Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ.

Biological processes are regulated by intermolecular interactions and chemical modifications that do not affect protein levels, thus escaping detection in classical proteomic screens. We demonstrate here that a global protein structural readout based on limited proteolysis-mass spectrometry (LiP-MS) detects many such functional alterations, simultaneously and in situ, in bacteria undergoing nutrient adaptation and in yeast responding to acute stress. The structural readout, visualized as structural barcodes, captured enzyme activity changes, phosphorylation, protein aggregation, and complex formation, with the resolution of individual regulated functional sites such as binding and active sites. Comparison with prior knowledge, including other 'omics data, showed that LiP-MS detects many known functional alterations within well-studied pathways. It suggested distinct metabolite-protein interactions and enabled identification of a fructose-1,6-bisphosphate-based regulatory mechanism of glucose uptake in E. coli. The structural readout dramatically increases classical proteomics coverage, generates mechanistic hypotheses, and paves the way for in situ structural systems biology.

Long-term outcomes and prognostic factors for survival of patients with ANCA-associated vasculitis.

BACKGROUND: Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors. METHODS: Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models. RESULTS: A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9-13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model. CONCLUSIONS: Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV.

Perspective on COVID-19 vaccination in patients with immune-mediated kidney diseases: consensus statements from the ERA-IWG and EUVAS.

Patients with immune-mediated kidney diseases are at increased risk of severe coronavirus disease 2019 (COVID-19). The international rollout of COVID-19 vaccines has provided varying degrees of protection and enabled the understanding of vaccine efficacy and safety. The immune response to COVID-19 vaccines is lower in most patients with immune-mediated kidney diseases; either related to immunosuppression or comorbidities and complications caused by the underlying disease. Humoral vaccine response, measured by the presence of antibodies, is impaired or absent in patients receiving rituximab, mycophenolate mofetil (MMF), higher doses of glucocorticoids and likely other immunosuppressants, such as cyclophosphamide. The timing between the use of these agents and administration of vaccines is associated with the level of immune response: with rituximab, vaccine response can only be expected once B cells start to recover and patients with transient discontinuation of MMF mount a humoral response more frequently. The emergence of new COVID-19 variants and waning of vaccine-induced immunity highlight the value of a booster dose and the need to develop mutant-proof vaccines. COVID-19 vaccines are safe, exhibiting a very low risk of de novo or relapsing immune-mediated kidney disease. Population-based studies will determine whether this is causal or coincidental. Such cases respond to standard management, including the use of immunosuppression. The Immunonephrology Working Group and European Vasculitis Society recommend that patients with immune-mediated kidney diseases follow national guidance on vaccination. Booster doses based on antibody measurements could be considered.

Frequency and characteristics of bacterial and viral low-grade infections of the intervertebral discs: a prospective, observational study.

STUDY DESIGN: Monocentric, prospective, observational study. OBJECTIVE: The clinical relevance of bacterial colonization of intervertebral discs is controversial. This study aimed to determine a possible relationship between bacterial and viral colonization and low-grade infection of the discs. METHODS: We investigated 447 disc samples from 392 patients. Microbiological culture was used to examine the samples for bacterial growth, polymerase chain reaction (PCR) was used for detection of herpes simplex virus types 1 and 2 (HSV-1, HSV-2) and Cytomegalovirus (CMV), and histopathological analysis was used to detect signs of inflammation. The results were compared between subgroups organized according to gender, age, location of the samples, surgical approach, preoperative C-reactive protein (CRP), preoperative and 6 months postoperative Oswestry Disability Index (ODI) and Neck Disability Index (NDI), and Modic changes (MC) of the corresponding endplates. Also, we assessed the occurrence of postoperative infections within 6 months. RESULTS: Microbiological culture was positive in 38.78% of the analyzed intervertebral discs. Altogether, 180 bacteria were isolated. Coagulase-negative staphylococci (CONS) (23.41%) and Cutibacterium acnes (18.05%) were the most frequently detected microorganisms. None of HSV-1, HSV-2, or CMV were detected. Male patients (p = 0.00036) and cervical segments (p = 0.00001) showed higher rates of positive culture results. Ventral surgical approaches ( p < 0.001) and Type 2 MC (p = 0.0127) were significantly associated with a positive microbiological result ( p< 0.001). Neither pre- nor postoperative ODI and NDI are associated with positive culture results. In 4 (1.02%) patients, postoperative spondylodiscitis occurred. CONCLUSIONS: With 447 segments from 392 patients, we present one of the largest studies to date. While disc degeneration caused by HSV-1, HSV-2, and CMV seems unlikely, we found positive microbiological culture results in 38.78% of all discs. The role of local skin flora and sample contamination should be the focus of further investigations. LEVEL OF EVIDENCE: III. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (ID: NCT04712487, https://www. CLINICALTRIALS: gov/ct2/show/study/NCT04712487 ).

