has affected humans in various aspects of life, including social, economic, cultural, and political. It is also true that researchers have made vigorous efforts to overcome COVID-19 throughout the world, but they still have a long way to go. Accordingly, innumerable therapeutics and vaccine candidates have been studied for their efficacies and have been tried clinically in a very short span of time. For example, the versatility of extracellular vesicles, which are membrane-bound particles released from all types of cells, have recently been highlighted in terms of their effectiveness, biocompatibility, and safety in the fight against COVID-19. Thus, here, we tried to explain the use of extracellular vesicles as therapeutics and for the development of vaccines against COVID-19. Along with the mechanisms and a comprehensive background of their application in trapping the coronavirus or controlling the cytokine storm, we also discuss the obstacles to the clinical use of extracellular vesicles and how these could be resolved in the future.

Aim: To use the Delphi technique to identify and prioritize recommendations for research and practice to improve the mental wellbeing of nurses and midwives in the United Kingdom (UK)., Background: Although there is evidence that self-reported mental wellbeing among nurses and midwives in the UK is poor, interventions have not adequately considered the wider context in which they work. The wide range of individual, organizational, occupational and wider sector-level factors that can influence wellbeing requires the involvement of different stakeholders to identify the most pressing actions required., Design: A three-round Delphi technique was conducted in 2019., Methods: In the first round, 16 subject matter experts generated, reviewed and discussed recommendations from a review of the research evidence with potential to support the mental wellbeing of nurses. A second group with 23 stakeholder representatives then rated and provided feedback on the developed recommendations through two additional rounds. Recommendations that received an 'essential' or 'important' rating from at least 80% of participants were retained and prioritized., Results: In total, 45 recommendations met the consensus agreement and were retained. More than half (57%) involved action at the organizational level, 27% to public policy and 13% to research. Only one recommendation is related to the individual. Collectively, these recommendations highlight the importance of taking direct action to tackle poor mental wellbeing among the workforce and initiating change at the policy and organizational level., Conclusion: Our findings emphasize the need to take a systemic approach to improving the mental health of nurses and midwives in the UK with input from different stakeholders. There is a clear consensus that action is needed at the organization and policy levels, rather than at the individual level as is current practice., Impact: This study provides a framework, alongside a set of practical recommendations, that provides a starting point for different stakeholders to understand, address and support the mental wellbeing of nurses and midwives. Although UK-focused, it has relevance to healthcare workforces internationally., (© 2022 John Wiley & Sons Ltd.)

Background and Objectives: De-escalation of dual-antiplatelet therapy through dose reduction of prasugrel improved net adverse clinical events (NACEs) after acute coronary syndrome (ACS), mainly through the reduction of bleeding without an increase in ischemic outcomes. Whether the benefits of de-escalation are sustained in highly thrombotic conditions such as ST-elevation myocardial infarction (STEMI) is unknown. We aimed to assess the efficacy and safety of de-escalation therapy in patients with STEMI or non-ST-segment elevation ACS (NSTE-ACS)., Methods: This is a pre-specified subgroup analysis of the HOST-REDUCE-POLYTECH-ACS trial. ACS patients were randomized to prasugrel de-escalation (5 mg daily) or conventional dose (10 mg daily) at 1-month post-percutaneous coronary intervention. The primary endpoint was a NACE, defined as a composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, clinically driven revascularization, stroke, and bleeding events of grade ≥2 Bleeding Academic Research Consortium (BARC) criteria at 1 year., Results: Among 2,338 patients included in the randomization, 326 patients were diagnosed with STEMI. In patients with NSTE-ACS, the risk of the primary endpoint was significantly reduced with de-escalation (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.48-0.89; p=0.006 for de-escalation vs. conventional), mainly driven by a reduced bleeding. However, in those with STEMI, there was no difference in the occurrence of the primary outcome (HR, 1.04; 95% CI, 0.48-2.26; p=0.915; p for interaction=0.271)., Conclusions: Prasugrel dose de-escalation reduced the rate of NACE and bleeding, without increasing the rate of ischemic events in NSTE-ACS patients but not in STEMI patients., Competing Interests: Dr. Hyo-Soo Kim has received research grants or speaker's fees from Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Dio, Medtronic, Abbott Vascular, Edwards Life Science, Amgen, and Behringer Ingelheim, outside of the submitted work. Dr. Kyung Woo Park reports speaker's fees from Daiichi Sankyo, AstraZeneca, Sanofi, Bristol-Myers Squibb, Bayer, and Pfizer, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022. The Korean Society of Cardiology.)

