Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues.

Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.

Reporting Incidents in the Psychiatric Intensive Care Unit: A Retrospective Study in an Italian University Hospital.

ABSTRACT: To evaluate the characteristics of the reported workplace violence in a psychiatric intensive care unit (PICU) by analyzing an electronic hospital incident reporting system (IRS). One hundred thirty reports were retrieved from January 2017 to June 2020, referring to assaults committed by patients (71% males) with an average age of 29.8 years (SD, 14.9). The most frequent psychiatric diagnosis was a neurodevelopmental disorder (33%). Physical aggression (84%) was more frequent than the other types of aggression. Nurses and unlicensed assistive personnel were the most frequent victims (65%). Aggressions were more frequent on Friday (18%) and between 4 p.m. and 8 p.m. (35%). A total of 64.9% of the incidents happened in the first 5 days of hospitalization. A significant association between physical aggression and diagnosis of neurodevelopmental disorder emerged. IRS could be helpful to identify high-risk patient groups and develop clinical strategies to reduce adverse events in clinical practice.

Forensic Analysis and Identification Processes in Mass Disasters: Explosion of Gun Powder in the Fireworks Factory.

A mass disaster is a situation that involves criticality between the number of victims and resources, in terms of both men and means, present on the site of an event that is mostly unexpected and sudden. In the multidisciplinary teams that intervene, the role of forensic pathologists, who are responsible for the direction and coordination of post-mortem operations, is central, and must remain so. The authors report the case of an explosion of a pyrotechnic artifice factory, as a result of which numerous victims and injuries are recorded. So, the team completed the autopsies and created a protocol to obtain biological samples (bones, blood, teeth, muscles), while the forensic pathologists contacted the families of the alleged victims and each provided a blood sample that was collected for the DNA. The geneticist, using the method of gene extraction and amplification, obtained the DNA from each bone, tooth, and muscle of blood taken from the victims and then compared it with that extracted from the blood samples of the relatives; the electropherograms showed at least one allele for each genetic marker of the "Combined DNA Index System" in common between the victims and the families, thus allowing to establish the identity of all the subjects involved in the event. Having established the identity of all workers, it was possible to determine their whereabouts in the environment at the time of the location of fires and explosions. The results of the various forensic analyzes (autopsies, genetic investigations and even traumatological investigations) have allowed us to validate a scientific method useful in all mass disasters even when any type of anthropological or forensic dental research is difficult.

Post-mortem persistence of SARS-CoV-2: a preliminary study.

Since the beginning of March 2020, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been the cause of millions of deaths worldwide. The need to better define the pathogenesis of coronavirus disease 19 (Covid-19) as well as to provide the correct statistical records concerning deaths related to this virus, inevitably involves the role of forensic pathology and routine autopsy practice. Currently, some data on macroscopic and microscopic features in autopsies performed in suspected Covid-19 cases are reported in the literature. The persistence of SARS-CoV-2 in cadavers has not yet been elucidated and only a few reports have emphasized the importance of evaluating the Virus RNA in post-mortem tissues. In this preliminary study, we observed that SARS-CoV-2 survives in multiple cadaver tissues many days after death despite some extreme conditions of post-mortem body preservation. The results of this on-going analysis could help improve the safety of working practices for pathologists as well as understanding the possible interaction between microbiological agents and the cadaver tissue's supravital reactions.

Medico-legal assessment of personal damage in older people: report from a multidisciplinary consensus conference.

Ageing of the global population represents a challenge for national healthcare systems and healthcare professionals, including medico-legal experts, who assess personal damage in an increasing number of older people. Personal damage evaluation in older people is complex, and the scarcity of evidence is hindering the development of formal guidelines on the subject. The main objectives of the first multidisciplinary Consensus Conference on Medico-Legal Assessment of Personal Damage in Older People were to increase knowledge on the subject and establish standard procedures in this field. The conference, organized according to the guidelines issued by the Italian National Institute of Health (ISS), was held in Bologna (Italy) on June 8, 2019 with the support of national scientific societies, professional organizations, and stakeholders. The Scientific Technical Committee prepared 16 questions on 4 thematic areas: (1) differences in injury outcomes in older people compared to younger people and their relevance in personal damage assessment; (2) pre-existing status reconstruction and evaluation; (3) medico-legal examination procedures; (4) multidimensional assessment and scales. The Scientific Secretariat reviewed relevant literature and documents, rated their quality, and summarized evidence. During conference plenary public sessions, 4 pairs of experts reported on each thematic area. After the last session, a multidisciplinary Jury Panel (15 members) drafted the consensus statements. The present report describes Conference methods and results, including a summary of evidence supporting each statement, and areas requiring further investigation. The methodological recommendations issued during the Conference may be useful in several contexts of damage assessment, or to other medico-legal evaluation fields.

