Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection.

BACKGROUND: Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. OBJECTIVE: This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. DESIGN: We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. RESULTS: Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. CONCLUSIONS: This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.

Preoperative nutritional screening by the specialist instead of the nutritional risk score might prevent excess nutrition: a multivariate analysis of nutritional risk factors.

BACKGROUND: The aim of the current study was to assess whether widely used nutritional parameters are correlated with the nutritional risk score (NRS-2002) to identify postoperative morbidity and to evaluate the role of nutritionists in nutritional assessment. METHODS: A randomized trial on preoperative nutritional interventions (NCT00512213) provided the study cohort of 152 patients at nutritional risk (NRS-2002 ≥3) with a comprehensive phenotyping including diverse nutritional parameters (n=17), elaborated by nutritional specialists, and potential demographic and surgical (n=5) confounders. Risk factors for overall, severe (Dindo-Clavien 3-5) and infectious complications were identified by univariate analysis; parameters with P<0.20 were then entered in a multiple logistic regression model. RESULTS: Final analysis included 140 patients with complete datasets. Of these, 61 patients (43.6%) were overweight, and 72 patients (51.4%) experienced at least one complication of any degree of severity. Univariate analysis identified a correlation between few (≤3) active co-morbidities (OR=4.94; 95% CI: 1.47-16.56, p=0.01) and overall complications. Patients screened as being malnourished by nutritional specialists presented less overall complications compared to the not malnourished (OR=0.47; 95% CI: 0.22-0.97, p=0.043). Severe postoperative complications occurred more often in patients with low lean body mass (OR=1.06; 95% CI: 1-1.12, p=0.028). Few (≤3) active co-morbidities (OR=8.8; 95% CI: 1.12-68.99, p=0.008) were related with postoperative infections. Patients screened as being malnourished by nutritional specialists presented less infectious complications (OR=0.28; 95% CI: 0.1-0.78), p=0.014) as compared to the not malnourished. Multivariate analysis identified few co-morbidities (OR=6.33; 95% CI: 1.75-22.84, p=0.005), low weight loss (OR=1.08; 95% CI: 1.02-1.14, p=0.006) and low hemoglobin concentration (OR=2.84; 95% CI: 1.22-6.59, p=0.021) as independent risk factors for overall postoperative complications. Compliance with nutritional supplements (OR=0.37; 95% CI: 0.14-0.97, p=0.041) and supplementation of malnourished patients as assessed by nutritional specialists (OR=0.24; 95% CI: 0.08-0.69, p=0.009) were independently associated with decreased infectious complications. CONCLUSIONS: Nutritional support based upon NRS-2002 screening might result in overnutrition, with potentially deleterious clinical consequences. We emphasize the importance of detailed assessment of the nutritional status by a dedicated specialist before deciding on early nutritional intervention for patients with an initial NRS-2002 score of ≥3.

The border of reproductive control: undocumented immigration as a risk factor for unintended pregnancy in Switzerland.

Unintended pregnancies reflect an unmet need for family planning, and are part of health disparities. Using the only database to inquire about pregnancy intention among women in Switzerland, this study examined the relationship between immigrant documentation and unintended pregnancy (UP). Among pregnant women presenting to a Swiss hospital, we compared pregnancy intention between documented and undocumented women. We used logistic regression to examine whether undocumented status was associated with UP after adjusting for other significant predictors. Undocumented women had more unintended pregnancies (75.2 vs. 20.6 %, p = 0.00). Undocumented status was associated with UP after adjustment (OR 6.23, 95 % CI 1.83-21.2), as was a history of psychological problems (OR 4.09, 95 % CI 1.32-12.7). Contraception non-use was notably associated with lower odds of UP (OR 0.01, 95 % CI 0.004-0.04). Undocumented status was significantly associated with UP, even after adjusting for well-recognized risk factors. This highlights the tremendous risk of undocumented status on UP among women in Switzerland.

