Perspectives of African stakeholders on gene drives for malaria control and elimination: a multi-country survey.

BACKGROUND: Gene drive modified mosquitoes (GDMMs) have the potential to address Africa's persistent malaria problem, but are still in early stages of development and testing. Continuous engagement of African stakeholders is crucial for successful evaluation and implementation of these technologies. The aim of this multi-country study was, therefore, to explore the insights and recommendations of key stakeholders across Africa on the potential of GDMMs for malaria control and elimination in the continent. METHODS: A concurrent mixed-methods study design was used, involving a structured survey administered to 180 stakeholders in 25 countries in sub-Saharan Africa, followed by 18 in-depth discussions with selected groups and individuals. Stakeholders were drawn from academia, research and regulatory institutions, government ministries of health and environment, media and advocacy groups. Thematic content analysis was used to identify key topics from the in-depth discussions, and descriptive analysis was done to summarize information from the survey data. RESULTS: Despite high levels of awareness of GDMMs among the stakeholders (76.7%), there was a relatively low-level of understanding of their key attributes and potential for malaria control (28.3%). When more information about GDMMs was provided to the stakeholders, they readily discussed their insights and concerns, and offered several recommendations to ensure successful research and implementation of the technology. These included: (i) increasing relevant technical expertise within Africa, (ii) generating local evidence on safety, applicability, and effectiveness of GDMMs, and (iii) developing country-specific regulations for safe and effective governance of GDMMs. A majority of the respondents (92.9%) stated that they would support field trials or implementation of GDMMs in their respective countries. This study also identified significant misconceptions regarding the phase of GDMM testing in Africa, as several participants incorrectly asserted that GDMMs were already present in Africa, either within laboratories or released into the field. CONCLUSION: Incorporating views and recommendations of African stakeholders in the ongoing research and development of GDMMs is crucial for instilling stakeholder confidence on their potential application. These findings will enable improved planning for GDMMs in Africa as well as improved target product profiles for the technologies to maximize their potential for solving Africa's enduring malaria challenge.

Requirements for market entry of gene drive-modified mosquitoes for control of vector-borne diseases: analogies to other biologic and biotechnology products.

Gene drive-modified mosquitoes (GDMMs) are proposed as new tools for control and elimination of malaria and other mosquito-borne diseases, and promising results have been observed from testing conducted in containment. Although still at an early stage of development, it is important to begin now to consider approval procedures and market entry strategies for the eventual implementation of GDMMs in the context of disease control programs, as these could impact future research plans. It is expected that, as for other types of new products, those seeking to bring GDMMs to market will be required to provide sufficient information to allow the regulator(s) to determine whether the product is safe and effective for its proposed use. There already has been much emphasis on developing requirements for the biosafety components of the "safe and effective" benchmark, largely concerned with their regulation as genetically modified organisms. Other potential approval requirements have received little attention, however. Although GDMMs are expected to be implemented primarily in the context of public health programs, any regulatory analogies to other public health products, such as pharmaceuticals, vaccines, or chemical pesticides, must take into account the characteristics of live mosquito products. Typical manufacturing standards related to product identity, potency or quality will need to be adapted to GDMMs. Valuable lessons can be drawn from the regulatory approval processes for other whole organism and genetically modified (GM) organism products. Supply chain requirements, such as scale of production, location and design of production facilities, and methods of distribution and delivery, will be dependent upon the characteristics of the particular GDMM product, the conditions of use, and the region to be served. Plans for fulfilling supply chain needs can build upon experience in the development of other live insect products for use in public health and agriculture. Implementation of GDMMs would benefit from additional research on enabling technologies for long-term storage of mosquito life stages, efficient mass production, and area-wide delivery of GDMMs. Early consideration of these practical requirements for market entry will help to mitigate downstream delays in the development of these promising new technologies.

The Promise and Challenge of Genetic Biocontrol Approaches for Malaria Elimination.

