Foam fractionation Tags (F-Tags) enabling surfactant-free, activity-preserving recovery of enzymes.

Enzymes have become important tools in many industries. However, the full exploitation of their potential is currently limited by a lack of efficient and cost-effective methods for enzyme purification from microbial production. One technology that could solve this problem is foam fractionation. In this study, we show that diverse natural foam-stabilizing proteins fused as F-Tags to ß-lactamase, penicillin G acylase, and formate dehydrogenase, respectively, are able to mediate foaming and recovery of the enzymes by foam fractionation. The catalytic activity of all three candidates is largely preserved. Under appropriate fractionation conditions, especially when a wash buffer is used, some F-Tags also allow nearly complete separation of the target enzyme from a contaminating protein. We found that a larger distance between the F-Tag and the target enzyme has a positive effect on the maintenance of catalytic activity. However, we did not identify any particular sequence motifs or physical parameters that influenced performance as an F-tag. The best results were obtained with a short helical F-Tag, which was originally intended to serve only as a linker sequence. The findings of the study suggest that the development of molecular tags that enable the establishment of surfactant-free foam fractionation for enzyme workup is a promising method. KEY POINTS: • Foam-stabilizing proteins mediate activity-preserving foam fractionation of enzymes • Performance as an F-Tag is not restricted to particular structural motifs • Separation from untagged protein benefits from low foam stability and foam washings.

Heart rate turbulence in acute ischemic stroke.

BACKGROUND: Heart rate turbulence (HRT), an ECG-based marker of autonomic cardiac regulation, has shown high prognostic value in patients with established cardiovascular diseases, while data in patients with acute ischemic stroke are scarce. PATIENTS AND METHODS: The HRT parameters turbulence onset and turbulence slope were analyzed using Holter-ECG recordings from patients with acute ischemic stroke, consecutively enrolled in the prospective observational HEBRAS study. HRT was categorized as normal (category 0; both parameters normal), abnormal (category 1; one parameter abnormal), or severely abnormal (category 2; both parameters abnormal). Outcomes of interest were functional outcome according to modified Rankin Scale (mRS) score at 3 months, mortality at 1 year, newly detected atrial fibrillation (AF), and evidence of focal myocardial fibrosis on cardiovascular MRI. RESULTS: HRT was assessed in 335 patients in sinus rhythm (median age 69 years, 37% female, median NIHSS score 2 on admission), including 262 (78%) with normal HRT, 47 (14%) with abnormal and 26 (8%) with severely abnormal HRT. Compared with normal HRT, severely abnormal HRT was associated with increased disability [higher mRS] at 3 months (adjusted odds ratio [aOR]: 2.9, 95% confidence interval [CI]: 1.3-6.6), new AF (aOR: 3.5, 95% CI: 1.1-10.6), MRI-detected myocardial fibrosis (aOR: 5.8, 95% CI: 1.3-25.9), but not with mortality at 1 year after stroke (aOR: 3.0, 95% CI: 0.7-13.9). Abnormal HRT was not associated with the analyzed outcomes. CONCLUSIONS: Severely abnormal HRT was associated with increased disability and previously unknown cardiac comorbidities. The potential role of HRT in selecting patients for extended AF monitoring and cardiac imaging should be further investigated.

Switching Vedolizumab from IV to SC Injection in Inflammatory Bowel Disease Patients with Active Disease: Real-World Experience from a German IBD Cohort.

BACKGROUND: Vedolizumab (VDZ) for subcutaneous (SC) injection was approved for use in Europe in 2020 and the US in 2023. Promising efficacy and tolerability have been proven in pivotal trials. However, real-world data on the SC use of VDZ, especially in patients with active disease, are still lacking. We aimed to determine treatment persistence and the drug's efficacy in inflammatory bowel disease (IBD) patients with active disease in comparison to patients in clinical remission. METHODS: Patients treated for IBD in a tertiary care center from July 2020 to December 2021 were included in this study. Clinical and biochemical parameters and data on treatment adherence were collected. VDZ trough levels and disease activity before and after the switch from intravenous (IV) to SC injections were monitored during routine checkups and were retrospectively analyzed. The patients were followed up until week 20. RESULTS: Eighty-two patients were included in the study. Of them, 35 patients had active disease (35/82 = 43%) at the time of the switch and 47 patients (47/82 = 57%) were in remission. In total, 10 patients experienced switch failure, 5 were switched back to IV VDZ, and 5 were swapped to a different biologic agent. We observed an increase in VDZ trough levels from the switch to week 8 and from the switch to week 20 in the remission group. Vedolizumab trough levels of 7.4, 51.4, and 33.45 ug/mL at the switch, week 8, and week 20 were identified to discriminate between remission and disease activity in our cohort. There was no new safety signal detected during the study period. CONCLUSIONS: The switch from IV to SC VDZ proved to be efficient, safe, and even capable of reducing residual disease activity.

