Robotics and AI into healthcare from the perspective of European regulation: who is responsible for medical malpractice?

The integration of robotics and artificial intelligence into medical practice is radically revolutionising patient care. This fusion of advanced technologies with healthcare offers a number of significant benefits, including more precise diagnoses, personalised treatments and improved health data management. However, it is critical to address very carefully the medico-legal challenges associated with this progress. The responsibilities between the different players concerned in medical liability cases are not yet clearly defined, especially when artificial intelligence is involved in the decision-making process. Complexity increases when technology intervenes between a person's action and the result, making it difficult for the patient to prove harm or negligence. In addition, there is the risk of an unfair distribution of blame between physicians and healthcare institutions. The analysis of European legislation highlights the critical issues related to the attribution of legal personality to autonomous robots and the recognition of strict liability for medical doctors and healthcare institutions. Although European legislation has helped to standardise the rules on this issue, some questions remain unresolved. We argue that specific laws are needed to address the issue of medical liability in cases where robotics and artificial intelligence are used in healthcare.

Medico-legal management of healthcare-associated infections: a cost-effectiveness analysis in an Italian tertiary hospital.

Introduction: Healthcare-associated infections are the main reported adverse event in healthcare, with significant economic costs that include those caused by medical malpractice claims. In Italy, there is a fault-based compensation system, but in this specific field, the burden of proof on the hospitals is particularly heavy. Hence, we aimed to verify the economic impact of the inclusion of experts in hospital infection surveillance into internal committees for claims assessment and to evaluate what would have been the economic impact of a mandatory no-fault system rather than the current system. Materials and methods: We compared two 4-year periods (T1: 2015-2018 and T2: 2019-2022), investigating the medical malpractice claims related to healthcare-associated infections in a large tertiary public hospital in Florence, Italy. Decisions of the internal committee, evolutions of the claims after the decision, and conclusions of the claims were registered. No-fault system simulations were used to evaluate the cost-effectiveness of the model. Results: We observed a decrease in the number of claims after the implementation of infection prevention and control (IPC) experts into the committee (a 24% decrease in rejections and a 19% increase in admissions). We found a 6806.98 euros difference (not statistically significant) in compensations in T1 and T2. Moreover, our simulations found that a no-fault compensation system - if alternative to the traditional fault-based approach - could lead to gains or losses for the plaintiffs depending on the approach chosen. (We observed a 52% mean decrease in compensations with a 150000 euros maximal indemnity and a 134% mean increase with an indemnity tailored considering also life expectancy). Discussion: Introducing experts in IPC into hospital committees for medico-legal claims management has proven to be cost-effective, offering a no-fault compensation system as an alternative to the traditional fault-based approach, supported by a properly evaluated maximal indemnity. Due to the limitations of our models, multicentric studies are recommended to verify our results.

Dental DNA Mutations Occurring after Death: A Novel Method for Post-Mortem Interval (PMI) Estimation.

Post-mortem interval (PMI) estimation remains one of the major challenges in forensic practice, especially for late PMIs beyond 7-10 days after the death of the subject. In 2022, an innovative method to investigate the occurrence of mutations induced by the death of a subject in the DNA of post-mortem dental pulps at different PMIs was developed, applying a next-generation sequencing (NGS) analysis. The present study aims to apply the same method of analysis to a small sample of teeth belonging to the same subject and analyzed at different PMIs/accumulated degree days (ADDs), and of teeth extracted from different subjects but analyzed at the same PMI/ADD to verify the repeatability of the results obtained in relation to the time elapsed since death. A total of 10 teeth were collected from 6 patients (3 males and 3 females) with PMI varying from 8 to 35 days, and ADD from 157.4 to 753.8. We found 1754 mutations in 56 genes, with more than 700 mutations having a prevalence > 5% and more than 300 variants considered of interest for the purposes of the study. Mutations that were not present at lower PMIs but manifested in later PMIs in pulps belonging to the same subject demonstrate that they can only have been acquired by the subject after death and according to the time elapsed since death. In total, 67 somatic mutations in 29 out of the 56 genes of the used panel occurred in a fashion that allows an association with specific PMI/ADD ranges (within 8 days, between 17 and 28, and beyond 30 days after death). The results suggest that temperature and humidity could influence the rate of DNA degeneration in dental pulps, thus PMI should be estimated in ADD more than days. The preliminary validation supports the hypothesis that the innovative method could be a useful tool for estimating the post-mortem interval even beyond the first week after death, but further analyses are needed to customize a specific genetic panel for forensic investigations and verify the influence of degenerative processes of soft tissues surrounding dental elements on DNA degeneration of pulps.

