Comparison of baseline patient characteristics in Italian oncology drug monitoring registries and clinical trials: a real-world cross-sectional study.

Background: Generalizability of registrative clinical trials to real-world clinical practice is influenced by comparability of patients in the two settings. We compared characteristics of cancer patients in registrative trials with real-world clinical practice in Italy. Methods: Data on age, sex and performance status (PS) were derived from web-based monitoring registries developed by Italian Medicines Agency (AIFA) and corresponding registrative trials reported in the European Public Assessment Reports (EPAR) of European Medicines Agency (EMA). Weighted means were calculated in registries and trials and differences were described. Multivariate analysis was performed using Principal Component Analysis and Cluster Analysis. Findings: From January, 2013 to April, 2023, 419,461 unique pairs of patients and therapeutic indications were recorded in 129 AIFA registries. Within 140 related trials, 87,452 patients had been enrolled. Median age and rate of elderly (≥65 years old) patients were higher in monitoring registries than in clinical trials [mean difference of median age 5.3 years, p < 0.001; mean difference of elderly rate 17.17% (95% CI 1.06, 1.48)]. Overall, rate of female patients was not different between registries and trials [mean difference -0.55% (95% CI -1.06, -0.05)]. Mean rate of patients with deteriorated PS was low both in trials (3.1%) and in registries (4.3%) with a mean difference of 1.27% (95% CI 1.06, 1.48). Two clusters were identified with multivariate analysis: one including more registries (higher median age and elderly rate, lower female rate, higher rate of deteriorated patients), the other more trials (lower median age and elderly rate, higher female rate, lower rate of deteriorated patients). Interpretation: This study supports that cancer patients enrolled in trials do only partially represent those who have been treated in Italy in clinical practice. Inclusiveness of registrative trials should be increased to ensure generalizability of results to real-world population. Funding: Partially supported by Italian Ministry of Health.

Dating Skin Lesions of Forensic Interest by Immunohistochemistry and Immunofluorescence Techniques: A Scoping Literature Review.

Wound age estimation is a significant issue in forensic pathology. Although various methods have been evaluated, no gold standard system or model has been proposed, and accurate injury time estimation is still challenging. The distinction between vital skin wounds-i.e., ante-mortem lesions-and skin alterations that occur after death is a crucial goal in forensic pathology. Once the vitality of the wound has been confirmed, the assessment of the post-trauma interval (PTI) is also fundamental in establishing the causal relationship between the traumatic event and death. The most frequently used techniques in research studies are biochemistry, molecular biology, and immunohistochemistry (IHC). Biochemical methods take advantage of the chemical and physical techniques. A systematic literature search of studies started on 18 February 2023. The search was conducted in the main databases for biomedical literature, i.e., PubMed and Scopus, for papers published between 1973 and 2022, focusing on different techniques of immunohistochemistry and immunofluorescence (IF) for estimating the PTI of skin wounds. The present study involves a comprehensive and structured analysis of the existing literature to provide a detailed and comprehensive overview of the different IHC techniques used to date skin lesions, synthesize the available evidence, critically evaluate the methodologies, and eventually draw meaningful conclusions about the reliability and effectiveness of the different markers that have been discovered and used in wound age estimation.

Liability and Medico-Legal Implications in Estimating the Likelihood of Having Attained 14 Years of Age in Pediatric Clinical Practice: A Pilot Study.

Accurate methods of age estimation are more essential than ever due to the rise in undocumented individuals without proper identification, often linked to illegal immigration and criminal activities. This absence of reliable records presents challenges within the legal systems, where age thresholds in the context of children's rights vary across countries. Age 14 has global significance, as established by the UN Convention on the Rights of the Child and the EU for administrative purposes. Accurate age estimation is crucial in medical decisions, reproductive health, and forensics. This study focuses on age estimation via dental radiographs, proposing a method for estimating the likelihood of having attained the age of 14. Orthopantomograms were analyzed from two samples, 191 Italian children (aged 5-15) and 822 Chilean subjects (aged 11-22), using dental maturity indices. These indices evaluated open tooth apices and complete root development. Statistical analysis confirmed the method's reliability in identifying individuals aged 14 or older, with sex-specific cut-offs. The proposed method particularly advocates an approach based on dental mineralization, which could surpass those relying on bone growth. The collaboration between medical experts, including pediatricians and diagnostic imaging specialists, is vital for standardized age estimation strategies. Ethical concerns regarding radiation exposure and accountability are recognized, although the method's low radiation doses are deemed acceptable. The proposed method will help health professionals to accurately predict whether or not the 14-year threshold has been reached, opening up new avenues of medico-legal interest and laying the foundations for a legal framework that would allow the pediatrician, when involved, to use a valid and recognized diagnostic approach.

