Prediction of pathological response to neoadjuvant treatment in rectal cancer with a two-protein immunohistochemical score derived from stromal gene-profiling.

BACKGROUND: Preoperative chemoradiotherapy followed by surgical mesorectal resection is the standard of care for locally advanced rectal carcinomas. Yet, predicting that patients will respond to treatment remains an unmet clinical challenge. EXPERIMENTAL DESIGN: Using laser-capture microdissection we isolated RNA from stroma and tumour glands from prospective pre-treatment samples (n = 15). Transcriptomic profiles were obtained hybridising PrimeView Affymetrix arrays. We modelled a carcinoma-associated fibroblast-specific genes filtering data using GSE39396. RESULTS: The analysis of differentially expressed genes of stroma/tumour glands from responder and non-responder patients shows that most changes were associated with the stromal compartment; codifying mainly for extracellular matrix and ribosomal components. We built a carcinoma-associated fibroblast (CAF) specific classifier with genes showing changes in expression according to the tumour regression grade (FN1, COL3A1, COL1A1, MMP2 and IGFBP5). We assessed these five genes at the protein level by means of immunohistochemical staining in a patient's cohort (n = 38). For predictive purposes we used a leave-one-out cross-validated model with a positive predictive value (PPV) of 83.3%. Random Forest identified FN1 and COL3A1 as the best predictors. Rebuilding the leave-one-out cross-validated regression model improved the classification performance with a PPV of 93.3%. An independent cohort was used for classifier validation (n = 36), achieving a PPV of 88.2%. In a multivariate analysis, the two-protein classifier proved to be the only independent predictor of response. CONCLUSION: We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer.

Extracolonic Cancer in Inflammatory Bowel Disease: Data from the GETECCU Eneida Registry.

OBJECTIVES: The objective of this study was (a) To know the prevalence and distribution of extracolonic cancer (EC) in patients with inflammatory bowel disease (IBD); (b) To estimate the incidence rate of EC; (c) To evaluate the association between EC and treatment with immunosuppressants and anti-tumor necrosis factor (TNF) agents. METHODS: This was an observational cohort study. INCLUSION CRITERIA: IBD and inclusion in the ENEIDA Project (a prospectively maintained registry) from GETECCU. EXCLUSION CRITERIA: Patients with EC before the diagnosis of IBD, lack of relevant data for this study, and previous treatment with immunosuppressants other than corticosteroids, thiopurines, methotrexate, or anti-TNF agents. The Kaplan-Meier method was used to evaluate the impact of several variables on the risk of EC, and any differences between survival curves were evaluated using the log-rank test. Stepwise multivariate Cox regression analysis was used to investigate factors potentially associated with the development of EC, including drugs for the treatment of IBD, during follow-up. RESULTS: A total of 11,011 patients met the inclusion criteria and were followed for a median of 98 months. Forty-eight percent of patients (5,303) had been exposed to immunosuppressants or anti-TNF drugs, 45.8% had been exposed to thiopurines, 4.7% to methotrexate, and 21.6% to anti-TNF drugs. The prevalence of EC was 3.6%. In the multivariate analysis, age (HR=1.05, 95% CI=1.04-1.06) and having smoked (hazards ratio (HR)=1.47, 95% confidence interval (CI)=1.10-1.80) were the only variables associated with a higher risk of EC. CONCLUSIONS: Neither immunosuppressants nor anti-TNF drugs seem to increase the risk of EC. Older age and smoking were associated with a higher prevalence of EC.

Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed. METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included. RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe. CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

Unclassifiable arrhythmic cardiomyopathy associated with Emery-Dreifuss caused by a mutation in FHL1.

Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non-dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL-1 disorder in X-linked cardiomyopathy.

Outcome of neuropsychiatric symptoms related to an antiretroviral drug following its substitution by nevirapine: the RELAX study.

