Characterization of a novel HDAC2 pathogenetic variant: a missing puzzle piece for chromatinopathies.

Histone deacetylases (HDACs) are enzymes pivotal for histone modification (i.e. acetylation marks removal), chromatin accessibility and gene expression regulation. Class I HDACs (including HDAC1, 2, 3, 8) are ubiquitously expressed and they often participate in multi-molecular protein complexes. To date, three neurodevelopmental disorders caused by mutations in genes encoding for HDACs (HDAC4, HDAC6 and HDAC8) and thus belonging to the group of chromatinopathies, have been described. We performed whole exome sequencing (WES) for a patient (#249) clinically diagnosed with the chromatinopathy Rubinstein-Taybi syndrome (RSTS) but negative for mutations in RSTS genes, identifying a de novo frameshift variant in HDAC2 gene. We then investigated its molecular effects in lymphoblastoid cell lines (LCLs) derived from the patient compared to LCLs from healthy donors (HD). As the variant was predicted to be likely pathogenetic and to affect the sequence of nuclear localization signal, we performed immunocytochemistry and lysates fractionation, observing a nuclear mis-localization of HDAC2 compared to HD LCLs. In addition, HDAC2 total protein abundance resulted altered in patient, and we found that newly identified variant in HDAC2 affects also acetylation levels, with significant difference in acetylation pattern among patient #249, HD and RSTS cells and in expression of a known molecular target. Remarkably, RNA-seq performed on #249, HD and RSTS cells shows differentially expressed genes (DEGs) common to #249 and RSTS. Interestingly, our reported patient was clinically diagnosed with RSTS, a chromatinopathy which known causative genes encode for enzymes antagonizing HDACs. These results support the role of HDAC2 as causative gene for chromatinopathies, strengthening the genotype-phenotype correlations in this relevant group of disorders.

Dysfunction in IGF2R Pathway and Associated Perturbations in Autophagy and WNT Processes in Beckwith-Wiedemann Syndrome Cell Lines.

Beckwith-Wiedemann Syndrome (BWS) is an imprinting disorder characterized by overgrowth, stemming from various genetic and epigenetic changes. This study delves into the role of IGF2 upregulation in BWS, focusing on insulin-like growth factor pathways, which are poorly known in this syndrome. We examined the IGF2R, the primary receptor of IGF2, WNT, and autophagy/lysosomal pathways in BWS patient-derived lymphoblastoid cell lines, showing different genetic and epigenetic defects. The findings reveal a decreased expression and mislocalization of IGF2R protein, suggesting receptor dysfunction. Additionally, our results point to a dysregulation in the AKT/GSK-3/mTOR pathway, along with imbalances in autophagy and the WNT pathway. In conclusion, BWS cells, regardless of the genetic/epigenetic profiles, are characterized by alteration of the IGF2R pathway that is associated with the perturbation of the autophagy and lysosome processes. These alterations seem to be a key point of the molecular pathogenesis of BWS and potentially contribute to BWS's characteristic overgrowth and cancer susceptibility. Our study also uncovers alterations in the WNT pathway across all BWS cell lines, consistent with its role in growth regulation and cancer development.

Drug-Drug Interactions of FXI Inhibitors: Clinical Relevance.

Inhibitors of the factor FXI represent a new class of anticoagulant agents that are facing clinical approval for the treatment of acute coronary syndrome (ACS), venous thromboembolism (VTE), and stroke prevention of atrial fibrillation (AF). These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. Besides their clinical efficacy and safety, based on their pharmacological heterogeneity, the use of these drugs in patients with comorbidities may undergo drug-drug interactions (DDIs) with other concomitant therapies. Although only little clinical evidence is available, it is possible to predict clinically relevant DDI by taking into consideration their pharmacokinetic properties, such as the CYP450-dependent metabolism, the interaction with drug transporters, and/or the route of elimination. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa.

NnU-Net versus mesh growing algorithm as a tool for the robust and timely segmentation of neurosurgical 3D images in contrast-enhanced T1 MRI scans.

