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Background: We aim to provide up-to-date real-world evidence on the persistence, adherence, healthcare resource utilization, and costs of multiple sclerosis (MS) by comparing ocrelizumab to other disease-modifying treatments (DMTs) and within different DMT sequences. Methods: We included 3371 people with MS who first received or switched DMT prescriptions from January 2018 to December 2022; they were identified through hospital discharge records, drug prescriptions, and exemption codes from the Campania Region (South Italy). We calculated persistence (time from the first prescription to discontinuation or switching to another DMT), adherence (proportion of days covered (PDC)), DMT costs, and MS hospital admissions and related costs. Results: The most frequently prescribed DMT was dimethyl fumarate (n = 815; age 38.90 ± 11.91 years; 69.5% females), followed by ocrelizumab (n = 682; age 46.46 ± 11.29 years; 56.3%); 28.8% of the patients treated with ocrelizumab were naïve to DMTs. Using ocrelizumab as a statistical reference, the risk of discontinuation was higher for other highly active (HR = 6.32; 95%CI = 3.16, 12.63; p < 0.01) and low-/medium-efficacy DMTs (HR = 10.10; 95%CI = 5.10, 19.77; p < 0.01); adherence was lower for other highly active DMTs (Coeff = −0.07; 95%CI = −0.10, −0.04; p < 0.01) and low-/medium-efficacy DMTs (Coeff = −0.16; 95%CI = −0.19, −0.14; p < 0.01). monthly DMT costs were higher for other highly active DMTs (Coeff = 77.45; 95%CI = 29.36, 125.53; p < 0.01) but lower for low-/medium-efficacy DMTs (Coeff = −772.31; 95%CI = −816.95, −727.66; p < 0.01). The hospital admissions and related costs of MS were similar between ocrelizumab, other highly active DMTs, and other low-/medium-efficacy DMTs, and with ocrelizumab as the first-line DMT after other highly active DMTs and after low-/medium-efficacy DMTs, which was possibly due to the low number of observations. Conclusions: From 2018 to 2022, ocrelizumab was among the most frequently prescribed DMTs, with 28.8% prescriptions to incident MS patients, confirming its relevance in clinical practice. Ocrelizumab was associated with the highest persistence and adherence, pointing towards its favorable benefit–risk profile. The costs of ocrelizumab were lower than those of other highly active DMTs.

Insulin resistance is the main mechanism in a whole series of pathological conditions, which are not only of metabolic interest but also of a systemic type. This phenomenon means that the body’s cells become less sensitive to the hormone insulin, leading to higher levels of insulin in the blood. Insulin resistance is a phenomenon that can be found in both men and women and in particular, in the latter, it is found mainly after menopause. Premenopause, hormonal fluctuations during the menstrual cycle, and the presence of estrogen can affect insulin sensitivity. Androgens, such as testosterone, are typically higher in men and can contribute to insulin resistance. In both sexes, different human body types affect the distribution and location of body fat, also influencing the development of diabetes and cardiovascular disease. Insulin resistance is also associated with some neurological and neurogenerative disorders, polycystic ovary syndrome, atherosclerosis, and some of the main neoplastic pathologies. A healthy lifestyle, including regular physical activity, a balanced diet, and self-maintenance, can help to prevent the onset of insulin resistance, regardless of gender, although the different habits between men and women greatly affect the implementation of preventative guidelines that help in fighting the manifestations of this metabolic disorder. This review may help to shed light on gender differences in metabolic diseases by placing a necessary focus on personalized medical management and by inspiring differentiated therapeutic approaches.

