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Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection. In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918. Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log10 IU/mL (1·71–7·20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament. Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations. Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).

BackgroundTo assess differences between patients referred to emergency departments by a primary care physician (PCP) and those presenting directly and the impact of referral on the likelihood of admission.Design of studyRetrospective cohort study.SettingEDs of two nonacademic general hospitals in a German metropolitan region.ParticipantsRandom sample of 1500 patients out of 80,845 presentations during the year 2019.ResultsAge was 55.8 ± 22.9 years, and 51.4% was female. A total of 34.7% presented by emergency medical services (EMS), and 47.7% were walk-ins. One-hundred seventy-four (11.9%) patients were referred by PCPs. Referrals were older (62.4 ± 20.1 vs 55.0 ± 23.1 years, p < .001) and had a higher Charlson Comorbidity Index (CCI) (3 (1–5) vs 2 (0–4); p < .001). Referrals received more ultrasound examinations independently from their admission status (27.6% vs 15.7%; p < .001) and more CT and laboratory investigations. There were no differences in sex, Manchester Triage System (MTS) category, or pain-scale values. Referrals presented by EMS less often (9.2% vs 38.5%; p < .001). Admission rates were 62.6% in referrals and 37.1% in non-referrals (p < .001). Referral (OR 3.976 95% CI: 2.595–6.091), parenteral medication in ED (OR 2.674 (1.976–3.619)), higher MTS category (1.725 (1.421–2.093)), transport by EMS (1.623 (1.212–2.172)), abnormal vital parameters (1.367 (0.953–1.960)), higher CCI (1.268 (1.196–1.344)), and trauma (1.268 (1.196–1.344)) were positively associated with admission in multivariable analysis, whereas ultrasound in ED (0.450 (0.308–0.658)) and being a nursing home resident (0.444 (0.270–0.728)) were negatively associated.ConclusionReferred patients were more often admitted. They received more laboratory investigations, ultrasound examinations, and computed tomographies. Difficult decisions regarding the necessity of admission requiring typical resources of EDs may be a reason for PCP referrals.

Polyfunctional CD4 or CD8 T cells are proposed to represent a correlate of immune control for persistent viruses as well as for vaccine mediated protection against infection. A well-suited methodology to study complex functional phenotypes of antiviral T cells is the combined staining of intracellular cytokines and phenotypic marker expression using polychromatic flow cytometry. In this study we analyzed the effect of an overnight resting period at 37 °C on the quantity and functionality of HIV-1, EBV, CMV, HBV and HCV specific CD4 and CD8 T-cell responses in a cohort of 21 individuals. We quantified total antigen specific T cells by multimer staining and used 10-color intracellular cytokine staining (ICS) to determine IFNγ, TNFα, IL2 and MIP1β production. After an overnight resting significantly higher numbers of functionally active T cells were detectable by ICS for all tested antigen specificities, whereas the total number of antigen specific T cells determined by multimer staining remained unchanged. Overnight resting shifted the quality of T-cell responses towards polyfunctionality and increased antigen sensitivity of T cells. Our data suggest that the observed effect is mediated by T cells rather than by antigen presenting cells. We conclude that overnight resting of PBMC prior to ex vivo analysis of antiviral T-cell responses represents an efficient method to increase sensitivity of ICS-based methods and has a prominent impact on the functional phenotype of T cells.