Public reporting is a way to promote quality of healthcare. However, evidence supporting improved quality of care using public reporting in patients with acute myocardial infarction (AMI) is disputed. This study aims to describe the impact of public reporting of AMI care on hospital quality improvement in Korea. Patients with AMI admitted to the emergency room with ICD-10 codes of I21.0 to I21.9 as the primary or secondary diagnosis were identified from the national health insurance claims data (2007-2012). Between 2007 and 2012, 43,240/83,378 (51.9%) patients manifested ST segment elevation myocardial infarction (STEMI). Timely reperfusion rate increased (β = 2.78, p = 0.001). The mortality rate of STEMI patients was not changed (β = -0.0098, p = 0.384) but that of NSTEMI patients decreased (β = -0.465, p = 0.001). Public reporting has a substantial impact on the process indicators of AMI in Korea because of the increased reperfusion rate. However, the outcome indicators such as mortality did not significantly change, suggesting that public reporting did not necessarily improve the quality of care.

Objectives: This paper reports findings exploring junior doctors' experiences of working during the COVID-19 pandemic in the UK., Design: Qualitative study using in-depth interviews with 15 junior doctors. Interviews were audio-recorded, transcribed, anonymised and imported into NVivo V.12 to facilitate data management. Data were analysed using reflexive thematic analysis., Setting: National Health Service (NHS) England., Participants: A purposive sample of 12 female and 3 male junior doctors who indicated severe depression and/or anxiety on the DASS-21 questionnaire or high suicidality on Paykel's measure were recruited. These doctors self-identified as having lived experience of distress due to their working conditions., Results: We report three major themes. First, the challenges of working during the COVID-19 pandemic, which were both personal and organisational. Personal challenges were characterised by helplessness and included the trauma of seeing many patients dying, fears about safety and being powerless to switch off. Work-related challenges revolved around change and uncertainty and included increasing workloads, decreasing staff numbers and negative impacts on relationships with colleagues and patients. The second theme was strategies for coping with the impact of COVID-19 on work, which were also both personal and organisational. Personal coping strategies, which appeared limited in their usefulness, were problem and emotion focused. Several participants appeared to have moved from coping towards learnt helplessness. Some organisations reacted to COVID-19 collaboratively and flexibly. Third, participants reported a positive impact of the COVID-19 pandemic on working practices, which included simplified new ways of working-such as consistent teams and longer rotations-as well as increased camaraderie and support., Conclusions: The trauma that junior doctors experienced while working during COVID-19 led to powerlessness and a reduction in the benefit of individual coping strategies. This may have resulted in feelings of resignation. We recommend that, postpandemic, junior doctors are assigned to consistent teams and offered ongoing support., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Changes in the dorsal cochlear nucleus (DCN) following exposure to noise play an important role in the development of tinnitus. As the development of several diseases is known to be associated with microRNAs (miRNAs/miRs), the aim of the present study was to identify the miRNAs that may be implicated in pathogenic changes in the DCN, resulting in tinnitus. A previously developed tinnitus animal model was used for this study. The study consisted of four stages, including identification of candidate miRNAs involved in tinnitus development using miRNA microarray analysis, validation of miRNA expression using reverse transcription‑quantitative PCR (RT‑qPCR), evaluation of the effects of candidate miRNA overexpression on tinnitus development through injection of a candidate miRNA mimic or mimic negative control, and target prediction of candidate miRNAs using mRNA microarray analysis and western blotting. The miRNA microarray and RT‑qPCR analyses revealed that miR‑375‑3p expression was significantly reduced in the tinnitus group compared with that in the non‑tinnitus group. Additionally, miR‑375‑3p overexpression via injection of miR‑375‑3p mimic reduced the proportion of animals with persistent tinnitus. Based on mRNA microarray and western blot analyses, connective tissue growth factor ( CTGF ) was identified as a potential target for miR‑375‑3p. Thus, it was inferred that CTGF downregulation by miR‑375‑3p may weaken with the decrease in miRNA expression, and the increased pro‑apoptotic activity of CTGF may result in more severe neuronal damage, contributing to tinnitus development. These findings are expected to contribute significantly to the development of a novel therapeutic approach to tinnitus, thereby bringing about a significant breakthrough in the treatment of this potentially debilitating condition.

