Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 111
Filtrar
1.
Mucosal Immunol ; 13(1): 118-127, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31619762

RESUMEN

We compared outer and inner foreskin tissue from adolescent males undergoing medical male circumcision to better understand signals that increase HIV target cell availability in the foreskin. We measured chemokine gene expression and the impact of sexually transmitted infections (STIs) on the density and location of T and Langerhans cells. Chemokine C-C ligand 27 (CCL27) was expressed 6.94-fold higher in the inner foreskin when compared with the outer foreskin. We show that the density of CD4+CCR5+ cells/mm2 was higher in the epithelium of the inner foreskin, regardless of STI status, in parallel with higher CCL27 gene expression. In the presence of STIs, there were higher numbers of CD4+CCR5+ cells/mm2 cells in the sub-stratum of the outer and inner foreskin with concurrently higher number of CD207+ Langerhans cells (LC) in both tissues, with the latter cells being closer to the keratin surface of the outer FS in the presence of an STI. When we tested the ability of exogenous CCL27 to induce T-cell migration in foreskin tissue, CD4 + T cells were able to relocate to the inner foreskin epithelium in response. We provide novel insight into the impact CCL27 and STIs on immune and HIV-1 target cell changes in the foreskin.

2.
Clin Infect Dis ; 2019 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-31781758

RESUMEN

BACKGROUND: TB is the major killer of people living with HIV globally, with suboptimal diagnostics and management contributing to high case-fatality rates. METHODS: A prospective cohort of confirmed (Xpert MTB/RIF and/or Determine TB-LAM Ag positive) TB patients identified through screening HIV-positive inpatients with sputum and urine diagnostics in Malawi and South Africa (STAMP trial). Urine was tested prospectively (intervention) or retrospectively (standard of care arm). We defined baseline clinical phenotypes using hierarchical cluster analysis, and also used Cox regression analysis to identify associations with early mortality (≤56 days). RESULTS: Of 322 patients with TB confirmed between October 2015 and September 2018, 78.0% had ≥1 positive urine test. Antiretroviral therapy (ART) coverage was 80.2% among those not newly diagnosed, but with median CD4 count 75 cells/µL and high HIV viral loads. Early mortality was 30.7% (99/322), despite near-universal prompt TB treatment. Older age, male sex, ART before admission, poor nutritional status, lower haemoglobin, and positive urine tests (TB-LAM and/or Xpert MTB/RIF) were associated with increased mortality in multivariate analyses. Cluster analysis (on baseline variables) defined 4 patient subgroups with early mortality ranging from 9.8% to 52.5%. Although unadjusted mortality was 9.3% lower in South Africa than Malawi, in adjusted models mortality was similar in both countries (HR 0.9, p=0.729). CONCLUSIONS: Mortality following prompt inpatient diagnosis of HIV-associated TB remained unacceptably high, even in South Africa. Intensified management strategies are urgently needed, for which prognostic indicators could potentially guide both development and subsequent use.

3.
Lancet Infect Dis ; 19(8): 794-796, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31155317
4.
PLoS Med ; 16(4): e1002776, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30951533

RESUMEN

BACKGROUND: The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. METHODS AND FINDINGS: A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30-43), 45.4% were female, median CD4 cell count at admission was 76 cells/µl (IQR 23-206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%-55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%-25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4-15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63-0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61-0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21-145). OR for mortality was 5.3 (95% CI 2.2-9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance). CONCLUSIONS: This risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality.


