Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.

AIMS: Lipoprotein(a) [Lp(a)] is a recognized causal risk factor for atherosclerotic cardiovascular disease but its role for acute ischaemic stroke (AIS) is controversial. In this study, we evaluated the association of Lp(a) with large artery atherosclerosis (LAA) stroke and risk of recurrent cerebrovascular events in AIS patients. METHODS AND RESULTS: For this analysis of the prospective, observational, multicentre BIOSIGNAL cohort study we measured Lp(a) levels in plasma samples of 1733 primarily Caucasian (98.6%) AIS patients, collected within 24 h after symptom onset. Primary outcomes were LAA stroke aetiology and recurrent cerebrovascular events (ischaemic stroke or transient ischaemic attack) within 1 year. We showed that Lp(a) levels are independently associated with LAA stroke aetiology [adjusted odds ratio 1.48, 95% confidence interval (CI) 1.14-1.90, per unit log10Lp(a) increase] and identified age as a potent effect modifier (Pinteraction =0.031) of this association. The adjusted odds ratio for LAA stroke in patients aged <60 years was 3.64 (95% CI 1.76-7.52) per unit log10Lp(a) increase and 4.04 (95% CI 1.73-9.43) using the established cut-off ≥100 nmol/l. For 152 recurrent cerebrovascular events, we did not find a significant association in the whole cohort. However, Lp(a) levels ≥100 nmol/l were associated with an increased risk for recurrent events among patients who were either <60 years [adjusted hazard ratio (HR) 2.40, 95% CI 1.05-5.47], had evident LAA stroke aetiology (adjusted HR 2.18, 95% CI 1.08-4.40), or had no known atrial fibrillation (adjusted HR 1.60, 95% CI 1.03-2.48). CONCLUSION: Elevated Lp(a) was independently associated with LAA stroke aetiology and risk of recurrent cerebrovascular events among primarily Caucasian individuals aged <60 years or with evident arteriosclerotic disease.

sIL2R ratio as early marker for response in hairy cell leukemia and the prognostic relevance of IL28B genotype to interferon-α therapy.

Interferon-α (IFNα) was the first effective drug therapy for hairy cell leukemia (HCL). Nowadays, it is used as an alternative treatment in selected patients. Due to unlimited treatment time, monitoring and early prediction of response are important. Moreover, IFNα is used in the therapy of chronic hepatitis C, where a single nucleotide polymorphism of interleukin-28B gene (IL28B) correlates with therapy response. The role of this polymorphism in therapy response of IFNα-treated patients with HCL is unknown. Thirty-seven HCL patients treated between 1978 and 2014 were included in this study. Treatment strategy and response parameters (blood cell counts, soluble interleukin-2 receptor (sIL2R), and bone marrow examination) have been assessed. Relative decrease of sIL2R was correlated with outcome parameters. Response parameters of IFNα-treated patients were correlated with IL28B polymorphism. Twenty-one patients were analyzed for the correlation of sIL2R ratio and outcome. After 1 and 3 months of therapy (IFNα or cladribine (CDA)), the median sIL2R level showed a relative decrease of 79 and 91%. These decreases significantly correlate with time to complete remission (CR, p = 0.029 and p = 0.018). Correlation analyses of IL28B genotype with outcome parameters are not significant. Six patients (16%) were diagnosed with secondary malignancies, and one death was registered (median follow-up time 14 years). IFNα is a safe, effective, and well-tolerated long-term treatment in HCL. Relative decreases of sIL2R levels correlate with time to CR and are useful as early predictor for response. There is no significant correlation between IL28B polymorphism and treatment response to IFNα. Graphical abstract.

Evaluation of two fully automated immunoassay based tests for the measurement of 1α,25-dihydroxyvitamin D in human serum and comparison with LC-MS/MS.

