Biomarkers of Inflammation and Oxidative Stress among Adult Former Smoker, Current E-Cigarette Users-Results from Wave 1 PATH Study.

BACKGROUND: Former smokers who currently use e-cigarettes have lower concentrations of biomarkers of tobacco toxicant exposure than current smokers. It is unclear whether tobacco toxicant exposure reductions may lead to health risk reductions. METHODS: We compared inflammatory biomarkers (high-sensitivity C-reactive protein, IL6, fibrinogen, soluble intercellular adhesion molecule-1) and an oxidative stress marker (F2-isoprostane) among 3,712 adult participants in Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study by tobacco user groups: dual users of cigarettes and e-cigarettes; former smokers who currently use e-cigarettes-only; current cigarette-only smokers; former smokers who do not currently use any tobacco; and never tobacco users. We calculated geometric means (GM) and estimated adjusted GM ratios (GMR). RESULTS: Dual users experienced greater concentration of F2-isoprostane than current cigarette-only smokers [GMR 1.09 (95% confidence interval, CI, 1.03-1.15)]. Biomarkers were similar between former smokers who currently use e-cigarettes and both former smokers who do not use any tobacco and never tobacco users, but among these groups most biomarkers were lower than those of current cigarette-only smokers. The concentration of F2-isoprostane decreased by time since smoking cessation among both exclusive e-cigarette users (P trend = 0.03) and former smokers who do not currently use any tobacco (P trend = 0.0001). CONCLUSIONS: Dual users have greater concentration of F2-isoprostane than smokers. Exclusive e-cigarette users have biomarker concentrations that are similar to those of former smokers who do not currently use tobacco, and lower than those of exclusive cigarette smokers. IMPACT: This study contributes to an understanding of the health effects of e-cigarettes.

Options in extracorporeal support of multiple organ failure.

Multiorgan failure is among the most frequent reasons of death in critically ill patients. Based on extensive and long-term use of renal replacement therapy, extracorporeal organ support became available for other organ failures. Initially, most of these techniques (e.g. extracorporeal membrane oxygenation, extracorporeal CO2 removal [ECCO2R] and extracorporeal liver support) were used as stand-alone single organ support systems. Considering multiple interactions between native organs ("crosstalk"), combined or integrated extracorporeal organ support (ECOS) devices are intriguing. The concept of multiple organ support therapy (MOST) providing simultaneous and combined support for different failing organs was described more than 15 years ago by Ronco and Bellomo. This concept also implicates overcoming the "compartmentalized" approach provided by different single organ specialized professionals by a multidisciplinary and multiprofessional strategy. The idea of MOST is supported by the failure of several recent studies on single organ support including liver and lung support. Improvement of outcome by ECOS necessarily depends on optimized patient selection, integrated organ support and limitation of its side effects. This implicates challenges for engineers, industry and healthcare professionals. From a technical viewpoint, modular combination of pre-existing technologies such as renal replacement, albumin-dialysis, ECCO2R and potentially cytokine elimination can be considered as a first step. While this allows for stepwise and individual combination of standard organ support facilities, it carries the disadvantage of large extracorporeal blood volume and surfaces as well as additive costs. The more intriguing next step is an integrated platform providing the capacity of multiple organ support within one device. (This article is freely available.).

A retrospective clinical and microbial analysis of 32 patients with bilomas.

BACKGROUND: Bilomas are defined collections of bile fluids mainly caused by iatrogenic injuries of the bile duct system. Owing to the infrequency of this disease, studies addressing bilomas are rare. METHODS: By using an endoscopic database, this retrospective study identified 32 patients with bilomas treated between 2004 to 2015, in order to analyse aetiology, clinical presentation, spectrum of pathogens, and resolution rate of bilomas. RESULTS: 65.6% of the study population (21/32) developed bilomas after surgery and 21.9% (7/32) after endoscopic retrograde cholangiography (ERC). Icterus, fever, and abdominal pain were the leading symptoms. 93.9% (46/49) of microbiological bile cultures revealed a positive microbiology. The predominant microorganisms were the group of Enterobacteriaceae (43.0%, 52/121), followed by Enterococcus spp. (32.2%, 39/121), and Candida spp. (9.1%, 11/121). Multiresistant bacteria like Enterobacteriaceae were isolated from one quarter of all patients. Single or multimodal treatment resulted in an overall complication rate of 4.8% (9/188). Clinical follow-up analysis showed a complete resolution rate of 78.3% for interventional therapy and 80% in the non-interventional group. CONCLUSIONS: Pathogen spectrum of bilomas mainly comprises the group of Enterobacteriacae and Enterococcus spp., with a high proportion of multiresistant bacteria. Different interventional approaches are available for biloma drainage, which seem to be safe and effective for most patients. TRIAL REGISTRATION: German Clinical Trials Register DRKS00015208 , retrospectively registered.

