Association Between Urinary Catecholamine Excretion and Urine Volume.

Several confounders must be considered in the evaluation of urinary catecholamine excretion. However, literature is contradictory about potential confounders. The aim of the present study was to assess correlations between catecholamine excretion and anthropometric or clinical parameters with special attention to urine volume. A total of 967 24-h urinary catecholamine measurements were performed in 593 patients for diagnostic purposes. The indication for urine examination was suspicion of secondary hypertension, phaeochromocytoma, or paraganglioma. From the patients examined, 57% were females and 43% were males. The patients' age ranged between 15 and 87 years with a median [Q1; Q3] of 51 [39; 62] years. Seventy-eight percent of the patients suffered from hypertension. Seventy percent of patients took one or more antihypertensive drugs. The most commonly used drugs were ACE inhibitors (43%), while α-blockers (15%) were the least used drugs. Urinary excretion was between 500 and 11 950 ml/24 h with a median of 2200 [1600; 2685] ml/24 h. The median body mass index (BMI) was 26.7 [24.0; 30.4] kg/m2. The excretion of all catecholamines was greater in men than in women (all p<0.0001). Epinephrine (p=0.0026), dopamine (p<0.0001), and metanephrine (p=0.0106) excretion decreased with age. BMI was associated with urinary excretion of dopamine (p<0.0001), norepinephrine (p=0.0026), normetanephrine (p<0.0001), and homovanillylmandelic acid (HVMA; p=0.0251). Urine volume correlated with urinary dopamine (p=0.0127), metanephrine (p<0.0001), normetanephrine (p=0.0070), and HVMA (p<0.0028) excretion. In addition to the established associations between urinary catecholamine excretion and age, gender, and BMI in the present study, urinary catecholamine excretion correlated also with urine volume.

Elimination of Contrast Agent Gadobutrol with Sustained Low Efficiency Daily Dialysis Compared to Intermittent Hemodialysis.

BACKGROUND: In patients with renal failure, gadolinium-based contrast agents (GBCA) can be removed by intermittent hemodialysis (iHD) to prevent possible toxic effects. There is no data on the efficacy of GBCA removal via sustained low efficiency daily dialysis (SLEDD) which is mainly used in intensive care unit (ICU) patients. METHODS: We compared the elimination of the GBCA gadobutrol in 6 ICU patients treated with SLEDD (6-12 h, 90 L dialysate) with 7 normal ward inpatients treated with iHD (4 h, dialysate flow 500 mL/min). Both groups received 3 dialysis sessions on 3 consecutive days starting after the application of gadobutrol. Blood samples were drawn before and after each session and total dialysate, as well as urine was collected. Gadolinium (Gd) concentrations were measured using mass spectrometry and eliminated Gd was calculated from dialysate and urine. RESULTS: The initial mean plasma Gd concentration was 385 ± 183 µM for the iHD and 270 ± 97 µM for the SLEDD group, respectively (p > 0.05). The Gd-reduction rate after the first dialysis session was 83 ± 9 and 67 ± 9% for the iHD and the SLEDD groups, respectively (p = 0.0083). The Gd-reduction rate after the second and third dialysis was 94-98 and 89-96% for the iHD and the SLEDD groups (p > 0.05). The total eliminated Gd was 89 ± 14 and 91 ± 4% of the dose in the iHD and the SLEDD groups, respectively (p > 0.05). Gd dialyzer clearance was 95 ± 22 mL/min and 79 ± 19 mL/min for iHD and SLEDD, respectively (p > 0.05). CONCLUSIONS: Gd-elimination with SLEDD is equally effective as iHD and can be safely used to remove GBCA in ICU patients.

Potential role of CT-textural features for differentiation between viral interstitial pneumonias, pneumocystis jirovecii pneumonia and diffuse alveolar hemorrhage in early stages of disease: a proof of principle.