Determination of neutralising anti-SARS-CoV-2 antibody half-life in COVID-19 convalescent donors.

Despite the burgeoning field of coronavirus disease-19 (COVID-19) research, the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralising antibodies remains unclear. This study validated two high-throughput immunological methods for use as surrogate live virus neutralisation assays and employed them to examine the half-life of SARS-CoV-2 neutralising antibodies in convalescent plasma donations made by 42 repeat donors between April and September 2020. SARS-CoV-2 neutralising antibody titres decreased over time but typically remained above the methods' diagnostic cut-offs. Using this longitudinal data, the average half-life of SARS-CoV-2 neutralising antibodies was determined to be 20.4 days. SARS-CoV-2 neutralising antibody titres appear to persist in the majority of donors for several months. Whether these titres confer protection against re-infection requires further study and is of particular relevance as COVID-19 vaccines become widely available.

[18F]fluorodeoxyglucose-positron emission tomography and glucose-transporter type 1 expression in untreated primary small bowel adenocarcinoma.

BACKGROUND: Literature reporting [18F]fluorodexoyglucose positron emission tomography (FDG-PET) of small bowel adenocarcinoma, a rare tumor, is sparse. To assess FDG uptake in small bowel adenocarcinoma, we retrospectively analyzed a large, single-center database and determined the expression of glucose-transporter type 1 (GLUT-1). METHODS: Screening of PET datasets in the database (N.=28,961 scans) for untreated histologically-confirmed primary small bowel adenocarcinoma revealed evaluable PET datasets for eight patients. Maximum and peak standardized uptake values (SUVmax and SUVpeak, respectively) were calculated via volume-of-interest (VOI) analysis. Additionally, GLUT-1 expression on tumor specimens was prospectively immunohistochemically assessed. RESULTS: All primary tumors showed high FDG uptake: mean SUVmax was 9.5±2.6 (range: 5.0-13.0) and SUVpeak, 8.1±2.3 (range: 3.9-10.7). Corresponding biopsy specimens (N.=7) demonstrated high GLUT-1 expression. CONCLUSIONS: Primary small bowel adenocarcinomas have a high GLUT-1 expression. Tumor lesions consistently demonstrated high FDG uptake pre-treatment, suggesting FDG-PET utility in staging and follow-up of these tumors.

Ficolin-3 Deficiency Is Associated with Disease and an Increased Risk of Systemic Lupus Erythematosus.

PURPOSE: Ficolin-3 deficiency is caused by a mutation (+1637delC) in the FCN3 gene. It is a rare condition and has been associated with both infection and autoimmune disease including systemic lupus erythematosus (SLE). Here we investigated if ficolin-3 deficiency is more frequent in patients than in controls and tried to identify a common phenotype among ficolin-3 deficient individuals. Since a significant part of patients identified with ficolin-3 deficiency was diagnosed with SLE, we explored whether the heterozygous state of the FCN3+1637delC variant represents a risk factor in the development of SLE. Further, we examined other possible causes of ficolin-3 deficiency when the FCN3+1637delC is not present. METHODS: A systematic literature search for studies measuring ficolin-3 was carried out. We examined 362 SLE patients and 596 controls for the presence of the variant FCN3+1637delC. We established assays for measurements of ficolin-3 and of auto-antibodies against ficolin-3. We sequenced the coding and non-coding regions of the FCN3 gene in an SLE patient with ficolin-3 deficiency not carrying the +1637delC. RESULTS: Ficolin-3 deficiency leads to an 8-time increased odds of having a disease (p < 0.05). Three out of nine patients with deficiency had SLE. The heterozygous state of the deficiency variant is not associated with increased risk of developing SLE (p = 0.18). CONCLUSION: By systematically reviewing the literature for the described cases of ficolin-3 deficiency, an autoimmune phenotype is emerging. Thirty-three percent of the ficolin-3 deficient patients had SLE. Heterozygosity for the FCN3 gene deletion causing the deficiency does not seem to be associated with the development of SLE.