Malaria remains an ongoing public health challenge, with over 600,000 deaths in 2021, of which approximately 96% occurred in Africa. Despite concerted efforts, the goal of global malaria elimination has stalled in recent years. This has resulted in widespread calls for new control methods. Genetic biocontrol approaches, including those focused on gene-drive-modified mosquitoes (GDMMs), aim to prevent malaria transmission by either reducing the population size of malaria-transmitting mosquitoes or making the mosquitoes less competent to transmit the malaria parasite. The development of both strategies has advanced considerably in recent years, with successful field trials of several biocontrol methods employing live mosquito products and demonstration of the efficacy of GDMMs in insectary-based studies. Live mosquito biocontrol products aim to achieve area-wide control with characteristics that differ substantially from current insecticide-based vector control methods, resulting in some different considerations for approval and implementation. The successful field application of current biocontrol technologies against other pests provides evidence for the promise of these approaches and insights into the development pathway for new malaria control agents. The status of technical development as well as current thinking on the implementation requirements for genetic biocontrol approaches are reviewed, and remaining challenges for public health application in malaria prevention are discussed.

Regulatory and policy considerations for the implementation of gene drive-modified mosquitoes to prevent malaria transmission.

Gene drive-modified mosquitoes (GDMMs) are being developed as possible new tools to prevent transmission of malaria and other mosquito-borne diseases. To date no GDMMs have yet undergone field testing. This early stage is an opportune time for developers, supporters, and possible users to begin to consider the potential regulatory requirements for eventual implementation of these technologies in national or regional public health programs, especially as some of the practical implications of these requirements may take considerable planning, time and coordination to address. Several currently unresolved regulatory questions pertinent to the implementation of GDMMs are examined, including: how the product will be defined; what the registration/approval process will be for placing new GDMM products on the market; how the potential for transboundary movement of GDMMs can be addressed; and what role might be played by existing multinational bodies and agreements in authorization decisions. Regulation and policies applied for registration of other genetically modified organisms or other living mosquito products are assessed for relevance to the use case of GDMMs to prevent malaria in Africa. Multiple national authorities are likely to be involved in decision-making, according to existing laws in place within each country for certain product classes. Requirements under the Cartagena Protocol on Biodiversity will be considered relevant in most countries, as may existing regulatory frameworks for conventional pesticide, medical, and biocontrol products. Experience suggests that standard regulatory processes, evidence requirements, and liability laws differ from country to country. Regional mechanisms will be useful to address some of the important challenges.

Investigating transmission of SARS-CoV-2 using novel face mask sampling: a protocol for an observational prospective study of index cases and their contacts in a congregate setting.

INTRODUCTION: This study aims to measure how transmission of SARS-CoV-2 occurs in communities and to identify conditions that lend to increased transmission focusing on congregate situations. We will measure SARS-CoV-2 in exhaled breath of asymptomatic and symptomatic persons using face mask sampling-a non-invasive method for SARS-CoV-2 detection in exhaled air. We aim to detect transmission clusters and identify risk factors for SARS-CoV-2 transmission in presymptomatic, asymptomatic and symptomatic individuals. METHODS AND ANALYSIS: In this observational prospective study with daily follow-up, index cases and their respective contacts are identified at each participating institution. Contact definitions are based on Centers for Disease Control and Prevention and local health department guidelines. Participants will wear masks with polyvinyl alcohol test strips adhered to the inside for 2 hours daily. The strips are applied to all masks used over at least 7 days. In addition, self-administered nasal swabs and (optional) finger prick blood samples are performed by participants. Samples are tested by standard PCR protocols and by novel antigen tests. ETHICS AND DISSEMINATION: This study was approved by the Colorado Multiple Institutional Review Board and the WHO Ethics Review Committee. From the data generated, we will analyse transmission clusters and risk factors for transmission of SARS-CoV-2 in congregate settings. The kinetics of asymptomatic transmission and the evaluation of non-invasive tools for detection of transmissibility are of crucial importance for the development of more targeted control interventions-and ultimately to assist with keeping congregate settings open that are essential for our social fabric. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (#NCT05145803).