BACKGROUND: Pulmonary involvement is common in several infectious and non-infectious diagnostic settings. Imaging findings consistently overlap and are therefore difficult to differentiate by chest-CT. The aim of this study was to evaluate the role of CT-textural features(CTTA) for discrimination between atypical viral (respiratory-syncitial-virus(RSV) and herpes-simplex-1-virus (HSV1)), fungal (pneumocystis-jirovecii-pneumonia(PJP)) interstitial pneumonias and alveolar hemorrhage. METHODS: By retrospective single-centre analysis we identified 46 consecutive patients (29 m) with RSV(n = 5), HSV1(n = 6), PJP(n = 21) and lung hemorrhage(n = 14) who underwent unenhanced chest CTs in early stages of the disease between 01/2016 and 02/2017. All cases were confirmed by microbiologic direct analysis of bronchial lavage. On chest-CT-scans, the presence of imaging features like ground-glass opacity(GGO), crazy-paving, air-space consolidation, reticulation, bronchial wall thickening and centrilobular nodules were described. A representative large area was chosen in both lungs and used for CTTA-parameters (included heterogeneity, intensity, average, deviation, skewness). RESULTS: Discriminatory CTTA-features were found between alveolar hemorrhage and PJP consisting of differences in mean heterogeneity(p < 0.015) and uniformity of skewness(p < 0.006). There was no difference between CT-textural features of diffuse alveolar hemorrhage and viral pneumonia or PJP and viral pneumonia. Visual HRCT-assessment yielded great overlap of imaging findings with predominance of GGO for PJP and airspace consolidation for pneumonia/alveolar hemorrhage. Significant correlations between HRCT-based imaging findings and CT-textural features were found for all three disease groups. CONCLUSION: CT-textural features showed significant differences in mean heterogeneity and uniformity of skewness. HRCT-based imaging findings correlated with certain CT-textural features showing that the latter have the potential to characterize structural properties of lung parenchyma and related abnormalities.

Quality Control of Serum and Plasma by Quantification of (4E,14Z)-Sphingadienine-C18-1-Phosphate Uncovers Common Preanalytical Errors During Handling of Whole Blood.

BACKGROUND: Nonadherence to standard operating procedures (SOPs) during handling and processing of whole blood is one of the most frequent causes affecting the quality of serum and plasma. Yet, the quality of blood samples is of the utmost importance for reliable, conclusive research findings, valid diagnostics, and appropriate therapeutic decisions. METHODS: UHPLC-MS-driven nontargeted metabolomics was applied to identify biomarkers that reflected time to processing of blood samples, and a targeted UHPLC-MS analysis was used to quantify and validate these biomarkers. RESULTS: We found that (4E,14Z)-sphingadienine-C18-1-phosphate (S1P-d18:2) was suitable for the reliable assessment of the pronounced changes in the quality of serum and plasma caused by errors in the phase between collection and centrifugation of whole blood samples. We rigorously validated S1P-d18:2, which included the use of practicality tests on >1400 randomly selected serum and plasma samples that were originally collected during single- and multicenter trials and then stored in 11 biobanks in 3 countries. Neither life-threatening disease states nor strenuous metabolic challenges (i.e., high-intensity exercise) affected the concentration of S1P-d18:2. Cutoff values for sample assessment were defined (plasma, ≤0.085 µg/mL; serum, ≤0.154 µg/mL). CONCLUSIONS: Unbiased valid monitoring to check for adherence to SOP-dictated time for processing to plasma or serum and/or time to storage of whole blood at 4 °C is now feasible. This novel quality assessment step could enable scientists to uncover common preanalytical errors, allowing for identification of serum and plasma samples that should be excluded from certain investigations. It should also allow control of samples before long-term storage in biobanks.

Clinical outcome and paravalvular leakage of the new balloon-expandable Edwards Sapien 3 valve in comparison to its predecessor model (Edwards Sapien XT) in patients undergoing transfemoral aortic valve replacement.

