Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Addressing guideline and policy changes during pragmatic clinical trials.

While conducting a set of large-scale multi-site pragmatic clinical trials involving high-impact public health issues such as end-stage renal disease, opioid use, and colorectal cancer, there were substantial changes to both policies and guidelines relevant to the trials. These external changes gave rise to unexpected challenges for the trials, including decisions regarding how to respond to new clinical practice guidelines, increased difficulty in implementing trial interventions, achieving separation between treatment groups, and differential responses across sites. In this article, we describe these challenges and the approaches used to address them. When deliberating appropriate action in the face of external changes during a pragmatic clinical trial, we recommend considering the well-being of the participants, clinical equipoise, and the strength and quality of the evidence associated with the change; involving those charged with data and safety monitoring; and where possible, planning for potential external changes as the trial is being designed. Any solution must balance the primary obligation to protect the well-being of participants with the secondary obligation to protect the integrity of the trial in order to gain meaningful answers to important public health questions.

Association of Scheduled vs Emergency-Only Dialysis With Health Outcomes and Costs in Undocumented Immigrants With End-stage Renal Disease.

Importance: In 40 of 50 US states, scheduled dialysis is withheld from undocumented immigrants with end-stage renal disease (ESRD); instead, they receive intermittent emergency-only dialysis to treat life-threatening manifestations of ESRD. However, the comparative effectiveness of scheduled dialysis vs emergency-only dialysis and the influence of treatment on health outcomes, utilization, and costs is uncertain. Objective: To compare the effectiveness of scheduled vs emergency-only dialysis with regard to health outcomes, utilization, and costs in undocumented immigrants with ESRD. Design, Setting, and Participants: Observational cohort study of 181 eligible adults with ESRD receiving emergency-only dialysis in Dallas, Texas, who became newly eligible and applied for private commercial health insurance in February 2015; 105 received coverage and were enrolled in scheduled dialysis; 76 were not enrolled in insurance for nonclinical reasons (eg, lack of capacity at a participating outpatient dialysis center) and remained uninsured, receiving emergency-only dialysis. We examined data on eligible persons during a 6-month period prior to enrollment (baseline period, August 1, 2014-January 31, 2015) until 12 months after enrollment (follow-up period, March 1, 2015-February 29, 2016), with an intervening 1-month washout period (February 2015). All participants were undocumented immigrants; self-reported data on immigration status was collected from Parkland Hospital electronic health records. Exposures: Enrollment in private health insurance coverage and scheduled dialysis. Main Outcomes and Measures: We used enrollment in health insurance and scheduled dialysis to estimate the influence of scheduled dialysis on 1-year mortality, utilization, and health care costs, using a propensity score-adjusted, intention-to-treat approach, including time-to-event analyses for mortality, difference-in-differences (DiD) negative binomial regression analyses for utilization, and DiD gamma generalized linear regression for health care costs. Results: Of 181 eligible adults with ESRD, 105 (65 men, 40 women; mean age, 45 years) received scheduled dialysis and 76 (38 men, 38 women; mean age, 52 years) received emergency-only dialysis. Compared with emergency-only dialysis, scheduled dialysis was significantly associated with reduced mortality (3% vs 17%, P = .001; absolute risk reduction, 14%; number needed to treat, 7; adjusted hazard ratio, 4.6; 95% CI, 1.2-18.2; P = .03), adjusted emergency department visits (-5.2 vs +1.1 visits/mo; DiD, -6.2; P < .001), adjusted hospitalizations (-2.1 vs -0.5 hospitalizations/6 months; DiD, -1.6; P < .001), adjusted hospital days (-9.2 vs +0.8 days/6 months; DiD, -9.9; P = .007), and adjusted costs (-$4316 vs +$1452 per person per month; DiD, -$5768; P < .001). Conclusions and Relevance: In this study, scheduled dialysis was significantly associated with reduced 1-year mortality, health care utilization, and costs compared with emergency-only dialysis. Scheduled dialysis should be the universal standard of care for all individuals with ESRD in the United States.

Personalized medicine and Hispanic health: improving health outcomes and reducing health disparities - a National Heart, Lung, and Blood Institute workshop report.

Persons of Hispanic/Latino descent may represent different ancestries, ethnic and cultural groups and countries of birth. In the U.S., the Hispanic/Latino population is projected to constitute 29% of the population by 2060. A personalized approach focusing on individual variability in genetics, environment, lifestyle and socioeconomic determinants of health may advance the understanding of some of the major factors contributing to the health disparities experienced by Hispanics/Latinos and other groups in the U.S., thus leading to new strategies that improve health care outcomes. However, there are major gaps in our current knowledge about how personalized medicine can shape health outcomes among Hispanics/Latinos and address the potential factors that may explain the observed differences within this heterogeneous group, and between this group and other U.S. demographic groups. For that purpose, the National Heart, Lung, and Blood Institute (NHLBI), in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Food and Drug Administration (FDA), held a workshop in which experts discussed (1) potential approaches to study medical treatments and health outcomes among Hispanics/Latinos and garner the necessary evidence to fill gaps of efficacy, effectiveness and safety of therapies for heart, lung, blood and sleep (HLBS) disorders and conditions--and their risk factors; (2) research opportunities related to personalized medicine to improve knowledge and develop effective interventions to reduce health disparities among Hispanics/Latinos in the U.S.; and (3) the incorporation of expanded sociocultural and socioeconomic data collection and genetic/genomic/epigenetic information of Hispanic/Latino patients into their clinical assessments, to account for individual variability in ancestry; physiology or disease risk; culture; environment; lifestyle; and socioeconomic determinants of health. The experts also provided recommendations on: sources of Hispanic/Latino health data and strategies to enhance its collection; policy; genetics, genomics and epigenetics research; and integrating Hispanic/Latino health research within clinical settings.