PURPOSE: This study evaluates the nnU-Net for segmenting brain, skin, tumors, and ventricles in contrast-enhanced T1 (T1CE) images, benchmarking it against an established mesh growing algorithm (MGA). METHODS: We used 67 retrospectively collected annotated single-center T1CE brain scans for training models for brain, skin, tumor, and ventricle segmentation. An additional 32 scans from two centers were used test performance compared to that of the MGA. The performance was measured using the Dice-Sørensen coefficient (DSC), intersection over union (IoU), 95th percentile Hausdorff distance (HD95), and average symmetric surface distance (ASSD) metrics, with time to segment also compared. RESULTS: The nnU-Net models significantly outperformed the MGA (p < 0.0125) with a median brain segmentation DSC of 0.971 [95CI: 0.945-0.979], skin: 0.997 [95CI: 0.984-0.999], tumor: 0.926 [95CI: 0.508-0.968], and ventricles: 0.910 [95CI: 0.812-0.968]. Compared to the MGA's median DSC for brain: 0.936 [95CI: 0.890, 0.958], skin: 0.991 [95CI: 0.964, 0.996], tumor: 0.723 [95CI: 0.000-0.926], and ventricles: 0.856 [95CI: 0.216-0.916]. NnU-Net performance between centers did not significantly differ except for the skin segmentations Additionally, the nnU-Net models were faster (mean: 1139 s [95CI: 685.0-1616]) than the MGA (mean: 2851 s [95CI: 1482-6246]). CONCLUSIONS: The nnU-Net is a fast, reliable tool for creating automatic deep learning-based segmentation pipelines, reducing the need for extensive manual tuning and iteration. The models are able to achieve this performance despite a modestly sized training set. The ability to create high-quality segmentations in a short timespan can prove invaluable in neurosurgical settings.

Benchmarking the CoW with the TopCoW Challenge: Topology-Aware Anatomical Segmentation of the Circle of Willis for CTA and MRA.

The Circle of Willis (CoW) is an important network of arteries connecting major circulations of the brain. Its vascular architecture is believed to affect the risk, severity, and clinical outcome of serious neuro-vascular diseases. However, characterizing the highly variable CoW anatomy is still a manual and time-consuming expert task. The CoW is usually imaged by two angiographic imaging modalities, magnetic resonance angiography (MRA) and computed tomography angiography (CTA), but there exist limited public datasets with annotations on CoW anatomy, especially for CTA. Therefore we organized the TopCoW Challenge in 2023 with the release of an annotated CoW dataset. The TopCoW dataset was the first public dataset with voxel-level annotations for thirteen possible CoW vessel components, enabled by virtual-reality (VR) technology. It was also the first large dataset with paired MRA and CTA from the same patients. TopCoW challenge formalized the CoW characterization problem as a multiclass anatomical segmentation task with an emphasis on topological metrics. We invited submissions worldwide for the CoW segmentation task, which attracted over 140 registered participants from four continents. The top performing teams managed to segment many CoW components to Dice scores around 90%, but with lower scores for communicating arteries and rare variants. There were also topological mistakes for predictions with high Dice scores. Additional topological analysis revealed further areas for improvement in detecting certain CoW components and matching CoW variant topology accurately. TopCoW represented a first attempt at benchmarking the CoW anatomical segmentation task for MRA and CTA, both morphologically and topologically.

Evaluation Metrics for Augmented Reality in Neurosurgical Preoperative Planning, Surgical Navigation, and Surgical Treatment Guidance: A Systematic Review.

BACKGROUND AND OBJECTIVE: Recent years have shown an advancement in the development of augmented reality (AR) technologies for preoperative visualization, surgical navigation, and intraoperative guidance for neurosurgery. However, proving added value for AR in clinical practice is challenging, partly because of a lack of standardized evaluation metrics. We performed a systematic review to provide an overview of the reported evaluation metrics for AR technologies in neurosurgical practice and to establish a foundation for assessment and comparison of such technologies. METHODS: PubMed, Embase, and Cochrane were searched systematically for publications on assessment of AR for cranial neurosurgery on September 22, 2022. The findings were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: The systematic search yielded 830 publications; 114 were screened full text, and 80 were included for analysis. Among the included studies, 5% dealt with preoperative visualization using AR, with user perception as the most frequently reported metric. The majority (75%) researched AR technology for surgical navigation, with registration accuracy, clinical outcome, and time measurements as the most frequently reported metrics. In addition, 20% studied the use of AR for intraoperative guidance, with registration accuracy, task outcome, and user perception as the most frequently reported metrics. CONCLUSION: For quality benchmarking of AR technologies in neurosurgery, evaluation metrics should be specific to the risk profile and clinical objectives of the technology. A key focus should be on using validated questionnaires to assess user perception; ensuring clear and unambiguous reporting of registration accuracy, precision, robustness, and system stability; and accurately measuring task performance in clinical studies. We provided an overview suggesting which evaluation metrics to use per AR application and innovation phase, aiming to improve the assessment of added value of AR for neurosurgical practice and to facilitate the integration in the clinical workflow.