Venous thromboembolism (VTE) is a potentially serious complication after total knee replacement (TKR), and recent guideline recommends thromboprophylaxis for VTE after TKR. The neutrophil-lymphocyte ratio (NLR) has emerged as a simple and new prognostic biomarker for several cardiovascular diseases. This study was performed to investigate the precise incidence of postoperative VTE and the role of NLR for predicting VTE in patients receiving thromboprophylaxis after TKR. We retrospectively enrolled 264 patients undergoing TKR who underwent routine screening enhanced pulmonary artery and lower extremity venography computed tomography (CT) scan within 7 postoperative days. Biochemical tests were performed within 2 weeks prior to surgery, and the NLR was defined as the absolute neutrophil count in peripheral blood divided by lymphocyte count. All patients received thromboprophylaxis with enoxaparin postoperatively. Of 264 patients, 102 (38.6%) were diagnosed with deep vein thrombosis (DVT) or pulmonary embolism on CT scan. Preoperative NLR was significantly higher in patients with postoperative VTE compared with that in patients without VTE (2.57 ± 1.59 vs. 2.11 ± 1.10, p  = 0.011). Receiver operating characteristic curve analysis showed that a preoperative NLR of 1.90 was the best cutoff value for the prediction of postoperative VTE (sensitivity 57.8%, specificity 55.6%, and area under curve 0.589). In the multivariate analysis, a preoperative NLR ≥1.90 was a sole independent predictor of postoperative VTE (odds ratio: 1.95, 95% computed tomography: 1.16-3.31, p  = 0.013). The present study shows a higher incidence of VTE (38.6%) after TKR in patients receiving thromboprophylaxis than that reported in previous studies. Furthermore, preoperative NLR was significantly higher in patients with postoperative VTE, and a high preoperative NLR (≥1.90) was an independent predictor of VTE after TKR. NLR measurement may be a simple and useful method for the prediction of VTE in patients undergoing TKR., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: Although the role of high-intensity lipid-lowering therapy in cardiovascular protection has broadened, concerns still exist about new-onset diabetes mellitus (NODM), especially in vulnerable patients. This study aimed to compare the effect of high-dose (4 mg/d) and usual dose (2 mg/d) pitavastatin on glucose metabolism in patients with hyperlipidemia and impaired fasting glucose (IFG)., Methods: In this 12-month study, glucose tolerance and lipid-lowering efficacy of high-dose pitavastatin (4 mg [study group]) was compared with that of usual dose pitavastatin (2 mg [control group]) in patients with hyperlipidemia and IFG. The primary end point was the change of glycosylated hemoglobin (HbA 1c ) after 24 weeks of treatment. The secondary end points were as follows: (1) NODM within 1 year after treatment, (2) change of lipid parameters, (3) changes of adiponectin, and (4) change of blood glucose and insulin levels., Findings: Of the total 417 patients screened, 313 patients with hypercholesterolemia and IFG were randomly assigned into groups. The mean (SD) change in HbA 1c was 0.06% (0.20%) in the study group and 0.03% (0.22%) in the control group (P = 0.27). Within 1 year, 27 patients (12.3%) developed NODM, including 12 (10.6%) of 113 patients in the study group and 15 (14.2%) of 106 in the control group (P = 0.43). The study group had a significantly higher reduction of total cholesterol and LDL-C levels and a higher increase in apolipoprotein A1/apolipoprotein B ratio (0.68 [0.40] vs 0.51 [0.35], P < 0.01)., Implications: The high-dose pitavastatin therapy did not aggravate glucose metabolism compared with the usual dose therapy. Moreover, it had a better effect on cholesterol-lowering and apolipoprotein distribution in the patients with hyperlipidemia and IFG., Competing Interests: DISCLOSURES The authors have indicated that they have no conflicts of interest regarding the content of this article., (Copyright © 2020. Published by Elsevier Inc.)

Background: There is limited data comparing the Xience everolimus-eluting stent (EES) and the Resolute zotarolimus-eluting stent (ZES) with the BioMatrix biolimus-eluting stent (BES)., Methods: This open-label, randomized, noninferiority trial enrolled all-comer patients to be randomly treated with either BES, EES, or ZES in a 1:1:1 ratio in 15 centers across South Korea. The primary end point was a device-oriented composite outcome consisting of cardiac death, target-vessel myocardial infarction, and clinically indicated target lesion revascularization at 24 months. The BES was compared with the EES and the ZES by intention-to-treat analyses with a noninferiority margin of 3.8%, respectively., Results: Because of slow recruitment and low event rates, this trial was prematurely terminated after enrollment of 1935 (75%) of the intended 2580 patients. Of the 1911 patients randomized to either EES (n=638), BES (n=634), or ZES (n =639), the rate of device-oriented composite outcome was 3.6%, 2.2%, and 3.9%, respectively, at 24 months (BES versus EES: absolute risk difference -1.4% [upper limit of 1-sided 95% CI: -3.2%]; P for noninferiority <0.001; BES versus ZES: absolute risk difference -1.7% [upper limit of 1-sided 95% CI: -3.6%]; P for noninferiority <0.001)., Conclusions: The BES was noninferior to either the EES or the ZES in all-comer patients for device-oriented composite outcome at the 24-month follow-up. However, caution is advised regarding interpretation of these results due to the premature termination of this study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01397175.

