Svetlana Hetjens

Comparison of Coronary Computed Tomography Angiography-Derived vs Invasive Fractional Flow Reserve Assessment: Meta-Analysis with Subgroup Evaluation of Intermediate Stenosis

RATIONALE AND OBJECTIVESnInvasive coronary angiography (ICA) with fractional flow reserve (FFR) assessment is the reference standard for the detection of hemodynamically relevant coronary lesions. We have investigated whether coronary computed tomography angiography (cCTA)-derived FFR (fractional flow reserve from coronary computed tomographic angiography [CT-FFR]) measurement improves diagnostic accuracy over cCTA.nnnMETHODS AND RESULTSnA literature search was performed for studies comparing invasive FFR, cCTA, and CT-FFR. The analysis included three prospective multicenter trials and two retrospective single-center studies; a total of 765 patients and 1306 vessels were included in the meta-analysis. Compared to invasive FFR on a per-lesion basis, CT-FFR reached a pooled sensitivity, specificity, positive predictive value, and negative predictive value of 83.7% (95% confidence interval [CI]: 78.1-89.3), 74.7% (95% CI: 52.2-97.1), 64.8% (95% CI: 52.1-77.5), and 90.1% (95% CI: 80.8-99.3) compared to 84.6% (95% CI: 78.1-91.1), 49.7% (95% CI: 31.1-68.4), 39.0% (95% CI: 28.0-50.1), and 87.3% (95% CI: 72.5-100.0) for cCTA alone. In 634 vessels with intermediate stenosis (30%-70%), sensitivity, specificity, positive predictive value, and negative predictive value were 81.4% (95% CI: 70.4-92.9), 71.7% (95% CI: 54.5-89.0), 59.4% (95% CI: 35.5-83.4), and 89.9% (95% CI: 85.0-94.7) compared to 90.2% (95% CI: 80.6-99.9), 35.4% (95% CI: 23.5-47.3), 50.7% (95% CI: 30.6-70.8), and 82.5% (95% CI: 64.5-100.0) for cCTA alone. The summary area under the receiver operating characteristic curve of CT-FFR was superior to cCTA alone on a per-vessel (0.90 [95% CI: 0.82-0.98] vs 0.74 [95% CI: 0.63-0.86]; Pu2009=u2009.0047) and for intermediate stenoses (0.76 [95% CI: 0.65-0.88] vs 0.57 [95% CI: 0.49-0.66]; Pu2009=u2009.0027).nnnCONCLUSIONnCT-FFR significantly improves specificity without noticeably altering the sensitivity of cCTA with invasive FFR as a reference standard for the detection of hemodynamically relevant stenosis.

Mitogen-activated protein kinases are required for effective infection of human choroid plexus epithelial cells by Listeria monocytogenes.

Listeria monocytogenes, a Gram-positive bacterium, can cause meningitis after invading the human central nervous system. The blood-cerebrospinal fluid barrier (BCSFB), located at the epithelium of the choroid plexus, is a possible entry site for L. monocytogenes into the brain, and inxa0vitro L. monocytogenes invades human choroid plexus epithelial papilloma (HIBCPP) cells. Although host cell signal transduction subsequent to infection by L. monocytogenes has been investigated, the role of mitogen-activated protein kinases (MAPK) is not clarified yet. We show that infection with L. monocytogenes causes activation of the MAPKs Erk1/2 and p38 preferentially when bacteria are added to the physiologically more relevant basolateral side of HIBCPP cells. Deletion of the listerial virulence factors Internalin (InlA) and InlB reduces MAPK activation. Whereas inhibition of either Erk1/2 or p38 signaling significantly attenuates infection of HIBCPP cells with L. monocytogenes, simultaneous inhibition of both MAPK pathways shows an additive effect, and Erk1/2 and p38 are involved in regulation of cytokine and chemokine expression following infection. Blocking of endocytosis with the synthetic dynamin inhibitor dynasore strongly abrogates infection of HIBCPP cells with L. monocytogenes. Concurrent inhibition of MAPK signaling further reduces infection, suggesting MAPKs mediate infection with L. monocytogenes during inhibition of dynamin-mediated endocytosis.