The wounding potential of assault rifles: analysis of the dimensions of entrance and exit wounds and comparison with conventional handguns. A multicentric study.

The appearance of a gunshot wound (GSW) is greatly influenced by the velocity of the projectile, where high-velocity projectiles (HVPs) are defined as ballistic agents reaching a muzzle velocity of > 600 m/s fired from assault rifles. The aim of the study is to present and explain the differences in the dimensions of entrance and exit wounds between the most used handguns and assault rifles and to propose a predictor of HVP, i.e., the ratio of exit and entrance wounds (EX/ENR). The surface area of entrance and exit GSWs and the EX/ENR were calculated. 66 perforating GSWs produced by NATO FMJ 7.62 × 52 mm and 5.56 × 42 mm fired from assault rifles were assigned to the HVP, while 64 lesions produced by conventional projectiles fired from revolvers and semi-automatic pistols were assigned to the low-velocity projectile (LVP) group. The dimensions of the exit wounds of the HVP group were significantly higher when compared to the LVP group (95% CI 0.9886-2.423, p < 0.05). The HVP group showed significantly higher values for the EX/ENR when compared to the LVP group (95% CI 2.617-7.173, p < 0.05). The evaluation of the EX/ENR can be considered an adequate tool to assess the type of weapon involved and to roughly estimate the associated wounding mechanisms, which can guide both the physician in the management and treatment of the patients affected by GSW, and the forensic pathologist in crime investigation.

A case of emergency reconstructive surgery following facial destructive gunshot wounds: clinical and medico-legal assessments.

BACKGROUND: Facial gunshot wounds present a complex challenge to both medical professionals and victims with significant physical, psychological, and economic implications for those who suffer these types of injuries. Reconstructive surgery offers satisfactory aesthetic and functional outcomes, improving a patient's quality of life. In these cases, the surgical procedure may encompass additional phases beyond those initially identified based on the type of wound and the extent of tissue destruction. As a result, each case necessitates thorough evaluation to determine an appropriate strategy. Nonetheless, it is worth noting that the outcomes achieved in terms of both aesthetics and functionality in this domain have the potential to be excellent. CASE PRESENTATION: A 66-year-old man attempted suicide with a shotgun, causing severe facial injuries and fractures. He had a history of depression and was taken to the emergency department promptly. CT scans revealed brain and facial bone injuries, and he underwent surgery to control bleeding and tracheostomy. Postoperative recovery was successful. The patient's condition stabilized, and he was discharged after 10 days. Follow-up visits showed gradual healing. Despite an offer for further facial reconstruction, he declined, satisfied with the achieved results. CONCLUSIONS: The present case report is intended to support the argument that effective facial reconstruction should be considered in the medico-legal assessment. It could be beneficial to introduce a new classification system and personalized evaluation methods with careful consideration given to treatment costs (which can be very high) and expected results. Since reconstructive surgery modifies damage and impacts the long-term costs of permanent impairments, its inclusion in the decision-making process would promote improved personalized care.

Real-World Effectiveness of PCSK9 Inhibitors in Reducing LDL-C in Patients With Familial Hypercholesterolemia in Italy: A Retrospective Cohort Study Based on the AIFA Monitoring Registries.

Background Information on the real-world use of proprotein convertase subtilisin kexin 9 inhibitors (PCKS9is) in familial hypercholesterolemia are limited. We evaluated the pattern of prescription and the long-term efficacy of alirocumab and evolocumab in Italian patients with familial hypercholesterolemia in clinical practice. Methods and Results The data set for analysis was extracted from the PCKS9i Italian Medicines Agency (AIFA) registry and included 2484 patients with heterozygous familial hypercholesterolemia (HeFH) and 62 patients with homozygous familial hypercholesterolemia (HoFH) who were prescribed PCKS9is from February 2017 to December 2021. As the follow-up schedules were not prespecified and could vary, persistence and adherence as well as low-density lipoprotein cholesterol (LDL-C) changes during 2 years of treatment were analyzed in a final cohort of 1299 patients with familial hypercholesterolemia. At baseline, 53.8% of patients with HeFH and 69.4% of patients with HoFH were receiving maximally tolerated lipid-lowering therapies, while 45.9% of patients with HeFH and 30.7% of patients with HoFH reported statin intolerance; mean LDL-C was 197.7±52.3 mg/dL in HeFH and 252.0±106.2 mg/dL in HoFH. The 6-month persistence and adherence to therapy were >85%, and LDL-C reduction reached 58.6% (to 79.7 mg/dL) in HeFH and 57.6% (to 95.1 mg/dL) in HoFH after 24 months of treatment. The European Atherosclerosis Society/European Society of Cardiology LDL-C goals were achieved in 43.3% of patients with HeFH and 37.5% of patients with HoFH. Conclusions PCKS9i prescribed to patients with familial hypercholesterolemia in clinical practice showed LDL-C-lowering efficacy similar to that observed in controlled trials. However, 2 of 5 HeFH cases and 2 of 6 HoFH cases achieved the recommended LDL-C goals. The full achievement of European Atherosclerosis Society/European Society of Cardiology LDL-C goals should require a lower threshold for PCKS9i initiation and a combination of multiple therapies.

