Evaluation of systemic inflammation in response to remote ischemic preconditioning in patients undergoing transcatheter aortic valve replacement (TAVR).

BACKGROUND: Systemic inflammation can occur after transcatheter aortic valve replacement (TAVR) and correlates with adverse outcome. The impact of remote ischemic preconditioning (RIPC) on TAVR associated systemic inflammation is unknown and was focus of this study. METHODS: We performed a prospective controlled trial at a single center and included 66 patients treated with remote ischemic preconditioning (RIPC) prior to TAVR, who were matched to a control group by propensity score. RIPC was applied to the upper extremity using a conventional tourniquet. Definition of systemic inflammation was based on leucocyte count, C-reactive protein (CRP), procalcitonin (PCT) and interleukin-6 (IL-6), assessed in the first 5 days following the TAVR procedure. Mortality was determined within 6 months after TAVR. RIPC group and matched control group showed comparable baseline characteristics. RESULTS: Systemic inflammation occurred in 66% of all patients after TAVR. Overall, survival after 6 months was significantly reduced in patients with systemic inflammation. RIPC, in comparison to control, did not significantly alter the plasma levels of leucocyte count, CRP, PCT or IL-6 within the first 5 days after TAVR. Furthermore, inflammation associated survival after 6 months was not improved by RIPC. Of all peri-interventional variables assessed, only the amount of the applied contrast agent was connected to the occurrence of systemic inflammation. CONCLUSIONS: Systemic inflammation frequently occurs after TAVR and leads to increased mortality after 6 months. RIPC neither reduces the incidence of systemic inflammation nor improves inflammation associated patient survival within 6 months.

T-cell receptor-α repertoire of CD8+ T cells following allogeneic stem cell transplantation using next-generation sequencing.

Alloreactivity or opportunistic infections following allogeneic stem cell transplantation are difficult to predict and contribute to post-transplantation mortality. How these immune reactions result in changes to the T-cell receptor repertoire remains largely unknown. Using next-generation sequencing, the T-cell receptor alpha (TRα) repertoire of naïve and memory CD8+ T cells from 25 patients who had received different forms of allogeneic transplantation was analyzed. In parallel, reconstitution of the CD8+/CD4+ T-cell subsets was mapped using flow cytometry. When comparing the influence of anti-T-cell therapy, a delay in the reconstitution of the naïve CD8+ T-cell repertoire was observed in patients who received in vivo T-cell depletion using antithymocyte globulin or post-transplantation cyclophosphamide in case of haploidentical transplantation. Sequencing of the TRα identified a repertoire consisting of more dominant clonotypes (>1% of reads) in these patients at 6 and 18 months post transplantation. When comparing donor and recipient, approximately 50% and approximately 80% of the donors' memory repertoire were later retrieved in the naïve and memory CD8+ T-cell receptor repertoire of the recipients, respectively. Although there was a remarkable expansion of single clones observed in the recipients' memory CD8+ TRα repertoire, no clear association between graft-versus-host disease or cytomegalovirus infection and T-cell receptor diversity was identified. A lower TRα diversity was observed in recipients of a cytomegalovirus-seropositive donor (P=0.014). These findings suggest that CD8+ T-cell reconstitution in transplanted patients is influenced by the use of T-cell depletion or immunosuppression and the donor repertoire.

To what extent is the low anterior resection syndrome (LARS) associated with quality of life as measured using the EORTC C30 and CR38 quality of life questionnaires?

PURPOSE: Treatment of rectal cancer often results in disturbed anorectal function, which can be quantified by the Low Anterior Resection Syndrome (LARS) score. This study investigates the association of impaired anorectal function as measured with the LARS score with quality of life (QoL) as measured with the EORTC-QLQ-C30 and CR38 questionnaires. METHODS: All stoma-free patients who had undergone sphincter-preserving surgery for rectal cancer from 2000 to 2014 in our institution were retrieved from a prospective database. They were contacted by mail and asked to return the questionnaires. QoL was evaluated in relation to LARS and further patient- and treatment factors using univariate and multivariate analysis. RESULTS: Of the eligible patients (n = 331), 261 (78.8%) responded with a complete LARS score. Mean score for global QoL according to the EORTC-QLQ-C30 questionnaire was 63 ± 21 for all patients. If major LARS was present, mean score decreased to 56 ± 19 in contrast to 67 ± 20 in patients with no/minor LARS (p < 0.001). In regression analysis, major LARS was furthermore associated with reduced physical, role, emotional, cognitive and social functioning as well as impaired body image, more micturition problems and poorer future perspective. It was not related to sexual function. The variance explained by major LARS in the differences of QoL was approximately 10%. CONCLUSION: The presence of major LARS after rectal resection for cancer is negatively associated with global health as well as many other aspects of QoL. Preserving anorectal function and treatment of LARS are potential measures to improve QoL in this patient group.

