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Facing ethical concerns in the age of precise gene therapy:Outlook on inherited arrhythmias

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World Journal of Cardiology 2024年第2期16卷 64-66页

作者： Federico Carbone fabrizio Montecucco Department of Internal Medicine University of GenoaGenoa 16132Italy IRCCS Ospedale Policlinico San Martino Genoa Italian Cardiovascular NetworkGenoa 16132Italy

This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias.As monogenic diseases with no or few therapeutic options available through standard care,inherited arrhythmias are ideal candidates to gene therapy in their treatment.Patients with inherited arrhythmias typically have a poor quality of life,especially young people engaged in agonistic sports.While genome editing for treatment of inherited arrhythmias still has theoretical application,advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease.However,clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias.Genomic off-target activity is a known technical issue,but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility.Meanwhile,the costeffectiveness may further limit an equal distribution of gene therapies.The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern.A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems,but potential concerns for universal healthcare systems in the long term as well.Altogether,those aspects strongly indicate a need of regulatory entities to manage those issues.

关键词： Ethics Inherited arrhythmias CRISPR/Cas9 Gene therapy Equitable accessibility

A Modified Iterative Learning Control Approach for the Active Suppression of Rotor Vibration Induced by Coupled Unbalance and Misalignment

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Chinese Journal of Mechanical Engineering 2024年第1期37卷 242-253页

作者： Yifan Bao Jianfei Yao fabrizio Scarpa Yan Li College of Mechanical and Electrical Engineering Beijing University of Chemical TechnologyBeijing 100029China State Key Laboratory of High-end Compressor and System Technology Beijing 100029China Beijing Key Laboratory of High-end Mechanical Equipment Health Monitoring and Self-Recovery Beijing University of Chemical TechnologyBeijing 100029China Key Lab of Engine Health Monitoring-Control and Networking of Ministry of Education Beijing University of Chemical TechnologyBeijing 100029China Bristol Composites Institute(ACCIS) University of BristolBristol BS81TRUK Dynamics and Control Research Group(DCRG) University of BristolBristol BS81TRUK

This paper proposes a modified iterative learning control(MILC)periodical feedback-feedforward algorithm to reduce the vibration of a rotor caused by coupled unbalance and parallel misalignment.The control of the vibration of the rotor is provided by an active magnetic actuator(AMA).The iterative gain of the MILC algorithm here presented has a self-adjustment based on the magnitude of the vibration.Notch filters are adopted to extract the synchronous(1×Ω)and twice rotational frequency(2×Ω)components of the rotor vibration.Both the notch frequency of the filter and the size of feedforward storage used during the experiment have a real-time adaptation to the rotational speed.The method proposed in this work can provide effective suppression of the vibration of the rotor in case of sudden changes or fluctuations of the rotor speed.Simulations and experiments using the MILC algorithm proposed here are carried out and give evidence to the feasibility and robustness of the technique proposed.

关键词： Rotor vibration suppression Modified iterative learning control Unbalance Parallel misalignment Active magnetic actuator

Deadwood position matters:Diversity and biomass of saproxylic beetles in a temperate beech forest

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Forest Ecosystems 2024年第1期11卷 120-130页

作者： Vaclav Zumr Oto Nakladal Josef gallo JiríRemes Faculty of Forestry and Wood Sciences Czech University of Life Sciences PragueKamýck a 129Praha 6-Suchdol16500Czech Republic

Deadwood plays a key role for biodiversity in forests.A significant number of beetles from this group are currently listed as endangered in the Red List.In addition to other management recommendations,there have been recent efforts to enrich stands with dead wood to promote biodiversity.An important parameter for forestry enterprises is the optimization of these interventions.The study investigated the abundance,species richness,gamma diversity,conservation value and biomass of saproxylic beetles in natural forests using window traps.A total of 89traps were used for saproxylic beetle monitoring,of which 29 were placed on lying logs,30 on snags and 30 as controls in forest stand space.A total of 35,011 beetles were recorded in 564 species(61 families).Notably,20,515 of these belong to saproxylic beetles(59%)in 311 species(55%),with 62 classified as Red-List species(20%).In the group of'all saproxylic beetles',the results indicate that a diversity and y diversity(q=0)remain consistent across various deadwood types,whileβdiversity showed significant differences.Significant differences were found in the Red-List species group,where a diversity and y diversity differed,with higher values observed in snags.Rarefaction based total species richness of site was estimated to be 391 species,including 74 Red-Listed species.Comparing the sample coverage of the studied stand categories showed that all saproxylic species exhibit a pronounced preference for inhabiting areas featuring lying logs.Conversely,Red-List species mainly inhabit snags,withβdiversity being more similar to snags and forest stand space.Notably,both the conservation value(weighted average by conservation status)and beetle biomass are significantly highest in snags,whereas stand space shows the lowest values across all measured saproxylic beetle indices.Furthermore,the use of traps set on the poles in forest stand space resulted in an underestimation of the actual stand richness by 20%-25%.Our results support the conclusion that snags are indispensable featur