In vitro organogenesis in some citrus species

In vitro organogenesis of Citrus was studied for the genotypes Citrus sinensis cv. 'Natal', C. limonia, C. volkameriana, and C. aurantium, with the use of epicotyl segments-derived explants, cultured in MT salts and vitamins medium supplemented with different concentrations of 6-benzylaminopurine (BAP - 0.0; 0.5; 1.0; 1.5 or 2.0 mg L-1). For the recalcitrant genotypes C. limonia and C. aurantium the in vitro organogenesis was also studied with internodal segments-derived explants, cultured in MT salts and vitamins medium supplemented with 0; 0.5; 1.0; 2.0, or 4.0 mg L-1 of BAP. The efficiency of culture medium supplementation with the combination of BAP (0.0; 1.0, or 2.0 mg L-1) and NAA (1-naphthaleneacetic acid - 0.0; 0.3, or 0.5 mg L-1) in the development of adventitious shoots was evaluated for C. aurantium. Culture medium supplementation with BAP is not essential for the adventitious shoots development in the four genotypes studied when epicotyl segments-derived explants are used. In general, culture media supplementation with BAP decreased the percentage of responsive explants excepted for C. sinensis cv. 'Natal' and C. limonia when the concentrations of 1.5 and 2.0 mg/L were used. The presence of cytokinin, in concentrations up to 2 mg/L, stimulated the in vitro organogenesis when internodal segments-derived explants were used for C. limonia and C. aurantium. For C. aurantium no adventitious shoots developed in explants (internodal segments) cultured in basal culture medium, without BAP supplementation. Although no statistic differences could be detected, culture media supplementation with the combination of BAP and NAA favored the development of adventitious shoots in C. aurantium. The best concentration of NAA varied according to BAP concentration. The results presented herein, show that Citrus in vitro organogenesis depends on the interaction of culture medium composition, explant differentiation level, and genotype.

Acute stroke chameleons in a university hospital : Risk factors, circumstances, and outcomes.

OBJECTIVE: To identify risk factors, circumstances, and outcomes for individuals with acute ischemic stroke (AIS) chameleons (AIS-C) arriving in the emergency department of a university hospital. METHODS: We retrospectively reviewed all patients with AIS from the prospectively constructed Acute Stroke Registry and Analysis of Lausanne during 8.25 years. AIS-C were defined as a failure to suspect stroke or as incorrect exclusion of stroke diagnosis. They were compared with patients diagnosed correctly at the time of admission. RESULTS: Forty-seven of 2,200 AIS were missed (2.1%). These AIS-C were either very mild or very severe strokes. Multivariate analysis showed a younger age in patients with AIS-C (odds ratio [OR] per year 0.98, p < 0.01), less prestroke statin treatment (OR 0.29, p = 0.04), and lower diastolic admission blood pressure (OR 0.98 p = 0.04). They showed less eye deviation (OR 0.21, p = 0.04) and more cerebellar strokes (OR 3.78, p < 0.01). AIS-C were misdiagnosed as other neurologic (42.6% of cases) or nonneurologic (17.0%) disease, as unexplained decreased level of consciousness (21.3%), and as concomitantly present disease (19.1%). At 12 months, patients with AIS-C had less favorable outcomes (adjusted OR 0.21, p < 0.01) and higher mortality (adjusted OR 4.37, p < 0.01). CONCLUSIONS: AIS are missed in patients with younger age with a lower cerebrovascular risk profile and may be masked by other acute conditions. Patients with chameleons present more often with milder strokes or coma, fewer focal signs and cerebellar strokes, and have higher disability and mortality rates at 12 months. These findings may be used to raise awareness in emergency departments to recognize and treat such patients appropriately.

Sociodemographic Factors and Clinical Conditions Associated to Hospitalization in Influenza A (H1N1) 2009 Virus Infected Patients in Spain, 2009-2010

The emergence and pandemic spread of a new strain of influenza A (H1N1) virus in 2009 resulted in a serious alarm in clinical and public health services all over the world. One distinguishing feature of this new influenza pandemic was the different profile of hospitalized patients compared to those from traditional seasonal influenza infections. Our goal was to analyze sociodemographic and clinical factors associated to hospitalization following infection by influenza A(H1N1) virus. We report the results of a Spanish nationwide study with laboratory confirmed infection by the new pandemic virus in a case-control design based on hospitalized patients. The main risk factors for hospitalization of influenza A (H1N1) 2009 were determined to be obesity (BMI≥40, with an odds-ratio [OR] 14.27), hematological neoplasia (OR 10.71), chronic heart disease, COPD (OR 5.16) and neurological disease, among the clinical conditions, whereas low education level and some ethnic backgrounds (Gypsies and Amerinds) were the sociodemographic variables found associated to hospitalization. The presence of any clinical condition of moderate risk almost triples the risk of hospitalization (OR 2.88) and high risk conditions raise this value markedly (OR 6.43). The risk of hospitalization increased proportionally when for two (OR 2.08) or for three or more (OR 4.86) risk factors were simultaneously present in the same patient. These findings should be considered when a new influenza virus appears in the human population.