Mixed Reality for Cranial Neurosurgical Planning: A Single-Center Applicability Study With the First 107 Subsequent Holograms.

BACKGROUND AND OBJECTIVES: Mixed reality (MxR) benefits neurosurgery by improving anatomic visualization, surgical planning and training. We aim to validate the usability of a dedicated certified system for this purpose. METHODS: All cases prepared with MxR in our center in 2022 were prospectively collected. Holographic rendering was achieved using an incorporated fully automatic algorithm in the MxR application, combined with contrast-based semiautomatic rendering and/or manual segmentation where necessary. Hologram segmentation times were documented. Visualization during surgical preparation (defined as the interval between finalized anesthesiological induction and sterile draping) was performed using MxR glasses and direct streaming to a side screen. Surgical preparation times were compared with a matched historical cohort of 2021. Modifications of the surgical approach after 3-dimensional (3D) visualization were noted. Usability was assessed by evaluating 7 neurosurgeons with more than 3 months of experience with the system using a Usefulness, Satisfaction and Ease of use (USE) questionnaire. RESULTS: One hundred-seven neurosurgical cases prepared with a 3D hologram were collected. Surgical indications were oncologic (63/107, 59%), cerebrovascular (27/107, 25%), and carotid endarterectomy (17/107, 16%). Mean hologram segmentation time was 39.4 ± 20.4 minutes. Average surgical preparation time was 48.0 ± 17.3 minutes for MxR cases vs 52 ± 17 minutes in the matched 2021 cohort without MxR (mean difference 4, 95% CI 1.7527-9.7527). Based on the 3D hologram, the surgical approach was modified in 3 cases. Good usability was found by 57% of the users. CONCLUSION: The perioperative use of 3D holograms improved direct anatomic visualization while not significantly increasing intraoperative surgical preparation time. Usability of the system was adequate. Further technological development is necessary to improve the automatic algorithms and reduce the preparation time by circumventing manual and semiautomatic segmentation. Future studies should focus on quantifying the potential benefits in teaching, training, and the impact on surgical and functional outcomes.

How we do it: the Zurich Microsurgery Lab technique for placenta preparation.

BACKGROUND: Perfused placentas provide an excellent and accessible model for microvascular dissection, microsuturing and microanastomosis training - particularly in the early microsurgical learning curve. This way, a significant amount of live animals can be spared. METHOD: We present the Zurich Microsurgery Lab protocol, detailing steps for obtaining, selecting, cleaning, flushing, cannulating, and preserving human placentas - as well as microsurgical training examples - in a tried-and-true, safe, cost-effective, and high-yield fashion. CONCLUSION: Our technique enables highly realistic microsurgical training (microdissection, microvascular repair, microanastomosis) based on readily available materials. Proper handling, preparation, and preservation of the perfused placenta models is key.

Application of virtual and mixed reality for 3D visualization in intracranial aneurysm surgery planning: a systematic review.

Background: Precise preoperative anatomical visualization and understanding of an intracranial aneurysm (IA) are fundamental for surgical planning and increased intraoperative confidence. Application of virtual reality (VR) and mixed reality (MR), thus three-dimensional (3D) visualization of IAs could be significant in surgical planning. Authors provide an up-to-date overview of VR and MR applied to IA surgery, with specific focus on tailoring of the surgical treatment. Methods: A systematic analysis of the literature was performed in accordance with the PRISMA guidelines. Pubmed, and Embase were searched to identify studies reporting use of MR and VR 3D visualization in IA surgery during the last 25 years. Type and number of IAs, category of input scan, visualization techniques (screen, glasses or head set), inclusion of haptic feedback, tested population (residents, fellows, attending neurosurgeons), and aim of the study (surgical planning/rehearsal, neurosurgical training, methodological validation) were noted. Results: Twenty-eight studies were included. Eighteen studies (64.3%) applied VR, and 10 (35.7%) used MR. A positive impact on surgical planning was documented by 19 studies (67.9%): 17 studies (60.7%) chose the tailoring of the surgical approach as primary outcome of the analysis. A more precise anatomical visualization and understanding with VR and MR was endorsed by all included studies (100%). Conclusion: Application of VR and MR to perioperative 3D visualization of IAs allowed an improved understanding of the patient-specific anatomy and surgical preparation. This review describes a tendency to utilize mostly VR-platforms, with the primary goals of a more accurate anatomical understanding, surgical planning and rehearsal.

