Illness Phase as a Key Assessment and Intervention Window for Psychosis.

The phenotype of schizophrenia, regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness stage, including temporal variation in neurobiology, can be targeted to develop phase-specific clinical assessment, biomarkers, and interventions. We review an earlier model whereby an initial glutamate signaling deficit progresses through different phases of allostatic adaptation, moving from potentially reversible functional abnormalities associated with early psychosis and working memory dysfunction, and ending with difficult-to-reverse structural changes after chronic illness. We integrate this model with evidence of dopaminergic abnormalities, including cortical D1 dysfunction, which develop during adolescence. We discuss how this model and a focus on a potential critical window of intervention in the early stages of schizophrenia impact the approach to research design and clinical care. This impact includes stage-specific considerations for symptom assessment as well as genetic, cognitive, and neurophysiological biomarkers. We examine how phase-specific biomarkers of illness phase and brain development can be incorporated into current strategies for large-scale research and clinical programs implementing coordinated specialty care. We highlight working memory and D1 dysfunction as early treatment targets that can substantially affect functional outcome.

Access to and affordability of CAR T-cell therapy in multiple myeloma: an EBMT position paper.

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic approach in the treatment of multiple myeloma, and the recent approval of the first two CAR T-cell products could result in improved outcomes. However, it remains a complex and expensive technology, which poses challenges to health-care systems and society in general, especially in times of crises. This potentially accelerates pre-existing inequalities as access to CAR T-cell therapy varies, both between countries, depending on the level of economic development, and within countries, due to structural disparities in access to quality health care-a parameter strongly correlated with socioeconomic status, ethnicity, and lifestyle. Here, we identify two important issues: affordability and access to CAR T-cell treatment. This consensus statement from clinical investigators, clinicians, nurses, and patients from the European Society for Blood and Marrow Transplantation (EBMT) proposes solutions as part of an innovative collaborative strategy to make CAR T-cell therapy accessible to all patients with multiple myeloma.

Implementation and Assessment of a Proning Protocol for Nonintubated Patients With COVID-19.

INTRODUCTION: The COVID-19 pandemic has caused over 1,250,000 deaths worldwide. With limited therapeutic options, proning nonintubated patients emerged as a safe and affordable intervention to manage hypoxemia. METHODS: A proning protocol to identify and prone eligible patients was implemented. Patients were encouraged to self-prone for 2-3 hours, 3 times daily. Investigators created educational materials for nurses and patients and developed a COVID-19-specific proning order within the electronic health record (EHR). Investigators completed an 800-person retrospective chart review to study the implementation of this protocol. RESULTS: From March 22, 2020, to June 5, 2020, 586 patients were admitted to the COVID-19 floor. Of these patients, 42.8% were eligible for proning. Common contraindications were lack of hypoxia, altered mental status, and fall risk. The proning protocol led to a significant improvement in provider awareness of patients appropriate for proning, increasing from 12% to 83%, as measured by placement of a proning order into the EHR. There was a significant improvement in all appropriate patients documented as proned, increasing from 18% to 45% of eligible patients. CONCLUSIONS: The creation of an effective hospital-wide proning protocol to address the exigencies of the COVID-19 pandemic is possible and may be accomplished in a short period of time.

Specific considerations for research on the effectiveness of multisectoral collaboration: methods and lessons from 12 country case studies.