Septic Tenosynovitis of the Hand: Factors Predicting Need for Subsequent Débridement.

BACKGROUND: Treatment of septic hand tenosynovitis is complex, and often requires multiple débridements and prolonged antibiotic therapy. The authors undertook this study to identify factors that might be associated with the need for subsequent débridement (after the initial one) because of persistence or secondary worsening of infection. METHODS: In this retrospective single-center study, the authors included all adult patients who presented to their emergency department from 2007 to 2010 with septic tenosynovitis of the hand. RESULTS: The authors identified 126 adult patients (55 men; median age, 45 years), nine of whom were immunosuppressed. All had community-acquired infection; 34 (27 percent) had a subcutaneous abscess and eight (6 percent) were febrile. All underwent at least one surgical débridement and had concomitant antibiotic therapy (median, 15 days; range, 7 to 82 days). At least one additional surgical intervention was required in 18 cases (median, 1.13 interventions; range, one to five interventions). All but four episodes (97 percent) were cured of infection on the first attempt after a median follow-up of 27 months. By multivariate analysis, only two factors were significantly associated with the outcome "subsequent surgical débridement": abscess (OR, 4.6; 95 percent CI, 1.5 to 14.0) and longer duration of antibiotic therapy (OR, 1.2; 95 percent CI, 1.1 to 1.2). CONCLUSION: In septic tenosynovitis of the hand, the only presenting factor that was statistically predictive of an increased risk of needing a second débridement was the presence of a subcutaneous abscess. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies.

PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.

Practice variability and efficacy of clonazepam, lorazepam, and midazolam in status epilepticus: A multicenter comparison.

OBJECTIVE: Benzodiazepines (BZD) are recommended as first-line treatment for status epilepticus (SE), with lorazepam (LZP) and midazolam (MDZ) being the most widely used drugs and part of current treatment guidelines. Clonazepam (CLZ) is also utilized in many countries; however, there is no systematic comparison of these agents for treatment of SE to date. METHODS: We identified all patients treated with CLZ, LZP, or MDZ as a first-line agent from a prospectively collected observational cohort of adult patients treated for SE in four tertiary care centers. Relative efficacies of CLZ, LZP, and MDZ were compared by assessing the risk of developing refractory SE and the number of antiseizure drugs (ASDs) required to control SE. RESULTS: Among 177 patients, 72 patients (40.62%) received CLZ, 82 patients (46.33%) LZP, and 23 (12.99%) MDZ; groups were similar in demographics and SE characteristics. Loading dose was considered insufficient in the majority of cases for LZP, with a similar rate (84%, 95%, and 87.5%) in the centers involved, and CLZ was used as recommended in 52% of patients. After adjustment for relevant variables, LZP was associated with an increased risk of refractoriness as compared to CLZ (odds ratio [OR] 6.4, 95% confidence interval [CI] 2.66-15.5) and with an increased number of ASDs needed for SE control (OR 4.35, 95% CI 1.8-10.49). SIGNIFICANCE: CLZ seems to be an effective alternative to LZP and MDZ. LZP is frequently underdosed in this setting. These findings are highly relevant, since they may impact daily practice.

Scoring criteria for portable monitor recordings: a comparison of four hypopnoea definitions in a population-based cohort.

RATIONALE: Limited-channel portable monitors (PMs) are increasingly used as an alternative to polysomnography (PSG) for the diagnosis of obstructive sleep apnoea (OSA). However, recommendations for the scoring of PM recordings are still lacking. Pulse-wave amplitude (PWA) drops, considered as surrogates for EEG arousals, may increase the detection sensitivity for respiratory events in PM recordings. OBJECTIVES: To investigate the performance of four different hypopnoea scoring criteria, using 3% or 4% oxygen desaturation levels, including or not PWA drops as surrogates for EEG arousals, and to determine the impact of measured versus reported sleep time on OSA diagnosis. METHODS: Subjects drawn from a population-based cohort underwent a complete home PSG. The PSG recordings were scored using the 2012 American Academy of Sleep Medicine criteria to determine the apnoea-hypopnoea index (AHI). Recordings were then rescored using only parameters available on type 3 PM devices according to different hypopnoea criteria and patients-reported sleep duration to determine the 'portable monitor AHIs' (PM-AHIs). MAIN RESULTS: 312 subjects were included. Overall, PM-AHIs showed a good concordance with the PSG-based AHI although it tended to slightly underestimate it. The PM-AHI using 3% desaturation without PWA drops showed the best diagnostic accuracy for AHI thresholds of ≥5/h and ≥15/h (correctly classifying 94.55% and 93.27% of subjects, respectively, vs 80.13% and 87.50% with PWA drops). There was a significant but modest correlation between PWA drops and EEG arousals (r=0.20, p=0.0004). CONCLUSION: Interpretation of PM recordings using hypopnoea criteria which include 3% desaturation without PWA drops as EEG arousal surrogate showed the best diagnosis accuracy compared with full PSG.

