Exploring Models for an International Legal Agreement on the Global Antimicrobial Commons: Lessons from Climate Agreements.

An international legal agreement governing the global antimicrobial commons would represent the strongest commitment mechanism for achieving collective action on antimicrobial resistance (AMR). Since AMR has important similarities to climate change-both are common pool resource challenges that require massive, long-term political commitments-the first article in this special issue draws lessons from various climate agreements that could be applicable for developing a grand bargain on AMR. We consider the similarities and differences between the Paris Climate Agreement and current governance structures for AMR, and identify the merits and challenges associated with different international forums for developing a long-term international agreement on AMR. To be effective, fair, and feasible, an enduring legal agreement on AMR will require a combination of universal, differentiated, and individualized requirements, nationally determined contributions that are regularly reviewed and ratcheted up in level of ambition, a regular independent scientific stocktake to support evidence informed policymaking, and a concrete global goal to rally support.

Governing the Global Antimicrobial Commons: Introduction to Special Issue.

Antimicrobial resistance is one of the greatest public health crises of our time. The natural biological process that causes microbes to become resistant to antimicrobial drugs presents a complex social challenge requiring more effective and sustainable management of the global antimicrobial commons-the common pool of effective antimicrobials. This special issue of Health Care Analysis explores the potential of two legal approaches-one long-term and one short-term-for managing the antimicrobial commons. The first article explores the lessons for antimicrobial resistance that can be learned from recent climate change agreements, and the second article explores how existing international laws can be adapted to better support global action in the short-term.

Making Use of Existing International Legal Mechanisms to Manage the Global Antimicrobial Commons: Identifying Legal Hooks and Institutional Mandates.

Antimicrobial resistance (AMR) is an urgent threat to global public health and development. Mitigating this threat requires substantial short-term action on key AMR priorities. While international legal agreements are the strongest mechanism for ensuring collaboration among countries, negotiating new international agreements can be a slow process. In the second article in this special issue, we consider whether harnessing existing international legal agreements offers an opportunity to increase collective action on AMR goals in the short-term. We highlight ten AMR priorities and several strategies for achieving these goals using existing "legal hooks" that draw on elements of international environmental, trade and health laws governing related matters that could be used as they exist or revised to include AMR. We also consider the institutional mandates of international authorities to highlight areas where additional steps could be taken on AMR without constitutional changes. Overall, we identify 37 possible mechanisms to strengthen AMR governance using the International Health Regulations, the Agreement on the Application of Sanitary and Phytosanitary Measures, the Agreement on Trade-Related Aspects of Intellectual Property Rights, the Agreement on Technical Barriers to Trade, the International Convention on the Harmonized Commodity Description and Coding System, and the Basel, Rotterdam, and Stockholm conventions. Although we identify many shorter-term opportunities for addressing AMR using existing legal hooks, none of these options are capable of comprehensively addressing all global governance challenges related to AMR, such that they should be pursued simultaneously with longer-term approaches including a dedicated international legal agreement on AMR.

The improvement in overall survival from unrelated donor transplantation in Australia and New Zealand is driven by a reduction in non-relapse mortality: A study from the ABMTRR.

Unrelated donors (UDs) are the commonest source for allogeneic transplantation (alloSCT), with higher non-relapse mortality (NRM) than siblings. We analyzed data from the Australasian Bone Marrow Transplant Recipient Registry from adults receiving a first UD alloSCT during 2001-2015, to determine whether and how NRM has changed. Predictors of outcome were determined using cox regression, accounting for time-interactions and competing risks. A total of 2308 patients met inclusion criteria. Changes over time included increasing age, utilization of peripheral blood cells, reduced intensity conditioning, and T-cell depletion. Three-year OS increased significantly from 44% in 2001-2005 to 58% in 2011-2015 (p < 0.001). This was attributed to a reduction in NRM from 35% to 24% (p < 0.001) with no change in relapse. Factors associated with increased NRM included age, male sex, CMV seropositivity, HLA mismatch, transplant more than 6 months from diagnosis, and T-cell depletion when administered during 2001-2005. Survival following UD SCT has improved by almost 15% over the past decade, driven by improvements in NRM. This has occurred despite increasing recipient age and appears to be due to better donor selection, reduced delays to transplantation, and improved prevention and management of GVHD.

A Framework for the Virtual Medical Interview Process: Considerations for the Applicant and the Interviewer.