BACKGROUND: 1α,25-Dihydroxyvitamin D [1,25(OH)2 vitD] is the bioactive form of vitamin D. Due to the very low concentrations of 1,25(OH)2 vitD in the blood and its lipophilic character, measurement of this parameter is analytically challenging. Requiring preceding manual extraction steps before analysis, previous assays have been laborious. METHODS: In the presented study, we evaluated the performance of two immunoassays from DiaSorin and from Immunodiagnostic Systems (IDS) which combine fully automated extraction and measurement of 1,25(OH)2 vitD. Imprecision and linearity were verified according to Clinical and Laboratory Standards Institute EP15-A3 and EP6-A guidelines, respectively. Ninety-three patient serum samples sent to our institute for determination of 1,25(OH)2 vitD, as well as 20 Vitamin D External Quality Assessment Scheme (DEQAS) samples, were used to evaluate correlation and agreement of 1,25(OH)2 vitD measurements between the two immunoassays and with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). RESULTS: Total imprecision was 5.2% or less for the DiaSorin test but reached 20.1% for the IDS iSYS test. 1,25(OH)2 vitD concentrations measured with the DiaSorin assay showed a strong correlation with 1,25(OH)2 vitD levels measured by LC-MS/MS and a good agreement with method specific means of DEQAS samples. By contrast, the IDS iSYS test overestimated 1,25(OH)2 vitD concentrations in human serum, particularly at higher concentrations. CONCLUSIONS: Due to its high sensitivity, low imprecision, broad measurement range, and good agreement with 1,25(OH)2 vitD concentrations measured by LC-MS/MS, the DiaSorin test is a valuable analytical option for the determination of 1,25(OH)2 vitD.

Reference intervals for 24 laboratory parameters determined in 24-hour urine collections.

BACKGROUND: Reference intervals for many laboratory parameters determined in 24-h urine collections are either not publicly available or based on small numbers, not sex specific or not from a representative sample. METHODS: Osmolality and concentrations or enzymatic activities of sodium, potassium, chloride, glucose, creatinine, citrate, cortisol, pancreatic α-amylase, total protein, albumin, transferrin, immunoglobulin G, α1-microglobulin, α2-macroglobulin, as well as porphyrins and their precursors (δ-aminolevulinic acid and porphobilinogen) were determined in 241 24-h urine samples of a population-based cohort of asymptomatic adults (121 men and 120 women). For 16 of these 24 parameters creatinine-normalized ratios were calculated based on 24-h urine creatinine. The reference intervals for these parameters were calculated according to the CLSI C28-A3 statistical guidelines. RESULTS: By contrast to most published reference intervals, which do not stratify for sex, reference intervals of 12 of 24 laboratory parameters in 24-h urine collections and of eight of 16 parameters as creatinine-normalized ratios differed significantly between men and women. For six parameters calculated as 24-h urine excretion and four parameters calculated as creatinine-normalized ratios no reference intervals had been published before. For some parameters we found significant and relevant deviations from previously reported reference intervals, most notably for 24-h urine cortisol in women. Ten 24-h urine parameters showed weak or moderate sex-specific correlations with age. CONCLUSIONS: By applying up-to-date analytical methods and clinical chemistry analyzers to 24-h urine collections from a large population-based cohort we provide as yet the most comprehensive set of sex-specific reference intervals calculated according to CLSI guidelines for parameters determined in 24-h urine collections.

No major effects of vitamin D3 (1,25 dihydroxyvitamin D3) on absorption and pharmacokinetics of folic acid and fexofenadine in healthy volunteers.

PURPOSE: In Caco-2 cells, folate uptake via the proton-coupled folate transporter (PCFT) increases significantly by a 3-day treatment with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Additionally, mRNA content and protein expression of the transporter OATP1A2 were increased up to ninefold with 1,25(OH)2D3. We investigated whether these in vitro findings can be confirmed in humans in vivo. METHODS: Ten healthy volunteers (six women) received 5 mg folic acid orally once before and once together with the last intake of a 10-day course of 0.5 µg 1,25(OH)2D3 orally. One hundred twenty milligrams fexofenadine, an OATP1A2 substrate, was taken in 1 day before the first folic acid intake, and again on the ninth day of 1,25(OH)2D3 intake. Duodenal biopsies were taken for transporter mRNA assessments once before and once on the ninth or tenth day of the vitamin D3 course. Serum folic acid and fexofenadine concentrations were quantified with a chemiluminescence immunoassay and LC-MS/MS, respectively. Pharmacokinetics were compared between periods with standard bioequivalence approaches. RESULTS: While geometric mean folic acid AUC0-2h, which mainly reflects absorption, was 0.403 and 0.414 mg/L·h before and after the vitamin D3 course (geometric mean ratio (GMR), 1.027; 90 % confidence interval (90 % CI), 0.788-1.340), the geometric mean fexofenadine AUC0-2h was 1.932 and 2.761 mg/L·h, respectively (GMR, 1.429; 90 % CI, 0.890-2.294). PCFT- and OATP1A2-mRNA expressions in duodenal biopsies were essentially unchanged. CONCLUSIONS: No significant changes in folic acid and fexofenadine absorption were observed after a 10-day course of 1,25(OH)2D3 in humans in vivo. This study underlines the importance of confirming in vitro findings in vivo in humans.