Thirteen Years of an International External Quality Assessment Scheme for Genotyping: Results and Recommendations

BACKGROUNDnSuboptimal laboratory procedures resulting in genotyping errors, misdiagnosis, or incorrect reporting bear greatly on a patients health management, therapeutic decisions made on their behalf, and ultimate outcome. Participation in external quality assessment (EQA) is a key element of quality assurance in molecular genetic diagnostics. Therefore, the Reference Institute for Bioanalytics has tried for 13 years to improve the quality of genetic testing by offering an EQA for different clinically relevant sequence variations.nnnMETHODSnWithin each of the biannual EQA schemes offered, up to 18 samples of lyophilized human genomic DNA were provided for up to 50 different molecular genetic tests. Laboratories were asked to use their routine procedures for genotyping. At least 2 expert peer assessors reviewed the final returns. Data from 2002 to 2014 were evaluated.nnnRESULTSnIn total, 82 462 reported results from 812 characterized samples were evaluated. Globally, the number of participants increased each year along with the number of sequence variations offered. The error rate decreased significantly over the years with an overall error rate of 1.44%. Additionally, a decreased error rate for samples repeated over time was noted. Interestingly, the error rate showed a high difference depending on the locus analyzed and the method used.nnnCONCLUSIONSnBased on the evaluation of this long-term EQA scheme, various recommendations can be given to improve the quality of molecular genetic testing, such as the use of 2 different methods for genotyping. Furthermore, some methods are inappropriate for analysis of certain sequence variations.

Indocyanine green tissue angiography affects anastomotic leakage after esophagectomy. A retrospective, case-control study

PURPOSEnOptimal perfusion of the gastric conduit during esophagectomy is elementary for the anastomotic healing since poor perfusion has been associated with increased morbidity due to anastomotic leaks. Until recently surgical experience was the main tool to assess the perfusion of the anastomosis. We hypothesized that anastomoses located in the zone of optimal ICG perfusion of the gastric conduit (optizone) have a reduced anastomotic leakage rate after esophagectomy.nnnMETHODSnIndocyanine green (ICG) fluorescence tissue angiography was used to evaluate the anastomotic perfusion in 35 patients undergoing esophagectomy with gastric conduit reconstruction. The transition point of the optizone to the malperfused area of the conduit was defined macroscopically and with the use of ICG angiography during the operation. The anastomosis was performed in the optizone whenever possible. The results of the ICG patients were retrospectively reviewed and compared with 55 patients previously operated without ICG angiography.nnnRESULTSnThe visual assessment of the conduit perfusion concurred with the ICG angiography in 27 cases. In 8 cases (22.8%) the ICG angiography deviated from the visual aspect. One case of anastomotic leakage was observed in the group of patients in which the anastomosis could be performed in the optizone (1/33; 3%) compared with 10 cases in the control group (18%; pxa0=xa00.04). In two cases we had to perform the anastomosis in an area of compromised ICG perfusion. Both patients developed an anastomotic leakage.nnnCONCLUSIONSnICG tissue angiography represents a feasible and reliable technical support in the evaluation of the anastomotic perfusion after esophagectomy. In this retrospective analysis we observed a significant decrease in anastomotic leakage rate when the anastomosis could be placed in the zone of good perfusion defined by ICG fluorescence. A prospective trial is needed in order to provide higher level evidence for the use of ICG fluorescence in reducing leakage rates after esophagectomy.

Tumor size and invasiveness matters for partial nephrectomy: External validation and modification of the arterial based complexity score

Outcome of partial nephrectomy (PN) depends on anatomic features of the renal tumor, which can be assessed by nephrometry scores. The aim was to externally validate and refine the Arterial Based Complexity (ABC) score and to compare it to established systems.