Head CT scan in emergency room: Is it still abused? Quantification and causes analysis of overprescription in an Italian Emergency Department.

In recent years, the increasing prescription of diagnostic imaging has been noted, due to advances in imaging technology and the development of defensive medicine. Overuse of diagnostic imaging significantly impacts the quality and costs of health care. Therefore, the purpose of this study was to quantify overprescription and investigate its causes through the evaluation of head computer tomography (CT) scan prescriptions. In this study, a set of 100 requests of CT scans was collected and analysed by three experts in guidelines and scientific evidences, evaluating prescription appropriateness. Then, the rate of overprescription was quantified and its causes identified as incorrect adoption of guidelines indications (32%) and as defensive medicine (6%). Therefore, in order to reduce inappropriate investigations, the findings of the present study suggest that the reduction in overprescription could be reached through the improvement of training of health personnel and the propagation of a no-blame culture aimed at minimizing defensive medicine.

Occult cardiac amyloidosis: the last chapter of a 2-year long story.

Amyloidosis is characterized by deposition of insoluble fibrillar proteins in organs and tissues. The prognosis depends on where in the body amyloid deposition occurs, the amount of deposition, and the symptoms, which are often unspecific. Cardiac involvement is commonly associated with the immunoglobulin light-chain amyloidosis (AL) and may lead to sudden death. The case of a 53-year-old man's death due to unsuspected, undiagnosed AL predominantly involving the myocardium has been reported. His medical history had begun with gastroenterological symptoms. Angina pectoris and brain stroke occurred in the following years. He died after two years during the surgical implantation of a cardioverter-defibrillator because of cardiogenic shock. Post-mortem histologic examination revealed the presence of amyloid material in the lymph nodes, lungs, liver, spleen, kidneys, adrenal glands, stomach, and heart. The cause of death was cardiac failure secondary to primary systemic amyloidosis predominantly involving the heart. This case demonstrates that amyloidosis should be considered within the differential diagnoses and actively investigated in patients with unspecific and long-lasting symptoms; medical liability may also be suspected.

[Correction: Adverse events and preventable consequences: retrospective study in five large Italian hospitals]. / Correzione: Eventi avversi e conseguenze prevenibili: studio retrospettivo in cinque grandi ospedali italiani.

[This corrects the Table 4 of the article: pmid: 22828228].

Off-label and unlicensed drug use among neonatal intensive care units in Southern Italy.

BACKGROUND: Many drugs used for neonates are unlicensed or off-label. An increased risk of medication errors and unexpected adverse drug reactions is associated with their use. This risk is even higher in preterm newborns, because of their physiological immaturity and the exposure to many different medicines. The objective of this study was to evaluate the use of unlicensed or off-label drugs in eight tertiary-level neonatal intensive care units (NICU) from two different southern Italian regions. METHODS: All drugs prescribed to newborns admitted to each NICU, during 1 month of observation, were recorded and classified as licensed, unlicensed or off-label, according, respectively, first, to their license status and, then, their indications, dose, treatment route, and duration of treatment specified in each specific marketing authorization. RESULTS: A total of 126 newborns were treated with at least one drug during the observation period. A total of 483 prescriptions referred to 87 different drugs, classified as licensed, unlicensed or off-label. Each newborn was exposed to three (median) different drugs; 88.6% were licensed and 11.4% unlicensed (range, according to different NICU, 1.9-26.7%). Among licensed drugs, 37.4% were used as off-label (range, 27.3-53.4%). CONCLUSIONS: The use of unlicensed or off-label drugs use is common practice in NICU, with wide variation in local policies and newborn characteristics. Well-designed and -conducted pharmaceutical studies in newborns are needed to increase the number of licensed drugs, thereby reducing any risk for patients due to over- or under-treatment, and also legal issues for clinicians.

A case of suicide by ingestion of caffeine.

Intentional or unintentional caffeine abuse due to excessive intake of beverages or energy drinks containing caffeine is relatively frequent. However, death due to caffeine intoxication is rare and case reports of fatalities from caffeine toxicity are relatively infrequent. In this report, we describe an autopsy case involving a 31 year-old man who intentionally took a large amount of caffeine tablets in the form of a weight loss supplement as part of a suicide plan. Caffeine femoral blood concentration (170 mg/l) was within the toxic and potentially lethal ranges reported in the literature in similar cases. Postmortem biochemistry results suggested depressed glomerular filtration rate and pre-renal failure at the time of death but failed to reveal myoglobinuria, glycosuria, ketonuria or ketonemia. Based on the absence of pathological findings at autopsy and the high blood caffeine level, death was attributed to acute caffeine toxicity. The case emphasizes the usefulness of performing exhaustive toxicology and searching for all potentially relevant information in order to formulate appropriate hypotheses concerning the cause and manner of death.

