Proteomic profiling for biomarker discovery in heparin-induced thrombocytopenia.

New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n=32; HIT ruled-out, n=38; positive heparin/PF4 [H/PF4] antibodies, n=28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using ELISA in above mentioned patients and an additional second dataset (n=49). HIT was defined as a positive heparin-induced platelet aggregation test (HIPA; washed platelet assay). Among 98 patients of the primary dataset, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive heparin/PF4 antibodies, and 3 in patients without HIT. The median OD of a polyspecific heparin/PF4 ELISA was 3.0, 0.9, and 0.3, respectively. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver-operating-characteristics-curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT.

Accuracy of Diagnosing Heparin-Induced Thrombocytopenia.

Importance: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice. Objective: To evaluate the current diagnostic practice for managing the suspicion of HIT. Design, Setting, and Participants: This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT. Exposures: Suspicion of HIT. Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests. Results: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively. Conclusions and Relevance: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

An Implantable Piezofilm Middle Ear Microphone: Performance in Human Cadaveric Temporal Bones.

PURPOSE: One of the major reasons that totally implantable cochlear microphones are not readily available is the lack of good implantable microphones. An implantable microphone has the potential to provide a range of benefits over external microphones for cochlear implant users including the filtering ability of the outer ear, cosmetics, and usability in all situations. This paper presents results from experiments in human cadaveric ears of a piezofilm microphone concept under development as a possible component of a future implantable microphone system for use with cochlear implants. This microphone is referred to here as a drum microphone (DrumMic) that senses the robust and predictable motion of the umbo, the tip of the malleus. METHODS: The performance was measured by five DrumMics inserted in four different human cadaveric temporal bones. Sensitivity, linearity, bandwidth, and equivalent input noise were measured during these experiments using a sound stimulus and measurement setup. RESULTS: The sensitivity of the DrumMics was found to be tightly clustered across different microphones and ears despite differences in umbo and middle ear anatomy. The DrumMics were shown to behave linearly across a large dynamic range (46 dB SPL to 100 dB SPL) across a wide bandwidth (100 Hz to 8 kHz). The equivalent input noise (over a bandwidth of 0.1-10 kHz) of the DrumMic and amplifier referenced to the ear canal was measured to be about 54 dB SPL in the temporal bone experiment and estimated to be 46 dB SPL after accounting for the pressure gain of the outer ear. CONCLUSION: The results demonstrate that the DrumMic behaves robustly across ears and fabrication. The equivalent input noise performance (related to the lowest level of sound measurable) was shown to approach that of commercial hearing aid microphones. To advance this demonstration of the DrumMic concept to a future prototype implantable in humans, work on encapsulation, biocompatibility, and connectorization will be required.

Novel Organism Verification and Analysis (NOVA) study: identification of 35 clinical isolates representing potentially novel bacterial taxa using a pipeline based on whole genome sequencing.

BACKGROUND: Reliable species identification of cultured isolates is essential in clinical bacteriology. We established a new study algorithm named NOVA - Novel Organism Verification and Analysis to systematically analyze bacterial isolates that cannot be characterized by conventional identification procedures MALDI-TOF MS and partial 16 S rRNA gene sequencing using Whole Genome Sequencing (WGS). RESULTS: We identified a total of 35 bacterial strains that represent potentially novel species. Corynebacterium sp. (n = 6) and Schaalia sp. (n = 5) were the predominant genera. Two strains each were identified within the genera Anaerococcus, Clostridium, Desulfovibrio, and Peptoniphilus, and one new species was detected within Citrobacter, Dermabacter, Helcococcus, Lancefieldella, Neisseria, Ochrobactrum (Brucella), Paenibacillus, Pantoea, Porphyromonas, Pseudoclavibacter, Pseudomonas, Psychrobacter, Pusillimonas, Rothia, Sneathia, and Tessaracoccus. Twenty-seven of 35 strains were isolated from deep tissue specimens or blood cultures. Seven out of 35 isolated strains identified were clinically relevant. In addition, 26 bacterial strains that could only be identified at the species level using WGS analysis, were mainly organisms that have been identified/classified very recently. CONCLUSION: Our new algorithm proved to be a powerful tool for detection and identification of novel bacterial organisms. Publicly available clinical and genomic data may help to better understand their clinical and ecological role. Our identification of 35 novel strains, 7 of which appear to be clinically relevant, shows the wide range of undescribed pathogens yet to define.