Barrett’s esophagus (BE) is an acquired pre-malignant condition that results from chronic gastroesophageal reflux. The malignant transformation occurred in 0.5% of patients/year and was independent of medical and endoscopic conservative treatments. Fatty acid synthase (FAS) is a multifunctional enzyme that catalyzes the synthesis of long-chain fatty acids from acetyl-coenzyme A, malonyl-coenzyme A, a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), and adenosine triphosphate. Activation of FAS is closely linked to malignant transformation. The aim of the present study was to evaluate the variation of FAS, p53, and Ki67 expressions in two groups of 21 BE patients each, after one year of continuous (group A) or discontinuous (group B) treatment with esomeprazole 40 mg/day in comparison to the initial expression. In both the two groups of BE patients, biopsies were taken from pathologic sites of the mucosa for histological and immuno-histochemical detection of FAS, Ki67, and p53 at entry and after one year of Esomeprazole 40 mg treatment. FAS expression was positive when a strong granular cytoplasmic staining was observed in esophageal cells. Ki67 and p53 were defined as positive when nuclear staining was clearly detected at ×10 magnification. FAS expression was reduced in 43% of patients treated with Esomeprazole continuously in comparison to the 10% of patients treated with Esomeprazole on demand (p = 0.002). Ki67 expression was reduced in 28% of continuously treated patients in comparison to 5% of patients treated on demand (p = 0.001). The p53 expression decreased in 19% of continuously treated patients in comparison to an increase in 2 patients (9%) treated on demand (p = 0.05). Continuously Esomeprazole treatment could help in the diminution of metabolic and proliferative activities in the esophageal columnar epithelium and in part it can help prevent the oxidative damage against cellular DNA, resulting in a diminution in p53 expression.

From the data in our possession derived from the literature, it has been shown that men have a high risk and appear to have a specific higher risk of suffering from thromboembolism than women, regardless of age group. Furthermore, at present, this difference between the two sexes has not yet been justified by scientific evidence. Taking this evidence into account, this review was designed to find information in the literature that could be potentially useful and that is crucial to knowledge about the differences between men and women in the genesis of thromboembolic disease. The role of the constitutional and physical factors underlying the difference between the two sexes, the different habitual lifestyles, the role of sex hormones, and what happens in situations such as venous thromboembolism in the course of a neoplastic disease or in the case of pregnancy. We have also focused our efforts on correlating the gender differences between men and women in thromboembolic disease with the dysregulation of the metabolism and the activation of the inflammatory response that often underlies this pathology.

The therapeutic management of atherosclerosis focuses almost exclusively on the reduction of plasma cholesterol levels. An important role in the genesis and evolution of atherosclerosis is played by chronic inflammation in promoting thrombosis phenomena after atheroma rupture. This review aims to take stock of the knowledge so far accumulated on the role of endemic HP infection in atherosclerosis. The studies produced so far have demonstrated a causal relationship between Helicobacter pylori (HP) and CVD. In a previous study, we demonstrated in HP-positive patients that thrombin and plasma fragment 1 + 2 production was proportionally related to tumor necrosis factor-alpha levels and that eradication of the infection resulted in a reduction of inflammation. At the end of our review, we can state that HP slightly affects the risk of CVD, particularly if the infection is associated with cytotoxic damage, and HP screening could have a clinically significant role in patients with a high risk of CVD. Considering the high prevalence of HP infection, an infection screening could be of great clinical utility in patients at high risk of CVD.

Nattokinase (NK) is a protease derived from food used mainly in the Japanese diet that has several properties. The main activity is related to improving fibrinolytic activities. Other activities have been demonstrated in the regulation of blood pressure by the action toward angiotensin proteases and in the antiplatelet activities. NK can be given orally and reaches its maximal concentration after 12 hours. In addition, an antithrombotic activity based on various NK activities has been proposed. First, increased fibrinolytic activity increases thrombus dissolution and/or the formation of atherosclerotic plaques; second, its enhanced antiplatelet action adds to clot dissolution. All activities have been studied in animals and humans in vitro and in vivo. Relevant adverse effects of NK therapy have not been described, however clinical experience is restricted to case series and volunteers and is not based on clinical studies, thus clinical trials are required to confirm.

Introduction. The Campania population is characterized by a high incidence and prevalence of heart failure (HF). The aim of this study is to describe the clinical epidemiology, comorbidities, and treatments in HF patients admitted to Internal Medicine Wards (IMW) in Campania. Materials and Methods. It is a retrospective, regional, multicentric, observational study including patients admitted to 15 IMW in Campania, with an HF diagnosis, over a period of three consecutive months. Results. We identified 427 patients, stratified by ejection fraction (EF) category (127 EF≤40%; 216 EF 41-49%; 84 EF≥50%). In comparison with HFpEF subjects, patients with HFrEF were younger (74 years vs. 9 years), more commonly male (67% vs. 32%), and more likely to have an ischaemic aetiology (45% vs. 25%). The most used drugs at the time of hospitalization and after were Diuretics (80.3/93.5%), BBs (69.6/92.6%), and Statins (52.1/63.7%), with statistically significant pre-/post- differences (P≤0.05). Conclusions. EF is more likely to be non-preserved in younger males and in patients with CAD etiology. Hospitalization influences in a statistically significant way the change or adjustment of therapy for almost all drugs.