Haemorrhage and Survival Times: Medical-Legal Evaluation of the Time of Death and Relative Evidence.

Haemorrhage is the name used to describe the loss of blood from damaged blood vessels (arteries, veins, capillaries). Identifying the time of haemorrhage remains a clinical challenge, knowing that blood perfusion of systemic tissues is poorly correlated with the perfusion of specific tissues. In forensic science, one of the most discussed elements is the time of death. This study aims to provide the forensic scientist with a valid model to establish a precise time-of-death interval in cases of exsanguination following trauma with vascular injury, which can be useful as a technical aid in the investigation of criminal cases. To calculate the calibre and resistance of the vessels, we used an extensive literature review of distributed one-dimensional models of the systemic arterial tree as a reference. We then arrived at a formula that allows us to estimate, based on a subject's total blood volume and the calibre of the injured vessel, a time interval within which a subject's death from haemorrhage from vascular injury falls. We applied the formula to four cases in which death had been caused by the injury of a single arterial vessel and obtained comforting results. The study model we have offered is only a good prospect for future work. In fact, we intend to improve the study by expanding the case and statistical analysis with particular regard to the interference factors to confirm its actual usability in practical cases; in this way, useful corrective factors can be identified.

Healthcare Liability and Thyroidectomy: When Is the Surgeon Wrong?

Thyroid surgeries can often lead to operative complications, sometimes with consequences on the patient's health. This often leads to claims for compensation but the assessments of consultants and judges are not always objective. Based on these considerations, the authors analyzed forty-seven sentences issued between 2013 and 2022 regarding claims of alleged medical malpractice. This analysis aims to examine the cases presented in the sentences and the evaluations proposed by the judges to offer ideas for objective evaluation by the legislation in force in Italy.

How Much Is an Abortion Worth? Was a Human "Not Formed"? An Italian Proposal.

INTRODUCTION: "Human capital" is defined as an integration of innate skills and knowledge acquired by investing in the formation of an individual; it is a real "capital" that pays off in the long term. In the Italian legal system, a human being is recognised as a "person" from the moment of birth. This determines the acquisition of the personal rights of an individual. Necessarily, therefore, by law, a fetus does not own such rights; nevertheless, it has an innate "potential" to acquire such rights after birth. OBJECTIVE: In Italian jurisprudence, in general, the damage from a loss of a parental relationship is justified by the condition of existential emptiness caused in the family by the loss of a child. Compensation for this damage in the event of abortion due to third-party responsibility presents a non-uniform recognition in the judgements of the Italian courts, but in any case, it is almost always recognised with limitations since the emotional relationship with the lost individual is defined only in terms of "potential". Consequently, in this matter, at least two questions can be raised: (i) Is the economic estimate of abortion based on objective and standardised criteria, or is it heavily influenced by subjective evaluation? (ii) Is it possible to find standard criteria that may act as guidelines to quantify the loss of that human capital "in progress"? METHODOLOGY: The authors try to answer these questions by analysing the different approaches to this issue adopted at an international level. CONCLUSIONS: In conclusion, the authors propose homogeneous criteria to quantify the damage caused by abortion.

Requests for Compensation in Cases Involving Patients' Falls in Healthcare Settings: A Retrospective Analysis.

Falls are the most frequent adverse events recorded in healthcare facilities. By employing a multifaceted strategy to ensure prevention interventions that are specific to the patient type and environmental risk management, risk factor evaluation may help to reduce falls in the hospital setting. Patient falls are one of the main causes of lawsuits against hospitals, which has led to the development of validated instruments that are beneficial in treating the patient after the incident and effective in minimizing the frequency of falls. The aim of our study is to evaluate compensation claims asserting healthcare culpability in situations where a patient fell in a hospital setting. The collected data relate to judgments issued in Italy until December 2022 regarding 30 episodes of falls that occurred between 2003 and 2018. Our research revealed that approximately 50% of Italian healthcare organizations lose the case in court when a patient falls in a hospital setting and dies or is injured. In half of these cases, the failure of the medical staff to use protective equipment against falls is what led to the court's acceptance of the compensation claim. In order to improve the quality of healthcare services, fall prevention techniques must continue to be implemented.