BACKGROUND: The success of the Sustainable Development Goals (SDGs) is predicated on multisectoral collaboration (MSC), and the COVID-19 pandemic makes it more urgent to learn how this can be done better. Complex challenges facing countries, such as COVID-19, cut across health, education, environment, financial and other sectors. Addressing these challenges requires the range of responsible sectors and intersecting services - across health, education, social and financial protection, economic development, law enforcement, among others - transform the way they work together towards shared goals. While the necessity of MSC is recognized, research is needed to understand how sectors collaborate, inform how to do so more efficiently, effectively and equitably, and ascertain similarities and differences across contexts. To answer these questions and inform practice, research to strengthen the evidence-base on MSC is critical. METHODS: This paper draws on a 12-country study series on MSC for health and sustainable development, in the context of the health and rights of women, children and adolescents. It is written by core members of the research coordination and country teams. Issues were analyzed during the study period through 'real-time' discussions and structured reporting, as well as through literature reviews and retrospective feedback and analysis at the end of the study. RESULTS: We identify four considerations that are unique to MSC research which will be of interest to other researchers, in the context of COVID-19 and beyond: 1) use theoretical frameworks to frame research questions as relevant to all sectors and to facilitate theoretical generalizability and evolution; 2) specifically incorporate sectoral analysis into MSC research methods; 3) develop a core set of research questions, using mixed methods and contextual adaptations as needed, with agreement on criteria for research rigor; and 4) identify shared indicators of success and failure across sectors to assess MSCs. CONCLUSION: In responding to COVID-19 it is evident that effective MSC is an urgent priority. It enables partners from diverse sectors to effectively convene to do more together than alone. Our findings have practical relevance for achieving this objective and contribute to the growing literature on partnerships and collaboration. We must seize the opportunity here to identify remaining knowledge gaps on how diverse sectors can work together efficiently and effectively in different settings to accelerate progress towards achieving shared goals.

An individually randomised controlled multi-centre pragmatic trial with embedded economic and process evaluations of early vocational rehabilitation compared with usual care for stroke survivors: study protocol for the RETurn to work After stroKE (RETAKE) trial.

BACKGROUND: Return to work (RTW) is achieved by less than 50% of stroke survivors. The rising incidence of stroke among younger people, the UK economic forecast, and clinical drivers highlight the need for stroke survivors to receive support with RTW. However, evidence for this type of support is lacking. This randomised controlled trial (RCT) will investigate whether Early Stroke Specialist Vocational Rehabilitation (ESSVR) plus usual care (UC) (i.e. usual NHS rehabilitation) is more clinically and cost-effective for supporting post-stroke RTW, than UC alone. METHODS: Seven hundred sixty stroke survivors and their carers will be recruited from approximately 20 NHS stroke services. A 5:4 allocation ratio will be employed to randomise participants to receive ESSVR plus UC, or UC alone. The individually tailored ESSVR intervention will commence within 12 weeks of stroke onset and be delivered for up to 12 months as necessary by trained RETAKE occupational therapists in the community, participants' homes or workplaces, and outpatient/inpatient therapy settings, via telephone, email, or SMS text message. Outcome data will be collected via self-report questionnaires administered by post or online at 3, 6, and 12 months follow-up. The primary outcome will be self-reported RTW and job retention at 12 months (minimum 2 h/week). Secondary outcomes will include mood, function, participation, health-related quality of life, confidence, intervention compliance, health and social care resource use, and mortality. An embedded economic evaluation will estimate cost-effectiveness and cost-utility analyses from National Health Service (NHS) and Personal Social Services (PSS) perspectives. An embedded process evaluation will employ a mixed methods approach to explore ESSVR implementation, contextual factors linked to outcome variation, and factors affecting NHS roll-out. DISCUSSION: This article describes the protocol for a multi-centre RCT evaluating the clinical- and cost-effectiveness of an early vocational rehabilitation intervention aimed at supporting adults to return to work following a stroke. Evidence favouring the ESSVR intervention would support its roll-out in NHS settings. TRIAL REGISTRATION: ISRCTN, ISRCTN12464275 . Registered on 26 February 2018.

The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy.

The new coronavirus SARS-CoV-2 has rapidly spread over the world causing the disease by WHO called COVID-19. This pandemic poses unprecedented stress on the health care system including programs performing allogeneic and autologous hematopoietic cell transplantation (HCT) and cellular therapy such as with CAR T cells. Risk factors for severe disease include age and predisposing conditions such as cancer. The true impact on stem cell transplant and CAR T-cell recipients in unknown. The European Society for Blood and Marrow Transplantation (EBMT) has therefore developed recommendations for transplant programs and physicians caring for these patients. These guidelines were developed by experts from the Infectious Diseases Working Party and have been endorsed by EBMT's scientific council and board. This work intends to provide guidelines for transplant centers, management of transplant candidates and recipients, and donor issues until the COVID-19 pandemic has passed.