OBJECTIVES: The primary objective was to evaluate the improvement in neuropsychiatric symptoms attributed to an antiretroviral drug after that drug was substituted with nevirapine. The secondary objective was to evaluate the impact on patient adherence and quality of life. METHODS: A prospective, observational study was carried out that included patients with HIV-1 plasma suppression for whom an antiretroviral drug was substituted with nevirapine because of central nervous system (CNS) side effects, a Pittsburgh Sleep Quality Index (PSQI) score > 5 or a Hospital Anxiety and Depression Scale (HADS) score ≥ 10, and who had not initiated psychoactive drug treatment during the prior 6 weeks. Evaluations were carried out at baseline and 1 and 3 months after the switch using the PSQI, HADS, Epworth Sleepiness Scale, Medical Outcomes Study-Short Form 30 items (MOS-SF-30) and Simplified Medication Adherence Questionnaire (SMAQ). RESULTS: A total of 129 patients were included in the study. The drug substituted was mainly efavirenz (89.9%), and reasons for the switch included sleep disturbances (75.2%), anxiety (65.1%), depression (38.7%), attention disturbances (31%), and other reasons (31%), with a mean of 2.4 neuropsychiatric disturbances per patient. A statistically significant improvement was observed in all the tests evaluating neuropsychiatric symptoms and adherence at 1 and 3 months. The CD4 lymphocyte count remained stable (P = 0.096). Three (2.3%) patients had a detectable plasma HIV-1 RNA at the end of the study. Nine patients (6.9%) withdrew because of nevirapine-related toxicity (rash in seven patients and hypertransaminasaemia in two patients, none of which were > grade 2). CONCLUSIONS: The switch to nevirapine from a drug causing neuropsychiatric disturbances (primarily efavirenz) in subjects with virological suppression was effective in resolving those disturbances, with an improvement in all the parameters studied. This led to better adherence to treatment and quality of life, with no detrimental effect on their immunological and virological control.

Identification of Environmental Chemicals Associated with the Development of Toxicant-associated Fatty Liver Disease in Rodents.

BACKGROUND: Toxicant-associated fatty liver disease (TAFLD) is a recently identified form of nonalcoholic fatty liver disease (NAFLD) associated with exposure to industrial chemicals and environmental pollutants. Numerous studies have been conducted to test the association between industrial chemicals/environmental pollutants and fatty liver disease both in vivo and in vitro. OBJECTIVES: The objective of the article is to report a list of chemicals associated with TAFLD. METHODS: Two federal databases of rodent toxicology studies-Toxicological Reference Database (ToxRefDB; Environmental Protection Agency) and Chemical Effects in Biological Systems (CEBS, National Toxicology Program)-were searched for liver end points. Combined, these 2 databases archive nearly 2,000 rodent studies. Toxicant-associated steatohepatitis (TASH) descriptors including fatty change, fatty necrosis, Oil red O-positive staining, steatosis, and lipid deposition were queried. RESULTS: Using these search terms, 123 chemicals associated with fatty liver were identified. Pesticides and solvents were the most frequently identified chemicals, while polychlorinated biphenyls (PCBs)/dioxins were the most potent. About 44% of identified compounds were pesticides or their intermediates, and >10% of pesticide registration studies in ToxRefDB were associated with fatty liver. Fungicides and herbicides were more frequently associated with fatty liver than insecticides. CONCLUSION: More research on pesticides, solvents, metals, and PCBs/dioxins in NAFLD/TAFLD is warranted due to their association with liver damage.

Comparison of the long-term outcome of two therapeutic strategies for the management of abdominal abscess complicating Crohn's disease: percutaneous drainage or immediate surgical treatment.

