Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Uno studio sperimentale per la diagnosi differenziale tra impiccamento e sospensione di cadavere: FOXO3 e troponina I come nuovi marcatori immunoistochimici

Lo studio della vitalità di una lesione è uno degli argomenti più interessanti e allo stesso tempo problematici in Patologia Forense [1]. La distinzione tra una lesione prodotta ante-mortem ed una prodotta post-mortem, valutazione di fondamentale importanza per la interpretazione della dinamica di morte e la risoluzione di casi giudiziari, viene generalmente effettuata sulla base di criteri istologici, che però spesso non si rivelano sufficientemente efficaci per permettere di porre una diagnosi differenziale basata su solide evidenze scientifiche. L’analisi istologica di vitalità si fonda fondamentalmente sulla ricerca di iniziali fenomeni infiammatori e di guarigione. Nel caso particolare del solco di compressione cutanea al collo, tipica lesione che contraddistingue le morti da impiccamento, tale incertezza in merito all’interpretazione del dato istologico è ulteriormente amplificata dal fatto che la protratta azione di compressione esercitata dal mezzo di sospensione determina alcune modificazioni istologicamente apprezzabili che, tuttavia, derivano esclusivamente da azione fisica meccanica e non da compartecipazione di fenomeni infiammatori (vitali), che dunque possono determinarsi anche nel caso di sospensione di cadavere. Appare, dunque, evidente che la distinzione tra impiccamento e sospensione di cadavere è tematica di estremo rilievo, soprattutto se si considera l’elevato numero di casi di impiccamento che ogni anno caratterizzano la casistica forense in tutto il mondo [5]. Ciononostante, al giorno d’oggi non esiste ancora una metodica standardizzata, validata e supportata da solide basi scientifiche, cui il patologo possa avvalersi per dimostrare una reazione di vitalità e conseguentemente determinare se una lesione sia stata provocata in vita o post-mortem. Nell’ambito della dimostrazione di vitalità di una lesione, un importante supporto giunge dalle metodiche immunoistochimiche volte a identificare le molecole coinvolte nella iniziale risposta cellulare all'insulto traumatico. L’attivazione di fenomeni infiammatori acuti/iperacuti in conseguenza dello stimolo lesivo è regolata dall’interazione di varie molecole e cellule, prevalentemente appartenenti al sistema immunitario, delineando così una sequenza temporale di interazioni molecolari. In linea teorica, quindi, risulta possibile valutare la vitalità di una lesione, ed eventualmente fornirne una datazione, sulla base della presenza, o meno, di specifiche molecole e cellule coinvolte in tale fase iniziale di risposta allo stimolo nocivo. Sulla scorta delle evidenze scientifiche raccolte sull’argomento e fin qui esposte, il presente lavoro si propone di studiare, mediante colorazioni immunoistochimiche, l’espressione e la localizzazione a livello tissutale di marker molecolari potenzialmente utili al fine della diagnosi differenziale tra impiccamento e sospensione di cadavere. Basandosi sul fatto che i tessuti cutaneo e muscolare, sottoposti ad una compressione in vita nel corso di impiccamento, subiscono un danno ischemico, abbiamo voluto indagare il profilo immunoistochimico di specifiche proteine. A livello cutaneo, è stata studiata l’espressione di FOXO3, fattore di trascrizione coinvolto nella regolazione dell’apoptosi, mentre a livello muscolare è stato studiato l’effetto che il danno miocitario ha sulla quantità e sulla localizzazione (intra- od extra-cellulare) della fast skeletal muscle troponina I (fs TnI), enzima coinvolto nella regolazione della contrazione muscolare. Il presente studio si prefigge di valutare l’espressione e la localizzazione a livello tissutale di FOXO3 e fsTnI, avvalendosi di tecniche immunoistochimiche, su campioni prelevati a livello di cute e muscoli del collo sottoioidei, in corrispondenza dal solco di compressione cutanea, di soggetti certamente deceduti per impiccamento in modalità suicidaria, al fine della diagnosi differenziale tra impiccamento e sospensione di cadavere. Lo scopo del lavoro, che fa parte di un più ampio filone di ricerca, è quello di valutare l’affidabilità di vari marcatori immunoistochimici, per determinare un panel di marker attendibili da utilizzare per confermare, o smentire, la diagnosi di impiccamento. È importante, infatti, in casi di pertinenza dell’Autorità Giudiziaria, affidarsi a criteri scientifici che forniscano una diagnosi di certezza. Allo stato attuale, non esistono attualmente sufficienti conoscenze sulla sensibilità e specificità di molecole coinvolte nell’apoptosi e nei processi infiammatori della lesione da impiccamento per effettuare una certa diagnosi di vitalità. Pertanto, il presente lavoro porterebbe un utile, immediato e concreto sviluppo delle conoscenze pratiche ed applicative nell'ambito della patologia forense. I risultati ottenuti dimostrano che la cute e gli strati muscolari in corrispondenza del solco da compressione cutanea da impiccamento presentano una deplezione rispettivamente di FOXO3 e fsTnI se paragonati a prelievi di tessuti indenni o lesionati post-mortem. In particolare, è stato possibile dimostrare che FOXO3 risulta depleto o completamente assente (13/13 casi, valore di intensità di colorazione di -2 e -3, valore medio – 2,81), mentre la fsTnI mostra un pattern di deplezione più vario con maggior frequenza di casi positivi (11/13 casi di deplezione, 2/13 casi di positività, valore di intensità di colore tra 0 e -3, valore medio – 1,68). È possibile, dunque, affermare che FOXO3 e fsTnI sono due validi marker immunoistochimici per la diagnosi differenziale di morte da impiccamento e sospensione di cadavere