Prognostic Significance of the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) in Patients with Myelofibrosis: A Retrospective Study.

In myelofibrosis, comorbidities (CMs) add prognostic information independently from the Dynamic International Prognostic Scoring System (DIPSS). The Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) offers a simple tool for CM assessment as it is calculable after having performed a careful history and physical examination, a small routine chemistry panel (including creatinine and liver enzymes) and a limited set of functional diagnostics. To assess the prognostic impact of the MDS-CI in addition to the DIPSS and the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70, we performed a retrospective chart review of 70 MF patients who had not received allogeneic stem cell transplantation (primary MF, n = 51; secondary MF, n = 19; median follow-up, 40 months) diagnosed at our institution between 2000 and 2020. Cardiac diseases (23/70) and solid tumors (12/70) were the most common CMs observed at MF diagnosis. Overall survival (OS) was significantly influenced by the MDS-CI (median OS MDS-CI low (n = 38): 101 months; MDS-CI intermediate (n = 25): 50 months; and high (n = 7): 8 months; p < 0.001). The MDS-CI added prognostic information after inclusion as a categorical variable in a multivariate model together with the dichotomized DIPSS or the dichotomized MIPSS70: MDS-CI high HR 14.64 (95% CI 4.42; 48.48), p = 0.0002, and MDS-CI intermediate HR 1.97 (95% CI 0.96; 4.03), p = 0.065, and MDS-CI high HR 19.65 (95% CI 4.71; 81.95), p < 0.001, and MDS-CI intermediate HR 1.063 (95% CI 0.65; 4.06), p = 0.2961, respectively. The analysis of our small and retrospective MF cohort suggests that the MDS-CI represents a useful tool to identify MF patients with an increased vulnerability due to comorbidities. However, analyses of larger cohorts are necessary to define the value of the MDS-CI as a prognostic tool in comparison with other comorbidity indices.

In-situ start and end of growing season dates of major European crop types from France and Bulgaria at a field level.

Crop phenology data offer crucial information for crop yield estimation, agricultural management, and assessment of agroecosystems. Such information becomes more important in the context of increasing year-to-year climatic variability. The dataset provides in-situ crop phenology data (first leaves emergence and harvest date) of major European crops (wheat, corn, sunflower, rapeseed) from seventeen field study sites in Bulgaria and two in France. Additional information such as the sowing date, area of each site, coordinates, method and equipment used for phenophase data estimation, and photos of the France sites are also provided. The georeferenced ground-truth dataset provides a solid base for a better understanding of crop growth and can be used to validate the retrieval of phenological stages from remote sensing data.

Human blood-labyrinth barrier on a chip: a unique in vitro tool for investigation of BLB properties.

Hearing loss is one of the leading causes of disability worldwide, usually as a result of hair cell damage in the inner ear due to aging, acoustic trauma, or exposure to antibiotics or chemotherapy. No drug therapies can protect or restore hearing and current in vitro and animal models used in drug discovery have a very low success rate, mostly due to major differences in anatomy and accessibility of the inner ear environment between species. The blood-labyrinth barrier (BLB) in the stria vascularis is a highly specialized capillary network that controls exchanges between the blood and interstitial space in the cochlea. The BLB is critical for normal hearing, functioning as a physical, transport, and metabolic barrier. To address its complexity and accessibility, we created the first micro-engineered human model of BLB on a chip using autogenous progenitor cells from adult temporal bones. We successfully isolated the BLB from post-mortem human tissue and established an endothelial cell and pericyte culture system on a BLB chip. Using biocompatible materials, we fabricated sustainable two chamber chips. We validated the size-dependent permeability limits of our BLB model by measuring the permeability to daptomycin (molecular weight 1.6 kDa) and midazolam (molecular weight 325.78 Da). Daptomycin did not pass through the BLB layer, whereas midazolam readily passed through the BLB in our system. Thus, our BLB-chip mimicked the integrity and permeability of human stria vascularis capillaries. This represents a major step towards establishing a reliable model for the development of hearing loss treatments.

