RESUMEN
The release of hemoglobin (Hb) occurs in some infectious and autoimmune diseases characterized by inflammation. As levels of haptoglobin (Hp) fall, free Hb can cause pathology. Humoral autoreactivity to human Hb was demonstrated in the sera of systemic lupus erythematosus (SLE), leishmania and malaria patients. Serum anti-murine Hb antibody levels in lupus-prone mice also exhibited an age-dependent increase, with progressive organ sequestration; significant isotypic correlation was observed with anti-dsDNA antibodies. A suggestive link between anti-Hb and anti-Sm responses was observed: Human lupus sera expressing anti-Sm antibody reactivity preferentially contained heightened levels of anti-Hb autoantibodies, and immunization of lupus-prone mice with Sm led to enhanced anti-murine Hb reactivity. Human and murine anti-Hb monoclonal antibodies were generated, some of which were preferentially reactive toward disease-associated methemoglobin. Epitope-mapping studies revealed evidence of intra-molecular cross-reactivity. One such autoantibody synergized with Hb to enhance the secretion of pro-inflammatory cytokines while eliciting the increased production of monocyte migratory signals from endothelial cells. Preferential usage of specific variable region gene segments was not observed, although somatic mutations were documented. These studies reveal that, while the etiology, specificity and sequences of anti-Hb autoreactive antibodies can vary, they occur quite frequently and can have inflammatory consequences.
Asunto(s)
Estructuras Animales/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Hemoglobinas/inmunología , Inflamación/inmunología , Proteínas Nucleares snRNP/inmunología , Envejecimiento/sangre , Envejecimiento/inmunología , Estructuras Animales/metabolismo , Animales , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Complejo Antígeno-Anticuerpo/farmacología , Autoanticuerpos/metabolismo , Autoantígenos/inmunología , Autoinmunidad/inmunología , Secuencia de Bases , Sitios de Unión/fisiología , Sitios de Unión de Anticuerpos/inmunología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Medios de Cultivo Condicionados/farmacología , Citocinas/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Haptoglobinas/metabolismo , Hemoglobinas/farmacología , Humanos , Isotipos de Inmunoglobulinas/sangre , Isotipos de Inmunoglobulinas/inmunología , Isotipos de Inmunoglobulinas/metabolismo , Región Variable de Inmunoglobulina/genética , Leishmaniasis/sangre , Leishmaniasis/inmunología , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Malaria/sangre , Malaria/inmunología , Metahemoglobina/inmunología , Metahemoglobina/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NZB , Datos de Secuencia Molecular , Monocitos/efectos de los fármacos , Monocitos/inmunología , Monocitos/metabolismo , Oxihemoglobinas/inmunología , VacunaciónRESUMEN
PURPOSE: The COVID-19 pandemic poses an unprecedented threat to global business relationships and dynamics. The pharmacovigilance function of pharmaceutical companies is particularly susceptible to changing external pressures because of its highly structured compliance activities. We conducted an industry-wide survey to provide insights on how the pharmacovigilance function responded to the challenges posed by the pandemic. We compared smaller companies and larger companies regarding impact on portfolios and operational activity metrics. METHODS: We conducted a survey through the Navitas Life Science annual benchmark of pvnetTM, a network of large enterprise (LE) companies, and pvconnectTM, a network of small and medium enterprise (SME) companies, using an online surveying tool during the first quarter of 2021. We collected information on pharmacovigilance activities, including quantitative measures of workload, costs, and key performance indicators, and qualitative data on the effects of the pandemic on product portfolios and operations. FINDINGS: Survey questions were posed to LE (pvnet) network members (n = 12) and SME (pvconnect) network members (n = 18) for the period from January 1 through December 31, 2020. The date of data collection was March 26, 2021. Descriptive median values of parameter metrics included the following: revenue ($28.4 billion for LE companies and $1.6 billion for SME companies), number of products (127 for LE companies and 19 for SME companies), and volume of individual case safety reports (391,000 for LE companies and 13,000 for SME companies). SME companies reported a greater impact on 2 survey categories, remote working and employee well-being, than did LE companies. However, LE companies reported a greater impact than did SME companies on all other survey categories: effect on strategic priorities, shift in product focus, workload changes, changes in sourcing model, effect on case reporting compliance, effect on business continuity, changes in pharmacovigilance technology strategy, impact of interactions with health authorities, effect on resource capacity, and impact on recruitment. IMPLICATIONS: Four major themes emerge from this survey: (1) shift to remote working, (2) recognition of the impact on employee well-being, (3) shift in strategic priorities, and (4) newly recognized aspects of risk mitigation. The COVID-19 pandemic has had a marked effect on every aspect of pharmaceutical companies' pharmacovigilance functions, although the effects appear to be different for LE companies than for SME companies.
