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Vladeta Ajdacic-Gross,1 Ana Buadze,1 En-Young N Wagner,2 Mario Müller,1 Erich Seifritz,1 Setareh Ranjbar,3 Jennifer Glaus,4 Enrique Castelao,3 Marie-Pierre F Strippoli,3 Caroline L Vandeleur,3 Martin Preisig,3 Roland von Känel2 1Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland; 2Department of Consultation-Liaison Psychiatry and Psychosomatic Medicine, University Hospital Zurich and University of Zurich, Zurich, Switzerland; 3Department of Psychiatry, Psychiatric Epidemiology and Psychopathology Research Center, Lausanne University Hospital and University of Lausanne, Prilly, Switzerland; 4Department of Psychiatry, Service of Child and Adolescent Psychiatry, Lausanne University Hospital and University of Lausanne, Lausanne, SwitzerlandCorrespondence: Vladeta Ajdacic-Gross, Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, PO Box 2019, CH-8032, Zürich, Switzerland, Tel +41 79 921 36 80, Email vladeta.ajdacic-gross@uzh.chAbstract: Previous research has unveiled an intriguing positive association between the AB blood group and mental disorders in general. In this study, we compared ABO blood groups with five major groups of mental disorders to attain a higher level of specificity. The analyses were conducted using data from the CoLaus|PsyCoLaus study (N=5111). They revealed that the AB blood group exhibited a positive association with both neurodevelopmental disorders (RR 2.29, CI 1.38– 3.82) and substance use disorders (RR 2.25, CI 1.38– 3.65) after adjusting for sex and childhood adversities. These associations could be replicated with respect to the familial aggregation of neurodevelopmental and substance use disorders. Large databases are needed to achieve more detailed results related to specific disorders.Plain Language Summary: Prior research has shown an interesting link between the AB blood group and mental disorders. In our study, we used data from a large Swiss population-based epidemiological cohort study to learn more about this connection. We examined the relationship between ABO blood groups and five major groups of mental disorders: neurodevelopmental, early onset anxiety, later onset anxiety, mood, and substance use disorders. Our analyses revealed associations between the AB blood group and neurodevelopmental and substance use disorders. The findings point to an unknown immunological mechanism that may play a role in the development of neurodevelopmental and substance use disorders.Keywords: ABO blood groups, neurodevelopmental disorders, substance use disorders, familial aggregation

Current therapies show limited efficacy against peritoneal metastases (PM) from pancreatic cancer. Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has emerged as a novel intraperitoneal drug delivery method. Recently, a dose-escalation study identified the safe dose of Nabpaclitaxel for PIPAC administration, an ideal intraperitoneal chemotherapy agent against pancreatic cancer. Combining systemic NabPaclitaxel-Gemcitabine with NabPaclitaxel-PIPAC may enhance disease control in pancreatic cancer patients with PM.

Abstract Background Risk stratification and treatment benefit prediction models are urgent to improve negative sentinel lymph node (SLN-) melanoma patient selection, thus avoiding costly and toxic treatments in patients at low risk of recurrence. To this end, the application of artificial intelligence (AI) could help clinicians to better calculate the recurrence risk and choose whether to perform adjuvant therapy. Methods We made use of AI to predict recurrence-free status (RFS) within 2-years from diagnosis in 94 SLN- melanoma patients. In detail, we detected quantitative imaging information from H&E slides of a cohort of 71 SLN- melanoma patients, who registered at Istituto Tumori “Giovanni Paolo II” in Bari, Italy (investigational cohort, IC). For each slide, two expert pathologists firstly annotated two Regions of Interest (ROIs) containing tumor cells alone (TUMOR ROI) or with infiltrating cells (TUMOR + INF ROI). In correspondence of the two kinds of ROIs, two AI-based models were developed to extract information directly from the tiles in which each ROI was automatically divided. This information was then used to predict RFS. Performances of the models were computed according to a 5-fold cross validation scheme. We further validated the prediction power of the two models on an independent external validation cohort of 23 SLN- melanoma patients (validation cohort, VC). Results The TUMOR ROIs have revealed more informative than the TUMOR + INF ROIs. An Area Under the Curve (AUC) value of 79.1% and 62.3%, a sensitivity value of 81.2% and 76.9%, a specificity value of 70.0% and 43.3%, an accuracy value of 73.2% and 53.4%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the IC cohort, respectively. An AUC value of 76.5% and 65.2%, a sensitivity value of 66.7% and 41.6%, a specificity value of 70.0% and 55.9%, an accuracy value of 70.0% and 56.5%, were achieved on the TUMOR and TUMOR + INF ROIs extracted for the VC cohort, respectively. Conclusions Our approach represents a first effort to develop a non-invasive prognostic method to better define the recurrence risk and improve the management of SLN- melanoma patients.