Normothermia after decompressive surgery for space-occupying middle cerebral artery infarction: a protocol-based approach.

BACKGROUND: Moderate hypothermia after decompressive surgery might not be beneficial for stroke patients. However, normothermia may prove to be an effective method of enhancing neurological outcomes. The study aims were to evaluate the application of a pre-specified normothermia protocol in stroke patients after decompressive surgery and its impact on temperature load, and to describe the functional outcome of patients at 12 months after treatment. METHODS: We analysed patients with space-occupying middle cerebral artery (MCA) infarction treated with decompressive surgery and a pre-specified temperature management protocol. Patients treated primarily with device-controlled normothermia or hypothermia were excluded. The individual temperature load above 36.5 °C was calculated for the first 96 h after hemicraniectomy as the Area Under the Curve, using °C x hours. The effect of temperature load on functional outcome at 12 months was analysed by logistic regression. RESULTS: We included 40 stroke patients treated with decompressive surgery (mean [SD] age: 58.9 [10.1] years; mean [SD] time to surgery: 30.5 [16.7] hours). Fever (temperature > 37.5 °C) developed in 26 patients during the first 96 h after surgery and mean (SD) temperature load above 36.5 °C in this time period was 62,3 (+/- 47,6) °C*hours. At one year after stroke onset, a moderate to moderately severe disability (modified Rankin Scale score of 3 or 4) was observed in 32% of patients, and a severe disability (score of 5) in 37% of patients, respectively. The lethality in the cohort at 12 months was 32%. The temperature load during the first 96 h was not an independent predictor for 12 month lethality (OR 0.986 [95%-CI:0.967-1.002]; p < 0.12). CONCLUSIONS: Temperature control in surgically treated patients with space-occupying MCA infarction using a pre-specified protocol excluding temperature management systems resulted in mild hyperthermia between 36.8 °C and 37.2 °C and a low overall temperature load. Future prospective studies on larger cohorts comparing different strategies for normothermia treatment including temperature management devices are needed.

Decannulation and Functional Outcome After Tracheostomy in Patients with Severe Stroke (DECAST): A Prospective Observational Study.

BACKGROUND: Tracheostomy is performed in ventilated stroke patients affected by persisting severe dysphagia, reduced level of consciousness, or prolonged mechanical ventilation. The study aim was to determine the frequency and predictors of successful decannulation and long-term functional outcome in tracheotomized stroke patients. METHODS: A prospective single-center observational study recruited ventilated patients with ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Follow-up visits were performed at hospital discharge, 3, and 12 months. Competing risk analyses were performed to identify predictors of decannulation. RESULTS: We included 53 ventilated stroke patients who had tracheostomy. One year after tracheostomy, 19 patients were decannulated (median [IQR] time to decannulation 74 [58-117] days), 13 patients were permanently cannulated, and 21 patients died without prior removal of the cannula. Independent predictors for decannulation in our cohort were patient age (HR 0.95 [95% CI: 0.92-0.99] per one year increase, p = 0.003) and absence of sepsis (HR 4.44 [95% CI: 1.33-14.80], p = 0.008). Compared to surviving patients without cannula removal, decannulated patients had an improved functional outcome after one year (median modified Rankin Scale score 4 vs. 5 [p < 0.001]; median Barthel index 35 vs. 5 [p < 0.001]). CONCLUSIONS: Decannulation was achieved in 59.4% of stroke patients surviving the first 12 months after tracheostomy and was associated with better functional outcome compared to patients without decannulation. Further prospective studies with larger sample sizes are needed to confirm our results.

Combining user logging with eye tracking for interactive and dynamic applications.