AIM: The management of abdominal abscesses complicating Crohn's disease is complex and involves a difficult choice between medical, radiological and surgical procedures. The long-term outcome was compared for two strategies for the management of abdominal abscess: percutaneous drainage (PD) followed by rescue surgery in the case of failure vs direct immediate surgery (IS). We also compared the results of IS with surgery performed after PD failure. METHODS: We retrospectively identified 44 patients with Crohn's disease with an abdominal abscess from January 2000 to December 2009. Therapeutic success was defined as abscess resolution and no reappearance within 1 year of follow-up. RESULTS: The first therapeutic approach was PD in 22 cases and IS in the other 22 cases. IS had a higher therapeutic success rate than PD (95.5% vs 27.2% respectively; P < 0.001). PD was the only independent variable related to treatment failure in the multivariate analysis after adjustment for possible confounders such as abscess size, multilocularity, presence of fistula and corticosteroid use (OR 88.26, 95% CI 7.38-1055.36; P < 0.001). Surgery after failure of PD (n = 16) was associated with longer total hospitalization (56.12 ± 35.89 vs 27.52 ± 15.11 days; P = 0.017) and longer postoperative stay (44.0 ± 83.7 vs 14.3 ± 30 days; P = 0.179) and needed a second operation more often (5/16, 31% vs 1/22, 4.5%; P = 0.065) than IS. CONCLUSIONS: Percutaneous drainage provided durable abscess resolution in only one-third of the patients compared with more than 90% of those treated with IS. In addition, surgery performed after PD failure results in a poorer outcome than IS.

[Evaluation of the efficiency of care in the ICU]. / Evaluación de eficiencia asistencial en UCI.

OBJECTIVE: To evaluate the efficiency of care in the ICU using a predictive model. DESIGN: A prospective, observational cohort study SETTINGS: Seventeen Spanish polyvalent ICUs. PATIENTS: A total of 1956 patients were initially considered (cohort A). Posteriorly, and at 6-year intervals, we documented cohorts B (n=453), C (n=2567) and D (n=711) in one of the studied ICUs. METHOD: Five standard severity indices were calculated for all cohorts, and with these the standardized mortality ratios (observed/calculated) for each cohort were compared. Multiple regression analysis was used to develop a predictive model of length of stay in the ICU (ICU-LOS). This model was used for calculation of the standardized LOS ratios for each cohort. We analyzed the organizational changes in the studied ICU during these periods in relation to the results obtained. RESULTS: The calculated probability of in-hospital death was 15.4%, versus 14.7% as calculated 24 hours after admission. Actual in-hospital mortality was 20.3%. A final multiple regression model was constructed. Standardized LOS and mortality ratios were 1.8 and 1.2 (cohort B), 0.97 and 1.07 (cohort C), and 0.63 and 1.07 (cohort D), respectively. The progressive improvement in the results observed was related to the introduced organizational and structural changes. CONCLUSIONS: The model developed in this study was a good predictor of actual ICU-LOS, and both LOS and mortality analysis could be a good tool for ICU care evaluation.

[Emergency detection of HIV infection in patients consulting for conditions potentially related to occult infection: Initial results of the "Urgències VIHgila" program]. / Detección en urgencias de infección por VIH en pacientes que consultan por condiciones potencialmente relacionadas con infección oculta: Resultados iniciales del programa "Urgències VIHgila".

OBJECTIVE: To estimate the prevalence of unknown HIV infection in patients who consulted in hospital emergency services (ED) for conditions defined in the SEMES-GESIDA Consensus Document (DC), evaluate the efficiency of its im-plementation and investigate the efficiency of HIV serology determination in other conditions. METHODS: Results were reviewed in 10 Catalan EDs for 12 months (July-21-June-22) after implementing CD recommendations: request HIV serology in case of suspected sexually transmitted infection, chemsex, post-exposure prophylaxis (PEP), mononucleosis syndrome, community pneumonia (18-65 y-o) or herpes zoster (18-65 y-o). Other reasons for request were included. Prevalence (%) of global seropositivity and for each circumstance was calculated, with a 95% confidence interval (95%CI). The efficient strategy was considered if the lower limit of the CI95%>0.1%. RESULTS: A total of5,107 HIV serologies were performed: 2,847(56%) in situations specified in CD, and 2,266 (44%) in other 138 circumstances. Forty-eight unknown HIV infections were detected (prevalence=0.94%;95%CI=0.69-1.24). The prevalence was somewhat higher in DC requests (30 cas-es 1.12%) than the rest (18 cases 0.71%; p=0.16). The individualized prevalence of CD reasons ranged between 7.41% (95%CI=0.91-24.3) in chemsex and 0.42% 95%CI=0.14-0.98) in PPE, always efficient except herpes zoster (0.76%; CI95%=0.02-4.18). In other reasons, cases were detected in 12 circumstances, and in four the determination could be efficient: lymphopenia (10%;CI95%=0.25-44.5), fever with polyarthralgia-polyarthritis (7.41%;CI95% =0.91-24.3), behavioral alteration-confusion-encephalopathy (3.45%;95%CI=0.42-11.9) and fever of unknown origin (2.50%;95%CI=0.82-5.74). CONCLUSIONS: The determination of HIV serology in HES in the processes defined by DC SEMES-GESIDA is efficient. Some circumstances are identified that could be added to those previously contemplated to increase efficiency.