OBJECTIVES: The aim of this study was to compare the 30-day procedural, clinical and echocardiographic outcome of the new balloon-expandable Edwards Sapien 3 (ES3) valve with the Edwards Sapien XT (ESXT). BACKGROUND: Post-implant paravalvular leaks (PVL) after transfemoral aortic valve replacement (TAVR) resulting in residual aortic regurgitation (AR) are a major limitation for long term outcome. New TAVR-devices have to eliminate this problem. METHODS: Transfemoral TAVR was performed in 209 consecutive intermediate-high-risk surgical patients (pts) with symptomatic aortic stenosis (ESXT n = 102, ES3 n = 107). Transthoracic echocardiography (TTE) and 3-dimensional computed tomography were used for valve size selection. Primary endpoint of the study was none/trace AR derived by TTE 30-days after TAVR. RESULTS: All pts underwent successfully TAVR with a combined device success of 100/102 (99%) in ESXT and 107/107 (100%) in ES3 pts. Fluoroscopy time (ESXT 11.8 ± 0.5 min vs. ES3 10.0 ± 0.5 min, P = 0.003) and contrast (ESXT 188.9 ± 5.6 mL vs. ES3 170.4 ± 4.7 mL, P = 0.04) were significantly lower in ES3 patients. 30-day clinical events did not differ. Transvalvular mean pressure gradients were significantly reduced to 7.4 ± 0.8 mmHg after ESXT and to 10.1± 0.4 mmHg after ES3 implantation. After 30 days none/trace AR was found in 34.3% (n = 35) of all ESXT pts in contrast to 89.7% (n = 96) of all ES3 patients. Moderate-to-severe AR was found rarely (ESXT 2.9% vs. ES3 0%, P = 0.073). CONCLUSIONS: Although there was no significant difference in 30 day mortality, the newer ES3 valve reduced significantly residual paravalvular leakage. © 2016 Wiley Periodicals, Inc.

Nasal high-flow oxygen therapy in patients with hypoxic respiratory failure: effect on functional and subjective respiratory parameters compared to conventional oxygen therapy and non-invasive ventilation (NIV).

BACKGROUND: Aim of the study was to compare the short-term effects of oxygen therapy via a high-flow nasal cannula (HFNC) on functional and subjective respiratory parameters in patients with acute hypoxic respiratory failure in comparison to non-invasive ventilation (NIV) and standard treatment via a Venturi mask. METHODS: Fourteen patients with acute hypoxic respiratory failure were treated with HFNC (FiO2 0.6, gas flow 55 l/min), NIV (FiO2 0.6, PEEP 5 cm H2O Hg, tidal volume 6-8 ml/kg ideal body weight,) and Venturi mask (FiO2 0.6, oxygen flow 15 l/min,) in a randomized order for 30 min each. Data collection included objective respiratory and circulatory parameters as well as a subjective rating of dyspnea and discomfort by the patients on a 10-point scale. In a final interview, all three methods were comparatively evaluated by each patient using a scale from 1 (=very good) to 6 (=failed) and the patients were asked to choose one method for further treatment. RESULTS: PaO2 was highest under NIV (129 ± 38 mmHg) compared to HFNC (101 ± 34 mmHg, p <0.01 vs. NIV) and VM (85 ± 21 mmHg, p <0.001 vs. NIV, p <0.01 vs. HFNC, ANOVA). All other functional parameters showed no relevant differences. In contrast, dyspnea was significantly better using a HFNC (2.9 ± 2.1, 10-point Borg scale) compared to NIV (5.0 ± 3.3, p <0.05), whereas dyspnea rating under HFNC and VM (3.3 ± 2.3) was not significantly different. A similar pattern was found when patients rated their overall discomfort on the 10 point scale: HFNC 2.7 ± 1.8, VM 3.1 ± 2.8 (ns vs. HFNC), NIV 5.4 ± 3.1 (p <0.05 vs. HFNC). In the final evaluation patients gave the best ratings to HFNC 2.3 ± 1.4, followed by VM 3.2 ± 1.7 (ns vs. HFNC) and NIV 4.5 ± 1.7 (p <0.01 vs. HFNC and p <0.05 vs. VM). For further treatment 10 patients chose HFNC, three VM and one NIV. CONCLUSIONS: In hypoxic respiratory failure HFNC offers a good balance between oxygenation and comfort compared to NIV and Venturi mask and seems to be well tolerated by patients. TRIAL REGISTRATION: GERMAN CLINICAL TRIALS REGISTER: DRKS00005132.