关键词： Snags Coleoptera Fagus sylvatica Unmanaged forests Red-list Coarse woody debris

Autoimmune pancreatitis:Cornerstones and future perspectives

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World Journal of Gastroenterology 2024年第8期30卷 817-832页

作者： Camilla gallo Giulia Dispinzieri Nicola Zucchini Pietro Invernizzi Sara Massironi Division of Gastroenterology and Center for Autoimmune Liver Diseases Department of Medicine and SurgeryFondazione IRCCS San Gerardo dei TintoriUniversity of Milano-BicoccaMonza 20900Italy Department of Pathology Fondazione IRCCS San Gerardo dei TintoriMonza 20900Italy

Autoimmune pancreatitis(AIP)is an autoimmune subtype of chronic pancreatitis resulting from the aberrant immune response against the pancreas,leading to inflammation and fibrosis.Although AIP is rare,its incidence is increasing and is often misdiagnosed as other pancreatic diseases.AIP is commonly classified into two types.Type 1 AIP(AIP-1)is typically associated with elevated serum immunoglobulin G4(IgG4)levels and systemic manifestations,while type 2 AIP is typically a more localized form of the disease,and may coexist with other autoimmune disorders,especially inflammatory bowel diseases.Additionally,there is emerging recognition of a third type(type 3 AIP),which refers to immunotherapy-triggered AIP,although this classification is still gaining acceptance in medical literature.The clinical manifestations of AIP mainly include painless jaundice and weight loss.Elevated serum IgG4 levels are particularly characteristic of AIP-1.Diagnosis relies on a combination of clinical,laboratory,radiological,and histological findings,given the similarity of AIP symptoms to other pancreatic disorders.The mainstay of treatment for AIP is steroid therapy,which is effective in most cases.Severe cases might require additional imm-unosuppressive agents.This review aims to summarize the current knowledge of AIP,encompassing its epidemiology,etiology,clinical presentation,diagnosis,and treatment options.We also address the challenges and controversies in diagnosing and treating AIP,such as distinguishing it from pancreatic cancer and managing long-term treatment,highlighting the need for increased awareness and knowledge of this complex disease.

关键词： Autoimmunity Pancreatitis Autoimmune pancreatitis Immunoglobulin G4 Steroids Relapse

Transanal eco-Doppler evaluation after hemorrhoidal artery embolization

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World Journal of Gastroenterology 2024年第17期30卷 2332-2342页

作者： Roberta Tutino Tommaso Stecca fabrizio Farneti Marco Massani Giulio Aniello Santoro Dipartimento Chirurgia Generale e Specialistica AOU Cittàdella Salute e della Scienza di TorinoTorino 10126Italy Division of General Surgery 1 Treviso Regional HospitalAULSS 2 Marca TrevigianaTreviso 31100Italy Division of Radiology Treviso Regional HospitalAULSS 2 Marca TrevigianaTreviso 31100Italy Tertiary Referral Pelvic Floor Center Division of General Surgery 2AULSS 2 Marca TrevigianaTreviso 31100Italy

BACKGROUND Hemorrhoidal artery embolization(Emborrhoid)is a novel method for the treatment of severe hemorrhoidal bleeding.Despite having a technical success rate of 93%-100%,the clinical success ranges between 63%and 94%,with a rebleeding rate of 13.6%.AIM To evaluate the effectiveness of this procedure in reducing hemorrhoidal flow and hemorrhoidal bleeding.METHODS This prospective observational pilot study was conducted at Division of General Surgery 1 and Tertiary Referral Pelvic Floor Center,Treviso Regional Hospital,Italy.In a 2 months period(February-March 2022),consecutive patients with hemorrhoidal bleeding scores(HBSs)≥4,Goligher scores of II or III,failure of non-operative management,and a candidate for Emborrhoid were included.Endoanal ultrasound with eco-Doppler was performed preoperatively and 1 month after the procedure.The primary endpoint was to quantify the changes in arterial hemorrhoidal flow after treatment.The secondary endpoint was to evaluate the correlation between the flow changes and the HBS.RESULTS Eleven patients underwent Emborrhoid.The overall pretreatment mean systolic peak(MSP)was 14.66 cm/s.The highest MSP values were found in the anterior left lateral(17.82 cm/s at 1 o’clock and 15.88 cm/s at 3 o’clock)and in the posterior right lateral(14.62 cm/s at 7 o’clock and 16.71 cm/s at 9 o’clock)quadrants of the anal canal.After treatment,the overall MSP values were significantly reduced(P=0.008)although the correlation between MSP and HBS changes was weak(P=0.570).A statistical difference was found between distal embolization compared with proximal embolization(P=0.047).However,the coil landing zone was not related to symptoms improvement(P=1.000).A significant difference in MSP changes was also reported between patients with type 1 and type 2 superior rectal artery(SRA)anatomy(P=0.040).No relationship between hemorrhoidal grades(P=1.000),SRA anatomy(P=1.000)and treatment outcomes was found.CONCLUSION The preliminary findings of this pilot study confirm that Emborrhoid was effective in