Stent designs with ultrathin struts may further increase the procedural success of challenging lesion subsets. The objective of this study was to assess the safety and efficacy of ultrathin strut, polymer-free sirolimus eluting stent (PF-SES) implantations in a large scale, unselected patient population.Adult patients underwent percutaneous coronary interventions (PCI) with a thin-strut PF-SES. Data from two all-comers observational studies having the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled. The accumulated target lesion revascularization (TLR) rate at 9-12 months was the primary endpoint. All dual antiplatelet therapy strategies according to the applicable guidelines were permissible.In total, 7243 patients were prospectively enrolled for PCI with PF-SES in stable coronary artery disease or acute coronary syndrome (ACS). Major risk factors in the overall cohort were diabetes (37.3%), ST elevation myocardial infarction (18.1%) and non-ST myocardial infarction (24.6%). The follow-up rate was 88.6% in the overall population. The TLR rate in the overall cohort was 2.2% whereas definite/probable stent thrombosis (ST) occurred in 0.7%. In patients with in-stent restenosis lesions, the major adverse cardiac events rate was 6.4% whereas the corresponding rate for isolated left main coronary artery (LMCA) disease was highest with 6.7% followed by patients with culprit lesions in vein bypasses (VB, 7.1%). The mortality rate in patients treated in VB lesions was highest with 5.4%, followed by the isolated LMCA subgroup (3.4%) and ACS (2.6%).PCI with PF-SES in an unselected patient population, is associated with low clinical event and ST rates. Furthermore, PF-SES angioplasty in niche indications demonstrated favorable safety and efficacy outcomes with high procedural success rates.

Background: The objective of this study was to assess regional and ethnic differences in an unselected patient population treated with polymer-free sirolimus-eluting stents (PF-SES) in Asia and Europe., Methods: Two all-comers observational studies based on the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were combined for data analysis to assure sufficient statistical power. The primary endpoint was the accumulated target lesion revascularization (TLR) rate at 9-12 months., Results: Of the total population of 7243 patients, 44.0% (3186) were recruited in the Mediterranean region and 32.0% (2317) in central Europe. The most prominent Asian region was South Korea (17.6%, 1274) followed by Malaysia (5.7%, 413). Major cardiovascular risk factors varied significantly across regions. The overall rates for accumulated TLR and MACE were low with 2.2% (140/6374) and 4.4% (279/6374), respectively. In ACS patients, there were no differences in terms of MACE, TLR, MI and accumulated mortality between the investigated regions. Moreover, dual antiplatelet therapy (DAPT) regimens were substantially longer in Asian countries even in patients with stable coronary artery disease as compared to those in Europe., Conclusions: PF-SES angioplasty is associated with low clinical event rates in all regions. Further reductions in clinical event rates seem to be associated with longer DAPT regimens., Competing Interests: All centers received a remuneration for each fully documented study patient. We report the following conflicts of interest: FK (lecturing fees B.Braun, Astra Zeneca), VK (consulting Medtronic, Abbott Vascular, Terumo) and MW/LW (full time employment at Medical Scientific Affairs, B.Braun Melsungen AG). All other authors have no other conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The optimal dose of beta blockers after acute myocardial infarction (MI) remains uncertain. We evaluated the effectiveness of low-dose nebivolol, a beta1 blocker and a vasodilator, in patients with acute MI. A total of 625 patients with acute MI from 14 teaching hospitals in Korea were divided into 2 groups according to the dose of nebivolol (nebistol®, Elyson Pharmaceutical Co., Ltd., Seoul, Korea): low-dose group (1.25 mg daily, n=219) and usual- to high-dose group (≥2.5 mg daily, n=406). The primary endpoints were major adverse cardiac and cerebrovascular events (MACCE, composite of death from any cause, non-fatal MI, stroke, repeat revascularization, rehospitalization for unstable angina or heart failure) at 12 months. After adjustment using inverse probability of treatment weighting, the rates of MACCE were not different between the low-dose and the usual- to high-dose groups (2.8% and 3.1%, respectively; hazard ratio: 0.92, 95% confidence interval: 0.38 to 2.24, p=0.860). The low-dose nebivolol group showed higher rates of MI than the usual- to high-dose group (1.2% and 0%, p=0.008). The 2 groups had similar rates of death from any cause (1.1% and 0.3%, p=0.273), stroke (0.4% and 1.1%, p=0.384), repeat PCI (1.2% and 0.8%, p=0.428), rehospitalization for unstable angina (1.2% and 1.0%, p=0.743) and for heart failure (0.6% and 0.7%, p=0.832). In patients with acute MI, the rates of MACCE for low-dose and usual- to high-dose nebivolol were not significantly different at 12-month follow-up., Competing Interests: CONFLICT OF INTEREST STATEMENT: None declared., (© Chonnam Medical Journal, 2020.)