Investigating cardiac genetic background in sudden infant death syndrome (SIDS).

Sudden infant death syndrome (SIDS) is still the leading cause of death for newborns in developed countries. The pathophysiological mechanisms have not been fully clarified, but in some of SIDS cases variants of genes associated with inherited cardiac conditions are found. In this study, an analysis of SCD-related genes was performed to determine the prevalence of rare pathogenic (P) or likely pathogenic (LP) variants that could provide an unambiguous explanation for the fatal event. A cohort of 76 SIDS cases underwent Next-Generation Sequencing (NGS) analysis with a custom panel of SCD-related genes. Rare variants were classified according to the guidelines provided by the American College of Medical Genetics and Genomics (ACMG) and the specifications of the ClinGen association. Post-mortem genetic testing identified 50 (65.8%) carriers of at least one variant in SCD genes. 104 rare genetic variants were found, 65.4% in genes encoding structural proteins. Only 4 out of 76 cases (5.3%) hosted at least a P or LP variant found in genes with structural or structural/arrhythmogenic functions (SLC22A5, SCN5A, MYL3and TTN). 99 variants were classified as of uncertain significance (VUS). The difference in the distribution of variants between gene groups by function was not statistically significant (chi square, p = 0,219). Despite this, most of the variants concerned structural genes that were supposed to have a close interaction with ion channels, thus providing an explanation for the arrhythmic event. Segregation analysis, reclassification of VUS variants and identification of new associated genes could clarify the implications of the current findings.

Negative Outcomes of Blepharoplasty and Thyroid Disorders: Is Compensation Always Due? A Case Report with a Literature Review.

BACKGROUND: Plastic surgery is one of the medical specialties with the highest risk of recurrent medical malpractice claims. The frequency of civil lawsuits represents an issue for the micro- and macro-economy of practitioners of these health treatments. This paper aims to discuss the medico-legal aspects and claim path in a case of a cosmetic blepharoplasty complicated by lagophthalmos wrongly related to the procedure but due to missed hyperthyroidism. CASE DESCRIPTION AND LITERATURE REVIEW: A 48-year-old woman who underwent cosmetic blepharoplasty with undiagnosed hyperthyroidism claimed that the lagophthalmos that occurred some months after the procedure was due to medical malpractice, due to an over-resection of the exuberant lower eyelid tissue. The review question was, "Are thyroid disfunctions usually considered contraindications to be communicated to patients who undergo blepharoplasty?", and the databases MEDLINE via PubMed, Embase, Scopus, Ovid, ISI Web of Science, Cochrane, and Google Scholar were used. RESULTS AND DISCUSSION: There were 21 eligible papers. The case highlights the importance and complexity of causal inference (such as unknown thyroid dysfunctions), related informed consent involving information on possible complications unrelated to malpractice, and guidelines recommending endocrinological consultation for cosmetic/functional blepharoplasty in patients at risk (e.g., female patients with a known history of thyroid disease).

Medicolegal and insurance issues regarding BRCA1 and BRCA2 gene tests in high income countries.

Hereditary breast and ovarian cancer syndrome is an autosomal dominant cancer susceptibility syndrome mainly due to variants in BRCA1 or BRCA2 genes. Patients presenting with BRCA1 or BRCA2 gene mutations have a lifetime risk of developing breast or ovarian cancer (80% and 40%, respectively). Genetic testing to explore the predisposition to develop cancer represents a pivotal factor in such cases, and this review wants to explore the main implications in terms of medicolegal liability and insurance issues. Medicolegal issues related to these diagnostic processes include: (a) failure to recommend the test; (b) failure to properly interpret the test; (c) failure to correctly translate results into clinical practice; (d) lack of informed consent; and (e) failure to refer patients to specialized genetic counseling. Such errors may lead to compensation since the legal burden inherent in the efficacy of prophylactic interventions is a proof that requires the so-called 'preponderance of the evidence'. Concerning insurance issues, the carriers of such alleles without cancer are healthy because the genetic predisposition is not a disease per se but represents a (relevant) health risk. However, disclosure of these conditions can be impelled by insurers. It can lead to so-called 'genetic discrimination' because insurance companies might use genetic information to limit insurance options or increase their costs. Many private and public healthcare funders do not cover risk reducing surgeries, even when recommended as part of a risk reduction management plan for BRCA gene mutation carriers. Here, positions on these matters from different high income countries are discussed, stressing the importance of a common supranational or international regulatory framework to reach a trade-off between the economic interests of insurers and the rights of carriers not to disclose extremely sensitive information.