Randomised controlled trial comparing preoperative carbohydrate loading with standard fasting in paediatric anaesthesia.

BACKGROUND: Preoperative fasting is a major cause of perioperative discomfort in paediatric anaesthesia and leads to postoperative insulin resistance, thus potentially enhancing the inflammatory response to surgery. Addressing these problems by preoperative carbohydrate intake has not been a well-defined approach in children. METHODS: We randomised 120 children scheduled for gastroscopy under general anaesthesia to either a control group of standard preoperative fasting or a study group receiving a carbohydrate beverage (PreOp™; Nutricia, Erlangen, Germany). Their stomach contents were aspirated endoscopically, and the volume and pH measured. Perioperative discomfort was evaluated using, among other parameters, an observational pain scale in ≤4-yr-olds and a VAS in >4-yr-olds. The investigators doing the endoscopies and outcome evaluations were blinded to the study group allocation. RESULTS: Compared with fasting, carbohydrate loading was associated with significantly less gastric content (P=0.01), fewer patients experiencing postoperative nausea (P=0.028), with no significant difference in postoperative vomiting. High preoperative VAS scores (>5) were recorded for only one child in the carbohydrate group vs five children in the fasting group. Bowel cleansing for simultaneous colonoscopies (n=61) made no difference to any of the intergroup findings. CONCLUSIONS: Preoperative carbohydrates can reduce nausea and gastric content, the latter being a surrogate parameter for the risk and severity of gastric aspiration into the lungs during anaesthesia. Our study adds knowledge for preoperative fasting guidelines in paediatric anaesthesia. CLINICAL TRIAL REGISTRATION: DRKS00005020.

Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma.

Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma associated with MYC translocation. Here, we describe drug response profiling of 42 blood cancer cell lines including 17 BL to 32 drugs targeting key cancer pathways and provide a systematic study of drug combinations in BL cell lines. Based on drug response, we identified cell line specific sensitivities, i.e. to venetoclax driven by BCL2 overexpression and partitioned subsets of BL driven by response to kinase inhibitors. In the combination screen, including BET, BTK and PI3K inhibitors, we identified synergistic combinations of PI3K and BTK inhibition with drugs targeting Akt, mTOR, BET and doxorubicin. A detailed comparison of PI3K and BTKi combinations identified subtle differences, in line with convergent pathway activity. Most synergistic combinations were identified for the BET inhibitor OTX015, which showed synergistic effects for 41% of combinations including inhibitors of PI3K/AKT/mTOR signalling. The strongest synergy was observed for the combination of the CDK 2/7/9 inhibitor SNS032 and OTX015. Our data provide a landscape of drug combination effects in BL and suggest that targeting CDK and BET could provide a novel vulnerability of BL.

Advanced hemodynamic monitoring in intensive care medicine : A German web-based survey study.

BACKGROUND: Advanced hemodynamic monitoring is recommended in patients with complex circulatory shock. OBJECTIVES: To evaluate the current attitudes and beliefs among German intensivists, regarding advanced hemodynamic monitoring, the actual hemodynamic management in clinical practice, and the barriers to using it. MATERIALS AND METHODS: Web-based survey among members of the German Society of Medical Intensive Care and Emergency Medicine. RESULTS: Of 284 respondents, 249 (87%) agreed that further hemodynamic assessment is needed to determine the type of circulatory shock if no clear clinical diagnosis can be made. In all, 281 (99%) agreed that echocardiography is helpful for this purpose (transpulmonary thermodilution: 225 [79%]; pulmonary artery catheterization: 126 [45%]). More than 70% of respondents agreed that blood flow variables (cardiac output, stroke volume) should be measured in patients with hemodynamic instability. The parameters most respondents agreed should be assessed in a patient with hemodynamic instability were mean arterial pressure, cardiac output, and serum lactate. Echocardiography is available in 99% of ICUs (transpulmonary thermodilution: 91%; pulmonary artery catheter: 63%). The respondents stated that, in clinical practice, invasive arterial pressure measurements and serum lactate measurements are performed in more than 90% of patients with hemodynamic instability (cardiac output monitoring in about 50%; transpulmonary thermodilution in about 40%). The respondents did not feel strong barriers to the use of advanced hemodynamic monitoring in clinical practice. CONCLUSIONS: This survey study shows that German intensivists deem advanced hemodynamic assessment necessary for the differential diagnosis of circulatory shock and to guide therapy with fluids, vasopressors, and inotropes in ICU patients.

Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

First description of spontaneous fungal peritonitis caused by Fusarium solani in a critically ill patient with liver cirrhosis.

Fusarium spp., common soil moulds, are emerging fungal pathogens in immunocompromised subjects. We report the first case of Fusarium solani peritonitis in a patient with liver cirrhosis. Because of the high morbidity and mortality associated with fusariosis, an aggressive approach to treatment as well as identification of the species and drug susceptibilities is warranted.

Persistence and reactivation of human adenoviruses in the gastrointestinal tract.

Reactivation of persistent human adenoviruses (HAdVs) is associated with high morbidity and mortality in paediatric haematopoietic stem cell transplant (HSCT) recipients. Although invasive HAdV infections mainly arise from the gastrointestinal (GI) tract, the specific sites of HAdV persistence are not well characterised. We prospectively screened biopsies from 143 non-HSCT paediatric patients undergoing GI endoscopy and monitored serial stool specimens from 148 paediatric HSCT recipients for the presence of HAdV by real-time PCR. Persistence of HAdV in the GI tract was identified in 31% of children, with the highest prevalence in the terminal ileum. In situ hybridisation and immunohistochemistry identified HAdV persistence in lymphoid cells of the lamina propria, whereas biopsies from five transplant recipients revealed high numbers of replicating HAdV in intestinal epithelial cells. The prevalence of HAdV species, the frequencies of persistence in the GI tract and reactivations post transplant indicated a correlation of intestinal HAdV shedding pre-transplant with high risk of invasive infection. HAdV persistence in the GI tract is a likely origin of infectious complications in immunocompromised children. Intestinal lymphocytes represent a reservoir for HAdV persistence and reactivation, whereas the intestinal epithelium is the main site of viral proliferation preceding dissemination. The findings have important implications for assessing the risk of life-threatening invasive HAdV infections.

The use of proton pump inhibitors and the spectrum and number of biliary pathogens in patients with acute cholangitis.

BACKGROUND: Knowledge of the bacterial spectrum for acute cholangitis is essential for adequate empiric antibiotic treatment. AIM: To analyse the relation of proton pump inhibitors (PPI) with biliary pathogens in patients with acute cholangitis. METHODS: This retrospective study identified 278 patients with 318 acute cholangitis episodes using an endoscopic database. The relationship between PPI and microbiological outcomes was assessed by logistic and poisson regression analysis for binary and count data. RESULTS: In total, 882 pathogens were isolated, of which, 120 cholangitis episodes occurred with PPI; 198 cholangitis episodes without PPI. Multivariate poisson regression analysis showed that PPI use resulted in a 23% increase in the number of biliary pathogens [3.14 vs. 2.55 (Δ = 0.59), P < 0.01], whereas stent therapy, previous interventional procedures (endoscopic retrograde cholangiography/percutaneous transhepatic cholangiography), genesis, age and sex showed no significant association with the number of biliary pathogens. Significantly, more cholangitis episodes with more than one pathogen isolated occurred during PPI treatment [103/120 (86%) vs. 151/198 (76%), P = 0.04]. Analysis of intrinsic anti-microbial resistance patterns was performed: Anti-microbial combination therapies were significantly more required to cover all isolated pathogens in cholangitis episodes with PPI than in cholangitis episodes without PPI (44/120 vs. 46/198, P = 0.01). Additionally, PPI use was associated with a significantly higher incidence of oropharyngeal flora in the biliary tract (53/120 vs. 61/198, P = 0.02). CONCLUSIONS: Proton pump inhibitors seem to influence biliary pathogens by increasing the number and broadening the spectrum of biliary pathogens. However, the findings of this hypothesis-generating study need to be tested by confirmatory studies.

Radial artery applanation tonometry for continuous non-invasive arterial pressure monitoring in intensive care unit patients: comparison with invasively assessed radial arterial pressure.

BACKGROUND: Radial artery applanation tonometry technology can be used for continuous non-invasive measurement of arterial pressure (AP). The purpose of this study was to evaluate this AP monitoring technology in intensive care unit (ICU) patients in comparison with invasive AP monitoring using a radial arterial catheter. METHODS: In 24 ICU patients (German university hospital), AP values were simultaneously recorded on a beat-to-beat basis using radial artery applanation tonometry (T-Line system; Tensys Medical, San Diego, CA, USA) and a radial arterial catheter (contralateral arm). The primary endpoint of the study was to investigate the accuracy and precision of the non-invasively assessed AP measurements with the Bland-Altman method based on averaged 10 beat AP epochs (n=2993 10 beat epochs). RESULTS: For mean AP (MAP), systolic AP (SAP), and diastolic AP (DAP), we observed a bias (±standard deviation of the bias; 95% limits of agreement; percentage error) of +2 mm Hg (±6; -11 to +15 mm Hg; 15%), -3 mm Hg (±15; -33 to +27 mm Hg; 23%), and +5 mm Hg (±7; -9 to +19 mm Hg; 22%), respectively. CONCLUSIONS: In ICU patients, MAP and DAP measurements obtained using radial artery applanation tonometry show clinically acceptable agreement with invasive AP determination with a radial arterial catheter. While the radial artery applanation tonometry technology also allows SAP measurements with high accuracy, its precision for SAP measurements needs to be further improved.