Background: Videoconferencing platforms are being used for the purposes of interviewing in academic medicine because of the coronavirus disease 2019 pandemic. We present considerations applicable to interviewers and interviewees in the virtual space, with a focus on medical school and residency applicants. Methods: We reviewed the literature regarding the virtual interview process for medical school and residency by searching PubMed using the following keywords and terms: "interview," "academic medicine," "medical school application," "residency application," "virtual interviews," and "videoconferencing." Our search identified 701 results, from which we selected 36 articles for review. Results: The garnered information focuses on strategies for optimizing the virtual interview process from the standpoint of both the interviewer and the interviewee. We discuss the advantages and disadvantages of the virtual interview process and present recommendations. Conclusion: While the future of the interview process for medical school and residency is uncertain, virtual interviewing is a common and growing practice that will continue to be at least part of the medical interview process for years to come. Interviewers and interviewees should prepare to adapt to the evolving changes in the process.

Developing New Online Course Accessibility Services for Faculty through Collaboration between Librarians and Campus Departments: A Case Study.

Literature has shown that inaccessible content is a barrier to student success and an impediment to student retention. Despite legal obligations for accessible course content, creators of course materials are often unaware of the benefits of improved accessibility and their personal liability. To address these accessibility issues, a partnership was developed between the library and two campus departments to create a formal, campus wide accessibility service that would make all online course content fully accessible on Day 1, through design initiatives rather than having faculty wait for an accommodation request, to foster student success and support faculty course development.

Combatting a "Twin-demic": A quantitative assessment of COVID-19 and influenza vaccine hesitancy in primary care patients.

Background: Public health officials anticipate severe health outcomes amidst the circulation of two major viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza. This study investigated intent to be vaccinated against COVID-19 and influenza, and sought to identify attitudes towards vaccines and barriers for vaccine acceptance. Methods: This observational cross-sectional study was conducted in the Louisiana State University Medicine Clinic from September 2020 to December 2020. Intent to be vaccinated against the COVID-19 and influenza virus was assessed through a brief questionnaire. Additionally, hesitancy and attitudes regarding vaccines were ascertained using validated 5-point Likert scales. In total, 280 patients completed the questionnaire. Results: A total of 248 patients were included in the final analysis. Overall 167 (67%, 95% CI = 61.1-73.0%) of patients were unsure or did not intend to be vaccinated against COVID-19, while only 19.3% (95% CI = 14.4-24.5%) were unsure or did not intend to be vaccinated against the influenza vaccine. Reasons for COVID-19 vaccine hesitancy included concern regarding side effects, fear of getting sick from the vaccine, and the absence of vaccine recommendations from their doctor. Concerningly, African American patients demonstrated decreased likelihood of receiving the COVID-19 vaccine. Conclusion: This survey revealed that only 1 in 3 adults intended to be vaccinated against COVID-19, while 8 out of 10 adults intended to receive the influenza vaccine. Patients who intended on getting the COVID-19 vaccine were less likely to be African American. Given the degree of hesitancy against COVID-19 vaccination, a multifaceted approach to facilitate vaccine uptake that includes vaccine education, behavioral change strategies, and health promotion, is paramount.

Mapping social distancing measures to the reproduction number for COVID-19.

In the absence of a vaccine, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) transmission has been controlled by preventing person-to-person interactions via social distancing measures. In order to re-open parts of society, policy-makers need to consider how combinations of measures will affect transmission and understand the trade-offs between them. We use age-specific social contact data, together with epidemiological data, to quantify the components of the COVID-19 reproduction number. We estimate the impact of social distancing policies on the reproduction number by turning contacts on and off based on context and age. We focus on the impact of re-opening schools against a background of wider social distancing measures. We demonstrate that pre-collected social contact data can be used to provide a time-varying estimate of the reproduction number (R). We find that following lockdown (when R= 0.7, 95% CI 0.6, 0.8), opening primary schools has a modest impact on transmission (R = 0.89, 95% CI 0.82-0.97) as long as other social interactions are not increased. Opening secondary and primary schools is predicted to have a larger impact (R = 1.22, 95% CI 1.02-1.53). Contact tracing and COVID security can be used to mitigate the impact of increased social mixing to some extent; however, social distancing measures are still required to control transmission. Our approach has been widely used by policy-makers to project the impact of social distancing measures and assess the trade-offs between them. Effective social distancing, contact tracing and COVID security are required if all age groups are to return to school while controlling transmission. This article is part of the theme issue 'Modelling that shaped the early COVID-19 pandemic response in the UK'.