Characterizing the vulnerability of frequent emergency department users by applying a conceptual framework: a controlled, cross-sectional study.

BACKGROUND: Frequent emergency department (ED) users meet several of the criteria of vulnerability, but this needs to be further examined taking into consideration all vulnerability's different dimensions. This study aimed to characterize frequent ED users and to define risk factors of frequent ED use within a universal health care coverage system, applying a conceptual framework of vulnerability. METHODS: A controlled, cross-sectional study comparing frequent ED users to a control group of non-frequent users was conducted at the Lausanne University Hospital, Switzerland. Frequent users were defined as patients with five or more visits to the ED in the previous 12 months. The two groups were compared using validated scales for each one of the five dimensions of an innovative conceptual framework: socio-demographic characteristics; somatic, mental, and risk-behavior indicators; and use of health care services. Independent t-tests, Wilcoxon rank-sum tests, Pearson's Chi-squared test and Fisher's exact test were used for the comparison. To examine the -related to vulnerability- risk factors for being a frequent ED user, univariate and multivariate logistic regression models were used. RESULTS: We compared 226 frequent users and 173 controls. Frequent users had more vulnerabilities in all five dimensions of the conceptual framework. They were younger, and more often immigrants from low/middle-income countries or unemployed, had more somatic and psychiatric comorbidities, were more often tobacco users, and had more primary care physician (PCP) visits. The most significant frequent ED use risk factors were a history of more than three hospital admissions in the previous 12 months (adj OR:23.2, 95%CI = 9.1-59.2), the absence of a PCP (adj OR:8.4, 95%CI = 2.1-32.7), living less than 5 km from an ED (adj OR:4.4, 95%CI = 2.1-9.0), and household income lower than USD 2,800/month (adj OR:4.3, 95%CI = 2.0-9.2). CONCLUSIONS: Frequent ED users within a universal health coverage system form a highly vulnerable population, when taking into account all five dimensions of a conceptual framework of vulnerability. The predictive factors identified could be useful in the early detection of future frequent users, in order to address their specific needs and decrease vulnerability, a key priority for health care policy makers. Application of the conceptual framework in future research is warranted.

Uncertainty evaluation in activity measurements using ionization chambers

Pressurized re-entrant (or 4 pi) ionization chambers (ICs) connected to current-measuring electronics are used for activity measurements of photon emitting radionuclides and some beta emitters in the fields of metrology and nuclear medicine. As a secondary method, these instruments need to be calibrated with appropriate activity standards from primary or direct standardization. The use of these instruments over 50 years has been well described in numerous publications, such as the Monographie BIPM-4 and the special issue of Metrologia on radionuclide metrology (Ratel 2007 Metrologia 44 S7-16, Schrader1997 Activity Measurements With Ionization Chambers (Monographie BIPM-4) Schrader 2007 Metrologia 44 S53-66, Cox et al 2007 Measurement Modelling of the International Reference System (SIR) for Gamma-Emitting Radionuclides (Monographie BIPM-7)). The present work describes the principles of activity measurements, calibrations, and impurity corrections using pressurized ionization chambers in the first part and the uncertainty analysis illustrated with example uncertainty budgets from routine source-calibration as well as from an international reference system (SIR) measurement in the second part.

A retrospective study of deep sternal wound infections: clinical and microbiological characteristics, treatment, and risk factors for complications.