Impact of a Pro-Active Infectious Disease Consultation on the Management of a Multidrug-Resistant Organisms Outbreak in a COVID-19 Hospital: A Three-Months Quasi-Experimental Study.

BACKGROUND: Antimicrobial and diagnostic stewardship (AS/DS) principles are crucial for the management of multidrug-resistant organisms (MDROs) infections. We evaluated the impact of a pro-active Infectious Disease (ID) consultation on the mortality risk of patients during an MDROs outbreak in a COVID-19 hospital. METHODS: A quasi-experimental study was performed in a dedicated COVID-19 hospital, including patients with suspected/confirmed infection and/or colonization by MDROs, which were managed as follows: (i) according to the standard of care during the pre-phase and (ii) in collaboration with a dedicated ID team performing a pro-active bedside evaluation every 48-72 h in the post-phase. RESULTS: Overall, 112 patients were included (pre-phase = 89 and post-phase = 45). The AS interventions included the following: therapy optimization (33%), de-escalation to narrow the spectrum (24%) or to lessen toxic drugs (20%), and discontinuation of antimicrobials (64%). DS included the request of additional microbiologic tests (82%) and instrumental exams (16%). With the Cox model, after adjusting for age, sex, COVID-19 severity, infection source, etiological agents, and post-phase attendance, only age predicted an increased risk of mortality, while attendance in the post-phase resulted in a decreased risk of mortality. CONCLUSIONS: Implementation of AS and DS intervention through a pro-active ID consultation may reduce the risk of 28-day mortality of COVID-19 patients with MDROs infections.

Extraction of DNA from bones in cases where expectations for success are low.

To resolve cases involving unidentified cadavers, the study of polymorphic DNA markers of old bones is an invaluable but often challenging tool used in forensic genetics. Some of the difficulties encountered involve the limited quantity of endogenous DNA, its subsequent degradation (a result of elapsed time, environmental conditions, and the microorganisms that develop during the postmortem phase), and the coextraction of substances that inhibit amplification reactions. For these reasons, it is necessary to direct research toward the development of new extraction techniques with the goal of obtaining adequate quantities of high-quality DNA.The aim of this study was to improve the collection of extracted DNA compared with the amount of DNA obtained with the NucleoSpin DNA Trace Kit (Macherey Nagel) protocol for the extraction of genomic DNA from human bones. A modified version of the standard protocol is presented.The modified method for the extraction of genomic DNA, followed by amplification reaction, allowed for identification of 4 cadavers and typification of 1 cadaver. The study carried out involved unidentified cadavers, or their remains, discovered after a long period from time of death.

[Adverse events and preventable consequences: retrospective study in five large Italian hospitals]. / Eventi avversi e conseguenze prevenibili: studio retrospettivo in cinque grandi ospedali italiani.

OBJECTIVE: To define the incidence of adverse events and their preventability in a representative sample of patients in five acute hospitals located in the North, the Centre and the South of Italy. Other objectives include the evaluation of the consequences of adverse events and their distribution according to specialties. DESIGN: Retrospective and multicentre study. The methodology is focused on the review of clinical records related to hospital admissions in the year 2008 with a sample of 5 hospitals belonging to the national healthcare system selected according to criteria of location (North, Centre and South of Italy) and complexity (regional reference hospitals). The clinical records included in the study were selected in a random way starting from the electronic archives of the hospital discharges of each participating centre. SETTING AND PARTICIPANTS: 7,573 clinical records were reviewed with a process of two stages managed by two reviewers each. The first stage of the review process involved 7 physicians, 1 nurse, 1 pharmacist and 1 biologist with skills and experiences in clinical risk management and in analysis of clinical documentation. The second stage was realized by 10 physicians (5 specialists, 3 experts in public health and 2 forensic physicians), also for the second stage every person involved had specific training in clinical risk management. The reviewers attended a 20-hour training course. MAIN OUTCOME MEASURES: Study of the incidence of adverse events identified during the admissions included. In the case of more than one adverse event for each admission, it is calculated the cumulative incidence of adverse events for each patient. We also considered the percentage of re-admitted patients for each adverse event, the percentage of adverse events which occurred in the phase of pre hospitalization and the degree of preventability of adverse events. A description of the identified adverse events was realized. The sample of the data included in the study was described in terms of included and excluded subjects with respect to the planned research design. Different products and results were tested and validated in the study and could be reused in the future research products. RESULTS: The overall average of the incidences of adverse events was 5.2%, the median was 5.5% and it is consistent with the expected results mentioned in the protocol of the study. The identified incidence of adverse events is lower than the median rate of international studies (9.2%). The distribution of adverse events for specialties underlines the majority of adverse events in the medical area (37.5%), in opposition to the results of other studies; the surgery is the second specialty for number of adverse events (30.1%), followed by the emergency room (6.2%) and obstetrics (4.4%). The study identified 56.7% of adverse events as preventable. The consequences of adverse events were classified in different typologies: the prolonged stay was the most frequent consequence, followed by the disability at discharge. The death of the patient had a median occurrence of 9.45%. The concordance between the two reviewers in the evaluation of the clinical records was very high (higher than 95%) except for two centres. CONCLUSIONS: The results were consistent with the results of other international studies similar in scope in terms of type of study (definition of the rate of adverse events) and epidemiological study design (retrospective study). The incidence rate, previously mentioned as 5.2%, coincides with the unfavorable rates of events determined in varied countries. The preventability resulted in an average of 56.7%. The variability of the results obtained in our inquiry are likely attributable to varied factors occurred during the study.

