Outcomes of Patients with Myeloid Malignancies and Cardiovascular Disease Undergoing Allogeneic Stem Cell Transplantation.

INTRODUCTION/BACKGROUND: Reduced-intensity conditioning (RIC) and non-myeloablative (NMA) regimens have enabled patients with cardiovascular disease (CVD) to undergo allogeneic stem cell transplantation (allo-HSCT). However, little is known about long-term outcomes, including cardiovascular (CV) complications. METHODS: We retrospectively studied 99 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who underwent allo-HSCT between September 1, 2013, and November 30, 2020. Overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), cumulative incidence of relapse and cumulative incidence of acute and chronic graft-versus host disease (GvHD) were compared in patients with and without CV risk factors or disease. RESULTS: Preexisting CVD was present in 34 of 99 patients (34%). CVD patients more commonly had reduced-intensity conditioning (91% vs 60%, p=0.001) and unrelated donors (56% vs 35%, p=0.04). Early adverse cardiac events occurred more frequently in the CVD vs. no-CVD group (38% vs 14%), particularly arrhythmias (21% vs 5%; p= 0.04). CVD patients tended to have poorer OS and PFS outcomes [HR=1.98, (1.00, 3.92); HR= 1.89, (0.96-3.72), respectively]. OS rate at 1, 2 and 3 years for CVD vs. no-CVD patients was 66% vs. 72%, 55% vs. 64%, and 46% vs. 62% respectively. Causes of death in the CVD and no-CVD groups were infections (53% vs 28%), relapsed disease (32% vs 52%), and CV events (10% vs 3%). CONCLUSION: Based on these data, predictive models to identify patients with CVD with higher risk of post-alloSCT complications and mortality and strategies to mitigate these risks should be developed. .

Artificial Intelligence Applications in Oral Cancer and Oral Dysplasia.

Oral squamous cell carcinoma (OSCC) is a highly unpredictable disease with devastating mortality rates that have not changed over the past decades, in the face of advancements in treatments and biomarkers, which have improved survival for other cancers. Delays in diagnosis are frequent, leading to more disfiguring treatments and poor outcomes for patients. The clinical challenge lies in identifying those patients at the highest risk of developing OSCC. Oral epithelial dysplasia (OED) is a precursor of OSCC with highly variable behavior across patients. There is no reliable clinical, pathological, histological, or molecular biomarker to determine individual risk in OED patients. Similarly, there are no robust biomarkers to predict treatment outcomes or mortality in OSCC patients. This review aims to highlight advancements in artificial intelligence (AI)-based methods to develop predictive biomarkers of OED transformation to OSCC or predictive biomarkers of OSCC mortality and treatment response. Biomarkers such as S100A7 demonstrate promising appraisal for the risk of malignant transformation of OED. Machine learning-enhanced multiplex immunohistochemistry workflows examine immune cell patterns and organization within the tumor immune microenvironment to generate outcome predictions in immunotherapy. Deep learning (DL) is an AI-based method using an extended neural network or related architecture with multiple "hidden" layers of simulated neurons to combine simple visual features into complex patterns. DL-based digital pathology is currently being developed to assess OED and OSCC outcomes. The integration of machine learning in epigenomics aims to examine the epigenetic modification of diseases and improve our ability to detect, classify, and predict outcomes associated with epigenetic marks. Collectively, these tools showcase promising advancements in discovery and technology, which may provide a potential solution to addressing the current limitations in predicting OED transformation and OSCC behavior, both of which are clinical challenges that must be addressed in order to improve OSCC survival.

Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease.