Deep sternal wound infection (DSWI) is a feared complication following cardiac surgery. This study describes clinical, microbiological, and treatment outcomes of DSWI and determines risk factors for complications. Of 55 patients with DSWI, 66% were male and mean age was 68.2years. Initial sternotomy was for coronary artery bypass graft in 49% of patients. Sternal debridement at mean 25.4±18.3days showed monomicrobial (94%), mainly Gram-positive infection. Secondary sternal wound infection (SSWI) occurred in 31% of patients, was mostly polymicrobial (71%), and was predominantly due to Gram-negative bacilli. Risk factors for SSWI were at least 1 revision surgery (odds ratio [OR] 4.8 [95% confidence interval {CI} 1.0-22.4], P=0.047), sternal closure by muscle flap (OR 4.6 [1.3-16.8], P=0.02), delayed sternal closure (mean 27 versus 14days, P=0.03), and use of vacuum-assisted closure device (100% versus 58%, P=0.008). Hospital stay was significantly longer in patients with SSWI (69days versus 48days, P=0.04).

Fosfomycin plus β-Lactams as Synergistic Bactericidal Combinations for Experimental Endocarditis Due to Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus.

The urgent need of effective therapies for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE) is a cause of concern. We aimed to ascertain the in vitro and in vivo activity of the older antibiotic fosfomycin combined with different beta-lactams against MRSA and glycopeptide-intermediate-resistant S. aureus (GISA) strains. Time-kill tests with 10 isolates showed that fosfomycin plus imipenem (FOF+IPM) was the most active evaluated combination. In an aortic valve IE model with two strains (MRSA-277H and GISA-ATCC 700788), the following intravenous regimens were compared: fosfomycin (2 g every 8 h [q8h]) plus imipenem (1 g q6h) or ceftriaxone (2 g q12h) (FOF+CRO) and vancomycin at a standard dose (VAN-SD) (1 g q12h) and a high dose (VAN-HD) (1 g q6h). Whereas a significant reduction of MRSA-227H load in the vegetations (veg) was observed with FOF+IPM compared with VAN-SD (0 [interquartile range [IQR], 0 to 1] versus 2 [IQR, 0 to 5.1] log CFU/g veg; P = 0.01), no statistical differences were found with VAN-HD. In addition, FOF+IPM sterilized more vegetations than VAN-SD (11/15 [73%] versus 5/16 [31%]; P = 0.02). The GISA-ATCC 700788 load in the vegetations was significantly lower after FOF+IPM or FOF+CRO treatment than with VAN-SD (2 [IQR, 0 to 2] and 0 [IQR, 0 to 2] versus 6.5 [IQR, 2 to 6.9] log CFU/g veg; P < 0.01). The number of sterilized vegetations after treatment with FOF+CRO was higher than after treatment with VAN-SD or VAN-HD (8/15 [53%] versus 4/20 [20%] or 4/20 [20%]; P = 0.03). To assess the effect of FOF+IPM on penicillin binding protein (PBP) synthesis, molecular studies were performed, with results showing that FOF+IPM treatment significantly decreased PBP1, PBP2 (but not PBP2a), and PBP3 synthesis. These results allow clinicians to consider the use of FOF+IPM or FOF+CRO to treat MRSA or GISA IE.

Myocardial perfusion scintigraphy in the detection of silent ischemia in asymptomatic diabetic patients

OBJECTIVE: This study was aimed to evaluate myocardial perfusion in asymptomatic patients with type 1 (DM1) and type 2 diabetes mellitus (DM2) without previous diagnoses of coronary artery disease (CAD) or cerebral infarction. MATERIALS AND METHODS: Fifty-nine consecutive asymptomatic patients (16 DM1, 43 DM2) underwent myocardial perfusion scintigraphy with 99mTc-sestamibi (MPS). They were evaluated for body mass index, metabolic control of DM, type of therapy, systemic arterial hypertension, dyslipidemia, nephropathy, retinopathy, peripheral neuropathy, smoking, and familial history of CAD. RESULTS: MPS was abnormal in 15 patients (25.4%): 12 (20.3%) with perfusion abnormalities, and 3 with isolated left ventricular dysfunction. The strongest predictors for abnormal myocardial perfusion were: age 60 years and above (p = 0.017; odds ratio [OR] = 6.0), peripheral neuropathy (p = 0.028; OR = 6.1), nephropathy (p = 0.031; OR = 5.6), and stress ECG positive for ischemia (p = 0.049; OR = 4.08). CONCLUSION: Silent myocardial ischemia occurs in more than one in five asymptomatic diabetic patients. The strongest predictors of ischemia in this study were: patient age, peripheral neuropathy, nephropathy, retinopathy and a stress ECG positive for ischemia.