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From mid-January to mid-February 2015, all confirmed Ebola virus disease (Ebola) cases that occurred in Liberia were epidemiologically linked to a single index patient from the St. Paul Bridge area of Montserrado County. Of the 22 confirmed patients in this cluster, eight (36%) sought and received care from at least one of 10 non-Ebola health care facilities (HCFs), including clinics and hospitals in Montserrado and Margibi counties, before admission to an Ebola treatment unit. After recognition that three patients in this emerging cluster had received care from a non-Ebola treatment unit, and in response to the risk for Ebola transmission in non-Ebola treatment unit health care settings, a focused infection prevention and control (IPC) rapid response effort for the immediate area was developed to target facilities at increased risk for exposure to a person with Ebola (Ring IPC). The Ring IPC approach, which provided rapid, intensive, and short-term IPC support to HCFs in areas of active Ebola transmission, was an addition to Liberia's proposed longer term national IPC strategy, which focused on providing a comprehensive package of IPC training and support to all HCFs in the country. This report describes possible health care worker exposures to the cluster's eight patients who sought care from an HCF and implementation of the Ring IPC approach. On May 9, 2015, the World Health Organization (WHO) declared the end of the Ebola outbreak in Liberia.
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Instituciones de Salud , Fiebre Hemorrágica Ebola/prevención & control , Control de Infecciones/métodos , Control de Infecciones/organización & administración , Adolescente , Adulto , Niño , Análisis por Conglomerados , Femenino , Personal de Salud , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Liberia/epidemiología , Masculino , Persona de Mediana Edad , Exposición Profesional , Adulto JovenRESUMEN
BACKGROUND: Tungiasis is a disease associated with extreme poverty. We aimed to evaluate the prevalence of tungiasis in six different settlements of the Sanumás indigenous community in a remote area in the Auaris region, Yanomami territory, Brazil. METHODS: We conducted an observational study to detect clinical and epidemiological factors associated with tungiasis using a cross-sectional strategy and multivariate logistic regression. Soil analysis was performed by visual and microscopic methods. RESULTS: We examined 555 persons, 45 of whom had active tungiasis; 18 cases were classified as mild, 16 as moderate and 11 as severe. The disease was significantly more prevalent in children than in adults (odds ratio (OR) 15.77; 95% confidence interval (CI) = 5.34-67.91; p < 0.001). Soil infestation was significantly related to the occurrence of human tungiasis (OR = 12.29; 95% CI = 3.75-45.88). The sex and GPS location of the houses were not related to the occurrence of tungiasis. CONCLUSIONS: We conclude that tungiasis is an important problem in the Sanumás community, especially for children. We suggest that interruption of the off-host transmission cycle, together with regular treatment [human and animal interventions], must be prioritized to achieve control of tungiasis in indigenous populations.
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INTRODUCTION: As a mid-size international pharmaceutical company, we initiated 4 years ago the launch of a dedicated high-throughput computing platform supporting drug discovery. The platform named 'Patrimony' was built up on the initial predicate to capitalize on our proprietary data while leveraging public data sources in order to foster a Computational Precision Medicine approach with the power of artificial intelligence. AREAS COVERED: Specifically, Patrimony is designed to identify novel therapeutic target candidates. With several successful use cases in immuno-inflammatory diseases, and current ongoing extension to applications to oncology and neurology, we document how this industrial computational platform has had a transformational impact on our R&D, making it more competitive, as well time and cost effective through a model-based educated selection of therapeutic targets and drug candidates. EXPERT OPINION: We report our achievements, but also our challenges in implementing data access and governance processes, building up hardware and user interfaces, and acculturing scientists to use predictive models to inform decisions.
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Inteligencia Artificial , Descubrimiento de Drogas , Humanos , Medicina de PrecisiónRESUMEN
While establishing worldwide collective immunity with anti SARS-CoV-2 vaccines, COVID-19 remains a major health issue with dramatic ensuing economic consequences. In the transition, repurposing existing drugs remains the fastest cost-effective approach to alleviate the burden on health services, most particularly by reducing the incidence of the acute respiratory distress syndrome associated with severe COVID-19. We undertook a computational repurposing approach to identify candidate therapeutic drugs to control progression towards severe airways inflammation during COVID-19. Molecular profiling data were obtained from public sources regarding SARS-CoV-2 infected epithelial or endothelial cells, immune dysregulations associated with severe COVID-19 and lung inflammation induced by other respiratory viruses. From these data, we generated a protein-protein interactome modeling the evolution of lung inflammation during COVID-19 from inception to an established cytokine release syndrome. This predictive model assembling severe COVID-19-related proteins supports a role for known contributors to the cytokine storm such as IL1ß, IL6, TNFα, JAK2, but also less prominent actors such as IL17, IL23 and C5a. Importantly our analysis points out to alarmins such as TSLP, IL33, members of the S100 family and their receptors (ST2, RAGE) as targets of major therapeutic interest. By evaluating the network-based distances between severe COVID-19-related proteins and known drug targets, network computing identified drugs which could be repurposed to prevent or slow down progression towards severe airways inflammation. This analysis confirmed the interest of dexamethasone, JAK2 inhibitors, estrogens and further identified various drugs either available or in development interacting with the aforementioned targets. We most particularly recommend considering various inhibitors of alarmins or their receptors, currently receiving little attention in this indication, as candidate treatments for severe COVID-19.