Incidence of both acute myeloid leukemia (AML) and cardiovascular disease (CVD) increases with age. We evaluated whether pre-existing CVD impacts clinical outcomes in AML. We retrospectively evaluated 291 consecutive adult AML patients treated at our institution, 2014-2020. Pretreatment comorbidities were identified by chart review. Outcomes included complete remission (CR) and CR with incomplete count recovery (CRi) rates, disease-free survival (DFS), overall survival (OS) and incidence of cardiovascular adverse events. CVD was present in 34% of patients at AML diagnosis. CVD patients had worse performance status (p=0.03) and more commonly had secondary AML (p=0.03) and received hypomethylating (HMA) agent-based therapy (72% vs 38%, p< 0.001). CVD (0.45 vs 0.71, p<0.001) and diabetes mellitus (HR= 0.24, 95% CI: 0.08 - 0.8, p= 0.01) were associated with lower probability of achieving CR/CRi. Accounting for age, performance status (PS), complex karyotype, secondary disease and treatment, CVD patients had shorter OS (HR=1.5, 95% CI: 1.1-2.2, p=0.002), with 1- and 3-year OS 44% vs 67% and 25% vs 40%, respectively, but there was no difference in cumulative incidence of relapse between patients with vs without CVD. Thus, CVD is an independent risk factor for lower response rate and shorter survival in AML patients.

Why Nonheme Iron Halogenases Do Not Fluorinate C-H Bonds: A Computational Investigation.

Selective halogenation is necessary for a range of fine chemical applications, including the development of therapeutic drugs. While synthetic processes to achieve C-H halogenation require harsh conditions, enzymes such as nonheme iron halogenases carry out some types of C-H halogenation, i.e., chlorination or bromination, with ease, while others, i.e., fluorination, have never been observed in natural or engineered nonheme iron enzymes. Using density functional theory and correlated wave function theory, we investigate the differences in structural and energetic preferences of the smaller fluoride and the larger chloride or bromide intermediates throughout the catalytic cycle. Although we find that the energetics of rate-limiting hydrogen atom transfer are not strongly impacted by fluoride substitution, the higher barriers observed during the radical rebound reaction for fluoride relative to chloride and bromide contribute to the difficulty of C-H fluorination. We also investigate the possibility of isomerization playing a role in differences in reaction selectivity, and our calculations reveal crucial differences in terms of isomer energetics of the key ferryl intermediate between fluoride and chloride/bromide intermediates. While formation of monodentate isomers believed to be involved in selective catalysis is shown for chloride and bromide intermediates, we find that formation of the fluoride monodentate intermediate is not possible in our calculations, which lack additional stabilizing interactions with the greater protein environment. Furthermore, the shorter Fe-F bonds are found to increase isomerization reaction barriers, suggesting that incorporation of residues that form a halogen bond with F and elongate Fe-F bonds could make selective C-H fluorination possible in nonheme iron halogenases. Our work highlights the differences between the fluoride and chloride/bromide intermediates and suggests potential steps toward engineering nonheme iron halogenases to enable selective C-H fluorination.

Pandemic-Induced Depression Among Older Adults with a History of Cancer During the COVID-19 Pandemic: Findings from the Canadian Longitudinal Study on Aging.

Purpose: The objectives of this study were to identify the prevalence of, and factors associated with, incident and recurrent depression in a sample of older adults with a history of cancer during the COVID-19 pandemic. Materials and Methods: Data were drawn from four waves of the Canadian Longitudinal Study on Aging Comprehensive Cohort (n=2486 with cancer). The outcome of interest was a positive screen for depression based on the CES-D-10 during the autumn of 2020. Results: Among older adults with cancer and no pre-pandemic history of depression (n=1765), 1 in 8 developed first onset depression during the pandemic. Among respondents with cancer and a history of depression (n=721), 1 in 2 experienced a recurrence of depression. The risk of both incident and recurrent depression was higher among those who were lonely, those with functional limitations, and those who experienced an increase in family conflict during the pandemic. The risk of incident depression only was higher among older women, those who did not engage in church or religious activities, those who experienced a loss of income during the pandemic, and those who became ill or had a loved one become ill or die during the pandemic. The risk of recurrent depression only was higher among those who felt isolated from others and those whose income did not satisfy their basic needs. Conclusion: Health care providers should continue to screen and provide mental health support to their cancer patients and those with a lifetime history of cancer, with consideration for those with the aforementioned vulnerabilities.

The SUPER reporting guideline suggested for reporting of surgical technique.