Predictive Power of Dependence and Clinical-Social Fragility Index and Risk of Fall in Hospitalized Adult Patients: A Case-Control Study.

OBJECTIVES: Accidental falls are among the leading hospitals' adverse events, with incidence ranging from 2 to 20 events per 1.000 days/patients. The objective of this study is to assess the relationship between in-hospital falls and the score of 3 DEPendence and Clinical-Social Fragility indexes. METHODS: A monocentric case-control study was conducted by retrieving data of in-hospital patients from the electronic health records. RESULTS: Significant differences between the mean scores at the hospital admission and discharge were found. The BRASS scale mean (SD) values at the admission and at the discharge were also significantly higher in cases of in-hospital falls: at the admission 10.2 (±7.7) in cases versus 7.0 (±8.0) in controls ( P = 0.003); at the discharge 10.0 (±6.4) versus 6.7 (±7.5) ( P = 0.001). Barthel index mean (SD) scores also presented statistically significant differences: at the admission 60.3 (±40.6) in cases versus 76.0 (±34.8) in controls ( P = 0.003); at discharge 51.3 (±34.9) versus 73.3 (±35.2) ( P = 0.000).Odds ratios were as follows: for Barthel index 2.37 (95% CI, 1.28-4.39; P = 0.003); for Index of Caring Complexity 1.45 (95% CI, 0.72-2.91, P = 0. 255); for BRASS index 1.95 (95% CI, 1.03-3.70, P = 0.026). With BRASS index, the area under the curve was 0.667 (95% CI, 0.595-0.740), thus indicating a moderate predictive power of the scale. CONCLUSIONS: The use of only Conley scale-despite its sensitivity and specificity-is not enough to fully address this need because of the multiple and heterogeneous factors that predispose to in-hospital falls. Therefore, the combination of multiple tools should be recommended.

Post-mortem Imaging of Brain/Spine Injuries: The Importance of a Comprehensive Forensic Approach.

In forensic investigations, the limitations of the traditional purely autoptic approach can be overcome through post-mortem imaging (virtopsy). Virtospy has several applications to the investigation of brain and spinal injuries, whose analysis can be of forensic interest, especially in cases of suspected malpractice. In this scoping review, we briefly describe the main applications of the two most common post-mortem radiological techniques (computed tomography (CT) and magnetic resonance imaging (MRI)) to the forensic investigation of brain and spinal injuries in cases of medical malpractice or traumatic (accidental/homicidal/suicidal) deaths. Although CT represents the traditional approach to post-mortem imaging, MRI is proving to be a valuable tool to investigate brain and spinal injuries and lesions. These post-mortem radiological techniques can also be used to guide the surgeons in simulated surgical procedures on corpses in the context of training programs, thus helping operators to improve technical and non-technical skills and to reduce the risk of avoidable errors.

Effectiveness of participatory video in lowering stigma against people with mental, neurological and substance use disorders in Kenya.

BACKGROUND: Globally, stigma associated with mental, neurological and substance use (MNS) disorders is rampant and a barrier to good health and overall well-being of people with these conditions. Person-centred digital approaches such as participatory video may reduce stigma, but evidence on their effectiveness in Africa is absent. AIMS: To evaluate the effectiveness of participatory video in reducing mental health-related stigma in a resource-limited setting. METHOD: We evaluated the effectiveness of using participatory video and face-to-face interaction between people with MNS disorders and a target audience in lowering stigma among 420 people living in Kilifi, Kenya. Changes in knowledge, attitudes and behaviour (KAB) were measured by comparing baseline scores with scores immediately after watching the participatory videos and 4 months after the intervention. Sociodemographic correlates of stigma scores were examined using multivariable linear regression models. RESULTS: Compared with baseline, KAB scores significantly improved at both time points, suggesting reduced stigma levels. At 4 months, the changes in scores were: knowledge (ß = 0.20, 95% CI 0.16-0.25; P < 0.01), liberal attitude (ß = 1.08, 95% CI 0.98-1.17; P < 0.01), sympathetic attitude (ß = 0.52, 95% CI 0.42-0.62; P < 0.01), tolerant attitude (ß = 0.72, 95% CI 0.61-0.83; P < 0.01) and behaviour (ß = 0.37, 95% CI 0.31-0.43; P < 0.01). Sociodemographic variables were significantly correlated with KAB scores; the correlations were not consistent across the domains. CONCLUSIONS: Participatory video is a feasible and effective strategy in improving knowledge, attitudes and intended behaviour in a resource-limited setting. Further studies are required to understand the mechanisms through which it lowers stigma and to examine long-term sustainability and the effectiveness of multicomponent interventions.