Secondary use of data extracted from a clinical information system to assess the adherence of tidal volume and its impact on outcomes.

OBJECTIVES: To extract data from clinical information systems to automatically calculate high-resolution quality indicators to assess adherence to recommendations for low tidal volume. DESIGN: We devised two indicators: the percentage of time under mechanical ventilation with excessive tidal volume (>8mL/kg predicted body weight) and the percentage of patients who received appropriate tidal volume (≤8mL/kg PBW) at least 80% of the time under mechanical ventilation. We developed an algorithm to automatically calculate these indicators from clinical information system data and analyzed associations between them and patients' characteristics and outcomes. SETTINGS: This study has been carried out in our 30-bed polyvalent intensive care unit between January 1, 2014 and November 30, 2019. PATIENTS: All patients admitted to intensive care unit ventilated >72h were included. INTERVENTION: Use data collected automatically from the clinical information systems to assess adherence to tidal volume recommendations and its outcomes. MAIN VARIABLES OF INTEREST: Mechanical ventilation days, ICU length of stay and mortality. RESULTS: Of all admitted patients, 340 met the inclusion criteria. Median percentage of time under mechanical ventilation with excessive tidal volume was 70% (23%-93%); only 22.3% of patients received appropriate tidal volume at least 80% of the time. Receiving appropriate tidal volume was associated with shorter duration of mechanical ventilation and intensive care unit stay. Patients receiving appropriate tidal volume were mostly male, younger, taller, and less severely ill. Adjusted intensive care unit mortality did not differ according to percentage of time with excessive tidal volume or to receiving appropriate tidal volume at least 80% of the time. CONCLUSIONS: Automatic calculation of process-of-care indicators from clinical information systems high-resolution data can provide an accurate and continuous measure of adherence to recommendations. Adherence to tidal volume recommendations was associated with shorter duration of mechanical ventilation and intensive care unit stay.

Prior influenza vaccine is not a risk factor for bacterial coinfection in patients admitted to the ICU due to severe influenza.

OBJECTIVE: To determine whether the prior usage of the flu vaccine is a risk factor for bacterial co-infection in patients with severe influenza. DESIGN: This was a retrospective observational cohort study of subjects admitted to the ICU. A propensity score matching, and logistic regression adjusted for potential confounders were carried out to evaluate the association between prior influenza vaccination and bacterial co-infection. SETTINGS: 184 ICUs in Spain due to severe influenza. PATIENTS: Patients included in the Spanish prospective flu registry. INTERVENTIONS: Flu vaccine prior to the hospital admission. RESULTS: A total of 4175 subjects were included in the study. 489 (11.7%) received the flu vaccine prior to develop influenza infection. Prior vaccinated patients were older 71 [61-78], and predominantly male 65.4%, with at least one comorbid condition 88.5%. Prior vaccination was not associated with bacterial co-infection in the logistic regression model (OR: 1.017; 95%CI 0.803-1.288; p=0.885). After matching, the average treatment effect of prior influenza vaccine on bacterial co-infection was not statistically significant when assessed by propensity score matching (p=0.87), nearest neighbor matching (p=0.59) and inverse probability weighting (p=0.99). CONCLUSIONS: No association was identified between prior influenza vaccine and bacterial coinfection in patients admitted to the ICU due to severe influenza. Post influenza vaccination studies are necessary to continue evaluating the possible benefits.

