Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust

PAI-1 and t-PA/PAI-1 complex potential markers of fibrinolytic bleeding after cardiac surgery employing cardiopulmonary bypass

Background: Enhanced bleeding remains a serious problem after cardiac surgery, and fibrinolysis is often involved. We speculate that lower plasma concentrations of plasminogen activator inhibitor - 1 (PAI-1) preoperatively and tissue plasminogen activator/PAI-1 (t-PA/PAI-1) complex postoperatively might predispose for enhanced fibrinolysis and increased postoperative bleeding.Methods: Totally 88 adult patients (mean age 66 ± 10 years) scheduled for cardiac surgery, were enrolled into a prospective study. Blood samples were collected pre-operatively, on admission to the recovery and at 6 and 24 hours postoperatively. Patients with a surgical bleeding that was diagnosed during reoperation were discarded from the study. The patients were allocated to two groups depending on the 24-hour postoperative chest tube drainage (CTD): Group I > 500ml, Group II ≤ 500ml. Associations between CTD, PAI-1, t-PA/PAI-1 complex and D-dimer were analyzed with SPSS.Results: Nine patients were excluded because of surgical bleeding. Of the 79 remaining patients, 38 were allocated to Group I and 41 to Group II. The CTD volumes correlated with the preoperative plasma levels of PAI-1 (r = - 0.3, P = 0.009). Plasma concentrations of preoperative PAI-1 and postoperative t-PA/PAI-1 complex differed significantly between the groups (P < 0.001 and P = 0.012, respectively). Group I displayed significantly lower plasma concentrations of fibrinogen and higher levels of D-dimer from immediately after the operation and throughout the first 24 hours postoperatively.Conclusions: Lower plasma concentrations of PAI-1 preoperatively and t-PA/PAI-1 complex postoperatively leads to higher plasma levels of D-dimer in association with more postoperative bleeding after cardiac surgery.publishersversionPeer reviewe

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Purpose The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Results Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. Conclusions No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation

Polymorphisms on PAI-1 and ACE genes in association with fibrinolytic bleeding after on-pump cardiac surgery

Publisher Copyright: © 2015 Ozolina et al.Background: Carriers of plasminogen activator inhibitor -1 (PAI-1) -675 genotype 5G/5G may be associated with lower preoperative PAI-1 plasma levels and higher blood loss after heart surgery using cardiopulmonary bypass (CPB). We speculate if polymorphisms of PAI-1 -844 A/G and angiotensin converting enzyme (ACE) intron 16 I/D also might promote fibrinolysis and increase postoperative bleeding. Methods: We assessed PAI-1 -844 A/G, and ACE intron 16 I/D polymorphisms by polymerase chain reaction technique and direct sequencing of genomic DNA from 83 open heart surgery patients that we have presented earlier. As primary outcome, accumulated chest tube drainage (CTD) at 4 and 24 h were analyzed for association with genetic polymorphisms. As secondary outcome, differences in plasma levels of PAI-1, t-PA/PAI-1 complex and D-dimer were determined for each polymorphism. SPSS® was used for statistical evaluation. Results: The lowest preoperative PAI-1 plasma levels were associated with PAI-1 -844 genotype G/G, and higher CTD, as compared with genotype A/A at 4 and 24 h after surgery. Correspondingly, 4 h after the surgery CTD was higher in carriers of ACE intron 16 genotype I/I, as compared with genotype D/D. PAI-1 plasma levels and t-PA/PAI-1 complex reached nadir in carriers of ACE intron 16 genotype I/I, in whom we also noticed the highest D-dimer levels immediately after surgery. Notably, carriers of PAI-1 -844 genotype G/G displayed higher D-dimer levels at 24 h after surgery as compared with those of genotype A/G. Conclusions: Increased postoperative blood loss secondary to enhanced fibrinolysis was associated with carriers of PAI-1 -844 G/G and ACE Intron 16 I/I, suggesting that these genotypes might predict increased postoperative blood loss after cardiac surgery using CPB.publishersversionPeer reviewe

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

La inteligibilidad vocal en las personas con laringectomía que se comunican con erigmofonía