Asunto(s)
Infecciones por VIH/diagnóstico , Infecciones por VIH/mortalidad , Lipopolisacáridos/orina , Tuberculosis/diagnóstico , Tuberculosis/mortalidad , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Infecciones Oportunistas Relacionadas con el SIDA/orina , Adulto , África del Sur del Sahara/epidemiología , Estudios de Cohortes , Femenino , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/orina , Hospitalización , Humanos , Pacientes Internos , Masculino , Tamizaje Masivo/métodos , Pronóstico , Proyectos de Investigación , Factores de Riesgo , Análisis de Supervivencia , Tuberculosis/orina , Urinálisis
5.
Lancet Glob Health ; 7(2): e200-e208, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30683239

RESUMEN

BACKGROUND: Testing urine improves the number of tuberculosis diagnoses made among patients in hospital with HIV. In conjunction with the two-country randomised Rapid Urine-based Screening for Tuberculosis to Reduce AIDS-related Mortality in Hospitalised Patients in Africa (STAMP) trial, we used a microsimulation model to estimate the effects on clinical outcomes and the cost-effectiveness of adding urine-based tuberculosis screening to sputum screening for hospitalised patients with HIV. METHODS: We compared two tuberculosis screening strategies used irrespective of symptoms among hospitalised patients with HIV in Malawi and South Africa: a GeneXpert assay (Cepheid, Sunnyvale, CA, USA) for Mycobacterium tuberculosis and rifampicin resistance (Xpert) in sputum samples (standard of care) versus sputum Xpert combined with a lateral flow assay for M tuberculosis lipoarabinomannan in urine (Determine TB-LAM Ag test, Abbott, Waltham, MA, USA [formerly Alere]; TB-LAM) and concentrated urine Xpert (intervention). A cohort of simulated patients was modelled using selected characteristics of participants, tuberculosis diagnostic yields, and use of hospital resources in the STAMP trial. We calibrated 2-month model outputs to the STAMP trial results and projected clinical and economic outcomes at 2 years, 5 years, and over a lifetime. We judged the intervention to be cost-effective if the incremental cost-effectiveness ratio (ICER) was less than US$750/year of life saved (YLS) in Malawi and $940/YLS in South Africa. A modified intervention of adding only TB-LAM to the standard of care was also evaluated. We did a budget impact analysis of countrywide implementation of the intervention. FINDINGS: The intervention increased life expectancy by 0·5-1·2 years and was cost-effective, with an ICER of $450/YLS in Malawi and $840/YLS in South Africa. The ICERs decreased over time. At lifetime horizon, the intervention remained cost-effective under nearly all modelled assumptions. The modified intervention was at least as cost-effective as the intervention (ICERs $420/YLS in Malawi and $810/YLS in South Africa). Over 5 years, the intervention would save around 51 000 years of life in Malawi and around 171 000 years of life in South Africa. Health-care expenditure for screened individuals was estimated to increase by $37 million (10·8%) and $261 million (2·8%), respectively. INTERPRETATION: Urine-based tuberculosis screening of all hospitalised patients with HIV could increase life expectancy and be cost-effective in resource-limited settings. Urine TB-LAM is especially attractive because of high incremental diagnostic yield and low additional cost compared with sputum Xpert, making a compelling case for expanding its use to all hospitalised patients with HIV in areas with high HIV burden and endemic tuberculosis. FUNDING: UK Medical Research Council, UK Department for International Development, Wellcome Trust, US National Institutes of Health, Royal College of Physicians, Massachusetts General Hospital.

6.
Lancet Infect Dis ; 19(4): e143-e147, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30344084

RESUMEN

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.