Purpose: The goal of this study was to compare the lipid-lowering efficacy of the combination of ezetimibe and low- or intermediate-intensity statin therapy versus that of high-intensity statin monotherapy., Methods: This study is a post hoc analysis of an 8-week, randomized, double-blind, Phase III trial. Patients who had hypercholesterolemia and required lipid-lowering treatment were randomly assigned to 1 of 6 treatment groups: rosuvastatin 5 mg (R5, n = 68), rosuvastatin 10 mg (R10, n = 67), rosuvastatin 20 mg (R20, n = 69), and ezetimibe 10 mg combined with rosuvastatin 5 mg (R5 + E10, n = 67), rosuvastatin 10 mg (R10 + E10, n = 68), and rosuvastatin 20 mg (R20 + E10, n = 68) daily. The effects of coadministration of ezetimibe and a low dose of rosuvastatin on lipid parameters and the target achievement rate were compared between the R5 + E10 and R10 treatment groups, the R5 + E10 and R20 treatment groups, and the R10 + E10 and R20 treatment groups., Findings: Reductions in total cholesterol, LDL-C, apolipoprotein B, the apolipoprotein B/A1 ratio, and non-HDL-C were not different between the R5 + E10 and R10 treatment groups (all, P > 0.017), the R5 + E10 and R20 treatment groups (all, P > 0.017), and the R10 + E10 and R20 treatment groups (all, P > 0.017). R5 + E10 treatment showed efficacy comparable to that of R10 or R20 in affording LDL levels <50% of the baseline level (R5 + E10 vs R10, 73.13% vs 62.69% [P = 0.1952]; R5 + E10 vs R20, 73.13% vs 73.91% [P = 0.9180]), LDL-C levels <70 mg/dL (R5 + E10 vs R10, 64.18% vs 55.22% [P = 0.2906]; R5 + E10 vs R20, 64.18% vs 62.32% [P = 0.8220]), and LDL-C levels <50% of the baseline level or <70 mg/dL (R5 + E10 vs R10, 77.61% vs 70.15% [P = 0.3255]; R5 + E10 vs R20, 77.61% vs 78.26% [P = 0.9273]). The R10 + E10 treatment group was better than the R20 treatment group in achieving the target LDL-C level <70 mg/dL (83.82% vs 62.32%; P = 0.0046), even among participants with a baseline LDL-C level >135 mg/dL (77.5% vs 48.8%, respectively; P = 0.0074)., Implications: Ezetimibe combined with low- or intermediate-intensity statin therapy has lipid-lowering efficacy comparable to or better than that of high-intensity rosuvastatin monotherapy. The results of the present study indicate that the combination treatment with ezetimibe is advantageous in that it permits dose reduction of rosuvastatin without compromising the lipid-lowering efficacy of rosuvastatin. ClinicalTrials.gov identifier: NCT02205606., (Copyright © 2019. Published by Elsevier Inc.)

Background and Objectives: In this second report from Korean percutaneous coronary intervention (K-PCI) registry, we sought to describe the updated information of PCI practices and Korean practice pattern of PCI (KP3)., Methods: In addition to K-PCI registry of 2014, new cohort of 2016 from 92 participating centers was appended. Demographic and procedural information, as well as in-hospital outcomes, of PCI was collected using a web-based reporting system. KP3 class C was defined as any strategy with less evidence from randomized trials and more aggressive for PCI than medical therapy or bypass-surgery., Results: In 2016, total 48,823 PCI procedures were performed at 92 participating centers. Mean age of the patients was 65.7±11.6 years, and 71.7% were males. Overall patient characteristics and PCI practices in 2016 were similar to those in 2014. The biggest change was the decrease in the in-hospital occurrence of myocardial infarction (MI;1.6%→0.7%, p<0.001). Many associations between PCI volumes and demographic/procedural characteristics observed in 2014 have disappeared. The median of door-to-balloon time was 62 minutes, and 83.3% of ST-elevation MI patients received primary PCI within 90 minutes, while the median of total ischemic time was 168 minutes and patients who had total ischemic time within 120 and 180 minutes were 29.1% and 54.1%, respectively. The proportion of KP3 class C cases in non-acute coronary syndrome patients decreased from 13.5% in 2014 to 12.1% in 2016 (p<0.001)., Conclusions: In this second report from K-PCI registry, we described the current practices of PCI and changes from 2014 to 2016 in Korea., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2019. The Korean Society of Cardiology.)

