Consensual end-of-life for depressed patients: a right or a danger?

Abstract: Recent events have brought the debate on end-of-life issues to the forefront, particularly regarding the principle of self-determination for depressed patients. Belgian legislation, in fact, allows for requesting euthanasia when patients, capable of expressing their own will consciously, suffer in an unbearable manner and find no meaning in continuing their existence, even in the absence of incurable and/or severely debilitating conditions. The state of the art is an increasing number of people who die from euthanasia. An open question is when a situation can be defined as unbearable. Moreover, does such an assessment necessarily lead to death, or are there other solutions? In our opinion, such a practice should be limited to prevent inappropriate applications that could lead to infringing depressed patients' rights.

The obligation of the physician to save the life of the detainee on a hunger strike: the opinion of the Italian National Bioethics Committee.

Abstract: The Cospito case has highlighted a widely debated bioethical issue regarding the need to choose between safeguarding the life of a detainee and their right to self-determination through the practice of a hunger strike. Recently, the Italian National Bioethics Committee has been called upon to give an opinion on this matter. On the other hand, the media resonance of this case has shed light on the need to pose an ethical and social question regarding such situations: does the physician have an obligation to protect the detainee's health at the expense of their free choice? To be able to answer, it is necessary to understand whether law no. 219/17 is applicable to this context.

First Case of Medically Assisted Suicide in Italy Set New Legal Perspectives.

Abstract: The first act of assisted suicide in Italy was recently carried out. This event is an absolute novelty for the country, affected by recent legislative changes aimed only at introducing the right to interrupt health treatments and, therefore, carry out exclusively omissive end-of-life acts. These normative provisions lay their foundations in a cultural context centered on the protection of the right to life and health; however, the cases that have occurred over time, including the famous story of DJ Fabo, have led the Constitutional Court to re-evaluate these dictates, introducing in 2019 the right to resort to assisted suicide procedures within well-defined areas, including incurability of the condition, the serious suffering of the individual and the retained ability to stand trial. The case addressed concerns a quadriplegic subject who was the victim of a road accident. Following consultation with a specialized institution, the subject made the decision to undergo an assisted sui-cide procedure in Italy. Having obtained the authorization from the competent authorities, he started a fundraiser to finance the devices and drugs required and, finally, he died. The opening by Italy towards the assisted suicide procedure represents a great step towards a broad context, as well as a decisive act for the purpose of protecting the right to self-determination of the individual. However, the current legislative framework presents significant criticalities and shortcomings. In first place, the dissonance between the laws in force and the judicial sentences is likely to generate problems of uneven application of the rules in a country dominated by the principle of Civil Law. Furthermore, the need for the applicant to fully self-finance the procedure clearly clashes with the constitutional principle of free access to care. Then emerges the need for a guideline document regarding the completion of the procedure itself, the times, methods and drugs implied, in order to significantly reduce the decision-making process by the ethics committees that still weighs on each individual case. Finally, conside-ring what has been observed on the subject of voluntary termination of pregnancy, it is necessary to ask what will be the general orientation of the doctors called to perform the act and whether they will be given the opportunity to express their refusal. The case analyzed could represent the beginning of a new era for Italian culture, but the large-scale application of assisted suicide procedures requires the introduction of legislative provisions that definitively eliminate the critical issues that have emerged so far.

Obstetric Violence in Italy: From Theoretical Premises to Court Judgments.