Real-World Effectiveness of Vedolizumab vs Anti-TNF in Biologic-naïve Crohn's Disease Patients: A 2-year Propensity-score-adjusted Analysis from the VEDOIBD-Study.

BACKGROUND: The aim of this observational, real-world evidence, modified intention-to-treat (mITT) study based on prospectively collected data from the VEDOIBD registry was to compare the effectiveness of vedolizumab (VEDO) vs antitumor necrosis factor (anti-TNF) in biologic-naïve Crohn's disease (CD) patients. METHODS: Between 2017 and 2020, 557 CD patients starting therapy with VEDO or anti-TNF were consecutively enrolled in 45 IBD centers across Germany. Per study protocol, the analysis excluded biologic-experienced patients and those with a missing Harvey-Bradshaw Index score, resulting in a final sample of 327 biologic-naïve CD patients. Clinical remission was measured using the Harvey-Bradshaw Index at the end of induction therapy and after 1 and 2 years. Switching to a different therapy was considered an outcome failure. Propensity score adjustment with inverse probability of treatment weighting was used to correct for confounding. RESULTS: The effectiveness of both VEDO (n = 86) and anti-TNF (n = 241) was remarkably high for induction treatment, but VEDO performed significantly less well than anti-TNF (clinical remission: 56.3% vs 73.9%, P < .05). In contrast, clinical remission after 2 years was significantly better for VEDO compared with anti-TNF (74.2% vs 44.7%; P < .05; odds ratio, 0.45; 95% CI, 0.22-0.94). Remarkably, only 17% of patients switched from VEDO to another biologic vs 44% who received anti-TNF. CONCLUSIONS: The results of this prospective, 2-year, real-world evidence study suggest that the choice of VEDO led to higher remission rates after 2 years compared with anti-TNF. This could support the role of VEDO as a first-line biologic therapy in CD.

Real-world effectiveness of vedolizumab compared to anti-TNF agents in biologic-naïve patients with ulcerative colitis: A two-year propensity-score-adjusted analysis from the prospective, observational VEDOIBD -study.

BACKGROUND: This observational real-world evidence (RWE) study is based on prospectively collected data from the VEDOIBD registry study. AIM: To compare the effectiveness of vedolizumab and anti-TNF agents in biologic-naïve patients with ulcerative colitis (UC) at the end of induction and during maintenance treatment. METHODS: Between 2017 and 2020, we enrolled 512 patients with UC starting therapy with vedolizumab or an anti-TNF agent in 45 IBD centres across Germany. We excluded biologic-experienced patients and those with missing partial Mayo (pMayo) outcomes; this resulted in a final sample of 314 (182 on vedolizumab and 132 on an anti-TNF agent). The primary outcome was clinical remission measured using pMayo score; any switch to a different biologic agent was considered an outcome failure (modified ITT analysis). We used propensity score adjustment with inverse probability of treatment weighting to correct for confounding. RESULTS: During induction therapy, clinical remission was relatively low and similar in vedolizumab- and anti-TNF-treated patients (23% vs. 30.4%, p = 0.204). However, clinical remission rates after two years were significantly higher for vedolizumab-treated patients than those treated with an anti-TNF agent (43.2% vs. 25.8%, p < 0.011). Among patients treated with vedolzumab, 29% switched to other biologics, versus 54% who had received an anti-TNF agent. CONCLUSION: After two years of treatment, vedolizumab resulted in higher remission rates than anti-TNF agents.

Enhanced diagnostic workup increases pathological findings in patients with acute ischaemic stroke: results of the prospective HEBRAS study.