Pragmatic clinical trials embedded in healthcare systems: generalizable lessons from the NIH Collaboratory.

BACKGROUND: The clinical research enterprise is not producing the evidence decision makers arguably need in a timely and cost effective manner; research currently involves the use of labor-intensive parallel systems that are separate from clinical care. The emergence of pragmatic clinical trials (PCTs) poses a possible solution: these large-scale trials are embedded within routine clinical care and often involve cluster randomization of hospitals, clinics, primary care providers, etc. Interventions can be implemented by health system personnel through usual communication channels and quality improvement infrastructure, and data collected as part of routine clinical care. However, experience with these trials is nascent and best practices regarding design operational, analytic, and reporting methodologies are undeveloped. METHODS: To strengthen the national capacity to implement cost-effective, large-scale PCTs, the Common Fund of the National Institutes of Health created the Health Care Systems Research Collaboratory (Collaboratory) to support the design, execution, and dissemination of a series of demonstration projects using a pragmatic research design. RESULTS: In this article, we will describe the Collaboratory, highlight some of the challenges encountered and solutions developed thus far, and discuss remaining barriers and opportunities for large-scale evidence generation using PCTs. CONCLUSION: A planning phase is critical, and even with careful planning, new challenges arise during execution; comparisons between arms can be complicated by unanticipated changes. Early and ongoing engagement with both health care system leaders and front-line clinicians is critical for success. There is also marked uncertainty when applying existing ethical and regulatory frameworks to PCTS, and using existing electronic health records for data capture adds complexity.

Perfeccionamiento de los servicios genéticos a gestantes y recién nacidos mediante la Red Informatizada de Salud SALGEN / Improvement genetics services to pregnant women and newborn by health informatic network SALGEN

La red informatizada de salud SALGEN se utiliza desde el 2009 en la atención genética a la gestante y el recién nacido en la provincia de Sancti Spíritus, insertada en las facilidades de conexión en tiempo real entre todas las instituciones de salud que brinda INFOMED. Se han atendido 34 452 gestantes hasta septiembre 2015, realizando evaluación de riesgo genético, pesquisa de anemia de hematíes falciformes, dosificación de alfafetoproteína, diagnóstico prenatal citogenético, ultrasonido de cada trimestre, características del parto y del recién nacido, pesquisas metabólicas neonatales y evaluación genético clínica del lactante. El software brinda160 reportes que han permitido evaluar la calidad de todos los procederes del programa de la atención genética a gestantes y recién nacidos y otras acciones organizativas del programa de atención materno infantil además de indicadores evaluativos para ecografía prenatal de acuerdo a estándares internacionales que son visualizados online por los especialistas como forma de autoevaluación. Los resultados validan al sistema informático para su utilización a nivel de cualquier policlínico, municipio o provincia del país. Este trabajo tiene por objetivo evidenciar la utilidad de SALGEN en el perfeccionamiento de la atención genética a gestantes y recién nacidos y en el control de calidad de acciones del Programa de Atención Materno Infantil (PAMI)(AU)

The Sancti Spíritus Provincial Medical Genetics Network has been using the Salgen informatics platform since 2009 for health care, administrative and research activities oconcerning pregnant mothers and newborns. The network uses the national Infomed backbone to provide real-time connection between community-based polyclinics in primary health care and the Provincial Medical Genetics Reference Center. Until September 2015 the platform has recorded 34 452 pregnant women and sequential clinical data on genetic risk assessment in early pregnancy, prenatal ultrasound, sickle cell anemia screening, alpha-fetoprotein levels, cytogenetic antenatal diagnosis, delivery and newborn characteristics, neonatal metabolic screening, and infant clinical assessment. The system makes health care results immediately available and provides 160 health alerts to enable timely preventive care for pregnant women. It also provides guidelines for processes and practices, and streamlines administrative and monitoring activities through statistical reports. The database generates indicators for assessing fetal growth and applies international standards for antenatal ultrasound quality control. Salgen can be use in any institution of primary health services, municipality or provinces of Cuba(AU)

A model system for mitochondrial biogenesis reveals evolutionary rewiring of protein import and membrane assembly pathways.

The controlled biogenesis of mitochondria is a key cellular system coordinated with the cell division cycle, and major efforts in systems biology currently are directed toward understanding of the control points at which this coordination is achieved. Here we present insights into the function, evolution, and regulation of mitochondrial biogenesis through the study of the protein import machinery in the human fungal pathogen, Candida albicans. Features that distinguish C. albicans from baker's yeast (Saccharomyces cerevisiae) include the stringency of metabolic control at the level of oxygen consumption, the potential for ATP exchange through the porin in the outer membrane, and components and domains in the sorting and assembling machinery complex, a molecular machine that drives the assembly of proteins in the outer mitochondrial membrane. Analysis of targeting sequences and assays of mitochondrial protein import show that components of the electron transport chain are imported by distinct pathways in C. albicans and S. cerevisiae, representing an evolutionary rewiring of mitochondrial import pathways. We suggest that studies using this pathogen as a model system for mitochondrial biogenesis will greatly enhance our knowledge of how mitochondria are made and controlled through the course of the cell-division cycle.