Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10.

APCs are important in the initiation of productive Ag-specific T cell responses and the induction of T cell anergy. The inflammatory status of the APC at the time of encounter with Ag-specific T cells plays a central role in determining such divergent T cell outcomes. A better understanding of the regulation of proinflammatory and anti-inflammatory genes in its natural setting, the chromatin substrate, might provide novel insights to overcome anergic mechanisms mediated by APCs. In this study, we show for the first time, to our knowledge, that treatment of BALB/c murine macrophages with the histone deacetylase inhibitor LAQ824 induces chromatin changes at the level of the IL-10 gene promoter that lead to enhanced recruitment of the transcriptional repressors HDAC11 and PU.1. Such an effect is associated with diminished IL-10 production and induction of inflammatory cells able of priming naive Ag-specific T cells, but more importantly, capable of restoring the responsiveness of anergized Ag-specific CD4(+) T cells.

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared with Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States.

BACKGROUND: The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations for third-party payer systems, physicians, and patients. OBJECTIVE: To develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as firstline therapy in metastatic melanoma, while accounting for differential effectiveness in programmed death-ligand 1 (PD-L1) positive and negative patients. METHODS: A 3-state Markov model (PD-L1 positive stable disease, PD-L1 negative stable disease, and progression and/or death) was developed using a U.S. societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free (PF) survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 U.S. dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. RESULTS: Nivolumab-ipilimumab combination therapy was not the cost-effective choice ($454,092 per PF quality-adjusted life-year [QALY]) compared with nivolumab monotherapy in a base case analysis at a willingness-to-pay threshold of $100,000 per PFQALY. Combination therapy and nivolumab monotherapy were cost-effective choices compared with ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment, but combination therapy had an improved incremental cost-effectiveness ratio (ICER) of $295,903 per PFQALY. Combination therapy became dominated by nivolumab, when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to < $21,555 per dose for combination therapy to have an ICER < $100,000 per PFQALY and to < $19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy. CONCLUSIONS: Nivolumab-ipilimumab combination therapy was not cost-effective compared with nivolumab monotherapy, which was the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions, and future cost-effectiveness studies are completed. DISCLOSURES: No funding supported this study. Merino was a contractor with EMD Serono at the time of this study but does not have any conflicts of interest and did not receive any funding related to this study. All other authors have no financial disclosures and no conflicts of interest. All the authors contributed to the study concept and design. Tran, McDowell, and Barcelon took the lead in data collection, along with Oh, Keyvani, and Merino. All authors except Merino contributed to data interpretation. The manuscript was written by Oh, Tran, McDowell, and Wilson and revised by Oh, Tran, McDowell, Wilson, and Keyvani. This analysis was presented at Academy of Managed Care Pharmacy Managed Care & Specialty Pharmacy Annual Meeting 2016, April 19-22, 2016, in San Francisco, California, and at the International Society for Pharmacoeconomics and Outcomes Research Annual International Meeting, May 21-25, 2016, in Washington DC.

Mid-term outcomes of endovascular popliteal artery aneurysm repair.

OBJECTIVE: This study documents mid-term outcomes of a series of endovascular popliteal aneurysm repairs compared with concurrent results of open surgical repair. METHODS: A retrospective chart review was done of all popliteal artery aneurysm repairs since January 1, 2000. Patency was defined as continued presence of palpable pulses or maintenance of postoperative ankle-brachial index +/- 0.15. Statistical methods included chi(2), t test, Fisher's exact test, and Kaplan-Meier plots with log-rank comparison. RESULTS: A total of 56 popliteal artery aneurysm repairs were performed. All endovascular popliteal aneurysm repairs (EVPAR, n = 15) were performed using Viabahn endoprostheses. Patients with open repair (OR, n = 41) underwent surgical bypass and aneurysm exclusion with great saphenous vein (n = 26), short saphenous vein (n = 3), or polytetrafluoroethylene (n = 12), through either a medial (n = 28) or posterior (n = 13) approach. All urgent cases received open repair. Technical success was 100% in both groups. Mean follow-up was 16.5 +/- 3 months (range, 0.5 to 56 months). Aneurysm size, location, and outflow were similar between groups. Primary patency, secondary patency, and survival did not differ between groups. Endoleaks were observed in three (20%) of 15 endovascular cases, and type I and III endoleaks were treated with additional endografts. CONCLUSION: To our knowledge, this represents the largest United States series of EVPAR to date. Early mid-term results of elective endovascular repair of popliteal artery aneurysms are encouraging. Further studies are warranted to define optimal indications for EVPAR and to generate long-term outcomes for this technique.

Infecciones relacionadas a catéter venoso central / Infections related to central veined catheter

Se realizó un estudio descriptivo prospectivo de la incidencia de infección asociado a catéter venoso central, la prevalencia de gérmenes, antibiograma y factores asociados en el Servicio de Terapia Intensiva del Dpto de Cuidados Críticos del Hospital Guillermo Almenara con un protocolo de diseño como es el cultivo de punta de catéter y hemocultivos simultaneo en vía periférica de 260 procedimientos de CVC durante el año de 1998. Se demostró la sensibilidad al 100 por ciento de vancomicina de los gérmenes prevalentes en sepsis e infección por catéter como es el estafilococo epidermides y el estafilococo aureus siendo esta la primera opción para terapia empírica en infecciones por catéter. Solo se identificó un caso de sepsis de más o igual que 15ufc. Se detectó 3 casos de bacteriemia según la definición de consenso (1.15 por ciento).