Imaging sequence for joint myocardial T1 mapping and fat/water separation.

PURPOSE: To develop and evaluate an imaging sequence to simultaneously quantify the epicardial fat volume and myocardial T1 relaxation time. METHODS: We introduced a novel simultaneous myocardial T1 mapping and fat/water separation sequence (joint T1 -fat/water separation). Dixon reconstruction is performed on a dual-echo data set to generate water/fat images. T1 maps are computed using the water images, whereas the epicardial fat volume is calculated from the fat images. A phantom experiment using vials with different T1 /T2 values and a bottle of oil was performed. Additional phantom experiment using vials of mixed fat/water was performed to show the potential of this sequence to mitigate the effect of intravoxel fat on estimated T1 maps. In vivo evaluation was performed in 17 subjects. Epicardial fat volume, native myocardial T1 measurements and precision were compared among slice-interleaved T1 mapping, Dixon, and the proposed sequence. RESULTS: In the first phantom, the proposed sequence separated oil from water vials and there were no differences in T1 of the fat-free vials (P = .1). In the second phantom, the T1 error decreased from 22%, 36%, 57%, and 73% to 8%, 9%, 16%, and 26%, respectively. In vivo there was no difference between myocardial T1 values (1067 ± 17 ms versus 1077 ± 24 ms, P = .6). The epicardial fat volume was similar for both sequences (54.3 ± 33 cm3 versus 52.4 ± 32 cm3 , P = .8). CONCLUSION: The proposed sequence provides simultaneous quantification of native myocardial T1 and epicardial fat volume. This will eliminate the need for an additional sequence in the cardiac imaging protocol if both measurements are clinically indicated.

Effects of six-week sprint interval or endurance training on calculated power in maximal lactate steady state.

The purpose of the study was to evaluate and compare the influence of sprint interval training (SIT) and endurance training (ET) on calculated power in maximal lactate steady state (PMLSS) (influenced by the maximal lactate production rate (⩒Lamax) and maximal oxygen uptake (⩒O2max)). Thirty participants were randomly assigned to the a) SIT, b) ET, or c) control group (n = 10 each). Each session consisted of four to six repetitions of 30 s all-out effort Wingate anaerobic tests (SIT) or 60 min cycling at 1.5 to 2.5 mmol∙L-1 blood lactate (analysed every 10 min). Both groups performed training on three days per week, over a period of six weeks. To measure ⩒Lamax and ⩒O2max, and to calculate PMLSS, sprint and ramp tests were performed at baseline and after two, four and six weeks of intervention. While SIT resulted in a significant reduction of ⩒Lamax (-0.08 ± 0.05 mmol∙L-1∙s-1, p=0.003) after two weeks and remained subsequently stable, ⩒O2max (+2.6 ± 2.4 ml∙min-1∙kg-1, p = 0.044) and PMLSS (+25 ± 14 W, p=0.002) increased, but not before six weeks of SIT. After two weeks of ET, ⩒Lamax remained unchanged, but ⩒O2max increased by increased by +2.9 ± 2.4 ml∙min-1∙kg-1, p=0.03, and after six weeks by 5.6 ± 3.5 ml∙min-1∙kg-1. The increase of PMLSS was significant after four weeks of ET (+16 ± 14 W, p=0.036) and increased to +32 ± 17 W after six weeks. Comparison of SIT and ET revealed no significant differences for ⩒Lamax, ⩒O2max or PMLSS after six weeks. The control group remained stable in all parameters. In both exercising groups there was a significant improvement of the calculated PMLSS due to different influences of ⩒Lamax and ⩒O2max.

Salsalate improves glycaemia in overweight persons with diabetes risk factors of stable statin-treated cardiovascular disease: A 30-month randomized placebo-controlled trial.

