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.

Sex- and Gender-Specific Drug Abuse Dynamics: The Need for Tailored Therapeutic Approaches.

Sex and gender have been gaining ever greater attention due to their associated risks, dynamics, patterns and protective factors underlying substance abuse and addiction. Such differentiations and the clarification of complexities thereof take on even greater relevance in light of drug abuse scope worldwide. According to the 2022 World Drug Report released by the United Nations Office on Drugs and Crime (UNODC), in 2020 an estimated 284 million people worldwide aged 15-64 had used a drug within the last 12 months. The authors have set out to shed a light on determinants and contributing factors of drug abuse based on sex and gender and outline policy and medicolegal remarks aimed at delineating sex- and gender-based approaches towards drug abuse therapeutic interventions that are both therapeutically and ethically/legally viable and grounded in an evidence-based set of standards. Neurobiological data suggest that estrogen may facilitate drug taking by interacting with reward- and stress-related systems. In animal research, the administration of estrogen increases drug taking and facilitates the acquisition, escalation, and reinstatement of cocaine-seeking behavior. From a medicolegal perspective, it is of utmost importance to take into account the whole picture constituting each patient profile, which certainly includes gender factors and contributors, when outlining a therapeutic approach. Failure to do so could lead to negligence-based malpractice allegations, in light of the scientific findings representing best practices with which clinicians need to comply when caring for SUD patients.

The Future Is Coming: Artificial Intelligence in the Treatment of Infertility Could Improve Assisted Reproduction Outcomes-The Value of Regulatory Frameworks.

Infertility is a global health issue affecting women and men of reproductive age with increasing incidence worldwide, in part due to greater awareness and better diagnosis. Assisted reproduction technologies (ART) are considered the ultimate step in the treatment of infertility. Recently, artificial intelligence (AI) has been progressively used in the many fields of medicine, integrating knowledge and computer science through machine learning algorithms. AI has the potential to improve infertility diagnosis and ART outcomes estimated as pregnancy and/or live birth rate, especially with recurrent ART failure. A broad-ranging review has been conducted, focusing on clinical AI applications up until September 2022, which could be estimated in terms of possible applications, such as ultrasound monitoring of folliculogenesis, endometrial receptivity, embryo selection based on quality and viability, and prediction of post implantation embryo development, in order to eliminate potential contributing risk factors. Oocyte morphology assessment is highly relevant in terms of successful fertilization rate, as well as during oocyte freezing for fertility preservation, and substantially valuable in oocyte donation cycles. AI has great implications in the assessment of male infertility, with computerised semen analysis systems already in use and a broad spectrum of possible AI-based applications in environmental and lifestyle evaluation to predict semen quality. In addition, considerable progress has been made in terms of harnessing AI in cases of idiopathic infertility, to improve the stratification of infertile/fertile couples based on their biological and clinical signatures. With AI as a very powerful tool of the future, our review is meant to summarise current AI applications and investigations in contemporary reproduction medicine, mainly focusing on the nonsurgical aspects of it; in addition, the authors have briefly explored the frames of reference and guiding principles for the definition and implementation of legal, regulatory, and ethical standards for AI in healthcare.

Telemedicine, Telepsychiatry and COVID-19 Pandemic: Future Prospects for Global Health.

There is no denying that demand for telemedicine and telepsychiatry services has been on the rise, as the COVID-19 pandemic engulfed the world and upset the daily lives and certainties of us all. Such growth, however, calls for a comprehensive analysis and assessment of the strengths and weaknesses inherent in such innovative approaches, which are bound to change and evolve as the fourth industrial revolution unfolds before our eyes. The authors have set out to analyze the complexities and distinctive features of telemedicine and telepsychiatry by focusing on the strengths and weaknesses of such approaches and analyzing research findings, recommendations, and guidelines by scientific societies and institutions, for the ultimate purpose of striking a tenable balance between technological innovations and the ethics and moral imperative of guaranteeing equal access to care for everyone, irrespective of social and financial status. The European regulatory and legislative scenario has been briefly outlined, and the standards for the medicolegal sustainability of such practices have been explored. Ultimately, in order to improve accessibility without compromising the quality of care, new broadly shared ethical standards, best practices, and guidelines need to be prioritized. National legislative initiatives and the international sharing of information need to be encouraged, for the ultimate purpose of optimizing and harmonizing telemedicine-based care for the sake of all patients. As technology moves forward and evolves, so must the normative standards and guidelines on which professionals must be able to rely when delivering telemedicine-based care in an ethically and legally viable fashion. From that perspective, addressing the digital divide means enabling more people to receive care and should therefore be seen as part and parcel of the effort to uphold the universal human right to health.