Case report: Impact of mixed reality on anatomical understanding and surgical planning in a complex fourth ventricular tumor extending to the lamina quadrigemina.

Background and importance: Tumors of the fourth ventricle account for 1%-5% of all intracranial neoplastic lesions and present with different configurations and anatomical challenges. Microsurgery represents the primary therapeutic strategy for the majority of fourth ventricular tumors, and adequate anatomical understanding and visualization are paramount to surgical planning and success. The authors present the case of a young patient with a complex fourth ventricular tumor, whose surgery was successfully planned using a novel mixed reality (MxR) system. Case description: We present a case of a 31-year-old woman with a lesion extending from the fourth ventricle to the lamina quadrigemina and causing symptomatic hydrocephalus occlusus. Through the combined use of routine 2D images and an interactive 3D anatomical model, an interhemispheric transtentorial approach was used to remove 98% of the lesion with successful functional outcomes. Conclusions: The application of advanced 3D visualization with a novel MxR system to the surgical planning of a complex fourth ventricular lesion proved relevant in designing the best surgical approach and trajectory to better identify potential intraoperative challenges and rehearse the patient-specific anatomy. The present case report endorses the implementation of advanced 3D visualization in routine perioperative practice.

Immunonutrition in Radical Cystectomy: State of the Art and Perspectives.

Preoperative nutritional status is a pivotal aspect to consider in patients with cancer undergoing radical cystectomy (RC), as those at risk of malnutrition or already malnourished are more prone to post-surgical complications. The loss of muscle mass is a major consequence of cancer-related malnutrition. It is associated with increased risk of hospital readmission, longer hospitalization, and higher mortality. Nowadays, the close relationship between nutritional and immunological aspects under stressful conditions, such as surgery, represents an emerging scientific and clinical issue. Indeed, the synergistic action of reduced food intake and systemic inflammation generates metabolic derangements with tissue catabolism, including skeletal muscle breakdown, which is, in turn, associated with immune system dysfunction. In order to offer an additional immune-nutritional boost to the post-surgical phase, particularly in malnourished patients, nutritional support may include oral nutritional supplements and/or enteral formulas enriched with specific nutrients such as omega-3 fatty acids, arginine, glutamine, and nucleotides, with acknowledged immune-modulating effects. In the present narrative review, we addressed the state of the art of the available scientific literature on the benefit of immunonutrition in patients undergoing RC for cancer and suggest possible future perspectives to be explored. Although the role of immunonutrition was found to be little explored in the context of urologic oncology, the preliminary available data on radical cystectomy, summarized in the present paper, are promising and suggest that it may improve postoperative outcomes through immunomodulation, regardless of nutritional status before surgery.

Feasibility and preliminary efficacy of brief tele-psychotherapy for COVID-19 patients and their first-degree relatives.

BACKGROUND: The SARS-CoV-2 pandemic compromised the mental health of COVID-19 patients and their family members. Due to social distancing and lockdown measures, a remote, tele-psychotherapy program for former or current COVID-19 patients and their relatives was implemented. OBJECTIVE: The primary goal of this project was to evaluate intervention feasibility. The secondary aim was to assess the impact of the intervention by means of pre-post psychological changes. METHODS: After a phone-based eligibility screening and remote neuropsychological testing, participants completed online self-reports assessing baseline COVID-related psychopathology. Next, participants attended eight tele-psychotherapy sessions. After treatment, the online self-reports were completed again. RESULTS: Of 104 enrolled participants, 88 completed the intervention (84.6 % completion rate). Significant pre-post improvements were observed for generalized anxiety (d = 0.38), depression (d = 0.37), insomnia (d = 0.43), post-traumatic psychopathology (d = 0.54), and general malaise (d = 0.31). Baseline cluster analysis revealed a subgroup of 41 subjects (47.6 %) with no psychopathology, and a second subgroup of 45 subject (52.3 %) with moderate severity. Thirty-three percent of the second group reached full symptom remission, while 66 % remained symptomatic after treatment. CONCLUSIONS: Remote brief tele-psychotherapy for COVID-19 patients and their first-degree relatives is feasible and preliminary efficacious at reducing COVID-related psychopathology in a subgroup of patients. Further research is needed to investigate distinct profiles of treatment response.