BACKGROUND: Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke (AIS). We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital. METHODS: Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke (HEBRAS) study at the Charité, Berlin, Germany. Patients with AIS without known atrial fibrillation (AF) underwent cardiovascular MR imaging (CMR), MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care. RESULTS: Among 356 patients with AIS (mean age 66 years, 37.6% female), enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care (17.7% vs 5.3%; p<0.001). Consequently, fewer patients were classified as cryptogenic after enhanced diagnostic workup (38.5% vs 45.5%, p<0.001). Routine care included echocardiography in 228 (64.0%) patients. CMR was successfully performed in 292 (82.0%) patients and revealed more often a prespecified pathological finding compared with routine echocardiography (16.1% vs 5.3%). Furthermore, study-related ECG monitoring (median duration 162 hours (IQR 98-210)) detected AF in 16 (4.5%) patients, while routine monitoring (median duration 51 hours (IQR 34-74)) detected AF in seven (2.0%) patients. CONCLUSIONS: Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke. TRIAL REGISTRATION NUMBER: NCT02142413.

Real-world Comparative Effectiveness of Ustekinumab vs Anti-TNF in Crohn's Disease With Propensity Score Adjustment: Induction Phase Results From the Prospective, Observational RUN-CD Study.

BACKGROUND: In addition to randomized controlled trials (RCTs), real-world studies on the effectiveness of ustekinumab (UST) in Crohn's disease (CD) are required inasmuch as RCTs are usually confined to selected patients, which may not represent everyday clinical practice. Within the framework of the prospective real-world RUN-CD registry, a total of approximately 900 CD patients from 44 inflammatory bowel disease centers from all over Germany starting a new therapy with UST or other biologics were screened for a real-world evidence (RWE) comparison of CD patients with UST vs antitumor necrosis factor (TNF). METHODS: A total of 618 CD patients with a nonrandomized biological therapy were qualified for this induction phase effectiveness RUN-CD study of UST vs anti-TNF. To reduce selection bias in estimations of treatment effects, the propensity score with inverse probability of treatment weighting was implemented. The results were reported as odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 339 UST and 279 anti-TNF patients were analyzed. The effectiveness of UST vs anti-TNF in terms of clinical remission (UST 65.4% vs anti-TNF 63.0%; OR, 1.11; 95% CI, 0.71-1.74) and steroid-free remission (UST 51.0% vs anti-TNF 53.8%; OR, 0.94; 95% CI, 0.60-1.47) was comparable at the end of induction therapy. Similar results were observed in the bio-naïve and bio-experienced UST vs anti-TNF groups. For both, the remission rates were higher in the bio-naïve than in the bio-experienced groups (P < .05). CONCLUSIONS: In this prospective, observational RUN-CD study, the RWE head-to-head comparison of UST vs anti-TNF showed similar induction effectiveness in both groups, remarkably higher than those found in prior RCTs.

The higher effectiveness outcome rates observed in patients treated with UST compared with pivotal studies in combination with its known favorable safety profile and an improved HRQoL support UST use as a first-line, advanced therapy in CD.

Early MOnitoring of REsponse (MORE) to Golimumab Therapy: Results of a Multicentre, Prospective Observational Trial.

BACKGROUND: The therapeutic goal of clinical remission in patients with moderate to severe ulcerative colitis (UC) is achieved after biological therapy only in 16-39%. Individualization of therapeutic intervention would benefit from prediction of early response. STUDY OBJECTIVE: The primary objective of our study was to assess golimumab (GLM) trough serum level of ≥2.5 µg/mL in combination with a reduction of faecal calprotectin (FC) of ≥50% at week 6 compared to baseline to predict clinical response at week 26 after regular GLM intake. METHODS: Patients with moderate to severe active UC and planned GLM treatment were recruited for a prospective, multicentre, observational study in Germany. Prediction of clinical response was assessed by FC and GLM trough level. Missing data were imputed as therapy failure according to the last observation carried forward method. RESULTS: Fifty nine patients have been enrolled. 54% of patients were anti-TNF naïve. Clinical response at week 6 was a significant predictor for achieving clinical response at week 26 (odds ratio [OR] 10.97, confidence interval [CI], 2.96-40.68; p < 0.001). Moreover, patients with a GLM trough level of ≥2.5 µg/mL and a ≥50% reduction of FC at week 6 had an OR of 5.33 (95% CI, 0.59-47.84) to achieve clinical response at week 26. CONCLUSION: Clinical response at week 6 is the best predictive marker for achieving clinical response at week 26. Consideration of significant reduction of FC and trough GLM serum levels could improve prediction of response.