Artificial Intelligence in Evaluation of Permanent Impairment: New Operational Frontiers.

Artificial intelligence (AI) and machine learning (ML) span multiple disciplines, including the medico-legal sciences, also with reference to the concept of disease and disability. In this context, the International Classification of Diseases, Injuries, and Causes of Death (ICD) is a standard for the classification of diseases and related problems developed by the World Health Organization (WHO), and it represents a valid tool for statistical and epidemiological studies. Indeed, the International Classification of Functioning, Disability, and Health (ICF) is outlined as a classification that aims to describe the state of health of people in relation to their existential spheres (social, family, work). This paper lays the foundations for proposing an operating model for the use of AI in the assessment of impairments with the aim of making the information system as homogeneous as possible, starting from the main coding systems of the reference pathologies and functional damages. Providing a scientific basis for the understanding and study of health, as well as establishing a common language for the assessment of disability in its various meanings through AI systems, will allow for the improvement and standardization of communication between the various expert users.

Long-Term Impacts of the COVID-19 Pandemic on Drug/Alcohol Use Prevalence in a Population with Substance Use Disorders.

As time passes, the long-term effects of the COVID-19 pandemic are becoming increasingly apparent. The extreme restrictions imposed during the pandemic have had detrimental impacts on the most vulnerable groups, such as individuals suffering from substance and/or alcohol disorders (SUDs). This study reports quarterly laboratory data on alcohol and drug use in 150 subjects with SUDs that were examined using hair analysis for 2 years before the start of pandemic until after the end of the Italian health emergency. Overall, it was found that the number of subjects who used heroin, cocaine, and MDMA all decreased during the 2020 and 2021 lockdowns, increasing during reopening and subsequently stabilizing close to pre-COVID levels. Cannabis use was less impacted, remaining stable throughout the pandemic. Alcohol and benzodiazepine use both increased significantly during the lockdowns, displaying an opposing trend. While benzodiazepine use progressively returned to baseline levels, alcohol remained at significantly increased levels, even in September 2022. Long-term heavy drinking combined with substance use should be seriously considered, since these results in several health and social problems alongside alcohol-related comorbidities. Thus, appropriate response plans should be implemented both during and after the pandemic, whilst focusing on those who are most vulnerable.

An atypical death from Rapunzel syndrome: a case report.

Trichotillomania is a psychiatric disorder characterized by recurring urges to pulling out hairs, eyelashes, or down in other parts of the body. Trichophagia, which is the urge to ingesting the pulled-out hairs, can cause Rapunzel syndrome, an unusual disorder where gastric trichobezoars can be found in the small intestine. Trichobezoars, amorphous masses composed of undigested food formed by hairs, can obstruct the gastrointestinal tract up to simulating symptoms typical of bowel obstruction. Rapunzel syndrome, named after Grimm's tale, may cause death, especially in the pediatric population, being it seldom over the age of 6; moreover, developing countries and environmental and familiar issues are listed as uncertain risk factors. The present case report deals with the death of a 4-year-old female occurred after lunch and following a series of vomit events; while no traumatic or pathological findings were revealed at the external examination, the autopsy revealed three large trichobezoars localized in the stomach and the small intestine. Despite death was due to gastrointestinal obstruction for multiple trichobezoars and collateral bronchoaspiration of dietary material, histological findings were totally non-specific, meaning that it is sometimes difficult to conclude that death is related to the primary pathological condition.

Evidence of D-shaped wounds in the intrasomatic bullet path: two case reports.

