A Critical Analysis of All-Cause Deaths during COVID-19 Vaccination in an Italian Province.

Immortal time bias (ITB) is common in cohort studies and distorts the association estimates between the treated and untreated. We used data from an Italian study on COVID-19 vaccine effectiveness, with a large cohort, long follow-up, and adjustment for confounding factors, affected by ITB, with the aim to verify the real impact of the vaccination campaign by comparing the risk of all-cause death between the vaccinated population and the unvaccinated population. We aligned all subjects on a single index date and considered the "all-cause deaths" outcome to compare the survival distributions of the unvaccinated group versus various vaccination statuses. The all-cause-death hazard ratios in univariate analysis for vaccinated people with 1, 2, and 3/4 doses versus unvaccinated people were 0.88, 1.23, and 1.21, respectively. The multivariate values were 2.40, 1.98, and 0.99. Possible explanations of this trend of the hazard ratios as vaccinations increase could be a harvesting effect; a calendar-time bias, accounting for seasonality and pandemic waves; a case-counting window bias; a healthy-vaccinee bias; or some combination of these factors. With 2 and even with 3/4 doses, the calculated Restricted Mean Survival Time and Restricted Mean Time Lost have shown a small but significant downside for the vaccinated populations.

[Vitamin D and COVID-19: a communication far from reality]. / Vitamina D e COVID-19: una comunicazione lontana dalla realtà.

The intake of Vitamin D against COVID-19 has theoretical bases. In the 3-year period of the pandemic, hundreds of favorable observational studies and some small randomized controlled trials (RCTs) have been produced.However, to date, RCTs of larger size and quality have unfavorable results and do not support its use, neither in oral form at various doses nor as injection boluses nor in prophylaxis nor in treatment of COVID-19, not even in severe or critical cases, nor to prevent deaths.The results of a recent sequential meta-analysis of a few RCTs, presented as 'definitive evidence', are biased by the weight of the improper inclusion of an observational study.Interference with correct information, both in the media and in scientific communication, risks obscuring in clinical practice the conclusions of the most valid studies available.

Autoimmune inflammatory reactions triggered by the COVID-19 genetic vaccines in terminally differentiated tissues.

As a result of the spread of SARS-CoV-2, a global pandemic was declared. Indiscriminate COVID-19 vaccination has been extended to include age groups and naturally immune people with minimal danger of suffering serious complications due to COVID-19. Solid immuno-histopathological evidence demonstrates that the COVID-19 genetic vaccines can display a wide distribution within the body, affecting tissues that are terminally differentiated and far away from the injection site. These include the heart and brain, which may incur in situ production of spike protein eliciting a strong autoimmunological inflammatory response. Due to the fact that every human cell which synthesises non-self antigens, inevitably becomes the target of the immune system, and since the human body is not a strictly compartmentalised system, accurate pharmacokinetic and pharmacodynamic studies are needed in order to determine precisely which tissues can be harmed. Therefore, our article aims to draw the attention of the scientific and regulatory communities to the critical need for biodistribution studies for the genetic vaccines against COVID-19, as well as for rational harm-benefit assessments by age group.

COVID-19 vaccination and all-cause and non-COVID-19 mortality. A revaluation of a study carried out in an Italian Province.

The COVID-19 vaccination prevents COVID-19 specific mortality. Well planned population-based studies, however, are necessary to evaluate the overall effectiveness of vaccination programmes. A study carried out in the province of Pescara is used to illustrate the potential biases that may affect such studies. The Pescara study analysed total and non-COVID-19 mortality and the occurrence of Potentially Vaccine-Related Serious Adverse Events (PVR-SAEs) in vaccinated and unvaccinated people, from January 2021, when vaccines became available, to July 2022. The study reported a lower probability of both total and non-COVID-19 death in vaccinated people. However, the authors did not include in the denominator of the unvaccinated cohort the population experience of the vaccinated cohort before vaccination (immortal time bias). Correcting the denominator of the unvaccinated cohort, the crude death rate of vaccinated and unvaccinated persons becomes the same. For the same reason, the unvaccinated non-COVID-19 mortality was overestimated, as was the mortality of people receiving only one or two vaccine doses. Confounding by indication and the healthy vaccinee bias will also be discussed, as well as the bias deriving by not considering the evolution of risk over time.

SARS-CoV-2-The Role of Natural Immunity: A Narrative Review.

