Sudden Cardiac Death, Post-Mortem Investigation: A Proposing Panel of First Line and Second Line Genetic Tests.

Investigating the causes of Sudden cardiac death (SCD) is always difficult; in fact, genetic cardiac conditions associated with SCD could be "silent" even during autopsy investigation. In these cases, it is important to exclude other aetiology and assist to ask for genetic investigations. Herein, the purpose of this review is to collect the most-implicated genes in SCD and generate a panel with indications for first line and second line investigations. A systematic review of genetic disorders that may cause SCD in the general population was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We subsequently listed the genes that may be tested in the case of sudden cardiac death when the autopsy results are negative or with no evidence of acquired cardiac conditions. To make genetic tests more specific and efficient, it is useful and demanded to corroborate autopsy findings with the molecular investigation as evident in the panel proposed. The genes for first line investigations are HCM, MYBPC3, MYH7, TNNT2, TNNI3, while in case of DCM, the most implicated genes are LMNA and TTN, and in second line for these CDM, ACTN2, TPM1, C1QPB could be investigated. In cases of ACM/ARVC, the molecular investigation includes DSP, DSG2, DSC2, RYR2, PKP2. The channelopathies are associated with the following genes: SCN5A, KCNQ1, KCNH2, KCNE1, RYR2. Our work underlines the importance of genetic tests in forensic medicine and clinical pathology; moreover, it could be helpful not only to assist the pathologists to reach a diagnosis, but also to prevent other cases of SCD in the family of the descendant and to standardise the type of analysis performed in similar cases worldwide.

Can Hemorrhagic Stroke Genetics Help Forensic Diagnosis in Pediatric Age (<5 Years Old)?

When stroke occurs in pediatric age, it might be mistakenly interpreted as non-accidental head injury (NAHI). In these situations, a multidisciplinary approach is fundamental, including a thorough personal and familial history, along with accurate physical examination and additional investigations. Especially when the clinical picture is uncertain, it is important to remember that certain genetic conditions can cause bleeding inside the brain, which may resemble NAHI. Pediatric strokes occurring around the time of birth can also be an initial sign of undiagnosed genetic disorders. Hence, it is crucial to conduct a thorough evaluation, including genetic testing, when there is a suspicion of NAHI but the symptoms are unclear. In these cases, a characteristic set of symptoms is often observed. This study aims to summarize some of the genetic causes of hemorrhagic stroke in the pediatric population, thus mimicking non-accidental head injury, considering elements that can be useful in characterizing pathologies. A systematic review of genetic disorders that may cause ICH in children was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We selected 10 articles regarding the main genetic diseases in stroke; we additionally selected 11 papers concerning patients with pediatric stroke and genetic diseases, or studies outlining the characteristics of stroke in these patients. The disorders we identified were Moyamoya disease (MMD), COL4A1, COL4A2 pathogenic variant, Ehlers-Danlos syndrome (E-D), neurofibromatosis type 1 (Nf1), sickle cell disease (SCD), cerebral cavernous malformations (CCM), hereditary hemorrhagic telangiectasia (HHT) and Marfan syndrome. In conclusion, this paper provides a comprehensive overview of the genetic disorders that could be tested in children when there is a suspicion of NAHI but an unclear picture.

Butane-related deaths in post-mortem investigations: A systematic review.

Volatile substance abuse is widespread among adolescents due to its easy availability and methods of consumption. Inhalant abuse represents a current problematic issue, causing significant morbidity and mortality due to direct toxicity on several target organs and displacement of gas which results in a lack of oxygen. This review aims to evaluate post-mortem and toxicological investigations in cases of suspected butane intoxication. We performed comprehensive research using the Preferred Reporting Items for Systematic Review (PRISMA) standards. Forty scientific papers fulfilled the inclusion criteria. A total of 58 cases of butane-related deaths were found. Among these, we found 11 cases of suicide (18%), 1 case of homicide (2%), 44 cases of accidental poisoning (76%), and 2 cases of work-related deaths (4%). Autopsy and post-mortem examinations were performed in 54 cases, whereas toxicological analyses were presented in 56 cases. In autopsy, pulmonary edema (51%) and poli-visceral congestion (59%) were the most common findings. When death by butane inhalation is hypothesized, autopsy and histological findings may be nonspecific, therefore toxicological investigations assume a crucial role along with attention to the methods used to collect biological samples.

miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine.