Purpose Tildrakizumab is a selective inhibitor of IL-23 approved for the treatment of moderate-to-severe plaque psoriasis in two dosages. We conducted a 16-week multicenter retrospective study to compare the effectiveness and safety of tildrakizumab 200 mg versus tildrakizumab 100 mg in patients with a high disease burden or high body weight.Materials and methods Our retrospective study included 134 patients treated with tildrakizumab 200 mg and 364 patients treated with tildrakizumab 100 mg from 28 Italian Dermatology Units affected by moderate-to-severe plaque psoriasis. The patients had a body weight above 90 kg or a high disease burden (Psoriasis Area and Severity Index [PASI] ≥ 16 or the involvement of difficult-to-treat areas). We evaluated the effectiveness of tildrakizumab at the week-16 visit in terms of PASI90, PASI100 and absolute PASI ≤ 2.Results After 16 weeks of treatment with tildrakizumab 200 mg, PASI90 was reached by 57.5% of patients and PASI100 by 39.6% of patients. At the same time point, 34.3% and 24.2% of patients treated with tildrakizumab 100 mg achieved PASI90 and PASI100, respectively.Conclusions Our data suggest that tildrakizumab 200 mg has better effectiveness than tildrakizumab 100 mg in patients with a body weight ≥ 90 kg and a high disease burden.

Glycolytic metabolism generates energy and intermediates for biomass production. Tumor-associated glycolysis is upregulated compared to normal tissues in response to tumor cell-autonomous or non-autonomous stimuli. The consequences of this upregulation are twofold. First, the metabolic effects of glycolysis become predominant over those mediated by oxidative metabolism. Second, overexpressed components of the glycolytic pathway (i.e. enzymes or metabolites) acquire new functions unrelated to their metabolic effects and which are referred to as “moonlighting” functions. These functions include induction of mutations and other tumor-initiating events, effects on cancer stem cells, induction of increased expression and/or activity of oncoproteins, epigenetic and transcriptional modifications, bypassing of senescence and induction of proliferation, promotion of DNA damage repair and prevention of DNA damage, antiapoptotic effects, inhibition of drug influx or increase of drug efflux. Upregulated metabolic functions and acquisition of new, non-metabolic functions lead to biological effects that support tumorigenesis: promotion of tumor initiation, stimulation of tumor cell proliferation and primary tumor growth, induction of epithelial-mesenchymal transition, autophagy and metastasis, immunosuppressive effects, induction of drug resistance and effects on tumor accessory cells. These effects have negative consequences on the prognosis of tumor patients. On these grounds, it does not come to surprise that tumor-associated glycolysis has become a target of interest in antitumor drug discovery. So far, however, clinical results with glycolysis inhibitors have fallen short of expectations. In this review we propose approaches that may allow to bypass some of the difficulties that have been encountered so far with the therapeutic use of glycolysis inhibitors.

Given the association of Epstein-Barr virus (EBV) with subjective perception of fatigue and demyelination in clinical conditions, the question about potential subclinical effects in the adult general population remains open. We investigate the association between individuals’ EBV immune response and perceived fatigue in a community dwelling cohort (n = 864, age 62 ± 10 years old; 49% women) while monitoring brain tissue properties. Fatigue levels are assessed with the established fatigue severity scale, the EBNA-1 and VCA p18 immunoglobulin G (IgG) chronic response – with multiplex serology and the estimates of local brain volume, myelin content, and axonal density - using relaxometry- and multi-shell diffusion-based magnetic resonance imaging (MRI). In our analysis we adjust for the effects of demographic and cardiovascular risk factors, sleep apnea, depression, and polygenic risk score for multiple sclerosis. We demonstrate that EBNA-1 IgG levels are positively associated with perceived levels of fatigue, whilst VCA p18 IgG levels show a positive correlation with myelin content and a negative one with an estimate of axonal g-ratio in male participants. In the context of EBVs immune response, the polygenic risk for multiple sclerosis is not associated with increased fatigue levels, brain myelination or atrophy. Our findings bring empirical evidence about the potential role of EBVs chronic immune response in perceived fatigue and hint towards a protective role of myelination specific for men. They underscore the added value of advanced assessment of brain tissue microstructure in uncovering the mechanisms behind frequent fatigue complaints associated with EBV infection and multiple sclerosis.