Background: Existing reporting guidelines pay insufficient attention to the detail and comprehensiveness reporting of surgical technique. The Surgical techniqUe rePorting chEcklist and standaRds (SUPER) aims to address this gap by defining reporting standards for surgical technique. The SUPER guideline intends to apply to articles that encompass surgical technique in any study design, surgical discipline, and stage of surgical innovation. Methods: Following the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network approach, 16 surgeons, journal editors, and methodologists reviewed existing reporting guidelines relating to surgical technique, reviewed papers from 15 top journals, and brainstormed to draft initial items for the SUPER. The initial items were revised through a three-round Delphi survey from 21 multidisciplinary Delphi panel experts from 13 countries and regions. The final SUPER items were formed after an online consensus meeting to resolve disagreements and a three-round wording refinement by all 16 SUPER working group members and five SUPER consultants. Results: The SUPER reporting guideline includes 22 items that are considered essential for good and informative surgical technique reporting. The items are divided into six sections: background, rationale, and objectives (items 1 to 5); preoperative preparations and requirements (items 6 to 9); surgical technique details (items 10 to 15); postoperative considerations and tasks (items 16 to 19); summary and prospect (items 20 and 21); and other information (item 22). Conclusions: The SUPER reporting guideline has the potential to guide detailed, comprehensive, and transparent surgical technique reporting for surgeons. It may also assist journal editors, peer reviewers, systematic reviewers, and guideline developers in the evaluation of surgical technique papers and help practitioners to better understand and reproduce surgical technique. Trial Registration: https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/#SUPER.

The SUPER reporting guideline suggested for reporting of surgical technique: explanation and elaboration.

Background: Surgical technique plays an essential role in achieving good health outcomes. However, the quality of surgical technique reporting remains heterogeneous. Reporting checklists could help authors to describe the surgical technique more transparently and effectively, as well as to assist reviewers and editors evaluate it more informatively, and promote readers to better understand the technique. We previously developed SUPER (surgical technique reporting checklist and standards) to assist authors in reporting their research that contains surgical technique more transparently. However, further explanation and elaboration of each item are needed for better understanding and reporting practice. Methods: We searched surgical literature in PubMed, Google Scholar and journal websites published up to January 2023 to find multidiscipline examples in various article types for each SUPER item. Results: We explain the 22 items of the SUPER and provide rationales item by item alongside. We provide 69 examples from 53 literature that present optimal reporting of the 22 items. Article types of examples include pure surgical technique, and case reports, observational studies and clinical trials that contain surgical technique. Examples are multidisciplinary, including general surgery, orthopaedical surgery, cardiac surgery, thoracic surgery, gastrointestinal surgery, neurological surgery, oncogenic surgery, and emergency surgery etc. Conclusions: Along with SUPER article, this explanation and elaboration file can promote deeper understanding on the SUPER items. We hope that the article could further guide surgeons and researchers in reporting, and assist editors and peer reviewers in reviewing manuscripts related to surgical technique.

In vivo CRISPR/Cas9 screening identifies Pbrm1 as a regulator of myeloid leukemia development in mice.

CRISPR/Cas9 screening approaches are powerful tool for identifying in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which the sequential acquisition of somatic mutations generates clonal diversity. Over time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We, first, modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs, followed by transplantation. We, then, performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of the polybromo BRG1/BRM-associated factor SWItch/Sucrose Non-Fermenting chromatin-remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with a significantly shortened latency. Pbrm1-deficient leukemia cells were less immunogenic and were characterized by attenuated interferon signaling and reduced major histocompatibility complex class II (MHC II) expression. We explored the potential relevance to human leukemia by assessing the involvement of PBRM1 in the control of interferon pathway components and found that PBRM1 binds to the promoters of a subset of these genes, most notably IRF1, which in turn regulates MHC II expression. Our findings revealed a novel role for Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening coupled with phenotypic readouts in vivo has helped identify a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.

Reasons for Initiation and Regular Use of Heated Tobacco Products among Current and Former Smokers in South Korea: Findings from the 2020 ITC Korea Survey.