Biomarkers of traumatic brain injury in vitreous humor: A pilot study.

BACKGROUND: Traumatic brain injury (TBI) is one of the major causes of morbidity and mortality worldwide. The patients' and injuries' heterogeneity associated with TBI, alongside with its variable clinical manifestations, make it challenging to make diagnosis and predict prognosis. Therefore, the identification of reliable prognostic markers would be relevant both to support clinical decision-making and forensic evaluation of polytraumatic deaths and cases of medical malpractice. This pilot study aimed to evaluate some of the main biomarkers specific for brain damage in sTBI and mmTBI deaths in samples of vitreous humor (VH) in order to verify whether predictors of prognosis in TBI can be found in this matrix. METHODS: VH were obtained from both eyes (right and left) of 30 cadavers (20 sTBI and 10 mmTBI) and analysed. These factors were evaluated: NSE (neuron-specific enolase), S100 calcium-binding protein (S100), glial fibrillary acidic protein (GFAP), Brain-derived neurotrophic factor (BDNF), Copeptin, Interleukin 6 (IL-6), Ferritin, Lactate dehydrogenase (LDH), C-Reactive Protein (CRP), Procalcitonin (PCT), Glucose and Neutrophil gelatinase-associated lipocalin (N-Gal). RESULTS: Four of the analysed proteins (LDH, ferritin, S100 and NSE) proved to be particularly promising. In particular, logistic regression analysis found a good discriminatory power. CONCLUSIONS: Given the peculiarity of the matrix and the poor standardization of the sampling, such promising results need to be furtherly investigated in serum before being implemented in the forensic practice.

Postmortem diagnosis of Takotsubo syndrome on autoptic findings: is it reliable? A systematic review.

Takotsubo syndrome (TTS) is a cardiac syndrome characterized by transient left ventricular systolic dysfunction in the absence of significant obstructive coronary artery disease. At the autopsy, its diagnosis is often challenging, since it is generally thought that it relates to no characteristic macroscopic or microscopic findings. In order to verify this last statement, we performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (PRISMA) criteria. To the best of our knowledge, it is the first systematic review addressing this issue. We identified recurring but not pathognomonic (microscopic) features of TTS: contraction band necrosis and non-specific inflammatory changes (e.g., interstitial infiltrates of mononuclear lymphocytes and macrophages) typically in the absence of microscopic findings typical of acute myocardial infarction. In cases of TTS-related sudden death, careful evaluation of anamnesis, autopsy data and post-mortem genetic results (to exclude other causes) should be considered to overcome the complexity of these cases.

Comparative Impact Analysis of Low-Deductible Insurance Versus In-house Hospital Assumption of Risk and Management on Medical Malpractice Claims.

OBJECTIVES: Claims management is critical to ensure the safe and high-quality medical care for which liability insurers and/or hospitals are responsible. The aim of this research is to determine whether increasing hospital malpractice risk exposure, with increasing deductibles, has an impact on malpractice claims and payouts. METHODS: The study was conducted at a single tertiary hospital, the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy. Payouts on closed reported and registered claims were analyzed during 4-study periods, which ranged from 1.5 million euro annual aggregate deductibles entirely managed by the insurance company to 5 million euro annual aggregate deductibles entirely managed by the hospital. We retrospectively analyzed 2034 medical malpractice claims submitted between January 1, 2007, and August 31, 2021. Four periods were examined depending on the claims management model adopted, ranging from total outsourcing to the insurer (period A) to an almost total hospital assumption of risk method (period D). RESULTS: We found that progressive hospital assumption of risk is associated with a decrease in the incidence of medical malpractice claims (average variation per year: -3.7%; P = 0.0029 if the 2 initial periods and the 2 last periods-characterized by the highest risk retention-are respectively aggregated and compared), an initial decrease in the mean claims cost followed by an increase that is still lower than the national increase (-5.4% on average), and an increase in the total claims cost (when compared with the period where the insurer solely managed claims). We also found that the rate of increase in payouts was less than the national average. CONCLUSIONS: The assumption of more malpractice risk by the hospital was associated with the adoption of numerous patient safety and risk management initiatives. The decrease in claims incidence could be due to the implementation of patient safety policies, while the cost increase could be attributed to inflation and rising costs of healthcare services and claims. Notably, only the hospital assumption of risk model with a high-deductible insurance coverage is sustainable for the studied hospital, while also being profitable for the insurer. In conclusion, as hospitals progressively assumed more risk and management responsibility of malpractice claims, there was a progressive decrease in the total number of claims, and a less rapid rise in claim payouts as compared with the national average. Even a small assumption of risk appeared to elicit meaningful changes in claim filings and payouts.