7.
Open Forum Infect Dis ; 5(11): ofy253, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30474046

RESUMEN

Background: Novel biomarkers are needed to assess response to antituberculosis therapy in smear-negative patients. Methods: To evaluate the utility of C-reactive protein (CRP) in monitoring response to antituberculosis therapy, we conducted a post hoc analysis on a cohort of adults with symptoms of tuberculosis and negative sputum smears in a high-tuberculosis and HIV prevalence setting in KwaZulu-Natal, South Africa. Serial changes in CRP, weight, and hemoglobin were evaluated over 8 weeks. Results: Four hundred twenty-one participants being evaluated for smear-negative tuberculosis were enrolled, and 33 were excluded. Two hundred ninety-five were treated for tuberculosis (137 confirmed, 158 possible), and 93 did not have tuberculosis. One hundred and eighty-three of 213 (86%) participants who agreed to HIV testing were HIV positive. At week 8, the on-treatment median CRP reduction in the tuberculosis group (interquartile range [IQR]) was 79.5% (25.4% to 91.7%), the median weight gain was 2.3% (-1.0% to 5.6%), and the median hemoglobin increase was 7.0% (0.8% to 18.9%); P < .0001 for baseline to week 8 comparison of absolute median values. Only CRP changed significantly at week 2 (median reduction [IQR], 75.1% [46.9% to 89.2%]) in the group with confirmed tuberculosis and in the possible tuberculosis group (median reduction [IQR], 49.0% [-0.4% to 80.9%]). Failure of CRP to reduce to ≤55% of the baseline value at week 2 predicted hospitalization or death in both tuberculosis groups, with 99% negative predictive value. Conclusions: Change in CRP may have utility in early evaluation of response to antituberculosis treatment and to identify those at increased risk of adverse outcomes.

8.
BMJ Open ; 8(9): e023377, 2018 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-30269073

RESUMEN

INTRODUCTION: Improved medicines' management could lead to real and sustainable improvements to the care of older adults. The overuse of mental health medicines has featured in many reports, and insufficient patient monitoring has been identified as an important cause of medicine-related harms. Nurse-led monitoring using the structured adverse drug reaction (ADRe) profile identifies and addresses the adverse effects of mental health medicines. Our study investigates clinical impact and what is needed to sustain utilisation in routine practice in care homes. METHODS AND ANALYSIS: This process evaluation will use interviews and observations with the participants of all five homes involved in earlier research, and five newly recruited homes caring for people prescribed mental health medicines. The ADRe profile is implemented by nurses, within existing resources, to check for signs and symptoms of ADRs, initiate amelioration and share findings with pharmacists and prescribers for medication review. Outcome measures are the numbers and nature of problems addressed and understanding of changes needed to optimise clinical gain and sustain implementation. Data will be collected by 30 observations and 30 semistructured interviews. Clinical gains will be described and narrated. Interview analysis will be based on the constant comparative method. ETHICS AND DISSEMINATION: Ethical approval was conferred by the National Health Service Wales Research Ethics Committee. If the ADRe profile can be sustained in routine practice, it has potential to (1) improve the lives of patients, for example, by reducing pain and sedation, and (2) assist in early identification of problems caused by ADRs. Therefore, in addition to peer-reviewed publications and conferences, we shall communicate our findings to healthcare professionals, policy-makers and sector regulators. TRIAL REGISTRATION NUMBER: NCT03110471.


Asunto(s)
Monitoreo de Drogas , Casas de Salud , Personal de Enfermería , Psicotrópicos/efectos adversos , Humanos , Estudios Observacionales como Asunto
9.
Am J Trop Med Hyg ; 99(5): 1336-1341, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30226135

RESUMEN

HIV-positive adults on treatment for multi drug-resistant tuberculosis (MDR-TB) experience high mortality. Biomarkers of HIV/MDR-TB treatment response may enable earlier treatment modifications that improve outcomes. To determine whether changes in C-reactive protein (CRP), D-dimer, and fibrinogen were associated with treatment outcome among those with HIV/MDR-TB coinfection, we studied 20 HIV-positive participants for the first 16 weeks of MDR-TB therapy. Serum CRP, fibrinogen, and D-dimer were measured at baseline and serially while on treatment. At baseline, all biomarkers were elevated above normal levels, with median CRP 86.15 mg/L (interquartile range [IQR] 29.25-149.32), D-dimer 0.85 µg/mL (IQR 0.34-1.80), and fibrinogen 4.11 g/L (IQR 3.75-6.31). C-reactive protein decreased significantly within 10 days of treatment initiation and fibrinogen within 28 days; D-dimer did not change significantly. Five (25%) participants died after a median of 32 days. Older age (median age of 38y among survivors and 54y among deceased, P = 0.008) and higher baseline fibrinogen (3.86 g/L among survivors and 6.37 g/L among deceased, P = 0.02) were significantly associated with death. After adjusting for other measured variables, higher CRP concentrations at the beginning of each measurement interval were significantly associated with a higher risk of death during that interval. Trends in fibrinogen and CRP may be useful for evaluating early response to treatment among individuals with HIV/MDR-TB coinfection.


