Intra-hospital variation of gut microbiota product, trimethylamine N-oxide (TMAO) predicts future major adverse cardiovascular events after myocardial infarction.

BACKGROUND AND AIMS: Trimethylamine N-oxide (TMAO) has been associated with atherosclerosis and poor outcome. We evaluated the prognostic impact of intra-hospital TMAO variation on patient outcome. METHODS AND RESULTS: Blood samples from 149 patients with acute myocardial infarction (AMI) were taken on admission and discharge. Plasma TMAO was determined by HPLC-MS. The endpoint was a composite three-point MACE (major adverse cardiovascular events) including all-cause mortality, re-infarction or the heart failure (HF) development. Median TMAO concentration on admission was significantly higher than on discharge, (respectively, 7.81 [3.47 - 19.98] vs 3.45 [2.3 - 4.78] µM,p<0.001). After estimating the 3.45 µM TMAO cut-off with the analysis of continuous hazard ratio, we divided our cohort into two groups. The first group included 75 (50.3%) patients whose TMAO levels remained below or decreased under cut-off (low-low/high-low; LL/HL), while the second group included 74 (49.7%) patients whose TMAO levels remained high or increased above the cut-off during hospitalisation (high-high/low-high; HH/LH). During the median 30-month follow-up, 21.5% patients experienced the composite endpoint. At Kaplan-Meier analysis, a trend of increasing MACE risk was observed in patients in the HH/LH group (p=0.05). At multivariable Cox analysis, patients from HH/LH group had more than two times higher risk of MACE during the follow-up than LL/HL group (HR=2.15 [95% CI, 1.03 - 4.5], p=0.04). Other independent predictors of MACE were older age and worse left ventricular systolic function. CONCLUSIONS: In patients with AMI, permanently high or increasing TMAO levels during hospitalisation are associated with a higher risk of MACE during long-term follow-up.

Cardiac SARS-CoV-2 Infection, Involvement of Cytokines in Postmortem Immunohistochemical Study.

In the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, significant attention was given to pulmonary manifestations. However, cardiac involvement is increasingly recognized as a critical factor influencing the prognosis, leading to myocardial damage, heart failure, acute coronary syndromes, potentially lethal arrhythmic events, and sudden cardiac death. Despite these findings, there is a lack of studies detailing the necroscopic, macroscopic, and microscopic cardiac changes associated with SARS-CoV-2. This study aimed to investigate the presence of SARS-CoV-2 viral proteins in cardiac tissue using immunohistochemical techniques to assess viral tropism. The analysis of cardiac tissue samples from deceased subjects, in different stages of conservation, confirmed to be positive for SARS-CoV-2 via reverse transcriptase-polymerase chain reaction (RT-PCR), showed immunopositivity for the SARS-CoV-2-NP viral antigen in 33% of cases. Notably, the presence of leukocyte infiltrates sufficient for diagnosing lymphocytic myocarditis was not observed. The central proinflammatory cytokines involved in the pathogenetic mechanism of coronavirus disease 19 (COVID-19) were researched using the immunohistochemical method. A significant increase in cytokine expression was detected, indicating myocardial involvement and dysfunction during SARS-CoV-2 infection. These findings suggest that the immunohistochemical detection of SARS-CoV-2 viral antigens and inflammatory cytokine expression in cardiac tissue could be crucial for a proper forensic assessment of the cause of death, even in sudden cardiac death.

Applicability of a Chemiluminescence Immunoassay to Screen Postmortem Bile Specimens and Its Agreement with Confirmation Analysis.

