Separate Manuscript Research Articles

Initial Experiences with Invasive Meningococcal Disease: Insights from Survivors and Their Caregivers.

Invasive meningococcal disease (IMD) has a low incidence but is a life-threatening illness with a 10-15% mortality rate. Even with timely treatment, survivors may experience acute and long-term health complications. While meningococcal vaccines are recommended for adolescents and young adults in the USA, vaccination coverage remains uneven across serotypes. This study investigated the physical, social, psychological, and economic burden of IMD on survivors and their caregivers in the USA during the acute phase (Part1, presented in this manuscript) and the long-term phase (Part2, presented in a separate manuscript) of IMD. This study implemented a non-interventional, mixed-methods approach using a bespoke survey and qualitative interviews (designed on the basis of a preliminary conceptual model of IMD) with US survivors and their caregivers. A total of 11 survivors (1 adolescent, 10 adults) and 3 caregivers participated in the study. Survivors contracted IMD during infancy (n = 2), childhood (n = 3), or adulthood (n = 6), and often described leading healthy lives pre-IMD. At IMD onset, interactions with the healthcare system impacted participants' experiences; confusion and care delays were common, and procedures were often invasive (e.g., amputations). Survivors commonly experienced symptoms including skin rash (7/11), fever (6/11), and unconsciousness (6/11), consistent with caregivers' reports. Survivors able to report on the short-term impacts of IMD (n = 9) described functional limitations (9/9), emotional impacts (6/9) such as fear and trauma, and school (6/9), work (4/9), and financial (5/9) challenges. Caregivers also experienced emotional impacts (3/3) and family (2/3), work (3/3), and financial (3/3) impacts during the acute phase. IMD places a significant humanistic burden on survivors and their caregivers during the acute phase. Results from Part1 of this study indicate a need for increased disease awareness and healthcare provider education, expeditious diagnosis, and improved access to prevention methods such as available meningococcal vaccines. A video abstract is available with this article. Video abstract (MP4 1,24,432kb).

Dynamic spatial price equilibrium, dynamic user equilibrium, and freight transportation in continuous time: A differential variational inequality perspective

In this paper we provide a statement of dynamic spatial price equilibrium (DSPE) in continuous time as a basis for modeling freight flows in a network economy. The model presented describes a spatial price equilibrium due to its reliance on the notion that freight movements occur in response to differences between the local and distant prices of goods for which there is excess demand; moreover, local and distant delivered prices are equated at equilibrium. We propose and analyze a differential variational inequality (DVI) associated with dynamic spatial price equilibrium to study the Nash-like aggregate game at the heart of DSPE using the calculus of variations and optimal control theory. Our formulation explicitly considers inventory and the time lag between shipping and demand fulfillment. We stress that such a time lag cannot be readily accommodated in a discrete-time formulation. We provide an in-depth analysis of the DVI's necessary conditions that reveals the dynamic user equilibrium nature of freight flows obtained from the DVI, alongside the role played by freight transport in maintaining equilibrium commodity prices and the delivered-price-equals-local-price property of spatial price equilibrium. By intent, our contribution is wholly theoretical in nature, focusing on a mathematical statement of the defining equations and inequalities for dynamic spatial price equilibrium (DSPE), while also showing there is an associated differential variational inequality (DVI), any solution of which is a DSPE. The model of spatial price equilibrium we present integrates the theory of spatial price equilibrium in a dynamic setting with the path delay operator notion used in the theory of dynamic user equilibrium. It should be noted that the path delay operator used herein is based on LWR theory and fully vetted in the published dynamic user equilibrium literature. This integration is new and constitutes a significant addition to the spatial price equilibrium and freight network equilibrium modeling literatures. Among other things, it points the way for researchers interested in dynamic traffic assignment to become involved in dynamic freight modeling using the technical knowledge they already possess. In particular, it suggests that algorithms developed for dynamic user equilibrium may be adapted to the study of urban freight modelled as a dynamic spatial price equilibrium. As such, our work provides direction for future DSPE algorithmic research and application. However, no computational experiments are reported herein; instead, the computing of dynamic spatial price equilibria is the subject of a separate manuscript.