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Alarminas/inmunología , Antivirales/farmacología , COVID-19/complicaciones , Reposicionamiento de Medicamentos , Neumonía/complicaciones , Neumonía/tratamiento farmacológico , Antivirales/inmunología , Antivirales/uso terapéutico , Humanos , Neumonía/inmunologíaRESUMEN
BACKGROUND: To date, no biological marker for treatment outcome in human African trypanosomiasis (HAT) has been described. The accuracy of biological markers for prediction of treatment outcome of HAT caused by Trypanosoma brucei gambiense was assessed. METHODS: Cerebrospinal fluid (CSF) white blood cell (WBC) count and immunoglobulin M (IgM), trypanosome-specific antibody, total protein, and interleukin-10 levels were determined before and up to 24 months after treatment of late-stage HAT. RESULTS: Treatment failure was experienced by 48 of 260 patients. Pretreatment CSF WBC counts > or = 102 cells/microL, IL-10 concentrations > or = 37 pg/mL, LATEX/IgM end titers > or = 1:32, LATEX/T. b. gambiense end titers > or = 1:2, and protein concentrations > or = 674 mg/L were associated with treatment failure. Six months after treatment, patients with CSF WBC counts < or = 5 cells/microL were at low risk of HAT recurrence (negative predictive value, >0.93). After 12 months, the combination of CSF WBC count > or = 8 cells/microL and LATEX/IgM end titer > or = 1:4 predicted treatment failure with 97% specificity and 79% sensitivity. Eighteen months after treatment, each marker accurately predicted treatment outcome. The combination of CSF WBC count > or = 8 cells/microL and LATEX/IgM end titer > or = 1:4 was 100% specific for treatment failure after 18 and 24 months. CONCLUSIONS: HAT-affected patients with elevated pretreatment CSF levels of WBC, interleukin-10, IgM, trypanosome-specific antibody, and total protein are at risk of treatment failure. Six months after treatment, patients with CSF WBC counts < or = 5 cells/microL can be considered to be cured. The assessment of a combination of CSF WBC count and LATEX/IgM level allowed accurate prediction of outcome beginning at 12 months after treatment, as did each individual marker at 18 months after treatment.
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Trypanosoma brucei gambiense/aislamiento & purificación , Tripanosomiasis Africana/tratamiento farmacológico , Tripanosomiasis Africana/parasitología , Animales , Anticuerpos Antiprotozoarios/líquido cefalorraquídeo , Biomarcadores , Líquido Cefalorraquídeo/química , Líquido Cefalorraquídeo/inmunología , Humanos , Inmunoglobulina M/líquido cefalorraquídeo , Interleucina-10/líquido cefalorraquídeo , Recuento de Leucocitos , Melarsoprol/uso terapéutico , Valor Predictivo de las Pruebas , Proteínas/análisis , Resultado del Tratamiento , Tripanocidas/uso terapéuticoRESUMEN
Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.
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Evaluación Preclínica de Medicamentos , Curación de Fractura , Osteoporosis/tratamiento farmacológico , Preparaciones Farmacéuticas , Ensayos Clínicos como Asunto , Humanos , Resultado del TratamientoRESUMEN
This study was aimed at evaluating the digestive tolerance of the new antiosteoporotic drug, strontium ranelate, and to compare it to that of another strontium salt, strontium chloride (SrCl2). Strontium ranelate, SrCl2, or placebo were administered orally (capsules) to 3 groups of 2 male and 2 female cynomolgus monkeys (Macaca fascicularis) once a day for 7 days at a dose of 2 g/day, which is the recommended therapeutic dose in man. Endoscopic examination of the oesophagus, the stomach and the first part of the duodenum was performed on fasted animals approximately 3 hr after the first (Day 1) and last dosing (Day 7), and, on Day 8 and Day 14 in case of lesions on Day 7. Strontium ranelate did not induce any acute or subchronic toxic effect on the gastric mucosa, the oesophagus and the first part of the duodenum. On the contrary, acute and superficial damages were noted on all animals receiving SrCl2 such as haemorrhagic and erosive lesions (formation of an ulcer in one male and a marked congestive antritis in one female). These effects were reversible after cessation of treatment. The microscopic examination of biopsies sampled at the site of gastric lesions revealed moderate granulocyte infiltration, indicating a local irritating origin of the lesions. Strontium ranelate by oral route is safe for the gastric mucosa while SrCl2 induced superficial and reversible lesions.