COVID-19 and female fertility: the flaws of Italian Law 40/2004 on assisted procreation in pandemic times.

BACKGROUND AND AIM: SARS-CoV-2 has infected over 614 million people worldwide, killing more than 6.5 million. COVID-19 impact on fertility may have far-reaching ramifications, considering that only in Italy, over 20 million people have been infected, many more considering unconfirmed cases. METHODS: The authors aimed to outline the repercussions of COVID-19 on female reproductive capabilities, through an analysis of underlying mechanisms and dynamics liable to cause long-term COVID-19 complications and sequelae, including direct virus-induced tissue damage. RESULTS: The entry receptor for SARS-CoV-2, Angiotensin-converting enzyme 2 (ACE2) can be found in several tissues and organs within the human body, including ovaries, oocytes and placenta. In order to assess the fertility-damaging potential of the disease, it is necessary to clarify highly complex mechanisms such as the ovarian renin-angiotensin system (OVRAS) affecting ovarian physiology and dysfunction. COVID-19 and its potential to undermine the fertility prospects of millions cannot be underestimated. It is therefore essential for lawmakers to solve inconsistencies such as those in Italy's Law 40/2004, which has been all but dismantled by Constitutional Court and European Court of Human Rights rulings, and cannot therefore offer a sufficient degree of certainty and reliability. CONCLUSIONS: When crafting novel, updated standards, norms and regulations to govern access to medically-assisted procreation, national leaders need to take into account the grave threat to fertility in a country such as Italy, which already has one of the world's lowest birth rates, posed by COVID-19 in light of currently available research findings outlining its impact on reproductive capacity.

Conscientious objection to abortion: how to strike a legal and ethical balance between conflicting rights?

The Italian Supreme Court ruling no. 18901 of May 13, 2021 has determined that doctors who are opposed to abortion can refuse to perform it on grounds of conscience, but such a refusal does not exempt them from providing assistance to the woman before and after the procedure itself. The legalization of abortion should be considered within a broader strategy to put an end to underground and unsafe abortions, to raise awareness and enhance reproductive education and accessibility to contraceptive methods. The authors have set out to briefly analyze the legal and ethical complexities inherent in the effort to reconcile women's reproductive autonomy and freedom of choice with conscience-based refusal on the part of numerous healthcare professionals. Such an apparent conflict highlights the need for an ethically tenable solution that takes into account the dignity of unborn children, based on the conviction of many healthcare professionals primarily based on moral and religious tenets, that life begins at conception as well as the reproductive freedom and autonomy of women.

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.

Traumatology: Adoption of the Sm@rtEven Application for the Remote Evaluation of Patients and Possible Medico-Legal Implications.

Telemedicine is the combination of technologies and activities that offer new remote ways of medical care. The Sm@rtEven application project is a remote assistance service that follows patients affected by lower limb fractures surgically treated at Galeazzi Orthopedic Institute (Milan, Italy). The Sm@rtEven application aims to evaluate the clinical conditions of patients treated for lower limb fracture after discharge from hospital using remote follow-up (FU). The project is not a substitute for traditional clinical consultations but an additional tool for a more complete and prolonged view over time. The Sm@rtEven application is installed on patients' smartphones and is used daily to communicate with healthcare personnel. In the first protocol, patients had to complete different tasks for 30 days, such as monitoring the load progression on the affected limb, the number of steps during the day, and body temperature and completing a questionnaire. A simplified protocol was proposed due to the pandemic and logistical issues. The revised protocol enrolled patients after more than 30 days of their operation, prioritized the rehabilitation phase, and required patients to use the app for fewer days. After an initial phase of correct use, a reduction in patient compliance was gradually reported in the first protocol. However, patient compliance in the second protocol remained high (96.25%) in the recording of all the required parameters. The Sm@rtEven application has proven to be a valuable tool for following patients remotely, especially during the pandemic. Telemedicine has the same value as traditional clinical evaluations, and it enables patients to be followed over long distances and over time, minimizing any discomfort.