Asunto(s)
Antituberculosos/uso terapéutico , Proteína C-Reactiva/análisis , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Fibrinógeno/análisis , Infecciones por VIH/microbiología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Factores de Edad , Biomarcadores/sangre , Recuento de Linfocito CD4 , Femenino , VIH/aislamiento & purificación , Infecciones por VIH/sangre , Infecciones por VIH/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Factores de Riesgo , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/sangre , Tuberculosis Resistente a Múltiples Medicamentos/virología
10.
Immunity ; 49(2): 342-352.e5, 2018 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-30097293

RESUMEN

Interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (ILC3) maintains gut homeostasis but can also promote inflammatory bowel disease (IBD). The regulation of ILC3-dependent colitis remains to be elucidated. Here we show that Foxp3+ regulatory T cells (Treg cells) prevented ILC3-mediated colitis in an IL-10-independent manner. Treg cells inhibited IL-23 and IL-1ß production from intestinal-resident CX3CR1+ macrophages but not CD103+ dendritic cells. Moreover, Treg cells restrained ILC3 production of IL-22 through suppression of CX3CR1+ macrophage production of IL-23 and IL-1ß. This suppression was contact dependent and was mediated by latent activation gene-3 (LAG-3)-an immune checkpoint receptor-expressed on Treg cells. Engagement of LAG-3 on MHC class II drove profound immunosuppression of CX3CR1+ tissue-resident macrophages. Our study reveals that the health of the intestinal mucosa is maintained by an axis driven by Treg cells communication with resident macrophages that withhold inflammatory stimuli required for ILC3 function.


Asunto(s)
Antígenos CD/metabolismo , Receptor 1 de Quimiocinas CX3C/metabolismo , Colitis/inmunología , Colitis/patología , Subunidad p19 de la Interleucina-23/inmunología , Mucosa Intestinal/patología , Macrófagos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Células Dendríticas/inmunología , Factores de Transcripción Forkhead/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Interleucina-10/inmunología , Interleucina-1beta/inmunología , Interleucinas/inmunología , Mucosa Intestinal/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T Reguladores/trasplante
11.
Lancet ; 392(10144): 292-301, 2018 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-30032978