OBJECTIVE: To assess long-term efficacy and safety of salsalate to improve glycemia in persons with diabetes risk, who are overweight with statin-treated, stable coronary heart disease. METHODS: Glycemic status was assessed in 192 persons without diabetes at baseline in a pre-specified secondary analysis from Targeting INflammation Using SALsalate in CardioVascular Disease (TINSAL-CVD), a multi-center, double-masked, randomized (1:1), placebo-controlled, parallel clinical trial. RESULTS: Participants were mostly Caucasian males, age 60±7 years, BMI 31.4±3.0 kg/m2 , fasting glucose 92.8±11.0 mg/dL, and HbA1c 5.8±0.3%. Reductions in mean fasting glucose -5.70 mg/dL (95%CI: -7.44 to -3.97 mg/dL, P<0.001), HbA1c -0.11% (95%CI: -0.210 to -0.002%, P=0.046) and glycated serum protein -81.8 µg/mL (95%CI: -93.7 to -69.9 µg/mL, P<0.001) were demonstrated in salsalate compared to placebo-assigned groups over 30 months. Reductions in fasting glucose and glycated serum protein were greater with salsalate compared to placebo in participants with prediabetes compared to a normoglycemic sub-group (Pinteraction =0.018). Salsalate lowered total white blood cell counts (mean difference -0.7x103 /µL, 95%CI: -1.0 to -0.4 x103 /µL, P<0.001) and increased adiponectin (mean difference 1.8 µg/mL, 95%CI: 0.9 to 2.6 µg/mL, P<0.001) and albuminurea (16.7 µg/mg, 95%CI: 6.4 to 27.1 µg/mg, P<0.001) compared to placebo, consistent with previous results for patients with type 2 diabetes taking salsalate for shorter times. CONCLUSIONS: Salsalate improves glycemia in obese persons at increased risk for diabetes, and hence may decrease risk of incident type 2 diabetes. Salsalate may inform new therapeutic approaches for diabetes prevention, but renal safety may limit clinical utility.

Coronary CT angiography versus standard evaluation in acute chest pain.

BACKGROUND: It is unclear whether an evaluation incorporating coronary computed tomographic angiography (CCTA) is more effective than standard evaluation in the emergency department in patients with symptoms suggestive of acute coronary syndromes. METHODS: In this multicenter trial, we randomly assigned patients 40 to 74 years of age with symptoms suggestive of acute coronary syndromes but without ischemic electrocardiographic changes or an initial positive troponin test to early CCTA or to standard evaluation in the emergency department on weekdays during daylight hours between April 2010 and January 2012. The primary end point was length of stay in the hospital. Secondary end points included rates of discharge from the emergency department, major adverse cardiovascular events at 28 days, and cumulative costs. Safety end points were undetected acute coronary syndromes. RESULTS: The rate of acute coronary syndromes among 1000 patients with a mean (±SD) age of 54±8 years (47% women) was 8%. After early CCTA, as compared with standard evaluation, the mean length of stay in the hospital was reduced by 7.6 hours (P<0.001) and more patients were discharged directly from the emergency department (47% vs. 12%, P<0.001). There were no undetected acute coronary syndromes and no significant differences in major adverse cardiovascular events at 28 days. After CCTA, there was more downstream testing and higher radiation exposure. The cumulative mean cost of care was similar in the CCTA group and the standard-evaluation group ($4,289 and $4,060, respectively; P=0.65). CONCLUSIONS: In patients in the emergency department with symptoms suggestive of acute coronary syndromes, incorporating CCTA into a triage strategy improved the efficiency of clinical decision making, as compared with a standard evaluation in the emergency department, but it resulted in an increase in downstream testing and radiation exposure with no decrease in the overall costs of care. (Funded by the National Heart, Lung, and Blood Institute; ROMICAT-II ClinicalTrials.gov number, NCT01084239.).

Sensitive troponin assays in patients with suspected acute coronary syndrome: Results from the multicenter rule out myocardial infarction using computer assisted tomography II trial.

BACKGROUND: Sensitive troponin (Tn) assays have been developed for the evaluation of patients with suspected acute coronary syndrome (ACS). We sought to compare the performance of a commercially available sensitive Tn I (sTnI) and precommercial highly sTnI (hsTnI) method to conventional Tn (cTn) assays. METHODS: Among patients with acute chest pain but normal cTn in the emergency department of 6 centers, sTnI and hsTnI were measured at baseline, 2 and 4 hours after presentation. Diagnostic accuracy of sTnI and hsTnI relative to cTn for diagnosis during index hospitalization as well as their associations with coronary artery disease in patients randomized to coronary computed tomographic angiography (CTA) was assessed. RESULTS: Overall, 322 patients were enrolled, of whom 161 had a CTA; 28 had ACS (8.7%), including 21 with unstable angina pectoris (UAP). Both sTnI and hsTnI values at baseline and second draw had significantly higher sensitivity for ACS and UAP than cTn and had significantly greater area under the receiver operator characteristic curve than cTn at first and second draws. Compared with cTn, 29% of ACS cases previously categorized as UAP were reclassified to acute myocardial infarction with sTnI or hsTnI. An hsTnI below limit of detection had 100% negative predictive value for ACS or significant coronary artery stenosis in those randomized to CTA. CONCLUSIONS: In patients with acute chest discomfort, use of sTnI and hsTnI methods led to significant improvement in the early diagnostic accuracy for ACS, reclassifying one-third of UAP to myocardial infarction. Very low values for hsTnI excluded underlying coronary artery disease.