Mapping the drivers of within-host pathogen evolution using massive data sets.

Differences among hosts, resulting from genetic variation in the immune system or heterogeneity in drug treatment, can impact within-host pathogen evolution. Genetic association studies can potentially identify such interactions. However, extensive and correlated genetic population structure in hosts and pathogens presents a substantial risk of confounding analyses. Moreover, the multiple testing burden of interaction scanning can potentially limit power. We present a Bayesian approach for detecting host influences on pathogen evolution that exploits vast existing data sets of pathogen diversity to improve power and control for stratification. The approach models key processes, including recombination and selection, and identifies regions of the pathogen genome affected by host factors. Our simulations and empirical analysis of drug-induced selection on the HIV-1 genome show that the method recovers known associations and has superior precision-recall characteristics compared to other approaches. We build a high-resolution map of HLA-induced selection in the HIV-1 genome, identifying novel epitope-allele combinations.

A restatement of the natural science evidence base on the effects of endocrine disrupting chemicals on wildlife.

Endocrine disrupting chemicals (EDCs) are substances that alter the function of the endocrine system and consequently cause adverse effects to humans or wildlife. The release of particular EDCs into the environment has been shown to negatively affect certain wildlife populations and has led to restrictions on the use of some EDCs. Current chemical regulations aim to balance the industrial, agricultural and/or pharmaceutical benefits of using these substances with their demonstrated or potential harm to human health or the environment. A summary is provided of the natural science evidence base informing the regulation of chemicals released into the environment that may have endocrine disrupting effects on wildlife. This summary is in a format (a 'restatement') intended to be policy-neutral and accessible to informed, but not expert, policy-makers and stakeholders.

Oral Health and Dental Students' Perceptions of Their Clinical Learning Environment: A Focus Group Study.

Creating an optimal clinical learning environment poses a challenge to health professions educators. To evaluate and improve the clinical learning environment, it is necessary to understand students' experiences of their environment and the factors they perceive as having an impact on their learning. The aim of this explorative qualitative study was to examine University of Otago Faculty of Dentistry students' perceptions of their clinical learning environment to gain insights into how learning outcomes could be enhanced. In 2015, all approximately 600 students at all levels of the Bachelor of Oral Health and Bachelor of Dental Surgery degrees at the University of Otago, Dunedin, New Zealand, were invited to participate in focus groups. Focus groups facilitated by the faculty education research fellow and another researcher employed for the project were conducted during the second half of the academic year. Transcribed data were analyzed using a general inductive approach. Twenty-one students from all levels of the two programs attended one of six confidential focus groups. Three broad themes were evident in the results from all groups: feedback processes, assessments and grading, and tutor interactions. In the focus groups, students expressed dissatisfaction regarding current feedback practices, types of feedback to benefit learning, consistency in the grading system, and impact of different educators' teaching styles on learning. These results indicated a need for further research and curricular efforts to promote good student-teacher relationships in the clinical learning environment, which are paramount for creating an optimal teaching and learning environment and enhancing student outcomes.

Increased T cell trafficking as adjunct therapy for HIV-1.

Although antiretroviral drug therapy suppresses human immunodeficiency virus-type 1 (HIV-1) to undetectable levels in the blood of treated individuals, reservoirs of replication competent HIV-1 endure. Upon cessation of antiretroviral therapy, the reservoir usually allows outgrowth of virus and approaches to targeting the reservoir have had limited success. Ongoing cycles of viral replication in regions with low drug penetration contribute to this persistence. Here, we use a mathematical model to illustrate a new approach to eliminating the part of the reservoir attributable to persistent replication in drug sanctuaries. Reducing the residency time of CD4 T cells in drug sanctuaries renders ongoing replication unsustainable in those sanctuaries. We hypothesize that, in combination with antiretroviral drugs, a strategy to orchestrate CD4 T cell trafficking could contribute to a functional cure for HIV-1 infection.

Impact of Interferon Lambda 4 Genotype on Interferon-Stimulated Gene Expression During Direct-Acting Antiviral Therapy for Hepatitis C.