High cut-off renal replacement therapy for removal of myoglobin in severe rhabdomyolysis and acute kidney injury: a case series.

BACKGROUND/AIM: Rhabdomyolysis is associated with the release of myoglobin into the circulation, promoting acute kidney injury (AKI). In severe rhabdomyolysis, dialysis-dependent AKI doubles mortality. Standard blood purification techniques have limited efficacy in removing myoglobin. We describe high cut-off (HCO) renal replacement therapy (RRT) as a novel approach for extracorporeal elimination of myoglobin in rhabdomyolysis-associated AKI. METHODS: With an in vivo molecular cut-off at 45 kDa, HCO filters are effective in removing myoglobin (17.8 kDa). Clearances across standard and HCO filters using continuous or intermittent RRT are reviewed in a case series of 11 patients with severe rhabdomyolysis and dialysis-dependent AKI. RESULTS: Median myoglobin clearance across standard high-flux filters was 3.3 (interquartile range 2.3-3.9) ml/min for sustained low-efficiency daily dialysis (SLEDD) batch hemodialysis (HD) and 3.7 (2.9-6.7) ml/min for conventional HD. Respective clearances using HCO filters (membrane surface area: 1.1 m(2)) were 21.7 (20.3-26.1) ml/min (SLEDD) and 44.2 (41.3-47.0) ml/min (HD). Corrected for filter size, up to 20-fold higher clearances were obtained using HCO filters, resulting in profound and sustained reduction of plasma myoglobin concentration. CONCLUSIONS: As a novel approach, HCO RRT allows for rapid and effective removal of myoglobin from the circulation. In light of the pathogenic role in AKI, reducing exposure of the kidney to myoglobin may improve renal recovery and patient outcome. Our data pave the way for prospective trials, addressing this issue.

Computed tomography angiography in patients with suspected pulmonary embolism-too often considered?

BACKGROUND: Pulmonary embolism (PE) is a major cause of morbidity and mortality associated with surgery and medical illnesses. In recent years, pulmonary computed tomography angiography (CTA) has become the diagnostic method of choice. However, it remains unclear when to perform CTA and how often a decision based on clinical judgment results in positive or negative findings. METHODS: In a retrospective study, 261 patients admitted for suspected PE were evaluated with pulmonary CTA. Decisions to order CTA were based on clinical judgment and optionally quantitative d-dimer assays. Clinical, radiologic, and laboratory data were revisited and compared in patients with and without proven PE. RESULTS: The patients' mean age was 63 ± 1 years; almost 30% of all participants had at least a moderately reduced renal function. Pulmonary CTA demonstrated PE in only 14.9%; both age and sex distribution was comparable in the PE and non-PE group. Proximal deep vein thrombosis or pathologic chest x-rays were significantly more likely in patients with PE (P < .001 and P < .05), whereas echocardiography results were comparable. d-dimer values were noticeably higher in the PE group (P < .001); however, C-reactive protein and troponin T levels were not helpful. CONCLUSIONS: Pulmonary CTA confirmed PE in only a minority of patients and may be overused. Clinical judgment in conjunction with d-dimer evaluation was of limited help to predict positive results but surprisingly comparable with previous results using pretest probability scoring systems. Using present and previous data, a simplified enhanced algorithm is proposed to reduce use of CTA.

[Intensive care monitoring]. / Intensivmedizinisches Monitoring.