Scintigraphic assessment of arterial embolism at mixed thrombin and technetium 99m injection therapy for femoral pseudoaneurysms.

BACKGROUND: Clinically evident arterial thrombosis is rare following thrombin injection therapy for femoral pseudoaneurysm. However, it is unclear to what extent injected thrombin may pass to the ipsilateral lower limb arteries. AIMS: To assess if technetium 99m injected at the time of thrombin injection for femoral artery pseudoaneurysm therapy passes into the adjacent lower limb arteries. METHODS: This was a prospective trial with institutional review board approval. Four consecutive patients with common femoral pseudoaneurysms and failed manual compression were enrolled. Under real-time colour flow doppler ultrasound, a mixture of 1000 IU thrombin and approximately 200 MBq technetium 99m was injected in 0.1-mL doses into the pseudoaneurysm until thrombosis occurred. Gamma camera imaging of the syringe before injection, the injected groin after thrombosis and the syringe after injection were performed. Analysis of the gamma camera information was performed to determine the amount of technetium 99m deposited in the arterial tree. RESULTS: All the procedures were technically successful. A mean of 33% (range 3-50%; SD 21) of the administered technetium 99m dose was deposited in the arterial circulation during pseudoaneurysm therapy. No clinically evident arterial thrombosis was identified. CONCLUSION: Technetium 99m is routinely deposited in the arterial circulation following injection of a mixture of thrombin and technetium for therapy of common femoral artery pseudoaneurysms. This suggests that arterial passage of thrombin is more common than clinically evident.

Impact of multisectoral health determinants on child mortality 1980-2010: An analysis by country baseline mortality.

INTRODUCTION: Some health determinants require relatively stronger health system capacity and socioeconomic development than others to impact child mortality. Few quantitative analyses have analyzed how the impact of health determinants varies by mortality level. METHODS: 149 low- and middle-income countries were stratified into high, moderate, low, and very low baseline levels of child mortality in 1990. Data for 52 health determinants were collected for these countries for 1980-2010. To quantify how changes in health determinants were associated with mortality decline, univariable and multivariable regression models were constructed. An advanced statistical technique that is new for child mortality analyses-MM-estimation with first differences and country clustering-controlled for outliers, fixed effects, and variation across decades. FINDINGS: Some health determinants (immunizations, education) were consistently associated with child mortality reduction across all mortality levels. Others (staff availability, skilled birth attendance, fertility, water and sanitation) were associated with child mortality reduction mainly in low or very low mortality settings. The findings indicate that the impact of some health determinants on child mortality was only apparent with stronger health systems, public infrastructure and levels of socioeconomic development, whereas the impact of other determinants was apparent at all stages of development. Multisectoral progress was essential to mortality reduction at all baseline mortality levels. CONCLUSION: Policy-makers can use such analyses to direct investments in health and non-health sectors and to set five-year child mortality targets appropriate for their baseline mortality levels and local context.

Roadmap to control HBV and HDV epidemics in China.