[Early functional treatment of intra-articular fractures of the proximal interphalangeal joint of the finger using a modified traction device]. / Die frühfunktionelle Therapie intraartikulärer Mittelgliedbasisfrakturen mit der modifizierten Traktionsschiene.

INTRODUCTION: Treatment of intra-articular fractures of the middle phalanx is both difficult and controversial. We report our experience of using a modified dynamic traction device (mTD) utilizing only one pin in the head of the middle phalanx and thus facilitating further open reconstructive surgery at the proximal interphalangeal joint (PIP). The pin does not necessarily have to be inserted in the movement axis of the joint. AIM OF THE STUDY: The aim of the study was to a) determine the effectiveness of the mTD, particularly in comparison with other distraction systems used in the treatment of middle phalanx fractures as described in the literature, and b) compare the results of patients treated using an mTD only with the results of those treated with an mTD in combination with additional open reconstructive surgery. PATIENTS AND METHODS: 26 patients with a mean age of 37 years were treated for intra-articular fractures of the base of the middle phalanx using an mTD in the period between 2007 and 2011. 13 of these patients also underwent additional open reconstructive surgery. 18 of the 26 patients (69%) were reevaluated after 33 months (range 9-44 months); 10 of these had undergone additional open reconstructive surgery. Follow-up of 14 of the patients included their completion of a structured questionnaire and calculation of their DASH scores as well as radiological and clinical examinations. 4 patients completed the questionnaire and had their DASH score calculated. Measurement of range of motion was performed by the treating general practitioner. Patient records were analysed with a particular focus on complications and duration of therapy. RESULTS: The mTD was used for an average of 34 days (range 8-53 days) and overall treatment took an average of 74 days (range 66-154 days). 4 pin tract infections were reported. The mean DASH score was 6.4. The mean range of motion in the PIP joint was 70° (range 30-110°). The range of motion of the PIP and DIP joints (61º) was significantly poorer in patients with additional surgery than that (82º) in patients with sole mTD treatment. Treatment with the mTD gave results similar to those obtained with other distraction devices with good subjective evaluation by the patients. CONCLUSION: Dynamic traction with the help of the modified traction devices is suitable for treating intra-articular fractures of the proximal interphalangeal joint, as demonstrated by a comparison with the literature. Patients who underwent additional open surgery showed less favorable results. The present method has the advantage that only one wire needs to be inserted subcapitaly at a distance from the fracture in the middle finger and this facilitates further surgical interventions.

Non-invasive continuous arterial pressure measurement based on radial artery tonometry in the intensive care unit: a method comparison study using the T-Line TL-200pro device.

BACKGROUND: The T-Line TL-200pro (TL-200pro) device (Tensys Medical, Inc., San Diego, CA, USA), based on radial artery tonometry, provides an arterial pressure (AP) waveform and beat-to-beat values of systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP). The aim of the study was to evaluate this non-invasive technique for continuous AP monitoring in medical intensive care unit (ICU) patients. METHODS: Arterial pressure measurements obtained using the TL-200pro technology were compared using Bland-Altman analysis with values measured directly from a femoral arterial catheter in 34 ICU patients. RESULTS: Arterial pressure values were analysed and compared in 4502 averaged 10-beat epochs. A bias of +0.72 mm Hg (95% limits of agreement -9.37 to +10.82 mm Hg) was observed for MAP. For SAP and DAP, there was a mean difference of -1.39 mm Hg (95% limits of agreement -18.74 to +15.96 mm Hg) and +4.36 mm Hg (95% limits of agreement -8.66 to +17.38 mm Hg), respectively. The percentage error for MAP, SAP, and DAP was 12%, 14%, and 21%, respectively. CONCLUSIONS: Arterial pressure measurement based on radial artery tonometry using the TL-200pro technology is feasible in medical ICU patients. The TL-200pro system is capable of providing MAP values with high accuracy (low mean difference) and precision (narrow limits of agreement) compared with MAP measured invasively using a femoral arterial catheter. The TL-200pro technology is promising for the measurement of SAP and DAP but further development is necessary to improve accuracy and precision.