Circular Economy (CE) is considered a possible solution to mitigate the environmental externalities of the tourism industry, with a view to more sustainable tourism by reducing environmental, social, and economic burdens in an integrated holistic approach. Moreover, the role of CE in tourism is highlighted by the possibility of achieving all sustainable development goals (SDGs) directly and indirectly using the links that connect SDG 12 with the others.From this point of view, this literature review was aimed at discussing the key strategies of CE applied to the tourism industry, focussing on the widespread problems of single-use plastic, excess food, and water consumption. The environmental and socio-economic benefits deriving from the application of the CE principles to waste management will be shown, by contributing to meeting all the SDGs. Many strategies have been proposed to make tourism circular and sustainable, and research revealed that those are mainly based on the concepts of reduce, reuse, recycle, and recover.This article confirmed the importance of – and the need for - research on CE in the tourism sector; further, by contributing to expanding research in this content area, it can stimulate the development and application of solutions that make the industry more efficient and resilient. This study was also conceived to raise the awareness of tourism stakeholders on the importance of CE to mitigate the negative externalities of the sector.

IntroductionThe management of cancer patients follows a Diagnostic Therapeutic and Care Pathway (PDTA) approach, aimed at achieving the optimal balance between care and quality of life. To support this process, precision medicine and innovative technologies [e.g., next-generation sequencing (NGS)] allow rapid identification of genetic-molecular alterations useful for the design of PDTA-approved therapies. If the standard approach proves inadequate, the Molecular Tumor Board (MTB), a group comprising specialists from diverse disciplines, can step in to evaluate a broader molecular profile, proposing potential therapies beyond evidence levels I–II or considering enrolment in clinical trials. Our aim is to analyze the role of the MTB in the entire management of patients in our institute and its impact on the strategy of personalized medicine, particularly when all approved treatments have failed.Materials and methodsIn alignment with European and national guidelines, a panel of clinicians and preclinical specialists from our institution was defined as the MTB core team. We designed and approved a procedure for the operation of this multidisciplinary group, which is the only one operating in the Puglia region.Results and discussionIn 29 months (2021–2023), we discussed and analyzed 93 patients. A total of 44% presented pathogenic alterations, of which 40.4% were potentially actionable. Only 11 patients were proposed for enrollment in clinical trials, treatment with off-label drugs, or AIFA (the Italian pharmaceutical agency for drugs)—5% funding. Our process indicators, time to analysis, and number of patient cases discussed are in line with the median data of other European institutions. Such findings underscore both the importance and usefulness of the integration of an MTB process into the care of oncology patients.

Basal cell carcinoma (BCC) is the most common malignant tumour in white populations. Multiple studies demonstrated that the aberrant activation of Hedgehog signaling is a driver of BCC development, and its blockade represents a potential therapeutic target. In Italy, clinicians can prescribe Hedgehog inhibitors (HhIs) Vismodegib and Sonidegib. To highlight the treatment choice of clinicians, we conducted an online survey between November 1 and November 18, 2020 with 33 Italian clinicians from 27 reference hospitals, in which each participant received an anonymous survey consisting of two multiple-choice questions on clinical efficacy and safety profile of Sonidegib and Vismodegib. Respondents reported their opinions on which efficacy and tolerability data of the pivotal phase-II BOLT trial were more relevant in the treatment choice of patients with locally advanced BCC (laBCC). This survey shows that overall response rate (ORR) and the duration of response (DoR) are the most expected across dermatologists and oncologists. The different pharmacokinetic profile of the two HhIs are behind their diverse toxicity spectrum, dose and schedule modification seem to address the choice between vismodegib and sonidegib among dermato-oncology prescribers.