Septicemia y Meningitis Neonatal / Septicemia and neonatal meningitis

Se hace una revisión de la septicemia y meningitis neonatal, la segunda causa de muerte hospitalaria neonatal en nuestro pais. Se ha hecho una revisión de laetiología y patogenia así como del cuadro clínico. Se recalca algunas medidas preventivas muy simples, que disminuirían la incidencia de esta enfermedad potencialmente mortal.

Osteoartritis infecciosa en el recién nacido de bajo peso. En la UCI del Hospital Edgardo Rebagliatti M. (IPSS) 1986-92 / Infectious osteoarthritis in the low weight infant. In the ICU of Hospital Edgardo Rebagliatti M. (IPSS) 1986-92

La osteoartritis infecciosa en RNBP no ha merecido mucha atención de los investigadores aunque su frecuencia en los últimos años parece estar en aumento. Nosotros revisamos las historias clínicas de 1986-1992 de todos los RN vivos en el HNERM y encontramos ocho casos de osteoartritis infecciosa en RNBP lo que dio una prevalencia de 1.26x1000 RNBP. En seis de ellos se aisló Estafilococo aureus del hueso y/o de la articulación afectada, otro Cándida albicans y en el restante no se pudo aislar ningún germen aunque su cuadro clínico, Rx y evolución fueron típicos de osteoartritis infecciosa. Se discute la patogenia, diagnóstico y el tratamiento que fue hecho al principio en forma empírica y luego de acuerdo a los resultados de los cultivos. Los ocho pacientes sobrevivieron y el único que tuvo secuelas luxación de cadera fue el paciente con Cándida albicans.

Ventilación pulmonar independiente en un politraumatizado / Independent pulmonary ventilation in a politraumatized patient

Se presenta el caso de un paciente de 34 años, politraumatizado, que en forma evolutiva presenta lesión pulmonar unilateral que no mejora con terapia de asistencia ventilatoria estándar, requiriendo ventilación pulmonar independiente (VPI). Revisamos esta modalidad de asistencia ventilatoria por su inusual aplicación en servicio de terapia intensiva con resultado exitoso

Diagnóstico de neumonía nosocomial por lavado broncoalveolar y cultivos cuantitativo en pacientes con ventilación mecánica UTI. DCC. HNGAI. Noviembre 95 - agosto 99 / Nosocomial diagnosis of neumonía by washing to bronchoalveolar and cultures quantitative in patients with mechanical ventilation UTI. DCC HNGGAI. November 95 - Agosto 99

Objetivos. Evaluar la utilidad del criterio clínico radiológico comparado con la confirmación bacteriológica por lavado broncoalveolar (BAL) y cultivo cuantitativo en el diagnóstico de neumonía nosocomial en el paciente con VM; Determinar la validez del recuento de organismos intracelulares (OICC) como marcador precoz de neumonía nosocomial en el paciente con VM; establecer la flora bacteriana prevalente que origina neumonía con seguridad en la UTI del DCC del HNGAI y, evaluar la factibilidad del uso rutinario de la técnica del BAL en la UTI. Métodos. Estudio prospectivo, analítico, observacional en pacientes con VM invasiva, sometidos a BAL por broncoscopio flexible o catéter telescopado, cuyas muestras fueron evaluados en el laboratorio del hospital para recuento de OICC y cultivo cuantitativo. Se confirmó el diagnóstico de neumonía con un recuento de colonias (UFC) mayor igual 10 a la cuarta y se utilizó como marcador precoz un recuento de de OICC> 2 por ciento. Se hicieron pruebas de significancia estadística con la prueba del chi cuadrado (X²) para un grado de libertad de 1. Resultados. Ingresaron al estudio 58 pacientes. Se diagnosticó neumonía nosocomial en el 74.1 por ciento, se obtuvieron 84 tipos de gérmenes, los principales fueron : pseudomona, acinetobacter, staphilococo y alcalígenes; la causa polimicrobiana fue la más frecuente, se estableció con un nivel estadístico altamente significativo (p=0.000003) que, más de dos criterios clínico radiológico son de confianza para diagnosticar neumonía nosocomial en el paciente con VM y que el recuento de OICC>2 por ciento también es un marcador precoz de neumonía con un nivel estadístico altamente significativo (p=0-000001). Además hubo una mortalidad de 53.5 por ciento que comparado con el grupo que no tuvo neumonía de 20 por ciento, se demostró que había significancia estadística(p=0.024). No hubo mortalidad relacionado al procedimiento. Conclusiones. Puede diagnosticarse neumonía nosocomial en el paciente con VM con bastante confianza con más de dos criterios clínico radiológico, el recuento de OICC>2 por ciento es un fiable marcador precoz de neumonía. La neumonía en el paciente en VM es polimicrobiana y principalmente causado por pseudomona, acinetobacter, y staphilococo. Es factible el uso rutinario de la técnica del lavado broncoalveolar.