PURPOSE: Hepatitis B virus (HBV) is endemic in China. Almost 10% of HBV infected individuals are also infected with hepatitis D virus (HDV) which has a 5-10 times higher mortality rate than HBV mono-infection. The aim of this manuscript is to devise strategies that can not only control HBV infections but also HDV infections in China under the current health care budget in an optimal manner. METHODS: Using a mathematical model, an annual budget of $10billion was optimally allocated among five interventions namely, testing and HBV adult vaccination, treatment for mono-infected and dually-infected individuals, second line treatment for HBV mono-infections, and awareness programs. RESULTS: We determine that the optimal strategy is to test and treat both infections as early as possible while applying awareness programs at full intensity. Under this strategy, an additional 19.8million HBV, 1.9million HDV infections and 0.25million lives will be saved over the next 10years at a cost-savings of $79billion than performing no intervention. Introduction of second line treatment does not add a significant economic burden yet prevents 1.4million new HBV infections and 15,000 new HDV infections. CONCLUSION: Test and treatment programs are highly efficient in reducing HBV and HDV prevalence in the population. Under the current health budget in China, not only test and treat programs but awareness programs and second line treatment can also be implemented that minimizes prevalence and mortality, and maximizes economic benefits.

Recognizing the impact of endemic hepatitis D virus on hepatitis B virus eradication.

BACKGROUND: Hepatitis delta virus (HDV) in conjunction with hepatitis B virus (HBV) increases adult morbidity and mortality. A number of studies have performed cost-benefit analyses for HBV interventions, but they have ignored the impact of HDV on these outcomes. METHODS: Using a mathematical model of HBV-HDV epidemiology, we compare health benefits and cost outcomes of four interventions: testing with HBV adult vaccination (diagnosis), diagnosis with antiviral treatment for HBV infections (mono-infections), diagnosis with antiviral treatment for HBV-HDV infections (dual-infections), and awareness programs. The relationship between optimal levels and outcomes of each of these interventions and HDV prevalence in HBV infected individuals ranging from 0 to 50% is determined. RESULTS: Over a 50 year period under no intervention, HBV prevalence, per capita total cost and death toll increase by 2.25%, -$11 and 2.6-fold respectively in moderate HDV endemic regions compared to mono-infected regions; the corresponding values for high HDV endemic regions are 4.2%, -$21 and 3.9-fold. Optimal interventions can be strategized similarly in mono and dually endemic regions. Only implementation of all four interventions achieves a very low HBV prevalence of around 1.5% in a moderate HDV endemic region such as China, with 2.8 million fewer deaths compared to no intervention. Although the policy of implementation of all four interventions costs additional $382 billion compared to no intervention, it still remains cost-effective with an incremental cost-effectiveness ratio of $1400/QALY. Very high efficacy awareness programs achieve less prevalence with fewer deaths at a lower cost compared to treatment and/or vaccination programs. CONCLUSION: HDV substantially affects the performance of any HBV-related intervention. Its exclusion results in over-estimation of the effectiveness of HBV interventions.

Cross-country analysis of strategies for achieving progress towards global goals for women's and children's health.

OBJECTIVE: To identify how 10 low- and middle-income countries achieved accelerated progress, ahead of comparable countries, towards meeting millennium development goals 4 and 5A to reduce child and maternal mortality. METHODS: We synthesized findings from multistakeholder dialogues and country policy reports conducted previously for the Success Factors studies in 10 countries: Bangladesh, Cambodia, China, Egypt, Ethiopia, the Lao People's Democratic Republic, Nepal, Peru, Rwanda and Viet Nam. A framework approach was used to analyse and synthesize the data from the country reports, resulting in descriptive or explanatory conclusions by theme. FINDINGS: Successful policy and programme approaches were categorized in four strategic areas: leadership and multistakeholder partnerships; health sector; sectors outside health; and accountability for resources and results. Consistent and coordinated inputs across sectors, based on high-impact interventions, were assessed. Within the health sector, key policy and programme strategies included defining standards, collecting and using data, improving financial protection, and improving the availability and quality of services. Outside the health sector, strategies included investing in girls' education, water, sanitation and hygiene, poverty reduction, nutrition and food security, and infrastructure development. Countries improved accountability by strengthening and using data systems for planning and evaluating progress. CONCLUSION: Reducing maternal and child mortality in the 10 fast-track countries can be linked to consistent and coordinated policy and programme inputs across health and other sectors. The approaches used by successful countries have relevance to other countries looking to scale-up or accelerate progress towards the sustainable development goals.