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial.

OBJECTIVES: The RITUXVAS trial reported similar remission induction rates and safety between rituximab and cyclophosphamide based regimens for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis at 12 months; however, immunosuppression maintenance requirements and longer-term outcomes after rituximab in ANCA-associated renal vasculitis are unknown. METHODS: Forty-four patients with newly diagnosed ANCA-associated vasculitis and renal involvement were randomised, 3:1, to glucocorticoids plus either rituximab (375 mg/m(2)/week×4) with two intravenous cyclophosphamide pulses (n=33, rituximab group), or intravenous cyclophosphamide for 3-6 months followed by azathioprine (n=11, control group). RESULTS: The primary end point at 24 months was a composite of death, end-stage renal disease and relapse, which occurred in 14/33 in the rituximab group (42%) and 4/11 in the control group (36%) (p=1.00). After remission induction treatment all patients in the rituximab group achieved complete B cell depletion and during subsequent follow-up, 23/33 (70%) had B cell return. Relapses occurred in seven in the rituximab group (21%) and two in the control group (18%) (p=1.00). All relapses in the rituximab group occurred after B cell return. CONCLUSIONS: At 24 months, rates of the composite outcome of death, end-stage renal disease and relapse did not differ between groups. In the rituximab group, B cell return was associated with relapse. TRIAL REGISTRATION NUMBER: ISRCTN28528813.

B-cell therapy in antineutrophil cytoplasmic antibody-associated vasculitis.

Until recently, standard of care for patients with generalized or severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has consisted of an induction regimen with cyclophosphamide (CYC) and corticosteroids followed by maintenance treatment with azathioprine. This regimen is associated with significant toxicity resulting in considerable morbidity and mortality whereas relapses are still not infrequent. In two controlled trials, the Rituximab in ANCA-associated Vasculitis study (RAVE) and the RITUXVAS trial of the European Vasculitis Study Group (EUVAS), rituximab (RTX) proved non-inferior to CYC for induction of remission. In addition, outcome at 18 months for the RAVE trial and 12 months for the RITUXVAS trial showed that RTX without maintenance treatment was as efficacious as CYC followed by azathioprine maintenance. To prevent relapses, which occur particularly in patients positive for PR3-ANCA, 500 mg RTX given every 6 months was shown to be superior to azathioprine in a French study. Thus, RTX is a new and promising therapeutic armamentarium for AAV although long-term safety has still to be established.

Prognostic value of pulmonary vein size in prediction of atrial fibrillation recurrence after pulmonary vein isolation: a cardiovascular magnetic resonance study.

BACKGROUND: The relationship between pulmonary vein (PV) anatomy and successful catheter ablation of atrial fibrillation (AF) is poorly understood METHODS: First-pass contrast enhanced PV magnetic resonance angiography was performed in 71 consecutive patients prior to PV isolation. PV diameter and cross-sectional area (CSA) were measured prior to PV isolation. Any symptomatic or asymptomatic AF >10s was considered a recurrence. Early recurrence was defined as recurrent AF ≤30 days after PV isolation, while late recurrence of AF was defined as recurrent AF >30 days after. RESULTS: At 1 year, 57% had any recurrence of AF while 41% had late recurrence of AF. Study subjects with one or more PV diameter in the top 10(th) percentile had trend toward more early recurrent AF (HR 1.99, p = 0.053). Study subjects with one or more PV CSA in the top 10th percentile had more late recurrent AF (HR 2.25, p = 0.039) and a trend toward more early recurrent AF (HR 1.94, p = 0.064). With multivariate analysis, PV size was not associated with early recurrent AF, but late recurrent AF was associated with one or more large PV, increased left atrial size, and non-paroxysmal AF. Study subjects with all three of these risk factors had a 100% rate of late recurrent AF at 1 year, while those with none had a 7% rate of late recurrent AF. CONCLUSIONS: Larger PV size is independently associated with more late recurrent AF after PV isolation. Determination of PV size prior to PV isolation may predict procedural success.