IntroductionGastric cancer (GC) is the fourth leading cause of cancer-related death worldwide with limited therapeutic options. The aim of this study was to analyze the value of adding surgery to the first-line treatment in patients with oligometastatic GC (OGC).MethodsThis retrospective study included patients with OGC who underwent induction chemotherapy followed by surgery of both primary tumor and synchronous metastasis between April 2012 and April 2022. Endpoints were overall survival (OS) and relapse-free survival (RFS) analyzed by the Kaplan–Meier method. Prognostic factors were assessed with the Cox model.ResultsData from 39 patients were collected. All cases were referred to our multidisciplinary tumor board (MTB) to evaluate the feasibility of radical surgery. After a median follow-up of 33.6 months (mo.), median OS was 26.6 mo. (95% CI 23.8–29.4) and median RFS was 10.6 mo. (95% CI 6.3–14.8). Pathologic response according to the Mandard criteria (TRG 1–3, not reached versus 20.5 mo. for TRG 4–5; HR 0.23, p=0.019), PS ECOG ≤ 1 (26.7 mo. for PS ≤ 1 versus 11.2 mo. for PS >1; HR 0.3, p=0.022) and a low metastatic burden (26.7 mo. for single site versus 12.9 mo. for ≥2 sites; HR 0.34, p=0.039) were related to good prognosis. No major intraoperative complications nor surgery-related deaths occurred in our series.DiscussionA sequential strategy of preoperative chemotherapy and radical surgical excision of both primary tumor and metastases was demonstrated to significantly improve OS and RFS. Multidisciplinary evaluation is mandatory to identify patients who could benefit from this strategy.

Abstract Aims Blood glucose control is central to the management of diabetes, and continuous glucose monitoring (CGM) improves glycemic control. We aimed to describe the perspectives of people with diabetes using CGM. Materials and methods We performed a systematic review of qualitative studies. Results Fifty‐four studies involving 1845 participants were included. Six themes were identified: gaining control and convenience (reducing pain and time, safeguarding against complications, achieving stricter glucose levels, and sharing responsibility with family); motivating self‐management (fostering ownership, and increasing awareness of glycemic control); providing reassurance and freedom (attaining peace of mind, and restoring social participation); developing confidence (encouraged by the endorsement of others, gaining operational skills, customizing settings for ease of use, and trust in the device); burdened with device complexities (bewildered by unfamiliar technology, reluctant to rely on algorithms, overwhelmed by data, frustrated with malfunctioning and inaccuracy, distressed by alerts, and bulkiness of machines interfering with lifestyle); and excluded by barriers to access (constrained by cost, lack of suppliers). Conclusions CGM can improve self‐management and confidence in patients managing diabetes. However, the technical issues, uncertainty in readings, and cost may limit the uptake. Education and training from the health professionals may help to reduce the practical and psychological burden for better patient outcomes.

(1) Background/Objectives: Nail psoriasis (NP) is a chronic and difficult-to-treat disease, which causes significant social stigma and impairs the patients’ quality of life. Moreover, nail psoriasis is a true therapeutic challenge for clinicians. The presence of nail psoriasis can be part of a severe form of psoriasis and can have predictive value for the development of psoriatic arthritis. Our real-world-evidence multicenter study aims to evaluate the efficacy of bimekizumab in nail psoriasis. (2) Methods: A retrospective analysis of a multicenter observational study included 834 patients affected by moderate-to-severe psoriasis, in 33 Dermatologic Units in Italy, treated with bimekizumab from December 2022 to September 2023. Clinimetric assessments were based on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) for the severity of nail psoriasis at 0, 12, 24, and 36 weeks. (3) Results: Psoriatic nail involvement was present in 27.95% of patients. The percentage of patients who achieved a complete clearance of NP in terms of PGA-F 0 was 31.7%, 57%, and 88.5% at week 4, 16, and 36, respectively. PASI 100 was achieved by 32.03% of patients at week 4, by 61.8% at week 16, and by 78.92% of patients at week 36. The mean baseline PASI was 16.24. The mean DLQI values for the entire group of patients at baseline, at week 4, at week 16, and at week 36 were 14.62, 3.02, 0.83, and 0.5, respectively. (4) Conclusions: Therapies that promote the healing of both the skin and nails in a short time can also ensure a lower risk of subsequently developing arthritis which is disabling over time. Bimekizumab proved to be particularly effective to treat NP, with a fast response in terms of complete clearance, with over 88.5% of patients free from NP after 36 weeks. The findings of our real-world study showed that patients with moderate-to-severe PsO and concomitant NP had significantly faster and more substantial improvements in NP up to 36 weeks with respect to previous research findings. Considering the rapid healing of the nail, the dual inhibition of IL17 A and F might have a great value in re-establishing the dysregulation of keratin 17 at the nail level.

