LAS ORGANIZACIONES INTELIGENTES

The present work approaches Open-to-Learning Organizations Theory and Concepts such as the building up of shared views, self-control, mental models, teamlearning and systemic thought. An intelligent organization is thus stablished as a result of engineering innovation.En este trabajo se aborda la teoría de las organizaciones abiertas al aprendizaje y los conceptos sobre la construcción de visiones compartidas, dominio personal, modelos mentales, aprendizaje en equipo y el pensamiento sistémico; estableciéndose la organización inteligente como un producto de la innovación en ingeniería

Linfoma hepático primario no Hodgkin de células T y B asociado a VEB: un reporte de caso

El linfoma hepático primario (LHP) es una forma rara de linfoma no Hodgkin que suele manifestarse clínicamente con dolor abdominal, pérdida de peso, hepatomegalia e ictericia, sin presencia de adenomegalias o invasión extrahepática. De todos lo linfomas este presenta una prevalencia 0.016%. La etiología no se encuentra bien definida, sin embargo, el LHP se ha reportado estar asociado al virus Epstein-Barr (VEB), el cual posee la capacidad promover el crecimiento de los linfocitos, mediante los mecanismos de expresión del antígeno nuclear de Epstein-Barr 1 (EBNA1), la proteína de membrana latente 1 (LMP1) y LMP2 que producen la proliferación de células B. Mientras que, la activación de citocinas proinflamatorias y expresión de genes latentes, conducen a la proliferación de células T. Presentamos el caso de una paciente de 68 años que acude por presentar pérdida de peso de 10 kg en un periodo de 3 meses, malestar general, dolor abdominal tipo cólico localizado en epigastrio y sensación de llenura precoz asociado a fiebre no cuantificada, episodios de náuseas, diarrea en múltiples ocasiones e ictericia en escleras en los últimos 5 días. Mediante biopsia, se identifica Linfoma no Hodgkin inmunofenotipo T y B.Primary liver lymphoma (LHP) is a rare form of non-Hodgkin lymphoma that usually manifests clinically with abdominal pain, weight loss, hepatomegaly and jaundice, without the presence of adenomegalies or extrahepatic invasion. Of all lymphomas, this has a prevalence of 0.016%. The etiology is not well defined, however LHP has been reported to be associated with the Epstein-Barr virus (EBV), which has the ability to promote lymphocyte growth, by means of the Epstein-Barr nuclear antigen expression mechanisms. 1 (EBNA1), the latent membrane protein 1 (LMP1) and LMP2 that produce B-cell proliferation. While, the activation of proinflammatory cytokines and latent gene expression, lead to the proliferation of T-cells. We present the case of a 68-year-old patient who presented with a 10 kg weight loss over a period of 3 months, malaise, abdominal cramps in the epigastrium and a feeling of early fullness associated with unquantified fever, nausea episodes, multiple diarrhea occasions and jaundice in scleras in the last 5 days. By biopsy, non-Hodgkin lymphoma immunophenotype T and B is identified

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING Intercept Pharmaceuticals

The MIT D-lab electricity-free PortaTherm™ incubator for remote testing with the QuantiFERON®-TB Gold In-Tube assay.

BACKGROUND: Use of the QuantiFERON®-TB Gold In-Tube assay (QFT-GIT) in remote areas is limited by the need to incubate blood samples within 12 h of collection. PortaTherm™ is a portable, electricity-free, phase-change incubator previously used for field collection of microbiological samples. OBJECTIVE: To determine whether the PortaTherm can be used for the reliable incubation of QFT-GIT samples, thus enabling QFT-GIT use in settings distant from laboratory facilities. METHODS: In a prospective comparative study in Peru, blood samples were collected from 50 participants and processed in three parallel QFT-GIT tests per participant; two were incubated in a conventional incubator; the third was incubated in the PortaTherm. RESULTS: All 150 QFT-GIT tests gave definitive results, and for 46 of the 50 participants all three tests were concordant, eight of which were positive. Four participants had one discordant result: two due to discordance of a conventional incubator QFT-GIT result, and two due to discordant PortaTherm QFT-GIT results. CONCLUSION: The QFT-GIT inter-incubator variability between the PortaTherm and conventional incubator was no greater than the intra-incubator variability for the conventional incubator, indicating that the PortaTherm is a suitable tool for incubating QFT-GIT whole blood samples in remote settings where access to a laboratory or electricity is limited

Culture-negative TB: Clinical Characteristics, Risk Factors and Treatment Outcomes