Long-Term Trajectory and Risk Factors of Healthcare Workers' Mental Health during COVID-19 Pandemic: A 24 Month Longitudinal Cohort Study.

BACKGROUND: Research has shown the substantial impact of the COVID-19 pandemic on healthcare workers' (HCWs) mental health, however, it mostly relies on data collected during the early stages of COVID-19. The aim of this study is to assess the long-term trajectory of HCWs' mental health and the associated risk factors. METHODS: a longitudinal cohort study was carried out in an Italian hospital. At Time 1 (July 2020-July 2021), 990 HCWs took part in the study and completed the General Health Questionnaire (GHQ-12), the Impact of Event Scale (IES-R), and the General Anxiety Disorder (GAD-7)questionnaire. McNemar's test measured changes in symptoms' trajectories, and random effects models evaluated risk factors associated with scores above the cut-off. RESULTS: 310 HCWs participated to the follow-up evaluation (Time 2; July 2021-July 2022). At Time 2, scores above cut-offs were significantly lower (p < 0.001) than at Time 1 for all scales (23% vs. 48% for GHQ-12; 11% vs. 25% for IES-R; 15% vs. 23% for GAD-7). Risk factors for psychological impairment were being a nurse (IES-R: OR 4.72, 95% CI 1.71-13.0; GAD-7: OR 2.82, 95% CI 1.44-7.17), a health assistant (IES-R: OR 6.76, 95% CI 1.30-35.1), or having had an infected family member (GHQ-12: OR 1.95, 95% CI 1.01-3.83). Compared to Time 1, gender and experience in COVID-19 units lost significance with psychological symptoms. CONCLUSIONS: data over more than 24 months from the pandemic onset showed improvement of HCWs' mental health; our findings suggested the need to tailor and prioritize preventive actions towards healthcare workforce.

Germline NUP98 Variants in Two Siblings with a Rothmund-Thomson-Like Spectrum: Protein Functional Changes Predicted by Molecular Modeling.

Two adult siblings born to first-cousin parents presented a clinical phenotype reminiscent of Rothmund-Thomson syndrome (RTS), implying fragile hair, absent eyelashes/eyebrows, bilateral cataracts, mottled pigmentation, dental decay, hypogonadism, and osteoporosis. As the clinical suspicion was not supported by the sequencing of RECQL4, the RTS2-causative gene, whole exome sequencing was applied and disclosed the homozygous variants c.83G>A (p.Gly28Asp) and c.2624A>C (p.Glu875Ala) in the nucleoporin 98 (NUP98) gene. Though both variants affect highly conserved amino acids, the c.83G>A looked more intriguing due to its higher pathogenicity score and location of the replaced amino acid between phenylalanine-glycine (FG) repeats within the first NUP98 intrinsically disordered region. Molecular modeling studies of the mutated NUP98 FG domain evidenced a dispersion of the intramolecular cohesion elements and a more elongated conformational state compared to the wild type. This different dynamic behavior may affect the NUP98 functions as the minor plasticity of the mutated FG domain undermines its role as a multi-docking station for RNA and proteins, and the impaired folding can lead to the weakening or the loss of specific interactions. The clinical overlap of NUP98-mutated and RTS2/RTS1 patients, accounted by converging dysregulated gene networks, supports this first-described constitutional NUP98 disorder, expanding the well-known role of NUP98 in cancer.

