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Despite their high clinical relevance, obtaining structural and biophysical data on transmembrane proteins has been hindered by challenges involved in their expression and extraction in a homogeneous, functionally-active form. The inherent enzymatic activity of receptor tyrosine kinases (RTKs) presents additional challenges. Oncogenic fusions of RTKs with heterologous partners represent a particularly difficult-to-express protein subtype due to their high flexibility, aggregation propensity and the lack of a known method for extraction within the native lipid environment. One such protein is the fibroblast growth factor receptor 3 fused with transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3), which has failed to express to sufficient quality or functionality in traditional expression systems. Cell-free protein expression (CFPE) is a burgeoning arm of synthetic biology, enabling the rapid and efficient generation of recombinant proteins. This platform is characterised by utilising an optimised solution of cellular machinery to facilitate protein synthesis in vitro. In doing so, CFPE can act as a surrogate system for a range of proteins that are otherwise difficult to express through traditional host cell-based approaches. Here, functional FGFR3-TACC3 was expressed through a novel cell-free expression system in under 48 h. The resultant protein was reconstituted using SMA copolymers with a specific yield of 300 µg/mL of lysate. Functionally, the protein demonstrated significant kinase domain phosphorylation ( t  <  0.0001 ). Currently, there is no published, high-resolution structure of any full-length RTK. These findings form a promising foundation for future research on oncogenic RTKs and the application of cell-free systems for synthesising functional membrane proteins.

Sampling of visitors to a major New York City tourist attraction during April–July 2016 revealed substantial levels of asymptomatic and symptomatic respiratory virus shedding among the ambulatory adult population. Abstract To determine rates of both symptomatic and asymptomatic infection among ambulatory adults, we collected nasopharyngeal swab specimens, demographic characteristics, and survey information from 1477 adult visitors to a New York City tourist attraction during April–July 2016. Multiplex polymerase chain reaction analysis was used to identify specimens positive for common respiratory viruses. A total of 7.2% of samples tested positive for respiratory viruses; among positive samples, 71.0% contained rhinovirus, and 21.5% contained coronavirus. Influenza virus, respiratory syncytial virus, and parainfluenza virus were also detected. Depending on symptomatologic definition, 57.7%–93.3% of positive samples were asymptomatic. These findings indicate that significant levels of asymptomatic respiratory viral shedding exist during summer among the ambulatory adult population.

Widespread use of at-home rapid COVID-19 antigen tests has been proposed as an important public health intervention to interrupt chains of transmission. Antigen tests may be preferred over PCR because they provide on-demand results for relatively low cost and can identify people when they are most likely to be infectious, particularly when used daily. Yet the extent to which a frequent antigen testing intervention will result in a positive public health impact for COVID-19 will depend on high acceptability and high adherence to such regimens. We conducted a mixed-methods study assessing acceptability of and adherence to a daily at-home mobile-app connected rapid antigen testing regimen among employees of a US-based media company. Acceptability was assessed across seven domains of the Theoretical Framework of Acceptability. Among 31 study participants, acceptability of the daily testing intervention was generally high, with participants reporting high perceived effectiveness, intervention coherence, and self-efficacy; positive affective attitude; acceptable degree of burden and opportunity cost; and assessing the intervention as ethical. 71% reported a preference to test daily using an at-home antigen test than weekly employment-based PCR. Mean adherence to the 21-day testing regimen was 88% with 43% of participants achieving 100% adherence, 48% testing at least every other day, and 10% testing less than every other day. Despite overall high acceptability and adherence, we identified three implementation challenges that must be addressed for frequent serial testing for COVID-19 to be implemented at scale and have a positive public health impact. First, users need guidance on how and when to adapt testing frequencies to different epidemiological conditions. Second, users and institutions need guidelines for how to safely store and share test results. Third, implementation of serial testing strategies must prioritize health equity and protect those most vulnerable to COVID-19.

Background Pre-exposure prophylaxis (PrEP) is an effective biomedical intervention to prevent HIV, however uptake of PrEP across the United States has been slow and uneven. Understanding “what it takes” to implement PrEP so that it reaches those groups with the highest rates of new diagnoses is a critically important and understudied question. This descriptive case study details the development of an implementation science tool to guide the introduction of PrEP into new settings. Methods The Universal Stages of Implementation Completion (U-SIC) was customized for the provision of PrEP services (PrEP-SIC) by using subject matter expert recommendations to operationalize PrEP implementation processes into discreet activities. Six clinical sites used the PrEP-SIC retrospectively and prospectively to assess the extent to which the PrEP-SIC activities mapped onto their experience of introducing oral daily, event-driven, and injectable PrEP into their clinical settings. Interviews with site champions and PrEP-SIC data, including proportion of activities completed, were analyzed to refine the PrEP-SIC and identify patterns of implementation behavior. Results Five themes emerged about the accuracy of the PrEP-SIC to capture real world implementation processes: (1) Some PrEP-SIC activities, such as generating a costing plan, are not reflected in real-world implementation; (2) Sites do not define sustainment as achieving a set of quantitative program goals, but rather as being able to continue a program through staffing turnovers and shortages; (3) Written protocols and reviewing clinic data for program improvement were identified as two key factors that differentiate sites that reached sustainment from sites that did not; (4) The PrEP-SIC is assessed as somewhat useful to guide introduction of PrEP, but pairing the tool with technical assistance or coaching would optimize its utility; (5) Implementation is cyclical and recursive and pre-implementation activities may need to be revisited over time to ensure sustainment. Conclusions The case study has resulted in a PrEP-SIC that accurately captures an idealized implementation process. Using a well-defined set of implementation activities as a roadmap with supportive services to clinics, like technical assistance or implementation coaching, could direct implementation efforts and facilitate the integration of PrEP into new clinical settings that reach the people who need PrEP the most.