Monitoring the function of essential organ systems is a hallmark of critical care. In combination with the medical history, physical examination and selective diagnostic tests. Monitoring facilitates the bed-side diagnosis of many diseases in critical care and guides therapeutic management while providing optimal patient safety. The availability of monitoring compensates in the very often complex and multimorbid patients and the very dynamic course of their diseases the lack of universally applicable treatment protocols, that are based on the results of randomized critical care trials. In the future clinical decision support systems based on artificial intelligence might support intensivists in the analysis of monitoring data in terms of individual prognosis assessment and choice of therapy.

Asymptomatic sustained ventricular fibrillation in a patient with left ventricular assist device.

Optimal medical treatment, cardiac resynchronization, and the use of an implantable cardioverter defibrillator are established therapies of severe congestive heart failure. In refractory cases, left ventricular assist devices are more and more used not only as bridging to cardiac transplantation but also as destination therapy. Ventricular arrhythmias may represent a life-threatening condition and often result in clinical deterioration in patients with congestive heart failure. We report a case of asymptomatic sustained ventricular fibrillation with preserved hemodynamics caused by a nonpulsatile left ventricular assist device. Consecutive adequate but unsuccessful discharges of the implantable cardioverter defibrillator were the only sign of the usually fatal arrhythmia, prompting the patient to consult emergency services. Electrolyte supplementation and initiation of therapy with amiodarone followed by external defibrillation resulted in successful restoration of a stable cardiac rhythm after 3.5 hours.

Course of lactate, pH and base excess for prediction of mortality in medical intensive care patients.

INTRODUCTION: As base excess had shown superiority over lactate as a prognostic parameter in intensive care unit (ICU) surgical patients we aimed to evaluate course of lactate, base excess and pH for prediction of mortality of medical ICU patients. MATERIALS AND METHODS: For lactate, pH and base excess, values at the admission to ICU, at 24 ± 4 hours, maximum or minimum in the first 24 hours and in 24-48 hours after admission were collected from all patients admitted to the Medical ICU of the University Hospital Tübingen between January 2016 until December 2018 (N = 4067 at admission, N = 1715 with ICU treatment > 48 h) and investigated for prediction of in-hospital-mortality. RESULTS: Mortality was 22% and significantly correlated with all evaluated parameters. Strongest predictors of mortality determined by ROC were maximum lactate in 24 h (AUROC 0.74, cut off 2.7 mmol/L, hazard ratio of risk group with value > cut off 3.20) and minimum pH in 24 h (AUROC 0.71, cut off 7.31, hazard ratio for risk group 2.94). Kaplan Meier Curves stratified across these cut offs showed early and clear separation. Hazard ratios per standard deviation increase were highest for maximum lactate in 24 h (HR 1.65), minimum base excess in 24 h (HR 1.56) and minimum pH in 24 h (HR 0.75). CONCLUSION: Lactate, pH and base excess were all suitable predictors of mortality in internal ICU patients, with maximum / minimum values in 24 and 24-48 h after admission altogether stronger predictors than values at admission. Base excess and pH were not superior to lactate for prediction of mortality.

Effect of an intensified individual nutrition therapy on serum metabolites in critically ill patients - A targeted metabolomics analysis of the ONCA study.

PURPOSE: The effect of medical nutrition on serum metabolomics has been poorly explored. The aim of the study was to investigate the relation between energy supply and metabolic profiles in critically ill patients. MATERIALS AND METHODS: Twenty mechanically ventilated patients on enteral nutrition (EN) or enteral/parenteral nutrition (EN/PN) were randomized into two groups. One group received an individual energy supply based on indirect calorimetry (IC group, n = 9), the other group received a standard energy supply based on a formula, the standard care group (SC group, n = 11). Targeted metabolomics was performed in early-, late- and post-acute metabolic phase. RESULTS: Individual versus standard care energy supply resulted in a metabolite class separation between the IC and the SC group (P < 0.001). In the SC group concentrations of four glucogenic amino acids and three biogenic amines increased between the early- and late-acute metabolic phase (P < 0.05). The metabolomics pattern differed between the routes of nutrition administration (P < 0.01). CONCLUSIONS: The amount of energy supply by EN or PN, besides other factors, seems to modulate serum metabolites. Nutrition therapy based on individualized energy supply is associated with a reduction of metabolites reflecting catabolism. Therefore, metabolomics could be a new tool to determine metabolic phases in critically ill patients.