WHAT DO THE MANUSCRIPTS HIDE? ABOUT THE DESCRIPTION OF A MANUSCRIPT PUBLISHED IN THE "SION" MAGAZINE

Maksoudian published in 1968 in the magazine “Sion” a description of the manuscript of 1311, supplementing the manuscript heritage of the medieval Artske, copied by the scribe Hovhannes in the “Desert of Artske” under the title Recently discovered Armenian manuscript in America. The manuscript contains the books of Solomon the Wise: Proverbs, Ecclesiastes, Song of Songs, Wisdom, as well as the work by Grigor Nyusatsi Interpretation of the Song of Songs. The article considers this description as an important source, equivalent to a manuscript, for the study of the written environment of Artske. In 1317 the Hovhannes, in the same Artske desert, made an exact copy of the manuscript (colophons and contents coincide), which is the manuscript number 76 of the Mashtots Matenadaran. The comparative textological-codicological analysis of these two manuscripts from the Artske Desert reveals new details both about the copyist Hovhannes and about the writing environment of Artske at the beginning of the 14th century; the worldly name of the copyist and the names of his relatives become known, of whom there is no mention in the colophon of the manuscript number 76. The article highlights the fact that Solomon's Proverbs, Ecclesiastes, Song of Songs and Wisdom were copied in a separate manuscript as a unique phenomenon of copying the biblical text, which justifies the presence in this copied text of noteworthy discrepancies that are absent in the readings of the Bible, considered authoritative, published by Hovhannes Zohrabian in 1805 year, and may contribute to a future work on the composition of the critical text of the Bible.

Using Kiln Dust to Improve Weak Subgrades for Pavement Construction: A Field Verification in Michigan, USA

Remove-and-replace with suitable material has been the primary solution used for improving subgrades in Michigan, USA, when weak subgrades are encountered in road construction. Considering the large extent of silty and clayey soils found in southeastern Michigan, where much of the population and the roads are located within the state, the earthwork associated with this solution is massive and expensive. The use of cement kiln dust (CKD) or lime kiln dust (LKD) as a subgrade stabilizer can be a cost-effective solution if there is sufficient evidence to prove that such stabilization is suitable for the soils and the climate in southeastern Michigan. This became the subject of a field and laboratory investigation carried out in Michigan and sponsored by the Michigan Department of Transportation. The findings from the laboratory portion of this research (which were published in a separate manuscript) proved CKD’s suitability for long-term stabilization and LKD’s capacity for being a stabilizer for short-term modifications of clayey soils found in southeastern Michigan. This study covers the field testing portion of this investigation. Two CKD-stabilized and another two LKD-stabilized subgrades, which were already in use for 4–6 years, were tested for strength, using dynamic cone penetration (DCP) tests. The California bearing ratios estimated from the DCP tests showed that the CKD-stabilized and LKD-stabilized subgrades could offer strength gains as high as 200–515% and 149–257% compared to in situ soils, respectively, even after 4–6 years in use.

Qualitative studies of the lived experiences of being in foster care: A scoping review protocol

The aim of this scoping review is to provide an overview of the existing qualitative research concerning the lived experiences of children and young people currently in foster care.IntroductionLived experience...

Proceedings of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition Monothematic Conference, 2020: "Acute Liver Failure in Children": Treatment and Directions for Future Research.

