Neutralizing antibodies to Omicron after the fourth SARS-CoV-2 mRNA vaccine dose in immunocompromised patients highlight the need of additional boosters

IntroductionImmunocompromised patients have been shown to have an impaired immune response to COVID-19 vaccines.MethodsHere we compared the B-cell, T-cell and neutralizing antibody response to WT and Omicron BA.2 SARS-CoV-2 virus after the fourth dose of mRNA COVID-19 vaccines in patients with hematological malignancies (HM, n=71), solid tumors (ST, n=39) and immune-rheumatological (IR, n=25) diseases. The humoral and T-cell responses to SARS-CoV-2 vaccination were analyzed by quantifying the anti-RBD antibodies, their neutralization activity and the IFN-γ released after spike specific stimulation.ResultsWe show that the T-cell response is similarly boosted by the fourth dose across the different subgroups, while the antibody response is improved only in patients not receiving B-cell targeted therapies, independent on the pathology. However, 9% of patients with anti-RBD antibodies did not have neutralizing antibodies to either virus variants, while an additional 5.7% did not have neutralizing antibodies to Omicron BA.2, making these patients particularly vulnerable to SARS-CoV-2 infection. The increment of neutralizing antibodies was very similar towards Omicron BA.2 and WT virus after the third or fourth dose of vaccine, suggesting that there is no preferential skewing towards either virus variant with the booster dose. The only limited step is the amount of antibodies that are elicited after vaccination, thus increasing the probability of developing neutralizing antibodies to both variants of virus.DiscussionThese data support the recommendation of additional booster doses in frail patients to enhance the development of a B-cell response directed against Omicron and/or to enhance the T-cell response in patients treated with anti-CD20

Direttive Anticipate di Trattamento nei pazienti oncologici: una prospettiva internazionale

Abstract La presente tesi vuole fornire spunti di riflessione su tematiche etiche e bioetiche la cui rilevanza è attuale e indiscussa, quello delle Direttive Anticipate di Trattamento, con particolare riferimento nei pazienti oncologici, e delle tematiche bioetiche ad esse connesse. Essa nasce da una ricerca effettuata nella banche dati mediche, giuridiche e bioetiche, con un approccio multidisciplinare e internazionale. Tale ricerca delinea un quadro della situazione attuale dal punto giuridico-normativo e bioeticistico, sulla base delle più aggiornate fonti bio-giuridiche, in primis nel nostro Paese e successivamente una veduta ed un confronto europeo, un confronto oltreoceano con l’analisi della situazione Statunitense e parallelamente un confronto con il resto del mondo. Il lavoro parte da un inquadramento delle stesse Direttive Anticipate nel contesto etico e bioetico, poiché un approccio medico-legale alle dinamiche delle Direttive Anticipate di Trattamento nei pazienti oncologici non può prescindere da una visuale “bioetica” della relazione medico-paziente e da un raccordo con i diritti inviolabili dell’uomo sanciti dalla nostra Costituzione. Si procederà poi ad un esame dei fondamenti legislativi che sono alla base delle stesse Direttive Anticipate e della rinuncia ad un trattamento medico, partendo dalla tutela della dignità umana sancita nella Convenzione di Oviedo, e proseguendo poi con i principi sanciti dal Comitato Nazionale per la Bioetica nel 2003 e proclamati dal nostro stesso Codice di Deontologia Medica, ultimo aggiornamento del 2014

Drugs of abuse in pregnancy, poor neonatal development, and future neurodegeneration. Is oxidative stress the culprit?

The abuse of licit and illicit drugs is a worldwide issue that is a cause for concern in pregnant women. It may lead to complications in pregnancy that may affect the mother, fetus, and /or neonate. The effects of any substance on the developing embryo and fetus are dependent upon dosing, timing, duration of drug exposure, and the extent of drug distribution. Teratogenic effects have been described when exposure takes place during the embryonic stage; however drugs have subtle effects, including abnormal growth and/or maturation, alterations in neurotransmitters and their receptors, and brain organization. The mechanisms by which intrauterine exposure to many substances may result in neuronal injury have not been completely elucidated. Oxidative stress and epigenetic changes have been recently implicated in the pathogenesis of long - term adverse health sequelae, and neuro-developmental impairment in the offspring of addicted mothers. Transgenerational epigenetics may also explain the alarming datum that developmental abnormalities, impairment in learning and memory, and attention deficit can occur even in the absence of direct fetal exposure, when drugs are consumed prior to conception. There is a growing body of evidence demonstrating a link between redox state unbalance, epigenetic markers, developmental anomalies, and neurodegeneration. The reviewed literature data uphold redox homeostasis disruption as an important factor in the pathogenesis of drug of abuse- induced neurodegeneration, and highlight the potential for new therapies that could prevent neurodegeneration through antioxidant and epigenetic modulatory mechanisms. This therefore reveals important targets for novel neuroprotective strategies

Multi-phase postmortem CT angiography (MPMCTA): a new axillary approach suitable in fatal thromboembolism.