Background: Recent studies suggest that obesity is a risk factor for Clostridium difficile infection, possibly due to disruptions in the intestinal microbiome composition. We hypothesized that body mass index (BMI) is associated with increased incidence of C. difficile infection in surgical patients., Methods: In this nationwide retrospective cohort study in 680 American College of Surgeons National Surgical Quality Improvement Program participating sites across the United States, the occurrence of C. difficile infection within 30 days postoperatively between different BMI groups was compared. All American College of Surgeons National Surgical Quality Improvement Program patients between 2015 and 2016 were classified as underweight, normal-weight, overweight, or obese class I-III if their BMI was less than 18.5, 18.5 to 25, 25 to 30, 30 to 35, 35 to 40 or greater than 40, respectively., Results: A total of 1,426,807 patients were included; median age was 58 years, 43.4% were male, and 82.9% were white. The postoperative incidence of C. difficile infection was 0.42% overall: 1.11%, 0.56%, 0.39%, 0.35%, 0.33% and 0.36% from the lowest to the highest BMI group, respectively (p < 0.001 for trend). In univariate then multivariable logistic regression analyses, adjusting for patient demographics (e.g., age, sex), comorbidities (e.g., diabetes, systemic sepsis, immunosuppression), preoperative laboratory values (e.g., albumin, white blood cell count), procedure complexity (work relative unit as a proxy) and procedure characteristics (e.g., emergency, type of surgery [general, vascular, other]), compared with patients with normal BMI, high BMI was inversely and incrementally correlated with the postoperative occurrence of C. difficile infection. The underweight were at increased risk (odds ratio, 1.15 [1.00-1.32]) while the class III obese were at the lowest risk (odds ratio, 0.73 [0.65-0.81])., Conclusion: In this nationwide retrospective cohort study, obesity is independently and in a stepwise fashion associated with a decreased risk of postoperative C. difficile infection. Further studies are warranted to explore the potential and unexpected association., Level of Evidence: Prognostic/Epidemiologic, Level IV.

In this study, we investigated the effects of cold challenge on adult hippocampal neurogenesis (AHN) and hippocampal gene expression and whether these are mediated by beigeing of peripheral fat tissues. Cold challenge (6 ± 2°C) for 1 and 4 weeks was found to induce beigeing effects in inguinal white adipose tissue based on hematoxylin and eosin staining as well as uncoupled protein-1 immunohistochemical staining. In the hippocampus, cold challenge for 1 or 4 weeks increased dentate gyrus neurogenesis and expression of genes related to AHN, including notch signaling, G protein-coupled receptor signaling, and adrenergic beta receptor-1. However, this enhancement of neurogenesis and gene expression by cold challenge was not shown by administration of CL 316,243, which induces peripheral beigeing similar to cold challenge but does not cross the blood-brain barrier. These results suggest that cold challenge promotes AHN and central expression of AHN-related, signaling, and β1-adrenergic receptors genes, and that peripheral beigeing by itself is not sufficient to mediate these effects. Considering the increase in AHN and gene expression changes, cold challenge may offer a novel approach to hippocampal modulation.

Introduction: Although the implementation of transradial intervention (TRI) has increased over the last few years, there are limited data on the impact of TRI on efficacy and safety in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). We sought to compare one-year clinical outcomes and bleeding complications of TRI with those of transfemoral intervention (TFI) in patients with NSTE-ACS., Methods: The Korean TRI registry was a cohort of 20 centres from 2012 to 2015. The primary efficacy endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiac death (CD), non-fatal myocardial infarction (MI) and repeat revascularisation (RR). Among the 1 319 patients with NSTE-ACS, 1 285 were finally analysed after excluding 34 due to lack of follow-up data. The patients were divided into TRI and TFI groups according to the final access site., Results: At one-year follow up, the TRI group showed a significantly lower rate of MACE, and a marginally significantly lower rate of CD than the TFI group in the crude population. However, in propensity-score matched analysis, the rate of MACE did not differ between the TRI and TFI groups. Regarding bleeding complications, the TRI group was associated with significantly lower rates of major bleeding in both the crude and matched populations. Independent predictors of MACE were chronic kidney disease (CKD) and multi-vessel disease (MVD)., Conclusions: In patients with NSTE-ACS, TRI was associated with favourable one-year clinical outcomes and lower bleeding complications compared to TFI. Independent predictors of MACE were clinical and angiographic profiles (CKD, MVD) rather than vascular access sites.

