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(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
A novel approach to measure brain-to-brain spatial and temporal alignment during positive empathy
(2022)
Empathy is defined as the ability to vicariously experience others’ suffering (vicarious pain) or feeling their joy (vicarious reward). While most neuroimaging studies have focused on vicarious pain and describe similar neural responses during the observed and the personal negative affective involvement, only initial evidence has been reported for the neural responses to others’ rewards and positive empathy. Here, we propose a novel approach, based on the simultaneous recording of multi-subject EEG signals and exploiting the wavelet coherence decomposition to measure the temporal alignment between ERPs in a dyad of interacting subjects. We used the Third-Party Punishment (TPP) paradigm to elicit the personal and vicarious experiences. During a positive experience, we observed the simultaneous presence in both agents of the Late Positive Potential (LPP), an ERP component related to emotion processing, as well as the existence of an inter-subject ERPs synchronization in the related time window. Moreover, the amplitude of the LPP synchronization was modulated by the presence of a human-agent. Finally, the localized brain circuits subtending the ERP-synchronization correspond to key-regions of personal and vicarious reward. Our findings suggest that the temporal and spatial ERPs alignment might be a novel and direct proxy measure of empathy.
In this paper we present a new approach to deterministic modelling of COVID-19 epidemic. Our model dynamics is expressed by a single prognostic variable which satisfies an integro-differential equation. All unknown parameters are described with a single, time-dependent variable R(t). We show that our model has similarities to classic compartmental models, such as SIR, and that the variable R(t) can be interpreted as a generalized effective reproduction number. The advantages of our approach are the simplicity of having only one equation, the numerical stability due to an integral formulation and the reliability since the model is formulated in terms of the most trustable statistical data variable: the number of cumulative diagnosed positive cases of COVID-19. Once this dynamic variable is calculated, other non-dynamic variables, such as the number of heavy cases (hospital beds), the number of intensive-care cases (ICUs) and the fatalities, can be derived from it using a similarly stable, integral approach. The formulation with a single equation allows us to calculate from real data the values of the sample effective reproduction number, which can then be fitted. Extrapolated values of R(t) can be used in the model to make reliable forecasts, though under the assumption that measures for reducing infections are maintained. We have applied our model to more than 15 countries and the ongoing results are available on a web-based platform [1]. In this paper, we focus on the data for two exemplary countries, Italy and Germany, and show that the model is capable of reproducing the course of the epidemic in the past and forecasting its course for a period of four to five weeks with a reasonable numerical stability.
Background and Objectives: We tested if a novel combination of predictors could improve the accuracy of outcome prediction after transfemoral transcatheter aortic valve implantation (TAVI). Materials and Methods: This prospective study recruited 169 participants (49% female; median age 81 years). The primary endpoint was midterm mortality; secondary endpoints were acute Valve Academic Research Consortium (VARC)-3 complication rate and post-TAVI in-hospital length of stay (LoS). EuroSCORE II (ESII), comorbidities (e.g., coronary artery disease), eGFR (estimated glomerular filtration rate; based on cystatin C), hemoglobin, creatinine, N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels and patient-reported outcome measures (PROMs, namely EuroQol-5-Dimension-5-Levels, EQ5D5L; Kansas City Cardiomyopathy Questionnaire, KCCQ; clinical frailty scale, CFS) at baseline were tested as predictors. Regression (uni- and multi-variate Cox; linear; binary logistic) and receiver operating characteristic (ROC)-curve analysis were applied. Results: Within a median follow-up of 439 (318–585) days, 12 participants died (7.1%). Independent predictors of mortality using multivariate Cox regression were baseline eGFR (p = 0.001) and KCCQ (p = 0.037). Based on these predictors, a Linear Prediction Score (LPS1) was calculated. The LPS1-area under the curve (AUC)-value (0.761) was significantly higher than the ESII-AUC value (0.597; p = 0.035). Independent predictors for LoS > 6 days (the median LoS) were eGFR (p = 0.028), NTproBNP (p = 0.034), and EQ5D5L values (p = 0.002); a respective calculated LPS2 provided an AUC value of 0.677 (p < 0.001). Eighty participants (47.3%) experienced complications. Male sex predicted complications only in the univariate analysis. Conclusions: The combination of KCCQ and eGFR can better predict midterm mortality than ES II alone. Combining eGFR, NTproBNP, and EQ5D5L can reliably predict LoS after TAVI. This novel method improves personalized TAVI risk stratification and hence may help reduce post-TAVI risk.
Mechanotransduction is elicited in cells upon the perception of physical forces transmitted via the extracellular matrix in their surroundings and results in signaling events that impact cellular functions. This physiological process is a prerequisite for maintaining the integrity of diarthrodial joints, while excessive loading is a factor promoting the inflammatory mechanisms of joint destruction. Here, we describe a mechanotransduction pathway in synovial fibroblasts (SF) derived from the synovial membrane of inflamed joints. The functionality of this pathway is completely lost in the absence of the disintegrin metalloproteinase ADAM15 strongly upregulated in SF. The mechanosignaling events involve the Ca2+-dependent activation of c-Jun-N-terminal kinases, the subsequent downregulation of long noncoding RNA HOTAIR, and upregulation of the metabolic energy sensor sirtuin-1. This afferent loop of the pathway is facilitated by ADAM15 via promoting the cell membrane density of the constitutively cycling mechanosensitive transient receptor potential vanilloid 4 calcium channels. In addition, ADAM15 reinforces the Src-mediated activation of pannexin-1 channels required for the enhanced release of ATP, a mediator of purinergic inflammation, which is increasingly produced upon sirtuin-1 induction.
Purpose: Auditory functional MRI (fMRI) often uses silent inter-volume delays for stimulus presentation. However, maintaining the steady-state of the magnetization usually requires constant delays. Here, a novel acquisition scheme dubbed “pre-Saturated EPI using Multiple delays in Steady-state” (SEPIMS) is proposed, using spin saturation at a fixed delay before each volume to maintain steady-state conditions, independent of previous spin history. This concept allows for variable inter-volume delays and thus for flexible stimulus design in auditory fMRI. The purpose was to compare the signal stability of SEPIMS and conventional sparse EPI (CS-EPI). Methods: The saturation module comprises two non-selective adiabatic saturation pulses. The efficiency of the saturation and its effect on the SEPIMS signal stability is tested in vitro and in vivo. Results: Data show that SEPIMS yields the same signal stability as CS-EPI, even for extreme variations between inter-volume delay durations. However, dual saturation pulses are required to achieve sufficiently high saturation efficiency in compartments with long T1 values. Importantly, spoiler gradient pulses after the EPI readout have to be optimized to avoid eddy-current-induced image distortions. Conclusion: The proposed SEPIMS sequence maintains high signal stability in the presence of variable inter-volume durations, thus allowing for flexible stimulus design.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
With respect to nosocomial influenza infections, the welfare of patients is best served by high rates of staff immunity against influenza. However, data from the Centers of Disease Control (CDC) in the USA and the Robert Koch-Institute (RKI) in Germany indicate that most of health care workers (HCWs) choose not to be vaccinated. Under voluntary influenza immunization standards, institutional influenza outbreaks occur every flu season. The question about the legality of implementation mandatory flu vaccination for HCWs is an ongoing debate, which covers several different positions.
To characterize the attitudes of German HCWs toward mandatory influenza immunization, an anonymous questionnaire was offered to HCWs of the University Hospital in Frankfurt/Main / Germany. Our study showed that almost 70% of the respondents would accept mandatory influenza vaccination.
In our opinion an annual influenza vaccination should be required for HCWs who care for immunocompromised patients and residents in long-term care if there will be a failure of voluntary vaccination programs. An informed declination should be obtained from employees who decline vaccination and these HCWs ought to work in uncritical areas of patient care.
Background: Brodalumab is a fully human monoclonal immunoglobulin IgG2 antibody that binds to the human IL-17 receptor subunit A and by that inhibits the biologic action of IL-17A, IL-17F, IL-17C and IL-17E. Therapy with fumaric acid esters (FAE) is a well established and widely used first-line systemic treatment for subjects with moderate-to-severe plaque psoriasis. Objectives: To compare brodalumab to FAE in terms of clinical efficacy, patient-reported outcomes and safety in subjects with moderate-to-severe plaque psoriasis who were naïve to systemic treatment. Methods: Eligible subjects were randomized 1 : 1 to 210 mg brodalumab injections or oral FAE according to product label in this 24-week, open-label, assessor-blinded, multi-centre, head-to-head phase 4 trial. The primary endpoints were having PASI75 and having sPGA score of 0 or 1 (sPGA 0/1). Subjects with missing values for the primary endpoints were considered non-responders. Results: A total of 210 subjects were randomized. 91/105 subjects completed brodalumab treatment and 58/105 subjects completed FAE treatment. At Week 24, significantly more subjects in the brodalumab group compared to the FAE group had PASI75 (81.0% vs. 38.1%, P < 0.001) and sPGA 0/1 (64.8% vs. 20.0%, P < 0.001). In the brodalumab group, the median time to both PASI75 and to PASI90 was significantly shorter than in the FAE group (4.1 weeks vs. 16.4 weeks, and 7.4 weeks vs. 24.4 weeks, respectively, P < 0.0001 for both). The rate of adverse events was lower in subjects treated with brodalumab compared to subjects treated with FAE (616.4 vs. 1195.8 events per 100 exposure years). No new safety signals were detected for brodalumab. Conclusions: Brodalumab was associated with rapid and significant improvements in signs and symptoms of moderate-to-severe plaque psoriasis, with a superior efficacy profile to what was observed with FAE in systemic-naïve subjects over 24 weeks.