A report from the Irish women in cardiology survey, exploring Europe's largest gender gap in cardiology.

Aims: In Ireland, 8% of public cardiology consultants are female; this is the lowest proportion in Europe. We sought to understand perceptions amongst Irish trainees and consultants regarding aspects of working in cardiology in order to identify areas that can be targeted to improve gender equality. Methods and Results: In September 2021, the Irish Cardiac Society distributed a questionnaire to trainees and consultants in the Republic and Northern Ireland. Ethical approval was obtained from the University College Dublin, Ireland. There were 94 respondents (50% male, 50% consultants) which equates to ∼30% of all trainees and consultants in all Ireland. Although females were more likely to be single, overall, they had additional child-care responsibilities compared with male counterparts. Despite 53% of the respondents preferring to work less than full time, 64% reported a perceived lack of support from their departments. Males were significantly more likely to go into procedural/high radiation sub-specialities. Bullying was reported by 53% of females. Almost 80% of females experienced sexism and 30% reported being overlooked for professional advancement based on their sex. Females also rated their career prospects lower than males. Key challenges for women were: sexism, maternity leave/child-care responsibilities, cardiology as a 'boys club' and lack of flexible training. There was interest from both males and females in a mentorship programme and support for women in leadership positions. Conclusion: Discrimination including sexism, bullying, and equal opportunity for professional advancement are key aspects that need to be addressed to improve gender balance in cardiology within Ireland and Northern Ireland.

Adults with Trisomy 21 Have Differential Antibody Responses to Influenza A.

Down syndrome is caused by an extra copy of chromosome 21. In the past two decades, the life expectancy of individuals with Down syndrome has significantly increased from early 20s to early 60s, creating a population of individuals of which little is known about how well they are protected against infectious disease. The goal of this work is to better understand if adults with Down syndrome are well protected against influenza following vaccination. We obtained plasma samples from 18 adults (average age = 31yo) with Down syndrome and 17 age/gender-matched disomic individuals, all vaccinated against influenza. Antibody concentration to influenza A was measured using ELISA and antibody titers were measured using a hemagglutinin inhibition assay. Statistical analysis was performed using Stata Statistical Software. Adults with Down syndrome had a significantly increased concentration of antibodies to a mixture of influenza A viral proteins; however, they had a significantly decreased titer to the Influenza A/Hong Kong compared to disomic controls. These findings suggest that more vigorous studies of B- and T-cell function in adults with Down syndrome with respect to influenza vaccination are warranted, and that this population may benefit from a high-dose influenza vaccine.

Evaluation of a survey for acute care programme directors on the utilisation of point-of-care ultrasound.

PURPOSE: Point-of-care ultrasound (POCUS) is ultrasound brought to the patient's bedside and performed in 'real time' by the healthcare provider. The utility of POCUS to facilitate management of the acutely ill patient has been demonstrated for multiple pathologies. However, the integration of ultrasonography and echocardiography training into residency curriculum varies across the acute care specialties. STUDY DESIGN: After an institutional review board approval, anaesthesiology, emergency medicine, family medicine, internal medicine, paediatrics and general surgery programme directors (PDs) were surveyed. The survey consisted of 11 questions evaluating the primary bedside assessment tool for common acute care situations, POCUS topics that the PDs were comfortable practising and topics that the PDs felt were useful for their specialty. Barriers to POCUS use, certification and documentation were also surveyed. RESULTS: Overall, 270 PD surveys were completed. The preferred primary assessment tool for common acute care situations varied with specialty; emergency medicine PDs consistently responded that POCUS was the diagnostic modality of choice (p<0.0001). The majority of the PDs reported lack of educational opportunities as the primary barrier to learning POCUS (64%). Most PDs indicated that POCUS examinations should be documented (95.7%), and 39% reported that departmental certification would be sufficient. CONCLUSIONS: This study is the first to evaluate differences in the preferred initial bedside assessment tool between the acute care specialties. Although POCUS is a superior tool for evaluating acute pathologies, disconnect between education and utilisation remains. This study highlights the need to incorporate POCUS into the acute care specialty curriculum.