With the progressive lengthening of the average age of the population, especially in some countries such as Italy, vaccination of the elderly is a fixed point on which most of the public health efforts are concentrating as epidemic infectious diseases, especially those of the winter, have a major impact on the progression of severe disease, hospitalization, and death. The protection of the elderly against acute infectious diseases should not only limit mortality but also have a positive impact on the fragility of these people in terms of less disability and fewer care needs. However, vaccination of the elderly population differs in efficacy and safety compared to that of other population categories since aging and the consequent loss of efficiency of the immune system lead to a reduction in the immunogenicity of vaccines without achieving a lasting antibody coverage. There are various strategies to avoid the failure of immunization by vaccines such as resorting to supplementary doses with adjuvant vaccines, increasing the dosage of the antigen used, or choosing to inoculate the serum relying on various routes of administration of the vaccine. Vaccination in the elderly is also an important factor in light of growing antibiotic resistance because it can indirectly contribute to combating antibiotic resistance, reducing theoretically the use of those agents. Furthermore, vaccination in old age reduces mortality from infectious diseases preventable with vaccines and reduces the same rate of resistance to antibiotics. Given the importance and complexity of the topic, in this review, we will deal with the main aspects of vaccination in the elderly and how it can influence mortality and healthcare costs, especially in those countries where population aging is more evident. Therefore, we conducted a systematic literature search in PubMed to identify all types of studies published up to 31 May 2023 that examined the association between vaccination and the elderly. Data extraction and quality assessment were conducted by two reviewers (PC and TC) who independently extracted the following data and assessed the quality of each study.

This narrative review aims to shed light on the role of gender differences, on the biological and molecular functions in the main pathological mechanisms that recognize the role of vitamin D. Vitamin D deficiency is widespread worldwide, but it is still very controversial whether the amount of vitamin D taken daily is actually the only problem related to its biological functions. Currently, the plasma concentration of 25-hydroxyvitamin D represents the only indicator of the circulating blood quota. The concept is that the biological function of vitamin D is not only linked to its circulating levels, but it is hypothesized that its biological functions depend, above all, on its total bioavailability. In particular, vitamin D circulates for the most part linked to albumin and vitamin D binding protein (DBP), which depend on various pathological conditions and physiologically, above all, the function of the latter is regulated by estrogens, glucocorticoids, and inflammatory cytokines. During her life, women undergo various changes in the hormonal and sexual sphere concerning menarche, possible pregnancies, and breastfeeding but also the use of contraceptives and, finally, the transition from the period of fertility to menopause. Each of these phases presents specific needs and, consequently, sometimes also specific criticalities. Studies on young women have shown that vitamin D deficiency is present in 58 to 91% of cases. Obesity, metabolic disorders, and variation in estrogen contraction may affect vitamin D deficiency due to the decreased bioavailability from dietary sources due to deposition in body fat compartments.

The global prevalence of overweight and obesity has dramatically increased in the last few decades, with a significant socioeconomic burden. In this narrative review, we include clinical studies aiming to provide the necessary knowledge on the role of the gut microbiota in the development of diabetic pathology and glucose-metabolism-related disorders. In particular, the role of a certain microbial composition of the fermentative type seems to emerge without a specific link to the development in certain subjects of obesity and the chronic inflammation of the adipose tissues, which underlies the pathological development of all the diseases related to glucose metabolism and metabolic syndrome. The gut microbiota plays an important role in glucose tolerance. Conclusion. New knowledge and new information is presented on the development of individualized therapies for patients affected by all the conditions related to reduced glucose tolerance and insulin resistance.