Bile has emerged as an alternative matrix for toxicological investigation of drugs in suspected forensic cases of overdose in adults and intoxications in children. Toxicological investigation consists in screening and, subsequently, confirming the result with specific techniques, such as liquid chromatography with tandem mass spectrometry (LC-MS/MS). As there is no screening test on the market to test postmortem bile specimens, the novelty of this study was in investigating the applicability of a chemiluminescence immunoassay, designed for other matrices and available on the market, on bile and validate its use, testing the agreement with LC-MS/MS analysis. Bile specimens were obtained from 25 forensic cases of suspected death from overdose and intoxication. Sample preparation for bile screening consists simply in centrifugation and dilution. Confirmation analysis allows simultaneous identification of 108 drugs and was validated on bile. Kappa analysis assessed a perfect agreement (0.81-1) between the assays for benzodiazepines, methadone, opiates, cocaine, oxycodone, cannabinoids, buprenorphine and pregabalin; a substantial agreement (0.41-0.6) was reported for barbiturates. No agreement was assessed for amphetamines, due to an abundance of putrefactive amines in postmortem specimens. In conclusion, this fast and easy immunoassay could be used for initial screening of bile specimens, identifying presence of drugs, except amphetamines, with reliability.

Ethnicity and Sudden Cardiac Death in Athletes: Insights from a Large United Kingdom Registry.

BACKGROUND AND AIMS: The relationship between ethnicity and causes of sudden cardiac death (SCD) in athletes is poorly understood. OBJECTIVES: To investigate etiology of SCD among different ethnicities in a large cohort of athletes. METHODS: Between 1994 and November 2022, 7880 cases of SCD were consecutively referred from all over the United Kingdom to our national cardiac pathology centre; 848 (11%) were athletes. All cases underwent detailed autopsy evaluation by expert cardiac pathologists. Clinical information was obtained from referring coroners. RESULTS: Most of athletes were white (n = 758; 89%). Black and Asian athletes were 51 (6%) and 39 (5%) respectively. A structurally normal heart, indicative of sudden arrhythmic death syndrome (SADS) was the most common autopsy finding (n = 385, 45%), followed by myocardial diseases (n = 275; 32%) cases, atherosclerotic coronary artery disease (CAD) (n = 58, 7%) and coronary artery anomalies (n = 29, 3%). In most of cases, death occurred during exercise (n = 737; 87%) . Arrhythmogenic cardiomyopathy (ACM) was more common in black (n = 13; 25%) than in white (n = 109; 14%) and Asian (n = 3; 8%) athletes (p = 0.03 between black and white athletes; p = 0.04 between black and Asian athletes); in contrast, CAD was more common in Asians (n = 6; 15% vs n = 51; 7% in whites vs 2% n = 1; in blacks, p = 0.02 between Asian and black athletes). Among white athletes, ACM was more common in individuals who died during exercise than in the ones who died at rest (p = 0.005). Such a difference was not observed in Asian and black athletes. In Asian athletes, CAD was the diagnosis at autopsy in 18% of individuals who died during exercise and in none of individuals who died at rest. CONCLUSIONS: A structurally normal heart at autopsy and myocardial diseases are the most common findings in athletes who died suddenly. While ACM is more common in black athletes, atherosclerotic CAD is more common in Asian athletes, with a strong association with exercise-induced SCD. ACM appears to be a driver of exercise-induced SCD in white athletes, however this is not the case in black and Asian athletes.

A sudden death in an athlete is an uncommon but highly tragic event which appears almost paradoxical, as athletes epitomize the healthiest segment of society. Inherited and familiar cardiac conditions are the main causes of sudden death in young individuals and athletes. Studies on this matter have mainly focused on Caucasian athletes and the frequency or the causes of sudden death in athletes of other ethnicities is largely unknown. Our study focusses on this aspect and reveals that causes of sudden death may highly vary among athletes of different race. The circumstances of death differ significantly among various ethnicities, even looking at the same underlying cardiac condition.

Higher-order G-quadruplex structures and porphyrin ligands: Towards a non-ambiguous relationship.