Biomarker profiling for risk of future heart failure (HFpEF) development.

BACKGROUND: The purpose of this study was to investigate the utility of BNP, hsTroponin-I, interleukin-6, sST2, and galectin-3 in predicting the future development of new onset heart failure with preserved ejection fraction (HFpEF) in asymptomatic patients at-risk for HF. METHODS: This is a retrospective analysis of the longitudinal STOP-HF study of thirty patients who developed HFpEF matched to a cohort that did not develop HFpEF (n = 60) over a similar time period. Biomarker candidates were quantified at two time points prior to initial HFpEF diagnosis. RESULTS: HsTroponin-I and BNP at baseline and follow-up were statistically significant predictors of future new onset HFpEF, as was galectin-3 at follow-up and concentration change over time. Interleukin-6 and sST2 were not predictive of future development of new onset HFpEF in this study. Unadjusted biomarker combinations of hsTroponin-I, BNP, and galectin-3 could significantly predict future HFpEF using both baseline (AUC 0.82 [0.73,0.92]) and follow-up data (AUC 0.86 [0.79,0.94]). A relative-risk matrix was developed to categorize the relative-risk of new onset of HFpEF based on biomarker threshold levels. CONCLUSION: We provided evidence for the utility of BNP, hsTroponin-I, and Galectin-3 in the prediction of future HFpEF in asymptomatic event-free populations with cardiovascular disease risk factors.

A Cross-Sectional Survey of Biosafety Professionals Regarding Genetically Modified Insects.

BACKGROUND: Genetic technologies such as gene editing and gene drive create challenges for existing frameworks used to assess risk and make regulatory determinations by governments and institutions. Insect genetic technologies including transgenics, gene editing, and gene drive may be particularly challenging because of the large and increasing number of insect species being genetically modified and the degree of familiarity with these organisms and technologies by biosafety officials charged with making containment decisions. METHODS: An anonymous online survey of biosafety professionals was distributed to the membership of ABSA International, a global society of biosafety professionals, to investigate their perspectives on their preparedness to meet these new challenges. RESULTS: Existing guidance used to make containment decisions for nongenetically modified insects was widely seen as adequate, and most respondents thought the available guidance for making containment decisions for genetically modified insects with and without gene drives was inadequate. Most respondents reported having less confidence in their decisions concerning containment of genetically modified insects compared to decisions involving genetically modified microbes, (noninsect) animals, and plants. CONCLUSIONS: These results reveal a need for additional support for biosafety professionals to improve the quality of and confidence in containment decisions regarding genetically modified insects with and without gene drive. These needs might be addressed by increasing training, updating existing guidance, creating new guidance, and creating a third-party accreditation entity to support institutions. Sixty percent of the respondents said they either would or might use a voluntary third-party accreditation service to support insect containment decisions.

Comparison of longitudinal change in sST2 vs BNP to predict major adverse cardiovascular events in asymptomatic patients in the community.