What can autopsy say about COVID-19? A case series of 60 autopsies.

INTRODUCTION: Autopsies in SARS-CoV-2 infected cadavers are mainly performed to distinguish patients who died with SARS-CoV-2 infection from those who died of COVID-19. The aim of the current study is to assess the most frequent autopsy findings in patients who died of COVID-19 and to establish an association with clinical records. MATERIALS AND METHODS: 60 patients died between April 2020 and March 2021 after SARS-CoV-2 infection underwent a full autopsy performed at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (Rome). Ante-mortem diagnosis of SARS-CoV-2 infection was microbiologically confirmed. RESULTS: 55 (92%) of cases had at least a comorbidity. At microscopic examination, 40 (67%) of the patients presented pulmonary intravascular coagulation with an inflammatory pattern. Pulmonary microangiopathy was a rare finding (n = 8; 13%). Myocardiosclerosis was the main heart finding (n = 44; 73%). Liver involvement with congestion and hypotrophy was found in 33 (55%) of cadavers. Renal tubular epithelial exfoliation (n = 12; 20%) and intravascular coagulation (n = 4; 7%) were frequent observations. During hospitalization 31% of patients (n = 19) developed acute kidney injury (AKI). CONCLUSIONS: Lungs and kidneys have been shown to play a pivotal role in COVID-19. The gradual worsening of renal function and AKI might be the result of the progressive collapse of cardiopulmonary system.

A Semi-Automatic Method on a Small Italian Sample for Estimating Sex Based on the Shape of the Crown of the Maxillary Posterior Teeth.

Teeth are known to be reliable substrates for human identification and are endowed with significant sexual dimorphism not only in the size but also in the shape of the crowns. In the preliminary phase of our study (already published in 2021), a novel sex estimation method based on dental morphometric geometric (GMA) analysis combined with the artificial neural network (ANN) was developed and validated on a single dental element (first upper premolar) with an accuracy rate of 80%. This study aims to experiment and validate the combination of GMA-ANN on the upper first and second left premolars and the upper left first molar to obtain a reliable classification model based on the sexual dimorphic traits of multiple maxillary teeth of Caucasian Italian adults (115 males and 115 females). A general procrustes superimposition (GPS) and principal component analysis (PCA) were performed to study the shape variance between the sexes and to reduce the data variations. The "set-aside" approach was used to validate the accuracy of the proposed ANN. As the main findings, the proposed method correctly classified 94% of females and 68% of males from the test sample and the overall accuracy gained was 82%, higher than the odontometric methods that similarly consider multiple teeth. The shape variation between male and female premolars represents the best dimorphic feature compared with the first upper molar. Future research could overcome some limitations by considering a larger sample of subjects and experimenting with the use of computer vision for automatic landmark positioning and should verify the present evidence in samples with different ancestry.

Potentiality of algorithms and artificial intelligence adoption to improve medication management in primary care: a systematic review.

OBJECTIVES: The aim of this study is to investigate the effect of artificial intelligence (AI) and/or algorithms on drug management in primary care settings comparing AI and/or algorithms with standard clinical practice. Second, we evaluated what is the most frequently reported type of medication error and the most used AI machine type. METHODS: A systematic review of literature was conducted querying PubMed, Cochrane and ISI Web of Science until November 2021. The search strategy and the study selection were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the Population, Intervention, Comparator, Outcome framework. Specifically, the Population chosen was general population of all ages (ie, including paediatric patients) in primary care settings (ie, home setting, ambulatory and nursery homes); the Intervention considered was the analysis AI and/or algorithms (ie, intelligent programs or software) application in primary care for reducing medications errors, the Comparator was the general practice and, lastly, the Outcome was the reduction of preventable medication errors (eg, overprescribing, inappropriate medication, drug interaction, risk of injury, dosing errors or in an increase in adherence to therapy). The methodological quality of included studies was appraised adopting the Quality Assessment of Controlled Intervention Studies of the National Institute of Health for randomised controlled trials. RESULTS: Studies reported in different ways the effective reduction of medication error. Ten out of 14 included studies, corresponding to 71% of articles, reported a reduction of medication errors, supporting the hypothesis that AI is an important tool for patient safety. CONCLUSION: This study highlights how a proper application of AI in primary care is possible, since it provides an important tool to support the physician with drug management in non-hospital environments.