Variability of body weight (BW) and height calls for indexation of volumetric hemodynamic parameters. Extravascular lung water (EVLW) has formerly been indexed to actual BW (BW(act)) termed EVLW-index (EVLWI). In overweight patients indexation to BW(act) might inappropriately lower indexed EVLWI(act). Several studies suggest indexation of EVLWI to predicted BW (EVLWI(pred)). However, data regarding association of EVLWI(act) and EVLW(pred) to mortality and PaO2/FiO2 are inconsistent. Two recent studies based on biometric database-analyses suggest indexation of EVLWI to height (EVLWI(height)). Therefore, our study compared the association of un-indexed EVLW, EVLWI(height), EVLW(pred) and EVLWI(act) to PaO2/FiO2 and Oxygenation index (OI = mean airway pressure*FiO2*/PaO2). A total of 2119 triplicate transpulmonary thermodilutions (TPTDs; PiCCO; Pulsion Medical-Systems, Germany) were performed in 50 patients from the evaluation, and 181 patients from the validation groups. Correlations of EVLW and EVLWI to PaO2/FiO2, OI and ROC-AUC-analyses regarding PaO2/FiO2<200 mmHg (primary endpoint) and OI>10 were performed. In the evaluation group, un-indexed EVLW (AUC 0.758; 95%-CI: 0.637-0.880) and EVLWI(height) (AUC 0.746; 95%-CI: 0.622-0.869) provided the largest ROC-AUCs regarding PaO2/FiO2<200 mmHg. The AUC for EVLWI(pred) was smaller (0.713). EVLWI(act) provided the smallest AUC (0.685). This was confirmed in the validation group: EVLWI(height) provided the largest AUC (0.735), EVLWI(act) (0.710) the smallest. In the merged data-pool, AUC was significantly greater for EVLWI(height) (0.729; 95%-CI: 0.674-0.784) compared to all other indexations including EVLWI(act) (ROC-AUC 0.683, p = 0.007) and EVLWI(pred) (ROC-AUC 0.707, p = 0.015). The association of EVLW(I) was even stronger to OI compared to PaO2/FiO2. In the merged data-pool, EVLWI(height) provided the largest AUC regarding \"OI>10\" (0.778; 95%-CI: 0.713-0.842) compared to 0.739 (95%-CI: 0.669-0.810) for EVLWI(act) and 0.756 (95%-CI: 0.688-0.824) for EVLWI(pred). Indexation of EVLW to height (EVLWI(height)) improves the association of EVLW(I) to PaO2/FiO2 and OI compared to all other indexations including EVLWI(pred) and EVLWI(act). Also considering two recent biometric database analyses, EVLWI should be indexed to height.

In intensive care unit (ICU) patients in whom bronchoalveolar lavage fluid (BALF) was analyzed for suspected infectious pulmonary disease, we investigated the association of herpes simplex virus (HSV) in the BALF with lung injury and patient outcome. In this retrospective cohort study, we included 201 patients treated in a medical ICU of a German university hospital in whom BALF samples were analyzed for the presence of HSV using quantitative polymerase chain reaction analysis. Eighty-seven patients (43%) were HSV-negative, and 114 patients (57%) were HSV-positive. At the day of BALF sampling (day 0), there was no clinically relevant (or statistically significant) difference in the Modified Clinical Pulmonary Infection Score, Lung Injury Score, and single indicator transpulmonary thermodilution–derived extravascular lung water index and pulmonary vascular permeability index between HSV-negative patients and HSV-positive patients or HSV-positive patients with greater than 105 HSV copies/mL. The ICU and hospital length of stay was statistically significantly longer in HSV-positive patients compared with HSV-negative patients. Intensive care unit and hospital mortality was not statistically significantly different between the groups. We did not find a clinically relevant or statistically significant association of HSV in the BALF of medical ICU patients with lung injury or with ICU and hospital mortality.

The aim of this study was to evaluate continuous vancomycin infusion (contV) in intensive care unit patients. A retrospective study in 164 patients treated with contV was conducted. They were compared with 75 patients treated with intermittent vancomycin infusion. The median duration of vancomycin therapy in the contV group was 6 (5%-95% percentile range, 2-21) days. The median daily vancomycin dose in the contV group was 960 (526-1723) mg, resulting in a median serum vancomycin plateau concentration of 19.8 (9.8-29.4) mg/L (target: 15-25 mg/L). The contV administration regime was sufficient regarding achievement of the target serum vancomycin concentration. However, in the contV group, serum vancomycin levels were frequently in a subtherapeutic range on treatment days 1 (44%), 2 (29%), and 3 (23%). In the contV group, serum vancomycin concentration determinations per treatment day were performed significantly less often compared with the intermittent vancomycin infusion group (0.38 [0.15-0.75] vs 0.43 [0.22-1.00], P = .041). In medical intensive care unit patients, contV is sufficient to achieve target serum vancomycin concentrations. Because contV frequently resulted in subtherapeutic drug levels on the first days of therapy, a higher loading or starting dose might be necessary.