Breast Cancer (BC) is one of the most common cancer types worldwide, and it is characterized by a complex etiopathogenesis, resulting in an equally complex classification of subtypes. MicroRNA (miRNA or miR) are small non-coding RNA molecules that have an essential role in gene expression and are significantly linked to tumor development and angiogenesis in different types of cancer. Recently, complex interactions among coding and non-coding RNA have been elucidated, further shedding light on the complexity of the roles these molecules fulfill in cancer formation. In this context, knowledge about the role of miR in BC has significantly improved, highlighting the deregulation of these molecules as additional factors influencing BC occurrence, development and classification. A considerable number of papers has been published over the past few years regarding the role of miR-125 in human pathology in general and in several types of cancer formation in particular. Interestingly, miR-125 family members have been recently linked to BC formation as well, and complex interactions (competing endogenous RNA networks, or ceRNET) between this molecule and target mRNA have been described. In this review, we summarize the state-of-the-art about research on this topic.

Sudden death due to butane abuse - An overview.

Volatile Solvents Abuse (VSA) poses major health risks, especially for young people and those living in precarious socio-economic conditions. Such substances can in fact bring about psychoactive effects such as euphoria, and even lead to sudden death from cardiac arrhythmias, respiratory depression, myocardial infarction, laryngospasm, encephalopathy, and rhabdomyolysis. The present case report is centered around a 23-year-old man who died in prison due to inhalation of a cooker gas mixture (n-butane, propane, and isobutane) inside a plastic bag. External examination and autopsy showed non-specific signs of asphyxia associated with edema and brain swelling. Histological signs of early myocardial damage and hypoxic-ischemic injury (HII) were highlighted in the brain and cerebellum, as well as activated macrophages and anthracotic-like material in the lungs. Toxicological investigations revealed the presence of propane, isobutane and n-butane in liquids and biological samples. Besides the cardiotoxic effect, there was an asphyctic component due to the plastic bag that may have facilitated death. The assessment of cerebral HII and cardiopulmonary damage in acute cases is very important to prove death by butane inhalation. In the forensic field, it may be useful to shed more light on intoxications, deaths, and butane encephalopathies, as the latter can be mistaken for a hypoxic-ischemic encephalopathy.

Point-of-Care Ultrasound (POCUS) in Adult Cardiac Arrest: Clinical Review.

Point-of-Care Ultrasound (POCUS) is a rapid and valuable diagnostic tool available in emergency and intensive care units. In the context of cardiac arrest, POCUS application can help assess cardiac activity, identify causes of arrest that could be reversible (such as pericardial effusion or pneumothorax), guide interventions like central line placement or pericardiocentesis, and provide real-time feedback on the effectiveness of resuscitation efforts, among other critical applications. Its use, in addition to cardiovascular life support maneuvers, is advocated by all resuscitation guidelines. The purpose of this narrative review is to summarize the key applications of POCUS in cardiac arrest, highlighting, among others, its prognostic, diagnostic, and forensic potential. We conducted an extensive literature review utilizing PubMed by employing key search terms regarding ultrasound and its use in cardiac arrest. Apart from its numerous advantages, its limitations and challenges such as the potential for interruption of chest compressions during image acquisition and operator proficiency should be considered as well and are discussed herein.

Stem Cells and Infertility: A Review of Clinical Applications and Legal Frameworks.