Elevation of cardiac biomarkers in stroke is associated with pathological findings on cardiac MRI-results of the HEart and BRain interfaces in Acute Stroke study.

INTRODUCTION: Cardiac biomarkers, such as high-sensitivity cardiac troponin T (hs-cTnT), are frequently elevated in ischemic stroke patients but the mechanisms underlying this elevation are insufficiently understood. We determined the presence of cardiac damage, assessed using cardiac magnetic resonance imaging (CMR), in stroke patients with elevated hs-cTnT and brain natriuretic peptide (BNP). METHODS: This is a post hoc analysis of the prospective, investigator-initiated, cross-sectional HEart and BRain interfaces in Acute Stroke (HEBRAS) study. All patients underwent the measurement of hs-cTnT and BNP as well as gadolinium-enhanced CMR in the acute phase of ischemic stroke. We performed unadjusted and adjusted logistic regression models to assess the association between hs-cTnT and BNP elevation and the presence of pathological CMR findings. RESULTS: Two hundred and thirty-three stroke patients (median age 67 years, 33% female) were included, of whom 43 (21%) had elevated hs-cTnT and 109 (47%) had elevated BNP. Hundred of the 233 (43%) patients had pathological findings on CMR had focal fibrosis as detected by late-gadolinium enhancement (LGE) in 51 (23%), left-ventricular hypertrophy (LVH) in 38 (16%), reduced LVEF in 32 (14%), and left-atrial dilatation in 34 (15%). After adjustment for potential confounders, both hs-cTnT (adjOR 5.0 (95%CI 2.1-11.7), p < 0.001) and BNP (adjOR 4.1 (95%CI 2.3-7.3), p < 0.001) were significantly associated with pathological findings on CMR. Hs-cTnT was associated with LGE, LVEF, and LVH, whereas BNP was associated with left-atrial dilatation and LVEF, LVH. CONCLUSION: Elevated cardiac biomarkers in acute stroke including CMR are strongly associated with pathological findings on CMR. In acute stroke patients, the elevation of cardiac biomarkers may identify patients who require a more thorough cardiology work-up.

Rsn-2-mediated directed foam enrichment of ß-lactamase.

Today, the availability of methods for the activity-preserving and cost-efficient downstream processing of enzymes forms a major bottleneck to the use of these valuable tools in technical processes. A promising technology appears to be foam fractionation, which utilizes the adsorption of proteins at a gas-liquid interface. However, the employment of surfactants and the dependency of the applicability on individual properties of the target molecules are considerable drawbacks. Here, we demonstrate that a reversible fusion of the large, surface-active protein Ranaspumin-2 (Rsn-2) to a ß-lactamase (Bla) enabled both surfactant-free formation of a stable foam and directed enrichment of the enzyme by the foaming. At the same time, Bla maintained 70% of its catalytic activity, which was in stark contrast to the enzyme without fusion to Rsn-2. Rsn-2 predominantly mediated adsorption. Comparable results were obtained after fusion to the structurally more complex penicillin G acylase (PGA) as the target enzyme. The results indicate that using a surface-active protein as a fusion tag might be the clue to the establishment of foam fractionation as a general method for enzyme downstream processing.

A Systematic Approach to Diagnostic Laboratory Software Requirements Analysis.

Genetics plays an ever-increasing role in medical diagnostics. The requirements for laboratory diagnostics are constantly changing due to new emerging diagnostic procedures, methodologies, devices, and regulatory requirements. Standard software already available for laboratories often cannot keep up with the latest developments or is focused on research rather than process automation. Although the software utilized in diagnostic laboratories is subject to regulatory requirements, there is no well-defined formal procedure for software development. Reference models have been developed to formalize these solutions, but they do not facilitate the initial requirements analysis or the development process itself. A systematic requirements engineering process is however not only essential to ensure the quality of the final product but is also required by regulations such as the European In Vitro Diagnostic Regulation and international standards such as IEC 62304. This paper shows, by example, the systematic requirements analysis of a system for qPCR-based (quantitative polymerase chain reaction) gene expression analysis. Towards this goal, a multi-step research approach was employed, which included literature review, user interviews, and market analysis. Results revealed the complexity of the field with many requirements to be considered for future implementation.