Digital Health Care, Telemedicine, and Medicolegal Issues in Orthopedics: A Review.

The use of technologies in medicine has great potential to reduce the costs of health care services by making appropriate decisions that provide timely patient care. The evolution of telemedicine poses a series of clinical and medicolegal considerations. However, only a few articles have dealt with telemedicine and orthopedics. This review assesses the ethical and medicolegal issues related to tele-orthopedics. A systematic review was performed including papers published between 2017 and 2021 focusing on the main medicolegal and clinical-governance aspects of tele-orthopedics. Most of the articles were published during the COVID-19 pandemic, confirming the impetus that the pandemic has also given to the spread of telemedicine in the orthopedic field. The areas of interest dealt with in the scientific evidence, almost exclusively produced in the USA, Europe, the UK, and Canada, are quality, patient satisfaction, and safety. The impact of telemedicine in orthopedics has not yet been fully evaluated and studied in terms of the potential medicolegal concerns. Most of the authors performed qualitative studies with poor consistency. Authorizations and accreditations, protection of patient confidentiality, and professional responsibility are issues that will certainly soon emerge.

Italian Legal Euthanasia: Unconstitutionality of the Referendum and Analysis of the "Italian" Problem.

The term "euthanasia" refers to medical interventions that involve the direct administration of a lethal drug to the patient who requests it and meets certain requirements. Currently in Italy euthanasia constitutes a crime and falls within the hypotheses foreseen and punished by Article 579 (Murder of consenting person) or by article 580 (Instigation or aid to suicide) of the penal code. On the contrary, medically assisted suicide in some cases and the suspension of treatment constitute an inviolable right pursuant to art. Thirty two of the Constitution and Law 219/2017. Thanks to the sentence 242/2019 of the Constitutional Court, in Italy it is instead possible to request medically assisted suicide, that is, the indirect help of a doctor to die. There are four conditions required: whoever requests it must be fully capable of understanding and willing, must have an irreversible pathology that is the bearer of severe physical or mental disease, and must survive thanks to life-saving treatments. The Italian referendum "Free until the end" aims to introduce legal euthanasia through the partial repeal of art. 579 c.p. which punishes the murder of the consenting party. The authors analyze the reasons for the referendum in the light of the Italian and European scenario, analyzing the first Italian case of assisted suicide immediately after the referendum which inevitably becomes a starting point for ethical and medico-legal reflection on the issue. On 02.15.2022 the Italian Constitutional Court declared the Referendum on Legal Euthanasia inadmissible.

COVID-19 Vaccination in Italian Children: The Limits of Parental Rights.

SARS-CoV-2 vaccination campaigns initially targeted the adult population. After the authorization of the main agencies, including the EMA (European Medicines Agency), the European Vaccination Plan now involves young people between the ages of 12-17 and 5-11. In assessing the child's "best interests", the refusal of vaccination by parents or guardians, in addition to the increased circulation of the virus, is responsible for the risk of social distancing. This reduction in social contacts, particularly during very sensitive ages such as adolescence, has been linked to the increased incidence of psychiatric illness, a significant reason for extending vaccination against SARS-CoV-2 in these younger children. One may consider that government should issue a law that allows the child to decide on the vaccination plan, even without the consent of the parents or guardians, without the need for a judge's ruling. The availability of the child should be the point of reference, according to the National Bioethics Committee, for consent to vaccination. The authors investigate the subject in depth in order to counteract vaccination hesitation, and promote the dissemination of correct scientific information, using every different possible communication tool, as well as social networks and schools.