User evaluations of interactive and dynamic applications face various challenges related to the active nature of these displays. For example, users can often zoom and pan on digital products, and these interactions cause changes in the extent and/or level of detail of the stimulus. Therefore, in eye tracking studies, when a user's gaze is at a particular screen position (gaze position) over a period of time, the information contained in this particular position may have changed. Such digital activities are commonplace in modern life, yet it has been difficult to automatically compare the changing information at the viewed position, especially across many participants. Existing solutions typically involve tedious and time-consuming manual work. In this article, we propose a methodology that can overcome this problem. By combining eye tracking with user logging (mouse and keyboard actions) with cartographic products, we are able to accurately reference screen coordinates to geographic coordinates. This referencing approach allows researchers to know which geographic object (location or attribute) corresponds to the gaze coordinates at all times. We tested the proposed approach through two case studies, and discuss the advantages and disadvantages of the applied methodology. Furthermore, the applicability of the proposed approach is discussed with respect to other fields of research that use eye tracking-namely, marketing, sports and movement sciences, and experimental psychology. From these case studies and discussions, we conclude that combining eye tracking and user-logging data is an essential step forward in efficiently studying user behavior with interactive and static stimuli in multiple research fields.

Severe methotrexate toxicity in elderly patients under diuretics.

OBJECTIVES: To explore the toxicity of low-dose methotrexate (MTX), an uncommon, but life-threatening event. METHODS: We analysed the presentation, course and risk factors of all patients admitted to the rheumatology ward with severe low-dose MTX toxicity. These patients were compared with patients without signs of relevant MTX toxicity. RESULTS: The 12 patients admitted for MTX toxicity included 7 patients with rheumatoid arthritis, 2 with psoriatic arthritis or psoriasis, 2 patients with giant cell arteritis and 1 with myositis. 1 patient died from infections, while 11 survived under folinic acid administration. All patients suffering from severe MTX toxicity were older than 70 years and were therefore compared with 400 patients who were also older than 70 years, but without MTX toxicity. Of these 400 control patients, the group of patients not on MTX (n=232) had more renal impairment than the group of patients on MTX (n=168). Compared with the 168 MTX-treated patients without toxicity, the 12 patients with life-threatening toxic events had a lower median estimated glomerular filtration rate (eGFR) at the routine visit preceding the acute event (64 (range 32-77) vs 69 (range 8 to >90) mL/min x 1.73, p=0.0251). A multivariate analysis found that patients with toxicity were more frequently treated with diuretics (6/12 vs 24/168), proton pump inhibitors (PPIs; 10/12 vs 70/168) and levetiracetam (2/12 vs 1/168). CONCLUSIONS: Patients older than 70 years with lower eGFR and being on diuretics, but also on PPIs and levetiracetam, have a significantly higher risk for MTX toxicity.

[Handover protocols in the emergency department]. / Übergabe und Übergabeschemata in der Notaufnahme.

Patient handovers are a vital juncture in the flow of medical information, and regardless of the mode of handover-oral, written, or combined-it often poses a risk of information loss. This could potentially jeopardize patient safety and influences subsequent treatment. The exchange of information in emergency care settings between paramedics and emergency personnel is particularly prone to errors due to situational specifics such as high ambient noise, the involvement of multiple disciplines, and the need for urgent decision-making in life-threatening situations. As handover training is not yet universally incorporated into education and ongoing training programs, there is a high degree of variability in how it is carried out in practice. However, strategies aimed at enhancing the handover process carry substantial potential for improving staff satisfaction, process quality, and possibly even having a positive prognostic impact.

Proximal tibia for alveolar augmentation and augmentative rhinoplasty-a suitable option? A retrospective clinical study on donor and recipient site morbidity.