The end of life of patients with COVID-19 in intensive care unit and the stress level on their family members: A cross-sectional study.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, hospital visits were suspended and video calls were offered to connect patients with their family members, especially toward the end of life (EoL). AIM: The primary aim was to describe EoL care for COVID-19 patients dying in an intensive care unit (ICU). The secondary aim was to explore whether making video calls and allowing visits was associated with lower death-related stress in family members. DESIGN: Single centre cross-sectional study. The setting was the ICU of a COVID-19 center in northern Italy, during the first year of the pandemic. Data on patients who died in the ICU were collected; death-related stress on their family members was measured using the Impact of Event Scale-Revised (IES-R). The statistical association was tested by means of logistic regression. RESULTS: The study sample included 70 patients and 56 family members. All patients died with mechanical ventilation, hydration, nutrition, analgesia and sedation ongoing. Resuscitation procedures were performed in 5/70 patients (7.1%). Only 6/56 (10.7%) of the family members interviewed had visited their loved ones in the ICU and 28/56 (50%) had made a video call. EoL video calls were judged useful by 53/56 family members (94.6%) but all (56/56, 100%) wished they could have visited the patient. High-stress levels were found in 38/56 family members (67.9%), regardless of whether they were allowed ICU access or made a video call. Compared with other degrees of kinship, patients' offspring were less likely to show a positive IES-R score (odds ratio [OR] 0.22, 95% confidence interval [CI] 0.05 to 0.89). CONCLUSIONS: During the first year of the COVID-19 pandemic, patients died without their family members at the bedside while on life-sustaining treatment. Stress levels were high in most family members, especially in patients' spouses. Video calls or ICU visits were judged favourably by family members but insufficient to alleviate death-related stress. RELEVANCE FOR CLINICAL PRACTICE: During a pandemic, ICU access by patients' family members should be considered, particularly as the time of death approaches. Although generally appreciated by family members, EoL video calls should be arranged together with other measures to alleviate death-related stress, especially for the patient's spouse.

Renal perfusion with histidine-tryptophan-ketoglutarate compared with Ringer's solution in patients undergoing thoracoabdominal aortic open repair.

OBJECTIVE: The objective of this study was to compare the efficacy of renal perfusion with Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) versus enriched Ringer's solution for renal protection in patients undergoing open thoracoabdominal aortic aneurysm (TAAA) repair. METHODS: Ninety consecutive patients scheduled for elective open TAAA repair were enrolled between 2015 and 2017 in a single-center, phase IV, prospective, parallel, randomized, double-blind trial (the CUstodiol versus RInger: whaT Is the Best Agent [CURITIBA] trial), and randomized to renal arteries perfusion with 4°C Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany; n = 45) or 4°C lactated Ringer's solution (n = 45). The incidence of acute kidney injury (AKI) in patients undergoing TAAA open surgery using Custodiol renal perfusion versus an enriched Ringer's solution was the primary end point. RESULTS: Ninety patients completed the study (45 patients in each group). The incidence of postoperative AKI was significantly lower in the Custodiol group (48.9% vs 75.6%; P = .02). In the multivariable model, only the use of Custodiol solution resulted as protective from the occurrence of any AKI (odds ratio, 0.230; 95% confidence interval, 0.086-0.614; P = .003), whereas TAAA type II extent was associated with the development of severe AKI (odds ratio, 4.277; 95% confidence interval, 1.239-14.762; P = .02). At 1-year follow-up, serum creatinine was not significantly different from the preoperative values in both groups. CONCLUSIONS: The use of Custodiol during open TAAA repair was safe and resulted in significantly lower rates of postoperative AKI compared with Ringer's solution. These findings support safety and efficacy of Custodiol in this specific setting, which is currently off-label.

Epigenetic disorders: Lessons from the animals-animal models in chromatinopathies.

Chromatinopathies are defined as genetic disorders caused by mutations in genes coding for protein involved in the chromatin state balance. So far 82 human conditions have been described belonging to this group of congenital disorders, sharing some molecular features and clinical signs. For almost all of these conditions, no specific treatment is available. For better understanding the molecular cascade caused by chromatin imbalance and for envisaging possible therapeutic strategies it is fundamental to combine clinical and basic research studies. To this end, animal modelling systems represent an invaluable tool to study chromatinopathies. In this review, we focused on available data in the literature of animal models mimicking the human genetic conditions. Importantly, affected organs and abnormalities are shared in the different animal models and most of these abnormalities are reported as clinical manifestation, underlying the parallelism between clinics and translational research.

Psychotherapeutic and Psychiatric Intervention in Patients With COVID-19 and Their Relatives: Protocol for the DigiCOVID Trial.