New directly acting antivirals (DAAs) provide very high cure rates in most patients infected by hepatitis C virus (HCV). However, some patient groups have been relatively harder to treat, including those with cirrhosis or infected with HCV genotype 3. In the recent BOSON trial, genotype 3, patients with cirrhosis receiving a 16-week course of sofosbuvir and ribavirin had a sustained virological response (SVR) rate of around 50%. In patients with cirrhosis, interferon lambda 4 (IFNL4) CC genotype was significantly associated with SVR. This genotype was also associated with a lower interferon-stimulated gene (ISG) signature in peripheral blood and in liver at baseline. Unexpectedly, patients with the CC genotype showed a dynamic increase in ISG expression between weeks 4 and 16 of DAA therapy, whereas the reverse was true for non-CC patients. Conclusion: These data provide an important dynamic link between host genotype and phenotype in HCV therapy also potentially relevant to naturally acquired infection. (Hepatology 2018; 00:000-000).

A restatement of the natural science evidence base concerning the health effects of low-level ionizing radiation.

Exposure to ionizing radiation is ubiquitous, and it is well established that moderate and high doses cause ill-health and can be lethal. The health effects of low doses or low dose-rates of ionizing radiation are not so clear. This paper describes a project which sets out to summarize, as a restatement, the natural science evidence base concerning the human health effects of exposure to low-level ionizing radiation. A novel feature, compared to other reviews, is that a series of statements are listed and categorized according to the nature and strength of the evidence that underpins them. The purpose of this restatement is to provide a concise entrée into this vibrant field, pointing the interested reader deeper into the literature when more detail is needed. It is not our purpose to reach conclusions on whether the legal limits on radiation exposures are too high, too low or just right. Our aim is to provide an introduction so that non-specialist individuals in this area (be they policy-makers, disputers of policy, health professionals or students) have a straightforward place to start. The summary restatement of the evidence and an extensively annotated bibliography are provided as appendices in the electronic supplementary material.

Evolution, human-microbe interactions, and life history plasticity.

A bacterium was once a component of the ancestor of all eukaryotic cells, and much of the human genome originated in microorganisms. Today, all vertebrates harbour large communities of microorganisms (microbiota), particularly in the gut, and at least 20% of the small molecules in human blood are products of the microbiota. Changing human lifestyles and medical practices are disturbing the content and diversity of the microbiota, while simultaneously reducing our exposures to the so-called old infections and to organisms from the natural environment with which human beings co-evolved. Meanwhile, population growth is increasing the exposure of human beings to novel pathogens, particularly the crowd infections that were not part of our evolutionary history. Thus some microbes have co-evolved with human beings and play crucial roles in our physiology and metabolism, whereas others are entirely intrusive. Human metabolism is therefore a tug-of-war between managing beneficial microbes, excluding detrimental ones, and channelling as much energy as is available into other essential functions (eg, growth, maintenance, reproduction). This tug-of-war shapes the passage of each individual through life history decision nodes (eg, how fast to grow, when to mature, and how long to live).

Investigating the effects of age-related spatial structuring on the transmission of a tick-borne virus in a colonially breeding host.

Higher pathogen and parasite transmission is considered a universal cost of colonial breeding due to the physical proximity of colony members. However, this has rarely been tested in natural colonies, which are structured entities, whose members interact with a subset of individuals and differ in their infection histories. We use a population of common guillemots, Uria aalge, infected by a tick-borne virus, Great Island virus, to explore how age-related spatial structuring can influence the infection costs borne by different members of a breeding colony. Previous work has shown that the per-susceptible risk of infection (force of infection) is different for prebreeding (immature) and breeding (adult) guillemots which occupy different areas of the colony. We developed a mathematical model which showed that this difference in infection risk can only be maintained if mixing between these age groups is low. To estimate mixing between age groups, we recorded the movements of 63 individually recognizable, prebreeding guillemots in four different parts of a major colony in the North Sea during the breeding season. Prebreeding guillemots infrequently entered breeding areas (in only 26% of watches), though with marked differences in frequency of entry among individuals and more entries toward the end of the breeding season. Once entered, the proportion of time spent in breeding areas by prebreeding guillemots also varied between different parts of the colony. Our data and model predictions indicate low levels of age-group mixing, limiting exposure of breeding guillemots to infection. However, they also suggest that prebreeding guillemots have the potential to play an important role in driving infection dynamics. This highlights the sensitivity of breeding colonies to changes in the behavior of their members-a subject of particular importance in the context of global environmental change.

Persistent HIV-1 replication maintains the tissue reservoir during therapy.

Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.