Zika virus (ZIKV), a mosquito-borne flavivirus that has recently emerged globally, poses a major threat to public health. To control this emerging disease, accurate diagnostics are required for monitoring current ZIKV outbreaks. Owing to the high nucleotide sequence similarity and cross-reactivity of ZIKV with other members of the Flaviviridae family, discrimination from other flavivirus infections is often difficult in endemic areas. ZIKV NS1 induces major virus-specific antibodies and is therefore utilized as a serological marker for ZIKV diagnosis. To identify ZIKV specific epitopes for clinical application, 33 NS1 peptides that are 15-30 amino acid in length covering whole NS1 were synthesized and analyzed linear B-cell epitopes with 38 human serum samples (20 ZIKV-positive and 18 ZIKV-negative). As a result of screening, eight epitope regions were identified. In particular, the Z8 and Z14 peptides located in the β-ladder surface region showed higher levels of binding activity in ZIKV-positive sera without cross-reactivity to other flaviviruses. These identified sensitive and specific epitopes provide a tool for design of diagnostics and structure-based vaccine antigens for ZIKV infection., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Modulation of RNA structure is essential in the life cycle of RNA viruses. Immediate replication upon infection requires RNA unwinding to ensure that RNA templates are not in intra- or intermolecular duplex forms. The calicivirus NS3, one of the highly conserved nonstructural (NS) proteins, has conserved motifs common to helicase superfamily 3 among six genogroups. However, its biological functions are not fully understood. In this study we report the oligomeric state and the nucleotide triphosphatase (NTPase) and RNA chaperone activities of the recombinant full-length NS3 derived from murine norovirus (MNV). The MNV NS3 has an Mg 2+ -dependent NTPase activity, and site-directed mutagenesis of the conserved NTPase motifs blocked enzyme activity and viral replication in cells. Further, the NS3 was found via fluorescence resonance energy transfer (FRET)-based assays to destabilize double-stranded RNA in the presence of Mg 2+ or Mn 2+ in an NTP-independent manner. However, the RNA destabilization activity was not affected by mutagenesis of the conserved motifs of NTPase. These results reveal that the MNV NS3 has an NTPase-independent RNA chaperone-like activity, and that a FRET-based RNA destabilization assay has the potential to identify new antiviral drugs targeting NS3.

Background: To determine whether the effectiveness and safety of fixed-dose combinations (FDCs) of amlodipine orotate/valsartan (AML/VAL) 5/160 mg are noninferior to those of valsartan/hydrochlorothiazide (VAL/HCTZ) 160/12.5 mg in hypertensive patients with inadequate response to valsartan 160 mg monotherapy., Methods: This 8-week, active-controlled, parallel-group, fixed-dose, multicenter, double-blind randomized controlled, and noninferiority trial was conducted at 17 cardiovascular centers in the Republic of Korea. Eligible patients had mean sitting diastolic blood pressure (msDBP) ≥90 mm Hg despite monotherapy with valsartan 160 mg for 4 weeks. Patients were randomly assigned to treatment with AML/VAL 5/160 mg FDC (AML/VAL) group or VAL/HCTZ 160/12.5 mg FDC (VAL/HCTZ) group once daily for 8 weeks. A total of 238 patients were enrolled (AML/VAL group, n = 121; VAL/HCTZ group, n = 117), of whom 228 completed the study., Results: At 8 weeks after randomization, msDBP was significantly decreased in both groups (-9.44 ± 0.69 mm Hg in the AML/VAL group and -7.47 ± 0.71 mm Hg in the VAL/HCTZ group, both P < .001 vs baseline). Between group difference was -1.96 ± 1.00 mm Hg, indicating that AML/VAL 5/160 mg FDC was not inferior to VAL/HCTZ 160/12.5 mg FDC at primary efficacy endpoint. Control rate of BP defined as the percentage of patients achieving mean sitting SBP (msSBP) <140 mm Hg or msDBP <90 mm Hg (target BP) from baseline to week 8 was significantly higher in the AML/VAL group than that in the VAL/HCTZ group (84.3% [n = 102] in the AML/VAL group vs 71.3% [n = 82] in the VAL/HCTZ group, P = .016). At 8 weeks after randomization, mean uric acid level was significantly increased in the VAL/HCTZ group compared to that at baseline (0.64 ± 0.08 mg/dL; P < .001). However, it was slightly decreased from baseline in the AML/VAL group (-0.12 ± 0.08 mg/dL; P = .085). The intergroup difference was significant (P < .001)., Conclusion: The effectiveness and safety AML/VAL 5/160 mg FDC are noninferior to those of VAL/HCTZ 160/12.5 mg FDC in patients with hypertension inadequately controlled by valsartan 160 mg monotherapy.