Introduction: Historical mistreatment and violence directed toward women's bodies extend to the field of medicine, and obstetric and gynecological practices are not immune to such misconduct. Obstetric violence (OV) refers to actions involving disrespectful, abusive, or coercive treatment directed at pregnant and birthing women. This includes institutional and personal attitudes that lead to the violation of women's autonomy, human rights, and sexual and reproductive health. Despite various international legislative initiatives and recommendations from the World Health Organization (WHO) addressing disrespectful and abusive treatment, OV is still poorly known to Italian public opinion. This study aims to investigate whether the concept of OV has been conversely assimilated in judicial decisions. Materials and methods: A retrospective analysis was conducted to scrutinize judgments in Italy until June 2023 related to OV. The Italian legal database 'De Jure Giuffrè', which collects sentences by various Courts, and the terms 'obstetric' and 'violence' as keywords were used for the research. Results: The full-text revision of the results (n. 41 sentences) al-lowed the selection of 5 eligible contributions covering the following issues: Informed Consent, Kristeller maneuver, Vaginal Birth After Cesarean (VBAC), Acceleration of childbirth without indication, and Episiotomy. The analysis of individual judgments was complemented by an examination of the key issues involved. Conclusions: The reviewed judgments frequently seemed to be grounded in technical aspects and inclined towards a predominant evaluation of childbirth outcomes. However, some encouraging aspects emerged, particularly in terms of attention to the female body, acknowledgment of consequences within the intimate-relational dimension, and a commitment to the principle of self-determination through the provision of free and informed consent. Ensuring the psychophysical well-being of women and unborn children, fostering positive interactions between pregnant women and medical staff, and actively working to reduce the grounds for litigation are among actual emerging priorities in healthcare. In this sense, fundamental elements include the implementation of continuous staff training and education as well as a focus on promoting the self-determination of women, leveraging new technologies for this purpose, and ensuring legal protection of their rights.

Secrets and lies of host-microbial interactions: MHC restriction and trans-regulation of T cell trafficking conceal the role of microbial agents on the edge between health and multifactorial/complex diseases.

Here we critically discuss data supporting the view that microbial agents (pathogens, pathobionts or commensals alike) play a relevant role in the pathogenesis of multifactorial diseases, but their role is concealed by the rules presiding over T cell antigen recognition and trafficking. These rules make it difficult to associate univocally infectious agents to diseases' pathogenesis using the paradigm developed for canonical infectious diseases. (Cross-)recognition of a variable repertoire of epitopes leads to the possibility that distinct infectious agents can determine the same disease(s). There can be the need for sequential infection/colonization by two or more microorganisms to develop a given disease. Altered spreading of infectious agents can determine an unwanted activation of T cells towards a pro-inflammatory and trafficking phenotype, due to differences in the local microenvironment. Finally, trans-regulation of T cell trafficking allows infectious agents unrelated to the specificity of T cell to modify their homing to target organs, thereby driving flares of disease. The relevant role of microbial agents in largely prevalent diseases provides a conceptual basis for the evaluation of more specific therapeutic approaches, targeted to prevent (vaccine) or cure (antibiotics and/or Biologic Response Modifiers) multifactorial diseases.

COVID-19 Risk Management: a Survey among Italian physicians.

Abstract: The COVID-19 pandemic had a significant global impact on public health. The increasing demand for intensive care and the closure of several health facilities has led to a reduction in the assistance of non-COVID patients. In our study, we investigated what changes health professionals have experienced in their professional activities and how they coped with them. A questionnaire was sent to 146 doctors, focused on three subjects: type of activity carried out during the pandemic; use of personal protective equipment (PPE) and recourse to vaccination; current medical liability profiles related to COVID-19. The questionnaire was completed by 111 doctors. The study showed no significant differences in the questionnaire response as regards the demographic and work variables of the participants (gender, age, area of specialties). Most of doctors assisted potentially positive patients, which also imposed derogations on their safety. Most of the complaints were about the low adequacy of PPE provision and about the compromission of specialist medical care. The interest in safety among participants was revealed by the high compliance to vaccination, with almost complete coverage. The questionnaires showed that most doctors (72,7%) believe that specialist medical care has been impaired during the COVID-19 pandemic. Secondly, a high percentage of participants (79.8%) expressed the need for both civil and criminal limitation of liability in connection with work in the management of SARS-Cov-2 patients. In conclusion, this survey tried to contribute to the identification of the main problems presented by healthcare professionals. Their versatility was a crucial element for the management of the pandemic, but also highlighted the need for health institutions to prepare pandemic plans in the future, with adequate and constant updating. Concerns were raised regarding financial deficits and legal protection. Political decisions must be entrusted to enhance medical assistance and to avoid the increasing phenomenon of defensive medicine.