Localized spatio-temporal constraints for accelerated CMR perfusion.

PURPOSE: To develop and evaluate an image reconstruction technique for cardiac MRI (CMR) perfusion that uses localized spatio-temporal constraints. METHODS: CMR perfusion plays an important role in detecting myocardial ischemia in patients with coronary artery disease. Breath-hold k-t-based image acceleration techniques are typically used in CMR perfusion for superior spatial/temporal resolution and improved coverage. In this study, we propose a novel compressed sensing-based image reconstruction technique for CMR perfusion, with applicability to free-breathing examinations. This technique uses local spatio-temporal constraints by regularizing image patches across a small number of dynamics. The technique was compared with conventional dynamic-by-dynamic reconstruction, and sparsity regularization using a temporal principal-component (pc) basis, as well as zero-filled data in multislice two-dimensional (2D) and three-dimensional (3D) CMR perfusion. Qualitative image scores were used (1 = poor, 4 = excellent) to evaluate the technique in 3D perfusion in 10 patients and five healthy subjects. On four healthy subjects, the proposed technique was also compared with a breath-hold multislice 2D acquisition with parallel imaging in terms of signal intensity curves. RESULTS: The proposed technique produced images that were superior in terms of spatial and temporal blurring compared with the other techniques, even in free-breathing datasets. The image scores indicated a significant improvement compared with other techniques in 3D perfusion (x-pc regularization, 2.8 ± 0.5 versus 2.3 ± 0.5; dynamic-by-dynamic, 1.7 ± 0.5; zero-filled, 1.1 ± 0.2). Signal intensity curves indicate similar dynamics of uptake between the proposed method with 3D acquisition and the breath-hold multislice 2D acquisition with parallel imaging. CONCLUSION: The proposed reconstruction uses sparsity regularization based on localized information in both spatial and temporal domains for highly accelerated CMR perfusion with potential use in free-breathing 3D acquisitions.

Comparison of calculated and experimental power in maximal lactate-steady state during cycling.

BACKGROUND: The purpose of this study was the comparison of the calculated (MLSSC) and experimental power (MLSSE) in maximal lactate steady-state (MLSS) during cycling. METHODS: 13 male subjects (24.2 ± 4.76 years, 72.9 ± 6.9 kg, 178.5 ± 5.9 cm, V˙O2max: 60.4 ± 8.6 ml min-1 kg-1, V˙Lamax: 0.9 ± 0.19 mmol l-1 s-1) performed a ramp-test for determining the V˙O2max and a 15 s sprint-test for measuring the maximal glycolytic rate (V˙Lamax). All tests were performed on a Lode-Cycle-Ergometer. V˙O2max and V˙Lamax were used to calculate MLSSC. For the determination of MLSSE several 30 min constant load tests were performed. MLSSE was defined as the highest workload that can be maintained without an increase of blood-lactate-concentration (BLC) of more than 0.05 mmol l-1 min-1 during the last 20 min. Power in following constant-load test was set higher or lower depending on BLC. RESULTS: MLSSE and MLSSC were measured respectively at 217 ± 51 W and 229 ± 47 W, while mean difference was -12 ± 20 W. Orthogonal regression was calculated with r = 0.92 (p < 0.001). CONCLUSIONS: The difference of 12 W can be explained by the biological variability of V˙O2max and V˙Lamax. The knowledge of both parameters, as well as their individual influence on MLSS, could be important for establishing training recommendations, which could lead to either an improvement in V˙O2max or V˙Lamax by performing high intensity or low intensity exercise training, respectively. Furthermore the validity of V˙Lamax -test should be focused in further studies.

Cortical signature of neurological soft signs in recent onset schizophrenia.

Motor symptoms such as neurological soft signs (NSS) are characteristic phenomena of schizophrenia at any stage of the illness. Neuroimaging studies in schizophrenia patients have shown regional thinning of the cortical mantle, but it is unknown at present whether NSS are related to cortical thickness changes. Whole brain high-resolution magnetic resonance imaging at 3 Tesla was used to investigate cortical thickness in 28 patients with recent-onset schizophrenia. Cortical reconstruction was performed with the Freesurfer image analysis suite. NSS were examined on the Heidelberg Scale and related to cortical thickness. Age, education, and medication were considered as potential confounders. Higher NSS scores were associated with morphological changes of cortical thickness in multiple areas comprising paracentral gyrus, postcentral lobule, precuneus, inferior parietal lobule and temporal lobe. Our results confirm the hypothesis of a significant relationship between cortical thickness changes and the extent of NSS in schizophrenia. Investigation of cortical thickness may help to explain subtle motor symptoms such as NSS in schizophrenia.

Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis.

BACKGROUND: Cyclophosphamide induction regimens for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are effective in 70 to 90% of patients, but they are associated with high rates of death and adverse events. Treatment with rituximab has led to remission rates of 80 to 90% among patients with refractory ANCA-associated vasculitis and may be safer than cyclophosphamide regimens. METHODS: We compared rituximab with cyclophosphamide as induction therapy in ANCA-associated vasculitis. We randomly assigned, in a 3:1 ratio, 44 patients with newly diagnosed ANCA-associated vasculitis and renal involvement to a standard glucocorticoid regimen plus either rituximab at a dose of 375 mg per square meter of body-surface area per week for 4 weeks, with two intravenous cyclophosphamide pulses (33 patients, the rituximab group), or intravenous cyclophosphamide for 3 to 6 months followed by azathioprine (11 patients, the control group). Primary end points were sustained remission rates at 12 months and severe adverse events. RESULTS: The median age was 68 years, and the glomerular filtration rate (GFR) was 18 ml per minute per 1.73 m(2) of body-surface area. A total of 25 patients in the rituximab group (76%) and 9 patients in the control group (82%) had a sustained remission (P=0.68). Severe adverse events occurred in 14 patients in the rituximab group (42%) and 4 patients in the control group (36%) (P=0.77). Six of the 33 patients in the rituximab group (18%) and 2 of the 11 patients in the control group (18%) died (P=1.00). The median increase in the GFR between 0 and 12 months was 19 ml per minute in the rituximab group and 15 ml per minute in the control group (P=0.14). CONCLUSIONS: A rituximab-based regimen was not superior to standard intravenous cyclophosphamide for severe ANCA-associated vasculitis. Sustained-remission rates were high in both groups, and the rituximab-based regimen was not associated with reductions in early severe adverse events. (Funded by Cambridge University Hospitals National Health Service Foundation Trust and F. Hoffmann-La Roche; Current Controlled Trials number, ISRCTN28528813.)

Utility of respiratory-navigator-rejected k-space lines for improved signal-to-noise ratio in three-dimensional cardiac MR.

PURPOSE: To develop and evaluate a technique that uses the k-space lines rejected by prospective respiratory navigator (NAV) to improve the signal-to-noise ratio (SNR) without increasing the scan time. METHODS: In conventional image reconstruction, the motion-corrupted k-space lines rejected by the NAV are not used. In this study, a set of translational motion parameters for the NAV-rejected lines and a phase-corrected average for the k-space line are estimated jointly using a maximum-likelihood approach and the information from the corresponding accepted k-space lines. Left coronary artery images were acquired in 10 healthy adult subjects, and the proposed approach incorporating the NAV-rejected lines was compared with the conventional dataset with NAV-accepted lines only, as well as a simple average of all k-space lines, in terms of SNR, normalized vessel sharpness and qualitative image scores on a four-point scale (1 = poor, 4 = excellent). Late gadolinium enhancement images of the left atrium were also acquired in 21 patients with atrial fibrillation pre- or post-pulmonary vein isolation. Images reconstructed with the proposed, conventional, and simple averaging methods were compared in terms of SNR, and subjective image quality on a four-point scale. RESULTS: For coronary MRI, there was a significant improvement in SNR with the proposed technique, but no significant difference in normalized vessel sharpness or qualitative image scores were observed with respect to the conventional method. Simple averaging resulted in an SNR gain, but significant loss in vessel sharpness and image quality. For late gadolinium enhancement, there was a significant increase in SNR, but no significant differences were observed in subjective image quality scores between the proposed and conventional methods. There was an SNR gain, but image quality loss for simple averaging, when compared with the conventional technique. In both coronary MRI and late gadolinium enhancement, the SNR gain of the proposed method was not significantly different than the maximum theoretical SNR gain. CONCLUSION: The proposed technique improves SNR using the additional information from NAV-rejected k-space lines, while providing similar image quality to standard reconstruction using motion-free k-space data only, with no increase in scan time.