关键词： Hemorrhoidal artery embolization Hemorrhoidal embolization Hemorrhoidal vascularization Transanal eco-Doppler Transanal ultrasound

Therapeutic advances in neural regeneration for Huntington’s disease

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Neural Regeneration Research 2024年第9期19卷 1991-1997页

作者： Francesco D’Egidio Vanessa Castelli Giorgia Lombardozzi fabrizio Ammannito Annamaria Cimini Michele d’Angelo Department of Life Health and Environmental SciencesUniversity of L’AquilaL’AquilaItaly

Huntington’s disease is a neurodegenerative disease caused by the expansion mutation of a cytosine-adenine-guanine triplet in the exon 1 of the HTT gene which is responsible for the production of the huntingtin (Htt) protein. In physiological conditions, Htt is involved in many cellular processes such as cell signaling, transcriptional regulation, energy metabolism regulation, DNA maintenance, axonal trafficking, and antiapoptotic activity. When the genetic alteration is present, the production of a mutant version of Htt (mHtt) occurs, which is characterized by a plethora of pathogenic activities that, finally, lead to cell death. Among all the cells in which mHtt exerts its dangerous activity, the GABAergic Medium Spiny Neurons seem to be the most affected by the mHtt-induced excitotoxicity both in the cortex and in the striatum. However, as the neurodegeneration proceeds ahead the neuronal loss grows also in other brain areas such as the cerebellum, hypothalamus, thalamus, subthalamic nucleus, globus pallidus, and substantia nigra, determining the variety of symptoms that characterize Huntington’s disease. From a clinical point of view, Huntington’s disease is characterized by a wide spectrum of symptoms spanning from motor impairment to cognitive disorders and dementia. Huntington’s disease shows a prevalence of around 3.92 cases every 100,000 worldwide and an incidence of 0.48 new cases every 100,000/year. To date, there is no available cure for Huntington’s disease. Several treatments have been developed so far, aiming to reduce the severity of one or more symptoms to slow down the inexorable decline caused by the disease. In this context, the search for reliable strategies to target the different aspects of Huntington’s disease become of the utmost interest. In recent years, a variety of studies demonstrated the detrimental role of neuronal loss in Huntington’s disease condition highlighting how the replacement of lost cells would be a reasonable strategy to overcome the neurodegeneration. In this view, num

关键词： cell therapy exosomes extracellular vesicles Huntingtin Huntington’s disease medium spiny neurons neurodegenerative disease neurogenesis neuronal loss stem cells

Inflammation as a cause of acute myocardial infarction in patients with myeloproliferative neoplasm

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World Journal of Cardiology 2024年第2期16卷 58-63页

作者： Amedeo Tirandi Elisa Schiavetta Elia Maioli fabrizio Montecucco Luca Liberale Department of Internal Medicine University of GenoaGenoa 16132Italy IRCCS Ospedale Policlinico San Martino Genoa–Italian Cardiovascular NetworkGenoa 16132Italy

Myeloproliferative neoplasms(MPN)are a group of diseases characterized by the clonal proliferation of hematopoietic progenitor or stem cells.They are clinically classifiable into four main diseases:chronic myeloid leukemia,essential thrombocythemia,polycythemia vera,and primary myelofibrosis.These pathologies are closely related to cardio-and cerebrovascular diseases due to the increased risk of arterial thrombosis,the most common underlying cause of acute myocardial infarction.Recent evidence shows that the classical Virchow triad(hypercoagulability,blood stasis,endothelial injury)might offer an explanation for such association.Indeed,patients with MPN might have a higher number and more reactive circulating platelets and leukocytes,a tendency toward blood stasis because of a high number of circulating red blood cells,endothelial injury or overactivation as a consequence of sustained inflammation caused by the neoplastic clonal cell.These abnormal cancer cells,especially when associated with the JAK2V617F mutation,tend to proliferate and secrete several inflammatory cytokines.This sustains a pro-inflammatory state throughout the body.The direct consequence is the induction of a pro-thrombotic state that acts as a determinant in favoring both venous and arterial thrombus formation.Clinically,MPN patients need to be carefully evaluated to be treated not only with cytoreductive treatments but also with cardiovascular protective strategies.