Herein, we evaluated the interaction of the tetracationic porphyrin H2TCPPSpm4 with three distinct DNA G-quadruplex (G4) models, i.e., the tetramolecular G4 d(TGGGGT)4 (Q1), the 5'-5' stacked G4-dimer [d(CGGAGGT)4]2 (Q2), and a mixture of 5'-5' stacked G-wires [d(5'-CGGT-3'-3'-GGC-5')4]n (Qn). The combined data obtained from UV-Vis, CD, fluorescence, PAGE, RLS, AFM, NMR, and HPLC-SEC experiments allowed us to shed light on the binding mode of H2TCPPSpm4 with the three G4 models differing for the type and the number of available G4 ending faces, the length of the G4 units, and the number of stacked G4 building blocks. Specifically, we found that H2TCPPSpm4 interacted with the shortest Q1 as an end-stacking ligand, whereas the groove binding mode was ascertained in the case of the Q2 and Qn G4 models. In the case of the interaction with Q1 and Qn, we found that H2TCPPSpm4 induces the formation of supramolecular aggregates at porphyrin/G4 ratios higher than 2:1, whereas no significant aggregation was observed for the interaction with Q2 up to the 5:1 ratio. These results unambiguously demonstrated the suitability of porphyrins for the development of specific G4 ligands or G4-targeting diagnostic probes, being H2TCPPSpm4 capable to distinguish between different G4s.

Application of Aquaporins as Markers in Forensic Pathology: A Systematic Review of the Literature.

The study of aquaporins (AQPs) in various forensic fields has offered a promising horizon in response to the need to have reliable elements for the identification of the manner of death and for the individuation of forensic markers for the timing of lesions and vitality of injury. In the literature, various tissues have been studied; the most investigated are the lungs, brain, kidneys, skin, and blood vessels. A systematic literature review on PubMed following PRISMA 2020 guidelines enabled the identification of 96 articles. In all, 34 of these were enrolled to identify Aquaporin-like (AQP-like) forensic markers. The analysis of the literature demonstrated that the most significant markers among the AQPs are as follows: for the brain, AQP4, which is very important in brain trauma and hypoxic damage; AQP3 in the skin lesions caused by various mechanisms; and AQP5 in the diagnosis of drowning. Other applications are in organ damage due to drug abuse and thrombus dating. The focus of this review is to collect all the data present in the literature about the forensic application of AQPs as forensic markers in the most important fields of application. In the current use, the individuation, validation, and application of markers in forensic investigation are very useful in real forensic applications in cases evaluated in court.

Persistence of vitamin D deficiency among Italian patients with acute myocardial infarction.

BACKGROUND AND AIMS: Vitamin D deficiency is a common cardiovascular risk factor associated with the development of atherosclerosis. We evaluated changes in 25(OH)D concentrations in 1510 patients with acute myocardial infarction (AMI) over a long observation period, including the COVID-19 pandemic. METHODS AND RESULTS: Patients were separated into four groups according to the year of enrolment, group 1 (2009-2010), group 2 (2014-2016), group 3 (2017-2019), and group 4 (2020-2022). The median 25(OH)D concentration in the overall cohort was 17.15 (10.3-24.7) ng/mL. The median plasma concentrations of 25(OH)D for groups 1, 2, 3, and 4 were 14.45 (7.73-22.58) ng/mL, 17.3 ng/mL (10.33-24.2), 18.95 (11.6-26.73) ng/mL and 19.05 (12.5-27.3) ng/mL, respectively. Although 25(OH)D levels increased over the years, the prevalence of vitamin D deficiency remained high in each group (68.4%, 61.4%, 53.8%, and 52% respectively). Hypovitaminosis D was predicted by the season influence (OR:2.03, p < 0.0001), higher body mass index (OR:1.25; p = 0.001), diabetes mellitus (OR:1.54; p = 0.001), smoking (OR:1.47; p = 0.001), older age (OR:1.07; p = 0.008), higher triglycerides levels (OR:1.02; p = 0.01), and female gender (OR:1.3; p = 0.038). After multivariable adjustment, vitamin D ≤ 20 ng/mL was an independent predictor of mortality. CONCLUSION: Vitamin D deficiency is highly prevalent and persistent in patients with AMI despite a trend towards increasing 25(OH)D concentrations over the years. The frequent lockdowns did not reduce the levels of 25(OH)D in the fourth group. Low levels of 25(OH)D are an independent predictor of mortality.

Exploring the DNA2-PNA heterotriplex formation in targeting the Bcl-2 gene promoter: A structural insight by physico-chemical and microsecond-scale MD investigation.