Infertility is a condition defined by the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person's capacity to reproduce either as an individual or with their partner. The authors have set out to succinctly investigate, explore, and assess infertility treatments, harnessing the potential of stem cells to effectively and safely treat infertility; in addition, this paper will present the legal and regulatory complexities at the heart of stem cell research, with an overview of the legislative state of affairs in six major European countries. For couples who cannot benefit from assisted reproductive technologies (ART) to treat their infertility, stem-cells-based approaches have been shown to be a highly promising approach. Nonetheless, lingering ethical and immunological uncertainties require more conclusive findings and data before such treatment avenues can become mainstream and be applied on a large scale. The isolation of human embryonic stem cells (ESCs) is ethically controversial, since their collection involves the destruction of human embryonic tissue. Overall, stem cell research has resulted in important new breakthroughs in the treatment of infertility. The effort to untangle the complex web of ethical and legal issues associated with such therapeutic approaches will have to rely on evidence-based, broadly shared standards, guidelines, and best practices to make sure that the procreative rights of patients can be effectively reconciled with the core values at the heart of medical ethics.

Traumatic Aneurysm Involving the Posterior Communicating Artery.

Traumatic intracranial aneurysms (TICAs) are rare, accounting for less than 1% of all intracranial aneurysms. However, they are associated with a mortality rate of over 50%. The case presented herein focuses on a posterior communicating artery TICA caused by violent aggression. A 41-year-old man with massive subarachnoid hemorrhage (SAH), on admission to hospital, had a CT angiography that showed a ruptured left posterior communicating artery aneurysm with continuous blood loss and underwent neurosurgical cooling. The CT scan also showed fractures of the mandible, mastoid and left styloid process, as well as brain contusions caused by blows and kicks. Despite medical treatment and surgery, after four days, he died. The assault dynamics were recorded by a camera in the bar. The damage was caused by kicks to the neck and head. The forensic neuropathological examination showed the primary injury (SAH, subdural hemorrhage, cerebral contusions, head-neck fractures), as well as secondary damage following the attack (cerebral infarcts, edema, supratentorial hernia, midbrain hemorrhage). The coil was intact and well positioned. In this case, circumstantial information, medical records, and the type of injury could shed light on the mechanism of the production of a TICA. In addition, the CT angiography and histological investigations helped to distinguish a recent and traumatic aneurysm from a pre-existing one. Following precise steps, the study of aneurysms can be helpful in clarifying their traumatic origin even when the victim was taking drugs. The aim of this study is also to share the diagnostic process that we used in the forensic field for the assessment of suspected traumatic aneurysms.

Death Due to Anaphylactic Reaction: The Role of the Forensic Pathologist in an Accurate Postmortem Diagnosis.

Background and Objectives: The diagnosis of anaphylaxis comprehensively depends on both situational information and laboratory investigations. For this purpose, serum tryptase concentration is examined as an indicator of systemic mast cell mediator release, linked to an underlying anaphylactic process. Increased levels of tryptase may occur in some events different from anaphylaxis, but usually information from crime scene investigations is lacking and autoptic findings are not specific. For legal reasons, it is required to achieve a definite diagnosis of mast cell degranulation that can lead to a certain diagnosis of death from anaphylaxis. Immunohistochemistry seems to be a relatively simple, reliable, and easily repeatable method that can assist the forensic pathologist in the differential diagnosis of death from anaphylaxis. Materials and Methods: This work provides an overview of the current literature on immunohistochemical methods useful in the determination process of anaphylactic-related deaths. A systematic search, according to the PRISMA statement, was performed in databases to identify studies investigating immunohistochemical targets related to anaphylaxis death. Results: This work underscores the importance of anaphylaxis mediators such as tryptase, CD117, and chymase in the immunohistochemical analysis of anaphylactic deaths. Conclusions: According to the reviewed literature, the diagnosis of death due to anaphylaxis should depend not just on the suspicion of an anaphylactic reaction but also on confirming mast cell degranulation through the identification of IHC positivity for inflammatory mediators, particularly in the respiratory tract.