Asunto(s)
COVID-19 , Farmacovigilancia , Humanos , COVID-19/epidemiología , Industria Farmacéutica , PandemiasRESUMEN
Coxsackievirus B3 (CVB3), a member of the Picornaviridae family, is considered to be one of the most important infectious agents to cause virus-induced myocarditis. Despite improvements in studying viral pathology, structure and molecular biology, as well as diagnosis of this disease, there is still no virus-specific drug in clinical use. Structural and nonstructural proteins produced during the coxsackievirus life cycle have been identified as potential targets for blocking viral replication at the step of attachment, entry, uncoating, RNA and protein synthesis by synthetic or natural compounds. Moreover, WIN (for Winthrop) compounds and application of nucleic-acid based strategies were shown to target viral capsid, entry and viral proteases, but have not reached to the clinical trials as a successful antiviral agent. There is an urgent need for diverse molecular libraries for phenotype-selective and high-throughput screening.
Asunto(s)
Antivirales/farmacología , Productos Biológicos/farmacología , Infecciones por Coxsackievirus/tratamiento farmacológico , Enterovirus/efectos de los fármacos , Miocarditis/tratamiento farmacológico , Animales , Antivirales/química , Productos Biológicos/química , Infecciones por Coxsackievirus/virología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Miocarditis/virologíaRESUMEN
BACKGROUND: Low-income and middle-income countries (LMICs) are under-represented in reports on the burden of antimicrobial resistance. We aimed to quantify the clinical effect of carbapenem resistance on mortality and length of hospital stay among inpatients in LMICs with a bloodstream infection due to Enterobacteriaceae. METHODS: The PANORAMA study was a multinational prospective cohort study at tertiary hospitals in Bangladesh, Colombia, Egypt, Ghana, India, Lebanon, Nepal, Nigeria, Pakistan, and Vietnam, recruiting consecutively diagnosed patients with carbapenem-susceptible Enterobacteriaceae (CSE) and carbapenem-resistant Entero-bacteriaceae (CRE) bloodstream infections. We excluded patients who had previously been enrolled in the study and those not treated with curative intent at the time of bloodstream infection onset. There were no age restrictions. Central laboratories in India and the UK did confirmatory testing and molecular characterisation, including strain typing. We applied proportional subdistribution hazard models with inverse probability weighting to estimate the effect of carbapenem resistance on probability of discharge alive and in-hospital death, and multistate modelling for excess length of stay in hospital. All patients were included in the analysis. FINDINGS: Between Aug 1, 2014, and June 30, 2015, we recruited 297 patients from 16 sites in ten countries: 174 with CSE bloodstream infection and 123 with CRE bloodstream infection. Median age was 46 years (IQR 15-61). Crude mortality was 20% (35 of 174 patients) for patients with CSE bloodstream infection and 35% (43 of 123 patients) for patients with CRE bloodstream infection. Carbapenem resistance was associated with an increased length of hospital stay (3·7 days, 95% CI 0·3-6·9), increased probability of in-hospital mortality (adjusted subdistribution hazard ratio 1·75, 95% CI 1·04-2·94), and decreased probability of discharge alive (0·61, 0·45-0·83). Multilocus sequence typing showed various clades, with marginal overlap between strains in the CRE and CSE clades. INTERPRETATION: Carbapenem resistance is associated with increased length of hospital stay and mortality in patients with bloodstream infections in LMICs. These data will inform global estimates of the burden of antimicrobial resistance and reinforce the need for better strategies to prevent, diagnose, and treat CRE infections in LMICs. FUNDING: bioMérieux.
Asunto(s)
Antibacterianos/uso terapéutico , Bacteriemia/tratamiento farmacológico , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Carbapenémicos/uso terapéutico , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Enfermedades Hematológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/epidemiología , Estudios de Cohortes , Países en Desarrollo , Infecciones por Enterobacteriaceae/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Emerging evidence indicates that the causative agent of tuberculosis is more genetically and functionally diverse than appreciated previously. The impact of this variation on the clinical manifestation of the disease remains largely unknown. In addition, there exists significant variability in the immune status of the host governing susceptibility to tuberculosis. The effect of these variations on the host pathogen interaction was investigated by taking varying pathogen phenotypes (virulent H37Rv, a-virulent H37Ra and a multidrug resistant strain #591) and varying host (18 MDR-TB and 16 fresh TB patients and 10 healthy, BCG-vaccinated individuals). The key question was whether the intracellular survival of Mycobacterium tuberculosis (MTB) in human monocyte-derived macrophages (MDM), an attribute of pathogenic potential, can be modulated by the immune status of the hosts or phenotype of MTB. The findings of this study indicate that induction of TNF-α may not be a global indicator of virulence of a strain. TNF-α release may be differentially regulated in response to the same strain depending upon the immune status of the host. Moreover, the phenotype of the infecting MTB and the host's immune status played a comparable role in the intracellular survival of MTB. This picture supports the hypothesis that in addition to the phenotype variation of the mycobacteria, the immune status of an individual will greatly influence the outcome of the host-pathogen interaction. These results may have a bearing on the future endeavors in vaccine development and TB control strategy.