Voluntary interruption of pregnancy (VIP) in Italy: interpretation of the current situation according to the report 2019-2020 of the Italian Ministry of Health.

Abstract: Voluntary interruption of pregnancy (VIP) in Italy is regulated by Law no. 194/1978. Its monitoring is carried out by the VIP Epidemio-logical Surveillance System, which periodically analyses the results of questionnaires compiled by the territorial healthcare structures and sent by each Region. The latest report, covering the years 2019 and 2020, highlights the adequacy of preventive and proactive strategies, an improvement in the quality and effectiveness of the service offered. Furthermore, considering the COVID-19 pandemic, the reorganization of the IVG application guidelines showed a considerable adaptation to the emergency context through measures such as the increase in pharmacological procedures compared to surgical procedures. The interpretation of the data shows that in Italy there is one of the lowest VIP rates in Europe, reflecting the effectiveness of campaigns that promote responsible procreation. Further implementations should be extended to the foreign population, which still shows a medium-high VIP rate. The efficiency of the service offered resulted to be high. The latter was assessed considering the waiting period required for the performance of the VIP procedure. Furthermore, the high percentage of conscientious objectors does not harm the healthcare service. The estimates show an adequate territorial coverage by the authorized structures compared to the female population of fertile age. In conclusion, the central action of planning, organization, and monitoring finds a valid ally in the territorial management entrusted to the Regions. The analyzed report reflects even more margins of efficiency and adequacy when considered within the particular historical context of the pandemic by COVID-19.

Italian law no. 1/2021 on the subject of vaccination against Covid-19 in people with mental disabilities within the nursing homes.

ABSTRACT: The Coronavirus Disease-19 (Covid-19) pandemic, in the last year, has resulted in a significant number of infections and deaths among nursing homes' residents. This phenomenon has set up the necessity to subject these patients, often suffering from mental disabilities to a vaccination against Covid-19. However, vaccination has long been the subject of public atten-tion, being regulated differently in many European countries. In Italy, the Ministry of Health has given priority, vaccination-wise, to health facilities' patients. The government has regulated through-law no. 1 of January 5, 2021, art. 5, the manifestation of consent to be Covid-19 vac-cinated in incapacitated subjects admitted to assisted health facilities. This rule arose from the need to protect fragile individuals as well as providing real dispositions for the involved health professionals. Nursing homes' elderly guests could be divided into four catego-ries: a) subjects capable to express their will (affected by physical problems); b) subjects who, due to varying degrees of incapacitation, have their own legal guardian, curator or support administrator, ap-pointed in accordance with the law; c) incapacitated subjects without legal representatives d) subjects who, pursuant to law no. 219/2017, have appointed their own trustee. This paper provides for a clear exemplification of all the possible scenarios identified by the Italian law no.1/2021.

Early combination treatment with existing HIV antivirals: an effective treatment for COVID-19?

OBJECTIVE: Since no effective therapy exists, we aimed to test existing HIV antivirals for combination treatment of Coronavirus disease 19 (COVID-19). MATERIALS AND METHODS: The crystal structures of SARS-CoV-2 main protein (Mpro) (PDB ID: 6Y2F) and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) (PDB ID: 7BV2) both available from Protein Data Bank were used in the study. Automated Docking by using blind and standard method both on Mpro and RdRp bound to the modified template-primer RNA was performed with AutoDock 4.2.6 program suite. Lamarckian genetic algorithm (LGA) was used for structures docking. All inhibitors were docked with all bonds completely free to rotate. RESULTS: Our molecular docking findings suggest that lopinavir, ritonavir, darunavir, and atazanavir activated interactions with the key binding sites of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) protease with a better inhibition constant (Ki) for lopinavir, ritonavir, and darunavir. Furthermore, we evidenced the ability of remdesivir, tenofovir, emtricitabine, and lamivudine to be incorporated in SARS-CoV-2 RdRp in the same protein pocket where poses the corresponding natural nucleoside substrates with comparable Ki and activating similar interactions. In principle, the four antiviral nucleotides might be used effectively against SARS-CoV-2. CONCLUSIONS: The combination of a protease inhibitor and two nucleoside analogues, drugs widely used to treat HIV infection, could be evaluated in clinical trials for the treatment of COVID-19.