Cost-Effectiveness of Peg-Interferon, Interferon and Oral Nucleoside Analogues in the Treatment of Chronic Hepatitis B and D Infections in China.

BACKGROUND AND OBJECTIVE: The cost-effectiveness of highly effective, but costly, peg-interferon (peg-IFN) treatment for chronic hepatitis B (CHB) infections in China is unknown. Endemic hepatitis D virus (HDV) may also modify the effectiveness of any HBV treatment option. The objective of this study is to determine the best antiviral treatment from a societal perspective in the Chinese population, which contains a mix of HBV and HDV infections. METHODS: A Markov model is developed to simulate the clinical course of CHB and chronic hepatitis D (CHD) individuals. For a hypothetical Chinese cohort of 10,000 individuals aged 30-60 years, cost-utility analysis is performed for therapies with: lamivudine, adefovir, telbivudine, entecavir, IFN and Peg-IFN. Costs and quality-adjusted life-years (QALYs) are discounted at 3 % annually. A one-way sensitivity analysis is also conducted. RESULTS: Lamivudine, adefovir, telbivudine, and entecavir are all cost-effective treatments compared to palliative care at an incremental cost-effectiveness ratio (ICER) of -$418, -$197, -$443 and -$317 per QALY, respectively (2015 US dollars). Peg-IFN yields a maximum 156,000 QALYs with an ICER of $1149 per QALY while IFN results in the highest cumulative mortality of 48 % along with the lowest QALY gained. Probabilistic sensitivity analyses confirm that only Peg-IFN and ETV are the only two cost-effective options at the current willingness-to-pay (WTP) of $12,000 in China. However, entecavir has a higher probability of being cost-effective than Peg-IFN at current WTP for all age groups. CONCLUSIONS: Peg-IFN generates maximum QALYs compared to lamivudine, adefovir, telbivudine and interferon, and presents itself as a cost-effective option at current WTP. Alternatively entecavir can be used in China, generating 10 % lower QALYs than Peg-IFN but costing less than palliative care.

Displaced and forgotten child refugees: A humanitarian crisis.

PURPOSE: To describe where child refugees are located, the risks they face, leading health problems, and how pediatric healthcare professionals can help. CONCLUSIONS: Children constitute approximately 46% of refugees worldwide. These refugees fled their home countries due to conflict and persecution, and cannot return because of race, religion, nationality, political opinion, or membership in a particular social group. PRACTICE IMPLICATIONS: Pediatric nurses have an unprecedented opportunity to advocate for child refugees by contributing to the international conversation on the human rights of immigrants.

Success factors for reducing maternal and child mortality.

Reducing maternal and child mortality is a priority in the Millennium Development Goals (MDGs), and will likely remain so after 2015. Evidence exists on the investments, interventions and enabling policies required. Less is understood about why some countries achieve faster progress than other comparable countries. The Success Factors for Women's and Children's Health studies sought to address this knowledge gap using statistical and econometric analyses of data from 144 low- and middle-income countries (LMICs) over 20 years; Boolean, qualitative comparative analysis; a literature review; and country-specific reviews in 10 fast-track countries for MDGs 4 and 5a. There is no standard formula--fast-track countries deploy tailored strategies and adapt quickly to change. However, fast-track countries share some effective approaches in addressing three main areas to reduce maternal and child mortality. First, these countries engage multiple sectors to address crucial health determinants. Around half the reduction in child mortality in LMICs since 1990 is the result of health sector investments, the other half is attributed to investments made in sectors outside health. Second, these countries use strategies to mobilize partners across society, using timely, robust evidence for decision-making and accountability and a triple planning approach to consider immediate needs, long-term vision and adaptation to change. Third, the countries establish guiding principles that orient progress, align stakeholder action and achieve results over time. This evidence synthesis contributes to global learning on accelerating improvements in women's and children's health towards 2015 and beyond.