Biomarker-based preventative and monitoring strategies are increasingly used for risk stratification in cardiovascular (CV) disease. The aim of this study was to investigate the utility of longitudinal change in B-type natriuretic peptide (BNP) and sST2 concentrations for predicting incident major adverse CV events (MACE) (heart failure, myocardial infarction, arrhythmia, stroke/transient ischaemic attack and CV death) in asymptomatic community-based patients with risk factors but without prevalent MACE at enrolment. The study population consisted of 282 patients selected from the longitudinal STOP-HF study of asymptomatic patients with risk factors for development of MACE. Fifty-two of these patients developed a MACE. The study was run in two phases comprising of an initial investigative cohort (n = 195), and a subsequent 2:1 (No MACE: MACE) propensity matched verification cohort (n = 87). BNP and sST2 were quantified in all patients at two time points a median of 2.5 years apart. Results highlighted that longitudinal change in sST2 was a statistically significant predictor of incident MACE, (AUC 0.60). A one-unit increment in sST2 change from baseline to follow up corresponded to approximately 7.99% increase in the rate of one or more incident MACE, independent of the baseline or follow-up concentration. In contrast, longitudinal change value of BNP was not associated with MACE. In conclusion, longitudinal change in sST2 but not BNP was associated with incident MACE in asymptomatic, initially event-free patients in the community. Further work is required to evaluate the clinical utility of change in sST2 in risk prediction and event monitoring in this setting.

Toward the Definition of Efficacy and Safety Criteria for Advancing Gene Drive-Modified Mosquitoes to Field Testing.

Mosquitoes containing gene drive systems are being developed as complementary tools to prevent transmission of malaria and other mosquito-borne diseases. As with any new tool, decision makers and other stakeholders will need to balance risks (safety) and benefits (efficacy) when considering the rationale for testing and deploying gene drive-modified mosquito products. Developers will benefit from standards for judging whether an investigational gene drive product meets acceptability criteria for advancing to field trials. Such standards may be formalized as preferred product characteristics and target product profiles, which describe the desired attributes of the product category and of a particular product, respectively. This report summarizes discussions from two scientific workshops aimed at identifying efficacy and safety characteristics that must be minimally met for an investigational gene drive-modified mosquito product to be deemed viable to move from contained testing to field release and the data that will be needed to support an application for first field release.

Correction to: The impact of perennial allergic rhinitis with/without allergic asthma on sleep, work and activity level.

[This corrects the article DOI: 10.1186/s13223-019-0391-9.].

Determining Indicators of High-Quality Application Activities for Team-Based Learning.

Objective. To determine the indicators of quality for application activities in pharmacy team-based learning (TBL). Methods. A modified Delphi process was conducted with pharmacy TBL experts. Twenty-three experts met the inclusion criteria, including having at least four years of TBL experience, designing at least eight TBL sessions, training others to use TBL, and authoring a peer-reviewed TBL pharmacy paper. In round 1, panelists responded to five open-ended questions about their successful TBL applications activities, including satisfaction with the activity and methods for creating positive student outcomes. In round 2, panelists indicated their level of agreement with the round 1 quality indicators using a four-point Likert rating. Consensus was set at 80% strongly agree/agree. In an open comment period, panelists provided suggestions to help expand the indicator descriptions. Indicators were verified based on TBL and the education literature. Results. Twenty panelists (87% of those eligible) responded in round 1 and 17 (85% participation) in round 2. Sixteen quality indicators were identified in round 1, with 14 achieving consensus in round 2. "Uses authentic pharmacy challenges or situations" (88% strongly agree/agree) and "incorporates or provides effective feedback to groups" (88% strongly agree/agree) met consensus. However, "has multiple right answers" (76% strongly agree/agree) and "incorporates elements from school specific emphases (eg, faith, underserved)" (53% strongly agree/agree) did not reach consensus. Conclusions. These indicators can assist faculty members in designing application activities to provide high-quality TBL exercises that promote deep thinking and engaged classroom discussion. The indicators could also guide faculty development and quality improvement efforts, such as peer review of application activities.

The impact of perennial allergic rhinitis with/without allergic asthma on sleep, work and activity level.