Antifungal activity of oils macerates of North Sardinia plants against Candida species isolated from clinical patients with candidiasis.

Antibiotic resistance is one of the bigger problem of public health: the rise of multi-drug resistant organisms causes a challenge in the treatment of infective diseases. Anti-Candida resistance to conventional antifungal agents has increased in the last period. Our research was intended to evaluate antimicrobial activity of oil macerate (OM) of Helichrysum microphyllum Cambess. subsp. tyrrhenicum Bacch., Brullo & Giusso and OM of Hypericum perforatum subsp. angustifolium against several clinical strains. The study included 30 patients with candidiasis who had not received any antifungal treatment before they were enrolled. A collection of 30 clinical isolates belonging to 5 different species of Candida spp. was selected for this study. The data obtained showed an interesting activity of both Oil Macerate especially against C. krusei and C. parapsilosis. On the contrary, H. microphyllum Oil Macerate has had a better activity than the H.perforatum especially in relation to C. glabrata and C. krusei.

Transglutaminase type 2 plays a key role in the pathogenesis of Mycobacterium tuberculosis infection.

BACKGROUND: Mycobacterium tuberculosis (MTB), the aetiological agent of tuberculosis (TB), is capable of interfering with the phagosome maturation pathway, by inhibiting phagosome-lysosome fusion and the autophagic process to ensure survival and replication in macrophages. Thus, it has been proposed that the modulation of autophagy may represent a therapeutic approach to reduce MTB viability by enhancing its clearance. OBJECTIVE: The aim of this study was to investigate whether transglutaminase type 2 (TG2) is involved in the pathogenesis of MTB. RESULTS: We have shown that either genetic or pharmacological inhibition of TG2 leads to a marked reduction in MTB replicative capacity. Infection of TG2 knockout mice demonstrated that TG2 is required for MTB intracellular survival in macrophages and host tissues. The same inhibitory effect can be reproduced in vitro using Z-DON, a specific inhibitor of the transamidating activity of TG2. Massive cell death observed in macrophages that properly express TG2 is hampered by the absence of the enzyme and can be largely reduced by the treatment of wild-type macrophages with the TG2 inhibitor. Our data suggest that reduced MTB replication in cells lacking TG2 is due to the impairment of LC3/autophagy homeostasis. Finally, we have shown that treatment of MTB-infected murine and human primary macrophages with cystamine, a TG2 inhibitor already tested in clinical studies, causes a reduction in intracellular colony-forming units in human macrophages similar to that achieved by the anti-TB drug capreomycin. CONCLUSION: These results suggest that inhibition of TG2 activity is a potential novel approach for the treatment of TB.

MAO inhibitory activity of bromo-2-phenylbenzofurans: synthesis, in vitro study, and docking calculations.

Monoamine oxidase (MAO) is an enzyme responsible for metabolism of monoamine neurotransmitters which play an important role in brain development and function. This enzyme exists in two isoforms, and it has been demonstrated that MAO-B activity, but not MAO-A activity, increases with aging. MAO inhibitors show clinical value because besides the monoamine level regulation they reduce the formation of by-products of the MAO catalytic cycle, which are toxic to the brain. A series of 2-phenylbenzofuran derivatives was designed, synthesized and evaluated against hMAO-A and hMAO-B enzymes. A bromine substituent was introduced in the 2-phenyl ring, whereas position 5 or 7 of the benzofuran moiety was substituted with a methyl group. Most of the tested compounds inhibited preferentially MAO-B in a reversible manner, with IC50 values in the low micro or nanomolar range. The 2-(2'-bromophenyl)-5-methylbenzofuran (5) was the most active compound identified (IC50 = 0.20 µM). In addition, none of the studied compounds showed cytotoxic activity against the human neuroblastoma cell line SH-SY5Y. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationship for this type of compounds.