Interassay Variability and Clinical Implications of Five Different Prostate-specific Antigen Assays.

Background and objective: Prostate-specific antigen (PSA) remains a critical marker for prostate cancer (PCa) detection and monitoring. Recognising historical variability in PSA assays and the evolution of assay technology and calibration, this study aims to reassess interassay variability using the latest generation of five assays in a contemporary cohort of men undergoing prostate biopsy. Methods: Five different commercially available PSA assays were tested in a blood sample of 76 men before undergoing a prostate biopsy. Total PSA (tPSA) and free-to-total PSA ratio (%fPSA) were compared across assays, using Roche (Basel, Switzerland) as the benchmark, and correlated with biopsy outcome to analyse the impact on PCa diagnosis. The statistical analysis included Passing-Bablok regression and Bland-Altman plots, with a p value threshold of <0.05 for significance. Key findings and limitations: Among the 76 men, 28 (36.8%) were diagnosed with significant PCa (defined as International Society of Urological Pathology grade ≥2). A high correlation was observed between tPSA and %fPSA values among the different PSA assays tested (r2 ≥ 0.9). The Passing-Bablok analysis showed that tPSA results varied substantially among the assays, with slopes ranging between 0.78 and 1.04. Compared with the tPSA of Roche, tPSA values were on average 20.7% lower by Beckman (Oststeinbeck, Germany), 15.2% lower by Abbott (Chicago, IL, USA), 6.1% lower by Diasorin (Saluggia, Italy), and 9.6% higher by Brahms (Hennigsdorf, Germany; p < 0.001 for all). The %fPSA values by Abbott and Brahms were higher at 15.7% and 10.6%, respectively (p < 0.001), while the Beckman and Diasorin values had minimal differences of -0.3% and 2.3%, respectively (p > 0.05). The variability across assays would have resulted in discrepancies in both the sensitivity and the specificity for tPSA and %fPSA by at least 14%, depending on the cut-offs applied. Conclusions and clinical implications: Despite the use of the latest PSA assays, relevant variability of tPSA and %fPSA results can be observed among different assays. There is an urgent need for standardised calibration methods and greater awareness among practitioners concerning interassay variability. Clinicians should acknowledge that clinically relevant thresholds may depend on the specific PSA assay and that ideally the same assay is applied over time for better clinical decision-making. Patient summary: Prostate-specific antigen (PSA) is a critical marker for prostate cancer (PCa) detection and monitoring. However, significant variations were observed in the results of the latest PSA assays. Thus, standardised calibration methods and greater awareness among practitioners concerning interassay variability are needed.

Pro-angiogenic and antibacterial copper containing nanoparticles in PLGA/amorphous calcium phosphate bone nanocomposites.

Large bone defects after trauma demand for adequate bone substitutes. Bone void fillers should be antibacterial and pro-angiogenic. One viable option is the use of composite materials like the combination of PLGA and amorphous calcium phosphate (aCaP). Copper stimulates angiogenesis and has antibacterial qualities. Either copper oxide (CuO) nanoparticles (NPs) were therefore added to PLGA/aCaP/CuO in different concentrations (1, 5 and 10 w/w %) or copper-doped tricalcium phosphate NPs (TCP with 2% of copper) were electrospun into PLGA/CuTCP nanocomposites. Bi-layered nanocomposites of PLGA/aCaP with different copper NPs (CuO or TCP) and a second layer of pristine PLGA were fabricated. Two clinical bacterial isolates (Staphylococcus aureus and Staphylococcus epidermidis) were used to assess antibacterial properties of the copper-containing materials. For angiogenesis, the chorioallantoic membrane (CAM) assay of the chicken embryo was performed. The higher the CuO content, the higher were the antibacterial properties, with 10 % CuO reducing bacterial adhesion most effectively. Vessel and cell densities were highest in the 5 % CuO containing scaffolds, while tissue integration was more pronounced at lower CuO content. The PLGA/aCaP/CuO (1 % CuO) behaved similar like PLGA/CuTCP in all angiogenic and antibacterial readouts, based on the same copper fraction. We conclude that CuO NPs or CuTCP NPs are useful components to increase angiogenic properties of nanocomposites and at the same time exhibiting antibacterial characteristics.