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Endoscopía Gastrointestinal , Esofagoscopía , Compuestos Organometálicos/toxicidad , Estómago/efectos de los fármacos , Tiofenos/toxicidad , Administración Oral , Animales , Biopsia , Evaluación Preclínica de Medicamentos , Duodeno/efectos de los fármacos , Duodeno/patología , Esófago/efectos de los fármacos , Esófago/patología , Macaca fascicularis , Modelos Animales , Compuestos Organometálicos/administración & dosificación , Compuestos Organometálicos/uso terapéutico , Osteoporosis/tratamiento farmacológico , Estómago/patología , Estroncio/administración & dosificación , Estroncio/uso terapéutico , Estroncio/toxicidad , Tiofenos/administración & dosificación , Tiofenos/uso terapéutico , Factores de TiempoRESUMEN
Bartonella henselae is associated with a wide spectrum of clinical manifestations, including cat scratch disease, endocarditis and meningoencephalitis, in immunocompetent and immunocompromised patients. We report the first molecularly confirmed case of B. henselae infection in an AIDS patient in state of Rio de Janeiro, Brazil. Although DNA sequence of B. henselae has been detected by polymerase chain reaction in a lymph node biopsy, acute and convalescent sera were nonreactive.
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Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Bartonella henselae/aislamiento & purificación , Enfermedad por Rasguño de Gato/diagnóstico , Adulto , Animales , Bartonella henselae/genética , Gatos , ADN Bacteriano/análisis , Humanos , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
Bartonella henselae is associated with a wide spectrum of clinical manifestations, including cat scratch disease, endocarditis and meningoencephalitis, in immunocompetent and immunocompromised patients. We report the first molecularly confirmed case of B. henselae infection in an AIDS patient in state of Rio de Janeiro, Brazil. Although DNA sequence of B. henselae has been detected by polymerase chain reaction in a lymph node biopsy, acute and convalescent sera were nonreactive.
Bartonella henselae está associada a um amplo espectro de manifestações clínicas, incluindo a doença da arranhadura de gato, endocardite, e meningoencefalite, em pacientes imunocompetentes e imunocomprometidos. Relatamos o primeiro caso confirmado por método molecular de B. henselae em um paciente com SIDA no estado do Rio de Janeiro, Brasil. Apesar da sequência de DNA de B. henselae ser detectada pela reação em cadeia da polimerase em uma biópsia do linfonodo, soros das fases aguda e convalescente foram não reativos.
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Adulto , Animales , Gatos , Humanos , Masculino , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Bartonella henselae/aislamiento & purificación , Enfermedad por Rasguño de Gato/diagnóstico , Bartonella henselae/genética , ADN Bacteriano/análisis , Reacción en Cadena de la PolimerasaRESUMEN
Strontium ranelate, a new agent for the treatment of osteoporosis, has been shown stimulate bone formation in various experimental models. This study examines the effect of strontium ranelate on gene expression in osteoblasts, as well as the formation of mineralized (von Kossa-positive) colony-forming unit-osteoblasts (CFU-obs). Bone marrow-derived stromal cells cultured for 21 days under differentiating conditions, when exposed to strontium ranelate, displayed a significant time- and concentration-dependent increase in the expression of the master gene, Runx2, as well as bone sialoprotein (BSP), but interestingly without effects on osteocalcin. This was associated with a significant increase in the formation of CFU-obs at day 21 of culture. In U-33 pre-osteoblastic cells, strontium ranelate significantly enhanced the expression of Runx2 and osteocalcin, but not BSP. Late, more mature osteoblastic OB-6 cells showed significant elevations in BSP and osteocalcin, but with only minimal effects on Runx2. In conclusion, strontium ranelate stimulates osteoblast differentiation, but the induction of the program of gene expression appears to be cell type-specific. The increased osteoblastic differentiation is the likely basis underlying the therapeutic bone-forming actions of strontium ranelate.