Lack of Response to HBHA in HIV-Infected Patients with Latent Tuberculosis Infection.

Heparin-binding haemagglutinin (HBHA) has been proposed as an immunological biomarker for discriminating active tuberculosis (TB) from latent TB infection (LTBI) and to identify those at higher risk of progressing to active disease. Few data are available in immune-compromised patients, which are those with increased risk of TB reactivation. The aim of this stusy was to evaluate the immune response to HBHA in HIV-infected subjects with LTBI (HIV-LTBI) or active TB (HIV-TB) in comparison with the immune response to additional Mycobacterium tuberculosis (Mtb) or HIV and CMV antigens. The responses are evaluated in relation to TB status and in the LTBI subjects with the progression to active TB within 2 years. Forty-one HIV-infected antiretroviral-naïve subjects were prospectively enrolled: 18 were HIV-TB and 23 HIV-LTBI. Whole blood was in vitro stimulated overnight with several antigens and mitogen. Interferon-γ response in the harvested plasma was evaluated by ELISA. Despite that CD4 cell count was significantly different between HIV-LTBI and HIV-TB, no differences were observed in response to Mtb- or HIV-specific antigens. Differently, low responses to HBHA were observed in both HIV-LTBI and HIV-TB subjects. Importantly, none of the six HIV-LTBI responding to HBHA developed TB, while two of 17 non-HBHA responders developed active disease. HIV-TB-coinfected subjects, regardless of their TB status, showed low responses to HBHA despite maintaining detectable responses to other antigens; moreover, among the HIV-LTBI, the lack of HBHA responses indicated an increased risk to develop active TB. These results, although preliminary, suggest that a positive response to HBHA in HIV-LTBI correlates with Mtb containment.

Toxicity of Mediterranean Scyphomedusae: An Overview.

Following in-depth analysis and examination, jellyfish toxins have been found to consist of a mixture of proteins, carbohydrates, and other non-proteinaceous components. What remains to be clarified is the specific chemical nature of jellyfish toxins due to their heat lability. This paper reviews current knowledge of the toxic properties of the most common Mediterranean scyphozoans (A. aurita, C. hysoscella, C. tuberculata, P. noctiluca, R. pulmo) and the activity of their venom.

PREPARATION OF B-CYCLODEXTRIN-THIABENDAZOLE-PIPERONYL BUTOXIDE SUPRAMOLECULAR COMPLEX AND ITS ACTIVITY AGAINST BLUE AND GREEN MOULD DECAY ON INOCULATED SATSUMA FRUIT.

The supramolecular complex of ß-cyclodextrin-thiabendazole-piperony butoxide (ßCD-TBZ/PBO) was prepared and its structure was characterized by 1H NMR. Additionally, the antifungal activity of ßCD-TBZ/PBO was investigated in comparison with the commercially available thiabendazole (TBZ) fungicide by in vitro tests and on artificially inoculated 'Okitsu' satsuma fruit dipped in water at 20 degrees C or at 50 degrees C to control postharvest blue (Penicillium italicum) and green mould (P. digitatum). ß-CD-TBZ/PBO is stable for several months when stored as powder in a dark bottle. At pH 7.0 the water solubility of the ßCD-TBZ/PBO complex was consistently higher than free TBZ. Water dip at 20 degrees C did not affect decay incidence caused by blue mould but favoured the development of green mould during 4-8 days of storage at 20 degrees C with respect to untreated (control) fruit. Water at 50 degrees C effectively reduced the incidence of blue mould and totally suppressed green mould during the first 4 days but lost its efficacy afterwards. By contrast, both TBZ and ßCD-TBZ/PBO had a lasting effect and were equally effective in controlling green and blue mould decay when applied at 20 degrees C and 60 mg L(-1) active ingredient (a.i.). When applied at 50 degrees C and 20 mg L(-1) a.i. the activity of the complex against blue mould was inferior than the corresponding treatment with TBZ. In vitro assays revealed a significant effectiveness of ßCD-TBZ/PBO complex at low concentration compared to commercial formulation of TBZ.