End-of-life in the operational functioning of public healthcare: ethical and legal issues.

BACKGROUND AND AIM: The article aims to outline the current scenario relative to the medical role in end-of-life issues. In order to do this, historical-legal references have been drawn upon relating to technical, legal and scientific thought and doctrine, as it has come down to us in the medical field through the evolution of ethical and philosophical frameworks. METHODS: The authors have conducted a thorough analysis of end-of-life legislative initiatives, in Italy and across the EU, and court rulings to outline possible ways to harmonize and reconcile the current medical ethics frameworks with the needs and rights of all, especially the most vulnerable among us. To that end, the necessary operational choices and adjustments have not yet been made by our legal system, from a technical, as well as moral, standpoint. RESULTS: An operational proposal has therefore been laid out to protect both healthcare providers and patients, in a relationship that goes beyond treatment in the strict sense, which prioritizes mutual needs as an integral part of a common, essential path. CONCLUSIONS: In order for doctors to consider themselves complete, they should in fact deal not only with life, but also with death.

Blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells as major adverse effects in CAR-T-related deaths: a literature review.

Background: CAR-T-related deaths observed worldwide are rare. The underlying pathogenetic mechanisms are the subject of study, as are the findings that enable diagnosis. A systematic literature search of the PubMed database and a critical review of the collected studies were conducted from the inception of this database until January 2023. The aim of the study is to determine when death is related to CAR-T cell therapy and to develop a shareable diagnostic algorithm. Methods: The database was searched by combining and meshing the terms ("CAR-t" OR "CART") AND ("Pathology" OR "Histology" OR "Histological" OR "Autopsy") AND ("Heart" OR "Cardiac" OR "Nervous System" OR "Kidney" OR "Liver") with 34 results and also the terms: [(Lethal effect) OR (Death)] AND (CAR-T therapy) with 52 results in titles, abstracts, and keywords [all fields]. One hundred scientific articles were examined, 14 of which were additional records identified through other sources. Fifteen records were included in the review. Results: Neuronal death, neuronal edema, perivascular edema, perivascular and intraparenchymal hemorrhagic extravasation, as well as perivascular plasmatodendrosis, have been observed in cases with fatal cerebral edema. A cross-reactivity of CAR-T cells in cases of fatal encephalopathy can be hypothesized when, in addition to the increased vascular permeability, there is also a perivascular lymphocyte infiltrate, which appears to be a common factor among most authors. Conclusion: Most CAR-T-related deaths are associated with blood-brain barrier breakdown, central nervous system cell damage, and infiltrated T cells. Further autopsies and microscopic investigations would shed more light on the lethal toxicity related to CAR-T cells. A differential diagnosis of CAR-T-related death is crucial to identifying adverse events. In this article, we propose an algorithm that could facilitate the comparison of findings through a systematic approach. Despite toxicity cases, CAR-T therapy continues to stand out as the most innovative treatment within the field of oncology, and emerging strategies hold the promise of delivering safer therapies in future.

Female obesity and infertility: outcomes and regulatory guidance.

Obesity has been associated with reduced fertility, although the dynamics and mechanisms which link excess weight to reduced fertility are not yet fully clarified. Obese women, especially those with central obesity, are less likely to conceive per cycle. Obese women suffer from perturbations of the hypothalamus-pituitary-ovary axis, disturbances of the menstrual cycle and are up to three times more likely to suffer from oligo/anovulation. A delicate hormonal balance regulates follicular development and the maturation of oocytes and it has been observed that obesity can alter the hormonal environment: adipocytes, in fact, are responsible for the production of a hormone called leptin (present in high quantities in obese women) which has been associated with reduced fecundity. In addition to compromising ovulation, obesity negatively affects the development and implantation of the endometrium. The expression of polycystic ovary syndrome (PCOS) is regulated, in part, by weight, so obese women with PCOS often have a more severe phenotype and higher subfertility rates. Furthermore, obesity impairs women's response to medically assisted procreation (MAP) treatments. The authors have set out to delineate a broad-ranging overview of obesity's impact on female fertility, by drawing upon sources spanning the 1994-2022 period. Assisted reproductive technology (ART) procedures are also discussed as they relate to obese patients. In addition the dynamics by which maternal obesity reportedly affects fetal, neonatal and child development have also been briefly enunciated.

