Introduction Sleep deprivation and electroconvulsive therapy (ECT) effectively ameliorate symptoms in major depressive disorder (MDD). In rodents, both are associated with an enhancement of cerebral adenosine levels, which in turn likely influence adenosinergic receptor expression. The aim of the current study was to investigate cerebral A1 adenosine receptor (A1AR) availability in patients with MDD as a potential mediating factor of antidepressant effects of ECT using [18F]CPFPX and positron emission tomography (PET). Methods Regional A1AR availability was determined before and after a series of ECT applications (mean number ± SD 10.4 ± 1.2) in 14 subjects (4 males, mean age 49.5 ± 11.8 years). Clinical outcome, measured by neuropsychological testing, and ECT parameters were correlated with changes in A1AR availability. Results ECT had a strong antidepressive effect (p < 0.01) while on average cerebral A1AR availability remained unaltered between pre-and post-ECT conditions (F = 0.65, p = 0.42, mean difference ± SD 3.93% ± 22.7%). There was no correlation between changes in clinical outcome parameters and regional A1AR availability, although individual patients showed striking bidirectional alterations of up to 30–40% in A1AR availability after ECT. Solely, for the mean seizure quality index of the applied ECTs a significant association with changes in A1AR availability was found (rs = −0.6, p = 0.02). Discussion In the present study, therapeutically effective ECT treatment did not result in coherent changes of A1AR availability after a series of ECT treatments. These findings do not exclude a potential role for cerebral A1ARs in ECT, but shift attention to rather short-termed and adaptive mechanisms during ECT-related convulsive effects.

The research includes a comparative analysis of the structure and floristic composition of different types of lawns along Belgrade roads (grass areas of roundabouts, dividing strips, areas near roads and grass areas of first order roads), their floristic composition, as well as determining changes over a period of 17 years. The analyses are based on the results of floristic research from 2002, as well as the results of field research conducted during 2019. A total of 114 plant species were recorded on the studied lawns along Belgrade roads, among which the highest proportion belongs to the category of weed species. The taxonomic analysis has shown a reduction in the recorded number of families and genera over the study period of 17 years Both studies indicate the absolute dominance of plants from the group of hemicryptophytes. The results of the research are used to provide guidelines and recommendations for improving the condition and structure of lawns along Belgrade roads. Also, they provide the basis for the future selection of adequate types of grass for the establishment of new lawns, as well as the repair of the existing ones, i.e. for the sustainable management of green spaces along city roads.

BACKGROUND: Avelumab, a monoclonal antibody targeting PD-L1, is currently approved in the USA in combination with axitinib for the first-line treatment of patients with aRCC. This analysis evaluated the relationship between potential covariates, including avelumab exposure, and the efficacy endpoints progression-free survival (PFS; by blinded independent central review per Response Evaluation Criteria in Solid Tumors [RECIST] criteria) and objective response (OR; per RECIST) in patients with aRCC. METHODS: Exposure metrics for all patients in JAVELIN Renal 101 who received avelumab 10 mg/kg every 2 weeks (Q2W) in combination with axitinib were derived from a population pharmacokinetic model (N=434). E-R analysis for PFS was conducted using parametric time-to-event (TTE) methodology. The hazard distribution was tested using exponential, Weibull, log-normal, and log-logistic distributions. E-R analysis for OR was performed using generalized binomial logistic regression. For OR, the full model included the influence of all potential covariates, while the final model retained statistically significant covariates after stepwise backwards elimination (α=0.15). For PFS, covariates were included in the full model based on forward addition (α=0.05), and the final model was determined using backward elimination (α=0.01). Model evaluation included TTE-visual predictive checks, the likelihood ratio test, the Hosmer-Lemeshow test, and receiver operating characteristic curves. RESULTS: The best fit to the PFS data was the log-normal distribution. Avelumab exposure (cycle 1 day 15 trough concentration) was associated with probability of longer PFS in both univariate and multivariate regression models. In addition, the favorable-risk group, according to baseline Heng criteria, was associated with probability of longer PFS relative to patients with intermediate prognosis using Heng criteria. Similarly, increasing avelumab exposure was associated with a higher probability of achieving OR. However, several factors have confounded the interpretation of the causal relationship between exposure and PFS or OR, including the imbalance of Heng prognostic criteria across exposure quartiles, correlation among covariates, and that data were from a single-dose regimen. No relationship was found between incidence of ADA or baseline PD-L1 status and the efficacy endpoints PFS or OR. CONCLUSION: The E-R analyses were considered exploratory and no definite conclusions could be made on the impact of exposure on PFS or OR, as other variables confounded interpretation of the relationship. Overall, the exposure from avelumab 10 mg/kg IV Q2W in combination with axitinib was associated with a manageable and tolerable safety profile and demonstrated superior efficacy compared with sunitinib in terms of PFS in treatment-naive patients with aRCC. Citation Format: Carlo Bello, Satjit Brar, Joanna C. Masters, Akash Khandelwal, Ana M. Novakovic, Ana Ruiz-Garcia, Jennifer Hibma. Exposure-response (E-R) analysis of efficacy for avelumab in combination with axitinib in patients with advanced renal cell carcinoma (aRCC) in JAVELIN Renal 101 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1364.