The final appearance of gunshot wounds is influenced by both the projectile's behavior from the muzzle to the terminal target and by the intrinsic characteristics of the anatomical compartments where the lesion(s) occur. The D-shaped morphology is an uncommon yet well-known finding in the forensic literature and has been described when the surface of impact with the skin is represented by the bullet's lateral projection. Two cases where D-shaped gunshot wounds were observed are hereby presented: in both cases, interaction with multiple intermediate targets (case 1) and a human intermediate target (case 2) had been documented and confirmed by the forensic examination. Despite the different dynamics of production, this peculiar morphology was described throughout most of the intrasomatic bullet path in both the victims. The discovery of D-shaped gunshot wounds can guide the forensic pathologist in the ballistic reconstruction of the event by supporting the hypothesis of an interaction with an intermediate target that has led to deviation from the initial trajectory and destabilization of the bullet associated with loss of kinetic energy.

Rust stains' response to environmental stresses: An experimental study on porcine skin.

Rust stains are rare marks typically caused by prolonged contact between skin and the iron components of the firearm. This study was aimed at showing how cutaneous iron deposits respond to physical and chemical changes that usually affect the integrity of biological tissues. Four samples of porcine skin were placed in contact with an iron plate. They were exposed to different stress conditions: carbonization, water immersion, sunlight exposure and burial. All the skin sections were stained with Hematoxylin and Eosin (H&E) and Perls Prussian Blue (PPB). The response to the different treatments was consistent among the skin sections, as none of the rust stains were significantly altered by the applied stresses. All the samples showed focal iron deposition in the examined sections, which appeared as blue-colored spots in a rose-to-red background. Rust mark formation is an "all or nothing" phenomenon leading to the appearance of a sign that is relatively fixed and cannot be easily modified by the most common environmental conditions. This feature suggests the permanence of rust stains both from a macroscopic and a microscopic point of view, using Perls Prussian Blue staining after the exposure of the skin samples to various environmental stresses within precise time intervals.

Mortality in SARS-CoV-2 Hospitalized Patients Treated with Remdesivir: A Nationwide, Registry-Based Study in Italy.

Remdesivir is the first drug approved for treatment of COVID-19 but current evidence for recommending its use for the treatment of moderate-to-severe disease is still controversial among clinical guidelines. We performed a nationwide, registry-based study including all Italian hospitalized patients with COVID-19 treated with remdesivir to assess the impact of major confounders on crude 15-day and 29-day mortality. Mortality was calculated using the Kaplan-Meier estimator and the Cox proportional-hazards model was applied to analyze the risks by patient's baseline features. In total, 16,462 patients treated with remdesivir from 29 October 2020 to 17 December 2020 were entered in the study. Crude 15-day and 29-day mortality were 7.1% (95% CI, 6.7-7.5%) and 11.7% (95% CI, 11.2-12.2%), respectively. Being treated within two days of admission reduced the risk of death by about 40% (HR 1.4, 95% CI, 1.2-1.6). Results from the largest cohort of remdesivir-treated patients suggests that mortality in SARS-CoV-2 hospitalized patients is substantially influenced by the days between SARS-CoV-2 diagnosis and drug prescription. Current recommendations and future clinical trials for remdesivir alone or in combination should carefully consider the target population and timing for best efficacy of treatment.

What about cerebral venous sinus thrombosis? A series of three autopsy cases.

Cerebral venous sinus thrombosis (CVST) is an uncommon cerebrovascular disorder that gained massive media attention in 2021, when an association between COVID-19 and its vaccines was found in several reported cases, raising the suspicion of a causative relation that is still debated. Three cases of CVST unrelated to COVID-19 are reported in this article to highlight the difficulty in the early recognition and management of this condition, as it occurs in a variety of diseases with different clinical and pathological manifestations. When the diagnosis cannot be achieved in the clinical setting, the role of the pathologist becomes essential in the determination of the cause of death and in the identification of the etiology of CVST. During the autopsy, coordination between the physician and the forensic pathologist is crucial to correlate the clinical presentation with the pathological picture.

"Rust stain": a rare mark in firearm suicide-a case report and review of the literature.

Rust stains are marks left by firearms in case of prolonged contact with the cutaneous surfaces. These peculiar signs along with other well-documented findings can guide the medical examiner in the determination of the manner of death, especially in case of firearm suicide. This paper presents the case of a 33-year-old male soldier who committed suicide by using a short-barreled weapon, whose trigger remained in contact with the first finger of his right hand, leading to the formation of a rust stain that perfectly reproduced its design. The forensic examination of the scene, the external cadaveric inspection, and the autopsy are described. For the evaluation of the histological findings typical of rust spots, the authors decided to replicate the phenomenon in an experimental setting using porcine skin. In order to provide an exhaustive overview on the formation and the features of rust stains, a review of the forensic literature concerning this rare mark was performed.