Purpose: Abnormalities in hemostasis and coagulation have been suggested in chronic renal failure (CRF). In this study, we compared processes of thrombus formation between rats with CRF and those with normal kidney function., Materials and Methods: CRF was induced by 5/6 ablation/infarction of the kidneys in Sprague-Dawley rats, and surviving rats after 4 weeks were used. Ferric chloride (FeCl₃)-induced thrombosis in the carotid artery was induced to assess thrombus formation. Whole blood clot formation was evaluated using rotational thromboelastometry (ROTEM). Platelet aggregation was assessed with impedance platelet aggregometry., Results: FeCl₃-induced thrombus formation was initiated faster in the CRF group than in the control group (13.2±1.1 sec vs. 17.8±1.0 sec, p=0.027). On histological examination, the maximal diameters of thrombi were larger in the CRF group than in the control group (394.2±201.1 μm vs. 114.0±145.1 μm, p=0.039). In extrinsic pathway ROTEM, the CRF group showed faster clot initiation (clotting time, 59.0±7.3 sec vs. 72.8±5.0 sec, p=0.032) and increased clot growth kinetics (α angle, 84.8±0.2° vs. 82.0±0.6°, p=0.008), compared to the control group. Maximal platelet aggregation rate was higher in the CRF group than in the control group (58.2±0.2% vs. 44.6±1.2%, p=0.006)., Conclusion: Our study demonstrated that thrombogenicity is increased in rats with CRF. An activated extrinsic coagulation pathway may play an important role in increasing thrombogenicity in CRF., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018.)

Norovirus (NoV) is a leading cause of epidemic acute non-bacterial gastroenteritis, and replicates through virion protein genome-linked (VPg)-primed or de novo RNA synthesis by RNA-dependent RNA polymerase (RdRp). VPg is a multifunctional protein that plays crucial roles in viral protein translation and genome replication. However, the interaction between the RdRp and this multifunctional VPg in NoV replication has been unknown. In this study, VPg derived from murine NoV (MNV) was found to mediate the formation of higher-order multimers or tubular fibrils of MNV RdRp, which led to significantly enhanced polymerase activity in vitro . The replication of MNV mutants containing a VPg-binding defective RdRp, based on the crystal structure of an RdRp-VPg(1-73) complex, was completely blocked in a cell culture system. Our data suggest that the interaction between RdRp and VPg plays a crucial role in the multimerization-mediated RdRp activity in vivo and consequently in MNV replication, which can provide a new target of therapeutic intervention for NoV outbreaks.

Background: The efficacy of a combination of a calcium channel blocker (CCB) plus chlorthalidone (diuretic) versus a CCB plus an angiotensin receptor blocker (ARB) in patients not responding to CCB monotherapy has not been evaluated previously. We plan to compare the efficacy and safety of S-amlodipine (CCB) plus chlorthalidone versus S-amlodipine plus telmisartan (ARB) combinations among hypertension patients unresponsive to amlodipine monotherapy., Methods/design: This study is a prospective, randomized, double-blind, multicenter, parallel, non-inferiority phase 4 study. Hypertension patients who have been treated with amlodipine (5 mg) or S-amlodipine (2.5 mg) monotherapy for ≥2 weeks and whose mean diastolic blood pressure (DBP) is greater than 90 mmHg will be randomized to either S-amlodipine (2.5 mg) plus chlorthalidone (25 mg) or S-amlodipine (2.5 mg) plus telmisartan (40 mg) therapy. The primary efficacy endpoint is mean sitting DBP change after 12 weeks of treatment. The study objective is to prove the non-inferiority of the former combination (test drug) as compared to the latter one (control) with a non-inferiority margin of 3 mmHg in mean DBP change. The secondary endpoints are 6-week DBP change, 6- and 12-week sitting systolic BP (SBP) change, and the attainment of the target BP (SBP < 140 mmHg or DBP < 90 mmHg). Urine albumin, albumin/creatinine ratio (ACR), pulse wave velocity, central BP, 24-h ambulatory BP monitoring, and body fluid composition analysis will be performed at each hospital's discretion. The sample size was estimated as 170 in total with 1:1 randomization., Discussion: This is the first study comparing the efficacy of a CCB plus chlorthalidone versus a CCB plus an ARB in patients who are not responding to CCB single therapy. The study result will help clinicians to choose between chlorthalidone and telmisartan in CCB-unresponsive patients., Trial Registration: ClinicalTrials.gov , NCT03226340. Registered on 2 December 2015.