Natriuretic Peptides to Classify Risk of Atrial Fibrillation Detection After Stroke: Analysis of the BIOSIGNAL and PRECISE Cohort Studies.

BACKGROUND AND OBJECTIVES: Prolonged cardiac monitoring (PCM) increases atrial fibrillation (AF) detection after ischemic stroke, but access is limited, and it is burdensome for patients. Our objective was to assess whether midregional proatrial natriuretic peptide (MR-proANP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) could classify people who are unlikely to have AF after ischemic stroke and allow better targeting of PCM. METHODS: We analyzed people from the Biomarker Signature of Stroke Aetiology (BIOSIGNAL) study with ischemic stroke, no known AF, and ≥3 days cardiac monitoring. External validation was performed in the Preventing Recurrent Cardioembolic Stroke: Right Approach, Right Patient (PRECISE) study of 28 days of cardiac monitoring in people with ischemic stroke or transient ischemic attack and no known AF. The main outcome is no AF detection. We assessed the discriminatory value of MR-proANP and NT-proBNP combined with clinical variables to identify people with no AF. A decision curve analysis was performed with combined data to determine the net reduction in people who would undergo PCM using the models based on a 15% threshold probability for AF detection. RESULTS: We included 621 people from the BIOSIGNAL study. The clinical multivariable prediction model included age, NIH Stroke Scale score, lipid-lowering therapy, creatinine, and smoking status. The area under the receiver-operating characteristic curve (AUROC) for clinical variables was 0.68 (95% CI 0.62-0.74), which improved with the addition of log10MR-proANP (0.72, 0.66-0.78; p = 0.001) or log10NT-proBNP (0.71, 0.65-0.77; p = 0.009). Performance was similar for the models with log10MR-proANP vs log10NT-proBNP (p = 0.28). In 239 people from the PRECISE study, the AUROC for clinical variables was 0.68 (0.59-0.76), which improved with the addition of log10NT-proBNP (0.73, 0.65-0.82; p < 0.001) or log10MR-proANP (0.79, 0.72-0.86; p < 0.001). Performance was better for the model with log10MR-proANP vs log10NT-proBNP (p = 0.03). The models could reduce the number of people who would undergo PCM by 30% (clinical and log10MR-proANP), 27% (clinical and log10NT-proBNP), or 20% (clinical only). DISCUSSION: MR-proANP and NT-proBNP help classify people who are unlikely to have AF after ischemic stroke. Measuring MR-proANP or NT-proBNP could reduce the number of people who need PCM by 30%, without reducing the amount of AF detected. TRIAL REGISTRATION INFORMATION: NCT02274727; clinicaltrials.gov/study/NCT02274727.

Sirolimus and kidney growth in autosomal dominant polycystic kidney disease.

BACKGROUND: In autosomal dominant polycystic kidney disease (ADPKD), aberrant activation of the mammalian target of rapamycin (mTOR) pathway is associated with progressive kidney enlargement. The drug sirolimus suppresses mTOR signaling. METHODS: In this 18-month, open-label, randomized, controlled trial, we sought to determine whether sirolimus halts the growth in kidney volume among patients with ADPKD. We randomly assigned 100 patients between the ages of 18 and 40 years to receive either sirolimus (target dose, 2 mg daily) or standard care. All patients had an estimated creatinine clearance of at least 70 ml per minute. Serial magnetic resonance imaging was performed to measure the volume of polycystic kidneys. The primary outcome was total kidney volume at 18 months on blinded assessment. Secondary outcomes were the glomerular filtration rate and urinary albumin excretion rate at 18 months. RESULTS: At randomization, the median total kidney volume was 907 cm3 (interquartile range, 577 to 1330) in the sirolimus group and 1003 cm3 (interquartile range, 574 to 1422) in the control group. The median increase over the 18-month period was 99 cm3 (interquartile range, 43 to 173) in the sirolimus group and 97 cm3 (interquartile range, 37 to 181) in the control group. At 18 months, the median total kidney volume in the sirolimus group was 102% of that in the control group (95% confidence interval, 99 to 105; P=0.26). The glomerular filtration rate did not differ significantly between the two groups; however, the urinary albumin excretion rate was higher in the sirolimus group. CONCLUSIONS: In adults with ADPKD and early chronic kidney disease, 18 months of treatment with sirolimus did not halt polycystic kidney growth. (Funded by Wyeth and others; ClinicalTrials.gov number, NCT00346918.)