RESUMEN

BACKGROUND: Current diagnostics for HIV-associated tuberculosis are suboptimal, with missed diagnoses contributing to high hospital mortality and approximately 374 000 annual HIV-positive deaths globally. Urine-based assays have a good diagnostic yield; therefore, we aimed to assess whether urine-based screening in HIV-positive inpatients for tuberculosis improved outcomes. METHODS: We did a pragmatic, multicentre, double-blind, randomised controlled trial in two hospitals in Malawi and South Africa. We included HIV-positive medical inpatients aged 18 years or more who were not taking tuberculosis treatment. We randomly assigned patients (1:1), using a computer-generated list of random block size stratified by site, to either the standard-of-care or the intervention screening group, irrespective of symptoms or clinical presentation. Attending clinicians made decisions about care; and patients, clinicians, and the study team were masked to the group allocation. In both groups, sputum was tested using the Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA). In the standard-of-care group, urine samples were not tested for tuberculosis. In the intervention group, urine was tested with the Alere Determine TB-LAM Ag (TB-LAM; Alere, Waltham, MA, USA), and Xpert assays. The primary outcome was all-cause 56-day mortality. Subgroup analyses for the primary outcome were prespecified based on baseline CD4 count, haemoglobin, clinical suspicion for tuberculosis; and by study site and calendar time. We used an intention-to-treat principle for our analyses. This trial is registered with the ISRCTN registry, number ISRCTN71603869. FINDINGS: Between Oct 26, 2015, and Sept 19, 2017, we screened 4788 HIV-positive adults, of which 2600 (54%) were randomly assigned to the study groups (n=1300 for each group). 13 patients were excluded after randomisation from analysis in each group, leaving 2574 in the final intention-to-treat analysis (n=1287 in each group). At admission, 1861 patients were taking antiretroviral therapy and median CD4 count was 227 cells per µL (IQR 79-436). Mortality at 56 days was reported for 272 (21%) of 1287 patients in the standard-of-care group and 235 (18%) of 1287 in the intervention group (adjusted risk reduction [aRD] -2·8%, 95% CI -5·8 to 0·3; p=0·074). In three of the 12 prespecified, but underpowered subgroups, mortality was lower in the intervention group than in the standard-of-care group for CD4 counts less than 100 cells per µL (aRD -7·1%, 95% CI -13·7 to -0·4; p=0.036), severe anaemia (-9·0%, -16·6 to -1·3; p=0·021), and patients with clinically suspected tuberculosis (-5·7%, -10·9 to -0·5; p=0·033); with no difference by site or calendar period. Adverse events were similar in both groups. INTERPRETATION: Urine-based tuberculosis screening did not reduce overall mortality in all HIV-positive inpatients, but might benefit some high-risk subgroups. Implementation could contribute towards global targets to reduce tuberculosis mortality. FUNDING: Joint Global Health Trials Scheme of the Medical Research Council, the UK Department for International Development, and the Wellcome Trust.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/orina , Países en Desarrollo , Seropositividad para VIH/orina , Tamizaje Masivo , Tuberculosis/orina , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Infecciones Oportunistas Relacionadas con el SIDA/mortalidad , Adulto , Método Doble Ciego , Farmacorresistencia Bacteriana , Femenino , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/mortalidad , Humanos , Malaui , Masculino , Persona de Mediana Edad , Rifampin/uso terapéutico , Sudáfrica , Esputo/microbiología , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Tuberculosis/mortalidad , Urinálisis
12.
Am J Trop Med Hyg ; 99(2): 317-322, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29893198

RESUMEN

Human immunodeficiency virus (HIV) infection is a major risk factor for the development of active tuberculosis (TB), one of the deadliest infectious diseases globally. The high mortality associated with the disease can be reduced by early diagnosis and prompt antituberculous treatment initiation. Facilities in TB-endemic regions are increasing the use of nucleic acid amplification (e.g., GeneXpert), which provides rapid results but may have suboptimal sensitivity in HIV-associated TB. Our objective was to evaluate the current practices for TB diagnosis at Edendale Hospital, a large regional hospital in KwaZulu-Natal, South Africa-a TB-endemic region with high HIV prevalence. In this cross-sectional study, all adult inpatients newly started on TB treatment at Edendale were identified over a 6-week period. Demographics, clinical information, diagnostic test results, and outcomes were documented. Pulmonary TB (PTB), extrapulmonary TB (EXTB), and PTB + EXTB were defined as disease evidence in the lungs, other organs, or both, respectively. Ninety-four cases were identified, of which 83% were HIV-associated. Only 30% of all TB patients were microbiologically confirmed, consisting of 7/16 (44%) HIV-uninfected and 21/78 (27%) HIV-infected TB patients. Smear microscopy and mycobacterial culture were seldom ordered. Ultrasound was performed in about one-third of suspected EXTB cases and was valuable in identifying abdominal TB. In this clinical setting with a high incidence of HIV-associated TB, TB diagnosis was more commonly based on clinical assessment and imaging results than on mycobacterial gold standard test confirmation.