South Korea is the world's second-largest heated tobacco product (HTP) market after Japan. HTP sales in South Korea have increased rapidly since May 2017, accounting for 10.6% of the total tobacco market in 2020. Despite this, little is known as to why HTP consumers who were current and former smokers started using HTPs and used them regularly. We analyzed cross-sectional data for 1815 adults (aged 19+) who participated in the 2020 International Tobacco Control (ITC) Korea Survey, of whom 1650 were HTP-cigarette consumers (those who reported smoking cigarettes and using HTPs ≥ weekly) and 165 were exclusive HTP consumers (using HTPs ≥ weekly) who were former or occasional smokers (smoking cigarette < weekly). Respondents were asked to report the reason(s) they used HTPs, with 25 possible reasons for HTP-cigarette consumers and 22 for exclusive HTP consumers. The most common reasons for initiating HTP use among all HTP consumers were out of curiosity (58.9%), family and friends use HTPs (45.5%), and they like the HTP technology (35.9%). The most common reasons for regularly using HTPs among all HTP consumers were that they were less smelly than cigarettes (71.3%), HTPs are less harmful to own health than cigarettes (48.6%), and stress reduction (47.4%). Overall, 35.4% of HTP-cigarette consumers reported using HTPs to quit smoking, 14.7% to reduce smoking but not to quit, and 49.7% for other reasons besides quitting or reducing smoking. In conclusion, several common reasons for initiating and regularly using HTPs were endorsed by all HTP consumers who were smoking, had quit smoking completely, or occasionally smoked. Notably, only about one-third of HTP-cigarette consumers said they were using HTPs to quit smoking, suggesting that most had no intention of using HTPs as an aid to quit smoking in South Korea.

Reporting guidelines for surgical technique could be improved: a scoping review and a call for action.

OBJECTIVES: To identify reporting guidelines related to surgical technique and propose recommendations for areas that require improvement. STUDY DESIGN AND SETTING: A protocol-guided scoping review was conducted. A literature search of MEDLINE, the EQUATOR Network Library, Google Scholar, and Networked Digital Library of Theses and Dissertations was conducted to identify surgical technique reporting guidelines published up to December 31, 2021. RESULTS: We finally included 55 surgical technique reporting guidelines, vascular surgery (n = 18, 32.7%) was the most common among the clinical specialties covered. The included guidelines generally showed a low degree of international and multidisciplinary cooperation. Few guidelines provided a detailed development process (n = 14, 25.5%), conducted a systematic literature review (n = 13, 23.6%), used the Delphi method (n = 4, 7.3%), or described post-publication strategy (n = 6, 10.9%). The vast majority guidelines focused on the reporting of intraoperative period (n = 50, 90.9%). However, of the guidelines requiring detailed descriptions of surgical technique methodology (n = 43, 78.2%), most failed to provide guidance on what constitutes an adequate description. CONCLUSION: Our study demonstrates significant deficiencies in the development methodology and practicality of reporting guidelines for surgical technique. A standardized reporting guideline that is developed rigorously and focuses on details of surgical technique may serve as a necessary impetus for change.

Predictors of Recurrent Venous Thrombosis After Cerebral Venous Thrombosis: Analysis of the ACTION-CVT Study.

BACKGROUND AND OBJECTIVE: Cerebral venous thrombosis (CVT) is a rare cause of stroke carrying a nearly 4% risk of recurrence after 1 year. There are limited data on predictors of recurrent venous thrombosis in patients with CVT. In this study, we aim to identify those predictors. METHODS: This is a secondary analysis of the ACTION-CVT study which is a multicenter international study of consecutive patients hospitalized with a diagnosis of CVT over a 6-year period. Patients with cancer-associated CVT, CVT during pregnancy, or CVT in the setting of known antiphospholipid antibody syndrome were excluded per the ACTION-CVT protocol. The study outcome was recurrent venous thrombosis defined as recurrent venous thromboembolism (VTE) or de novo CVT. We compared characteristics between patients with vs without recurrent venous thrombosis during follow-up and performed adjusted Cox regression analyses to determine important predictors of recurrent venous thrombosis. RESULTS: Nine hundred forty-seven patients were included with a mean age of 45.2 years, 63.9% were women, and 83.6% had at least 3 months of follow-up. During a median follow-up of 308 (interquartile range 120-700) days, there were 5.05 recurrent venous thromboses (37 VTE and 24 de novo CVT) per 100 patient-years. Predictors of recurrent venous thrombosis were Black race (adjusted hazard ratio [aHR] 2.13, 95% CI 1.14-3.98, p = 0.018), history of VTE (aHR 3.40, 95% CI 1.80-6.42, p < 0.001), and the presence of one or more positive antiphospholipid antibodies (aHR 3.85, 95% CI 1.97-7.50, p < 0.001). Sensitivity analyses including events only occurring on oral anticoagulation yielded similar findings. DISCUSSION: Black race, history of VTE, and the presence of one or more antiphospholipid antibodies are associated with recurrent venous thrombosis among patients with CVT. Future studies are needed to validate our findings to better understand mechanisms and treatment strategies in patients with CVT.