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of schizophrenia. As BDNF regulates axonal and dendritic growth, altered BDNF levels in schizophrenia patients might underlie changes in structural connectivity that have been identified by magnetic resonance imaging (MRI). We investigated a possible correlation between BDNF serum levels, fiber tract architecture, and regional grey matter volumes in 19 schizophrenia patients and a gender- and age-matched control group. Two patients had to be excluded due to abnormalities in their MRI scans. Serum samples were obtained to determine BDNF levels, and T1- as well as diffusion-weighted sequences were acquired. We, then, investigated correlations between BDNF serum levels with neuroimaging parameters, using Voxel-based Morphometry (VBM) and Tract-based Spatial Statistics (TBSS). We found a significant negative correlation between BDNF serum levels and FA values in the right inferior fronto-occipital fasciculus and the right superior longitudinal fasciculus. These regions also showed a decrease in AD values in schizophrenia patients. Grey matter volumes were reduced in patients but there was no correlation between regional grey matter volumes and BDNF. The right superior longitudinal fasciculus has been repeatedly identified to exhibit microstructural changes in schizophrenia patients. Our findings of a negative correlation between BDNF and FA values in patients might indicate that BDNF is upregulated to compensate decreased structural connectivity as it induces neural plasticity and shows increased levels in damaged tissue. These findings of our pilot study are encouraging leads for future research in larger samples.

This study was done with the aim to comparatively analyze the taxonomic and phytogeographical spectrum of lawns along the Belgrade roads. The analysis was done using the results of a floristic research done in 2001, combined with results of the field research conducted in 2019. A comparative analysis of the obtained results has shown that a lower heterogeneity of the floral elements and plant taxa was recorded in the studied lawns in 2019, when compared to the previous research period. Such a reduction in heterogeneity is the result of more intensive measures of lawn care, and of a stronger anthropogenic influence, which has led to a homogenization of the lawn flora.

[This corrects the article DOI: 10.3389/fpsyt.2019.00275.].

Avelumab, an anti–programmed death‐ligand 1 monoclonal antibody approved for the treatment of metastatic Merkel cell carcinoma and platinum‐treated urothelial carcinoma, was initially approved with a 10 mg/kg weight‐based dose. We report pharmacokinetic (PK)/pharmacodynamic analyses for avelumab comparing weight‐based dosing and a flat 800 mg dose, developed using data from 1,827 patients enrolled in 3 clinical trials (NCT01772004, NCT01943461, and NCT02155647). PK metrics were simulated for weight‐based and flat‐dosing regimens and summarized by quartiles of weight. Derived exposure metrics were used in simulations of exposure‐safety (various tumors) and exposure‐efficacy (objective responses; Merkel cell or urothelial carcinoma). Flat dosing was predicted to provide similar exposure to weight‐based dosing, with slightly lower variability. Exposure‐safety and exposure‐efficacy simulations suggested similar benefit:risk profiles for the two dosing regimens. These pharmacometric analyses provided the basis for the US Food and Drug Administration approval of a flat dose of avelumab 800 mg every 2 weeks in approved indications.

Numerous neuroimaging studies have revealed structural brain abnormalities in schizophrenia patients. There is emerging evidence that dysfunctional nerve growth factor (NGF) signaling may contribute to structural brain alterations found in these patients. In this pilot study, we investigated whether there was a correlation between NGF serum levels and gray matter volume (GMV) in schizophrenia patients. Further, we investigated whether there was an overlap between the correlative findings and cross-sectional GMV differences between schizophrenia patients (n = 18) and healthy controls (n = 19). Serum NGF was significantly correlated to GMV in the left prefrontal lobe, the left midcingulate cortex, and the brainstem in schizophrenia patients. However, we did not find any correlations of NGF serum levels with GMV in healthy controls. Schizophrenia patients showed smaller GMV than healthy controls in brain regions located in the bilateral limbic system, bilateral parietal lobe, bilateral insula, bilateral primary auditory cortex, left frontal lobe, and bilateral occipital regions. In a conjunction analysis, GMV in the left midcingulate cortex (MCC) appears negatively correlated to NGF serum levels in the group of schizophrenia patients and also to be reduced compared to healthy controls. These results suggest an increased vulnerability of schizophrenia patients to changes in NGF levels compared to healthy controls and support a role for NGF signaling in the pathophysiology of schizophrenia. As our pilot study is exploratory in nature, further studies enrolling larger sample sizes will be needed to further corroborate our findings and to investigate the influence of additional covariates.

Background/Aims: From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary (“hair”) bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound. How these morphological defects translate into hearing phenotypes is not clear. Methods: Here, we studied global and conditional Gnai3 and Gnai2 mouse mutants deficient for either one or both Gαi proteins. Comparative analyses of global versus Foxg1-driven conditional mutants that mainly delete in the inner ear and telencephalon in combination with functional tests were applied to dissect essential and redundant functions of different Gαi isoforms and to assign specific defects to outer or inner hair cells, the auditory nerve, satellite cells or central auditory neurons. Results: Here we report that lack of Gαi3 but not of the ubiquitously expressed Gαi2 elevates hearing threshold, accompanied by impaired hair bundle elongation and shape in high-frequency cochlear regions. During the crucial reprogramming of the immature inner hair cell (IHC) synapse into a functional sensory synapse of the mature IHC deficiency for Gαi2 or Gαi3 had no impact. In contrast, double-deficiency for Gαi2 and Gαi3 isoforms results in abnormalities along the entire tonotopic axis including profound deafness associated with stereocilia defects. In these mice, postnatal IHC synapse maturation is also impaired. In addition, the analysis of conditional versus global Gαi3-deficient mice revealed that the amplitude of ABR wave IV was disproportionally elevated in comparison to ABR wave I indicating that Gαi3 is selectively involved in generation of neural gain during auditory processing. Conclusion: We propose a so far unrecognized complexity of isoform-specific and overlapping Gαi protein functions particular during final differentiation processes.

Introduction Chronic right ventricular pacing can deteriorate cardiac function. Consequently, pacemaker system upgrades are more frequently indicated. These interventions can be hindered by venous thrombosis. In literature, it is rarely described that this problem is resolved by implanting a new lead for left ventricle (LV) stimulation on the opposite side of the previously implanted pacemaker and then subcutaneously transferring it to the old pocket. Case outline A 75-year-old male patient was hospitalized due to a planned pacemaker upgrade in December 2015. A dual-chamber pacemaker had been implanted due to sinus node dysfunction in 2011. During the previous 18 months he had been complaining about symptoms of heart failure. An upgrade to the cardiac resynchronization therapy (CRT) with a new CRT-P device was indicated due to the LV dilatation with the ejection fraction decrease, clinical deterioration, and the presence of high percentage of ventricular pacing. In October 2015, the mentioned intervention was unsuccessful due to total left subclavian vein thrombosis on the side of the previously implanted pacemaker. Anticoagulation therapy was ordinated and the reevaluation was postponed. During this hospitalization, venography confirmed total left subclavian vein thrombosis despite the anticoagulation therapy. It was decided to implant a new LV lead on the right side and then subcutaneously shift it by pre-sternal tunneling to the previous left prepectoral pocket. The intervention was uneventful. The first controls have shown stable pacemaker parameters. Conclusion This case report confirms that contralateral lead placement and subcutaneous pre-sternal tunneling of the lead is feasible and safe in patients with an implanted pacemaker, an indication for system upgrade and ipsilateral vein obstruction.