Oncofertility and Reproductive Counseling in Patients with Breast Cancer: A Retrospective Study.

INTRODUCTION: Improving the prognosis of breast cancer patients is of utmost importance in terms of increasing survival rates. Modern medicine has therefore prioritized better quality of life for patients, even after the disease, through a better management of the potential long-term side effects induced by anticancer treatments. Fertility preservation and family planning are therefore crucial issues to be addressed in all cancer patients of reproductive age. Along those lines, a new branch of medicine with distinct multidisciplinary characteristics has developed over the years: oncofertility. Although both national and international guidelines value reproductive counseling as an essential aspect of the diagnostic-therapeutic pathway, part and parcel of the informed consent process, it is not included within the protocols adopted by the operating units for the care and management of neoplastic diseases. OBJECTIVE: This study aimed to evaluate the activity of the Breast Unit of the Policlinico Umberto I Hospital, Rome, Italy, and the degree of compliance with guidelines. By knowing the strengths and weaknesses of such approaches, the standards of care offered to breast cancer patients can be improved. MATERIALS AND METHODS: A retrospective study based on a review of medical records was conducted between 2014 and 2021. Patients under 40 years of age diagnosed with non-metastatic malignancies were included who received chemotherapy treatment, namely neoadjuvant, adjuvant or adjuvant hormone therapy. RESULTS: The data were extracted from the medical records of 51 patients who met the inclusion criteria, 41% of whom received reproductive counseling, and of these, 43% decided to undertake a path of fertility preservation. Factors such as the absence of children and young age reportedly favored both the interest in counseling proposals by the medical staff and the decision to undertake a path of fertility preservation. CONCLUSIONS: The study shows that there has been growing interest in the topic of oncofertility, especially in light of law 219/2017. Therefore, since 2018, multiple proposals for reproductive counseling have been set forth, but there was not an equally growing demand for fertility preservation practices, which can be explained by the invasive nature of such practices, the patients' concern about their own state of health, and poor or inadequate information. Such impediments highlight the importance of standardized counseling and the need for a multidisciplinary medical team to support the patient in the decision-making process. The study also revealed a drop in the number of patients receiving counseling due to the COVID-19 pandemic, contrary to the positive trend that was recorded prior to the pandemic.

Uterus Transplantation and the redefinition of core bioethics precepts.