Impact of an interdisciplinary nutrition support team (NST) on the clinical outcome of critically ill patients. A pre/post NST intervention study.

BACKGROUND: Intensive care unit (ICU) patients are at particular risk for malnutrition with major impact for outcome and prognosis. Nutrition support teams (NST) have been proposed to improve nutrition care in ICU patients. OBJECTIVE: To assess the effectiveness of an interdisciplinary NST on anthropometry and clinical outcome of ICU patients. METHODS: Before NST implementation, we assessed 120 patients (before NST group; SAPS II score 44 ± 16), afterwards 60 patients (after NST group), of whom 29 received NST guidance (after NST + group; SAPS II 65 ± 19) and 31 not (after NST - group; SAPS II, 54 ± 16). The primary outcome parameter was length of stay in the hospital (hospital-LOS). Severity of disease was assessed by the APACHE II score and the nutritional risk (NUTRIC) score. RESULTS: NST intervention resulted in a more pronounced improvement of disease severity (APACHE II, from 27 ± 8 to 18 ± 6, p < 0.001; NUTRIC, from 7 ± 2 to 4 ± 2, p < 0.001) compared to no NST intervention (APACHE II from 24 ± 7 to 21 ± 7, p < 0.05; NUTRIC from 6 ± 2 to 5 ± 2, p < 0.01). The mean hospital-LOS was not reduced, neither in the NST intervention group nor in the control group without NST intervention. NST intervention failed to improve nutritional status or mortality compared to no NST intervention. CONCLUSION: In our study the NST intervention had a positive effect on disease severity, but failed to improve mortality, hospital-LOS or nutritional status in ICU patients, likely because of a large patient heterogeneity. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02200874).

Characterization and outcome following Puumala virus infection: a retrospective analysis of 75 cases.

BACKGROUND: Infection with the Puumala virus (PUUV), which belongs to the Hantavirus family, is a common but often neglected cause of acute kidney injury (AKI) in endemic areas of Europe. The objective of the present study was to systematically analyse clinical presentation and renal outcomes following PUUV infection. METHODS: In a retrospective study, we analysed data from 75 patients who were admitted to two large hospitals in Germany over an 8-year period and who tested positive for PUUV infection. Clinical and laboratory data were collected from patient files; creatinine levels before admission and during follow-up were obtained from phone calls. RESULTS: Patients were between 16 and 82 years old (average +/- SD, 40.4 +/- 13.4) with a male to female ratio of 2.5:1. They showed a wide variety of clinical presentations with renal failure being the cause of admission in only 50%. AKI developed in 95% of patients who showed maximum creatinine levels of 4.3 +/- 0.3 mg/dl. Four patients required temporary dialysis, and one patient died from pulmonary complications. Thrombocytopaenia (137 +/- 11 x 10(3)/microl) was present in almost all cases, and elevated levels of lactate dehydrogenase (LDH) and C-reactive protein (CRP) were observed in 57 and 100% of patients, respectively. Urinalysis revealed mild to nephrotic proteinuria in 85%, which was often associated with haemoglobinuria. All patients showed full recovery of renal function and return to pre-existing normal serum creatinine levels. CONCLUSION: In a majority of cases, PUUV infection results in thrombocytopenic AKI. Fever is a requirement for diagnosis, while elevated LDH and CRP values are also frequently observed. Overall, early renal outcomes were excellent.

[Rational therapeutic decisions in intensive care patients]. / Rationale Therapieentscheidungen bei Intensivpatienten.