Introduction Approval of the first long‐acting injectable antiretroviral therapy (LAI ART) medication heralded a new era of HIV treatment. However, the years since approval have been marked by implementation challenges. The “Accelerating Implementation of Multilevel Strategies to Advance Long‐Acting Injectable for Underserved Populations (ALAI UP Project)” aims to accelerate the systematic and equitable delivery of LAI ART. Methods We coded and analysed implementation barriers according to the Consolidated Framework for Implementation Research (CFIR) domains, desired resources and programme goals from questionnaire short‐answer responses by clinics across the United States responding to ALAI UP's solicitation to participate in the project between November 2022 and January 2023. Results Thirty‐eight clinics responded to ALAI UP's solicitation. The characteristics of LAI ART as an innovation (cost, complexity of procurement, dosing interval, limited eligibility) precipitated and interacted with barriers in other CFIR domains. Barriers included obtaining coverage for the cost of medication (27/38 clinics) (outer setting); need for new workflows and staffing (12/38) and/or systems to support injection scheduling/coordination (16/38), transportation and expanded clinic hours (13/38) (inner setting); and patient (10/38) and provider (7/38) education (individuals). To support implementation, applicants sought: technical assistance to develop protocols and workflows (18/38), specifically strategies to address payor challenges (8/38); additional staff for care coordination and benefits navigation (17/38); opportunities to share experiences with other implementing clinics (12/38); patient‐facing materials to educate and increase demand (7/38); and support engaging communities (6/38). Clinics’ LAI ART programme goals varied. Most prioritized delivering LAI ART to their most marginalized patients struggling to achieve viral suppression on oral therapy, despite awareness that current US Food and Drug Administration approval is only for virally suppressed patients. The goal for LAI ART reach after 1 year of implementation ranged from ≤10% of patients with HIV on LAI ART (17/38) to ≥50% of patients (2/38). Conclusions Diverse clinic types are interested in offering LAI ART and most aspire to use LAI ART to support their most vulnerable patients sustain viral suppression. Dedicated resources centred on equity and relevant to context and population are needed to support implementation. Otherwise, the introduction of LAI ART risks exacerbating, not ameliorating, health disparities.

Viral respiratory infections are an important public health concern due to their prevalence, transmissibility, and potential to cause serious disease. Disease severity is the product of several factors beyond the presence of the infectious agent, including specific host immune responses, host genetic makeup, and bacterial coinfections. To understand these interactions within natural infections, we designed a longitudinal cohort study actively surveilling respiratory viruses over the course of 19 months (2016 to 2018) in a diverse cohort in New York City. We integrated the molecular characterization of 800+ nasopharyngeal samples with clinical data from 104 participants. Transcriptomic data enabled the identification of respiratory pathogens in nasopharyngeal samples, the characterization of markers of immune response, the identification of signatures associated with symptom severity, individual viruses, and bacterial coinfections. Specific results include a rapid restoration of baseline conditions after infection, significant transcriptomic differences between symptomatic and asymptomatic infections, and qualitatively similar responses across different viruses. We created an interactive computational resource (Virome Data Explorer) to facilitate access to the data and visualization of analytical results.

The lack of capacity for governance of Ministries of Health (MoHs) is frequently advanced as an explanation for health systems failures in low- and middle-income countries (LMICs). But do we understand what governance capacities MoHs should have? Existing frameworks have not fully captured the dynamic and contextually determined role of MoHs, and there are few frameworks that specifically define capacities for governance. We propose a multidimensional framework of capacities for governance by MoHs that encompasses both the \"hard\" ( de jure , explicit and functional) and \"soft\" ( de facto , tacit, and relational) dimensions of governance, and reflects the diversification of their mandates in the context of the Sustainable Development Goals (SDGs). Four case studies illustrate different aspects of the framework. We hope that the framework will have multiple potential benefits including benchmarking MoH governance capacities, identifying and helping analyze capacity gaps, and guiding strategies to strengthen capacity.

Background Respiratory viral infections are a major cause of morbidity and mortality worldwide. However, their characterization is incomplete because prevalence estimates are based on syndromic surveillance data. Here, we address this shortcoming through the analysis of infection rates among individuals tested regularly for respiratory viral infections, irrespective of their symptoms. Methods We carried out longitudinal sampling and analysis among 214 individuals enrolled at multiple New York City locations from fall 2016 to spring 2018. We combined personal information with weekly nasal swab collection to investigate the prevalence of 18 respiratory viruses among different age groups and to assess risk factors associated with infection susceptibility. Results 17.5% of samples were positive for respiratory viruses. Some viruses circulated predominantly during winter, whereas others were found year round. Rhinovirus and coronavirus were most frequently detected. Children registered the highest positivity rates, and adults with daily contacts with children experienced significantly more infections than their counterparts without children. Conclusion Respiratory viral infections are widespread among the general population with the majority of individuals presenting multiple infections per year. The observations identify children as the principal source of respiratory infections. These findings motivate further active surveillance and analysis of differences in pathogenicity among respiratory viruses.

Respiratory viruses are common in human populations, causing significant levels of morbidity. Understanding the distribution of these viruses is critical for designing control methods. However, most data available are from medical records and thus predominantly represent symptomatic infections. Estimates for asymptomatic prevalence are sparse and span a broad range. In this study, we aimed to measure more precisely the proportion of infections that are asymptomatic in a general, ambulatory adult population. We recruited participants from a New York City tourist attraction and administered nasal swabs, testing them for adenovirus, coronavirus, human metapneumovirus, rhinovirus, influenza virus, respiratory syncytial virus, and parainfluenza virus. At recruitment, participants completed surveys on demographics and symptomology. Analysis of these data indicated that over 6% of participants tested positive for shedding of respiratory virus. While participants who tested positive were more likely to report symptoms than those who did not, over half of participants who tested positive were asymptomatic. Most observation of human respiratory virus carriage is derived from medical surveillance; however, the infections documented by this surveillance represent only a symptomatic fraction of the total infected population. As the role of asymptomatic infection in respiratory virus transmission is still largely unknown and rates of asymptomatic shedding are not well constrained, it is important to obtain more-precise estimates through alternative sampling methods. We actively recruited participants from among visitors to a New York City tourist attraction. Nasopharyngeal swabs, demographics, and survey information on symptoms, medical history, and recent travel were obtained from 2,685 adults over two seasonal arms. We used multiplex PCR to test swab specimens for a selection of common respiratory viruses. A total of 6.2% of samples (168 individuals) tested positive for at least one virus, with 5.6% testing positive in the summer arm and 7.0% testing positive in the winter arm. Of these, 85 (50.6%) were positive for human rhinovirus (HRV), 65 (38.7%) for coronavirus (CoV), and 18 (10.2%) for other viruses (including adenovirus, human metapneumovirus, influenza virus, and parainfluenza virus). Depending on the definition of symptomatic infection, 65% to 97% of infections were classified as asymptomatic. The best-fit model for prediction of positivity across all viruses included a symptom severity score, Hispanic ethnicity data, and age category, though there were slight differences across the seasonal arms. Though having symptoms is predictive of virus positivity, there are high levels of asymptomatic respiratory virus shedding among the members of an ambulatory population in New York City. IMPORTANCE Respiratory viruses are common in human populations, causing significant levels of morbidity. Understanding the distribution of these viruses is critical for designing control methods. However, most data available are from medical records and thus predominantly represent symptomatic infections. Estimates for asymptomatic prevalence are sparse and span a broad range. In this study, we aimed to measure more precisely the proportion of infections that are asymptomatic in a general, ambulatory adult population. We recruited participants from a New York City tourist attraction and administered nasal swabs, testing them for adenovirus, coronavirus, human metapneumovirus, rhinovirus, influenza virus, respiratory syncytial virus, and parainfluenza virus. At recruitment, participants completed surveys on demographics and symptomology. Analysis of these data indicated that over 6% of participants tested positive for shedding of respiratory virus. While participants who tested positive were more likely to report symptoms than those who did not, over half of participants who tested positive were asymptomatic.

The role of ministries of health has changed, progressively shifting from direct provision of health services to overall stewardship of the health sector, including financing and oversight of private providers.1 Health reforms have triggered that shift, fostering new institutions, such as national medicines agencies, public health agencies, disease control agencies (eg, National Cancer Agencies) or health financing organisations responsible for risk and fund pooling, purchasing of health services, or targeting the poor or vulnerable groups. Health systems processes must move from a top-down to inclusive policy, planning and implementation processes, increasingly adopting a people-centred approach.3 Democratic rights, human rights, equity and ethics values have become prominent in national policy debates. In response to this call, twenty-first century health systems need to be participatory, inclusive and pluralist, following Whole of Society and Whole of Government principles.3 4 People’s voice is a core driver of health systems’ performance towards Universal Health Coverage.5 In such a context, governance arrangements are changing and rely more on inclusion, participation and co-production.6 This paper presents a framework to help understand health systems governance; examine what we know about this important health system function, and what has been less explored, leaving an important gap in our health system knowledge and practice. Missing links The past decade experienced an increase of the literature on health system governance; various frameworks presenting attributes or dimensions of governance have emerged and define the nature and scope of this function.11 12 In a review published in 2014, Barbazza and Tello highlight the challenge of reaching a consensus and communicating a clear agenda on governance in health.10 They conclude that frameworks and tools defining governance have been developed independently, seldom building on strengths and weaknesses as well as practical applications of previous instruments; they lack a shared frame of reference which would enable governance to become a truly actionable health system function.