BACKGROUND: Autologous bone grafts are essential in reconstructive oral and maxillofacial surgery, and depending on the donor site, they can be associated with specific harvesting morbidities. One of the most commonly applied bone grafts is the iliac crest bone graft, irrespective of other grafts, which might be associated with an easier surgical procedure or the possibility of harvesting them under local anaesthesia. Objective of the study is the clinical evaluation of proximal tibia bone grafts regarding their eligibility for maxillofacial bone grafting. METHODS: In this retrospective study, proximal tibia bone grafts were examined with regard to associated donor and recipient site morbidity and their suitability for alveolar ridge augmentation and rhinoplasty. RESULTS: In total, 21 tibia grafts were included. Fifty-seven percent of the bone grafts were used for alveolar ridge reconstruction, and 43% were used for augmentative rhinoplasty. No significant complications occurred during or after harvesting, but in 14.3% of the patients, minor wound healing disorders were recorded at the donor site, and in 19% of the patients, they were recorded at the recipient site. Statistically, patient sex, age, nicotine and alcohol abuse and metabolic diseases had no significant influence on the complication rate. Graft harvesting under local anaesthesia and at summer temperatures was associated with significantly more complications at the harvesting site (p < 0.05). In cases of dental implant insertion into augmented sites, the implants (n = 31) were followed up for a median period of 40.5 months, during this time 86.7% of the implants survived. CONCLUSION: The proximal tibia is a suitable donor site for harvesting autologous bone grafts for alveolar ridge augmentation or rhinoplasty because the donor site morbidity is low, and in contrast to iliac crest bone grafts, they can be harvested under local anaesthesia, which might be advantageous for outpatient surgeries.

Expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells regulates proliferation, differentiation, and maintenance of hematopoietic stem and progenitor cells.

The melanoma cell adhesion molecule defines mesenchymal stromal cells in the human bone marrow that regenerate bone and establish a hematopoietic microenvironment in vivo. The role of the melanoma cell adhesion molecule in primary human mesenchymal stromal cells and the maintenance of hematopoietic stem and progenitor cells during ex vivo culture has not yet been demonstrated. We applied RNA interference or ectopic overexpression of the melanoma cell adhesion molecule in human mesenchymal stromal cells to evaluate the effect of the melanoma cell adhesion molecule on their proliferation and differentiation as well as its influence on co-cultivated hematopoietic stem and progenitor cells. Knockdown and overexpression of the melanoma cell adhesion molecule affected several characteristics of human mesenchymal stromal cells related to osteogenic differentiation, proliferation, and migration. Furthermore, knockdown of the melanoma cell adhesion molecule in human mesenchymal stromal cells stimulated the proliferation of hematopoietic stem and progenitor cells, and strongly reduced the formation of long-term culture-initiating cells. In contrast, melanoma cell adhesion molecule-overexpressing human mesenchymal stromal cells provided a supportive microenvironment for hematopoietic stem and progenitor cells. Expression of the melanoma cell adhesion molecule increased the adhesion of hematopoietic stem and progenitor cells to human mesenchymal stromal cells and their migration beneath the monolayer of human mesenchymal stromal cells. Our results demonstrate that the expression of the melanoma cell adhesion molecule in human mesenchymal stromal cells determines their fate and regulates the maintenance of hematopoietic stem and progenitor cells through direct cell-cell contact.

Malignancy in chronic pancreatitis: analysis of diagnostic procedures and proposal of a clinical algorithm.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis, and some benign conditions and syndromes, including chronic pancreatitis (CP), are risk factors for pancreatic carcinoma. However, the differential diagnosis of CP from PDAC is difficult for clinicians because PDAC frequently causes inflammation within the pancreas. Therefore, patients with CP exhibit not only an elevated risk of cancer, but they are also in danger of underdiagnosis. METHODS: The present study retrospectively analyzed 29 patients with pancreatic cancer who fulfilled our definition of "chronic pancreatitis" to identify characteristics to aid in the differential diagnosis between chronic pancreatitis with and without pancreatic cancer. All parameters were subjected to univariate analysis. RESULTS: We identified several factors that differed significantly between the CP patients and patients with CP and synchronous PDAC, and these characteristics were used to develop a diagnostic algorithm. The performance of the algorithm was externally validated in a different panel of patients from the Department of Surgery, Medical Faculty Mannheim. CONCLUSION: The present study succeeded in identifying characteristics that significantly differed in patients with and without PDAC in CP. These characteristics were integrated in a diagnostic algorithm that might help to improve diagnostic of PDAC in CP.

Significant decrease of the pathological stage I rectal carcinoma in the era of neoadjuvant therapy-A matter of concern.