Phototherapy with UVB narrowband, UVA/UVBnb, and UVA1 differentially impacts serum 25-hydroxyvitamin-D3.

BACKGROUND: Ultraviolet (UV) B radiation increases serum 25-hydroxyvitamin-D3 [25(OH)D], but the influence of UVA1 and UVA/narrowband UVB (UVBnb) phototherapy on serum vitamin D is unknown. OBJECTIVE: We sought to investigate the influence of UVBnb, UVA1, and UVA/UVBnb phototherapy on serum levels of 25(OH)D and related parameters in patients with an inflammatory skin condition. METHODS: 25(OH)D, as well as calcium, parathormone, phosphate, and albumin were measured before therapy, 2 weeks after start, and after completion of the phototherapy. Diagnoses were divided in 4 groups: atopic dermatitis, psoriasis, morphea, and others. RESULTS: We surveyed 116 dermatologic patients undergoing phototherapy with UVA1 (n = 38), UVA/UVBnb (n = 30), or UVBnb (n = 48) 2 to 3 times a week for 53 to 90 days. UVBnb phototherapy increased serum 25(OH)D from 22.1 to 39.5 ng/mL after the therapy (P < .001). The lower the baseline 25(OH)D level was, the steeper the increase in 25(OH)D was upon application of UVBnb phototherapy. UVA/UVBnb therapy also increased serum 25(OH)D, from 23.9 to 50.3 ng/mL (P = .003). Conversely, in the UVA1 therapy group, 25(OH)D serum levels decreased significantly from 21.9 to 19.0 ng/mL (P < .001). LIMITATIONS: The study design was open trial without randomization. An influence of a precise skin disease cannot be excluded because of the heterogeneous diagnoses. Bias may have arisen from patient preference for treatment at our center, referral, unrecognized differences in underlying skin disease, and other factors. CONCLUSION: Phototherapy with UVBnb and UVA/UVBnb increased 25(OH)D serum level significantly. UVA1 therapy alone induced a reduction in serum 25(OH)D concentrations.

Early serum procalcitonin level after primary total hip replacement.

BACKGROUND: Procalcitonin (PCT) is a useful surrogate marker for the differentiation of postoperative infection and unspecific inflammatory reaction after surgery. It is known that postoperative course of the PCT serum level varies with type of surgery. No data exists about the postoperative course of serum PCT levels after primary total hip replacement (THR). PURPOSE: To characterize early postoperative serum PCT levels in uneventful primary THR compared to postoperative levels of different frequently used inflammatory blood parameters. METHOD: We prospectively investigated 31 patients. Blood samples were taken preoperatively and for 5 days postoperatively. PCT levels were compared with C-reactive protein (CRP), interleukin-6 (IL-6), and blood leucocyte counts (WBC). RESULTS: In uneventful THR PCT levels showed a uniform low-level course with a peak at the second postoperative day. At the fifth day values returned to almost preoperative levels. On contrary, CRP levels remained high during the entire observational period. Only IL-6 levels showed a peak at postoperative day one with a quick and uniform return to preoperative levels. CONCLUSION: Similar to observations in cardiothoracic, intestinal, and neural surgeries, postoperative course of PCT after primary THR showed a uniform low-level course with a peak at the second postoperative day but below expected levels in systemic infections.

Effects of enhanced adsorption haemofiltration versus haemoadsorption in severe, refractory septic shock with high levels of endotoxemia: the ENDoX bicentric, randomized, controlled trial.