Hyperacute fatal course in a hypercalcemic crisis

A 39-year-old woman, with a not significant past medical history, entered the Emergency Department complaining about nausea, vomiting, constipation, anorexia, deep asthenia, and diffuse muscle aches with cramps. She referred sporadic diarrhea (one episode) the day before and a worsening headache in the past three days; she also complained about polyuria and polydipsia not investigated for one year. The clinical examination was not significant, apart from the evidence of skin and mucosal dryness, tachycardia, and diffuse abdominal pain. The laboratory tests revealed hypokalemia and elevated beta-human chorionic gonadotropin (β-hCG) plasma levels. An ultrasound abdominal imaging was consistent with kidney lithiasis. Suspecting a hyperemesis gravidarum in a patient with kidney lithiasis, a rehydrating therapy was administered as long as potassium reintegration. During the hospital stay, the patient became drowsy. A haemogasanalysis revealed very high calcium values: 3,379 mmol/L (n.v. 1,120-1,320 mmol/L). Lab tests confirmed very high levels of calcium 21,1 mg/dL (n.v. 9-10,5 mg/dL), as long as increased parathormone (PTH) > 3000 pg/mL (normal values 14-65 pg/mL), and hypokalemia (3,2 mEq/L n.v. 3,50 – 4,50). Ultrasound exam of the neck revealed the presence of a left parathyroid nodule measuring 2,5 x 1,6 cm. Before having time to start an appropriate therapy, the patient died

Four cases of sodium nitrite suicidal ingestion. A new trend and a relevant forensic pathology and toxicology challenge

Sodium nitrite (NaNO2) is an inorganic compound commonly used as a food additive, antifreeze admixture, and fertilizer. Its toxicity mechanism is mainly represented by the oxidation of ferrous iron to ferric iron of one of the four heme structures in haemoglobin with the onset of methaemoglobin. The mechanism of death by sodium nitrite toxicity is severe hypoxia. We present four cases of suicidal sodium nitrite ingestion that closely occurred within a two months-period. Self-poisoning with sodium nitrite actually represents an increasing trend in nitrates' related deaths. In order to reach a precise diagnosis of NaNO2 intoxication, a complete toxicological analysis should be carried out including not only MetHb blood levels but also nitrites and nitrites in standard or alternative matrices as a routine procedure. Autopsy should be carefully performed to detect common indicators of hypoxia or more rarely evident typical by themselves-non specific signs of sodium nitrite toxicity. Suicidal manner of death should be carefully considered when circumstantial data support that ingestion of large amounts of NaNO2 occurred as a consequence of a self-injurious behaviour. Relevant informations include victim's previous Internet or book researches about paths to follow to commit suicide with sodium nitrate, employment and past medical history, with strong regard to psychiatric diseases as well as eventual taking psycotropic drugs. Finally, an accurate integration of autoptic and toxicological results with circumstantial data is necessary to make correct diagnosis of death due to acute respiratory failure secondary to suicidal sodium nitrite ingestion

Death after the Administration of COVID-19 Vaccines Approved by EMA: Has a Causal Relationship Been Demonstrated?