Peptide Nucleic Acids (PNAs) represent a promising tool for gene modulation in anticancer treatment. The uncharged peptidyl backbone and the resistance to chemical and enzymatic degradation make PNAs highly advantageous to form stable hybrid complexes with complementary DNA and RNA strands, providing higher stability than the corresponding natural analogues. Our and other groups' research has successfully shown that tailored PNA sequences can effectively downregulate the expression of human oncogenes using antigene, antisense, or anti-miRNA approaches. Specifically, we identified a seven bases-long PNA sequence, complementary to the longer loop of the main G-quadruplex structure formed by the bcl2midG4 promoter sequence, capable of downregulating the expression of the antiapoptotic Bcl-2 protein and enhancing the anticancer activity of an oncolytic adenovirus. Here, we extended the length of the PNA probe with the aim of including the double-stranded Bcl-2 promoter among the targets of the PNA probe. Our investigation primarily focused on the structural aspects of the resulting DNA2-PNA heterotriplex that were determined by employing conventional and accelerated microsecond-scale molecular dynamics simulations and chemical-physical analysis. Additionally, we conducted preliminary biological experiments using cytotoxicity assays on human A549 and MDA-MB-436 adenocarcinoma cell lines, employing the oncolytic adenovirus delivery strategy.

A Hospital Medical Record Quality Scoring Tool (MeReQ): Development, Validation, and Results of a Pilot Study.

Hospital medical records are valuable and cost-effective documents for assessing the quality of healthcare provided to patients by a healthcare facility during hospitalization. However, there is a lack of internationally validated tools that measure the quality of the whole hospital medical record in terms of both form and content. In this study, we developed and validated a tool, named MeReQ (medical record quality) tool, which quantifies the quality of the hospital medical record and enables statistical modeling using the data obtained. The tool was applied to evaluate a sample of hospital individual patient medical records from a secondary referral hospital and to identify the departments that require quality improvement interventions and the effects of improvement actions already implemented.

Yield of molecular autopsy in sudden cardiac death in athletes: data from a large registry in the UK.

AIMS: Sudden cardiac death (SCD) may occur in apparently healthy individuals, including athletes. The aim was to investigate the diagnostic role of post-mortem genetic testing, molecular autopsy (MA), in elucidating the cause of SCD in athletes. METHODS AND RESULTS: We reviewed a database of 6860 consecutive cases of SCD referred to our specialist cardiac pathology centre. All cases underwent detailed cardiac autopsy, and 748 were deemed to be athletes. Of these, 42 (6%) were investigated with MA (28 using a targeted sequencing, 14 exome sequencing). Variants were classified as pathogenic, likely pathogenic, or variant of unknown significance using international guidelines. Clinical information was obtained from referring coroners who completed a detailed health questionnaire. Out of the 42 decedents (average age 35 years old, 98% males) who were investigated with MA, the autopsy was in keeping with a structurally normal heart [sudden arrhythmic death syndrome (SADS)] in n = 33 (78%) cases, followed by arrhythmogenic cardiomyopathy (ACM) in eight (19%) individuals and idiopathic left ventricular fibrosis in one (2%). Death occurred during exercise and at rest in 26 (62%) and 16 (38%) individuals, respectively. Variants that were adjudicated clinically actionable were present in seven cases (17%). There was concordance between the genetic and phenotypic findings in two cases of ACM (in FLNC and TMEM43 genes). None of the variants identified in SADS cases were previously linked to channelopathies. Clinically actionable variants in cardiomyopathy-associated genes were found in five cases of SADS. CONCLUSION: The yield of MA in athletes who died suddenly is 17%. In SADS cases, clinically actionable variants were found in cardiomyopathy-associated genes and not in channelopathy-associated genes. Arrhythmogenic cardiomyopathy is a common cause of SCD in athletes, and one in four decedents with this condition had a clinically actionable variant in FLNC and TMEM43 genes.

Quantification of 108 illicit drugs and metabolites in bile matrix by LC-MS/MS for the toxicological testing of sudden death cases.