BACKGROUND: Neoadjuvant treatment (nTx) for rectal cancer is commonly reserved for UICC stages II/III. Patients with stage I tumours (T1-2N0M0) are not candidates for nTx. The accuracy of treatment allocation depends on the precision of clinical staging, which is liable to understaging and overstaging. The study aimed at exploring changes in the proportion of stage pI patients with the introduction of nTx over a 26-year period. MATERIALS AND METHODS: All consecutive patients with histologically proven rectal cancer excluding carcinoma in situ were retrieved from a prospective database of our colorectal unit. Time periods were defined as per the use of nTx: baseline phase 1994-1997; implementation phase 1998-2005 and guideline phase 2006-2019. Trends over time regarding proportion of applied nTx and stage pI tumours were investigated. RESULTS: Overall, 1468 patients met the inclusion criteria. There were no major differences in patients' characteristics, especially proportion of synchronous metastases (stage IV) over time. nTx was applied to 1.2% of patients without metastases in the baseline phase, to 29.6% in the implementation phase, and to 59.6% in the guideline phase (p < 0.001). Corresponding proportions for patients with stage pI were 31.0%, 26.3% and 14.2%, respectively (p < 0.001). CONCLUSION: With a stable proportion of stage IV carcinomas indicating no major changes in the patient cohorts, we could document a significant decrease of stage pI patients with increasing use of nTx. This trend clearly signals overtreatment caused by clinical T- and N-staging. More precise criteria are needed to better select patients with rectal cancer for nTx.

Team Prenotification Reduces Procedure Times for Patients With Acute Ischemic Stroke Due to Large Vessel Occlusion Who Are Transferred for Endovascular Therapy.

Background: The clinical benefit from endovascular therapy (EVT) for patients with acute ischemic stroke is time-dependent. We tested the hypothesis that team prenotification results in faster procedure times prior to initiation of EVT. Methods: We analyzed data from our prospective database (01/2016-02/2018) including all patients with acute ischemic stroke who were evaluated for EVT at our comprehensive stroke center. We established a standardized algorithm (EVT-Call) in 06/2017 to prenotify team members (interventional neuroradiologist, neurologist, anesthesiologist, CT and angiography technicians) about patient transfer from remote hospitals for evaluation of EVT, and team members were present in the emergency department at the expected patient arrival time. We calculated door-to-image, image-to-groin and door-to-groin times for patients who were transferred to our center for evaluation of EVT, and analyzed changes before (-EVT-Call) and after (+EVT-Call) implementation of the EVT-Call. Results: Among 494 patients in our database, 328 patients were transferred from remote hospitals for evaluation of EVT (208 -EVT-Call and 120 +EVT-Call, median [IQR] age 75 years [65-81], NIHSS score 17 [12-22], 49.1% female). Of these, 177 patients (54%) underwent EVT after repeated imaging at our center (111/208 [53%) -EVT-Call, 66/120 [55%] +EVT-Call). Median (IQR) door-to-image time (18 min [14-22] vs. 10 min [7-13]; p < 0.001), image-to-groin time (54 min [43.5-69.25] vs. 47 min [38.3-58.75]; p = 0.042) and door-to-groin time (74 min [58-86.5] vs. 60 min [49.3-71]; p < 0.001) were reduced after implementation of the EVT-Call. Conclusions: Team prenotification results in faster patient assessment and initiation of EVT in patients with acute ischemic stroke. Its impact on functional outcome needs to be determined.

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing.

The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 (TBL1XR1) and cAMP response element binding protein (CREBBP), we newly identifed JAK3 as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, JAK3 mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5-10% of cases included members of the collagen family (collagen type XII alpha 1/2 (COL12A1, COL1A2)) and DOCK8. Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of TNFAIP3, and revealed recurrent gains of the NOTCH target HES4, and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (>10% of cases) mutated protein-coding genes in OAML is now largely known.

Asleep at the automated wheel-Sleepiness and fatigue during highly automated driving.