Bile duct injury following cholecystectomy: delayed referral to a tertiary care center is strongly associated with malpractice litigation.

BACKGROUND: Bile duct injury (BDI) following cholecystectomy is associated with malpractice litigation. Aim of this study was to evaluate risk factors for litigation in patients with BDI referred in a tertiary care center. METHODS: Patients treated for BDI between 1994 and 2016. Stabilized inverse probability therapy weighting was used and multivariable logistic regression analysis identified risk factors for malpractice litigation. RESULTS: Of the 211 treated patients, 98 met the inclusion criteria: early-referral group (<20 days; 51.0%), late-referral (≥20 days; 49.0%). 36 patients (36.7%) initiated malpractice litigation with verdict in favor of plaintiff in 86.7% of cases (median payment = €90 500, up to €600 000). Attempts at surgical and endoscopic repair before referral were significantly higher in late-referral group. Failed postoperative management (delayed referral, attempts at repair before referral) was one of the strongest predictors for litigation. Risk of litigation progressively increased from 23.8%, when referral time was within 19 days, to 54.5% (61-120 days), to 60.0% (121-210 days) and to 65.1% (211-365 days). DISCUSSION: Litigation rate after BDI was 37%. Delayed referral to tertiary care center was one of the strongest predictors for litigation. Prompt referral to tertiary experienced centers without any attempt at repair may reduce the risk of litigation.

Molecular autopsy: Twenty years of post-mortem diagnosis in sudden cardiac death.

In the forensic medicine field, molecular autopsy is the post-mortem genetic analysis performed to attempt to unravel the cause of decease in cases remaining unexplained after a comprehensive forensic autopsy. This negative autopsy, classified as negative or non-conclusive, usually occurs in young population. In these cases, in which the cause of death is unascertained after a thorough autopsy, an underlying inherited arrhythmogenic syndrome is the main suspected cause of death. Next-generation sequencing allows a rapid and cost-effectives genetic analysis, identifying a rare variant classified as potentially pathogenic in up to 25% of sudden death cases in young population. The first symptom of an inherited arrhythmogenic disease may be a malignant arrhythmia, and even sudden death. Early identification of a pathogenic genetic alteration associated with an inherited arrhythmogenic syndrome may help to adopt preventive personalized measures to reduce risk of malignant arrhythmias and sudden death in the victim's relatives, at risk despite being asymptomatic. The current main challenge is a proper genetic interpretation of variants identified and useful clinical translation. The implications of this personalized translational medicine are multifaceted, requiring the dedication of a specialized team, including forensic scientists, pathologists, cardiologists, pediatric cardiologists, and geneticists.

Reevaluation of ambiguous genetic variants in sudden unexplained deaths of a young cohort.

Sudden death cases in the young population remain without a conclusive cause of decease in almost 40% of cases. In these situations, cardiac arrhythmia of genetic origin is suspected as the most plausible cause of death. Molecular autopsy may reveal a genetic defect in up to 20% of families. Most than 80% of rare variants remain classified with an ambiguous role, impeding a useful clinical translation. Our aim was to update rare variants originally classified as of unknown significance to clarify their role. Our cohort included fifty-one post-mortem samples of young cases who died suddenly and without a definite cause of death. Five years ago, molecular autopsy identified at least one rare genetic alteration classified then as ambiguous following the American College of Medical Genetics and Genomics' recommendations. We have reclassified the same rare variants including novel data. About 10% of ambiguous variants change to benign/likely benign mainly because of improved population frequencies. Excluding cases who died before one year of age, almost 21% of rare ambiguous variants change to benign/likely benign. This fact makes it important to discard these rare variants as a cause of sudden unexplained death, avoiding anxiety in relatives' carriers. Twenty-five percent of the remaining variants show a tendency to suspicious deleterious role, highlighting clinical follow-up of carriers. Periodical reclassification of rare variants originally classified as ambiguous is crucial, at least updating frequencies every 5 years. This action aids to increase accuracy to enable and conclude a cause of death as well as translation into the clinic.