Systemic Capillary Leak Syndrome (SCLS) is a rare disorder characterized by increased capillary hyperpermeability leading to hypovolemic shock due to a markedly increased shift of fluid and protein from the intravascular to the interstitial space. Hemoconcentration, hypoalbuminemia and a monoclonal gammopathy are characteristic laboratory findings. Here we present a patient who suffered from SCLS with hypovolemic shock and compartment syndrome of both lower legs and thighs. Volume and catecholamine management was guided using transpulmonary thermodilution. Extended hemodynamic monitoring for volume and catecholamine management as well as monitoring of muscle compartment pressure is of crucial importance in SCLS patients.

Objective To assess the effect of reducing intra-abdominal pressure (IAP) by paracentesis on renal resistive index (RI), hemodynamics and renal function. Design and setting Uncontrolled trial in a university gastroenterological intensive care unit. Patients Twelve spontaneously breathing cirrhotic patients with hepatorenal syndrome, tense ascites and a clinical indication for paracentesis. Interventions Paracentesis and substitution of albumin. Measurements and results Hemodynamic variables were assessed by transpulmonary thermodilution, RI was determined by Doppler ultrasound of renal interlobar arteries. After paracentesis and albumin substitution, there was a significant decrease of IAP (20 mmHg (19–22) to 12 mmHg (10–13), systemic vascular resistance index (from 1,243 dyn s/cm 5 /m 2 (1,095–1,745) to 939 dyn s/cm 5 /m 2 (812–1,365); p  = 0.005) and RI (from 0.848 (0.810–0.884) to 0.810 (0.780–0.826); p  = 0.003). Arterial compliance increased from 1.33 mL/mmHg (0.89–1.74) to 1.71 mL/mmHg (1.21–2.12), pulse pressure index remained unchanged. Creatinine clearance (ClCreat) increased significantly from 5 mL/min (0–28) to 9 mL/min (0–36) ( p  = 0.018) and urinary output from 12 mL/h (0–49) to 16 mL/h (0–64) ( p  = 0.043). Conclusions In patients with cirrhosis, HRS and tense ascites, IAP may contribute to renal dysfunction. Reduction of IAP following paracentesis and albumin substitution may improve ClCreat, probably by improving renal blood flow as reflected by decreasing RI in Doppler ultrasound.

Background and objective Stroke volume variation (SVV) has high sensitivity and specificity in predicting fluid responsiveness. However, sinus rhythm (SR) and controlled mechanical ventilation (CV) are mandatory for their application. Several studies suggest a limited applicability of SVV in intensive care unit (ICU) patients. We hypothesized that the applicability of SVV might be different over time and within certain subgroups of ICU patients. Therefore, we analysed the prevalence of SR and CV in ICU patients during the first 24 h of PiCCO-monitoring (primary endpoint) and during the total ICU stay. We also investigated the applicability of SVV in the subgroups of patients with sepsis, cirrhosis, and acute pancreatitis. Methods The prevalence of SR and CV was documented immediately before 1241 thermodilution measurements in 88 patients. Results: In all measurements, SVV was applicable in about 24%. However, the applicability of SVV was time-dependent: the prevalence of both SR and CV was higher during the first 24 h compared to measurements thereafter (36.1% vs. 21.9%; P <0.001). Within different subgroups, the applicability during the first 24 h of monitoring ranged between 0% in acute pancreatitis, 25.5% in liver failure, and 48.9% in patients without pancreatitis, liver failure, pneumonia or sepsis. Conclusions The applicability of SVV in a predominantly medical ICU is only about 25%–35%. The prevalence of both mandatory criteria decreases over time during the ICU stay. Furthermore, the applicability is particularly low in patients with acute pancreatitis and liver failure.