Due to the lack of active involvement in the driving situation and due to monotonous driving environments drivers with automation may be prone to become fatigued faster than manual drivers (e.g. Schömig et al., 2015). However, little is known about the progression of fatigue during automated driving and its effects on the ability to take back manual control after a take-over request. In this driving simulator study with Nö=ö60 drivers we used a three factorial 2ö×ö2ö×ö12 mixed design to analyze the progression (12ö×ö5ömin; within subjects) of driver fatigue in drivers with automation compared to manual drivers (between subjects). Driver fatigue was induced as either mainly sleep related or mainly task related fatigue (between subjects). Additionally, we investigated the drivers' reactions to a take-over request in a critical driving scenario to gain insights into the ability of fatigued drivers to regain manual control and situation awareness after automated driving. Drivers in the automated driving condition exhibited facial indicators of fatigue after 15 to 35ömin of driving. Manual drivers only showed similar indicators of fatigue if they suffered from a lack of sleep and then only after a longer period of driving (approx. 40ömin). Several drivers in the automated condition closed their eyes for extended periods of time. In the driving with automation condition mean automation deactivation times after a take-over request were slower for a certain percentage (about 30%) of the drivers with a lack of sleep (Mö=ö3.2; SDö=ö2.1ös) compared to the reaction times after a long drive (Mö=ö2.4; SDö=ö0.9ös). Drivers with automation also took longer than manual drivers to first glance at the speed display after a take-over request and were more likely to stay behind a braking lead vehicle instead of overtaking it. Drivers are unable to stay alert during extended periods of automated driving without non-driving related tasks. Fatigued drivers could pose a serious hazard in complex take-over situations where situation awareness is required to prepare for threats. Driver fatigue monitoring or controllable distraction through non-driving tasks could be necessary to ensure alertness and availability during highly automated driving.

Sequential H. pylori eradication and radiation therapy with reduced dose compared to standard dose for gastric MALT lymphoma stages IE & II1E: a prospective randomized trial.

BACKGROUND: In Helicobacter pylori (H. pylori) positive stage I gastric low-grade MALT lymphoma, eradication is the accepted first-line therapy. The role of eradication therapy in lymphoma > stage IE is still unclear. However, about 20% of patients show persistent lymphoma following successful eradication or primary H. pylori-negative lymphoma. A prospective study for salvage radiation therapy with standard 36 Gy in comparison to a reduced dose of 25.2 Gy is still missing. METHODS: A prospective, multicentre study investigated the efficacy of eradication in H. pylori-positive gastric low-grade MALT lymphoma stages IE and II1E (HELYX I). Refractory lymphoma or H. pylori-negative patients were treated in a prospective, randomised, multicentre, phase II study to receive either 25.2 Gy or 36 Gy radiotherapy (HELYX II). RESULTS: 102 patients (3 drop outs) were included in HELYX I: 75/99 (75.8%) showed complete remission after a median of 2.8 months. 18 (18.2%) had partial remission (PR) and 6 (6.0%) no change (NC). 29 patients (7 drop outs) were randomized in HELYX II (7 primarily H. pylori-negative, 15 patients from HELYX I with refractory disease after eradication). All patients achieved stable CR irrespective of radiation dose. Both presence of the t(11,18) translocation (OR 9.0, p = 0.01) and monoclonality of the tumour cells (OR 6.3, p = 0.006) were predictors for persistant lymphoma after eradication therapy. CONCLUSIONS: Most H. pylori-positive low grade gastric MALT lymphoma stage IE and II1E respond with stable CR after eradication therapy. In patients with refractory disease or H. pylori negative low grade gastric MALT lymphoma a dosage-reduced radiation therapy with 25.2 Gy is an effective standard dose in stage IE and II1E. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00154440.

Clinical evaluation of ketamine and lidocaine intravenous infusions to reduce isoflurane requirements in horses under general anaesthesia.