Changes in responses to nicotine vaping product warnings and leaflets in England compared with Canada, the US and Australia: findings from the 2016-2018 ITC Four Country Smoking and Vaping Surveys.

BACKGROUND AND AIMS: In May 2017, black-and-white text nicotine addiction warning labels ('warnings') and health and safety leaflets ('leaflets') became mandatory for nicotine vaping products (NVPs) in England, in accordance with the European Union's Tobacco Products Directive. We compared changes over time in noticing warnings and leaflets, recall of warnings about nicotine and concerns about using NVP due to noticing warnings in England, compared with Canada, the US and Australia, where no warnings and leaflets were mandated. DESIGN: 19 005 adult (aged 18+) NVP users, smokers and quitters of cigarettes and NVP from the 2016 and 2018 International Tobacco Control Four Country Smoking and Vaping Surveys in England, Canada, the US and Australia, recruited via probability and non-probability sampling. FINDINGS: Noticing warnings increased in England from 4.9% (2016) to 9.4% (2018) (adjusted OR/AOR=1.64, 95% CI=1.15-2.36); this change was larger than changes in Canada (AOR=2.51, 95% CI=1.71-3.69) and the US (AOR=2.22, 95% CI=1.45-3.39). Recall of a nicotine warning increased in England from 86% (2016) to 94.9% (2018) (AOR=5.50, 95% CI=1.57-19.27) but not significantly elsewhere. Noticing leaflets increased in England from 14.6% (2016) to 19.1% (2018) (AOR=1.42, 95% CI=1.15-1.74); this change was larger than in Canada (AOR=1.42, 95% CI=1.12-1.79), the US (AOR=1.55, 95% CI=1.17-2.06) and Australia (AOR=1.51, 95% CI=1.02-2.22). Among those noticing warnings, concern about NVP use did not change significantly between 2016 and 2018 (all countries p>0.081). CONCLUSIONS: Introduction of mandatory NVP warnings and leaflets in England was associated with small increases in noticing them but not with changes in concerns about NVP use.

Associations Between Noticing Nicotine Vaping Product Health Warning Labels, Harm Perceptions, and Use Among Adult Vapers, Current and Former Smokers. Findings From the 2018 ITC Four Country Smoking and Vaping Survey.

BACKGROUND: The number of countries mandating a nicotine addiction warning label ("warnings") on nicotine vaping products (NVPs) has been increasing. This study examined associations between noticing NVP warnings, perceptions of NVPs, and intentions to use NVPs. AIM AND METHODS: Cross-sectional analysis of 12 619 adult NVP users, cigarette smokers, concurrent users of both cigarettes and NVPs, and quitters who participated in the 2018 International Tobacco Control (ITC) Project Four Country Smoking and Vaping Survey (England, Australia, Canada, USA). Logistic regression analyses examined associations between noticing warnings in the past 30 days and perceptions of nicotine harm, NVP harm relative to cigarettes, and NVP addictiveness relative to cigarettes. Associations were also explored between noticing warnings and intentions to use NVPs. RESULTS: Noticing warnings was higher among NVP users (18.8%) than nonusers (2.1%). Noticing warnings was associated with perceiving nicotine to pose little or no harm to health among NVP users, but there was no association among nonusers. There was little evidence of an association between noticing warnings and perceptions of NVP harms relative to smoking among NVP users and non-users. Noticing warnings was associated with perceiving NVPs as less addictive than cigarettes among nonusers but not NVP users. Among exclusive smokers, noticing warnings was associated with intending to start using NVPs. Among NVP users, there was little evidence of an association between noticing warnings and intentions to continue using/stopping NVPs. CONCLUSIONS: Noticing NVP warnings was not associated with increased NVP and nicotine harm perceptions or decreased intentions to use NVPs among adult smokers and vapers. IMPLICATIONS: Our findings suggest that noticing NVP warnings may not influence NVP risk perceptions or deter NVP use among adult smokers and vapers. Future research should investigate the impact of warnings on youth and adults who have never smoked or vaped.