Asunto(s)
Infecciones por VIH/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis/diagnóstico , Adulto , Estudios Transversales , Enfermedades Endémicas , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/microbiología , Humanos , Masculino , Registros Médicos , Microscopía , Persona de Mediana Edad , Mycobacterium tuberculosis/genética , Técnicas de Amplificación de Ácido Nucleico , Prevalencia , Factores de Riesgo , Sudáfrica/epidemiología , Esputo/microbiología , Tuberculosis/epidemiología , Tuberculosis Pulmonar/epidemiología , Ultrasonografía
13.
Cancer Discov ; 8(7): 836-849, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29657135

RESUMEN

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.


Asunto(s)
Antineoplásicos/uso terapéutico , Mutación , Neoplasias/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Antineoplásicos/farmacología , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/genética , Neoplasias/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-ret/metabolismo , Pirazoles/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
14.
Pathogens ; 7(1)2018 Feb 27.
Artículo en Inglés | MEDLINE | ID: mdl-29495442

RESUMEN

Sputum smear-negative HIV-associated active tuberculosis (TB) is challenging to diagnose. CD14 is a pattern recognition receptor that is known to mediate monocyte activation. Prior studies have shown increased levels of soluble CD14 (sCD14) as a potential biomarker for TB, but little is known about its value in detecting smear-negative HIV-associated TB. We optimized a sandwich ELISA for the detection of sCD14, and tested sera from 56 smear-negative South African (39 culture-positive and 17 culture-negative) HIV-infected pulmonary TB patients and 24 South African and 43 US (21 positive and 22 negative for tuberculin skin test, respectively) HIV-infected controls. SCD14 concentrations were significantly elevated in smear-negative HIV-associated TB compared with the HIV-infected controls (p < 0.0001), who had similar concentrations, irrespective of the country of origin or the presence or absence of latent M. tuberculosis infection (p = 0.19). The culture-confirmed TB group had a median sCD14 level of 2199 ng/mL (interquartile range 1927-2719 ng/mL), versus 1148 ng/mL (interquartile range 1053-1412 ng/mL) for the South African controls. At a specificity of 96%, sCD14 had a sensitivity of 95% for culture-confirmed smear-negative TB. These data indicate that sCD14 could be a highly accurate biomarker for the detection of HIV-associated TB.

15.
Antioxidants (Basel) ; 6(4)2017 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-29143759

RESUMEN

This overview was directed towards understanding the relationship of brain functions with dietary choices mainly by older humans. This included food color, flavor, and aroma, as they relate to dietary sufficiency or the association of antioxidants with neurodegenerative diseases such as dementia and Alzheimer's disease. Impairment of olfactory and gustatory function in relation to these diseases was also explored. The role of functional foods was considered as a potential treatment of dementia and Alzheimer's disease through inhibition of acetylcholinesterase as well as similar treatments based on herbs, spices and antioxidants therein. The importance of antioxidants for maintaining the physiological functions of liver, kidney, digestive system, and prevention of cardiovascular diseases and cancer has also been highlighted. Detailed discussion was focused on health promotion of the older person through the frequency and patterns of dietary intake, and a human ecology framework to estimate adverse risk factors for health. Finally, the role of the food industry, mass media, and apps were explored for today's new older person generation.

16.
Nat Biotechnol ; 35(10): 936-939, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28854175

RESUMEN

We present a tool to measure gene and protein expression levels in single cells with DNA-labeled antibodies and droplet microfluidics. Using the RNA expression and protein sequencing assay (REAP-seq), we quantified proteins with 82 barcoded antibodies and >20,000 genes in a single workflow. We used REAP-seq to assess the costimulatory effects of a CD27 agonist on human CD8+ lymphocytes and to identify and characterize an unknown cell type.