Background: Allergic respiratory diseases such as allergic rhinitis (AR) and allergic asthma (AA) are common conditions that can influence sleep and daytime functioning. However, the significance of this impact is unclear-particularly in perennial allergy sufferers. This study investigates the impact of perennial allergy on sleep, daily activities and productivity. Methods: Adults with self-reported or physician-diagnosed perennial AR aged ≥ 18 years were recruited in Denmark, France, Germany and Sweden. Allergy sufferers were identified using online panels closely matching national population characteristics for each country. Impact on sleep, work, productivity and activity (by the Work, Productivity and Activity Index) were analysed. Descriptive analyses were conducted. Results: In total, 511 subjects with perennial AR (47.4% also with seasonal allergy) completed the survey. Most subjects (77.5%) had a physician-diagnosis of AR; 46.4% were diagnosed with both AA and AR. Most subjects (65.2%) reported sensitisation to house dust mites. Of all subjects, 66.0% reported sleep problems. Subjects with sleep problems woke, on average, 3.8 times per night, with 92.0% taking 15+ min to fall asleep (22.2% took 60+ min). Upon waking at night, 40.8% struggled to get back to sleep, and 69.2% had difficulties waking in the morning due to tiredness. Disturbances in daily functioning due to sleep issues were reported in 85.5-95.0% of subjects with sleep problems across all aspects investigated. Overall work and activity impairment were 53.3% and 47.1%, respectively. Sleep issues were more frequent (78.1% vs 54.7%) in those diagnosed with both AR and AA compared to AR alone, and more burdensome, with a greater impact on daily functioning (47.0% vs 33.3%) and impairment in work and activity (62.0% and 54.9% vs 39.3% and 35.2%, respectively). Of all subjects, 20.5% were receiving AIT at the time of the survey; of these, 36.4% reported moderate or great improvement in sleep due to allergy treatment. Conclusions: In perennial AR sufferers, sleep problems are common and impact on daily functioning, with results indicating a greater burden in those with both AR and AA compared to AR alone.

Team-Based Learning for Immunology Courses in Allied Health Programs.

Immunology is now a major component of studies in human biology, with many diseases having immune system involvement. Because so many areas of study include aspects of immunological knowledge, how to teach and incorporate immunology must be evaluated and assessed at all levels of education including K-12, undergraduate, graduate, medical, and professional programs. Traditional teaching methods such as lecture have significant shortcomings which make them less appealing to students today who are more digitally inclined and demand more active and engaging learning environments. Herein, we describe and propose the use of the active learning model of Team-Based Learning (TBL) to incorporate immunology into medical and professional programs. TBL is defined as an evidence based collaborative learning strategy taught in a three-step cycle: pre-class preparation, in-class readiness assurance testing (RAT), and application-focused exercises. In TBL, students are assigned to 6-7 member teams. Students complete the in-class RAT individually followed by taking the RAT as a team (T-RAT). Following the RAT and T-RAT, the instructor can then provide immediate feedback on concepts that proved especially difficult. The remainder of class time is then spent with teams working case studies and applications relative to the instructional topic or disease. Teams decide the best outcome or answer for a given application and report their answers simultaneously in class, followed by a discussion facilitated by the instructor. Research indicates that students involved in active learning classes, such as those using TBL have significantly increased levels of student engagement and high performance on examinations. This review will highlight how to implement TBL into a professional program (medical, dental, nursing, or pharmacy), how to assess student performance and provide real world examples of case studies and applications.

Antibiotic Hypersensitivity Mechanisms.

Antibiotics are commonly prescribed to treat a variety of bacterial infections. As with all medications, hypersensitivity reactions may occur and clinicians should be able to recognize them accurately and recommend appropriate management. Antibiotic related hypersensitivity reactions may be one of four different types: Type I reactions, which are IgE mediated and may lead to anaphylaxis; Type II reactions that are antibody-mediated and may result in thrombocytopenia, neutropenia, or hemolytic anemia; Type III reaction that involves an immune complex formation such as vasculitis; and Type IV reactions that consist of four subtypes and typically include a rash of varying level of severity with or without systemic signs and symptoms. Herein, we describe the mechanisms of different types of allergic reactions to commonly prescribed antibiotics and offer recommendations for management. Further, we briefly refer to antibiotic reactions that mimic hypersensitivity reactions but are not immune mediated, such as pseudoallergies and serum sickness-like reactions.