Abstract Background Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of response. As factors released in the blood, EVs and soluble forms could be relevant in monitoring treatment efficacy and adaptive resistance to ICI. Methods We used pre-therapy plasma samples of 110 MM patients and longitudinal samples of 46 patients. Elisa assay and flow cytometry (FCM) were used to measure sPD-L1 and sPD1 concentrations and the percentage of PD1+ EVs and PD-L1+ EVs, released from tumor and immune cells in patients subsets. Transwell assays were conducted to investigate the impact of EVs of each patient subset on MM cells invasion and interaction between tumor cells and macrophages or dendritic cells. Viability assays were performed to assess EVs effect on MM cells and organoids sensitivity to anti-PD1. FCM was used to investigate immunosuppressive markers in EVs and immune cells. Results The concentrations of sPD1 and sPD-L1 in pre-treatment and longitudinal samples did not correlate with anti-PD1 response, instead only tumor-derived PD1+ EVs decreased in long responders while increased during disease progression in responders. Notably, we observed reduction of T cell derived EVs expressing LAG3+ and PD1+ in long responders and their increase in responders experiencing progression. By investigating the impact of EVs on disease progression, we found that those isolated from non-responders and from patients with progression disease accelerated tumor cells invasiveness and migration towards macrophages, while EVs of long responders reduced the metastatic potential of MM cells and neo-angiogenesis. Additionally, the EVs of non-responders and of progression disease patients subset reduced the sensitivity of MM cells and organoids of responder to anti-PD1 and the recruitment of dendritic cells, while the EVs of progression disease subset skewed macrophages to express higher level of PDL-1. Conclusion Collectively, we suggest that the detection of tumor-derived PD1 + EVs may represent a useful tool for monitoring the response to anti-PD1 and a role for EVs shed by tumor and immune cells in promoting tumor progression and immune dysfunction. Graphical Abstract

BackgroundDesmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.Case presentationWe report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.ConclusionEfficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.

IntroductionTrisomy 21 (T21), which causes Down syndrome (DS), is the most common chromosomal aneuploidy in humankind and includes different clinical comorbidities, among which the alteration of the immune system has a heavy impact on patient’s lives. A molecule with an important role in immune response is zinc and it is known that its concentration is significantly lower in children with T21. Different hypotheses were made about this metabolic alteration and one of the reasons might be the overexpression of superoxide dismutase 1 (SOD1) gene, as zinc is part of the SOD1 active enzymatic center.MethodsThe aim of our work is to explore if there is a linear correlation between zinc level and immune cell levels measured in a total of 217 blood samples from subjects with T21. Furthermore, transcriptome map analyses were performed using Transcriptome Mapper (TRAM) software to investigate whether a difference in gene expression is detectable between subjects with T21 and euploid control group in tissues and cells involved in the immune response such as lymphoblastoid cells, thymus and white blood cells.ResultsOur results have confirmed the literature data stating that the blood zinc level in subjects with T21 is lower compared to the general population; in addition, we report that the T21/control zinc concentration ratio is 2:3, consistent with a chromosomal dosage effect due to the presence of three copies of chromosome 21. The transcriptome map analyses showed an alteration of some gene’s expression which might explain low levels of zinc in the blood.DiscussionOur data suggest that zinc level is not associated with the levels of immunity cells or proteins analyzed themselves and rather the main role of this ion might be played in altering immune cell function.

Abstract The presentation will focus on long-term weight changes in patients with major depressive disorder who use antidepressants. Research studying weight change over periods of more than 12 months is scarce and the effects of depressive episodes and antidepressants on weight changes have rarely been assessed simultaneously. Using data of a prospective population-based CoLaus|PsyCoLaus study, data on the associations of antidepressant use prior to baseline and during a 5.5-year follow-up with changes in adiposity markers and multiple adjustments including for the effects of depressive episodes will be presented. The cohort included 2479 randomly selected 35 to 66 year-old white residents (mean age 49.9 years, 53.3% women) of an urban area who accepted the physical and psychiatric evaluations at baseline and follow-up (76.8% participation at the follow-up). Diagnostic information on mental disorders, treatment use including psychotropic drugs was elicited using a semi-structured interview. Independently of the effect of antidepressants used during the follow-up and the effects of depressive episodes, the number of any antidepressant compounds used prior to baseline was associated with lower increase of body mass index (BMI), whereas the use of antidepressants during the follow-up was associated with steeper increase in BMI and waist circumference. Within AD classes, the use of tricyclic AD (TCA) and selective serotonin reuptake inhibitor (SSRI) prior to baseline was associated with lower increase, the use of SSRI during follow-up was associated with steeper increases in BMI. Similarly, the use of SSRI prior to baseline was associated with lower increase, the use of TCA and SSRI during the follow-up was associated with steeper increase in waist circumference. Finally, the use of SSRI during follow-up was also associated with steeper increase in fat mass. The findings support unfavorable obesogenic effects of sustained treatment not only with TCAs but also with SSRIs, suggesting that the benefit of long-term administration of these AD classes should be carefully weighed against the potential risk of weight gain. Disclosure of Interest None Declared

Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conserved pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and fungi, thereby orchestrating the ensuing inflammatory/immune responses. Among TLRs, TLR3 recognizes viral dsRNA and triggers antiviral response cascades upon activation. Epigenetic regulation, mediated by histone deacetylase (HDAC), has been demonstrated to control several cellular functions in response to various extracellular stimuli. Employing epigenetic target modulators, such as epidrugs, is a current therapeutic option in several cancers and holds promise in treating viral diseases. This study aims to elucidate the impact of TLR3 stimulation on the plasticity of human mesothelial cells (MCs) in PD patients and to investigate the effects of HDAC1-3 inhibition. Treatment of MCs from PD patients with the TLR3 agonist polyinosinic:polycytidylic acid (Poly(I:C)), led to the acquisition of a bona fide mesothelial-to-mesenchymal transition (MMT) characterized by the upregulation of mesenchymal genes and loss of epithelial-like features. Moreover, Poly(I:C) modulated the expression of several inflammatory cytokines and chemokines. A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs). Treatment with MS-275 facilitated MMT reversal and inhibited the interferon signature, which was associated with reduced STAT1 phosphorylation. However, the modulation of inflammatory cytokine/chemokine production was not univocal, as IL-6 and CXCL8 were augmented while TNF-α and CXCL10 were decreased. Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis.

BackgroundFrequent hemodialysis provided more than three times per week may lower mortality and improve health-related quality of life. Yet, the evidence is inconclusive. We evaluated the benefits and harms of frequent hemodialysis in people with kidney failure compared with standard hemodialysis.MethodsWe performed a systematic review of randomized controlled trials including adults on hemodialysis with highly sensitive searching in MEDLINE, Embase, CENTRAL, and Google Scholar on 3 January 2024. Data were pooled using random-effects meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. We adjudicated evidence certainty using GRADE.ResultsFrom 11,142 unique citations, only seven studies involving 518 participants proved eligible. The effects of frequent hemodialysis on physical and mental health were imprecise due to few data. Frequent hemodialysis probably had uncertain effect on death from all cause compared with standard hemodialysis (relative risk 0.79, 95% confidence interval 0.33-1.91, low certainty evidence). Data were not reported for death from cardiovascular causes, major cardiovascular events, fatigue or vascular access.ConclusionThe evidentiary basis for frequent hemodialysis is incomplete due to clinical trials with few or no events reported for mortality and cardiovascular outcome measures and few participants in which patient-reported outcomes including health-related quality of life and symptoms were reported.

Abstract Introduction Adverse childhood events (ACEs) have been linked to widespread chronic pain (CP) in various cross-sectional studies, mainly in clinical populations. However, the independent role of different ACEs on the development of different types of CP remains elusive. Accordingly, we aimed to prospectively assess the associations between specific types of ACEs with the development of multisite CP in a large population-based cohort. Methods Data stemmed from the three first follow-up evaluations of CoLaus|PsyCoLaus, a prospective population-based cohort study of initially 6734 participants (age range: 35–75 years). The present sample included 1537 participants with 2161 analyzable intervals (49.7% men, mean age 57.3 years). Diagnostic criteria for ACEs were elicited using semi-structured interviews and CP was assessed by self-rating questionnaires. Multinomial logistic regressions with generalized estimating equations method analyzed the relationship between the different ACEs measured in the beginning of the interval and the risk of developing multisite CP during the follow-up. Sensitivity analyses were performed to assess the predictive value of ACEs on multisite CP with neuropathic features. Results Participants with a history of parental divorce or separation had an increased risk of developing multisite CP at during follow-up in comparison to those without (RR1.98; 95% CI 1.13–3.47). A strong association was highlighted between parental divorce or separation and the risk of subsequent CP with neuropathic characteristics (RR 4.21, 95% CI 1.45–12.18). Conclusion These results highlight the importance of psychotherapeutic management of people experiencing parental separation to prevent CP in the future.