The effects of the COVID-19 pandemic on the use of the performance-enhancing drugs.

The coronavirus disease (COVID-19) pandemic has been impacting the whole society in every aspect of the daily life, comprising the sport field. Several restrictive strategies have been implemented by governments in an effort to stem the spread of the disease and salvage public health. Such efforts have severely constrained access to non-essential services, leading to the closure of non-essential points of gathering and business and the enforcement of rigorous social distancing and prolonged lockdowns, in addition to masking and stay-at-home mandates. However necessary, there is no denying that such extremely rigorous, and to most people unprecedented, measures have adversely affected the global economy and the daily lives of everyone of us, including professional and amateur athletes (1). The most important sport events were postponed or cancelled, including the 2020 Tokyo Olympic Games. But how was the phenomenon of performance-enhancing drug (PED) use impacted and how was the most concerning issue affecting the integrity of sport affected by the pandemic control restrictions? The World Anti-doping Agency (WADA) was established in 1999, whereas its code was implemented in 2004 in order to articulate and enforce doping control initiatives and provide educational strategies aimed at preventing PED use (2). Nonetheless, it is worth noting that the prevalence of PED use among athletes is mostly unchanged since the foundation of WADA. Unfortunately, the use of the performance-enhancing drugs is not limited to athletic performances, but it concerns other settings as well. Nowadays, several strategies for doping control are adopted such as education, deterrence, detection, enforcement and rule of law (3), but the most important anti-dissemination strategy is constituted by information campaigns, especially addressed to youngsters, meant to raise awareness as to the serious health risks involved in PED use. Currently, the primary drivers of anabolic androgenic steroids (ASA) use are 1) the determination to improve performances and prevail no matter what the cost may be; 2) the economic benefits, popularity and fame; 3) greater stamina and resistance. This public health issue has raised particular concerns due to the recent ASA market developments, which is somewhat similar to the illicit market of narcotic drugs. Moreover, it has to be considered that the higher stress and psychosocial condition related to pandemic social restrictions has fueled and exacerbated substance use disorders (4). The prevalence of doping in sport causes unfairness and damages the very fabric of our society, especially insofar as it involves children and young adults who look up to athletes as role models. In this concern, the impact of the COVD-19 pandemic may have led to substantial modifications in substance use patterns and an increased risk of substitution, adulteration, contamination, and dilution with a potentially harmful substance (5, 6). During the COVID-19 lockdown, WADA and stakeholders suspended or scaled down doping control programs, testing and other activities. As a consequence, athletes have seen the unexpected opportunity to misuse AAS without the possible risk of testing positive (7). This has been controversial, considering the measures taken by governments to flatten the pandemic curve in order to safeguard public health. Indeed, all the technologies implemented for teleworking, such as teaching students on-line, telehealth applications, prescriptions and referrals, and treating patients in hospitals/care homes via video links can also be applied to enhance and uphold sport integrity. Conversely, anti-doping testing for professional competitive athletes has increased, due to the lockdown raising suspicion about doping opportunities. The U.S. Anti-doping Agency has put in place novel measures to combat the lack of anti-doping testing during the pandemic: these include a "in-home self-test" that requires athletes to provide urine and small blood samples at home to be tested in the anti-doping laboratory, under supervision provided by video-conference (8). As such, reports from forensic science and toxicology laboratories are crucial for the early detection and response to such events. Furthermore, toxicology laboratories should assure their continue effort in providing new methods and technologies designed to tackle the consumption of illicit substances and to monitor the constantly changing illegal drug markets (9). The most recent WADA code revision has certainly brought about important progress in the ongoing fight against PED abuse. Indeed, it has introduced the possibility to store the samples for 10 years after the first analysis, maintaining the same legal value if re-tested and use for prosecution purposes (10). In that regard, the prospect of re-testing the same sample with newly developed analytical methods based on innovative technologies may represent a strong deterrent for doping users, since anti-doping research rapidly evolves (6), largely by implementing the same approaches used to fight new psychoactive substances (NPS) use (11,12). It is worth noting that the NPS phenomenon bears several similarities with doping, especially due to the constant emergence of new substances and methods aimed at circumventing current legal restrictions. In Italy, the National Antidoping Organization (NADO-Italia) is in charge of guaranteeing compliance with WADA rules and the transposition of the List of Prohibited Substances and Methods. However, the gap between elite athletes and amateur athletes is still broad and unaddressed, since non-professional sport competitions are not adequately overseen, and neither are the competing athletes . This difference may give rise to an important public health issue, on account of the adverse effects of uncontrolled doping agents consumption. In this concern, the Italian anti-doping law created the "Section of the Technical Health Committee for Supervision and Control on Doping and for Health Protection in Sport Activities", that carries out, among its other tasks, the following activities on amateur sport: 1) updating each year the list of banned substances and practices, adapting it to the WADA list; 2) determining cases, criteria and methodologies for anti-doping controls; 3) promoting research projects and information/training campaigns meant to protect health in sports and tackle doping (13). In conclusion, regarding the highly complex dynamics triggered by the pandemic, new and unexpected challenges have come to the fore in the ongoing fight against substance abuse in its every aspect, such as NPS (14), ASA consumption by amateur athletes, or other substance abuse settings, e.g. driving under the influence of psychotropic substances (15). The current Italian antidoping approach for amateur athletes seems to be a promising strategy to bridge the gap between professional sports and amateur sports. Moreover, youngsters should be thoroughly educated as to the threats posed by such substances, so that they can realize how profoundly and severely drug abuse can affect not only their sport career, but their health and well-being overall.