BACKGROUND: Both natural immunity and vaccine-induced immunity to COVID-19 may be useful to reduce the mortality/morbidity of this disease, but still a lot of controversy exists. AIMS: This narrative review analyzes the literature regarding these two immunitary processes and more specifically: (a) the duration of natural immunity; (b) cellular immunity; (c) cross-reactivity; (d) the duration of post-vaccination immune protection; (e) the probability of reinfection and its clinical manifestations in the recovered patients; (f) the comparisons between vaccinated and unvaccinated as to the possible reinfections; (g) the role of hybrid immunity; (h) the effectiveness of natural and vaccine-induced immunity against Omicron variant; (i) the comparative incidence of adverse effects after vaccination in recovered individuals vs. COVID-19-naïve subjects. MATERIAL AND METHODS: through multiple search engines we investigated COVID-19 literature related to the aims of the review, published since April 2020 through July 2022, including also the previous articles pertinent to the investigated topics. RESULTS: nearly 900 studies were collected, and 246 pertinent articles were included. It was highlighted that the vast majority of the individuals after suffering from COVID-19 develop a natural immunity both of cell-mediated and humoral type, which is effective over time and provides protection against both reinfection and serious illness. Vaccine-induced immunity was shown to decay faster than natural immunity. In general, the severity of the symptoms of reinfection is significantly lower than in the primary infection, with a lower degree of hospitalizations (0.06%) and an extremely low mortality. CONCLUSIONS: this extensive narrative review regarding a vast number of articles highlighted the valuable protection induced by the natural immunity after COVID-19, which seems comparable or superior to the one induced by anti-SARS-CoV-2 vaccination. Consequently, vaccination of the unvaccinated COVID-19-recovered subjects may not be indicated. Further research is needed in order to: (a) measure the durability of immunity over time; (b) evaluate both the impacts of Omicron BA.5 on vaccinated and healed subjects and the role of hybrid immunity.

Comparison of hospitalizations and deaths from COVID-19 2021 versus 2020 in Italy: surprises and implications.

Data from the Istituto Superiore di Sanità (ISS) emphasized by the media indicate that COVID-19 vaccination reduces related infections, hospitalizations and deaths. However, a comparison showed significantly more hospitalizations and intensive care unit accesses in the corresponding months and days in 2021 versus 2020 and no significant differences in deaths. The combination of non-alternative hypotheses may help explain the discrepancy between the results in the entire population and the vaccination's success claimed by the ISS in reducing infections, serious cases and deaths: a bias: counting as unvaccinated also "those vaccinated with 1 dose in the two weeks following the inoculation", and as incompletely vaccinated also "those vaccinated with 2 doses within two weeks of the 2nd inoculation".a systematic error: counting as unvaccinated also "vaccinated with 1 dose in the two weeks following the inoculation", and as incompletely vaccinated also "vaccinated with 2 doses within two weeks of the 2nd inoculation". Many reports show an increase in COVID-19 cases in these time-windows, and related data should be separated levels of protective effectiveness in vaccinated people, often considered stable, actually show signs of progressive reduction over time, which could contribute to reducing the overall population resultunvaccinated people show more severe disease than in 2020, supporting also in humans the theory of imperfect vaccines, which offer less resistance to the entry of germs than the resistance later encountered inside the human body. This favors the selection of more resistant and virulent mutants, that can be spread by vaccinated people. This damages first the unvaccinated people, but ultimately the whole community. An open scientific debate is needed to discuss these hypotheses, following the available evidence (as well as to discuss the inconsistent theory of unvaccinated young people as reservoirs of viruses/mutants), to assess the long-term and community impact of different vaccination strategies.

[New European guidelines for the management of dyslipidaemias: their aggressiveness is not legitimated by current evidence]. / Nuove linee guida europee sulla gestione delle dislipidemie: aggressività non giustificata dalle prove esistenti.