[Inferior temporal electrodes in 24-h EEG]. / Subtemporale Elektroden im 24­Stunden-EEG.

BACKGROUND: To improve the sensitivity of the EEG in the diagnosis and classification of seizures or epilepsy, long-term recording with inferior temporal electrodes are recommended. MATERIAL AND METHODS: The spatial distribution of epileptiform discharges from 24­h EEG with 25 electrodes (10-20, extended by F9/F10, T9/T10, P9/P10) was retrospectively analyzed in 25 cases. RESULTS: Maximum negativity was located below the 10-20 electrodes in 84%. Epileptiform discharges were more clearly detected on inferior temporal electrodes in 64%. In the intention-to-test population of 77 patients the number needed to test with extra electrodes was estimated as 5. CONCLUSION: Recording EEG with 25 electrodes for 24 h improves the detection and localization of temporal epileptiform discharges also in geriatric patients with suspected nonlesional epilepsy.

[Effects of SARS-CoV-2 Infection on Symptoms and Therapy of Inflammatory Bowel Disease]. / Auswirkungen einer SARS-CoV-2-Infektion auf Symptomatik und Therapie chronisch-entzündlicher Darmerkrankungen.

INTRODUCTION: The influence of a SARS-CoV-2 infection on inflammatory bowel disease (IBD) has not yet been well characterized and it is unclear whether this requires an adaptation of the immunosuppressive therapy. METHODS: A national register was established for the retrospective documentation of clinical parameters and changes in immunosuppressive therapy in SARS-CoV-2 infected IBD patients. RESULTS: In total, only 3 of 185 IBD patients (1.6 %) were tested for SARS-CoV-2 infection because of abdominal symptoms. In the course of COVID-19 disease, 43.5 % developed diarrhea, abdominal pain or hematochezia (risk of hospitalization with vs. without abdominal symptoms: 20.0 % vs. 10.6 %, p < 0.01). With active IBD at the time of SARS-CoV-2 detection, there was an increased risk of hospitalization (remission 11.2 %, active IBD 23.3 % p < 0.05). IBD-specific therapy remained unchanged in 115 patients (71.4 %); the most common change was an interruption of systemic therapy (16.2 %). DISCUSSION: New abdominal symptoms often appeared in SARS-CoV-2 infected IBD patients. However, these only rarely led to SARS-CoV-2 testing. A high IBD activity at the time of SARS-CoV-2 detection was associated with an increased risk of hospitalization.

Profile of patients with inflammatory bowel disease in conjunction with unmet needs and decision-making for choosing a new biologic therapy: a baseline analysis of the VEDOIBD-Study.

PURPOSE: We characterized the profile of Crohn's disease (CD) or ulcerative colitis (UC) biologic-naïve patients (starting a new therapy with vedolizumab or TNFα-antagonists), their baseline disease activity predictors, and their perception of the quality of life (HRQoL). METHODS: The VEDOIBD-Study is a real-world study on the effectiveness of vedolizumab vs other biologics as induction and maintenance therapy for CD and UC. A total of 627 CD and 546 UC patients were enrolled from IBD-experienced centers across Germany. In both biologic-naïve vedolizumab (n=397) and anti-TNF (n=359) patients, CD and UC disease severity and HRQoL predictors were analyzed with logistic regression. The results were reported as odds ratio (OR) and 95% confidence interval (CI). RESULTS: When compared to biologic-naïve anti-TNF patients, a first biological therapy with vedolizumab was considered for older CD patients, with a less complicated though longer disease course, and with a history of comorbidities. No differences in (unmet) needs were observed among patients with UC. The presence of extra-intestinal manifestations in biologic-naïve anti-TNF patients with CD (OR (95% CI): 3.83 (1.69-8.68)) and, in both biologic-naïve groups of patients with UC, stool frequency (2.00 (1.25-3.19); 1.82 (1.10-3.02), respectively) and rectal bleeding (2.24 (1.20-4.18); 1.92 (1.19-3.11), respectively) emerged as the most important predictors of disease severity, which in turn were also significantly associated with a worse HRQoL. CONCLUSION: This study highlights the existence of unmet medical needs of patients with CD or UC, for whom a new biological therapy is planned as part of the VEDOIBD-Study, which considerably impacts their HRQoL.