Interrupted versus continuous suturing for vesicourethral anastomosis during radical prostatectomy: protocol for a systematic review and meta-analysis

Introduction Radical prostatectomy is the mainstay of treatment for prostate cancer. The vesicourethral anastomosis is a critical step, which most likely impacts urinary continence and urethral stenosis. To date, it still remains unclear whether interrupted and continuous suturing for the anastomosis have different outcomes. Therefore, the aim of this systematic review and meta-analysis is to compare different suture techniques for vesicourethral anastomosis in terms of surgical and functional parameters. Methods and analysis A comprehensive literature search will be conducted covering MEDLINE, Embase, Web of Science, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. Studies comparing interrupted versus continuous suturing will be included in the analyses. No language restrictions will be applied. Screening, data extraction, statistical analysis and reporting will be done in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality assessment will be performed with the help of the Cochrane Collaboration’s tool for assessing risk of bias and the Newcastle-Ottawa Scale for assessing quality of non-randomised studies. The quality of evidence will be evaluated with the Grading of Recommendations Assessment, Development and Evaluation. The primary outcome will be the time until removal of the urinary catheter. Secondary outcomes include rate of extravasation, length of hospital stay, time needed to perform the anastomosis, continence level at defined postoperative intervals and development of urethral strictures. Quantitative analysis will be calculated if meaningful. Ethics and dissemination In order to meet the highest ethical and methodological standards. we followed the PRISMA Protocol 2015 checklist. Each item was answered appropriately. For systematic reviews the ethical issues are strictly methodological as only data that were published earlier will be used. The full manuscript will be submitted to a peer-reviewed journal. Furthermore, the results will be presented on national and international congresses. Trial registration number International prospective register of systematic reviews PROSPERO CRD42017076126.

Defining the target prior to prostate fusion biopsy: the effect of MRI reporting on cancer detection

PurposeDefinition of targets in multiparametric MRI (mpMRI) prior to MRI/TRUS fusion prostate biopsy either by urologist or radiologist, as a prose report or by illustration is crucial for accurate targeted biopsies (TB). The objective was to analyze the effect of MRI reporting on target definition and cancer detection.Methods202 patients underwent MRI/TRUS fusion biopsy with Artemis™ (Eigen, USA). mpMRI results were submitted in written form to urologists, who marked the targets in the proprietary software. An expert uroradiologist reviewed and marked mpMRI targets blinded to biopsy data. We compared number, localization and volume of targets between the observers and analyzed whether variations impaired TB results by bivariate and logistic regression models.ResultsInterobserver variability was moderate regarding number and low regarding localization of targets. Urologists overestimated target volumes significantly compared to radiologists (pu2009=u20090.045) and matching target volume between both observers was only 43.9%. Overall cancer detection rate was 69.8 and 52.0% by TB. A higher matching target volume was a significant predictor of cancer in TB (pu2009<u20090.001). Logistic regression revealed prostate volume and PI-RADS as independent predictors. Defining targets in incorrect T2w slices in the cranio-caudal axis are one presumable reason for missing cancer in TB.ConclusionsA high concordance of the target definition between radiologist and urologist is mandatory for accurate TB. Optimized ROI definition is recommended to improve TB results, preferably as contouring in MRI sequences by the radiologist or, if not feasible, by precise MRI reports including specific localization in sequence and slice as well as an illustration. High prostate volume and low PI-RADS score have to be considered as limiting factors for target definition.

Detecting Anti-IIa and Anti-Xa Direct Oral Anticoagulant (DOAC) Agents in Urine using a DOAC Dipstick

&NA; The assessment of the anticoagulant effect of direct oral anticoagulants (DOACs) can be important for rapid medical decision‐making, especially in patients needing immediate management. An assay that screens for the absence or presence of a DOAC would help accelerate treatment in these situations. Chromogenic and coagulation methods have several limitations, including limited accuracy, long turnaround time, and their need of specialized laboratories. Oral factor Xa and thrombin inhibitors are also eliminated by the kidneys and can be detected in patient urine samples using a single, rapid, sensitive, and patient‐specific qualitative assay. In these tests, the presence or absence of a DOAC in urine can be identified by visually observing specific colors after a few minutes. Several studies have demonstrated the robustness and repeatability of these assays. The specific colors of the test strip also detect creatinine in the urine, which shows whether DOAC excretion is reduced, thus suggesting renal impairment. Persons with amblyopia may use a specific reader. Current indications for using the DOAC Dipstick test include emergency medical situations with severe bleeding and thrombotic events or before urgent major surgical interventions to accelerate medical decision‐making.