The Hepatology Committee of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) aims to educate pediatric gastroenterologists, members of ESPGHAN and professionals from other specialties promoting an exchange of clinical expertise in the field of pediatric hepatology. The 2020 single topic ESPGHAN monothematic 3-day conference on pediatric liver disease, was organized in Athens, Greece and was entitled " Acute Liver Failure" (ALF). ALF is a devastating disease with high mortality and in a considerable fraction of patients, the cause remains unresolved. As knowledge in diagnosis and treatment of ALF in infants and children has increased in the past decades, the objective was to update physicians in the field with developments in medical therapy and indications for liver transplantation (LT) and to identify areas for future research in clinical and neurocognitive outcomes in ALF. We recently reported the epidemiology, diagnosis, and initial intensive care management issues in separate manuscript. Herewith we report on the medical treatment, clinical lessons arising from pediatric studies, nutritional and renal replacement therapy (RRT), indications and contraindications for LT, neurocognitive outcomes, new techniques used as bridging to LT, and areas for future research. Oral presentations by experts in various fields are summarized highlighting key learning points. The current report summarizes the current insights in medical treatment of pediatric ALF and the directions for future research.

Clinical outcomes of pre-attached reinforced stapler reloads in bariatric surgery: A prospective case series

BackgroundStaple line reinforcement during surgery may decrease morbidity or reduce the risk of staple line leaks and bleeding. There is debate regarding the benefit, safety, and best form of reinforcement. This case series characterizes the safety of a stapler with a pre-attached buttress in bariatric surgeries. MethodsThis prospective, multicenter, post-market study examined the use of stapler reloads with built in reinforcement material. The primary endpoint is the incidence of reported device-related adverse events up to 30 days after laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG) surgeries. Specific outcomes included bleeding (≥50 mL), leaks, and 30-day readmissions. OutcomesA total of 51 patients (19 RYGB, 32 SG) were assessed after exclusion criteria were applied. Intraoperatively, no leaks or bleeding related to the staple line occurred. Four patients (8% overall, 3 RYGB, 1 SG) experienced bleeding unrelated to the staple line and staple line intervention, in these cases, was not required. Four subjects (8%, all SG) required readmission and each were attributed as unrelated to the investigational device. No unanticipated device-related events were observed. Two adverse events (bleeding) occurred post-operatively that were attributed as possibly related to the device; both were endoscopically managed. ConclusionsThis study demonstrates that there were no serious safety concerns from the AEs observed related to reinforced reload use during or in the 30-day course after 51 common bariatric procedures in a multicenter setting. Trial registrationThe study was registered with clinicaltrials.gov (NCT02500537). Thoracic subjects from this study are described in a separate manuscript.

The passion from the Middle Dutch Life of Jesus : Critical edition of a fourteenth-century passion harmony from Red Cloister (MS. Paris, Bibliothèque Mazarine, 920) Het lijdensverhaal uit het middelnederlandse Leven van Jezus

© 2021 Ons Geestelijk Erf. All rights reserved.In this article excerpts from the Life of Jesus are edited and commented upon. The edition mainly comprises one of the oldest (1325-1350) and most extensive Middle Dutch passion harmonies. This passion harmony is preserved in MS. Paris, Bibliotheque Mazarine, 920, fols. 126v-144v. The Paris manuscript offers a broad selection of religious texts, including texts of Ruusbroec, Hadewijch and Hugo of Saint-Victor. Whereas this Paris convolute dates from the 15th century, the edited excerpts are part of a production unit of this convolute dating from the 14th century. This production unit originally functioned as a separate manuscript and is seen as concrete example of the literary traffic between religiously kindred spirits ('Godsvrienden') in Brabant and the Upper Rhine.

Drivers of Innovation Ambidexterity on Small Medium Enterprises (SMEs) Performance

The development of the broiler poultry industry has experienced a significant increase along with the increasing public demand for meat consumption. However, in 2019, many broiler poultry farmers are forced to close down their businesses because the price of broilers in living conditions continues to be below the Production Cost. Further, broiler poultry farmers also experience obstacles including unpredictable price fluctuations and intense competition. Innovation ambidexterity is the innovation capability in managing exploration and exploitation simultaneously to improve firm performance. Several influential factors in increasing innovation ambidexterity include technological capability, owner-manager characteristic, and environmental dynamism. This study aims to develop a model that describes innovation ambidexterity in broiler poultry farmers to improve firm performance. This study also analyzes the factors that can influence innovation ambidexterity and its effect on firm performance. This research mainly uses quantitative methods for its analysis. The sampling technique uses non-probability sampling with convenience sampling technique. Data collection was conducted by distributing 223 questionnaires to broiler poultry farmers in West Java. The analysis technique uses Partial Least Square - Structural Equation Modeling (PLS-SEM) which includes measurement model analysis and structural model analysis. The results of this study indicate that innovation ambidexterity has a direct influence on firm performance, while the influence of environmental dynamism on firm performance is partly mediated by innovation ambidexterity. In addition, technological capability and owner-manager characteristics have a positive influence on innovation ambidexterity and have an indirect influence on firm performance. In the near future, implications of this study will be discussed in a separate manuscript.