BackgroundDespite the significant progress achieved in understanding the pathology and clinical management of SARS-CoV-2 infection, still pathogenic and clinical issues need to be clarified. Treatment with modulators of epigenetic targets, i.e., epidrugs, is a current therapeutic option in several cancers and could represent an approach in the therapy of viral diseases.ResultsAim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).MeT5A cells, a pleura MC line, were pre-treated with different specific class I and IIb HDAC inhibitors. Unexpectedly, treatment with HDAC1-3 inhibitors significantly increased ACE2/TMPRSS2 expression, suggesting a role in favoring SARS-CoV-2 infection. We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor. ACE2/TMPRSS2 expression was validated by Western Blot (WB) and immunofluorescence. The involvement of HDAC inhibition in receptor induction was confirmed by HDAC1/HDAC2 silencing. In accordance to the ACE2/TMPRSS2 expression data, MS-275 increased SARS-CoV-2 replication and virus propagation in Vero E6 cells.Notably, MS-275 was able to increase ACE2/TMPRSS2 expression and SARS-CoV-2 production, although to a lesser extent, also in the lung adenocarcinoma cell line Calu-3 cells.Mechanistically, treatment with MS-275 increased H3 and H4 histone acetylation at ACE2/TMPRSS2 promoters, increasing their transcription.ConclusionThis study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients.

Abstract Background Sleep spindles have been involved in sleep stabilization and sleep-related memory mechanisms and their deficit emerged as possible biomarker in schizophrenia. However, whether this sleep phenotype is also present in other disorders that share psychotic symptoms remains unclear. To address this gap, we assessed sleep spindles in participants of a prospective population-based cohort who underwent psychiatric assessment (CoLaus|PsyCoLaus) and polysomnographic recording (HypnoLaus). Methods Sleep was recorded using ambulatory polysomnography in participants (N = 1037) to the PsyCoLaus study. Sleep spindle parameters were measured in people with a lifelong diagnosis of schizophrenia (SZ), schizoaffective depressive (SAD), schizoaffective manic (SAM), bipolar disorder type I (BP-I) and type II (BP-II). The associations between lifetime diagnostic status (independent variables, SZ, SAD, SAM, BPD-I, BPD-II, controls) and spindle parameters (dependent variables) including density, duration, frequency and maximum amplitude, for all (slow and fast), slow- and fast-spindle were assessed using linear mixed models. Pairwise comparisons of the different spindle parameters between the SZ group and each of the other psychiatric groups was performed using a contrast testing framework from our multiple linear mixed models. Results Our results showed a deficit in the density and duration of sleep spindles in people with SZ. They also indicated that participants with a diagnosis of SAD, SAM, BP-I and BP-II exhibited different sleep spindle phenotypes. Interestingly, spindle densities and frequencies were different in people with a history of manic symptoms (SAM, BP-I, and BP-II) from those without (SZ, SAD). Conclusions Although carried out on a very small number of participants due to the low prevalence of these disorders in general population, this pilot study brought new elements that argued in favor of a deficit of sleep spindles density and duration in people with schizophrenia. In addition, while we could expect a gradual change in intensity of the same sleep spindle parameters through psychotic diagnoses, our results seem to indicate a more complex situation in which the frequency of sleep spindles might be more impacted by diagnoses including a history of mania or hypomania. Further studies with a larger number of participants are required to confirm these effects.

Abstract Background The occurrence of psychotic features within mood episodes in patients with bipolar I disorder (BD I) has been associated in some studies with a more severe clinical and socio-professional profile. In contrast, other studies establishing the associations of psychotic features in BD I, and in particular of mood-congruent (MC) and mood-incongruent (MI) features, with clinical characteristics have yielded contradictory results. However, many pre-existing studies have been affected by serious methodological limitations. Using a sample of thoroughly assessed patients with BD I our aims were to: (1) establish the proportion of those with MI and MC features, and (2) compare BD I patients with and without psychotic features as well as those with MI to those with MC features on a wide array of socio-demographic and clinical characteristics including course, psychiatric comorbidity and treatment. Methods A sample of 162 treated patients with BD I (60.5% female, mean age = 41.4 (s.d: 10.2) years) was recruited within a large family study of mood disorders. Clinical, course and treatment characteristics relied on information elicited through direct diagnostic interviews, family history reports and medical records. Results (1) A total of 96 patients (59.3%) had experienced psychotic features over their lifetime. Among them, 44.8% revealed MI features at least once in their lives. (2) Patients with psychotic features were much less likely to be professionally active, revealed alcohol abuse more frequently and used health care, particularly inpatient treatment, more frequently than those without psychotic features. Within patients with psychotic symptoms, those with MI features showed more clinical severity in terms of a higher likelihood of reporting hallucinations, suicidal attempts and comorbid cannabis dependence. Conclusion Our data provide additional support for both the distinction between BD-I with and without psychotic features as well as the distinction between MI and MC psychotic features. The more severe course of patients with psychotic features, and particularly those with MI psychotic features, highlights the need for thorough psychopathological evaluations to assess the presence of these symptoms to install appropriate treatment.