Sudden death could occur after assumption of illicit drugs for recreational purposes in adults or after intoxication in children, and toxicological testing would help identify the cause of the death. Analytical methods sensitive and specific for the quantification of a great number of drugs and metabolites in at least 2 matrices should be used. Bile, collected postmortem, may be considered a specimen alternative to blood and urine to perform toxicological testing because of its extended detection window. The present study proposed a LC-MS/MS method to quantify 108 drugs and metabolites in bile. Compounds belonging to the drugs of abuse classes of amphetamines, benzodiazepines, cocaine derivatives, barbiturates, opioids, z-drugs, and psychedelics were analyzed. The sample preparation is simple and does not require solid-phase extraction. The proposed method showed an appropriate selectivity, specificity, accuracy, and precision of the calibrators and quality controls tested (precision < 15%; accuracy < 100 ± 15%). The sensitivity allowed to identify low amounts of drugs (e.g., morphine limit of detection = 0.2 µg/L; limit of quantification = 1.1 µg/L). There is no significant matrix effect, except for buprenorphine and 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol. Carry-over was not present. Analytes were stable at least for 1 month at - 20 °C. Analyzing 13 postmortem specimens, methadone (50%), and cocaine (37.5%) resulted to be the most prevalent consumed substances; the concentrations quantified in bile resulted to be higher than the ones in blood suggesting bile as a potential new matrix for identifying illicit drugs and their metabolites.

Subcellular Effectors of Cocaine Cardiotoxicity: All Roads Lead to Mitochondria-A Systematic Review of the Literature.

Cocaine abuse is a serious public health problem as this drug exerts a plethora of functional and histopathological changes that potentially lead to death. Cocaine causes complex multiorgan toxicity, including in the heart where the blockade of the sodium channels causes increased catecholamine levels and alteration in calcium homeostasis, thus inducing an increased oxygen demand. Moreover, there is evidence to suggest that mitochondria alterations play a crucial role in the development of cocaine cardiotoxicity. We performed a systematic review according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) scheme to evaluate the mitochondrial mechanisms determining cocaine cardiotoxicity. Among the initial 106 articles from the Pubmed database and the 17 articles identified through citation searching, 14 final relevant studies were extensively reviewed. Thirteen articles included animal models and reported the alteration of specific mitochondria-dependent mechanisms such as reduced energy production, imbalance of membrane potential, increased oxidative stress, and promotion of apoptosis. However, only one study evaluated human cocaine overdose samples and observed the role of cocaine in oxidative stress and the induction of apoptosis though mitochondria. Understanding the complex processes mediated by mitochondria through forensic analysis and experimental models is crucial for identifying potential therapeutic targets to mitigate or reverse cocaine cardiotoxicity in humans.

Mental health law: a comparison of compulsory hospital admission in Italy and the UK.

In Europe, the mental health law legal framework has had several changes throughout the years to achieve and develop new reforms, better mental health care, and protect the human rights of patients. The UK national data shows rising detention rates and the disproportionate use of the legal framework among people from black and minority ethnic groups. At the national level, compulsory admissions are lower in Italy; it also shows that it has increased in the last few years in both countries. The lack of ethnic national data, especially in Italy, limited the ability to understand compulsory admission, discrimination, and stigma in mental health. The present study aims to compare the legal framework of mental health law and compulsory hospital admission in Italy and the UK. A review of each country's latest amendments to mental health law and the number of compulsory hospital admissions was conducted to understand the impact of changes in mental health care.

Polymorphism of G-quadruplexes formed by short oligonucleotides containing a 3'-3' inversion of polarity: From G:C:G:C tetrads to π-π stacked G-wires.

G-wires are supramolecular DNA structures based on the G-quadruplex (G4) structural motif obtained by the self-assembly of interlocked slipped G-rich oligonucleotide (ON) strands, or by end-to-end stacking of G4 units. Despite the increasing interest towards G-wires due to their potential applications in DNA nanotechnologies, the self-assembly process to obtain G-wires having a predefined length and stability is still neither completely understood nor controlled. In our previous studies, we demonstrated that the d(5'CG2-3'-3'-G2C5') ON, characterized by the presence of a 3'-3'-inversion of polarity site self-assembles into a G-wire structure when annealed in the presence of K+ ions. Herein, by using CD, PAGE, HPLC size exclusion chromatography, and NMR investigations we studied the propensity of shorter analogues having sequences 5'CGn-3'-3'-GmC5' (with n = 1 and 1 ≤ m ≤ 3) to form the corresponding G-quadruplexes and stacked G-wires. The results revealed that the formation of G-wires starting from d(5'CGn-3'-3'-GmC5') ONs is possible only for the sequences having n and m > 1 in which both guanosines flanking the 5'-ending cytosines are not involved into the 3'-3' phosphodiester bond.