The relationship between running distance and coaches' perception of team performance in professional soccer player during multiple seasons.

This study analyzed how the physical movement profile of soccer matches evolved throughout a season by assessing the variability of different metrics depending on the season phase. In addition, the evolution of running distances was investigated in the relation to the team performance based on the coaches' perception. Games from four consecutives Spanish LaLiga seasons (n = 1520) were recorded using an optical tracking system (i.e., ChyronHego). Total distance (TD), distance covered between 14 and 21 km h-1 (MIRD), 21-24 km h-1 (HIRD), and > 24 km h-1 (VHIRD) were analyzed, as well as the number of efforts between 21 and 24 km h-1 (Sp21) and > 24 km h-1 (Sp24). Seasons were divided into four phases (P): P1 (matches 1-10), P2 (11-19), P3 (20-29), and P4 (30-38). Linear mixed models revealed that soccer players covered significantly greater distances and completed a higher number of sprints in P2 and P3. Also, team performance evaluated by soccer coaches was positively related to TD, HIRD, VHIRD and Sp21 in P1. A negative relationship was observed between team performance and distance covered at speeds below 21 km h-1 in P2 and P3. Team performance was negatively related to TD, MIRD, and HIRD, and Sp21 in P4. As conclusion, the team performance perceived by coaches is related to the movement profile throughout a season, and it significantly influences the evolution of soccer players' movement profiles. Specifically, it seems that the players of the best teams have the best physical performance at the beginning of the season with respect to the rest of the phases.

Impact of Aspergillus spp. isolation in the first 24 hours of admission in critically ill patients with severe influenza virus pneumonia.

OBJECTIVE: To determine the incidence and impact of Aspergillus spp. isolation (AI) on ICU mortality in critically ill patients with severe influenza pneumonia during the first 24h of admission. DESIGN: Secondary analysis of an observational and prospective cohort study. SETTING: ICUs voluntary participating in the Spanish severe Influenza pneumonia registry, between June 2009 and June 2019. PATIENTS: Consecutive patients admitted to the ICU with diagnosis of severe influenza pneumonia, confirmed by real-time polymerase chain reaction. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Incidence of AI in respiratory samples. Demographic variables, comorbidities, need for mechanical ventilation and the presence of shock according at admission. Acute Physiology and Chronic Health Evaluation II (APACHE II) scale calculated on ICU admission. RESULTS: 3702 patients were analyzed in this study. AI incidence was 1.13% (n=42). Hematological malignancies (OR 4.39, 95% CI 1.92-10.04); HIV (OR 3.83, 95% CI 1.08-13.63), and other immunosuppression situations (OR 4.87, 95% CI 1.99-11.87) were factors independently associated with the presence of Aspergillus spp. The automatic CHAID decision tree showed that hematologic disease with an incidence of 3.3% was the most closely AI related variable. Hematological disease (OR 2.62 95% CI 1.95-3.51), immunosuppression (OR 2.05 95% CI 1.46-2.88) and AI (OR 3.24, 95% CI 1.60-6.53) were variables independently associated with ICU mortality. CONCLUSIONS: Empirical antifungal treatment in our population may only be justified in immunocompromised patients. In moderate-high risk cases, active search for Aspergillus spp. should be implemented.

Computed tomography measurements of parapneumonic effusion indicative of thoracentesis.