To the Editor, The first uterus transplantation (UTx) to be successfully carried out in Italy occurred at the Transplant Center of the Policlinico di Catania, on 21st August 2020. The patient, a 30-year-old woman with absolute uterine factor infertility (AUFI) due to Rokitansky syndrome, is now set to undergo a medically assisted reproductive procedure aimed at implanting her own oocytes, which had been stored via cryopreservation, following in vitro fertilization. Only UTx from deceased donors has been approved in Italy, although most UTx attempts and live births worldwide have been achieved from live donors, mostly closely related to the recipient (1). If UTx becomes a mainstream surgical practice for women who could not otherwise experience pregnancy, such an option will mark a point where the set of moral and ethical precepts which we espouse could soon become obsolete. Still, UTx is undoubtedly a milestone bound to give rise to even more complex bioethical issues. In fact, it encompasses the ethical complexities inherent in MAP as well as those arising from its status as a non-life saving transplantation, but rather a "life-giving" one (2). Moreover, since the development of UTx was primarily motivated by the potential to allay dissatisfaction and unhappiness stemming from the discrepancy between procreative ability and reproductive aspirations, it can be viewed as "life-enhancing" as well. An important framework providing perspective is the revised version of the Montreal Criteria for the Ethical Feasibility of Uterine Transplantation (3). Nevertheless, such a set of criteria is emblematic of how fast scientific innovation can outpace fundamental bioethics standards, and may itself be already outdated, in that it requires the recipient to be a "genetic female", whereas research on the possibility to perform UTx on transgender women is already in progress. That future scenario goes to the heart of UTx and its fundamental purpose: not life-saving but, as far as transgender women are concerned, life-enhancing. Research has clarified the primary motivation for which transgender women would opt for UTx. Findings from a recent survey unequivocally reflect the "life-enhancing" purpose: an overwhelming 90% majority of respondents expressed the belief that having a transplanted, functioning uterus and vagina would benefit their sex life and perceived sense of femininity, improving quality of life overall (4). Such findings are rather similar to those regarding the perceptions of biological women with AUFI: 95% of respondents in a UK study exploring the attitudes of women toward uterus transplant stated that, despite the additional risks posed, they would choose uterus transplant over surrogacy and adoption (5). Hence, it is not unreasonable to assume that in transgender women, UTx may go a long way towards the achievement of reproductive aspirations, benefit quality of life overall, and be effective in allaying dysphoric symptoms. After all, gender dysphoria entails discomfort and even distress with one's biological sex. It has the potential to severely affect quality of life overall. Treating gender dysphoria in transgender women relies on a multidisciplinary approach involving medical, psychological, and surgical specialists. Psychological input, hormonal therapy, or gender affirmation surgery are all potential options according to a highly individualized assessment for each patient. Nonetheless, UTx intended as a means for transgender women to foster their sense of femininity does present considerable contraindications. UTx is in fact ephemeral in nature: following childbirth, the graft has to be removed in order to eliminate the need for immunosuppressive medications. If on the other hand UTx were performed for reasons other than reproduction, i.e. to improve dysphoric symptoms, the duration of the graft would have to be significantly longer, hence a worse risk-benefit ratio. From a merely reproductive perspective, however, it is worth bearing in mind that transgender women may deem pregnancy as the final and conclusive stage in the process of reconfiguring their life aspirations according to the gender with which they psychologically identify. Certainly, the safety of the procedure into a biologically male body will likely be more complicated and risky than performing UTx in a female body. One of the pioneer scientists who first mastered UTx has acknowledged that transgendered pregnancy may be feasible, but in addition to the anatomical barriers, he has expressed ethical concerns (6). The fundamental ethical question that needs an answer is: if UTx becomes mainstream, safe and effective for biological women with AUFI, would there be any morally tenable grounds as to why transgender women should be denied such an opportunity for gestation? In countries where transgendered women who have transitioned are granted the same legal rights as their female counterparts, this will become a relevant question if UTx is offered as clinical treatment in women. Arguably, UTx and ever more innovative MAP procedures pose ethical quandaries bound to grow as such practices become available on a large scale (7). Already, in vitro fertilization entails the separation between sexuality and procreation, which has made it possible for same-sex couples and singles to have children through heterologous fertilization (8). Such practices are governed with varying degrees of restrictions by each country, which reflects the diversity of approaches in terms of ethical acceptability (9). Advances in embryo manipulation through genome editing could soon pave the way for the eradication of diseases before birth, or even the enhancement of humans yet to be born (10), a whole new frontier in beginning of life bioethics for which we are unprepared. Ultimately, we feel it may all go down to whether procreative liberty ought to be deemed as entailing an absolute right to gestate, and whether transgender women can be denied such a right without infringing upon ethical precepts of equality and non-discrimination. Current bioethics approaches need to undergo a radical update if we are to successfully meet the challenges posed by fast-growing scientific advances, set to shape and mold our lives ever more dramatically.