Determination of Anti-Xa Inhibitor Plasma Concentrations Using a Universal Edoxaban Calibrator.

A universal calibrator for the determination of all anti-Xa inhibitors would support laboratory processes. We aimed to test the clinical performance of an anti-Xa assay utilizing a universal edoxaban calibrator to determine clinically relevant concentrations of all anti-Xa inhibitors. Following a pilot study, we enrolled 553 consecutive patients taking rivaroxaban, edoxaban, or apixaban from nine study centers in a prospective cross-sectional study. The Technochrom® anti-Xa assay was conducted using the Technoview® edoxaban calibrator. Using ultra-high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), anti-Xa inhibitor drug concentrations were determined. Sensitivities and specificities to detect three clinically relevant drug concentrations (30 µgL-1, 50 µgL-1, 100 µgL-1) were determined. Overall, 300 patients treated with rivaroxaban, 221 with apixaban, and 32 with edoxaban were included. The overall correlation coefficient (rs) was 0.95 (95% CI 0.94, 0.96). An area under the receiver operating characteristic curve of 0.96 for 30 µgL-1, 0.98 for 50 µgL-1, and 0.99 for 100 µgL-1 was found. The sensitivities were 92.3% (95% CI 89.2, 94.6), 92.7% (89.4, 95.1), and 94.8% (91.1, 97.0), respectively (specificities 82.2%, 93.7%, and 94.4%). In conclusion, the clinical performance of a universal, edoxaban-calibrated anti-Xa assay was solid and most drug concentrations were predicted correctly.

Limited concordance of heparin/platelet factor 4 antibody assays for the diagnosis of heparin-induced thrombocytopenia: an analysis of the TORADI-HIT study.

BACKGROUND: Anecdotal reports suggest that the correlation between heparin/platelet factor 4 (PF4) antibody assays for the diagnosis of heparin-induced thrombocytopenia (HIT) is limited. OBJECTIVES: To investigate the correlation between widely used assays and examine possible factors contributing to variability. METHODS: This is a large, prospective cohort study with 10 participating tertiary care hospitals including 1393 patients with suspected HIT in clinical practice. HIT was defined by a positive heparin-induced platelet activation (HIPA) assay (washed platelet reference standard test). Three different immunoassays were used to measure heparin/PF4 antibodies: chemiluminescent immunoassay, enzyme-linked immunosorbent assay, and particle gel immunoassay. Various factors that could influence the assays were examined: sex (male or female), age (<65 years or ≥65 years), unfractionated heparin exposure, presence of thrombosis, cardiovascular surgery, and intensive care unit. Spearman's correlation coefficients were calculated. Z-scores and diagnostic odds ratios were determined in the aforementioned subgroups of patients. RESULTS: Among 1393 patients, 119 were classified as HIT-positive (prevalence, 8.5%). The median 4Ts score was 5 (IQR, 4-6) in patients with HIT compared with 3 (IQR, 2-4) in patients without HIT. Correlations (rs) between immunoassays were weak (0.53-0.65). Inconsistencies between immunoassays could not be explained by further analyses of z-scored test results and diagnostic odds ratios in subgroups of patients. CONCLUSION: The correlation between widely used heparin/PF4 antibody assays was weak, and key factors could not explain this variability. Standardization of immunoassays is requested to improve comparability.

CRP/Albumin Ratio and Glasgow Prognostic Score Provide Prognostic Information in Myelofibrosis Independently of MIPSS70-A Retrospective Study.