Developing the surgical technique reporting checklist and standards: a study protocol.

BACKGROUND: Standardized and transparent reporting of surgical technique is the cornerstone of effective dissemination, implementation and improvement. However, current reporting of surgical techniques is inadequate. The existing guidelines potentially applied to guide surgical technique reporting are with a minimal highlight of the surgical technique, lack requirements explaining what extent and dimensions need to be described in detail, or are unlikely to extrapolate to a wide range of surgical techniques. This study aims to formulate a rigorous protocol to develop a surgical technique reporting checklist and standards (SUPER) that defines what a clear, comprehensive and detailed surgical technique report should be contained. METHODS: This protocol is designed following the classic guidance for developing reporting guidelines recommended by the EQUATOR network. RESULTS: The development team will consist of surgeons (~80%), methodologists, and journal editors. The draft checklist sources will include a scoping review of existing reporting guidelines related to surgical technique, surgical technique articles from 15 top journals published in the last year, and brainstorming by the multidisciplinary development team. The final SUPER checklist will be formed after three rounds of Delphi surveys, one round of face-to-face meeting, and a month-long pilot test. The SUPER checklist will be published as open-access and be used in combination with existing reporting guidelines related to surgical techniques (e.g., IDEAL). This protocol will steer the SUPER checklist's development, allowing us to further elaborate surgical technique reporting for all surgical specialties, and enabling a more favorable experience for surgeons, nurses, medical students, residents, editors, and reviewers. TRIAL REGISTRATION: This trial is registered at the EQUATOR network on December 18th, 2020. Available at: https://www.equator-network.org/library/reporting-guidelines-under-development/reporting-guidelines-under-development-for-other-study-designs/.

Evidence on reporting guidelines for surgical technique in clinical disciplines: a scoping review protocol.

BACKGROUND: The reporting of surgical techniques is of mixed quality, with most at a very minimal level. Reporting guidelines that could be applied to guide surgical technique reporting vary in methodology for development, discipline coverage, dimension coverage and detail requested. However, a scoping review that could indicate the gaps and efforts needed in surgical technique reporting guidelines is lacking and warranted. This study aims to design a methodological rigour protocol to guide the development of a scoping review of surgical technique reporting guidelines. METHODS: This protocol is designed following the 2020 manual proposed by the Joanna Briggs Institute. To further ensure the soundness of the protocol, we also included multidisciplinary professionals (including methodologists, clinicians, and journal editors) to refine the protocol. DISCUSSION: Seven key steps for developing the scoping review are identified and presented in detail, including (I) identifying the research questions; (II) inclusion criteria; (III) search strategy; (IV) source of evidence selection; (V) data extraction; (VI) analysis of the evidence; and (VII) presentation of the results. Guided by this protocol, the subsequent scoping review will inform us the overview of surgical technique reporting guidelines and precisely guide our direction and next steps in improving surgical technique reporting guidelines. TRIAL REGISTRATION: This protocol is not registered as the PROSPERO database only accepts registration of systematic review protocols while does not accept registration of scoping review protocols.

Global sales of oral antibiotics formulated for children.

OBJECTIVE: To investigate international consumption patterns of child-appropriate oral formulations of antibiotics by formulation type, with a focus on dispersible tablets, using data from a global sales database. METHOD: Antibiotic sales data for 2015 covering 74 countries and regional country groups were obtained from the MIDAS® pharmaceutical sales database, which includes samples of pharmacy wholesalers and retailers. The focus was on sales of child-appropriate oral formulations of Access antibiotics in the 2017 World Health Organization's WHO Model list of essential medicines for children. Sales volumes are expressed using a standard unit (i.e. one tablet, capsule, ampoule or vial or 5 mL of liquid). Sales were analysed by antibiotic, WHO region and antibiotic formulation. FINDINGS: Globally, 17.7 billion standard units of child-appropriate oral antibiotic formulations were sold in 2015, representing 24% of total antibiotic sales of 74.4 billion units (both oral and parenteral) in the database. The top five child-appropriate Access antibiotics by sales volume were amoxicillin, amoxicillin with clavulanic acid, trimethoprim-sulfamethoxazole, cefalexin and ampicillin. The proportion of the top five sold for use as a syrup varied between 42% and 99%. Dispersible tablets represented only 22% of all child-appropriate oral formulation sales and made up only 15% of sales of 10 selected Access antibiotics on the model list for children. CONCLUSION: Globally most child-appropriate oral antibiotics were not sold as dispersible tablets in 2015, as recommended by WHO. There is a clear need for novel solid forms of antibiotics suitable for use in children.

Perceptions of Harmfulness of Heated Tobacco Products Compared to Combustible Cigarettes among Adult Smokers in Japan: Findings from the 2018 ITC Japan Survey.

In Japan, the tobacco industry promotes heated tobacco products (HTPs) as a reduced-risk tobacco product. This study examines: (1) smokers' harm perceptions of HTPs relative to combustible cigarettes; (2) differences in relative harm perceptions between exclusive smokers and smokers who use HTPs (concurrent users) and between concurrent users based on frequency of product use; and (3) if smokers who were exposed to HTP advertising hold beliefs that are consistent with marketing messages of lower harmfulness. This cross-sectional study included 2614 adult exclusive cigarette smokers and 986 concurrent users who reported their perceptions of harmfulness of HTPs compared to cigarettes, as well as their exposure to HTP advertising in the last six months. Among all smokers, 47.5% perceive that HTPs are less harmful than cigarettes, 24.6% perceive HTPs to be equally as harmful, 1.8% perceive HTPs as more harmful, and 26.1% did not know. Concurrent users are more likely than exclusive smokers to believe that HTPs are less harmful (62.1% versus 43.8%, p < 0.0001) and less likely to report that they did not know (14.3% versus 29.4%, p < 0.0001). Frequent HTP users are more likely than infrequent users to believe that HTPs are less harmful (71.7% versus 57.1%, p ≤ 0.001). Believing that HTPs are less harmful than cigarettes was associated with noticing HTP advertising on TV (p = 0.0005), in newspapers/magazines (p = 0.0001), on posters/billboards (p < 0.0001), in stores where tobacco (p < 0.0001) or where HTPs (p < 0.0001) are sold, on social media (p < 0.0001), or in bars/pubs (p = 0.04). HTP users were significantly more likely than non-HTP users to believe that HTPs are less harmful than cigarettes, with this belief being more prominent among frequent users. Smokers who have been exposed to HTP advertising were more likely to perceive HTPs as less harmful than cigarettes.

Survey Methods of the 2018 International Tobacco Control (ITC) Japan Survey.

This paper describes the methods of the Wave 1 (2018) International Tobacco Control (ITC) Japan Survey. The respondents were adults aged 20 years and older in one of four user groups: (1) cigarette-only smokers who smoked at least monthly and used heated tobacco products (HTPs) not at all or less than weekly, (2) HTP-only users who used HTPs at least weekly and smoked cigarettes not at all or less than monthly, (3) cigarette-HTP dual users who smoked at least monthly and used HTPs at least weekly, and (4) non-users who had never smoked or who smoked less than monthly and used HTPs less than weekly. Eligible respondents were recruited by a commercial survey firm from its online panel. Respondents were allocated proportionally to sample strata based on demographic, geographic, and user type specifications benchmarked to a national reference. Survey weights, accounting for smoking/HTP use status, sex, age, education, and geography, were calibrated to benchmarks from a nationally representative survey in Japan. Response rate was 45.1% and cooperation rate was 96.3%. The total sample size was 4615 (3288 cigarette smokers, 164 exclusive HTP users, 549 cigarette-HTP dual users, and 614 non-users). The 2018 ITC Japan Survey sampling design and survey data collection methods will allow analyses to examine prospectively the use of cigarettes and HTPs in Japan and factors associated with the use of both products and of transitions between them.

Exposure to and perceptions of health warning labels on nicotine vaping products: findings from the 2016 International Tobacco Control Four Country Smoking and Vaping Survey.