BACKGROUND: The COVID-19 pandemic is negatively impacting the mental health of both patients with COVID-19 and the general population. As current guidelines are limiting in-person contacts to reduce the spread of the virus, the development of a digital approach to implement in psychiatric and psychological consultations is needed. In this paper, we present the DigiCOVID protocol, a digital approach to offer remote, personalized psychological and psychiatric support to former or current patients with COVID-19 and their relatives. OBJECTIVE: The main goal of this project is to evaluate the feasibility, acceptability, and usability of the DigiCOVID protocol. Furthermore, we also aim to assess the impact of the abovementioned protocol by means of pre-post changes in psychological clinical variables. METHODS: Participants undergo an initial telephonic screening to ensure inclusion criteria are met. Secondly, participants complete a video-assisted neuropsychological IQ test as well as web-based self-reports of health and general well-being. Participants are then assigned to a psychotherapist who offers 8 teletherapy sessions. At the end of the therapy cycle, the web-based questionnaires are administered for a posttreatment evaluation. RESULTS: As of April 2022, we enrolled a total of 122 participants, of which 94 have completed neuropsychological tests and web-based questionnaires. CONCLUSIONS: Our study aims at testing the feasibility and preliminary efficacy of DigiCOVID, a remote telemedicine protocol for the improvement of psychological and psychiatric health in patients with COVID-19 and their relatives. To date, the approach used seems to be feasible and highly customizable to patients' needs, and therefore, the DigiCOVID protocol might pave the way for future telepsychiatry-based interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT05231018; https://clinicaltrials.gov/ct2/show/NCT05231018?term=NCT05231018 &draw=2&rank=1. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39080.

The Complexity of the Human-Animal Bond: Empathy, Attachment and Anthropomorphism in Human-Animal Relationships and Animal Hoarding.

The human-animal relationship is ancient, complex and multifaceted. It may have either positive effects on humans and animals or poor or even negative and detrimental effects on animals or both humans and animals. A large body of literature has investigated the beneficial effects of this relationship in which both human and animals appear to gain physical and psychological benefits from living together in a reciprocated interaction. However, analyzing the literature with a different perspective it clearly emerges that not rarely are human-animal relationships characterized by different forms and levels of discomfort and suffering for animals and, in some cases, also for people. The negative physical and psychological consequences on animals' well-being may be very nuanced and concealed, but there are situations in which the negative consequences are clear and striking, as in the case of animal violence, abuse or neglect. Empathy, attachment and anthropomorphism are human psychological mechanisms that are considered relevant for positive and healthy relationships with animals, but when dysfunctional or pathological determine physical or psychological suffering, or both, in animals as occurs in animal hoarding. The current work reviews some of the literature on the multifaceted nature of the human-animal relationship; describes the key role of empathy, attachment and anthropomorphism in human-animal relationships; seeks to depict how these psychological processes are distorted and dysfunctional in animal hoarding, with highly detrimental effects on both animal and human well-being.

Segmentation techniques of brain arteriovenous malformations for 3D visualization: a systematic review.

BACKGROUND: Visualization, analysis and characterization of the angioarchitecture of a brain arteriovenous malformation (bAVM) present crucial steps for understanding and management of these complex lesions. Three-dimensional (3D) segmentation and 3D visualization of bAVMs play hereby a significant role. We performed a systematic review regarding currently available 3D segmentation and visualization techniques for bAVMs. METHODS: PubMed, Embase and Google Scholar were searched to identify studies reporting 3D segmentation techniques applied to bAVM characterization. Category of input scan, segmentation (automatic, semiautomatic, manual), time needed for segmentation and 3D visualization techniques were noted. RESULTS: Thirty-three studies were included. Thirteen (39%) used MRI as baseline imaging modality, 9 used DSA (27%), and 7 used CT (21%). Segmentation through automatic algorithms was used in 20 (61%), semiautomatic segmentation in 6 (18%), and manual segmentation in 7 (21%) studies. Median automatic segmentation time was 10 min (IQR 33), semiautomatic 25 min (IQR 73). Manual segmentation time was reported in only one study, with the mean of 5-10 min. Thirty-two (97%) studies used screens to visualize the 3D segmentations outcomes and 1 (3%) study utilized a heads-up display (HUD). Integration with mixed reality was used in 4 studies (12%). CONCLUSIONS: A golden standard for 3D visualization of bAVMs does not exist. This review describes a tendency over time to base segmentation on algorithms trained with machine learning. Unsupervised fuzzy-based algorithms thereby stand out as potential preferred strategy. Continued efforts will be necessary to improve algorithms, integrate complete hemodynamic assessment and find innovative tools for tridimensional visualization.