Background: In recent years, due to the epidemiological transition, the burden of very complex patients in hospital wards has increased. Telemedicine usage appears to be a potential high-impact factor in helping with patient management, allowing hospital personnel to assess conditions in out-of-hospital scenarios. Methods: To investigate the management of chronic patients during both hospitalization for disease and discharge, randomized studies (LIMS and Greenline-HT) are ongoing in the Internal Medicine Unit at ASL Roma 6 Castelli Hospital. The study endpoints are clinical outcomes (from a patient’s perspective). In this perspective paper, the main findings of these studies, from the operators’ point of view, are reported. Operator opinions were collected from structured and unstructured surveys conducted among the staff involved, and their main themes are reported in a narrative manner. Results: Telemonitoring appears to be linked to a reduction in side-events and side-effects, which represent some of most commons risk factors for re-hospitalization and for delayed discharge during hospitalization. The main perceived advantages are increased patient safety and the quick response in case of emergency. The main disadvantages are believed to be related to low patient compliance and an infrastructural lack of optimization. Conclusions: The evidence of wireless monitoring studies, combined with the analysis of activity data, suggests the need for a model of patient management that envisages an increase in the territory of structures capable of offering patients subacute care (the possibility of antibiotic treatments, blood transfusions, infusion support, and pain therapy) for the timely management of chronic patients in the terminal phase, for which treatment in acute wards must be guaranteed only for a limited time for the management of the acute phase of their diseases.

Abstract Acute pancreatitis, the most frequent hospitalization reason in internal medicine ward among gastrointestinal diseases, is burdened by high mortality rate. The disease manifests mainly in a mild form, but about 20-30% patients have a severe progress that requires intensive care. Patients presenting with acute pancreatitis should be clinically evaluated for organ failure signs and symptoms. Stratifying patients in the first days from symptoms onset is essential to determine therapy and care setting. The aim of our study is to evaluate prognostic factors for acute pancreatitis patients, hospitalized in internal medicine wards, and moreover, understanding the role of various prognostic scores validated in intensive care setting in predicting in-hospital mortality and/or admission to intensive care unit. We conducted a retrospective study enrolling all patients with diagnosis of acute pancreatitis admitted took an internal medicine ward between January 2013 and May 2019. Adverse outcome was considered in-hospital mortality and/or admission to intensive care unit. In total, 146 patients (137 with positive outcome and 9 with adverse outcome) were enrolled. The median age was (67.89 ± 16.44), with a slight prevalence of male (55.1%) compared to female (44.9%). C protein reactive (p = 0.02), creatinine (p = 0.01), sodium (p = 0.05), and troponin I (p = 0.013) after 48 h were significantly increased in patients with adverse outcome. In our study, progression in SOFA score independently increases the probability of adverse outcome in patients hospitalized with acute pancreatitis. SOFA score > 5 is highly predictive of in-hospital mortality (O.R. 32.00; C.I. 6.73-152.5; p = 0.001) compared to other scores. The use of an easy tool, validated in intensive care setting such as SOFA score, might help to better stratify the risk of in-hospital mortality and/or clinical worsening in patients hospitalized with acute pancreatitis in internal medicine ward.

Cerebral sinus venous thrombosis (CSVT) is a relatively rare acute disorder of cerebral circulation, but it can potentially be associated with serious sequelae and a poor prognosis. The neurological manifestations associated with it are often not adequately taken into consideration given the extreme variability and nuances of its clinical presentation and given the need for radiological methods suitable for this type of diagnosis. CSVT is usually more common in women, but so far there are little data available in the literature on sex-specific characteristics regarding this pathology. CSVT is the result of multiple conditions and is therefore to be considered a multifactorial disease where at least one risk factor is present in over 80% of cases. From the literature, we learn that congenital or acquired prothrombotic states are to be considered extremely associated with the occurrence of an acute episode of CSVT and its recurrences. It is, therefore, necessary to fully know the origins and natural history of CSVT, in order to implement the diagnostic and therapeutic pathways of these neurological manifestations. In this report, we summarize the main causes of CSVT considering the possible influence of gender, bearing in mind that most of the causes listed above are pathological conditions closely linked to the female sex.

Older age is a major risk factor for adverse outcomes of COVID-19, potentially due to immunosenescence and chronic low-grade inflammation, both characteristics of older adults which synergistically contribute to their vulnerability. Furthermore, older age is also associated with decreased kidney function and is consequently associated with an increased risk of cardiovascular disease. All of this in the course of COVID-19 infection can worsen and promote the progression of chronic kidney damage and all its sequelae. Frailty is a condition characterized by the decline in function of several homeostatic systems, leading to increased vulnerability to stressors and risk of adverse health outcomes. Thus, it is very likely that frailty, together with comorbidities, may have contributed to the high vulnerability to severe clinical manifestations and deaths from COVID-19 among older people. The combination of viral infection and chronic inflammation in the elderly could cause multiple unforeseen harmful consequences, affecting overall disability and mortality rates. In post-COVID-19 patients, inflammation has been implicated in sarcopenia progression, functional activity decline, and dementia. After the pandemic, it is imperative to shine a spotlight on these sequelae so that we can be prepared for the future outcomes of the ongoing pandemic. Here, we discuss the potential long-term consequences of SARS-CoV-2 infection and its possibility of causing permanent damage to the precarious balance existing in the frail elderly with multiple pathologies.