La réduction de la mortalité maternelle et infantile est une priorité des objectifs du Millénaire pour le développement (OMD) et le restera probablement après l'échéance de 2015. Il existe des données sur les investissements, les interventions et les politiques habilitantes nécessaires. On comprend mal pourquoi certains pays ont réalisé des progrès plus rapidement que d'autres pays comparables. Les Facteurs de réussite des études sur la santé des femmes et des enfants ont cherché à combler ce manque de connaissances en utilisant les analyses statistiques et économétriques des données provenant de 144 pays à faible revenu et à revenu intermédiaire et recueillies depuis 20 ans: une analyse comparative qualitative booléenne; une étude bibliographique et des études spécifiques à chaque pays pour les 10 pays à progression rapide pour les points 4 et 5a des OMD. Il n'existe pas de formule standard ­ les pays à progression rapide ont déployé des stratégies personnalisées et se sont adaptés rapidement aux changements. Cependant, ces pays ont en commun des approches efficaces visant 3 grands axes afin de réduire la mortalité maternelle et infantile. Premièrement, ils impliquent de nombreux secteurs pour traiter les facteurs déterminants et cruciaux pour la santé. Près de la moitié de la réduction de la mortalité infantile dans les pays à faible revenu et à revenu intermédiaire depuis 1990 résulte des investissements dans le secteur de la santé, l'autre moitié étant attribuée aux investissements réalisés dans les secteurs extérieurs à la santé. Deuxièmement, ces pays utilisent des stratégies pour mobiliser les partenaires dans la société, en utilisant des données solides et opportunes pour la prise de décisions et la responsabilisation, ainsi qu'une approche de planification triple pour prendre en considération les besoins immédiats, la vision à long terme et l'adaptation aux changements. Troisièmement, ces pays établissent des principes directeurs qui orientent les progrès, harmonisent les actions des parties prenantes et génèrent des résultats dans le temps. Cette synthèse de données contribue à l'ensemble des connaissances requises pour accélérer les améliorations sur la santé des femmes et des enfants en vue de l'échéance de 2015 et au-delà.

La reducción de la mortalidad materna e infantil es una prioridad en los Objetivos de Desarrollo del Milenio (ODM), y probablemente lo seguirá siendo después de 2015. Existen evidencias sobre las inversiones, las intervenciones y las políticas necesarias, pero se sabe menos acerca de por qué algunos países logran un progreso más rápido que otros países comparables. Los estudios relativos a los Factores de Éxito en la Salud de las Mujeres y los Niños han tratado de abordar esta brecha de conocimiento por medio de análisis estadísticos y econométricos de datos de 144 países de ingresos bajos y medianos (PIBM) a lo largo de más de 20 años, análisis comparativos cualitativos booleanos, revisión de la literatura y revisiones específicas de cada país en 10 países bien encarrilados para los ODM 4 y 5a. No existe una fórmula estándar, estos países despliegan estrategias a medida y se adaptan rápidamente a los cambios. Sin embargo, comparten ciertos enfoques eficaces a la hora de abordar tres áreas principales para reducir la mortalidad materna e infantil. En primer lugar, involucran a numerosos sectores para hacer frente a los factores sanitarios decisivos. Alrededor de la mitad de la reducción de la mortalidad infantil en los PIBM desde 1990 es el resultado de inversiones en el sector de la salud, y la otra mitad se atribuye a las inversiones realizadas en sectores fuera del ámbito sanitario. En segundo lugar, estos países utilizan estrategias para movilizar a socios a través de la sociedad, utilizando evidencias oportunas y sólidas para la toma de decisiones y la rendición de cuentas, así como un enfoque de planificación triple para considerar las necesidades inmediatas, la visión a largo plazo y la adaptación al cambio. En tercer lugar, los países establecen principios rectores que orientan el progreso, armonizan las acciones de las partes interesadas y logran resultados en el tiempo. Este compendio de evidencias contribuye al aprendizaje global sobre cómo acelerar las mejoras en la salud de mujeres y niños hacia el 2015 y más adelante.