OBJECTIVE: To compare isoflurane alone or in combination with systemic ketamine and lidocaine for general anaesthesia in horses. STUDY DESIGN: Prospective, randomized, blinded clinical trial. ANIMALS: Forty horses (ASA I-III) undergoing elective surgery. METHODS: Horses were assigned to receive isoflurane anaesthesia alone (ISO) or with ketamine and lidocaine (LKI). After receiving romifidine, diazepam, and ketamine, the isoflurane end-tidal concentration was set at 1.3% and subsequently adjusted by the anaesthetist (unaware of treatments) to maintain a light plane of surgical anaesthesia. Animals in the LKI group received lidocaine (1.5 mg kg(-1) over 10 minutes, followed by 40 microg kg(-1) minute(-1)) and ketamine (60 microg kg(-1) minute(-1)), both reduced to 65% of the initial dose after 50 minutes, and stopped 15 minutes before the end of anaesthesia. Standard clinical cardiovascular and respiratory parameters were monitored. Recovery quality was scored from one (very good) to five (very poor). Differences between ISO and LKI groups were analysed with a two-sample t-test for parametric data or a Fischer's exact test for proportions (p < 0.05 for significance). Results are mean +/- SD. RESULTS: Heart rate was lower (p = 0.001) for LKI (29 +/- 4) than for ISO (34 +/- 6). End-tidal concentrations of isoflurane (ISO: 1.57% +/- 0.22; LKI: 0.97% +/- 0.33), the number of horses requiring thiopental (ISO: 10; LKI: 2) or dobutamine (ISO:8; LKI:3), and dobutamine infusion rates (ISO:0.26 +/- 0.09; LKI:0.18 +/- 0.06 microg kg(-1) minute(-1)) were significantly lower in LKI compared to the ISO group (p < 0.001). No other significant differences were found, including recovery scores. CONCLUSIONS AND CLINICAL RELEVANCE: These results support the use of lidocaine and ketamine to improve anaesthetic and cardiovascular stability during isoflurane anaesthesia lasting up to 2 hours in mechanically ventilated horses, with comparable quality of recovery.

Cerebral Venous Drainage in Patients With Space-Occupying Middle Cerebral Artery Infarction: Effects on Functional Outcome After Hemicraniectomy.

Background: Cerebral venous drainage might influence brain edema characteristics and functional outcome of patients with severe ischemic stroke. The purpose of the study was to evaluate whether hypoplasia of transverse sinuses or the internal jugular veins is associated with poor functional outcome in patients with space-occupying middle cerebral artery (MCA) infarction who underwent decompressive surgery. Methods: We performed a retrospective analysis of patients with space-occupying MCA infarction treated with decompressive surgery at our university hospital. The transverse sinuses and the internal jugular veins were evaluated on baseline images and categorized as normal, hypoplastic or occluded. We defined composite variables for ipsilateral, contralateral or any abnormal cerebral venous drainage. We assessed the functional outcome at 12 months with the modified Rankin scale (mRS) score and defined poor functional outcome as mRS scores 5 and 6. Results: We analyzed 88 patients with available baseline imaging data [mean [SD] patient age 53 (±9) years; median[IQR] time to decompressive surgery 31(22-51) h]. At 12 months 44 patients (50%) had a poor outcome. In univariate analysis neither ipsilateral (OR 1.98;95%CI: 0.75-5.40), nor contralateral (OR 1.56;95%CI: 0.59-4.24) or any (OR 1.6; 95%CI: 0.68-3.79) hypoplasia or occlusion of venous drainage were significantly associated with poor functional outcome. In multivariate analyses, higher patient age (OR 1.07;95%CI 1.01-1.14) and baseline stroke severity (OR 3.42;95%CI 1.31-9.40) were independent predictors of poor functional outcome, but not ipsilateral hypoplasia or occlusion of venous drainage (OR 1.31;95%CI 0.47-3.67). Conclusions: The cerebral venous drainage pattern was not significantly associated with poor functional outcome in our cohort of patients with space-occupying MCA infarction who underwent decompressive surgery.

Quantitative prediction of long-term molecular response in TKI-treated CML - Lessons from an imatinib versus dasatinib comparison.

Longitudinal monitoring of BCR-ABL transcript levels in peripheral blood of CML patients treated with tyrosine kinase inhibitors (TKI) revealed a typical biphasic response. Although second generation TKIs like dasatinib proved more efficient in achieving molecular remission compared to first generation TKI imatinib, it is unclear how individual responses differ between the drugs and whether mechanisms of drug action can be deduced from the dynamic data. We use time courses from the DASISION trial to address statistical differences in the dynamic response between first line imatinib vs. dasatinib treatment cohorts and we analyze differences between the cohorts by fitting an established mathematical model of functional CML treatment to individual time courses. On average, dasatinib-treated patients show a steeper initial response, while the long-term response only marginally differed between the treatments. Supplementing each patient time course with a corresponding confidence region, we illustrate the consequences of the uncertainty estimate for the underlying mechanisms of CML remission. Our model suggests that the observed BCR-ABL dynamics may result from different, underlying stem cell dynamics. These results illustrate that the perception and description of CML treatment response as a dynamic process on the level of individual patients is a prerequisite for reliable patient-specific response predictions and treatment optimizations.