In myelofibrosis, the C-reactive protein (CRP)/albumin ratio (CAR) and the Glasgow Prognostic Score (GPS) add prognostic information independently of the Dynamic International Prognostic Scoring System (DIPSS). Their prognostic impact, if molecular aberrations are considered, is currently unknown. We performed a retrospective chart review of 108 MF patients (prefibrotic MF n = 30; primary MF n = 56; secondary MF n = 22; median follow-up 42 months). In MF, both a CAR > 0.347 and a GPS > 0 were associated with a shorter median overall survival (21 [95% CI 0-62] vs. 80 months [95% CI 57-103], p < 0.001 and 32 [95% CI 1-63] vs. 89 months [95% CI 65-113], p < 0.001). Both parameters retained their prognostic value after inclusion into a bivariate Cox regression model together with the dichotomized Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70: CAR > 0.374 HR 3.53 [95% CI 1.36-9.17], p = 0.0095 and GPS > 0 HR 4.63 [95% CI 1.76-12.1], p = 0.0019. An analysis of serum samples from an independent cohort revealed a correlation of CRP with levels of interleukin-1ß and albumin with TNF-α, and demonstrated that CRP was correlated to the variant allele frequency of the driver mutation, but not albumin. Albumin and CRP as parameters readily available in clinical routine at low costs deserve further evaluation as prognostic markers in MF, ideally by analyzing data from prospective and multi-institutional registries. Since both albumin and CRP levels reflect different aspects of MF-associated inflammation and metabolic changes, our study further highlights that combining both parameters seems potentially useful to improve prognostication in MF.

Effect of freezing and embalming of human cadaveric whole head specimens on bone conduction.

BACKGROUND AND AIMS: Conserved specimens do not decay and therefore permit long-term experiments thereby overcoming limited access to fresh (frozen) temporal bones for studies on middle ear mechanics. We used a Thiel conservation method which is mainly based on a watery solution of salts. In contrast to pure Formalin, Thiel conservation aims to preserve the mechanical proprieties of human tissue. The aim of this study is to examine the effect of Thiel conservation on bone conduction in the same specimen before and after conservation. METHODS: Nine ears of five defrosted whole heads were stimulated with a direct, electrically driven, bone anchored hearing system (Baha, Baha SuperPower). The motion produced by bone conduction stimulation was measured with a single point laser Doppler vibrometer (LDV) at the promontory, the ossicular chain, and the round window through a posterior tympanotomy. After the initial experiments, the entire whole heads were placed in Thiel solution. In order to enable direct comparison between fresh frozen and Thiel specimens, our Thiel conservation did not include intravascular and intrathecal perfusion. The measurements were repeated 3 and 12 months later. To determine the effect of freezing, defrosting, and embalming on the whole heads, CT scans were performed at different stages of the experimental procedure. Additionally, three extracted temporal bones were stimulated a Baha, motion of the promontory measured by LDV and embalmed in Thiel solution to investigate the direct impact of Thiel solution on the bone. RESULTS: The averaged magnitude of motion on the promontory increased in whole head specimens by a mean of 10.3 dB after 3 months of Thiel embalming and stayed stable after 12 months. A similar effect was observed for motion at the tympanic membrane (+7.2 dB), the stapes (+9.5 dB), and the round window (+4.0 dB). In contrast to the whole head specimens, the motion of the extracted temporal bones did not change after 3 months of Thiel embalming (-0.04 dB in average). CT scans of the whole heads after conservation showed a notable brain volume loss mostly >50% as well as a remarkable change in the consistency and structure of the brain. Partial changes could already be observed before the Thiel embalming but after 1-2 days of defrosting. In an additional experiment, a substitution of brain mass and weight by Thiel fluid did not lead to new deterioration in sound transmission. In contrast, a frozen (non-defrosted) whole head showed a distinctively reduced magnitude of promontory motion before defrosting. DISCUSSION: For our setup, the vibration of the ear due to bone conduction in the same whole head specimens significantly increased after Thiel conservation. Such an increase was not observed in extracted temporal bone specimens. Due to brain changes in the CT scans, we investigated the consequences of the brain volume changes and structure loss on the frozen brain before defrosting. The loss of brain volume alone could not explain the increase of ear vibrations, as we did not observe a difference when the volume was replaced with Thiel fluid. However, freezing and defrosting of the entire brain seems to have a major influence. Beside the destructive effect of freezing on the brain, the modified conservation method without perfusion changed the brain structure. In conclusion, bone conduction in whole heads depends on the physical condition of the brain, rather than on the conservation.