BACKGROUND: Endotoxin adsorption is a promising but controversial therapy in severe, refractory septic shock and conflicting results exist on the effective capacity of available devices to reduce circulating endotoxin and inflammatory cytokine levels. METHODS: Multiarm, randomized, controlled trial in two Swiss intensive care units, with a 1:1:1 randomization of patients suffering severe, refractory septic shock with high levels of endotoxemia, defined as an endotoxin activity ≥ 0.6, a vasopressor dependency index ≥ 3, volume resuscitation of at least 30 ml/kg/24 h and at least single organ failure, to a haemoadsorption (Toraymyxin), an enhanced adsorption haemofiltration (oXiris) or a control intervention. Primary endpoint was the difference in endotoxin activity at 72-h post-intervention to baseline. In addition, inflammatory cytokine, vasopressor dependency index and SOFA-Score dynamics over the initial 72 h were assessed inter alia. RESULTS: In the 30, out of 437 screened, randomized patients (10 Standard of care, 10 oXiris, 10 Toraymyxin), endotoxin reduction at 72-h post-intervention-start did not differ among interventions (Standard of Care: 12 [1-42]%, oXiris: 21 [10-51]%, Toraymyxin: 23 [10-36]%, p = 0.82). Furthermore, no difference between groups could be observed neither for reduction of inflammatory cytokine levels (p = 0.58), nor for vasopressor weaning (p = 0.95) or reversal of organ injury (p = 0.22). CONCLUSIONS: In a highly endotoxemic, severe, refractory septic shock population neither the Toraymyxin adsorber nor the oXiris membrane could show a reduction in circulating endotoxin or cytokine levels over standard of care. Trial registration ClinicalTrials.gov. NCT01948778. Registered August 30, 2013. https://clinicaltrials.gov/study/NCT01948778.

The Role of Electrocardiographic Markers for Predicting Atrial Fibrillation in Patients with Acute Ischemic Stroke: Data from the BIOSIGNAL Cohort Study.

BACKGROUND AND AIMS: P-wave abnormalities in the 12-lead electrocardiogram (ECG) have been associated with a higher risk of acute ischemic stroke (AIS) as well as atrial fibrillation (AF). This study aimed to assess pre-determined ECG criteria during sinus rhythm in unselected AIS patients and their value for predicting newly diagnosed atrial fibrillation (NDAF) after hospital admission. METHODS: P-wave alterations were measured on 12-lead ECG on admission in all consecutively enrolled patients without known AF between October 2014 and 2017. The outcome of interest was NDAF, identified by prolonged electrocardiographic monitoring within one year after the index AIS. Univariable and multivariable logistic regression was applied to assess the magnitude and independence of the association between pre-selected ECG markers and NDAF. The discriminatory accuracy was evaluated with the area under the receiver operating characteristic curve (AUC), and the incremental prognostic value was estimated with the net reclassification index. RESULTS: NDAF was detected in 87 (10%) of 856 patients during a follow-up of 365 days. Out of the pre-selected ECG parameters, advanced interatrial block (aIAB) and PR interval in lead II were independently associated with NDAF in univariable regression analysis. Only aIAB remained a significant predictor in multivariable analysis. Adding aIAB to the best-performing multivariable regression model improved the discriminatory accuracy to predict NDAF from an AUC of 0.78 (95%-CI 0.77-0.80) to 0.81 (95%-CI 0.80-0.83, p < 0.001). CONCLUSION: aIAB is independently and highly associated with NDAF in patients with AIS, has high inter-rater reliability, and therefore may be helpful to refine diagnostic work-up to search for AF in AIS.

Serum S-100B adds incremental value for the prediction of symptomatic intracranial hemorrhage and brain edema after acute ischemic stroke.