Background: Although culture remains the standard for TB diagnosis, 15–20% of patients diagnosed and treated for TB are culture-negative. We explored clinical characteristics, risk factors and treatment outcomes for culture-negative TB in a Peruvian cohort. Methods: We recruited 4,500 index TB patients and 10,160 household contacts in Lima, Peru, and enrolled 692 secondary patients diagnosed with TB during follow-up of household contacts. We analyzed smear and culture status, sociodemographic factors, clinical characteristics and TB treatment outcomes to compare culture-negative and positive patients. Results: Of the 4,880 adult patients, 915 (18.8%) were culture-negative. Culture-negative patients were less likely to report symptoms of TB disease and disease of longer duration. A multivariate analysis showed no statistically significant difference in loss to follow-up, treatment failure or recurrence between the culture-negative and -positive groups but a higher rate of death among culture-negative patients with an adjusted OR of 1.65 (95% CI 1.05–2.60). In a multivariate analysis of determinants of culture negativity, older age, substance use and being a secondary case were associated with culture status. Conslusion: More recognition and awareness of culture-negative TB is key for early and correct diagnosis to reduce transmission and improve treatment outcomes

Latent TB and Depressive Symptoms in Household Contacts of Persons with Active TB

Background: Depression is common among persons with TB and is associated with poor clinical outcomes. However, little is known about the relationship between latent TB infection (LTBI) and depression. We assessed the association between LTBI and depressive symptoms among household contacts (HHCs) of patients receiving TB treatment. Methods: We enrolled 1,009 HHCs of 307 patients receiving TB treatment in Lima, Peru, during 2016–2018. At enrollment, HHC LTBI status was assessed using the interferon-gamma release assay (IGRA). Depressive symptoms were assessed at baseline and 12 months later using the Patient Health Questionnaire-9 (PHQ-9) with a cut-off of ≥5. We used logistic regression to estimate the odds ratio (OR) for PHQ-9 ≥5, comparing HHCs with and without baseline LTBI. Results: Among 921 HHCs, 374 (41.0%) had LTBI at baseline, and 69 (12.4%) of 567 HHCs had PHQ-9 ≥5. Compared to HHCs without LTBI at enrollment, those with LTBI had almost two times the odds of PHQ-9 ≥5 at follow-up after controlling for potential confounders (adjusted OR 1.93, 95% CI 1.09–3.39); this association was driven by greater severities of depressive symptoms. Conclusion: HHCs with LTBI had increased odds of depressive symptoms 1 year later. This population may benefit from mental health screening and interventions integrated into TB programs

Prevalence of Pyrazinamide Resistance and Wayne Assay Performance Analysis in a Tuberculosis Cohort in Lima, Peru

Background: Multidrug-resistant tuberculosis (MDR-TB) regimens often contain pyrazinamide (PZA) even if susceptibility to the drug has not been confirmed. This gap is due to the limited availability and reliability of PZA susceptibility testing. Objectives: To estimate the prevalence of PZA resistance using the Wayne assay among TB patients in Lima, Peru, to describe characteristics associated with PZA resistance and to compare the performance of Wayne with that of BACTEC™ MGIT™ 960. Methods: PZA susceptibility using the Wayne assay was tested in patients diagnosed with culture-positive pulmonary TB from September 2009 to August 2012. Factors associated with PZA resistance were evaluated. We compared the performance of the Wayne assay to that of MGIT 960 in a convenience sample. Results: The prevalence of PZA resistance was 6.6% (95%CI 5.8–7.5) among 3277 patients, and 47.7% (95%CI 42.7–52.6) among a subset of 405 MDR-TB patients. In multivariable analysis, MDR-TB (OR 86.0, 95%CI 54.0–136.9) and Latin American-Mediterranean lineage (OR 3.40, 95%CI 2.33–4.96) were associated with PZA resistance. The Wayne assay was in agreement with MGIT 960 in 83.9% of samples (κ 0.66, 95%CI 0.56–0.76). Conclusion: PZA resistance was detected using the Wayne assay in nearly half of MDR-TB patients in Lima. This test can inform the selection and composition of regimens, especially those dependent on additional resistance

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

Phenotypic drug susceptibility testing is the current gold standard for detecting Mycobacterium tuberculosis susceptibility to antituberculous drugs. Pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. Here we performed latent class analysis (LCA) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. We then compared this consensus measure to the 2-month culture results for patients with multidrug-resistant tuberculosis (MDR-TB) who were treated for 2 months with first-line antituberculous drugs before their resistance results were known. Among 121 patients with MDR-TB, 60 (49.6%) were resistant to pyrazinamide by the Wayne method (L. G. Wayne, Am Rev Respir Dis 109:147-151, 1974), 71 (58.7%) were resistant by the Bactec MGIT 960 method, and 68 (56.2%) were resistant by pncA sequencing. LCA grouped isolates with positive results by at least two assays into a category which we considered the consensus gold standard for pyrazinamide resistance. The sensitivity and specificity for this consensus gold standard were 82.4% and 92.5%, respectively, for the Wayne method; 95.6% and 88.7%, respectively, for the Bactec MGIT 960 method; and 92.6% and 90.6%, respectively, for pncA sequencing. After we adjusted for other factors associated with poor outcomes, including age, sex, alcohol use, and baseline ethambutol resistance, patients whose isolates were resistant by the LCA-derived consensus gold standard were more likely to be culture positive at 2 months with an odds ratio of 1.95 (95% confidence interval, 0.74 to 5.11), but this result was not statistically significant. These findings underscore the need for improved diagnostics for routine use in programmatic settings