Patients with parapneumonic effusions (PPE) measuring <1 cm by lateral decubitus radiograph (LDR) or <5 cm by lateral erect radiograph (LER) do not require thoracentesis. No such data exist for chest computed tomography (CCT). The objective of this study was to identify a PPE measurement by CCT that indicates the need for thoracentesis. A secondary data analysis of two pneumonia databases was conducted to identify patients with PPE. Measurements of PPE using LDR, LER and CCT were correlated by linear regression analysis. The clinical outcome of community-acquired pneumonia patients managed with the newly defined CCT measurement was evaluated. PPE was identified in 419 out of 1,460 patients with possible pneumonia. PPE measurements of 1 cm and 5 cm by LDR and LER, respectively, correlated with a measurement of 2.5 cm by CCT. Out of 95 patients with CCT measurements <2.5 cm, 31 poor clinical outcomes were reported: outcome was PPE related (n = 1); outcome was PPE unrelated (n = 26); and outcome was not evaluable (n = 4). The single case of poor outcome also measured <1 cm by LDR. This study indicates that patients with community-acquired pneumonia and a PPE measuring <2.5 cm by CCT can be managed without the need for thoracentesis.

[Study on the clinicopathological correlation in the secondary acute respiratory distress syndrome]. / Estudio sobre la correlación clínico-patológica en el síndrome de distrés respiratorio agudo secundario.

OBJECTIVE: This study has aimed to study the clinicopathological correlation of patients with secondary acute respiratory distress syndrome (ARDS), specifically having extrapulmonary causes. SETTING: A 22 beds intensive care unit. DESIGN: An observational study of case series. PATIENTS: Seventeen patients whose death was caused by acute respiratory distress syndrome were included. INTERVENTION: A systematic histopathological study was made of all the pulmonary lobes of patients who died in our ICU with the clinical diagnosis of secondary ARDS, who had undergone an autopsy between 1999 and 2009. The Kappa analysis was used to analyze the grade of correlation between the clinical and the pathological diagnosis. RESULTS: The autopsy confirmed to cases of false positive in 17 patients with ARDS (11%). The kappa value was 0.77, so that the concordance analysis was considered to be satisfactory. CONCLUSIONS: The clinical criteria for ARDS correlate well with acute alveolar damage (AAD) in the autopsy study in patients with secondary ARDS, although some false positive cases can be observed.

Prior influenza vaccine is not a risk factor for bacterial coinfection in patients admitted to the ICU due to severe influenza.

OBJECTIVE: To determine whether the prior usage of the flu vaccine is a risk factor for bacterial co-infection in patients with severe influenza. DESIGN: This was a retrospective observational cohort study of subjects admitted to the ICU. A propensity score matching, and logistic regression adjusted for potential confounders were carried out to evaluate the association between prior influenza vaccination and bacterial co-infection. SETTINGS: 184 ICUs in Spain due to severe influenza. PATIENTS: Patients included in the Spanish prospective flu registry. INTERVENTIONS: Flu vaccine prior to the hospital admission. RESULTS: A total of 4175 subjects were included in the study. 489 (11.7%) received the flu vaccine prior to develop influenza infection. Prior vaccinated patients were older 71 [61-78], and predominantly male 65.4%, with at least one comorbid condition 88.5%. Prior vaccination was not associated with bacterial co-infection in the logistic regression model (OR: 1.017; 95%CI 0.803-1.288; p=0.885). After matching, the average treatment effect of prior influenza vaccine on bacterial co-infection was not statistically significant when assessed by propensity score matching (p=0.87), nearest neighbor matching (p=0.59) and inverse probability weighting (p=0.99). CONCLUSIONS: No association was identified between prior influenza vaccine and bacterial coinfection in patients admitted to the ICU due to severe influenza. Post influenza vaccination studies are necessary to continue evaluating the possible benefits.

Trans-acting element(s) operating across species barriers positively regulate expression of major histocompatibility complex class II genes.