The Sahidic Tripartite Isaiah: Origins and Transmission within the Coptic Manuscript Culture

Abstract This study shows that the book of Isaiah was sometimes divided by Coptic scribes into three parts, each of them being copied individually into a separate manuscript. By surveying the available evidence, the author argues that this practice originated in the 4th century CE and was in use until the 8th century CE. The origins and eventual disappearance of tripartite Isaiah must be connected with the transformations that affected Coptic codices and scribal traditions from late antiquity to the medieval period.

Understanding health care professionals' attitudes towards working in teams and interprofessional collaborative competencies: A mixed methods analysis

Abstract Background To meet the challenge of preparing health care professionals for collaborative practice, it is crucial to understand factors that influence their ability to collaborate effectively. Method This study employed a convergent parallel mixed methods design to better understand health care professional' attitudes towards working in teams and their interprofessional collaborative competencies. The quantitative strand utilized validated questionnaires to measure attitudes and collaborative competencies, and the qualitative strand utilized open ended questions to understand how health care professionals work in teams and the interprofessional collaborative competencies they feel they need to work in teams. This article reports the findings from the qualitative strand and mixed methods analysis; the quantitative results are published in a separate manuscript. Results A descriptive content analysis was completed to analyze the qualitative data, which resulted in three categories: (1) Communication, which includes two subcategories, Effective Communication and Ineffective Communication, (2) Value, and (3) Roles. Conclusion The findings from this study suggest that interprofessional collaboration appears to be influenced by numerous factors, including the type of formal interprofessional education health care professionals complete and how often formal IPE is completed. Equally important is the need to integrate principles related to effective communication, role clarification, and strategies to uphold relationships where value, trust, respect, and validation occur.

JA:2021-25. Increasing Efficiency and Reliability of Agricultural Injury and Fatality Coding with Standard Operating Procedures: Lessons Learned from AgInjuryNews.org

ABSTRACT Purpose: News media reports of agricultural injuries can be useful to better inform safety and health stakeholders and prevention efforts. These data are particularly useful for youth incidents, since the National Institute of Occupational Safety and Health discontinued their survey-based agriculture surveillance program in 2015, leaving a gap in reliable, consistent data on both youth and adult agricultural injuries and fatalities. In this study we describe how coding data derived from news reports, with a detailed Standard Operating Procedure (SOP) and refined inclusion/exclusion criteria, can lead to more efficient workflows to capture and code agricultural injury data. Methods: To capture quality data and improve inter-rater reliability we employ a multi-coder process. The first coder enters primary data into the Case Report Form (CRF), and a second coder reviews these data points for agreement. While reviewing for agreement, the second coder diverges into two other occupational/agricultural injury coding schemas (Occupational Illness and Injury Classification System [OIICS] and Farm and Agricultural Injury Classification [FAIC]) and employs an additional multi-coder and interrater reliability process, adding to the multifaceted workflow and detailed data output. This secondary coding schema and reliability ratings are discussed in a separate manuscript. Any discrepancies from the initial review are then discussed and settled between first and second coders. All CRFs are sent to another team member who reviews >10% and publishes the reports for public use on AgInjuryNews.org. International cases endure a similar process, but without OIICS or FAIC coding. In partnership with the Canadian Agricultural Safety Association, our team began Canadian injury report capture and coding in the fall of 2019. Findings: We developed a structured and detailed SOP for coding agricultural data obtained from news reports. Use of the SOP and refined inclusion/exclusion criteria were crucial when: 1) onboarding additional coders; 2) employing multiple coders; 3) refining search terms in data collection; 4) coding of emerging technologies and trends; and 5) improving the efficiency and quality of the data. Translation: Coders’ ability to reference a thoroughly vetted SOP and inclusion/exclusion criteria may lead to improved data coding for agricultural injuries and fatalities.

Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study

Background: Drug repurposing is an attractive strategy to rapidly develop affordable therapy against COVID-19. The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 comparable to that of hydroxychloroquine. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized patients with COVID-19 were randomly assigned to receive standard of care with or without itraconazole. The primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. Other outcomes included time to sustained clinical improvement, duration of supplemental oxygen and evolution of nasopharyngeal viral load. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to prevent viral transmission. The clinical trial was prematurely discontinued after evaluation of the preclinical studies and interim analysis that showed no trends for a more favorable outcome with itraconazole: mean cumulative score of the clinical status 49 vs 47, ratio of geometric means 1.01 (95% CI 0.85 to 1.19), median time to clinical improvement 10 vs 9 days, hazard ratio 0.94 (95% CI 0.56 to 1.60) for itraconazole vs standard of care. Interpretation: Despite in vitro activity, itraconazole was not effective in a preclinical COVID-19 hamster model. A proof-of-concept clinical study was ended prematurely because of futility. Trial Registration: (EudraCT 2020-001243-15)Funding: Covid-19-Fund KU Leuven, Research Foundation - Flanders (FWO), Horizon 2020, Bill and Melinda Gates FoundationDeclaration of Interests: Initial dug screening and discovery of the antiviral effect of itraconazole was done in collaboration with Johnson & Johnson and described in a separate manuscript. Scientists from Johnson & Johnson also performed drug measurements on hamster samples and provided guidance on the dosing regimens for the preclinical studies. The company had no role in the design, execution, analysis, publication or funding of the clinical trial.Author Conflict of Interests: None to declare.Ethics Approval Statement: The institutional Ethical Committee approved all animal experiments (license P065-2020).The study was conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. The protocol was approved by the institutional Ethics Committee and by the Belgian Federal Agency for Medicines and Health Products (EudraCT 2020-001243-15). The trial was part of the DAWn clinical studies.

Scribes and paper of the late 16th century Yegorov-Barsov Chronograph

Thе article is dedicated to description of two late sixteenth-century manuscripts containing the Russian Chronograph in the 1512 recension. Held today in two separate Moscow manuscript collections, they were identifi ed as parts of a single whole in the work of M. V. Shchepkina and T. N. Protasieva, yet they have not previously been comprehensively de-scribed. The article off ers a detailed analysis of the watermarks, hands, orthography, and language (in particular regarding accentuation) of this bifurcated chronograph.The fi rst manuscript is kept as no. 202 in the collection of E. E. Yegorov in the Russian State Library. The second is no. 1695 in the collection of E. V. Barsov in the State Historical Museum. The Yegorov manuscript was written on the same type of paper by three distinct scribes, whereas the Barsov manuscript was written on seven diff erent types of paper yet in a single hand that may be identifi ed as that of one of the scribes of the Yegorov manuscript. Furthermore, it has been possible to identify one of the watermarks in the Barsov manuscript precisely: it is watermark no. 1700 in the E. Laucevič ius’ catalogue — the Polish Topór coat of arms beneath a crescent moon on a cartouche, which is represented in Lithuanian manuscripts of 1593 and 1594. The pages of the Yegorov manuscript are two-thirds given to illumina-tion, whereas the Barsov manuscript provides space only for miniatures and initials. It has been proposed by A. A. Turilov that this bifurcated chronograph was intended for Тsar Fedor Ioannovich, but was not com-pleted due to his death in 1598.

Arthrogryposis multiplex congenita definition: Update using an international consensus-based approach.

Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent. Some have described it as a diagnosis or syndrome, others as a term or clinical finding. This lack of common language can lead to confusion in clinical and research communities. The aim of this study was to develop a consensus-based definition for AMC using international expert opinion. A consensus-based definition will help harmonize research and clinical endeavors and will facilitate communication among families, clinicians, and researchers. This article describes the methodology used leading to a proposed definition of AMC. First, a literature review was conducted to identify AMC definitions used in included studies. The most commonly used words in the definitions were extracted. Second, a group of eight experts in AMC was selected to identify elements considered critically important to the definition of AMC. Third, based on these critical elements and the literature review, a definition was drafted by the research team. Fourth, a modified Delphi consensus process was conducted using electronic surveys with 25 experts in the field of AMC from eight countries. Survey results were analyzed quantitatively and qualitatively and drafts were modified accordingly. Three rounds of surveys were completed until consensus was reached on a definition of AMC. An annotation of this definition, developed by a panel of international experts, is provided in a separate manuscript in this special issue.

Population-Based Human Papillomavirus Serosurvey Reveals HPV16/18 Herd Effect But No Clear Type-Replacement in Unvaccinated Females 6 Years Post Gender-Neutral Vaccination in a Cluster Randomised Trial

Background: Human papillomavirus (HPV) basic reproductive numbers are low, except for HPV type 16. Thus, vaccination can induce herd effects to reduce the prevalence of many HPV types, especially if gender-neutral vaccination strategy and a vaccine with broad protection against HPV types are used. Methods: We used a cluster-randomized trial implemented in 2007-2009 among early, 1992-1995 born adolescents to create differential herd effects in 11 communities with gender-neutral (Arm A), and 11 communities with girls-only (Arm B) HPV16/18 vaccination achieving 20% coverage in Arm A boys and 45% coverage in Arm A and Arm B girls. In 11 control communities, devoid of any opportunistic HPV vaccination, hepatitis B-virus vaccination covered 30% of boys and 50% of girls. Seroprevalence was assessed for 17 HPV types in consecutive calendar-time (2005-07, 2008-10, 2011-13, 2014-16) strata comprising unvaccinated adolescent and young adult females, who were respectively 19 years or younger, and 20 to 22 years of age at the time of serum sampling. Sexual risk-taking behaviour core-group was defined by herpes simplex virus type-2 antibody positivity. From observed data probabilistic networks and simulated equal size seroprevalence datasets (N=100,000) were also derived. Findings: Following gender-neutral vaccination significant HPV16/18 herd effects were rapidly detected in the adolescent core-group of the gender-neutral vaccination Arm A. HPV51 prevalence tended to increase later in the post-vaccination era (2014-16) among adolescent core-group girls-only vaccination Arm B, as also supported by the simulations. Interpretation: Low to moderate coverage HPV vaccination induces a strong herd effect against HPV16/18 infection reducing circulation of vaccine-targeted HPV types following gender-neutral vaccination. The ecological niche vacated is not immediately filled. Funding Statement: This study was partially funded by Academy of Finland, Finnish Cancer Organizations and EU FP7 networks PREHDICT and CoheaHR. GlaxoSmithKline Biologicals SA funded the community randomized HPV-040 trial (NCT00534638), (data to be published in a separate manuscript) however was not in any way involved in the conduct of this study. This study received some support via a personal grant from the Ministry of Health, Government of Catalonia (PERIS SLT002/16/00496).The study was supported by grants from the Swedish Cancer Society (CAN 2015/399 and CAN 2017/459), from the Swedish Foundation for Strategic Research (grant number RB13-0011) and from Karolinska Institutet (Dnr. 2018-01523). ML received funding from KI to his Professorship (Dnr. 2-3698/2017). Declaration of Interests: JD and ML have received grants from Merck & Co. Inc and the GSK group of companies through their employers the Karolinska Institute (both JD and ML), or the University of Tampere (ML) for conducting HPV vaccination studies. Ethics Approval Statement: The community randomized study obtained permissions from the Ethical Review Board of Pirkanmaa Hospital District (R07113M 14.6.2007) and the Ethical Review Board of North Bothnia Hospital District (EETTMK:111/2009). Informed consent to use the FMC serum samples for research purposes is granted by the pregnant women when they donate their 1st trimester sample for screening of congenital infections.