Decisions about the initiation, continuation and termination of life-supporting treatments are a permanent challenge in intensive care units (ICUs). Decisions should be based on patient preferences and the medical indication. The medical indication is mainly the result of an assessment of the patient's prognosis and the applicable therapeutic options. Factors influencing the short term prognosis are mostly the severity of the acute leading disease, the number and severity of other organ failures and the response to initial treatment. Long term prognosis is dominated by the severity and number of comorbidities, age and the resulting frailty. Because in many patients all these informations are not available at the time of admission, in these cases a time-limited trial is often justified to gather all this information before a decision is made. These principles of decision making can also applied to situations in which ICU-capacities are limited (e. g. COVID-19 pandemic).

Life-threatening pneumonitis after first-line treatment with osimertinib for primary T790M mutated non-small cell lung cancer.

Epithelial growth factor receptor (EGFR) directed tyrosine kinase inhibitor (TKI) treatment is the standard approach in patients with advanced, EGFR-mutated non-small cell lung cancer (NSCLC). Although benefit/risk ratio is favorable for these TKI and side effects are manageable in the vast majority of patients, severe and even life-threatening side effects have been reported. TKI-induced interstitial lung disease (ILD) has been reported for single cases in modest severity, predominantly in EGFR-TKI pretreated patients. Here, we report a case of successful stabilization of a life-threatening ILD in a de novo T790M mutated NSCLC during first-line treatment with osimertinib. As osimertinib will be used more often in many EGFR-positive NSCLC patients in the future, this potentially life-threatening side effect should receive special attention, especially in first-line treatment.

A novel flow cytometry-based assay to measure compromised B cell receptor signaling as a prognostic factor in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. In the past years, new therapeutic approaches (e.g., ibrutinib or venetoclax) have been established and greatly improved treatment of CLL. However, complete control or cure of the disease have not been reached so far. Thus, reliable prognostic markers are an imperative for treatment decisions. Recent studies have revealed an essential role for B cell receptor (BCR) signaling in the pathogenesis, prognosis, and therapy of CLL. A heterogeneous response to receptor stimulation with anti-IgM treatment culminating in different calcium flux capabilities has been demonstrated by several authors. However, the methods employed have not reached clinical application. Here, we report on a flow cytometry-based assay to evaluate calcium flux capabilities in CLL and demonstrate that compromised BCR signaling with diminished calcium flux is associated with a significantly better clinical outcome and progression free survival. In summary, our data strongly support the role of compromised BCR signaling as an important prognostic marker in CLL and establish a novel diagnostic tool for its assessment in clinical settings.

Optimization of Nutrition Therapy with the Use of Calorimetry to Determine and Control Energy Needs in Mechanically Ventilated Critically Ill Patients: The ONCA Study, a Randomized, Prospective Pilot Study.

BACKGROUND: Adequate nutrition therapy in critically ill patients poses a challenge because of the variable energy and substrate needs. The objective was to investigate whether nutrition therapy involving indirect calorimetry (IC), instead of equations for assessment of energy needs, could improve the nutrition status of critically ill patients. METHODS: Forty mechanically ventilated patients were randomized into a group in which energy needs were controlled by calorimetry (IC group) and a group treated with a formula-based approach reflecting standard care (SC group). The primary outcome was change in the phase angle (PhA), a bioelectrical impedance parameter related to nutrition status and prognosis. RESULTS: The mean IC-based energy requirement was lower than the formula-based estimate (21.1 ± 6.4 versus [vs] 25 kcal/kg/d, P < .01). The IC group reached 98% ± 8% of the energy goal, whereas the SC group reached only 79% ± 29% (P < 0.05), although mean intake was similar in both groups. The protein intake goal was better met in the IC group (91% ± 24%) than the SC group (73% ± 33%). The PhA of the IC group did not change during treatment, whereas that of the SC group tended to decrease by 0.36° ± 0.86° (P = .077). A shorter length of stay in intensive care was observed in the IC than in the SC group (13 ± 8 vs 24 ± 20 days, P < .05). CONCLUSION: Intensified individual nutrition therapy involving IC appears to be useful for improving nutrition status in critically ill patients.

Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter's syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well-accepted model of CLL. Upon B cell-specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter's syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild-type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next-generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease.