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Abstract Background Magnetic resonance imaging (MRI)-guided pulsed focused ultrasound combined with the infusion of microbubbles (pFUS+MB) induces transient blood-brain barrier opening (BBBO) in targeted regions. pFUS+MB, through the facilitation of neurotherapeutics’ delivery, has been advocated as an adjuvant treatment for neurodegenerative diseases and malignancies. Sterile neuroinflammation has been recently described following pFUS+MB BBBO. In this study, we used PET imaging with [18F]-DPA714, a biomarker of translocator protein (TSPO), to assess for neuroinflammatory changes following single and multiple pFUS+MB sessions. Methods Three groups of Sprague-Dawley female rats received MRI-guided pFUS+MB (Optison™; 5–8 × 107 MB/rat) treatments to the left frontal cortex and right hippocampus. Group A rats were sonicated once. Group B rats were sonicated twice and group C rats were sonicated six times on weekly basis. Passive cavitation detection feedback (PCD) controlled the peak negative pressure during sonication. We performed T1-weighted scans immediately after sonication to assess efficiency of BBBO and T2*-weighted scans to evaluate for hypointense voxels. [18F]DPA-714 PET/CT scans were acquired after the BBB had closed, 24 h after sonication in group A and within an average of 10 days from the last sonication in groups B and C. Ratios of T1 enhancement, T2* values, and [18F]DPA-714 percent injected dose/cc (%ID/cc) values in the targeted areas to the contralateral brain were calculated. Histological assessment for microglial activation/astrocytosis was performed. Results In all groups, [18F]DPA-714 binding was increased at the sonicated compared to non-sonicated brain (%ID/cc ratios > 1). Immunohistopathology showed increased staining for microglial and astrocytic markers in the sonicated frontal cortex compared to contralateral brain and to a lesser extent in the sonicated hippocampus. Using MRI, we documented BBB disruption immediately after sonication with resolution of BBBO 24 h later. We found more T2* hypointense voxels with increasing number of sonications. In a longitudinal group of animals imaged after two and after six sonications, there was no cumulative increase of neuroinflammation on PET. Conclusion Using [18F]DPA-714 PET, we documented in vivo neuroinflammatory changes in association with pFUS+MB. Our protocol (utilizing PCD feedback to minimize damage) resulted in neuroinflammation visualized 24 h post one sonication. Our findings were supported by immunohistochemistry showing microglial activation and astrocytosis. Experimental sonication parameters intended for BBB disruption should be evaluated for neuroinflammatory sequelae prior to implementation in clinical trials.

Blood-brain barrier opening (BBBO) with pulsed Focused Ultrasound (pFUS) and microbubbles (MB) has received increasing interest as a method for neurotherapeutics of the central nervous system. In general, conventional MRI [i.e., T2w, T2∗w, gadolinium (Gd) enhanced T1w] is used to monitor the effects of pFUS+MB on BBBO and/or assess whether sonication results in parenchymal damage. This study employed multimodal MRI techniques and 18F-Fludeoxyglucose (FDG) PET to evaluate the effects of single and multiple weekly pFUS+MB sessions on morphology and glucose utilization levels in the rat cortex and hippocampus. pFUS was performed with 0.548 MHz transducer with a slow infusion over 1 min of OptisonTM (5–8 × 107 MB) in nine focal points in cortex and four in hippocampus. During pFUS+MB treatment, Gd-T1w was performed at 3 T to confirm BBBO, along with subsequent T2w, T2∗w, DTI and glucose CEST (glucoCEST)-weighted imaging by high field 9.4 T and compared with FDG-PET and immunohistochemistry. Animals receiving a single pFUS+MB exhibited minimal hypointense voxels on T2∗w. Brains receiving multiple pFUS+MB treatments demonstrated persistent T2w and T2∗ abnormalities associated with changes in DTI and glucoCEST when compared to contralateral parenchyma. Decreased glucoCEST contrast was substantiated by FDG-PET in cortex following multiple sonications. Immunohistochemistry showed significantly dilated vessels and decreased neuronal glucose transporter (GLUT3) expression in sonicated cortex and hippocampus without changes in neuronal counts. These results suggest the importance to standardize MRI protocols in concert with advanced imaging techniques when evaluating long term effects of pFUS+MB BBBO in clinical trials for neurological diseases.

Antidromic stimulation of the rat trigeminal ganglion triggers the release of substance P (SP) and calcitonin gene-related peptide (CGRP) from sensory nerve terminals of the capsaicin sensitive C-fibers. These pro-inflammatory neuropeptides produce a marked hyperemia in the anterior segment of the eye, accompanied by increased intraocular pressure, breakdown of the blood-aqueous barrier and myosis. To assess the effects of neurogenic inflammation on the retina, specifically on the immunostaining of neurotransmitters and neurotrophins, as well as on the expression of neurotrophin receptors in the retina. RT-PCR was also accomplished in control and stimulated animals to confirm the immunohistochemical results. In the electrically stimulated eyes, immunostaining for SP, CGRP, VIP and nNOS demonstrated a marked increase in the RPE/POS (Retinal Pigment Epithelium/Photoreceptor Outer Segments), in the inner and outer granular layers and in the ganglion cells in comparison to the control eyes. CGRP and SP were found increased in stimulated animals and this result has been confirmed by RT- PCR. Changes in neurotrophin immunostaining and in receptor expression were also observed after electric stimulation of trigeminal ganglia. Decrease of BDNF and NT4 in the outer and inner layers and in ganglion cells was particularly marked. In stimulated rat retinas immunostaining and RT-PCR showed a NGF expression increase. Neurotrophin receptors remained substantially unchanged. These studies demonstrated, for the first time, that antidromic stimulation of the trigeminal ganglion and subsequent neurogenic inflammation affect immunostaining of retinal cell neurotransmitter/ neuropeptides and neurotrophins as well as the expression of neurotrophin receptors.

Introduction The premenstrual dysphoric disorder (PMDD) is a new distinct diagnostic entity in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). However, the severe premenstrual (PM) symptoms associated with PMDD result in functional impairment, globally, it remains highly underdiagnosed, underscoring the need for enhanced clinical recognition. Objectives This ongoing study aims to assess the prevalence and symptom profile of PMDD in a sample of Hungarian women. It is part of a comprehensive research process aiming to validate a prospective PMDD diagnostic questionnaire (Daily Record of Severity of Problems, DRSP) in order to facilitate the diagnosis of the disorder. Methods The study was performed in three steps. Firstly, retrospective data were collected from 112 women. Probable PMDD was assessed using the DSM-5 Based Screening Tool, while anxio-depressive symptoms and well-being were evaluated using the Beck Depression Inventory, the state subscale of the State-Trait Anxiety Inventory, and the WHO Well-Being Scale. Subsequently, prospective data were obtained from 9 women who completed the DRSP along with the aforementioned mood questionnaires during both their PM and follicular phases. Results In the first research phase, the sample was divided into women with probable PMDD diagnosis (PMDD group, n=68) and women without probable PMDD diagnosis (nonPMDD group, n=45) based on the DSM-5-Based Screening Tool. The PMDD group reported significantly more severe depressive (F(1; 56.2) = 19.394, p≤0.001) and anxiety (F(1; 35.6)=17.714, p≤0.001) symptoms and lower well-being (F(1; 44.3)=4.288, p=0.04) compared to the non-PMDD group, irrespective of the menstrual phase they experienced. In the second and third research phases based on the DRSP, the sample was divided into women with probable PMDD diagnosis (PMDD group, n= 3) and those without probable PMDD diagnosis (nonPMDD group, n=6). A statistically significant association was observed between the classifications according to the DSM-5 Based Screening Tool and the DRSP (p=0.048; Cramer’s V=0.79). The PMDD group showed a tendency of lower well-being and more severe anxio-depressive symptoms than the nonPMDD group (Well-being: between phases p=0.93, between groups p=0.06; BDI-II: between phases p=0.79, between groups p=0.07; STAI-S: between phases p=0.87, between groups p=0.17). Conclusions The prevalence of PMDD was high in our sample. Women with probable PMDD retrospectively reported substantial affective difficulties and a decline in subjective well-being, regardless of their menstrual cycle. Prospective preliminary findings suggest a trend toward differentiation associated with probable PMDD. These results highlight the need for prospective clinical studies addressing the psychological symptoms of women with PM issues and the importance of appropriate treatment of the clinical appearance of PMDD. Disclosure of Interest None Declared

Introduction COVID-19 has increased the levels of psychological stress experienced by the dental team, and higher level of constant stress negatively impacts mental health. Objectives The study aimed to 1) assess dentists’ level of stress and compare it to normal population data; 2) identify the hierarchy of coping strategies chosen by dentists and their perception of those chosen by team members to manage psychological stress caused by the pandemic; and 3) to ascertain the effects of these coping strategies on dentists’ higher stress level. Methods Data from an electronic test battery comprising of general demographic and dental-related variables was collected from 182 licenced Hungarian dentists at the outset of the pandemic. Responses to an empirical series of questions regarding their perceived level of stress, choice of interventional coping skills and their perception of those used by team members were recorded. Results Dentists’ level of stress was significantly lower than the stress level measured in a Hungarian normal population (t (386)=-2.227, p=0.027), while financial status has a moderating effect (F(3,176)=4.851, p=0.003). The hierarchy of coping strategies chosen by the dentist indicated that physical activity and exercise, particularly in groups settings (M=4.78, SD=0.463), and socialization with family (M=4.72, SD=0.626) were the most effective coping management strategies, superior to financial compensation, shifting work patterns, systems level change, and decisions within the team structure. Inclusionary strategies with family (M=4.64, SD=0.587), participating in individual leisure activities (M=4.49, SD=0.621) and socializing with friends (M=4.44, SD=0.825) were seen by dentists as more important to team members. Regression analysis was used to ascertain whether the use of these coping strategies increased the likelihood of having higher levels of perceived stress. The model was significant (F(4,169)=8.292, p≤0.001) with R2 of 16.4%. Older age (B=-0.179, S.E.=0.050, t =-3.582, p≤0.001), gender (B=4.214, S.E.=1.423, t=2.961, p=0.004), active participation in developing COVID-19 protocols (B=-1.619, S.E.=0.575, t =-2.815, p=0.005) and socialization with family (B=-2.108, S.E.=1.058, t =-1.993, p=0.048) were the most effective coping mechanisms for having lower levels of perceived stress. Conclusions Our study provided insights into the value of importance attributed to perceived stress and a series of coping strategies used by the respondents and their perception of value ascribed to the same series by their team members. Active participation both in family life and in professional environment proved to be protective in such a highly stressful time like the COVID-19 pandemic. Disclosure of Interest None Declared

Introduction Premenstrual dysphoric disorder (PMDD) is a newly introduced category in the 5th version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and is highly underdiagnosed worldwide, despite its strong connections to anxiodepressive symptom severity and perceived well-being. Objectives Firstly in Hungary, our aim was to: (a)assess whether even a probable PMDD diagnosis is associated with elevated levels of depressive and anxiety symptoms, and decreased perception of well-being on an adult women sample; (b)to evaluate whether women with a probable PMDD diagnosis report greater fluctuation of their affect during the different phases of their menstrual cycle; (c)to examine whether the elevated levels of anxiodepressive symptoms and lower well-being increase the statistical likelihood of having a probable PMDD diagnosis. Methods An online test battery was designed to examine probable PMDD diagnosis, severity of anxiodepressive symptoms and well-being. 393 adult women were screened for eligibility in the study (exclusion criteria involved: irregular cycle; use of hormonal contraceptives), from which 112 were included in the final analyses. DSM-5-Based Screening Tool for Women’s Perceptions of Premenstrual Symptoms, Beck’s Depression Inventory, Spielberger’s State Anxiety Inventory, and the WHO-5 Well-Being Index were assessed. Results Based on the DSM-5-Based Screening Tool, the sample was divided into 1)women with probable PMDD diagnosis (PMDD group,n=67) and 2)women without probable PMDD (nonPMDD group,n=45). Menstruation cycles were sorted into menstrual, from-menstruation-to-ovulation, early luteal and late luteal phases. The PMDD group exhibited significantly higher depressive (F(1;56,2)=19.394, p≤0.001) and anxiety (F(1;35,6)=17.714,p≤0.001) symptom severity and lower scores of well-being (F(1;44,3)=4.288,p=0.0442) compared to the nonPMDD group regardless of which menstrual cycle they were in. Binomial logistic regression model was used to test whether higher anxiodepressive symptoms and lower scores of well-being increase the likelihood of having PMDD: the model was significant (χ2(2)=27.287, p≤0.001), and it explained 29.2% of the variance in PMDD. Elevated levels of anxiety (B=0.058, S.E.=0.022, Waldχ2(1)=7.142, p=0.008,OR=1.060) and depressive (B=0.085,S.E.=0.031,Waldχ2(1)=7.480,p=0.006,OR=1.089) symptoms increased significantly the likelihood of having a probable PMDD diagnosis. Conclusions Women with even a probable PMDD diagnosis exhibited significantly elevated levels of anxiodepressive symptoms and lower scores of well-being regardless of which menstrual phase they were assessed in compared to women without meeting the criteria of the PMDD screening tool. These preliminary results underscore the need for prospective clinical studies of differences in affective symptoms exhibited in PMDD. Disclosure of Interest None Declared

Introduction Elevated levels of anxio-depressive symptoms and perceived stress are widely researched in case of female factor infertility; however, there is scant information on their emergence in case of male factor infertility. Objectives The aim of the present study is to assess whether a 5-course paramedical counselling accompanying infertility treatment would have a decreasing impact on anxio-depressive symptom severity and perceived stress and would increase the level of self-esteem in infertile men. Methods 108 patients were divided into control (n = 51) and experimental (n = 57) groups, where the latter participated in the aforementioned paramedical counselling. Anxio-depressive symptom severity was measured with the Beck Depression Inventory and the Spielberger’s State Anxiety Inventory; perceived stress was registered with the Perceived Stress Scale and Brief Stress and Coping Inventory, while self-esteem was evaluated by the Rosenberg Self-Esteem Scale. Results Participation in an infertility programme itself affected positively patients’ self-esteem and decreased their levels of depressive symptom severity (t(50) = 2.738, p = 0.009, 95%CI = 0.167 – 1.088), but an additional 5-session paramedical counselling resulted in a significant lowering of state anxiety symptoms (t(106) = -2.093, p = 0.039, 95%CI = -6.372 – 0.173) contrasted with infertile men not receiving this additional counselling. Conclusions Conclusion: Screening for psychological factors is advisable in the course of an infertility treatment, and the implementation of an accompanying paramedical counselling focusing on the alleviation of concomitant psychopathological symptoms would be advisable among male infertile patients. Disclosure No significant relationships.

Non-destructive prompt gamma activation analysis (PGAA), neutron radiography (NR) and high resolution time-of-flight neutron diffraction (TOF-ND) have been applied to investigate metal archaeological artefacts belonging to the Academia Georgica Treiensis (AGT) collection. 8 archaeological items have been analysed, by using the facilities of the Budapest Neutron Centre (BNC). Some of these objects mostly dating back probably to the VI-IV century B.C. and presumed to be discovered in the Marche Region, Italy. The primary goal of the analyses was to advance the correct technological and material description of the objects, providing scientific data for further and more comprehensive comparative analyses also covering the find material from the close archaeological sites. The neutron investigations allowed determining the bulk composition, also providing either a qualitative and quantitative assessment of the phase composition and the structural properties of the constituents, or radiographic images, which would finally help to identify possible manufacturing techniques. Additional examinations, carried out by external milli-beam particle induced X-ray emission spectroscopy (PIXE), provided quantitative analyses of major and trace elements (e.g., Fe, Pb and As) in order to recognize the constitutive alloys and to supply information on the near-surface elemental composition, complementary to the data characteristic for the bulk. The obtained results, thought to be useful to set up a classification according to the chemical composition, and this way allow achieving important information related to the possible provenance of the objects.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health., (© 2024. The Author(s).)

We investigated the association between the SDF-1-3' (c801G > A) variant and the development of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR) in a Hungarian cohort. SDF-1-3' (c801G > A) was genotyped in 103 patients with diabetic retinopathy and 31 age- and sex-matched non-diabetic controls. Central retinal and choroidal thickness was measured by swept-source optical coherence tomography. The distribution of heterozygous and homozygous SDF-1-3' (c801G > A) genotypes was similar in diabetic and control subjects. The SDF-3'(c801AA) genotype was associated with DME ( n = 94 eyes, allele distribution p = 0.006, genotype distribution p = 0.01 OR: 2.48, 95% CL: 1.21-5.08) in both univariable and multivariable modelling, independent of duration and type of diabetes, HbA1C, hypertension and microalbuminuria ( p = 0.03). DME occurred earlier in patients carrying the SDF-1 (c801A) allele (Kaplan-Meier analysis, log-rank test p = 0.02). A marginally significant association was found between the presence of the SDF-1 (c801A) allele and the development of PDR ( n = 89 eyes, p = 0.06). The SDF-1-3' (c801A) allele also showed a correlation with central retinal ( p = 0.006) and choroidal ( p = 0.08) thickness. SDF-1-3' (c801G > A) is involved in the development of macular complications in DM independent of critical clinical factors, suggesting that SDF-1 may be a future therapeutic target for high-risk patients, especially those carrying the SDF-1 (c801A) allele.

Machine learning-based systems have become instrumental in augmenting global efforts to combat cervical cancer. A burgeoning area of research focuses on leveraging artificial intelligence to enhance the cervical screening process, primarily through the exhaustive examination of Pap smears, traditionally reliant on the meticulous and labor-intensive analysis conducted by specialized experts. Despite the existence of some comprehensive and readily accessible datasets, the field is presently constrained by the limited volume of publicly available images and smears. As a remedy, our work unveils APACC (Annotated PAp cell images and smear slices for Cell Classification), a comprehensive dataset designed to bridge this gap. The APACC dataset features a remarkable array of images crucial for advancing research in this field. It comprises 103,675 annotated cell images, carefully extracted from 107 whole smears, which are further divided into 21,371 sub-regions for a more refined analysis. This dataset includes a vast number of cell images from conventional Pap smears and their specific locations on each smear, offering a valuable resource for in-depth investigation and study., (© 2024. The Author(s).)

A simple and cheap way to recognize cervical cancer is using light microscopic analysis of Pap smear images. Training artificial intelligence-based systems becomes possible in this domain, e.g., to follow the European recommendation to screen negative smears to reduce false negative cases. The first step for such a process is segmenting the cells. A large and manually segmented dataset is required for this task, which can be used to train deep learning-based solutions. We describe a corresponding dataset with accurate manual segmentations for the enclosed cells. Altogether, the APACS23 (Annotated PAp smear images for Cell Segmentation 2023) dataset contains about 37 000 manually segmented cells and is separated into dedicated training and test parts, which could be used for an official benchmark of scientific investigations or a grand challenge., (© 2024. The Author(s).)

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms., Competing Interests: Declaration of interests S.H., C.M.G., L.A.B., and J.V.H. own intellectual property on the classification of SCLC from DNA methylation and gene expression. S.H. reports consulting fees from Guardant Health, AstraZeneca, Boehringer Ingelheim, and Qiagen. C.M.G. is a member of the advisory board at Jazz Pharmaceuticals, AstraZeneca, and Bristol Myers Squibb and served as speaker for AstraZeneca and BeiGene. L.A.B. received consulting fees and research funding from AstraZeneca, GenMab, and Sierra Oncology and research funding from ToleroPharmaceuticals and served as advisor or consultant for PharmaMar, AbbVie, Bristol-Myers Squibb, Alethia, Merck, Pfizer, Jazz Pharmaceuticals, Genentech, and Debiopharm Group. J.V.H. served as advisor for AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, and Chugai Pharmaceuticals and received research support from AstraZeneca, GlaxoSmithKline, and Spectrum as well as royalties and licensing fees from Spectrum., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Primary open-angle glaucoma remains a global issue, lacking a definitive treatment. Increased intraocular pressure (IOP) is considered the primary risk factor of the disease and it can be caused by fibrotic-like changes in the trabecular meshwork (TM) such as increased tissue stiffness and outflow resistance. Previously, we demonstrated that the sigma-1 receptor (S1R) agonist fluvoxamine (FLU) has anti-fibrotic properties in the kidney and lung. In this study, the localization of the S1R in TM cells was determined, and the anti-fibrotic efficacy of FLU was examined in both mouse and human TM cells. Treatment with FLU reduced the F-actin rearrangement, inhibited cell proliferation and migration induced by the platelet-derived growth factor and decreased the levels of fibrotic proteins. The protective role of the S1R in fibrosis was confirmed by a more pronounced increase in alpha smooth muscle actin and F-actin bundle and clump formation in primary mouse S1R knockout TM cells. Furthermore, FLU demonstrated its protective effects by increasing the production of nitric oxide and facilitating the degradation of the extracellular matrix through the elevation of cathepsin K. These findings suggest that the S1R could be a novel target for the development of anti-fibrotic drugs and offer a new therapeutic approach for glaucoma.

The trabecular meshwork (TM) route is the principal outflow egress of the aqueous humor. Actin cytoskeletal remodeling in the TM and extracellular matrix (ECM) deposition increase TM stiffness, outflow resistance, and elevate intraocular pressure (IOP). These alterations are strongly linked to transforming growth factor-β2 (TGFβ2), a known profibrotic cytokine that is markedly elevated in the aqueous humor of glaucomatous eyes. Sigma-1 receptor (S1R) has been shown to have neuroprotective effects in the retina, but data are lacking about its role in the TM. In this study, we identified the presence of S1R in mouse TM tissue and investigated the effect of an S1R agonist fluvoxamine (FLU) on TGFβ2-induced human TM cells regarding cell proliferation; ECM-related functions, including F-actin reorganization; and the accumulation of ECM elements. TGFβ2 increased the proliferation, cytoskeletal remodeling, and protein levels of fibronectin, collagen type IV, and connective tissue growth factor, and decreased the level of matrix metalloproteinase-2. Most importantly, FLU reversed all these effects of TGFβ2, suggesting that S1R agonists could be potential candidates for preserving TM function and thus maintaining normal IOP.

Background: No targeted drugs are currently available against small cell lung cancer (SCLC). BCL-2 family members are involved in apoptosis regulation and represent therapeutic targets in many malignancies., Methods: Expression of BCL-2 family members in 27 SCLC cell lines representing all known four SCLC molecular subtypes was assessed by qPCR, Western blot and mass spectrometry-based proteomics. BCL-2 and MCL-1 inhibition (venetoclax and S63845, respectively) was assessed by MTT assay and flow cytometry and in mice bearing human SCLC tumours. Drug interactions were calculated using the Combenefit software. Ectopic BAX overexpression was achieved by expression plasmids., Results: The highest BCL-2 expression levels were detected in ASCL1- and POU2F3-driven SCLC cells. Although sensitivity to venetoclax was reflected by BCL-2 levels, not all cell lines responded consistently despite their high BCL-2 expression. MCL-1 overexpression and low BAX levels were both characteristic for venetoclax resistance in SCLC, whereas the expression of other BCL-2 family members did not affect therapeutic efficacy. Combination of venetoclax and S63845 resulted in significant, synergistic in vitro and in vivo anti-tumour activity and apoptosis induction in double-resistant cells; however, this was seen only in a subset with detectable BAX. In non-responding cells, ectopic BAX overexpression sensitised to venetoclax and S63845 and, furthermore, induced synergistic drug interaction., Conclusions: The current study reveals the subtype specificity of BCL-2 expression and sheds light on the mechanism of venetoclax resistance in SCLC. Additionally, we provide preclinical evidence that combined BCL-2 and MCL-1 targeting is an effective approach to overcome venetoclax resistance in high BCL-2-expressing SCLCs with intact BAX., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Anti-vascular endothelial growth factor (VEGF) therapy is currently the most effective therapy of exudative age-related macular degeneration (AMD). The aim of this study was to assess long-term benefits of intensive aflibercept and ranibizumab anti-VEGF therapy in patients with exudative AMD., Methods: Two clinical trial sites recruited their original subjects for a re-evaluation 7 years after the baseline visit of the phase-3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (VIEW 2) trial. Forty-seven eyes of 47 patients with AMD originally treated with ranibizumab (14 eyes) or aflibercept (33 eyes) were included., Results: Mean number of injections was 17.8 ± 3.0 during participation in the VIEW 2 trial. Fourteen of 47 (30%) eyes were given additional injections with a mean number of 5.7 ± 4.5 after the trial. At a mean follow-up time of 82 ± 5 months best corrected visual acuity (BCVA) remained stable or improved (≤ 10 letters lost) in 55% of patients in the entire study population, in 43% in the ranibizumab group and in 60% in the aflibercept group. In both groups combined mean BCVA was 54 ± 13 letters at baseline, 65 ± 17 letters at the end of the intensive phase and 45 ± 25 letters at the end of follow-up. There was no statistically significant difference in BCVA between the two groups at baseline (p = 0.88) and at the end of follow-up (p = 0.40). Macular atrophy was observed in 96% of eyes, average area was 7.22 ± 6.31 mm 2 with no statistically significant difference between groups (p = 0.47). Correlation between BCVA at end-of-follow-up and the area of atrophy was significant (p < 0.001). At the end of follow-up, fluid was detected in 7 of 47 eyes (15%) indicating disease activity., Conclusion: Long-term efficacy of aflibercept and ranibizumab was largely consistent. Following a two-year intensive therapy with as-needed regimen, BCVA was maintained or improved in almost half of the patients and in the ranibizumab group and more than half of the patients in the aflibercept group with very few injections. In a remarkable proportion of eyes, BCVA declined severely which underlines the need for long-term follow-ups and may indicate a more prolonged intensive therapy., Trial Registrations: VIEW 2 study: ClinicalTrials.gov ID: NCT00637377, date of registration: March 18, 2008. Long-term follow-up: IRB nr.: SE RKEB 168/2022, ClinicalTrials.gov ID: NCT05678517, date of registration: December 28, 2022, retrospectively registered., (© 2023. The Author(s).)

Serious mental illness is a chronic condition that requires long-term pharmacological treatment. Adherence to oral antipsychotic medication has specific nuances that affects patients and physicians alike. For patients with serious mental illness, nonadherence increases their risk of hospitalization and relapse. Nonadherence is a formidable barrier for physicians in accurately assessing medication efficacy and helping patients achieve their fullest potential. A digital adherence system approved by the Food and Drug Administration can provide near-real time aripiprazole ingestion information. The system records ingestions through an embedded ingestible sensor in oral aripiprazole, which sends a transient local signal to a patch worn on the patient's torso that is then stored on a paired smartphone app. With patient permission, these data can be viewed remotely by their physician, along with a patient's mood, activity, and time spent resting. Such data are able to do the following: reveal broad patterns of medication adherence behavior to the patient as well as their physician; help physicians and patients understand and create more realistic expectations for adherence; promote discussion of treatment options; and minimize therapeutic appointment time devoted to determining actual adherence, thereby maximizing the time available to address each patient's distinctive reasons for their adherence pattern. Crucially, extra time created during appointments can be used to strengthen the therapeutic relationship, which may translate into both improvements in adherence and patient attitude toward their medication. Future investigations are needed to examine how this technology impacts the development of training and best practice guidelines for its use. Otherwise, the potential benefits of this technology may be lost, or worse, inadequate and inappropriate use may harm the therapeutic relationship., (©Anabel G Richey, Ildiko Kovacs, Sara Browne. Originally published in JMIR Mental Health (https://mental.jmir.org), 02.12.2022.)

Background: The microanatomical steps of malignant pleural mesothelioma (MPM) vascularization and the resistance mechanisms to anti-angiogenic drugs in MPM are unclear., Methods: We investigated the vascularization of intrapleurally implanted human P31 and SPC111 MPM cells. We also assessed MPM cell's motility, invasion and interaction with endothelial cells in vitro ., Results: P31 cells exhibited significantly higher two-dimensional (2D) motility and three-dimensional (3D) invasion than SPC111 cells in vitro . In co-cultures of MPM and endothelial cells, P31 spheroids permitted endothelial sprouting (ES) with minimal spatial distortion, whereas SPC111 spheroids repealed endothelial sprouts. Both MPM lines induced the early onset of submesothelial microvascular plexuses covering large pleural areas including regions distant from tumor colonies. The development of these microvascular networks occurred due to both intussusceptive angiogenesis (IA) and ES and was accelerated by vascular endothelial growth factor A (VEGF-A)-overexpression. Notably, SPC111 colonies showed different behavior to P31 cells. P31 nodules incorporated tumor-induced capillary plexuses from the earliest stages of tumor formation. P31 cells deposited a collagenous matrix of human origin which provided "space" for further intratumoral angiogenesis. In contrast, SPC111 colonies pushed the capillary plexuses away and thus remained avascular for weeks. The key event in SPC111 vascularization was the development of a desmoplastic matrix of mouse origin. Continuously invaded by SPC111 cells, this matrix transformed into intratumoral connective tissue trunks, providing a route for ES from the diaphragm., Conclusions: Here, we report two distinct growth patterns of orthotopically implanted human MPM xenografts. In the invasive pattern, MPM cells invade and thus co-opt peritumoral capillary plexuses. In the pushing/desmoplastic pattern, MPM cells induce a desmoplastic response within the underlying tissue which allows the ingrowth of a nutritive vasculature from the pleura., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-21-828/coif). BD, BH and VL were supported by the Austrian Science Fund (FWF I2872 to BH; FWF I3522 to VL; FWF I3977 and I4677 to BD). BD, ZM, IH, SP and AC acknowledge funding from the Hungarian National Research, Development and Innovation Office (KH130356 and KKP126790 to BD; 2020-1.1.6-JÖVŐ and TKP2021-EGA-33 to BD and ZM; ANN128666 to IH; SNN 114490 to SP; ANN 132225 to AC). VL is a recipient of the Bolyai Research Scholarship of the Hungarian Academy of Sciences and the UNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology. ZM was supported by the UNKP-20-3 and UNKP-21-3 New National Excellence Program of the Ministry for Innovation and Technology of Hungary, and by the Hungarian Respiratory Society (MPA #2020). ZL was supported by the ESMO Translational Research Fellowship. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Candida auris is a multidrug-resistant fungus against which in some clinical situations amphotericin B (AMB) remains the alternative or first line drug. We compared daily 1 mg/kg of AMB efficacy in a neutropenic murine bloodstream infection model against 10 isolates representing four C. auris clades (South Asian n = 2; East Asian n = 2; South African n = 2; South American n = 4; two of which were of environmental origin). Five days of AMB treatment significantly increased the survival rates in mice infected with isolates of the East Asian clade, and 1 isolate each from the South African and South American clades (originated from bloodstream), but not in mice infected with the South Asian and 2 environmental isolates from the South American clades. AMB treatment decreased the fungal burden in mice infected with the 2 isolates each from East Asian and South African, and 1 out of 2 bloodstream isolates from South American clades in the hearts (p < 0.01), kidneys (p < 0.01) and brain (p < 0.05). AMB treatment, regardless of clades, significantly decreased colony forming units in the urine at day 3. However, histopathological examination in AMB-treated mice revealed large aggregates of yeast cells in the kidneys and hearts, and focal lesions in the cerebra and cerebelli, regardless of precise C. auris clade. Our clade-specific data confirm that the efficacy of AMB against C. auris is weak, explaining the therapeutic failures in clinical situations. Our results draw attention to the necessity to maximize the killing at the start of treatment to avoid later complications in the heart and central nervous system.

Loss of midbrain dopamine neurons causes the cardinal symptoms of Parkinson's disease. However, not all dopamine neurons are equally vulnerable and a better understanding of the cell-type specific properties relating to selective dopamine neuron degeneration is needed. Most midbrain dopamine neurons express the vesicular glutamate transporter VGLUT2 during development and a subset continue to express low levels of VGLUT2 in adulthood, enabling the co-release of glutamate. Moreover, VGLUT2 expression in dopamine neurons can be neuroprotective since its genetic disruption was shown to sensitize dopamine neurons to neurotoxins. Here, we show that in response to toxic insult, and in two distinct models of alpha-synuclein stress, VGLUT2 dopamine neurons were resilient to degeneration. Dopamine neurons expressing VGLUT2 were enriched whether or not insult induced dopamine neuron loss, suggesting that while VGLUT2 dopamine neurons are more resilient, VGLUT2 expression can also be transcriptionally upregulated by injury. Finally, we observed that VGLUT2 expression was enhanced in surviving dopamine neurons from post-mortem Parkinson's disease individuals. These data indicate that emergence of a glutamatergic identity in dopamine neurons may be part of a neuroprotective response in Parkinson's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In trauma and orthopedic surgery, limb ischemia-reperfusion (I/R) remains a great challenge. The effect of preventive protocols, including surgical conditioning approaches, is still controversial. We aimed to examine the effects of local ischemic pre-conditioning (PreC) and post-conditioning (PostC) on limb I/R. Anesthetized rats were randomized into sham-operated (control), I/R (120-min limb ischemia with tourniquet), PreC, or PostC groups (3 × 10-min tourniquet ischemia, 10-min reperfusion intervals). Blood samples were taken before and just after the ischemia, and on the first postoperative week for testing hematological, micro-rheological (erythrocyte deformability and aggregation), and metabolic parameters. Histological samples were also taken. Erythrocyte count, hemoglobin, and hematocrit values decreased, while after a temporary decrease, platelet count increased in I/R groups. Erythrocyte deformability impairment and aggregation enhancement were seen after ischemia, more obviously in the PreC group, and less in PostC. Blood pH decreased in all I/R groups. The elevation of creatinine and lactate concentration was the largest in PostC group. Histology did not reveal important differences. In conclusion, limb I/R caused micro-rheological impairment with hematological and metabolic changes. Ischemic pre- and post-conditioning had additive changes in various manners. Post-conditioning showed better micro-rheological effects. However, by these parameters it cannot be decided which protocol is better.

Background: A link between mental health and freedom of choice has long been established, in fact, the loss of freedom of choice is one of the possible defining features of mental disorders. Freedom of choice has internal and external aspects explicitly identified within the capability approach, but received little explicit attention in capability instruments. This study aimed to develop a feasible and linguistically and culturally appropriate Hungarian version of the Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH) for mental health outcome measurement., Methods: Following forward and back translations, a reconciled Hungarian version of the OxCAP-MH was developed following professional consensus guidelines of the International Society for Pharmacoeconomics and Outcomes Research and the WHO. The wording of the questionnaire underwent cultural and linguistic validation through content analysis of cognitive debriefing interviews with 11 Hungarian speaking mental health patients in 2019. Results were compared with those from the development of the German version and the original English version with special focus on linguistic aspects., Results: Twenty-nine phrases were translated. There were linguistic differences in each question and answer options due to the high number of inflected, affixed words and word fragments that characterize the Hungarian language in general. Major linguistic differences were also revealed between the internal and external aspects of capability freedom of choices which appear much more explicit in the Hungarian than in the English or German languages. A re-analysis of the capability freedom of choice concepts in the existing language versions exposed the need for minor amendments also in the English version in order to allow the development of future culturally, linguistically and conceptually valid translations., Conclusion: The internal and external freedom of choice impacts of mental health conditions require different care/policy measures. Their explicit consideration is necessary for the conceptually harmonised operationalisation of the capability approach for (mental) health outcome measurement in diverse cultural and linguistic contexts., (© 2021. The Author(s).)

The COVID-19 pandemic has had a major impact on cardiovascular emergencies. The aim of this study was to investigate the impact of the COVID-19 pandemic on a regional network for management of ST-segment elevation acute myocardial infarction (STEMI)., Methods: We report a single center's experience of patients hospitalized for ACS in a high-volume hub of a STEMI network during the lockdown (in the first pandemic trimester), compared with the same time interval of the previous year and including all consecutive patients referred for an AMI during the second trimester of 2020 (from April to June) or during the same time interval of the previous year, 2019., Results: The absolute number of hospital admissions for AMI decreased by 22.3%, while the non-AMI hospitalizations decreased by 77.14% in Q2-2020 compared to Q2-2019 (210 vs. 48, p < 0.0001). As a consequence, the percentage of AMI cases from the total number of hospital admission increased from 38% to 68% ( p < 0.0001), AMI becoming the dominant pathology. In the STEMI group there was a significant reduction of 55% in the absolute number of late STEMI presentations. Functionality of the STEMI network at the hub level did not present a significant alteration with only a minor increase in the door-to-balloon time, from 34 min to 41 min. However, at the level of the network we recorded a lower number of critical cases transferred to the interventional center, with a dramatic reduction of 56.1% in the number of critical STEMI cases arriving in the acute cardiac care unit (17.0% vs. 7.3%, p -0.04 for KILLIP class III, and 21.17% vs. 11.11%, p = 0.08 for resuscitated out of hospital cardiac arrest)., Conclusions: The COVID-19 outbreak did not have a major impact on the interventional center's functionality, but it limited the capacity of the regional STEMI network to bring the critical patient with complicated STEMI to the cathlab in time during the first months of the lockdown. Even a very well-functioning STEMI network like the one in Central Romania had difficulties bringing the most critical STEMI cases to the cathlab in time.