Background: Early identification of patients developing symptomatic intracranial hemorrhage and symptomatic brain edema after acute ischemic stroke is essential for clinical decision-making. Astroglial protein S-100B is a marker of blood-brain barrier disruption, which plays an important role in the formation of intracranial hemorrhage and brain edema. In this study, we assessed the prognostic value of serum S-100B for the development of these complications. Methods: Serum S-100B levels were measured within 24 h from symptom onset in 1749 consecutive acute ischemic stroke patients from the prospective, observational, multicenter BIOSIGNAL cohort study (mean age 72.0 years, 58.3% male). To determine symptomatic intracranial hemorrhage or symptomatic brain edema, follow-up neuroimaging was performed in all patients receiving reperfusion therapy or experiencing clinical worsening with an NIHSS increase of ⩾4. Results: Forty six patients (2.6%) developed symptomatic intracranial hemorrhage and 90 patients (5.2%) developed symptomatic brain edema. After adjustment for established risk factors, log10S-100B levels remained independently associated with both symptomatic intracranial hemorrhage (OR 3.41, 95% CI 1.7-6.9, p = 0.001) and symptomatic brain edema (OR 4.08, 95% CI 2.3-7.1, p < 0.001) in multivariable logistic regression models. Adding S-100B to the clinical prediction model increased the AUC from 0.72 to 0.75 (p = 0.001) for symptomatic intracranial hemorrhage and from 0.78 to 0.81 (p < 0.0001) for symptomatic brain edema. Conclusions: Serum S-100B levels measured within 24 h after symptom onset are independently associated with the development of symptomatic intracranial hemorrhage and symptomatic brain edema in acute ischemic stroke patients. Thus, S-100B may be useful for early risk-stratification regarding stroke complications.

Continuous population-level monitoring of SARS-CoV-2 seroprevalence in a large European metropolitan region.

Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response against three SARS-CoV-2 proteins. We used TRABI for continuous seromonitoring of hospital patients and blood donors (n = 72'250) in the canton of Zurich from December 2019 to December 2020 (pre-vaccine period). We found that antibodies waned with a half-life of 75 days, whereas the cumulative incidence rose from 2.3% in June 2020 to 12.2% in mid-December 2020. A follow-up health survey indicated that about 10% of patients infected with wildtype SARS-CoV-2 sustained some symptoms at least twelve months post COVID-19. Crucially, we found no evidence of a difference in long-term complications between those whose infection was symptomatic and those with asymptomatic acute infection. The cohort of asymptomatic SARS-CoV-2-infected subjects represents a resource for the study of chronic and possibly unexpected sequelae.

Hybrid nanocomposite as a chest wall graft with improved vascularization by copper oxide nanoparticles.

Chest wall repair can be necessary after tumor resection or chest injury. In order to cover or replace chest wall defects, autologous tissue or different synthetic materials are commonly used, among them the semi-rigid gold standard Gore-Tex® and prolene meshes. Synthetic tissues include composite materials with an organic and an inorganic component. On the basis of previously reported hybrid nanocomposite poly-lactic-co-glycolic acid amorphous calcium phosphate nanocomposite (PLGA/aCaP), a CuO component was incorporated to yield (60%/35%/5%). This graft was tested in vitro by seeding with murine adipose-derived stem cells (ASCs) for cell attachment and migration. The graft was compared to PLGA/CaCO3 and PLGA/hydroxyapatite, each providing the inorganic phase as nanoparticles. Further characterization of the graft was performed using scanning electron microscopy. Furthermore, PLGA/aCaP/CuO was implanted as a chest wall graft in mice. After 4 weeks, total cell density, graft integration, extracellular matrix components such as fibronectin and collagen I, the cellular inflammatory response (macrophages, F4/80 and lymphocytes, CD3) as well as vascularization (CD31) were quantitatively assessed. The nanocomposite PLGA/aCaP/CuO showed a good cell attachment and cells migrated well into the pores of the electrospun meshes. Cell densities did not differ between PLGA/aCaP/CuO and PLGA/CaCO3 or PLGA/hydroxyapatite, respectively. When applied as a chest wall graft, adequate stability for suturing into the thoracic wall could be achieved. Four weeks post-implantation, there was an excellent tissue integration without relevant fibrotic changes and a predominating collagen I matrix deposition within the graft. Slightly increased inflammation, reflected by increased infiltration of macrophages could be observed. Vascularization of the graft was significantly enhanced when compared with PLGA/aCaP (no CuO). We conclude that the hybrid nanocomposite PLGA/aCaP/CuO is a viable option to be used as a chest wall graft. Surgical implantation of the material is feasible and provides stability and enough flexibility. Proper tissue integration and an excellent vascularization are characteristics of this biodegradable material.