关键词： Inflammation Myeloproliferative neoplasm Acute coronary syndrome Myocardial infarction Thrombosis Cancer

Non-anatomical liver resection for hepatocellular carcinoma:the SegSubTe classification to overcome the problem of heterogeneity

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Hepatobiliary & Pancreatic Diseases International 2024年第3期23卷 265-271页

作者： Mattia Garancini Alessandro Fogliati Mauro Alessandro Scotti Cristina Ciulli Francesca Carissimi Antonio Rovere Luca Gianotti fabrizio Romano Unit of Hepatobiliopancreatic Surgery Department of SurgeryASST-MonzaSan Gerardo HospitalUniversity of Milano-Bicoccavia Pergolesi 33MonzaMB 20052Italy Interventional Radiology Department of RadiologyASST-MonzaSan Gerardo HospitalMilano-Bicocca Universityvia Pergolesi 33MonzaMB 20052Italy

Background:The superiority of anatomical resection(AR)vs.non-anatomical resection(NAR)in the surgical management of hepatocellular carcinoma(HCC)is debated.ARs are well-defined procedures,whereas the lack of NAR standardization results in heterogeneous outcomes.This study aimed to introduce the SegSubTe classification for NAR detailing the appropriateness of the level of surgical section of the Glissonean pedicles feeding the tumor.Methods:A single-center retrospective analysis of pre-and postoperative imaging of consecutive patients treated with NAR for single HCC between 2012 and 2020 was conducted.The quality of surgery was assessed classifying the type of vascular supply and the level of surgical section(segmental,subsegmental or terminal next to the tumor)of vascular pedicles feeding the HCCs;then,the population was divided in“SegSubTe-IN”or“SegSubTe-OUT”groups,and the tumor recurrence and survival were analyzed.Results:Ninety-seven patients who underwent NAR were included;76%were SegSubTe-IN and 24%were SegSubTe-OUT.Total disease recurrence,local recurrence and cut-edge recurrence in the SegSubTe-IN vs.SegSubTe-OUT groups were 50%vs.83%(P=0.006),20%vs.52%(P=0.003)and 16%vs.39%(P=0.020),respectively.SegSubTe-OUT odds ratio for local recurrence was 4.1 at univariate regression analysis.One-,three-,and five-year disease-free survival rates in the SegSubTe-IN vs.SegSubTe-OUT groups were 81%,58%and 35%vs.46%,21%and 11%,respectively(P<0.001).Conclusions:The SegSubTe classification is a useful tool to stratify and standardize NAR for HCC,aiming at improving long-term oncological outcomes and reducing the heterogeneity of quality of NAR for HCC.

关键词： Hepatocellular carcinoma Intraoperative ultrasound Liver surgery Computed tomography Surgical procedure

Selective internal radiation therapy segmentectomy:A new minimally invasive curative option for primary liver malignancies?

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World Journal of Gastroenterology 2024年第18期30卷 2379-2386页

作者： Riccardo Inchingolo Francesco Cortese Antonio Rosario Pisani fabrizio Acquafredda Roberto Calbi Riccardo Memeo Fotis Anagnostopoulos Stavros Spiliopoulos Unit of Interventional Radiology “F.Miulli”Regional General HospitalBari 70021Italy Interdisciplinary Department of Medicine Section of Nuclear MedicineUniversity of Bari“Aldo Moro”Bari 70121Italy Department of Radiology General Regional Hospital“F.Miulli”Acquaviva delle Fonti 70021Italy Unit of Hepato-Pancreatic-Biliary Surgery “F.Miulli”Regional General HospitalBari 70021Italy The Second Radiology Department National and Kapodistrian University of AthensChaidari Athens 12461Greece

Transarterial radioembolization or selective internal radiation therapy(SIRT)has emerged as a minimally invasive approach for the treatment of tumors.This percutaneous technique involves the local,intra-arterial delivery of radioactive microspheres directly into the tumor.Historically employed as a palliative measure for liver malignancies,SIRT has gained traction over the past decade as a potential curative option,mirroring the increasing role of radiation segmentectomy.The latest update of the BCLC hepatocellular carcinoma guidelines recognizes SIRT as an effective treatment modality comparable to other local ablative methods,particularly well-suited for patients where surgical resection or ablation is not feasible.Radiation segmentectomy is a more selective approach,aiming to deliver high-dose radiation to one to three specific hepatic segments,while minimizing damage to surrounding healthy tissue.Future research efforts in radiation segmentectomy should prioritize optimizing radiation dosimetry and refining the technique for super-selective administration of radiospheres within the designated hepatic segments.

关键词： Transarterial radioembolization Selective internal radiation therapy Radiation segmentectomy Hepatocellular carcinoma Primary liver malignancies Personalised dosimetry