Comparison between incus short process and long process coupling of the vibrant soundbridge in human temporal bones.

OBJECTIVE: The Vibrant Soundbridge (VSB) is one of the most widely used implantable hearing devices. It consists of a vibrating floating mass transducer (FMT) that is connected to a middle ear structure. The standard coupling devices for sensorineural hearing loss are short process (SP) or long process (LP) couplers. DESIGN AND STUDY SAMPLE: This study directly compared the electro-mechanical performance of the SP- and LP-coupled FMT of the VSB in the same temporal bone specimen (n = 10). We measured velocity magnitudes and total harmonic distortions (THD) of the stapes (ST) and the round window (RW) using laser Doppler Vibrometry (LDV). RESULTS: Comparison shows a maximally 10 dB higher magnitude for the LP coupler at ST and RW for frequencies below 600 Hz, whereas the SP coupler shows a maximally 20 dB higher magnitude at the ST and RW for frequencies above 600 Hz. THD show similar behaviour with less distortion at 500 Hz for the LP coupler and less distortions for the SP coupler in higher frequencies. CONCLUSIONS: Our experiments showed that the SP coupling may be mechanically favourable, in terms of magnitude and distortion, for the transmission of FMT vibrations at higher frequencies.

A machine-learning model for reducing misdiagnosis in heparin-induced thrombocytopenia: A prospective, multicenter, observational study.

Background: Diagnosing heparin-induced thrombocytopenia (HIT) at the bedside remains challenging, exposing a significant number of patients at risk of delayed diagnosis or overtreatment. We hypothesized that machine-learning algorithms could be utilized to develop a more accurate and user-friendly diagnostic tool that integrates diverse clinical and laboratory information and accounts for complex interactions. Methods: We conducted a prospective cohort study including 1393 patients with suspected HIT between 2018 and 2021 from 10 study centers. Detailed clinical information and laboratory data were collected, and various immunoassays were conducted. The washed platelet heparin-induced platelet activation assay (HIPA) served as the reference standard. Findings: HIPA diagnosed HIT in 119 patients (prevalence 8.5%). The feature selection process in the training dataset (75% of patients) yielded the following predictor variables: (1) immunoassay test result, (2) platelet nadir, (3) unfractionated heparin use, (4) CRP, (5) timing of thrombocytopenia, and (6) other causes of thrombocytopenia. The best performing models were a support vector machine in case of the chemiluminescent immunoassay (CLIA) and the ELISA, as well as a gradient boosting machine in particle-gel immunoassay (PaGIA). In the validation dataset (25% of patients), the AUROC of all models was 0.99 (95% CI: 0.97, 1.00). Compared to the currently recommended diagnostic algorithm (4Ts score, immunoassay), the numbers of false-negative patients were reduced from 12 to 6 (-50.0%; ELISA), 9 to 3 (-66.7%, PaGIA) and 14 to 5 (-64.3%; CLIA). The numbers of false-positive individuals were reduced from 87 to 61 (-29.8%; ELISA), 200 to 63 (-68.5%; PaGIA) and increased from 50 to 63 (+29.0%) for the CLIA. Interpretation: Our user-friendly machine-learning algorithm for the diagnosis of HIT (https://toradi-hit.org) was substantially more accurate than the currently recommended diagnostic algorithm. It has the potential to reduce delayed diagnosis and overtreatment in clinical practice. Future studies shall validate this model in wider settings. Funding: Swiss National Science Foundation (SNSF), and International Society on Thrombosis and Haemostasis (ISTH).

The UmboMic: A PVDF Cantilever Microphone.