The March 2021 Italian constitutional court ruling on surrogacy: a prelude to common European legislation for the sake of reproductive health?

PURPOSE: Surrogacy is an arrangement by which a surrogate mother bears a child for another couple or person, and is often thought of as a form of 'treatment' for couples (or even individuals) with fertility or sterility issues. Still, surrogacy entails ethical issues related to gender, fundamental human rights, exploitation and inequality. MATERIALS AND METHODS: Starting from the Italian state of affairs, the authors have set out to briefly expound upon such complexities, taking into account relevant jurisprudence on the subject, with a particular focus on inter-country surrogacy and second-parent adoption, which can themselves engender significant legal dilemmas. When residents of countries where surrogacy is banned travel abroad and hire a surrogate, that may lead to considerable legal hurdles as well. RESULTS: In Italy and elsewhere, the courts have all too often had to fill the vacuum left by the lack of targeted legislation. The Italian Constitutional Court has recently urged lawmakers to enact new legislation to uphold the minor's best interests. In fact, while some countries recognise the surrogate as the legal parent, others ascribe parenthood to the commissioning parents. That discrepancy can lead to a 'clash of laws', resulting in children ending up stateless and unable to maintain an already established family relationship. CONCLUSIONS: Just like fundamental protection of human rights and public health, the regulation of revolutionary technologies that change the very notion of reproduction, parenthood, and human identity needs to be governed by uniform standards, shared at least by nations which espouse common core values.

Medically assisted procreation in times of COVID-19: what impact on health care system organization and the reproductive rights of couples?

BACKGROUND AND AIM: The emergency caused by the spread of COVID-19 has overwhelmed health care facilities and required the reorganization of health systems in many nations worldwide. A year after its appearance, measures aimed at further containing disease transmission through massive vaccination campaigns. In pregnancy, vaccination should be administered with caution, in light of the lack of reliable data, since pregnant women have been excluded from experimentation. The pandemic has had a significant impact on assisted reproduction procedures in Italy. Methods: The authors have set out to analyze the measures issued by the Italian government in order to counter the spread of COVID-19, in addition to the national and international guidelines on assisted reproduction. DISCUSSION: The purpose of these documents is precautionary in nature: such measures are based on the principles of responsibility and solidarity, essential to stave off the saturation of health systems, curb contagion, but also to lay out a set of rules to starting a pregnancy while preserving the health of couples, operators and newborns. The authors also expound upon the rights claimed by couples seeking access to MAP (i.e. the right to become a parent, the couple's right to health, interest in demographic development). Conclusions: The coronavirus disease 2019 (COVID-19) has had a major impact on infertile couples. Since the pandemic broke out, Italy, like most European countries, has interrupted most ordinary activities of the centers operating in the field of assisted fertilization. We believe that access to assisted fertilization techniques by sterile and infertile couples should be part of the right to health rather than of the supposed right to become parents or the increase in the birth rate, also evoked as the COVID-19 pandemic unfolded. The current system of compensation and reimbursements needs to be reconfigured in order to prevent any form of discrimination.