Le linee guida 2019 delle Società europee di cardiologia e dell'aterosclerosi sulla gestione delle dislipidemie hanno aumentato l'aggressività diagnostico-terapeutica e non distinguono prevenzione primaria e secondaria, con parziale eccezione per gli ultra75enni. Raccomandano nuovi target di cLDL: per pazienti a rischio molto alto si raccomanda una riduzione a <55 mg/dl e >=50% rispetto al basale; per pazienti a rischio alto una riduzione a <70 mg/dl e >=50% del basale; per pazienti a rischio moderato una riduzione a <100 mg/dl; per pazienti a rischio basso una riduzione a <116 mg/dl. In base alle carte SCORE e ai dati di mortalità cardiovascolare in Italia, quasi tutti i maschi dai 70 anni e le donne dai 70-75 anni risulterebbero ad alto rischio per solo effetto dell'età. Anche quasi tutti i 60enni sarebbero a rischio moderato, con target di cLDL <100, e spesso necessità di aggiungere costosi ipolipemizzanti per chi già assume statine. Le prove supportano ben poco tale aggressività. Infatti, anche negli studi randomizzati controllati (RCT) i benefici su esiti cardiovascolari non fatali subiscono esagerazioni sistematiche, quello meno distorto e di maggior interesse per gli assistiti è la mortalità totale. Questa, con terapie ipocolesterolemizzanti più intensive, non si è ridotta nelle metanalisi di RCT con pazienti con cLDL tra 80 e <100 mg/dl al basale; con inibitori di PCSK9, pazienti con questi valori mostrano persino tendenza all'aumento della mortalità totale. Dunque, abbassare il cLDL a <80 mg/dl può non giovare neppure ad anziani coronaropatici. A oggi, ciò vale ancora di più per anziani nella popolazione generale, in cui una revisione sistematica di studi di coorte ha mostrato relazioni nulle o più spesso inverse tra cLDL e mortalità. Le nuove linee guida europee forzano le prove disponibili, trascurano il principio di precauzione e non possono esser base per un equo consenso informato.

Hesperidin and SARS-CoV-2: New Light on the Healthy Function of Citrus Fruits.

Among the many approaches to Coronavirus disease 2019 (COVID-19) prevention, the possible role of nutrition has so far been rather underestimated. Foods are very rich in substances, with a potential beneficial effect on health, and some of these could have an antiviral action or be important in modulating the immune system and in defending cells from the oxidative stress associated with infection. This short review draws the attention on some components of citrus fruits, and especially of the orange (Citrus sinensis), well known for its vitamin and flavonoid content. Among the flavonoids, hesperidin has recently attracted the attention of researchers, because it binds to the key proteins of the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several computational methods, independently applied by different researchers, showed that hesperidin has a low binding energy, both with the coronavirus "spike" protein, and with the main protease that transforms the early proteins of the virus (pp1a and ppa1b) into the complex responsible for viral replication. The binding energy of hesperidin to these important components is lower than that of lopinavir, ritonavir, and indinavir, suggesting that it could perform an effective antiviral action. Furthermore, both hesperidin and ascorbic acid counteract the cell damaging effects of the oxygen free radicals triggered by virus infection and inflammation. There is discussion about the preventive efficacy of vitamin C, at the dose achievable by the diet, but recent reviews suggest that this substance can be useful in the case of strong immune system burden caused by viral disease. Computational methods and laboratory studies support the need to undertake apposite preclinical, epidemiological, and experimental studies on the potential benefits of citrus fruit components for the prevention of infectious diseases, including COVID-19.

[Using face masks outdoor: beginning a debate to rediscuss current policies]. / Mascherine "chirurgiche" all'aperto: avviare un dibattito per ridiscutere le disposizioni attuali.

During the COVID-19 pandemic, international organizations, institutions, and experts firstly recommended face masks for the population only in symptomatic subjects, but today various countries recommend or require their use even outdoor. In Italy, there was an obligation in closed places accessible to the public, including means of transport, and always if the safety distance was not continuously guaranteed. Various regions have long imposed obligations everywhere but at one's own home, and now the mandate has become national. This contribution critically analyses the randomised controlled trials (RCTs) on the effectiveness of medical masks in preventing respiratory infections in university/community contexts and outdoor gatherings, with questions and answers based on reasoning where possible based on evidence. It discusses whether the evidence supporting the WHO positions is weak compared to more stringent policies; it considers some underestimated adverse effects of the prolonged use of masks in the community and especially outdoors, not only by persons doing physical activity. This paper discusses some differences between SARS and COVID-19 in the potential impact of the masks and proposes to consider the most valid evidence available, avoiding prolonged/continuous use without valid needs for face masks, especially outdoors, waiting for others pragmatic RCTs that clarify conclusively a net balance between expected benefits and possible damages. KEYWORDS: facemasks effectiveness; medical masks safety - side effects; medical masks and SARS-CoV-2.