Abstract Background Down syndrome (DS) is caused by the presence of an extra copy of full or partial human chromosome 21 (Hsa21). Partial (segmental) trisomy 21 (PT21) is the duplication of only a delimited region of Hsa21 and can be associated or not to DS: the study of PT21 cases is an invaluable model for addressing genotype–phenotype correlation in DS. Previous works reported systematic reanalyses of 132 subjects with PT21 and allowed the identification of a 34-kb highly restricted DS critical region (HR-DSCR) as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS. Methods We report clinical data and cytogenetic analysis of two children with PT21, one with DS and the other without DS. Moreover, we performed a systematic bibliographic search for any new PT21 report. Results Clinical and cytogenetic analyses of the two PT21 children have been reported: in Case 1 the duplication involves the whole long arm of Hsa21, except for the last 2.7 Mb, which are deleted as a consequence of an isodicentric 21: the HR-DSCR is within the duplicated regions and the child is diagnosed with DS. In Case 2 the duplication involves 7.1 Mb of distal 21q22, with a deletion of 2.1 Mb of proximal 20p, as a consequence of an unbalanced translocation: the HR-DSCR is not duplicated and the child presents with psychomotor development delay but no clinical signs of DS. Furthermore, two PT21 reports recently published (named Case 3 and 4) have been discussed: Case 3 has DS diagnosis, nearly full trisomy for Hsa21 and a monosomy for the 21q22.3 region. Case 4 is a baby without DS and a 0.56-Mb duplication of 21q22.3. Genotype–phenotype correlation confirmed the presence of three copies of the HR-DSCR in all DS subjects and two copies in all non-DS individuals. Conclusions The results presented here are fully consistent with the hypothesis that the HR-DSCR is critically associated with DS diagnosis. No exception to this pathogenetic model was found. Further studies are needed to detect genetic determinants likely located in the HR-DSCR and possibly responsible for core DS features, in particular intellectual disability.

Objectives: To prospectively investigate the association between Effort-Reward Imbalance (ERI) and over-commitment and the scores of the burnout dimensions over a 4 years follow-up period considering potential confounders.Methods: Data stemmed from CoLaus|PsyCoLaus, a population-based cohort study including 575 participants (mean age 55 years, 50% men). Participants completed the Maslach Burnout Inventory-General Survey, ERI and over-commitment questionnaires at baseline (T1) and after a 4 years follow-up (T2), and provided demographic, behavioral, psychiatric, personality and social support information through self-reported questionnaires and semi-structured interviews. Serially adjusted linear regression models were used.Results: ERI and over-commitment were not associated longitudinally with any of the burnout dimensions when controlling for confounders. One standard deviation increases in the scores of exhaustion, cynicism and professional efficacy were associated with one standard deviation increase in the scores of the same burnout dimensions longitudinally, and these associations were independent of the effects of ERI and over-commitment.Conclusion: Future studies should re-examine the effect of ERI and over-commitment on workers’ burnout, considering the effects of confounders.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of gastric cancer (GC), which still represents the third leading cause of cancer-related death in Western countries. However, ICI treatment outcomes vary between individuals and need to be optimized. Recent studies have shown that gut microbiota could represent a key influencer of immunotherapy responses. At the same time, the nutritional status and diet of GC patients are also predictive of immunotherapy treatment response and survival outcomes. The objective of this narrative review is to gather recent findings about the complex relationships between the oral, gastric, and gut bacterial communities, dietary factors/nutritional parameters, and immunotherapy responses. Perigastric/gut microbiota compositions/functions and their metabolites could be predictive of response to immunotherapy in GC patients and even overall survival. At the same time, the strong influence of diet on the composition of the microbiota could have consequences on immunotherapy responses through the impact of muscle mass in GC patients during immunotherapy. Future studies are needed to define more precisely the dietary factors, such as adequate daily intake of prebiotics, that could counteract the dysbiosis of the GC microbiota and the impaired nutritional status, improving the clinical outcomes of GC patients during immunotherapy.