Impact of the Microbial Origin and Active Microenvironment on the Shape of Biogenic Elemental Selenium Nanomaterials.

The shape of nanomaterials affects their colloidal properties, cellular uptake, and fate in the environment. The microbial origin and microenvironment can play a role in altering the shape of the nanomaterial. However, such studies have never been conducted. Here, we demonstrate that the selenium nanomaterials produced by Escherichia coli K-12 are stable and remain as BioSe-Nanospheres under thermophilic conditions, while those produced by anaerobic granular sludge transform to BioSe-Nanorods, due to a lower quantity of proteins coating these nanoparticles, which has been verified by proteomics analysis as well as using chemically synthesized selenium nanomaterials. Furthermore, the presence of Bacillus safensis JG-B5T transform the purified BioSe-Nanospheres produced by E. coli K-12 to BioSe-Nanorods, though they are not transformed in the absence of B. safensis JG-B5T. This is due to the production of peptidases by B. safensis JG-B5T that cleaves the protein coating the BioSe-Nanospheres produced by E. coli K-12, leading to their transformation to trigonal BioSe-Nanorods, which is the thermodynamically more stable state. These findings suggest that the fate of selenium and probably other redox-active elements released from the biological wastewater treatment units needs to be reevaluated and improved by including microbial criteria for better accuracy.

[Joint DGN, OGNMB and SGNM S1 guideline for radiosynoviorthesis]. / Gemeinsame Handlungsempfehlung (S1-Leitlinie) von DGN, OGNMB und SGNM ­ Radiosynoviorthese ­ Stand: 9/2019 ­ AWMF-Registernummer: 031-023.

This recommendation is intended to provide a guideline for radiosynoviorthesis (RSO) in the effective local treatment of chronic inflammatory (non-infectious) joint diseases. It was developed in an interdisciplinary manner and describes the general objectives, definitions, clinical background information, indication and contraindications of this radionuclide therapy. The requirements to be met by a treatment center, the results of pretherapeutic examinations as well as recommendations on how the treatment should be carried out. Here, organizational and technical issues have been considered. Furthermore, information on the surveillance and follow-up of the treated patients can be found. In general, treatment and follow-up should be done in in close cooperation of the participating disciplines.

Heart Rate Variability and Recurrent Stroke and Myocardial Infarction in Patients With Acute Mild to Moderate Stroke.

Objectives: In patients with acute ischemic stroke, reduced heart rate variability (HRV) may indicate poor outcome. We tested whether HRV in the acute phase of stroke is associated with higher rates of mortality, recurrent stroke, myocardial infarction (MI) or functional outcome. Materials and Methods: Patients with acute mild to moderate ischemic stroke without known atrial fibrillation were prospectively enrolled to the investigator-initiated Heart and Brain interfaces in Acute Ischemic Stroke (HEBRAS) study (NCT02142413). HRV parameters were assessed during the in-hospital stay using a 10-min section of each patient's ECG recording at day- and nighttime, calculating time and frequency domain HRV parameters. Frequency of a combined endpoint of recurrent stroke, MI or death of any cause and the respective individual events were assessed 12 months after the index stroke. Patients' functional outcome was measured by the modified Rankin Scale (mRS) at 12 months. Results: We included 308 patients (37% female, median NIHSS = 2 on admission, median age 69 years). Complete follow-up was achieved in 286/308 (93%) patients. At 12 months, 32 (9.5%), 5 (1.7%) and 13 (3.7%) patients had suffered a recurrent stroke, MI or death, respectively. After adjustment for age, sex, stroke severity and vascular risk factors, there was no significant association between HRV and recurrent stroke, MI, death or the combined endpoint. We did not find a significant impact of HRV on a mRS ≥ 2 12 months after the index stroke. Conclusion: HRV did not predict recurrent vascular events in patients with acute mild to moderate ischemic stroke.

Measurement as a Performance Driver: The Case for a National Measurement System to Improve Patient Safety.

