Explore the vast range of titles available.

Background Cocaine is the most frequently used stimulant worldwide, with increasing consumption rates in Europe. Cocaine use is associated with great harm to individuals and society. As of today, psychotherapeutic interventions for cocaine use disorder (CUD) demonstrate only modest effect sizes, and no pharmacotherapy has been approved due to gaps in understanding the disease. However, a novel pharmacotherapeutic target, i.e. glutamatergic neurotransmission, emerged from animal models of addiction. Specifically, after chronic cocaine administration, glutamate concentrations in the nucleus accumbens (NAcc) of rodents are reduced, while there is an overflow of glutamate during cue-induced cocaine-seeking. Recently, this glutamatergic imbalance has also been observed in humans with CUD. Additionally, promising findings with regard to novel psychotherapeutic approaches came from neurofeedback training (NFT) studies where participants use cognitive strategies to regulate their activity within a specific brain region based on “real-time” feedback about its activity as assessed by real-time functional magnetic resonance imaging (rt-fMRI). For example, participants with CUD successfully learned to regulate their brain activity in reward areas of the midbrain using reward imagery and to reconstitute reward sensitivity to non-drug related reinforcers like, e.g. social interactions, athletic or professional achievements. We therefore investigate the therapeutic potential and the underlying mechanisms of two interventions, a single dose of ketamine and a reward imagery rt-fMRI NFT in 120 participants with CUD. Methods We examine a single ketamine infusion, three sessions of reward imagery rt-fMRI NFT, and the combination of those interventions contrasted to a placebo infusion or a sham NFT in 120 participants with CUD. The study is designed in a randomized, placebo-controlled, double-blind fashion with four study arms. Discussion We expect both interventions to have a positive effect on the proportion of cocaine use days. We predict glutamate levels in the reward system to increase with the ketamine infusion and to reduce craving, a re-enhanced sensitivity towards natural rewards resulting from the rt-fMRI NFT, and synergistic effects of the combined interventions. This neurobiologically informed approach has the potential to open new avenues for the treatment of CUD through individualised and integrated pharmaco-psychotherapy. Trial registration. NCT06125054 ClinicalTrials.gov. Registered on October 26, 2023.

Abstract Slow waves, the hallmark feature of deep nonrapid eye movement sleep, do potentially drive restorative effects of sleep on brain and body functions. Sleep modulation techniques to elucidate the functional role of slow waves thus have gained large interest. Auditory slow wave stimulation is a promising tool; however, directly comparing auditory stimulation approaches within a night and analyzing induced dynamic brain and cardiovascular effects are yet missing. Here, we tested various auditory stimulation approaches in a windowed, 10 s ON (stimulations) followed by 10 s OFF (no stimulations), within-night stimulation design and compared them to a SHAM control condition. We report the results of three studies and a total of 51 included nights and found a large and global increase in slow-wave activity (SWA) in the stimulation window compared to SHAM. Furthermore, slow-wave dynamics were most pronouncedly increased at the start of the stimulation and declined across the stimulation window. Beyond the changes in brain oscillations, we observed, for some conditions, a significant increase in the mean interval between two heartbeats within a stimulation window, indicating a slowing of the heart rate, and increased heart rate variability derived parasympathetic activity. Those cardiovascular changes were positively correlated with the change in SWA, and thus, our findings provide insight into the potential of auditory slow wave enhancement to modulate cardiovascular restorative conditions during sleep. However, future studies need to investigate whether the potentially increased restorative capacity through slow-wave enhancements translates into a more rested cardiovascular system on a subsequent day.

Pregnant women are at increased risk for severe SARS-CoV-2 infection and adverse neonatal outcome, primarily preterm birth and stillbirth. Our study aimed to investigate to which extent SARS-CoV-2 affects placental tissue and if viral replication within the placenta is evident, thus if there is a correlation between placental damage and adverse pregnancy outcome such as stillbirth. We prospectively collected placentas from 61 SARS-CoV-2 infected pregnant women and 10 controls. Histopathological, immunohistochemical, and hybridization studies were performed on all placentas with antibodies for SARS-CoV-2 proteins, ACE2, various immune cells, and inflammatory markers or probes for SARS-CoV-2 genes and an antisense strand. The measured scores of SARS-CoV-2 glycoprotein, nucleocapsid, and antisense strand indicating replication correlated with both the severity of maternal symptoms and presence of stillbirth. Specifically, 15/61 placentas exhibited replication, while the three cases with stillbirth had high or maximal replication scores. ACE2-H-score was significantly higher in COVID-19 patients, while the expression of various immune cells did not differ statistically. In multivariate analysis, presence of maternal comorbidities correlated with presence of severe COVID-19 infection. We report evidence of active SARS-CoV-2 replication in the placenta after maternal infection in pregnancy in a case-control setting in a large population. Intensity of placental viral replication as well as viral levels were higher in women with severe or critical COVID-19 disease, supporting the rationale that severity of maternal SARS-CoV-2 infection could correlate with the severity of placentitis. Replication was maximal in cases of stillbirth, which suggests direct placental involvement in the pathophysiology of this dramatic outcome. Continuing to advocate for preventive measures against COVID-19 during pregnancy, including (re)vaccination, as well as appropriately counseling women with diagnosed infection, are of utter importance.

Aims Although the number of patients suffering from heart failure with preserved ejection fraction (HFpEF) increases, the routine diagnosis remains a challenge. In the absence of a pathognomonic sign for HFpEF or specific treatment strategies, a prognosis‐based characterization of suspected patients remains promising for both the risk stratification of the patients and a disease definition. The Heart Failure Association (HFA) of the European Society of Cardiology has introduced an algorithm with different levels of likelihood regarding the diagnosis of HFpEF, the HFA‐PEFF score. We aimed to evaluate the predictive value of this algorithm in a large cohort regarding mortality, symptom burden, and the functional status. Methods and results DIAST‐CHF is a multicentre, population‐based, prospective, observational study in subjects with at least one risk factor for HFpEF between the age of 50 and 85. We calculated the HFA‐PEFF score (n = 1668) and analysed the risk groups for overall mortality, cardiovascular hospitalization, and submaximal functional capacity (6‐min walk distance) at baseline and after a follow‐up period of 10 years. Patients with high HFA‐PEFF score values 5&6 showed a higher mortality than those with an intermediate score (score values 2–4) and low score values (high 21.3% vs. intermediate 10.1% vs. low 4.3%, P < 0.001). Also, the burden of MACE (death, cardiovascular hospitalization, new myocardial infarction, first diagnosis of HF) was increased in the high score values group (high 40.7% vs. intermediate 25.9% vs. low 13.9%, P < 0.001). Similarly, patients with higher scores had higher cumulative incidences of cardiovascular hospitalizations (P = 0.011). Subjects with higher scores also had lower 6‐min walk distance both at baseline and during follow‐up. Conclusions The HFA‐PEFF score provides a reliable instrument to stratify suspected HFpEF patients by their risk for mortality, symptom burden, and functional status in cohort at risk with a follow‐up period of 10 years. As high HFA‐PEFF scores are associated with worse outcome, the HFA‐PEFF algorithm describes a defining approach towards HFpEF.

There is a lack of real-world data directly comparing different valve prostheses for transaortic valve replacement (TAVR). We aimed to compare early clinical outcomes at 30-days between the self-expandable Portico valve (Abbott) with the balloon-expandable Edwards Sapien 3 valve (Edwards Lifesciences) (ES3). Out of 1,901 patients undergoing TAVR between January 2018 and December 2021, all patients who received either Portico valve or ES3 valve via transfemoral TAVR were matched using nearest-neighbor (1:1) propensity scoring. Primary endpoints were single safety endpoints and early safety composite endpoints defined by Valve Academic Research Consortium-2 (VARC-2) criteria. The secondary endpoint was to analyze risk predictors for new permanent pacemaker (PPM) implantation in TAVR. Out of 661 complete cases, a total of 434 patients were successfully matched based on age, sex, Euro Score II and STS-score. In the matched cohort, 217 received either a Portico or valve and 217 received an ES3 valve. The VARC-2 early safety composite scores indicated a significantly greater overall 30-day safety risk in the Portico group at 9.2% (  = 20) compared to 3.7% (  = 8) in the ES3 group (  = 0.032). The requirement for new permanent pacemaker (PPM) implantation was also higher in the Portico group, at 21.2% (  = 46) vs. 13.4% (  = 29) in the ES3 group (  = 0.042). 30-day mortality was higher was 3.7% (  = 8) in Portico group compared to 0.9% in ES3 group (  = 0.11). Furthermore, implantation of the Portico valve was identified as a significant risk predictor for new PPM implantation, alongside higher age, preprocedural atrioventricular block (AVB) and longer total procedure duration. This study shows significantly higher rates of early clinical complications for Portico valve prostheses compared to ES3. These findings should be especially taken into consideration when selecting valve prosthesis for high-risk patients.

Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of recombinant adeno-associated virus (rAAV)-mediated overexpression of human insulinlike growth factor (hIGF)-I to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival and anabolic effects of the rAAV-hIGF-I treatment in primary human normal and OA chondrocytes in vitro and in explant cultures in situ compared with control (reporter) vector delivery. Efficient, prolonged IGF-I secretion via rAAV stimulated the biological activities of OA chondrocytes in all the systems evaluated over extended periods of time, especially in situ , where it allowed for the long-term reconstruction of OA cartilage (at least for 90 d). Remarkably, production of high, stable amounts of IGF-I in OA cartilage using rAAV advantageously modulated the expression of central effectors of the IGF-I axis by downregulating IGF-I inhibitors (IGF binding protein (IGFBP)-3 and IGFBP4) while upregulating key potentiators (IGFBP5, the IGF-I receptor and downstream mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK-1/2) and phosphatidylinisitol-3/Akt (PI3K/Akt) signal transduction pathways), probably explaining the enhanced responsiveness of OA cartilage to IGF-I treatment. These findings show the benefits of directly providing an IGF-I sequence to articular cartilage via rAAV for the future treatment of human osteoarthritis.

Background: Transcatheter aortic valve implantation (TAVI) is the treatment of choice for symptomatic aortic stenosis in patients with moderate to high surgical risk. When transfemoral access is unsuitable, alternative routes such as transapical (TAP) or transaxillary (TAX) routes must be considered. This study compares the in-hospital mortality and clinical outcomes of TAP vs. TAX TAVI. Methods: We conducted a retrospective analysis of 76 patients who underwent TAP or TAX TAVI between 2018 and 2021 at our department. Inverse probability of treatment weighting (IPTW) was used to account for baseline differences. Results: Among 1901 TAVI procedures, a total of 76 was selected of which TAP was performed in 34.2% (n = 26), and TAX in 65.8% (n = 50) of cases. Self-expanding CoreValve Evolut R valve prostheses were used in 96% of TAX cases, while balloon-expandable Edwards SAPIEN 3 valve prostheses were exclusively implanted in TAP cases. After IPTW adjustment, baseline characteristics, including EuroSCORE II, LVEF, and NYHA class, were comparable. TAX was associated with a higher pacemaker implantation rate (22.6% vs. 0%; p = 0.032), while TAP had a higher incidence of late bacteremia (13.4% vs. 1.6%; p = 0.027) and longer hospitalization (19 [13, 28] vs. 10 [8, 21] days; p = 0.016). In-hospital (0% vs. 2.1%; p = 0.388), 30-day (3.4% vs. 3.5%; p = 0.957), and 3-year mortality (6.7% vs. 4.8%; p = 0.709) were similar. Device implantation success was 100% in both groups. Major bleeding and vascular complications were rare. Balloon predilatation was more frequent in TAX (57.6% vs. 13.3%; p = 0.002). Rates of mild and moderate aortic regurgitation did not differ. Conclusions: In patients unsuitable for transfemoral TAVI, TAP was associated with lower pacemaker rates but longer hospitalization and increased late bacteremia compared to TAX. Both approaches showed comparable safety and efficacy, emphasizing the need for individualized access selection.

Background: Transcatheter aortic valve replacement (TAVR) has emerged as a well-established option for patients with severe aortic stenosis who present high or extreme surgical risk. Direct comparisons of outcomes between different valve prostheses are important to assist operators in making an informed device selection. We aimed to perform a comparative analysis of early clinical outcomes at 30 days and long-term outcomes up to 3 years after TAVR using self-expandable Portico or CoreValve Evolut R valve prostheses. Methods: Out of 396 patients treated with either Portico or CoreValve Evolut R valves from January 2018 to December 2021, 79 patients were assigned to each group after 1:1 propensity score matching based on baseline parameters. Peri- and postprocedural outcomes at 30 days and up to a 3-year follow-up period were retrospectively collected according to the Valve Academic Research Consortium (VARC-2) criteria. Results: The immediate survival rate was 100% in both groups. The 30-day mortality was 0.0% in the Portico group and 1.3% in the CoreValve Evolut group (p = 1). Minor postprocedural bleeding was more frequent in the Evolut group both at 30 days (8.9% vs. 0%, p = 0.02) and at 3 years (11.4% vs. 3.8%, p = 0.133). There were no statistically significant differences regarding the combined safety endpoint (p = 1), acute kidney injury (AKIN 2 or AKIN 3) (p = 1; p = 0.477), or new pacemaker implantation (p = 0.31), at either 30 days or 3 years. Postprocedural myocardial infarction and stroke showed comparable rates in both groups. Conclusions: In terms of early clinical outcomes, no statistically significant differences were observed between the two groups of self-expandable valve prostheses, except for a significantly higher rate of minor bleeding in the Evolut group at 30 days. Notably, this trend of increased minor bleeding in the Evolut group persisted over the 3-year follow-up period, although the difference did not reach statistical significance. Both groups demonstrated low rates of all-cause mortality and clinical complications at long-term follow-up. The choice of valve should be customized to the individual characteristics of each patient.

Objectives Melanoma-associated antigens A had been detected repeatedly in oral squamous cell carcinoma, but not in healthy mucosa. Additionally, patients with MAGE-A expressing cancers are regarded to have a worse survival prognosis, so that MAGE-A are supposed to be part of carcinogenesis. Which role these antigens fulfill within OSCC is still, up today, largely unknown. This study examines the hypothesis that MAGE-A is being produced in OSCC but not in mucosa tissue and if MAGE-A has any correlation to clinical patient’s parameters like tumor size, lymph node metastasis, distant metastasis, overall survival, and recurrence. Materials and methods For this purpose, 50 tumor samples and 39 mucosa samples were analyzed by means of PCR and immunohistochemical staining with the antibody 6C1. Results Forty of 41 stained tumor samples showed a positive antibody reaction with a maximum staining rate of 53%. Sixteen mucosa samples showed a mild positive reaction. The PCR revealed a linear expression pattern of MAGE-A in which the genes are proportionally expressed in OSCC. We did not find any relationship between MAGE-A and tumor size, overall survival, or recurrence. There was also no connection between MAGE-A and tumor parameters Hif-1 and LDH. Their expression was detected tendentially in tumors with higher staging, advanced lymph node metastasis, and rising age of the patients. The genes MAGE-A3+6 and MAGE-A4 had a statistically significant correlation with lymph node metastasis ( p  = 0.007 and p = 0.004). Patients got distant metastasis and influence of MAGE-A on metastatic behavior could not be verified. The genes MAGE-A3 and -A4 are consequently qualified as tumor markers in the field of diagnosis and follow-up of OSCC. Conclusions and clinical relevance Two genes have great potential as target proteins in immunotherapy. The genes MAGE-A3+6 and MAGE-A4 had a statistically significant correlation with lymph node metastasis.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) remains a common condition with no pharmacological treatment. Physical activity (PA) improves symptoms and quality of life (QoL), but no clear recommendations exist on PA in HFpEF patients. We investigated the association of PA (amount/intensity) on clinical phenotype in HFpEF. Methods and results The Aldosterone in Diastolic Heart Failure trial investigated spironolactone vs. placebo in stable HFpEF patients. At baseline, all patients underwent detailed phenotypization including echocardiography, cardiopulmonary exercise testing, 6 minute walking test (6MWT), and QoL assessment (36-item Short-Form questionnaire). PA was assessed by a self-report questionnaire, classified in metabolic equivalents of task (MET) and analysed with regard to exercise capacity, diastolic function, and QoL. Four hundred twenty-two patients (52% women, age 67 ± 8 years, New York Heart Association II and III) were classified by weekly MET hours into a low (<70), middle (70–140), or high (>140) level of PA. Total PA correlated positively with 6MWT distance (r = 0.17; P = 0.002) and physical function of QoL (r = 0.10; P = 0.05), but not with peak oxygen uptake (peakVO2). In contrast, both 6MWT distance and peakVO2 were significantly higher in patients who performed high-intensity PA for >8 h/week (P < 0.001, P = 0.02, respectively). Time of high-intensity PA was related to higher 6MWT distance (r = 0.21, P < 0.001), peakVO2, and better physical function of QoL (both r = 0.13, P = 0.01), whereas low-intensity PA did not show significant associations. Interestingly, PA was not related to any measure of diastolic function. Conclusions A higher amount of PA is related to higher submaximal exercise capacity and physical function of QoL. Regarding maximal exercise capacity, only high-intensity PA showed significant association in HFpEF patients.