Identifying gaps in primary healthcare policy and governance in low-income and middle-income countries: protocol for an evidence gap map

IntroductionThere are gaps in the primary healthcare (PHC) delivery in majority of low-income and middle-income countries (LMICs) due to epidemiological transition, emergence of outbreaks or war, and often lack of...

Moderate Coverage Vaccination Eradicates Oncogenic Human Papillomaviruses if a Gender-Neutral Strategy is Applied

Background: Very high coverage human papillomavirus (HPV) vaccination of girls has the potential to eradicate some HPV types but low coverage vaccination does not. The protection of unvaccinated individuals by herd effect (HE) varies by HPV type and vaccination strategy. By combining community-randomized trial data and mathematical modeling we show that gender-neutral vaccination is superior for achieving eradication of oncogenic HPVs. Methods: We randomized 33 communities into gender-neutral HPV16/18 vaccination (A), HPV16/18 vaccination of girls only (B), and hepatitis B-virus vaccination of boys and girls (C). From 2007-2010 11,622/40,852 resident boys and 20,513/39,420 resident girls born 1992-1995 consented to the study. At follow-up in 2010-14, cervicovaginal samples from vaccinated and unvaccinated girls were typed for HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59/66/68. Trial-based vaccine efficacy (VE) and HE, estimated among non-HPV vaccinated arm A/B girls using arm C controls, were weighted for mean protective effectiveness (PE) estimation, and used for modeling eradication. Findings The HPV18/31/33 HE and PE were significant in younger birth cohorts: four years post vaccination HE and PE were 150% and 40% stronger in the gender-neutral than in the girls-only arm. HPV18/31/33 have moderate to fast clearance rates enabling eradication, and corresponding HEs from vaccinated to unvaccinated arose rapidly. HPV18/31/33 eradication in adolescents/young adults is predicted in 20 years with 75% coverage of gender-neutral vaccination, eradication of HPV16 is predicted within 30 years. Interpretation While low coverage with a girls-only vaccination strategy leaves most females unprotected, HPV-disease eradication of oncogenic HPVs is certain with moderate coverage gender-neutral vaccination strategy. Funding: This ancillary study was partially funded by Academy of Finland, Finnish Cancer Organizations and EU FP7 networks PREHDICT and CoheaHR. GlaxoSmithKline Biologicals SA funded the primary study HPV-040 (NCT00534638, data to be published in a separate manuscript) but was not involved in the conduct of this ancillary study. GlaxoSmithKline Biologicals SA was provided the opportunity to review this manuscript for accuracy of primary HPV-040 data but the authors are solely responsible for final content and interpretation. V.N.P. was supported by a personal grant from the Ministry of Health, Government of Catalonia (PERIS SLT002/16/00496). Declaration of Interest: D.A., J.D., G.G., M.L. and J.P. have received grants from Merck & Co. Inc. or the GSK group of companies through their employers [Family Federation Finland (DA), Karolinska Institute (J.D., M.L.), Universities of Tampere (M.L.) or Helsinki (J.P.) or Imperial College London (G.G.)] for HPV vaccination studies. G.D. is currently a full time employee of Takeda Vaccines, but was working for GSK Biologicals at the time the study was planned and conducted. He holds several patents in the HPV field which have been assigned to the GSK groups of companies and has stock shares in both the GSK groups of companies and Takeda. Ethical Approval: The HPV-040 study (Eudra-CT-2007-001731-55, NCT00534638), and parallel ancillary studies on Chlamydia trachomatis screening (Dnro 111/2009) and HPV screening (ETL-code 13149, NCT02149030) were approved by Finnish ethical committees of the Pirkanmaa and PohjoisPohjanmaa hospital districts in 2007, 2009 and 2013, respectively.