COVID-19-Related Myocarditis: Are We There Yet? A Case Report of COVID-19-Related Fulminant Myocarditis.

There is increasing evidence of cardiac involvement in COVID-19 cases, with a broad range of clinical manifestations spanning from acute life-threatening conditions such as ventricular dysrhythmias, myocarditis, acute myocardial ischemia and pulmonary thromboembolism to long-term cardiovascular sequelae. In particular, acute myocarditis represents an uncommon but frightening complication of SARS-CoV-2 infection. Even if many reports of SARS CoV-2 myocarditis are present in the literature, the majority of them lacks histological confirmation of cardiac injury. Here, we report a case of a young lady, who died suddenly a few days after testing positive for SARS-CoV-2, whose microscopic and genetics features suggested a direct cardiac involvement compatible with fulminant myocarditis.

Oxidative Stress Markers in Human Brain and Placenta May Reveal the Timing of Hypoxic-Ischemic Injury: Evidence from an Immunohistochemical Study.

During pregnancy, reactive oxygen species (ROS) serve as crucial signaling molecules for fetoplacental circulatory physiology. Oxidative stress is thought to sustain the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). A retrospective study was performed on the brains and placentas of fetuses and newborns between 36-42 weeks of gestation (Group_1: Fetal intrauterine deaths, Group_2: Intrapartum deaths, Group_3: Post-partum deaths, Control group sudden neonatal death); all groups were further divided into two subgroups (Subgroup_B [brain] and Subgroup_P [placenta]), and the study was conducted through the immunohistochemical investigations of markers of oxidative stress (NOX2, 8-OHdG, NT, iNOS), IL-6, and only on the brain samples, AQP4. The results for the brain samples suggest that NOX2, 8-OHdG, NT, iNOS, and IL-6 were statistically significantly expressed above the controls. iNOS was more expressed in the fetal intrauterine death (Group_1) and less expressed in post-partum death (Group_3), while in intrapartum death (Group_2), the immunoreactivity was very low. IL-6 showed the highest expression in the brain cortex of the fetal intrauterine death (Group_1), while intrapartum death (Group_2) and post-partum death (Group_3) showed weak immunoreactivity. Post-partum death (Group_3) placentas showed the highest immunoreactivity to NOX2, which was almost double that of the fetal intrauterine death (Group_1) and intrapartum death (Group_2) placentas. Placental tissues of fetal intrauterine death (Group_1) and intrapartum death (Group_2) showed higher expression of iNOS than post-partum death (Group_3), while the IL-6 expression was higher in the fetal intrauterine death (Group_1) than the post-partum death (Group_3). The AQP4 was discarded as a possible marker because the immunohistochemical reaction in the three groups of cases and the control group was negative. The goal of this study, from the point of view of forensic pathology, is to provide scientific evidence in cases of medical liability in the Obstetric field to support the clinical data of the timing of HIE.

Evaluation of a Set of miRNAs in 26 Cases of Fatal Traumatic Brain Injuries.