Postmortem computed tomography is widely used in the forensic pathology setting as supplementing medico-legal investigations and being capable of providing significant data that affect final conclusions and adding new quality to recording postmortem observations. The integra- tion with angiographic methods [postmortem computed tomography angiography and multiphase postmortem CT angiography (MPMCTA)] allows the examination of the cardiovascular system and it is increasingly being utilised in the field of forensic pathology. However, using the stand- ardised procedure that establishes the femoral vessels on one side of the corpse as an access point to the vascular system, visualisation of the vascular tree below the can- nula insertion site is excluded. Consequently, visualisa- tion of the vascular anatomy and morphology of the lower limbs is impossible and lesions such as thrombosis of the superficial and deep venous system may remain elusive. Bearing in mind the high incidence of pulmonary throm- boembolism in forensic case studies and the difficulties in postmortem diagnosis, we propose a new axillary approach for MPMCTA that allows the full detection of the vascular system of the lower limbs

Amniotic fluid embolism: moving diagnosis through the time. From the mechanical pulmonary vascular occlusion until an immuno - inflammatory pathogenesis?

Amniotic fluid embolism (AFE) is a rare, catastrophic syndrome that presents during labor and delivery or immediately postpartum. Efforts to develop a clinical diagnostic test are ongoing; however the diagnosis still relies on rapid bedside evaluation and depends on the exclusion of other diseases. Classically, the diagnosis was made at autopsy, with the demonstration of squamous cells or debris in the maternal pulmonary vasculature. Clinico-pathological correlations have strengthened the evidence for a role of the immune system in the pathogenesis of AFE and have lead to the development of new laboratory tests, such as the serum tryptase and complement measurements, which should provide scientific support for the presumed immunological mechanism of AFE. Recently, studies on the effects of amniotic fluid (AF) on platelet - neutrophil aggregation and neutrophil/platelet activation have opened new insight in the comprehension of the mechanisms underlying AFE, suggesting that a severe inflammatory response might have a paramount causative role, so opening new diagnostic and therapeutic perspectives. Considering the complex interplay between the different mechanisms involved in the pathogenesis of AFE, the diagnosis still arises from a complex diagnostic puzzle in which clinical, macroscopic, laboratory, histological and immunohistochemical data converge toward AFE

Colloid cyst of the third ventricle, hypothalamus, and heart: a dangerous link for sudden death.

Colloid cysts are rare congenital, intracranial neoplasms, commonly located in the third ventricle. Colloid cysts are endodermal congenital malformations. The cysts commonly range in size from 1--2 cm in diameter, although large cysts >3 cm in size have been reported. The components of the cyst include an outer fibrous capsule over an inner epithelium. The epithelium is usually a single layer of mucin-producing or ciliated cells. Such cysts contain mucoid and gelatinous material, which is positive for both Periodic acid Schiff (PAS) and mucicarmen staining. Although colloid cysts usually represent histopathologically benign neoplasms, they can result in sudden, unexpected and potentially lethal complications. The mechanism(s) of death is still a controversial subject and several mechanisms have been postulated to explain the sudden onset of severe symptoms and of fatal rapid deterioration in patients with colloid cysts. In this case, macroscopic and histological findings addressed the diagnosis of colloid cyst of the third ventricle with diffuse myocardial injury (coagulative myocytolysys or contraction band necrosis, CBN) and led us to conclude that acute cardiac arrest due to hypothalamus stimulation in the context of colloid cyst of the third ventricle was the cause of death. As the hypothalamic structures which are involved in neuroendocrine and autonomic regulation playing a key role in cardiovascular control are located close to the walls of the third ventricle which is the most frequent anatomical site of colloid cyst, this may suggest that reflex cardiac effects due to the compression of the hypothalamic cardiovascular regulatory centers by the cyst explain the sudden death in patients harboring a colloid cyst when signs of hydrocephalus or brain herniation are lacking

Role of Oxidative Stress in Cocaine-induced Cardiotoxicity and Cocaine-related Death.

Cocaine-induced cardiovascular disorders such as hypertension, thrombosis, myocardial dysfunction, cardiac dysrhythmias and endocarditis have received widespread attention in the context of cocaine abuse. The number of sudden deaths from cardiac causes, including myocardial infarction, ventricular tachyarrhythmia or aortic dissection, is also increasing. This manuscript will highlight the recent employment of study about cocaine cardiotoxicity and oxidative stress. Evidence has revealed that cardiac oxidative stress is a prominent early event of cocaine administration, which severely compromises the cardiac antioxidant cellular system and causes cardiac antioxidant cellular system injuries. Oxidative damage such as peroxidation of membrane phospholipids and depletion of nonenzymatic antioxidants such as glutathione have been found in the myocardium of chronic cocaine-treated animals and in patients. The data indicate that cocaine administration compromised the heart's antioxidant defense system. About the mechanisms involved in the cellular damage, the evidence that cocaine causes apoptosis in the heart comes from in vivo study. In animals model after short-term and long term-cocaine administration, the investigators demonstrates the role of Reactive Oxygen Species as a trigger of cardiac injury induced by cocaine. Cocaine also increased infiltration of inflammatory cells in the heart, and apoptotic cells were predominantly found near inflammatory cells. The role of oxidative stress in cocaine-induced apoptosis in the heart is wide studied and documented