ABSTRACT: Safety metrics in healthcare settings stand apart from those in all other industries. Despite improvements in the measurement and prevention of adverse health outcomes following the 1999 Institute of Medicine report, no fully operational national-level program for monitoring patient harm exists. Here, we review the annual rate of fatal adverse events in healthcare settings in the United States on the basis of previous research, assess the current state of measurements of patient harm, propose a national standard to both quantify harm and act as a performance driver for improved safety, and discuss additional considerations such as accountability and implications for tort reform under this standard. On the basis of experiences in other sectors, we propose a federally mandated, nonpunitive national system that relies on accurate measurement as a driver of performance.

Evaluation of left ventricular function in patients with acute ischaemic stroke using cine cardiovascular magnetic resonance imaging.

AIMS: Heart failure (HF) is frequent in patients with acute ischaemic stroke (AIS) and associated with higher morbidity and mortality. Assessment of cardiac function in AIS patients using cardiovascular MRI (CMR) may help to detect HF. We report the rate of systolic and diastolic dysfunction in a cohort of patients with AIS using CMR and compare cine real-time (CRT) sequences with the reference of segmented cine steady-state free precession sequences. METHODS AND RESULTS: Patients with AIS without known atrial fibrillation were prospectively enrolled in the HEart and BRain Interfaces in Acute Ischemic Stroke (HEBRAS) study (NCT02142413) and underwent CMR at 3 Tesla within 7 days after AIS. Validity of CRT sequences was determined in 50 patients. A total of 229 patients were included in the analysis (mean age 66 years; 35% women; HF 2%). Evaluation of cardiac function was successful in 172 (75%) patients. Median time from stroke onset to CMR was 82 h (interquartile range 56-111) and 54 h (interquartile range 31-78) from cerebral MRI to CMR. Systolic dysfunction was observed in 43 (25%) and diastolic dysfunction in 102 (59%) patients. Diagnostic yield was similar using CRT or segmented cine imaging (no significant difference in left ventricular ejection fraction, myocardial mass, time to peak filling rate, and peak filling rate ratio E/A). Intraobserver and interobserver agreement was high (κ = 0.78-1.0 for all modalities). CONCLUSIONS: Cardiovascular MRI at 3 Tesla is an appropriate method for the evaluation of cardiac function in a selected cohort of patients with AIS. Systolic and diastolic dysfunction is frequent in these patients. CRT imaging allows reliable assessment of systolic and diastolic function.

3D printing of radioactive phantoms for nuclear medicine imaging.

BACKGROUND: For multicenter clinical studies, PET/CT and SPECT/CT scanners need to be validated to ensure comparability between various scanner types and brands. This validation is usually performed using hollow phantoms filled with radioactive liquids. In recent years, 3D printing technology has gained increasing popularity for manufacturing of phantoms, as it is cost-efficient and allows preparation of phantoms of almost any shape. So far, however, direct 3D printing with radioactive building materials has not yet been reported. The aim of this work was to develop a procedure for preparation of 99mTc-containing building materials and demonstrate successful application of this material for 3D printing of several test objects. METHOD: The desired activity of a [99mTc]pertechnetate solution eluted from a 99Mo/99mTc-generator was added to the liquid 3D building material, followed by a minute amount of trioctylphosphine. The resulting two-phase mixture was thoroughly mixed. Following separation of the phases and chemical removal of traces of water, the radioactive building material was diluted with the required volume of non-radioactive building material and directly used for 3D printing. RESULTS: Using our optimized extraction protocol with trioctylphosphine as complex-forming phase transfer agent, technetium-99m was efficiently transferred from the aqueous 99Mo/99mTc-generator eluate into the organic liquid resin monomer. The observed radioactivity concentration ratio between the organic phase and the water phase was > 2000:1. The radioactivity was homogeneously distributed in the liquid resin monomer. We did not note differences in the 3D printing behavior of the radiolabeled and the unlabeled organic liquid resin monomers. Radio-TLC and SPECT studies showed homogenous 2D and 3D distribution of radioactivity throughout the printed phantoms. The radioactivity was stably bound in the resin, apart from a small amount of surface-extractable radioactivity under harsh conditions (ethanol at 50 °C). CONCLUSIONS: 3D printing of radioactive phantoms using 99mTc-containing building materials is feasible. Compared to the classical fillable phantoms, 3D printing with radioactive building materials allows manufacturing of phantoms without cold walls and in almost any shape. Related procedures with longer-lived radionuclides will enable production of phantoms for scanner validation and quality control.