People who have had a total laryngectomy and have completely extirpated their larynx have, in a variable degree, altered the functions of this organ: sphincter, respiratory, and vocal. Regarding the latter and its final product: the voice, the loss is complete, so it is necessary to rehabilitate this function so that the person can communicate. The aim of this work is to evaluate the vocal intelligibility of laryngectomized individuals who have been rehabilitated with erygmophony. Material and method: prospective design in 17 laryngectomized individuals that use the erygmophonic voice to communicate. They were studied with VHI-30, narrow band spectrogram, perceptual evaluation (GRABS and CAPE-V) and, in a novel way, assessing the vocal intelligibility through the reading and recognition of bisyllabic words. Results: VHI-30 shows that laryngectomized individuals perceive their voice as a mild and moderate limitation. The spectrogram shows substantial differences between the erygmophonic voice and the laryngeal physiological voice. Perceptual evaluation indicates moderate/severe affectation in GRABS and medium/severe involvement in CAPE-V. In the verbal intelligibility, the medium-low values (88%) are predominant, but there are patients with high values (12%). No statistically significant relationships were found between VHI-30, perceptual evaluation, and verbal intelligibility. Conclusions: the evaluation of the intelligibility of the erygmophonic voice provides the rehabilitator with useful and easy-to-read data on the communicative capacity of persons with total laryngectomy, complementing other objective (spectrogram) and subjective assessment procedures (VHI-30, GRABS and CAPE-V).Las personas a las que se le ha realizado una laringectomía total y extirpado completamente su laringe ven alteradas en grado variable las funciones propias de ese órgano: esfinteriana, respiratoria y vocal. Respecto a esta última y su producto final: la voz, la pérdida es completa, por lo que es necesario rehabilitar dicha función para que la persona pueda comunicarse. El objetivo de este trabajo es valorar la inteligibilidad vocal de las personas laringectomizadas que hayan sido rehabilitadas con erigmofonía. Material y métodos: diseño prospectivo en 17 personas laringectomizadas que utilizan la voz erigmofónica para comunicarse. Se estudiaron con el VHI-30, espectrograma de banda estrecha, evaluación perceptual (GRABS y CAPE-V) y, de forma novedosa, valorando la inteligibilidad vocal a través de la lectura y reconocimiento de palabras bisílabas. Resultados: el VHI-30 muestra que las personas laringectomizadas perciben su voz como una limitación leve y moderada. El espectrograma presenta diferencias sustanciales entre la voz erigmofónica y la voz laríngea fisiológica. La evaluación perceptual indica una afectación moderada/severa en GRABS y media/grave en CAPE-V. En la inteligibilidad verbal predominan los valores medios-bajos (88%), pero hay pacientes con valores altos (12%). No se han encontrado relaciones estadísticamente significativas entre el VHI-30, la evaluación perceptual y la inteligibilidad verbal. Conclusiones: la valoración de la inteligibilidad de la voz erigmofónica proporciona al rehabilitador datos útiles y de fácil adquisición sobre la capacidad comunicativa de las personas con laringectomía total, que permiten complementar otros procedimientos de valoración objetiva (espectrograma) y subjetiva (VHI-30, GRABS y CAPE-V)

Polimorfismo genético en el paciente crítico. Parte II: aplicaciones especiales de los polimorfismos genéticos. Farmacogenética y terapia génica

En el primer manuscrito se describieron los trabajos más importantes en relación con el polimorfismo genético en el paciente crítico respecto a la inflamación y la sepsis. En la presente Revisión se discute la importancia de los aspectos genéticos en relación con la coagulación y el síndrome de distrés respiratorio agudo (SDRA). Además, se hace notar cómo la variabilidad genética individual puede influir en pacientes traumáticos y grandes cirugías, como la cirugía cardíaca, participando en fenómenos fisiopatológicos que rodean a este tipo de intervenciones. Finalmente, se analiza el potencial papel de los genes como tratamiento: farmacogenética y terapia génica. A la luz de los datos disponibles, será posible la utilización de marcadores genéticos que ayudarán a estratificar a los pacientes por grados de riesgo y a identificar a aquellos con un peor pronóstico. Además, la identificación de las variaciones genéticas individuales que participan en enfermedades complejas ha permitido que aumente el interés por la terapia génica

Polimorfismo genético en el paciente crítico (I): Aspectos generales, inflamación y sepsis

El diagnóstico y el tratamiento en las unidades de cuidados intensivos (UCI) resulta difícil, debido, en parte, a la naturaleza compleja de la enfermedad y también a la imposibilidad, en algunas ocasiones, de comunicación con el paciente. Los recientes avances tecnológicos y la secuenciación del genoma humano ofrecen una oportunidad interesante para incrementar el conocimiento en la enfermedad aguda. El objetivo de este trabajo es revisar el concepto de polimorfismo genético en el paciente crítico, para lo que se ha realizado una revisión de la bibliografía (Medline) de 1995 a 2002. En la pasada década, con el avance de la medicina molecular, el conocimiento de los mecanismos fisiopatológicos ha aumentado exponencialmente; además, es incuestionable la contribución de la genética al existir enfermedades monogénicas y poligénicas. La respuesta del sistema inmunitario a la agresión se produce a través de repuestas celulares y humorales primarias, secundarias y terciarias. En este contexto, el papel del sustrato genético en la respuesta inflamatoria determina una gran variabilidad individual en el comportamiento de los mediadores. La información genética individual puede utilizarse para identificar a grupos de pacientes con un riesgo elevado de desarrollar sepsis o disfunción multiorgánica y determinar a los pacientes que pueden beneficiarse de una terapéutica basada en el bloqueo de mediadores

An exploratory study in breast cancer of factors involved in the use and communication with health professionals of Internet information

Objective To study the impact of the spontaneous use of Internet on breast cancer patients and on their relationship with health professionals. Methods A mixed methodology was used. Two questionnaires were designed through three focus groups, and then administered to 186 patients and 59 professionals in order to assess: (1) patients' use of Internet for health-related information and (2) the impact of this information on patients' psychological outcomes and on their relationship with professionals. Results Patients spent more time looking for illness-related information after diagnosis, using interactive communities more than static information websites. Patients and professionals disagreed about the use of Internet in terms of the knowledge it provides, and its psychological impact. The main barrier reported by patients regarding the sharing of online information with their professionals was the belief that it would damage their relationship. Conclusions Both professionals and patients have a protectionist conception of the therapeutic relationship. This attitude tends to dismiss the positive impact that the use of Internet and the new communication tools may have in cancer patients. New resources should provide an "Internet Prescription" and modes of interaction to facilitate a more open digital communication