BACKGROUND AND AIMS: The presence and content of health warning labels (HWLs) on nicotine vaping products (NVPs), such as electronic cigarettes, varies by country and manufacturer. We compared proportions of people who report (i) noticing HWLs on NVPs and (ii) feeling concerned having noticed HWLs, by country and by smoking or vaping status. We also examined recall of HWL content and whether this varies by country. DESIGN: Cross-sectional survey. SETTING: Australia (AU), Canada (CA), England (EN) and the United States (US). At the time of data collection, HWLs on NVPs were only mandatory in EN. PARTICIPANTS: A total of 11 561 respondents from the following samples in the 2016 International Tobacco Control Four Country Project: (1) re-contacted smokers and quitters who had participated in the previous wave of the project; (2) newly recruited current smokers and recent quitters; and (3) newly recruited current vapers from CA, EN and US. MEASUREMENTS: Outcomes included: (1) having noticed HWLs on NVPs, (2) feeling concerned having noticed HWLs, and (3) recall of HWL message content. FINDINGS: Compared with respondents in EN, respondents in CA were more likely to report having noticed HWLs [odds ratio (OR) = 1.58, P = 0.02], whereas respondents in AU (OR = 0.76, P = 1.00) and the US (OR = 1.54, P = 0.09) were not significantly more or less likely to report having noticed HWLs. Compared with concurrent smokers and vapers, daily smokers, non-daily smokers and quitters were less likely to report having noticed HWLs (ORs = 0.21, 0.33 and 0.19, respectively, all P < 0.001). There were no significant differences in reports of noticing HWLs when comparing concurrent smokers and vapers with daily (OR = 1.62, P = 0.91) or non-daily (OR = 1.15, P = 1.00) vapers. There were no significant differences by country in reporting that HWLs made them concerned about using NVPs. Daily vapers were less likely to report feeling concerned than concurrent users (OR = 0.11, P = 0.017). Among those who reported reading HWLs (n = 688), there was little evidence of differences in recall of the HWL content. CONCLUSIONS: Respondents in England, where health warning labels on nicotine vaping products are mandatory, were not significantly more likely to report having noticed such warnings than those in Australia, Canada and the United States where warnings are not mandatory.

Potential factors of specialists' willingness to write editorial and commentary: a retrospective study based on 5,091 invitations.

BACKGROUND: Editorials and commentaries (E/C) are common article categories and usually solicited by editors in many journals. However, not all experts accept invitation for an E/C essay for a variety of reasons. We conducted this study to explore the potential influence factors contributing whether an invitation to write E/C is accepted by a specialist. METHODS: Data of invited E/C from all journals of AME Publishing Company between January 1st, 2018 and December 31st, 2018 were retrospectively identified and consecutively collected. Acceptance of writing E/C from experts was recorded as "positive", while acceptance without submission, refusal, or no response, were all recorded as "negative". Factors that could potentially affect invitation acceptance were generally categorized as being related to three areas: original studies, inviting journals, and experts. RESULTS: A total of 5,091 invitations were sent to 4,788 experts from 79 different countries or areas to write E/C on 695 research papers from 43 journals, with a total positive acceptance rate of 18.88%. Greece (40.54%), India (36.8%), and Brazil (35.42%) were the top three countries for acceptance rate. Surgeons (surgeons 23.80% vs. non-surgeons 17.05%; P<0.001) and oncologists (oncologists 22.57% vs. non-oncologists 17.58%; P=0.029) were more likely to accept the E/C invitations. The acceptance rate decreased with the increasing number of published articles of an expert (P=0.005). The acceptance rate was the highest (28.03%) when an inviting journal was indexed in both SCIE and PubMed. ABS, VATS and JTD ranked as the top three journals with the highest invitation acceptance rate. The impact factor of journals on which original papers were published had a negative correlation with the invitation acceptance rate (P=0.015). Database-related studies had the highest acceptance rate (21.66%), while translational (16.49%) and basic studies (16.56%) had a significantly lower acceptance rate among all study types. CONCLUSION: Original studies, inviting journals, and expert-related factors were all influence factors on the acceptance rate/willingness to write of E/C from invitations.