Objective: We present the "UmboMic," a prototype piezoelectric cantilever microphone designed for future use with totally-implantable cochlear implants. Methods: The UmboMic sensor is made from polyvinylidene difluoride (PVDF) because of its low Young's modulus and biocompatibility. The sensor is designed to fit in the middle ear and measure the motion of the underside of the eardrum at the umbo. To maximize its performance, we developed a low noise charge amplifier in tandem with the UmboMic sensor. This paper presents the performance of the UmboMic sensor and amplifier in fresh cadaveric human temporal bones. Results: When tested in human temporal bones, the UmboMic apparatus achieves an equivalent input noise of 32.3 dB SPL over the frequency range 100 Hz to 7 kHz, good linearity, and a flat frequency response to within 10 dB from about 100 Hz to 6 kHz. Conclusion: These results demonstrate the feasibility of a PVDF-based microphone when paired with a low-noise amplifier. The reported UmboMic apparatus is comparable in performance to a conventional hearing aid microphone. Significance: The proof-of-concept UmboMic apparatus is a promising step towards creating a totally-implantable cochlear implant. A completely internal system would enhance the quality of life of cochlear implant users.

Mild COVID-19 induces early, quantifiable, persistent troponin I elevations in elder men.

Importance: Elderly patients, especially men, are at risk of increased morbidity from coronavirus disease 2019 (COVID-19). Long-term data on troponin I levels in longitudinal observational studies of outpatients with mild to moderate COVID-19 are scarce. Objective: This controlled cohort study aimed to evaluate the course of troponin I concentrations over a long period in convalescent COVID-19 outpatients with mild to moderate symptoms. Setting and participants: In this cohort study, individuals with PCR-confirmed, mild to moderate SARS-CoV-2 infection as well as control individuals with confirmed negative PCR and negative SARS-CoV-2 serology were included. Study visits were performed from April 2020 through July 2021 (initialized during the first wave of the corona pandemic in Switzerland). A study visit in patients comprised blood draws every week in the first month and additionally after 8 weeks. This course was repeated in patients observed long-term. Results: This study enrolled 278 individuals from the Canton of St. Gallen, Switzerland, aged 12-92 years (59.5% women), who had mild to moderate COVID-19 symptoms (outpatients only) and a diagnosis confirmed by positive RT-PCR. Fifty-four of the participants with confirmed SARS-CoV-2 infection were followed for 14 months with repeat cycles of the testing protocol. In addition, 115 symptomatic patients that were PCR and serology negative were enrolled in the same time period as a control group. In COVID-19 patients, low-level troponin I concentrations (cTnI) were significantly increased from baseline until week 9 after positive RT-PCR diagnosis in men older than 54 years [ΔcTnI = 5.0 ng/L (median); 95% CI 4.1-6.0; p = 0.02]. The troponin I concentration remained elevated throughout 14 months in men older than 54 years within the cohort with a prolonged observation period. This statistically significant change in troponin I concentration was not dependent on co-morbidities in this group. ALT, Creatinine, BNP, and D-Dimer values after convalescence did not differ in comparison to the control cohort. Conclusion: In this analysis of individuals with confirmed SARS-CoV-2 infection, hs troponin I levels of men aged 54 or older significantly increased after infection. They remained elevated for at least 14 months after diagnosis. This suggests the possibility of an ongoing, long-term, low-grade myocardial injury. Further studies with focus on elderly patients and a prolonged observational period are necessary to elucidate whether the phenomenon observed is associated with detectable structural changes to the heart muscle or is without further clinical consequences.

Correction to: Optical Anisotropy and Momentum-Dependent Excitons in Dibenzopentacene Single Crystals.

[This corrects the article DOI: 10.1021/acsomega.2c01987.].

Prothrombinase-Induced Clotting Time to Measure Drug Concentrations of Rivaroxaban, Apixaban, and Edoxaban in Clinical Practice: A Cross-Sectional Study.