In forensic medicine, identifying novel biomarkers for use as diagnostic tools to ascertain causes of death is challenging because of sample degradation. To that aim, a cohort (n = 26) of fatal traumatic brain injuries (TBIs) were tested for three candidate miRNAs (namely, miR-124-3p, miR-138-5p, and miR144-3p). For each case, three FFPE specimens (coup area (CA), contrecoup area (CCA), and the corpus callosum (CC)) were investigated, whereas the FFPE brain tissues of 45 subjects (deceased due to acute cardiovascular events) were used as controls. Relative quantification via the ∆∆Ct method returned significantly higher expression levels of the three candidate miRNAs (p < 0.01) in the TBI cases. No difference was detected in the expression levels of any miRNA investigated in the study among the CA, CCA, and CC. Furthermore, the analyzed miRNAs were unrelated to the TBI samples' post-mortem intervals (PMIs). On the contrary, has-miR-124-3p ahashsa-miR-144-3p were significantly correlated (p < 0.01) with the agonal time in TBI deaths. Since the RNA was highly degraded in autoptic FFPE tissues, it was impossible to analyze the mRNA targets of the miRNAs investigated in the present study, highlighting the necessity of standardizing pre-analytical processes even for autopsy tissues.

Molecular Autopsy in Asphyxia Deaths: Diagnostic Perspectives of miRNAs in the Evaluation of Hypoxia Response.

The forensic investigation of asphyxia deaths still poses a challenge due to the need to demonstrate vital exposure to hypoxic insult according to high levels of evidence. The pulmonary effects of hypoxia are complex and the understanding of the mechanisms underlying the acute pneumotoxicity induced by hypoxia is still incomplete. Redox imbalance has been suggested as the protagonist of the main acute changes in pulmonary function in the hypoxic context. The development of knowledge in biochemistry and molecular biology has allowed research in forensic pathology to identify some markers useful in immunohistochemical diagnostics of asphyxia deaths. Several studies have highlighted the diagnostic potential of markers belonging to the HIF-1α and NF-kB pathways. The central role of some highly specific microRNAs has recently been recognized in the complex molecular mechanisms involved in the hypoxia response; thus, several research activities are currently aimed at identifying miRNAs involved in the regulation of oxygen homeostasis (hypoxamiR). The aim of the manuscript is to identify, the miRNAs involved in the early stages of the cellular response to hypoxia, in order to characterize the possible implications in the forensic field of the determination of expression profiles. At present, more than 60 miRNAs involved in the hypoxia response with different expression profiles (upregulation and downregulation) have been identified. Despite the multiple and different effects on reprogramming following the hypoxic insult, the evaluation of the diagnostic implications of hypoxamiRs in the forensic field presupposes a specific treatment of the influences on HIF-1α regulation, cell cycle progression, DNA repair, and apoptosis.

Sudden Cardiac Death Among Adolescents in the United Kingdom.

BACKGROUND: Causes and precipitating factors of sudden cardiac death (SCD) in adolescents are poorly understood. OBJECTIVES: The authors sought to investigate the etiologies of SCD and their association with physical activity in a large cohort of adolescents. METHODS: Between 1994 and June 2022, 7,675 cases of SCD were consecutively referred to our national cardiac pathology center; 756 (10%) were adolescents. All cases underwent detailed autopsy evaluation by expert cardiac pathologists. Clinical information was obtained from referring coroners. RESULTS: A structurally normal heart, indicative of sudden arrhythmic death syndrome was the most common autopsy finding (n = 474; 63%). Myocardial diseases were detected in 163 cases (22%), including arrhythmogenic cardiomyopathy (n = 36; 5%), hypertrophic cardiomyopathy (n = 31; 4%), idiopathic left ventricular hypertrophy (n = 31; 4%), and myocarditis (n = 30; 4%). Coronary artery anomalies were identified in 17 cases (2%). Decedents were competitive athletes in 128 cases (17%), and 159 decedents (21%) died during exercise. Arrhythmogenic cardiomyopathy was diagnosed in 8% of athletes compared with 4% of nonathletes (P = 0.05); coronary artery anomalies were significantly more common in athletes (9% vs 1%; P < 0.001), as well as commotio cordis (5% compared with 1% in nonathletes; P = 0.001). The 3 main comorbidities were asthma (n = 58; 8%), epilepsy (n = 44; 6%), and obesity (n = 40; 5%). CONCLUSIONS: Sudden arrhythmic death syndrome and myocardial diseases are the most common conditions diagnosed at autopsy in adolescent victims of SCD. Among causes of SCD, arrhythmogenic cardiomyopathy, coronary artery anomalies, and commotio cordis are more common in young athletes than in similar age sedentary individuals.