More than eight billion doses of COVID-19 vaccines have been administered globally so far and 44.29% of people are fully vaccinated. Pre-authorization clinical trials were carried out and the safety of vaccines is still continuously monitored through post-commercialization surveillance. However, some people are afraid of vaccine side effects, claiming they could lead to death, and hesitate to get vaccinated. Herein, a literature review of COVID-19-vaccine-related deaths has been carried out according to the PRISMA standards to understand if there is a causal relationship between vaccination and death and to highlight the real extent of such events. There have been 55 cases of death after COVID-19 vaccination reported and a causal relationship has been excluded in 17 cases. In the remaining cases, the causal link between the vaccine and the death was not specified (8) or considered possible (15), probable (1), or very probable/demonstrated (14). The causes of deaths among these cases were: vaccine-induced immune thrombotic thrombocytopenia (VITT) (32), myocarditis (3), ADEM (1), myocardial infarction (1), and rhabdomyolysis (1). In such cases, the demonstration of a causal relationship is not obvious, and more studies, especially with post-mortem investigations, are needed to deepen understanding of the possible pathophysiological mechanisms of fatal vaccine side effects. In any event, given the scarcity of fatal cases, the benefits of vaccination outweigh the risks and the scientific community needs to be cohesive in asserting that vaccination is fundamental to containing the spread of SARS-CoV-2

Insulin and Oral Hypoglycemic Drug Overdose in Post-Mortem Investigations: A Literature Review

Background and Objectives: Insulin and oral hypoglycemic agents are drugs widely used in the world population due to their therapeutic effects on diabetes mellitus. Despite these benefits, they can also cause accidental or voluntary drug overdose. This review aims to evaluate post-mortem investigations in cases of suspected hypoglycemic drug overdose. Materials and Methods: We performed a comprehensive search using the Preferred Reporting Items for Systematic Review (PRISMA) standards; we systematically searched the PubMed, Science Direct Scopus, Google Scholar, and Excerpta Medica Database (EM-BASE) databases from the point of database inception until August 2022. The following inclusion criteria were used: (1) original research articles, (2) reviews and mini-reviews, (3) case reports/series, (4) and only papers written in English. Results: Thirty-three scientific papers, including original research articles, case reports, and case series, fulfilled the inclusion criteria. A total of 109 cases of insulin or hypoglycemic drug overdose were found. There were 71 cases of suicide (65%), 25 cases of accidental poisoning (23%), and 13 cases of homicide (12%). The most commonly used drug was insulin (95.4%). Autopsy and post-mortem examinations were performed in 84 cases, while toxicological investigations were performed in 79 cases. The most common gross findings in the autopsy were pulmonary edema (55.7%) and congestion (41.8%), while the most common histological finding was neuronal depletion or necrosis (29.1%). Conclusions: In the suspicion of death from insulin or overdose from oral hypoglycemic agents, autopsy findings may be nonspecific, and the search for injection marks can be positive at the external examination. Significant post-mortal alterations can interest biological samples and an early autopsy investigation is recommended

6-Monoacetylmorphine-antibody distribution in tissues from heroin-related death cases: An experimental study to investigate the distributive response

Heroin, a semisynthetic opioid drug synthesized from morphine, is the 3,6-diacetyl ester of morphine (diacetylmorphine). The post-mortem diagnosis of heroin-related death could be an issue and usually rely on a combination of investigations, including the autopsy, histological and toxicological analysis. We conducted the present study to evaluate the correlation between the heroin concentration in biological fluids (peripheral blood, bile and urine) and the post-mortem anti-6-MAM antibody expression in various tissues (brain, heart, lung, liver and kidney) using immunohistochemical staining. A quantitative analysis of the immunohistochemical reaction was carried out. 45 cases of heroin-related death investigated at the Forensic Pathology Institutes of the University of Rome, Foggia and Pisa were included. The control group was composed of 15 cases of death due to other causes, without brain lesions and negative toxicological analysis for drugs. We found a positive immunohistochemical reaction in different organs and it was related to the timing of heroin metabolization. No reaction was found in the control group. Our findings show that immunohistochemistry can be a valuable tool for the post-mortem diagnosis of acute heroin abuse. A better understanding of the timing of heroin's metabolism can be useful in the forensic field and for future therapeutic applications

SARS-CoV-2 and the brain: A review of the current knowledge on neuropathology in COVID-19

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the new coronavirus responsible for the pandemic disease in the last year, is able to affect the central nervous system (CNS). Compared with its well-known pulmonary tropism and respiratory complications, little has been studied about SARS-CoV-2 neurotropism and pathogenesis of its neurological manifestations, but also about postmortem histopathological findings in the CNS of patients who died from COVID-19 (coronavirus disease 2019). We present a systematic review, carried out according to the Preferred Reporting Items for Systematic Review standards, of the neuropathological features of COVID-19. We found 21 scientific papers, the majority of which refer to postmortem examinations; the total amount of cases is 197. Hypoxic changes are the most frequently reported alteration of brain tissue, followed by ischemic and hemorrhagic lesions and reactive astrogliosis and microgliosis. These findings do not seem to be specific to SARS-CoV-2 infection, they are more likely because of systemic inflammation and coagulopathy caused by COVID-19. More studies are needed to confirm this hypothesis and to detect other possible alterations of neural tissue. Brain examination of patients dead from COVID-19 should be included in a protocol of standardized criteria to perform autopsies on these subjects