Pediatric acute lymphoblastic leukemia—Conquering the CNS across the choroid plexus

Despite the high prevalence of central nervous system (CNS) involvement in relapsing pediatric acute lymphoblastic leukemia (ALL), our understanding of CNS invasion is still vague. As lymphoblasts have to overcome the physiological blood-CNS barriers to enter the CNS, we investigated the cellular interactions of lymphoblasts with the choroid plexus (CP) epithelium of the blood-cerebrospinal fluid barrier (BCSFB). Both a precurser B cell ALL (pB-ALL) cell line (SD-1) and a T cell ALL (T-ALL) cell line (P12-Ishikawa) were able to actively cross the CP epithelium in a human in vitro model. We could illustrate a transcellular and (supposedly) paracellular transmigration by 3-dimensional immunofluorescence microscopy as well as electron microscopy. Chemotactic stimulation with CXCL12 during this process led to a significantly increased transmigration and blocking CXCL12/CXCR4-signaling by the CXCR4-inhibitor AMD3100 inhibited this effect. However, CXCR4 expression in primary ALL samples did not correlate to CNS disease, indicating that CXCR4-driven CNS invasion across the BCSFB might be a general property of pediatric ALL. Notably, we present a unique in vitro BCSFB model suitable to study CNS invasion of lymphoblasts in a human setting, providing the opportunity to investigate experimental variables, which may determine CNS disease childhood ALL.

Patient Benefit Following Bimodal CI-provision: Self-reported Abilities vs. Hearing Status

Objectives: Patient-reported outcomes gain importance for the assessment of auditory abilities in cochlear implant users and for the evaluation of auditory rehabilitation. Aims of the study were to explore the interrelation of self-reported improvements in auditory ability with improvements in speech comprehension and to identify factors other than audiological improvement that affect self-reported auditory ability. Study Design: Explorative prospective analysis using a within-subjects repeated measures design. Setting: Academic tertiary care center. Participants: Twenty-seven adult participants with bilateral sensorineural hearing loss who received a HiRes 90K CI and continued use of a HA at the non-implanted ear (bimodal hearing). Intervention: Cochlear implantation. Main Outcome Measures: Self-reported auditory ability/disability assessed by the comparative version of the Speech, Spatial and Qualities of Hearing Scale (SSQ-B), and monosyllable as well as sentence comprehension in quiet and within speech modulated noise from different directions assessed pre- as well as 3 and 6 months post-implantation. Results: Data of 17 individuals were analyzed. At the endpoint of the study, improvement of self-reported auditory ability was significant. Regarding audiometric measures, significant improvement was seen for CI-aided pure tone thresholds, for monaural CI-assisted and bimodal sentence comprehension in quiet and in speech-modulated noise that was presented from the same source or at the side of the HA-ear. Correlations between self-reported and audiometric improvements remained weak, with the exception of the improvement seen for monaural CI-aided sentence comprehension in quiet and self-perceived improvement of sound quality. Considerable correlations existed between self-reported improvements and current level of depression and anxiety, and with general self-efficaciousness. Regression analyses substantiated a positive influence of self-efficaciousness on self-reported improvement in speech comprehension and between the improvement of monaural CI-aided sentence comprehension in quiet and perceived sound quality as well as a negative influence of anxiety on self-reported improvement in spatial hearing. Self-reported improvements were significantly better in the subgroup with intensive as compared to regular rehabilitation. Conclusions: Self-reported auditory ability/disability represents an important measure for the success of bimodal CI-provision. It is influenced by personal and mental health factors that may improve CI-rehabilitation results if addressed during rehabilitation.