Asunto(s)
Proteínas/metabolismo , Análisis de la Célula Individual/métodos , Linfocitos T CD4-Positivos/metabolismo , Humanos , Activación de Linfocitos/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de Proteína , Análisis de Secuencia de ARN
17.
J Obstet Gynaecol Can ; 39(8): 645-651.e1, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28729097

RESUMEN

BACKGROUND: Obstetric surgical site infections (SSIs) are common and expensive to the health care system but remain under reported given shorter postoperative hospital stays and suboptimal post-discharge surveillance systems. SSIs, for the purpose of this paper, are defined according to the Center for Disease Control and Prevention (1999) as infection incurring within 30 days of the operative procedure (in this case, Caesarean section [CS]). PRIMARY OBJECTIVE: Demonstrate the feasibility of real-life use of a patient driven SSIs post-discharge surveillance system consisting of an online database and mobile phone technology (surgical mobile app - how2trak) among women undergoing CS in a Canadian urban centre. SECONDARY OBJECTIVE: Estimate the rate of SSIs and associated predisposing factors. METHODS: Prospective cohort of consecutive women delivering by CS at one urban Canadian hospital. Using surgical mobile app-how2trak-predetermined demographics, comorbidities, procedure characteristics, and self-reported symptoms and signs of infection were collected and linked to patients' incision self-portraits (photos) on postpartum days 3, 7, 10, and 30. RESULTS: A total of 105 patients were enrolled over a 5-month period. Mean age was 31 years, 13% were diabetic, and most were at low risk of surgical complications. Forty-six percent of surgeries were emergency CSs, and 104/105 received antibiotic prophylaxis. Forty-five percent of patients (47/105) submitted at least one photo, and among those, one surgical site infection was detected by photo appearance and self-reported symptoms by postpartum day 10. The majority of patients whom uploaded photos did so multiple times and 43% of them submitted photos up to day 30. Patients with either a diagnosis of diabetes or self-reported Asian ethnicity were less likely to submit photos. CONCLUSIONS: Post-discharge surveillance for CS-related SSIs using surgical mobile app how2trak is feasible and deserves further study in the post-discharge setting.


Asunto(s)
Cesárea , Aplicaciones Móviles , Fotograbar , Autoinforme , Infección de la Herida Quirúrgica/diagnóstico , Adulto , Profilaxis Antibiótica , Canadá , Teléfono Celular , Estudios de Cohortes , Estudios de Factibilidad , Femenino , Humanos , Internet , Cuidados Posoperatorios , Embarazo , Estudios Prospectivos , Factores de Riesgo , Infección de la Herida Quirúrgica/prevención & control , Adulto Joven
18.
Open Forum Infect Dis ; 4(3): ofx123, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28721354

RESUMEN

BACKGROUND: Evaluation of patients with suspected tuberculosis and negative sputum smears for acid-fast bacilli (AFB) is challenging, especially in high human immunodeficiency virus coinfection settings where sputum smears have lower sensitivity for detecting AFB. METHODS: We examined the utility of chest radiographs for detecting smear-negative pulmonary tuberculosis. Three hundred sixty sputum smear-negative patients who were referred from primary care clinics in the KwaZulu-Natal province of South Africa were evaluated. Chest radiographs were read by experienced pulmonologists using a previously validated Chest X-Ray Reading and Recording System (CRRS). RESULTS: Agreement between observers using CRRS was high at 91% with a Cohen's kappa of 0.64 (95% confidence interval [CI] = 0.52-0.76). Against a reference standard of sputum culture, sensitivity was 93% (95% CI = 86%-97%), whereas specificity was 14% (95% CI = 10%-19%). Performance against clinical diagnosis (following World Health Organization guidelines) was similar with sensitivity of 92% (95% CI = 88%-95%) and specificity of 20% (95% CI = 13%-28%). CONCLUSION: The low specificity of CRRS in this setting indicates poor diagnostic utility for detecting pulmonary tuberculosis.

19.
Cancer Res ; 77(16): 4378-4388, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28611044

RESUMEN

GITR is a T-cell costimulatory receptor that enhances cellular and humoral immunity. The agonist anti-mouse GITR antibody DTA-1 has demonstrated efficacy in murine models of cancer primarily by attenuation of Treg-mediated immune suppression, but the translatability to human GITR biology has not been fully explored. Here, we report the potential utility of MK-4166, a humanized GITR mAb selected to bind to an epitope analogous to the DTA-1 epitope, which enhances the proliferation of both naïve and tumor-infiltrating T lymphocytes (TIL). We also investigated the role of GITR agonism in human antitumor immune responses and report here the preclinical characterization and toxicity assessment of MK-4166, which is currently being evaluated in a phase I clinical study. Expression of human GITR was comparable with that of mouse GITR in tumor-infiltrating Tregs despite being drastically lower in other human TILs and in many human peripheral blood populations. MK-4166 decreased induction and suppressive effects of Tregsin vitro In human TIL cultures, MK-4166 induced phosphorylation of NFκB and increased expression of dual specificity phosphatase 6 (DUSP6), indicating that MK-4166 activated downstream NFκB and Erk signaling pathways. Furthermore, MK-4166 downregulated FOXP3 mRNA in human tumor infiltrating Tregs, suggesting that, in addition to enhancing the activation of TILs, MK-4166 may attenuate the Treg-mediated suppressive tumor microenvironment. Cancer Res; 77(16); 4378-88. ©2017 AACR.


Asunto(s)
Anticuerpos/farmacología , Proteína Relacionada con TNFR Inducida por Glucocorticoide/inmunología , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos/inmunología , Línea Celular Tumoral , Femenino , Proteína Relacionada con TNFR Inducida por Glucocorticoide/agonistas , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Microambiente Tumoral
20.
Mol Cell Proteomics ; 16(4 suppl 1): S277-S289, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-28223349

RESUMEN

Better and more diverse biomarkers for the development of simple point-of-care tests for active tuberculosis (TB), a clinically heterogeneous disease, are urgently needed. We generated a proteomic Mycobacterium tuberculosis (Mtb) High-Density Nucleic Acid Programmable Protein Array (HD-NAPPA) that used a novel multiplexed strategy for expedited high-throughput screening for antibody responses to the Mtb proteome. We screened sera from HIV uninfected and coinfected TB patients and controls (n = 120) from the US and South Africa (SA) using the multiplex HD-NAPPA for discovery, followed by deconvolution and validation through single protein HD-NAPPA with biologically independent samples (n = 124). We verified the top proteins with enzyme-linked immunosorbent assays (ELISA) using the original screening and validation samples (n = 244) and heretofore untested samples (n = 41). We identified 8 proteins with TB biomarker value; four (Rv0054, Rv0831c, Rv2031c and Rv0222) of these were previously identified in serology studies, and four (Rv0948c, Rv2853, Rv3405c, Rv3544c) were not known to elicit antibody responses. Using ELISA data, we created classifiers that could discriminate patients' TB status according to geography (US or SA) and HIV (HIV- or HIV+) status. With ROC curve analysis under cross validation, the classifiers performed with an AUC for US/HIV- at 0.807; US/HIV+ at 0.782; SA/HIV- at 0.868; and SA/HIV+ at 0.723. With this study we demonstrate a new platform for biomarker/antibody screening and delineate its utility to identify previously unknown immunoreactive proteins.


Asunto(s)
Proteínas Bacterianas/inmunología , Infecciones por VIH/sangre , Mycobacterium tuberculosis/metabolismo , Análisis por Matrices de Proteínas/métodos , Proteómica/métodos , Determinación de Anticuerpos Séricos Bactericidas/métodos , Tuberculosis/inmunología , Adulto , Anciano , Biomarcadores/sangre , Coinfección , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/inmunología , Curva ROC , Sudáfrica , Estados Unidos , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA