Distinguishing Characteristics of Admissions to Various Types of Posthospital Brain Injury Rehabilitation Programs.

OBJECTIVE: Describe and compare the demographic characteristics and disability profiles of individuals admitted to 6 types of posthospital brain injury rehabilitation (PHBIR) programs. SETTING: Data from Residential Neurobehavioral, Residential Neurorehabilitation, Home and Community Neurorehabilitation, Day Treatment, Outpatient Neurorehabilitation, and Supported Living programs serving individuals with acquired brain injury (ABI). PARTICIPANTS: Two thousand twenty-eight individuals with traumatic brain injury (TBI), stroke, or other ABI. MAIN MEASURES: Sex, age, time since injury, and Mayo-Portland Adaptability Inventory, 4th edition (MPAI-4). DESIGN: Retrospective analyses of demographic variables and MPAI-4 Total, Index, and subscale Rasch-derived T-scores on admission comparing diagnostic categories and program types within diagnostic categories. RESULTS: Participants with TBI were predominantly male, and those with stroke were generally older. Admissions to more intensive and supervised programs (residential neurobehavioral and residential neurorehabilitation) generally showed greater disability than admissions to home and community programs who were more disabled than participants in day treatment and outpatient programs. Residential neurobehavioral and supported living program participants generally were male and had TBI. Home and community admissions tended to be more delayed than residential neurorehabilitation admissions. The majority of those with other ABI were admitted to outpatient rather than more intensive programs. Additional analyses demonstrated significant differences in MPAI-4 profiles among the various program types. CONCLUSIONS: Admissions with TBI, stroke, and other ABI to PHBIR differ in demographic factors and disability profiles. When examined within each diagnostic category, demographic features and disability profiles also distinguish among admissions to the various program types. Results provide insights about decision-making in referral patterns to various types of PHBIR programs, although other factors not available for analysis (eg, participant/family preference, program, and funding availability) likely also contribute to admission patterns.

Meningococcal Disease in the Post-COVID-19 Era: A Time to Prepare.

The global invasive meningococcal disease (IMD) landscape changed considerably during the COVID-19 pandemic, as evidenced by decreased incidence rates due to COVID-19 mitigation measures, such as limited social contact, physical distancing, mask wearing, and hand washing. Vaccination rates were also lower during the pandemic relative to pre-pandemic levels. Although policymakers may have shifted their focus away from IMD vaccination programs to COVID-19 vaccination programs, strong arguments support implementation and prioritization of IMD vaccination programs; IMD cases have increased in some countries and IMD rates may even have exceeded pre-pandemic levels. Additional concerns include increased susceptibility due to vaccination coverage gaps, increased incidence of other respiratory pathogens, immunity debt from lockdown restrictions, and increased IMD epidemiologic variability. The full range of benefits of widely available and effective meningococcal vaccines needs to be considered, especially in health technology assessments, where the broad benefits of these vaccines are neither accurately quantified nor captured in implementation policy decisions. Importantly, implementation of meningococcal vaccination programs in the current IMD climate also appeals to broader healthcare principles, including preparedness rather than reactive approaches, generally accepted benefit-risk approaches to vaccination, historical precedent, and the World Health Organization's goal of defeating meningitis by 2030. Countries should therefore act swiftly to bolster existing meningococcal vaccination strategies to provide broad coverage across age groups and serogroups given the recent increases in IMD incidence.

Rule of Prevention: a potential framework to evaluate preventive interventions for rare diseases.

Background: The benefits of preventive interventions lack comprehensive evaluation in standard health technology assessments (HTA), particularly for rare and transmissible diseases. Objective: To identify possible considerations for future HTA using analogies between the treatment and prevention of rare diseases. Study design: An Expert panel meeting assessed whether one HTA assessment framework can be applied to assess both rare disease treatments and preventive interventions. Experts also evaluated the range of value elements currently included in HTAs and their applicability to rare, transmissible, and/or preventable diseases. Results: A broad range of value should be considered when assessing rare, transmissible disease prevention. Although standard HTA can be applied to transmissible diseases, the risk of local outbreaks and the need for large-scale prevention programs suggest a modified assessment framework, capable of incorporating prevention-specific value elements in HTAs. A 'Rule of Prevention' framework was proposed to allow broader value considerations anchored to severity, equity, and prevention benefits in decision-making for preventive interventions for rare transmissible diseases. Conclusion: The proposed prevention framework introduces an explicit initial approach to consistently assess rare transmissible diseases, and to incorporate the broader value of preventive interventions compared with treatment.

Immunization technologies: Time to consider new preventative solutions for respiratory syncytial virus infections.

New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb) to prevent Respiratory Syncytial Virus (RSV) lower respiratory tract disease in infants during their first RSV season. The lack of precedent for mAbs for broad population protection creates challenges in the assessment of upcoming prophylactic long-acting mAbs for RSV, with associated consequences in legislative and registration categorization, as well as in recommendation, funding, and implementation pathways. We suggest that the legislative and regulatory categorization of preventative solutions should be decided by the effect of the product in terms of its impact on the population and health-care systems rather than by the technology used or its mechanism of action. Immunization can be passive and active, both having the same objective of prevention of infectious diseases. Long-acting prophylactic mAbs work as passive immunization, as such, their recommendations for use should fall under the remit of National Immunization Technical Advisory Groups or other relevant recommending bodies for inclusion into National Immunization Programs. Current regulations, policy, and legislative frameworks need to evolve to embrace such innovative preventative technologies and acknowledge them as one of key immunization and public health tools.

Vaccines for a sustainable planet.

The health of the planet is one objective of the United Nations' Sustainable Development Goals. Vaccines can affect not only human health but also planet health by reducing poverty, preserving microbial diversity, reducing antimicrobial resistance, and preventing an increase in pandemics that is fueled partly by climate change.

The Societal Value of Vaccines: Expert-Based Conceptual Framework and Methods Using COVID-19 Vaccines as a Case Study.

Health technology assessments (HTAs) of vaccines typically focus on the direct health benefits to individuals and healthcare systems. COVID-19 highlighted the widespread societal impact of infectious diseases and the value of vaccines in averting adverse clinical consequences and in maintaining or resuming social and economic activities. Using COVID-19 as a case study, this research work aimed to set forth a conceptual framework capturing the broader value elements of vaccines and to identify appropriate methods to quantify value elements not routinely considered in HTAs. A two-step approach was adopted, combining a targeted literature review and three rounds of expert elicitation based on a modified Delphi method, leading to a conceptual framework of 30 value elements related to broader health effects, societal and economic impact, public finances, and uncertainty value. When applying the framework to COVID-19 vaccines in post-pandemic settings, 13 value elements were consensually rated highly important by the experts for consideration in HTAs. The experts reviewed over 10 methods that could be leveraged to quantify broader value elements and provided technical forward-looking recommendations. Limitations of the framework and the identified methods were discussed. This study supplements ongoing efforts aimed towards a broader recognition of the full societal value of vaccines.

Capturing the value of vaccination within health technology assessment and health economics: Literature review and novel conceptual framework.

BACKGROUND: Vaccination provides significant health gains to individuals and society and can potentially improve health equity, healthcare systems and national economies. Policy decisions, however, are rarely informed by comprehensive economic evaluations (EE) including vaccination's wide-ranging value. The objective of this analysis was to focus on health technology assessment systems to identify relevant value concepts in order to improve current EE of non-pandemic vaccines. METHODS: Following a literature review, a novel Value of Vaccination (VoV) framework was developed with experts in vaccine EE from developed countries with established health technology assessment systems. RESULTS: Forty-four studies presenting value frameworks or concepts applicable to vaccination were included. Eighteen unique value concepts relevant to EE were identified and defined. These were categorised within the VoV framework using three dimensions, moving from a narrow payer perspective to a more expansive and societal perspective. The dimensions were: (I) conventional payer perspective concepts (e.g., health gains in vaccinees, direct medical costs); (II) conventional societal perspective concepts (e.g., indirect health/economic gains to caregivers/households, productivity in vaccinees); and (III) novel societal concepts (e.g., financial risk protection, peace of mind, societal health gains, healthcare systems security, political stability, social equity and macroeconomic gains). While good quality evidence and methods are available to support concepts in Dimensions I and II, further work is needed to generate the required evidence for vaccination impact on Dimension III concepts. CONCLUSIONS: The devastating effect on nations of the COVID-19 pandemic has helped to highlight the potential far-reaching benefits that many vaccination programmes can offer. This VoV framework is particularly relevant to policy decisions considering EE, and the potential future expansion of non-pandemic vaccination value considerations. The framework helps to understand and compare current value considerations across countries and payer versus societal perspectives. It provides decision-makers with a transparent and logical path to broaden consideration of VoV in EE.

Capturing the value of vaccination within health technology assessment and health economics: Country analysis and priority value concepts.

BACKGROUND: A value of vaccination framework for economic evaluation (EE) identified unique value concepts for the broad benefits vaccination provides to individuals, society, healthcare systems and national economies. The objectives of this paper were to work with experts in developed countries to objectively identify three priority concepts to extend current EE. METHODS: The previously developed classification of value concepts in vaccination distinguished 18 concepts, categorised as conventional payer and societal perspective concepts and novel broader societal concepts. Their inclusion in current EE guidelines was assessed. Experts identified eight criteria relevant to decision-making and measurement feasibility, which were weighted and used to score each concept. The relative ranking of concepts by importance and the gaps in guidelines were used to identify three priority concepts on which to focus immediate efforts to extend EE. RESULTS: The EE guidelines review highlighted differences across countries and between guidelines and practice. Conventional payer perspective concepts (e.g., individual and societal health gains and medical costs) were generally included, while gaps were evident for conventional societal perspective concepts (e.g., family/caregiver health and economic gains). Few novel broader societal benefits were considered, and only in ad hoc cases. The top-three concepts for near-term consideration: macroeconomic gains (e.g., benefiting the economy, tourism), social equity and ethics (e.g., equal distribution of health outcomes, reduced health/financial equity gaps) and health systems strengthening, resilience and security (e.g., efficiency gains, reduced disruption, increased capacity). CONCLUSIONS: Gaps, inconsistencies and limited assessment of vaccination value in EE can lead to differences in policy and vaccination access. The three priority concepts identified provide a feasible approach for capturing VoV more broadly in the near-term. Robust methods for measuring and valuing these concepts in future assessments will help strengthen the evidence used to inform decisions, improving access to vaccines that are demonstrably good value for money from society's point of view.

OxVent: Design and evaluation of a rapidly-manufactured Covid-19 ventilator.

BACKGROUND: The manufacturing of any standard mechanical ventilator cannot rapidly be upscaled to several thousand units per week, largely due to supply chain limitations. The aim of this study was to design, verify and perform a pre-clinical evaluation of a mechanical ventilator based on components not required for standard ventilators, and that met the specifications provided by the Medicines and Healthcare Products Regulatory Agency (MHRA) for rapidly-manufactured ventilator systems (RMVS). METHODS: The design utilises closed-loop negative feedback control, with real-time monitoring and alarms. Using a standard test lung, we determined the difference between delivered and target tidal volume (VT) at respiratory rates between 20 and 29 breaths per minute, and the ventilator's ability to deliver consistent VT during continuous operation for >14 days (RMVS specification). Additionally, four anaesthetised domestic pigs (3 male-1 female) were studied before and after lung injury to provide evidence of the ventilator's functionality, and ability to support spontaneous breathing. FINDINGS: Continuous operation lasted 23 days, when the greatest difference between delivered and target VT was 10% at inspiratory flow rates >825 mL/s. In the pre-clinical evaluation, the VT difference was -1 (-90 to 88) mL [mean (LoA)], and positive end-expiratory pressure (PEEP) difference was -2 (-8 to 4) cmH2O. VT delivery being triggered by pressures below PEEP demonstrated spontaneous ventilation support. INTERPRETATION: The mechanical ventilator presented meets the MHRA therapy standards for RMVS and, being based on largely available components, can be manufactured at scale. FUNDING: Work supported by Wellcome/EPSRC Centre for Medical Engineering,King's Together Fund and Oxford University.

Country score tool to assess readiness and guide evidence generation of immunization programs in aging adults in Europe.

Objectives: Delaying of policies for immunization of aging adults, low vaccine uptake, and the lack of supportive evidence at the national level could diminish the value in health and economics of such programs. This study aims to develop a "country score tool" to assess readiness and to facilitate evidence generation for aging adult immunization programs in Europe, and examine the comprehensiveness, relevance, acceptability, and feasibility of the tool. Methods: The tool was developed in two phases. First, a modified Delphi process was used to construct the tool. The process included a literature review, stakeholder consultations, and a three-round Delphi study. The Delphi panel included researchers, supra-national and national decision-makers of immunization programs recruited from five countries, using snowball sampling method. The consensus was predefined at the agreement rate of 70%. Pilot testing of the tool was conducted in the Netherlands, Germany, Serbia, and Hungary involving researchers in the field of health technology assessment. After assessing the countries' readiness, researchers evaluated four features, namely comprehensiveness, relevance, acceptability, and feasibility of the tool via an online survey that included 5-scale Likert questions. The percentages of affirmative answers including "agree" and "totally agree" choices were presented. Results: The review identified 16 tools and frameworks that formed the first version of our tool with 14 items. Eight experts were involved in the Delphi panel. Through three Delphi rounds, four items were added, one was dropped, and all others were amended. The consensus was achieved on the tool with 17 items divided into decision-making and implementation parts. Each item has a guiding question, corresponding to explanations and rationales to inform assessment with readiness scores. Eight researchers completed the pilot testing. The tool was rated as comprehensive (75%), relevant (100%), acceptable (75%), and feasible (88%) by participants. Conclusion: Through a thorough and transparent process, a country score tool was developed helping to identify strengths, weaknesses, and evidential requirements for decision-making and implementation of immunization programs of aging adults. The tool is relevant for different European contexts and shows good comprehensiveness, acceptability, and feasibility.

Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits.

Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N6-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.

Response to the COVID-19 Pandemic Among Posthospital Brain Injury Rehabilitation Providers.

Rehabilitation after significant acquired brain injury (ABI) to address complex independent activities of daily living and return to family and community life is offered primarily after initial hospitalization in outpatient day treatment, group home, skilled nursing, and residential settings and in the home and community of the person served. The coronavirus 2019 pandemic threatened access to care and the health and safety of staff, persons served, and families in these settings. This article describes steps taken to contain this threat by 7 leading posthospital ABI rehabilitation organizations. Outpatient and day treatment facilities were temporarily suspended. In other settings, procedures for isolation, transportation, cleaning, exposure control, infection control, and use of personal protective equipment (PPE) were reinforced with staff. Visitation and community activities were restricted. Staff and others required to enter facilities were screened with symptom checklists and temperature checks. Individuals showing symptoms of infection were quarantined and tested, as possible. New admissions were carefully screened for infection and often initially quarantined. Telehealth played a major role in reducing direct interpersonal contact while continuing to provide services both to outpatients and within facilities. Salary, benefits, training, and managerial support were enhanced for staff. Despite early outbreaks, these procedures were generally effective, with preliminary initial infections rates of only 1.1% for persons served and 2.1% for staff. Reductions in admissions, services, and unanticipated expenses (eg, PPE, more frequent and thorough cleaning) had a major negative financial effect. Providers continue to be challenged to adapt rehabilitative approaches and to reopen services.

Global vaccine action plan lessons learned I: Recommendations for the next decade.

The Global Vaccine Action Plan 2011-2020 (GVAP) was developed to realize the ambitions of the Decade of Vaccines - that all individuals and communities enjoy lives free from vaccine-preventable diseases. It included a comprehensive monitoring and evaluation/accountability framework to assess progress towards global targets with recommendations for corrective actions. While many of the GVAP targets are very unlikely to be met by the end of 2020, substantial progress has nevertheless been made, establishing a strong foundation for a successor global immunization strategy, the Immunization Agenda 2030 (IA2030). The Strategic Advisory Group of Experts on immunization has made a series of recommendations to ensure that the lessons learned from GVAP inform the development and implementation of IA2030.

Collaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism in mice.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Here, we outline a role for hnRNPs in gene regulatory circuits controlling sterol homeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways. Liver-specific deletion of RALY alters hepatic lipid content and serum cholesterol level. In vivo interrogation of chromatin architecture and genome-wide RALY-binding pattern reveal insights into its cooperative interactions and mode of action in regulating cholesterogenesis. Interestingly, we find that RALY binds the promoter region of the master metabolic regulator Srebp2 and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. Our work offers insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact health and disease states.