Critical research concepts in tuberculosis vaccine development.

A new and improved vaccine against tuberculosis (TB) would provide a powerful tool to conquer one of the most insidious infectious diseases of mankind. Protection afforded by bacillus Calmette-Guérin (BCG) has been shown to be limited and inconsistent, especially in adults that are known to transmit TB disease. In the last two decades, several new vaccines have been developed and tested with the aim to elicit robust and long-lived T-cell responses against Mycobacterium tuberculosis antigens. Although much progress has been made in the TB vaccine field, there is an urgent need to address critical research questions about TB immunity with a special focus on designing vaccines aimed at preventing infection and transmission of TB. Here, we discuss the rationale behind the current immunization strategies being implemented for TB vaccines and provide some suggestions for hypothesis driven research to encourage the development of novel TB vaccines.

Curcumin and curcumin-like molecules: from spice to drugs.

Curcumin is the major yellow pigment extracted from turmeric, a commonly used spice in Asian cuisine and extensively employed in ayurvedic herbal remedies. A number of studies have shown that curcumin can be a prevention and a chemotherapeutic agent for colon, skin, oral and intestinal cancers. Curcumin is also well known for its antiinflammatory and antioxidant properties, showing high reactivity towards peroxyl radicals, and thus acting as a free radical scavenger. Recently, experimental studies have demonstrated that curcumin might be used in the prevention and the cure of Alzheimer's disease. Indeed, curcumin injected peripherally in vivo into aged Tg mice crossed the blood-brain barrier and bound to amyloid plaques, reducing amyloid levels and plaque formation decisively. The present review will resume the most recent developments in the medicinal chemistry of curcumin and curcumin-like molecules.

HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker?

BACKGROUND: Human papillomavirus 16 infection has been proven to be associated with oropharyngeal squamous cell carcinomas (SCCs) and is probably the main reason of the reported increase in the incidence. The role of high-risk (HR) HPV for carcinogenesis of other sites in the head and neck awaits confirmation. With the aim to evaluate the prevalence of HPV infection and the reliability of different diagnostic tools in SCCs of different sites, 109 consecutive untreated head and neck SCCs were enrolled, and fresh tumour samples collected. METHODS: Human papillomavirus DNA was detected by Digene Hybrid Capture 2 (HC2). Human papillomavirus E6 and E7 mRNA were detected by NucliSENS EasyQ HPVv1. P16 expression was evaluated by immunohistochemistry. RESULTS: In all, 12.84% of cases were infected by HR genotypes and 1.84% by low-risk genotypes. Human papillomavirus 16 accounted for 87% of HR infections. The overall agreement between DNA and RNA detection is 99.1%. Although p16 expression clearly correlates with HPV infection (P=0.0051), the inter-rater agreement is poor (k=0.27). The oropharynx showed the highest HR HPV infection rate (47.6%) and was also the only site in which p16 immunohistochemistry revealed to be a fair, but not excellent, diagnostic assay (κ=0.61). CONCLUSION: The prognostic role of HR HPV infection in oropharyngeal oncology, with its potential clinical applications, underscores the need for a consensus on the most appropriate detection methods. The present results suggest that viral mRNA detection could be the standard for fresh samples, whereas DNA detection could be routinely used in formalin-fixed, paraffin-embedded samples.