Investigation of Stethoscope Technology for En Route Care

ObjectiveOccupational challenges in air transport domains make auscultation with traditional stethoscopes difficult. This study aimed to investigate two commercial off-the-shelf stethoscopes for use in high noise military patient transport environments. The stethoscopes were assessed by Aeromedical Evacuation providers in a simulated C-130 trainer on live standardized mock patients. Device 1 was a dual-mode stethoscope developed for rotary wing military airframes. Device 2 was an electronic stethoscope developed for high noise civilian environments. Twenty clinicians performed cardiopulmonary auscultation using the devices on the same two standardized patients in a simulated C-130 then completed a subjective questionnaire on their ability to identify heart and lung sounds. Results indicated the dual-mode stethoscope had limited utility with clinician likeliness of use rated as low (median = 2; interquartile range = 1.75-3.25), whereas the electronic stethoscope had potential utility with likeliness of use rated as good (median = 4; interquartile range = 3.25-5). We conclude that further examination of devices capable of auscultation in high noise military environments is needed. In-flight testing of device 2 for use by end users has been completed and will be reported in a separate manuscript.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancy.

Peritoneal surface malignancies have historically presented a treatment challenge for clinicians. Not infrequently, epithelial cancers can seed the peritoneal cavity. Neoplasms of the appendix can result in peritoneal dissemination of disease and pseudomyxoma peritonei; in colon cancer, up to 25% with recurrent disease will develop a peritoneal surface predominant pattern of recurrence (1), and among those resected advanced gastric cancer, the majority of patients who recur in the first five years following surgery will develop peritoneal disease (2). Among the approximately 21,290 cases of ovarian cancer cases estimated to be diagnosed in 2015 (3), most will present in an advanced disease state, many with evidence of peritoneal carcinomatosis. In addition to epithelial derived cancers, 10-15% of the approximately 2,500 cases of malignant mesothelioma diagnosed in the U.S. will develop in the peritoneal cavity (4). For all these tumor histologies, cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been considered in the treatment algorithm for selected patients. Over time, CRS/HIPEC has seen an increased utilization in treating select patients with peritoneal disease patterns previously considered inoperable, and has been associated with favorable survival outcomes. In patients with colorectal peritoneal carcinomatosis, a recent retrospective study of 539 patients undergoing a complete cytoreduction reported a median overall survival of 32.6 months (5). No doubt these observed improved outcomes compared to historical cohorts are multifactorial, reflecting improvements in systemic therapies, refinements in surgical techniques and perioperative care, and a better understanding of tumor biology contributing to better patient selection for surgery. Nonetheless, the remarkably favorable data are compelling and speak for the importance of consideration of CRS/ HIPEC in the context of a multidisciplinary approach for patients with peritoneal surface malignancy. This issue of Journal of Gastrointestinal Oncology (JGO) focuses on CRS/HIPEC and its application for various cancers. A paper led by the editors highlight some of the important historical developments in the evolution of CRS and HIPEC. Dr. Paul Sugarbaker and colleagues share their extensive expertise discussing surgical techniques of CRS/ HIPEC and pharmacology of intraperitoneal chemotherapy, while Dr. Goodman provides an excellent review of the selection of chemotherapeutic agents used for this procedure. Dr. Low presents an interesting summary on the use of MRI in the pre-operative evaluation and surveillance of patients being considered for or treated with CRS/HIPEC. Finally, each of the five tumor histologies discussed above is considered in depth in a separate manuscript, including two original papers studying CRS/HIPEC for high grade appendiceal cancer and ovarian cancer. Also in this issue is an important section on quality issues pertaining to CRS/HIPEC, including a review paper discussing the morbidity and mortality associated with the procedure. These procedures can be extensive, and not without risk, and consideration of these factors in the clinical decision making is essential. Dr. Lambert provides a very thoughtful synopsis of the palliative role of CRS/HIPEC, and Dr. Turaga discusses the impact of surgical volume in centers of these procedures on surgical outcomes. Dr. Votanopoulos presents a review of the indications and outcomes following repeat HIPEC surgery, which can be sometimes considered in select patients. Finally, Dr. Nash discusses current