Prothrombinase-induced clotting time (PiCT) is proposed as a rapid and inexpensive laboratory test to measure direct oral anticoagulant (DOAC) drug levels. In a prospective, multicenter cross-sectional study, including 851 patients, we aimed to study the accuracy of PiCT in determining rivaroxaban, apixaban, and edoxaban drug concentrations and assessed whether clinically relevant drug levels could be predicted correctly. Citrated plasma samples were collected, and the Pefakit® PiCT was utilized. Ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to measure drug concentrations. Cut-off levels were established using receiver-operating characteristics curves. We calculated sensitivities and specificities with respect to clinically relevant drug concentrations. Spearman's correlation coefficient between PiCT and drug concentrations was 0.85 in the case of rivaroxaban (95% CI 0.82, 0.88), 0.66 for apixaban (95% CI 0.60, 0.71), and 0.78 for edoxaban (95% CI 0.65, 0.86). The sensitivity to detect clinically relevant drug concentrations was 85.1% in the case of 30 µg L-1 (95% CI 82.0, 87.7; specificity 77.9; 72.1, 82.7), 85.7% in the case of 50 µg L-1 (82.4, 88.4; specificity 77.3; 72.5, 81.5), and 85.1% in the case of 100 µg L-1 (80.9, 88.4; specificity 73.2%; 69.1, 76.9). In conclusion, the association of PiCT with DOAC concentrations was fair, and the majority of clinically relevant drug concentrations were correctly predicted.

Optical Anisotropy and Momentum-Dependent Excitons in Dibenzopentacene Single Crystals.

High-quality single crystals of the organic semiconductor (1,2;8,9)-dibenzopentacene were grown via physical vapor transport. The crystal structure-unknown before-was determined by single-crystal X-ray diffraction; polarization-dependent optical absorption measurements display a large anisotropy in the ac plane of the crystals. The overall Davydov splitting is ∼110 meV, which is slightly lower than that in the close relative pentacene (120 meV). Momentum-dependent electron energy-loss spectroscopy measurements show a clear exciton dispersion of the Davydov components. An analysis of the dispersion using a simple 1D model indicates smaller electron- and hole-transfer integrals in dibenzopentacene as compared to pentacene. The spectral weight distribution of the excitation spectra is strongly momentum-dependent and demonstrates a strong momentum-dependent admixture of Frenkel excitons, charge-transfer excitons, and vibrational modes.

Accuracy of a Single, Heparin-Calibrated Anti-Xa Assay for the Measurement of Rivaroxaban, Apixaban, and Edoxaban Drug Concentrations: A Prospective Cross-Sectional Study.

Background: Applying a single anti-Xa assay, calibrated to unfractionated heparin to measure rivaroxaban, apixaban, and edoxaban would simplify laboratory procedures and save healthcare costs. Aim: We hypothesized that a heparin-calibrated anti-Xa assay would accurately measure rivaroxaban, apixaban, and edoxaban drug concentrations and correctly predict clinically relevant drug levels. Methods: This analysis is part of the Simple-Xa study, a prospective multicenter cross-sectional study conducted in clinical practice. Patients treated with rivaroxaban, apixaban, or edoxaban were included. Anti-Xa activity was measured using the Siemens INNOVANCE® Heparin assay. Drug concentrations were determined using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cut-off levels were determined in a derivation dataset (50% of patients) and sensitivities and specificities were calculated in a verification dataset (50% of patients). Results: Overall, 845 patients were available for analysis. Correlation coefficients (r s ) between the heparin-calibrated anti-Xa assay and drug concentrations were 0.97 (95% CI 0.97, 0.98) for rivaroxaban, 0.96 (0.96, 0.97) for apixaban, and 0.96 (0.94, 0.99) for edoxaban. The area under the receiver operating characteristics curve (ROC) was 0.99 for all clinically relevant drug concentrations. In the verification dataset, the sensitivity was 94.2% (95% CI 90.8-96.6) for 30 µg L-1, 95.8% (92.4-98.0) for 50 µg L-1, and 98.7% (95.5-99.9) for 100 µg L-1. Specificities were 86.3% (79.2-91.7), 89.8% (84.5-93.7), and 88.7% (84.2-92.2), respectively. Conclusion: In a large prospective study in clinical practice, a strong correlation of heparin-calibrated anti-Xa measurements with LC-MS/MS results was observed and clinically relevant drug concentrations were predicted correctly.