Raji, a human B lymphoma line, expresses high levels of major histocompatibility complex (MHC) class II antigens. Conversely, none of the detectable human Ia antigens is present in RJ 2.2.5, an immunoselected Raji variant. Clonal analysis, biochemical characterization, and nucleic acid hybridization studies of hybrids between mouse spleen cells and RJ 2.2.5 show that MHC class II gene expression is regulated in trans by a factor which, as judged by dominance studies, has the characteristics of an activator. Such a positive trans acting factor is expressed in mouse spleen cells, and is able to implement MHC class II gene expression across species boundaries. Expression of this factor in spleen cells strongly suggests that it plays a role in in vivo regulation of Ia expression. Additional data suggest that different subsets of class II genes such as DR and DQ may, in part, be regulated by different mechanisms. It has also been possible to show that the amount of In chain-specific mRNA, present at reduced levels in RJ 2.2.5 cells compared to the parental Raji cells, drastically increased in human X mouse cells hybrids reexpressing human Ia antigens, suggesting that the In chain gene and the class II genes, although located on different chromosomes, are regulated in a concerted fashion, either directly through the same implementing factor, or indirectly through a cascade mechanism.

aIr-1, a newly found locus on mouse chromosome 16 encoding a trans-acting activator factor for MHC class II gene expression.

RJ 2.2.5 is a human B cell line that has lost the capacity to express MHC class II genes. The human class II-positive phenotype is restored in somatic cell hybrids between RJ 2.2.5 and mouse spleen cells. By karyotype and molecular studies of an informative family of hybrids we have now shown that the reexpression of human class II gene products, as well as the maintenance of the mouse class II-positive phenotype, correlates with the presence of mouse chromosome 16. Thus, the existence on this mouse chromosome of a newly found locus, designated by us aIr-1, that determines a trans-acting activator function for class II gene expression, is established. Possible implications of this finding are discussed.

An enhancer factor defect in a mutant Burkitt lymphoma cell line.

RJ 2.2.5 is an immunoselected mutant of the Burkitt lymphoma line Raji. It fails to display MHC class II antigens at the cell surface due to a transcriptional defect. We have identified the function of a regulatory factor that is defective in RJ 2.2.5 cells; this factor is absolutely required for the activity of an MHC class II gene enhancer.

Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans.

Previous studies indicated that CD3-CD16+ natural killer (NK) cells are capable of specific alloantigen recognition. Thus, alloreactive NK clones lysed normal allogeneic target cells (phytohemagglutinin [PHA] blasts) bearing the stimulating alloantigen but did not lyse autologous cells or the majority of unrelated allogeneic cells. In this study we investigated whether NK cells isolated from single individuals could exhibit different allospecificities. To this end, we derived large numbers of CD3-CD16+ clones (in the presence of PHA) from fresh CD3- peripheral blood lymphocytes. Cloning efficiencies ranged between 5 and 10%. The resulting CD3-CD16+ clones were tested for their reactivity against a panel of allogeneic PHA blasts (derived from six donors). In a given individual (A), four distinct groups of clones could be identified according to their pattern of reactivity (over 400 clones have been analyzed). Clones that could be assigned to one or another group of specificity represented 36% of all clones derived from this donor. The remaining clones did not display cytolytic activity against any of the allogeneic target cells used in the panel. None of the clones lysed autologous (A) PHA blasts, yet, these cells were lysed by the representative clones G10 and H12 specific for donor A. Clones displaying a cytolytic pattern of reactivity identical to that defined for donor A were present in other individuals studied, however not all groups of allospecific clones were necessarily represented in different individuals. Allospecific clones belonging to the various groups were homogeneous in the expression of EB6/GL183-triggering surface molecules, and could thus be assigned to one or another of the previously defined subsets of NK cells. Genetic analysis of the new NK-defined alloantigens was performed in representative families. The corresponding characters were found to segregate independently and, at least for three of them, an autosomic recessive type of inheritance could be demonstrated. Moreover, the comparative analysis of the segregation of the major histocompatibility complex haplotypes and the recessive or dominant alleles of the genes governing the five specificities analyzed indicated that there is no independent sampling between the two genetic traits, thus suggesting that the genes regulating the NK-defined specificities are carried by chromosome 6. Finally, some donors expressed more than one specificity, thus providing evidence for an NK-defined complex haplotype.