High-Affinity Cu(I)-Chelator with Potential Anti-Tumorigenic Action-A Proof-of-Principle Experimental Study of Human H460 Tumors in the CAM Assay.

Human lung cancer ranks among the most frequently treated cancers worldwide. As copper appears critical to angiogenesis and tumor growth, selective removal of copper represents a promising strategy to restrict tumor growth. To this end, we explored the activity of the novel high-affinity membrane-permeant Cu(I) chelator PSP-2 featuring a low-zeptomolar dissociation constant. Using H460 human lung cancer cells, we generated small tumors on the chorioallantoic membrane of the chicken embryo (CAM assay) and studied the effects of topical PSP-2 application on their weight and vessel density after one week. We observed a significant angiosuppression along with a marked decrease in tumor weight under PSP-2 application compared to controls. Moreover, PSP-2 exposure resulted in lower ki67+ cell numbers at a low dose but increased cell count under a high dose. Moreover, HIF-1α+ cells were significantly reduced with low-dose PSP-2 exposure compared to high-dose and control. The total copper content was considerably lower in PSP-2 treated tumors, although statistically not significant. Altogether, PSP-2 shows promising potential as an anti-cancer drug. Nevertheless, further animal experiments and application to different tumor types are mandatory to support these initial findings, paving the way toward clinical trials.

Measurement of Midregional Pro-Atrial Natriuretic Peptide to Discover Atrial Fibrillation in Patients With Ischemic Stroke.

BACKGROUND: Midregional pro-atrial natriuretic peptide (MR-proANP) is a promising biomarker to differentiate the underlying etiology of acute ischemic stroke (AIS). OBJECTIVES: This study aimed to determine the role of MR-proANP for classification as cardioembolic (CE) stroke, identification of newly diagnosed atrial fibrillation (NDAF), and risk assessment for major adverse cardiovascular events (MACE). METHODS: This study measured MR-proANP prospectively collected within 24 hours after symptom-onset in patients with AIS from the multicenter BIOSIGNAL (Biomarker Signature of Stroke Aetiology) cohort study. Primary outcomes were CE stroke etiology and NDAF after prolonged cardiac monitoring, as well as a composite outcome of MACE (recurrent cerebrovascular events, myocardial infarction, or cardiovascular death) within 1 year. Logistic/Poisson and subproportional hazard regression were applied to evaluate the association between MR-proANP levels and outcomes. Additionally, a model for prediction of NDAF was derived and validated as a decision tool for immediate clinical application. RESULTS: Between October 1, 2014, and October 31, 2017, this study recruited 1,759 patients. Log10MR-proANP levels were associated with CE stroke (OR: 7.96; 95% CI: 4.82-13.14; risk ratio: 3.12; 95% CI: 2.23-4.37), as well as NDAF (OR: 35.3; 95% CI: 17.58-71.03; risk ratio: 11.47; 95% CI: 6.74-19.53), and MACE (subdistributional HR: 2.02; 95% CI: 1.32-3.08) during follow-up. The model to predict NDAF including only age and MR-proANP levels had a good discriminatory capacity with an area under the curve of 0.81 (95% CI: 0.76-0.86), was well calibrated (calibration in the large: -0.086; calibration slope 1.053), and yielded higher net-benefit compared with validated scores to predict NDAF (AS5F score, CHA2DS2-VASc [Congestive Heart Failure, Hypertension, Age ≥65 or ≥75, Diabetes, Prior Cardioembolic Event, (female) Sex, or Vascular Disease] score). CONCLUSIONS: MR-proANP is a valid biomarker to determine risk of NDAF and MACE in patients with AIS and can be used as a decision tool to identify patients for prolonged cardiac monitoring. (Biomarker Signature of Stroke Aetiology Study: The BIOSIGNAL study [BIOSIGNAL]; NCT02274727).

Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes.

Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory-like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selectin-mediated interactions of tumor cells with platelets and leukocytes activated endothelial cells and induced production of C-C chemokine ligand 5 (CCL5). Inhibition of CCL5-dependent monocyte recruitment during the early phase of metastasis by a CCL5 receptor antagonist strongly reduced tumor cell survival and attenuated metastasis. Collectively, these findings demonstrate that the endothelial expression of CCL5 contributes to the formation of a permissive metastatic microenvironment.