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has infected millions of individuals around the World. Hypertension (HT), chronic heart disease (CHD), and diabetes mellitus (DM), particularly in the elderly, increase susceptibility to SARS-CoV-2 infection. However, conflicting results [such as coronavirus 2019 (COVID-19) disease vulnerability, case fatality, etc.] have been reported about the response to infection and COVID-19 outcomes in men and women. Therefore, understanding predictors of Intensive Care Unit (ICU) admission might help future planning and management of the disease. We conducted a multicenter survey about COVID-19 involving internists from Internal Medicine Wards. This survey indirectly allowed us to analyze the information of 2400 patients hospitalized in 35 wards of Internal Medicine of the Campania Region between July and October 2020. Our investigation has detected that the infection is more frequent in males, and the number of male patients hospitalized in ICU is also higher than females, with a large proportion of hypertensive patients. Extensive prospective studies are required to confirm this finding and explore the mechanisms for which hypertensive males are exposed to a higher proportion of admission to ICU and higher case fatality rates.

The endothelium plays a fundamental role in the biological processes that ensure physiological vessel integrity, synthesizing numerous substances that are capable of modulating the tone of vessels, inflammation and the immune system, and platelet function. Endothelial dysfunction refers to an anomaly that develops at the level of the tunica that lines the internal surface of arterial and venous vessels, or, more precisely, an alteration to normal endothelial function, which involves the loss of some structural and/or functional characteristics. Studies on sex differences in endothelial function are conflicting, with some showing an earlier decline in endothelial function in men compared to women, while others show a similar age of onset between the sexes. Since increased cardiovascular risk coincides with menopause, female hormones, particularly estrogen, are generally believed to be cardioprotective. Furthermore, it is often proposed that androgens are harmful. In truth, these relationships are more complex than one might think and are not just dependent on fluctuations in circulating hormones. An increase in serum uric acid is widely regarded as a possible risk factor for cardiovascular disease; however, its role in the occurrence of endothelial dysfunction has not yet been elucidated. Several studies in the literature have evaluated sex-related differences in the association between elevated uric acid levels and cardiovascular events, with conflicting results. The association between uric acid and cardiovascular disease is still controversial, and it is not yet clear how gender differences affect the serum concentration of these substances. This review was primarily aimed at clarifying the effects of uric acid at the level of the vascular endothelium and describing how it could theoretically cause damage to endothelial integrity. The second aim was to determine if there are gender differences in uric acid metabolism and how these differences interact with the vascular endothelium.

Acute kidney injury (AKI) is a major clinical problem associated with increased morbidity and mortality. Despite intensive research, the clinical outcome remains poor, and apart from supportive therapy, no other specific therapy exists. Furthermore, acute kidney injury increases the risk of developing chronic kidney disease (CKD) and end-stage renal disease. Acute tubular injury accounts for the most common intrinsic cause of AKI. The main site of injury is the proximal tubule due to its high workload and energy demand. Upon injury, an intratubular subpopulation of proximal epithelial cells proliferates and restores the tubular integrity. Nevertheless, despite its strong regenerative capacity, the kidney does not always achieve its former integrity and function and incomplete recovery leads to persistent and progressive CKD. Clinical and experimental data demonstrate sexual differences in renal anatomy, physiology, and susceptibility to renal diseases including but not limited to ischemia-reperfusion injury. Some data suggest the protective role of female sex hormones, whereas others highlight the detrimental effect of male hormones in renal ischemia-reperfusion injury. Although the important role of sex hormones is evident, the exact underlying mechanisms remain to be elucidated. This review focuses on collecting the current knowledge about sexual dimorphism in renal injury and opportunities for therapeutic manipulation, with a focus on resident renal progenitor stem cells as potential novel therapeutic strategies.

In COVID-19 disease, are reported gender differences in relation to severity and death. The aim of this review is to highlight gender differences in the immune response to COVID-19. The included studies were identified using PubMed, until 30 October 2020. The search included the following keywords: SARS-CoV-2, COVID-19, gender, age, sex, and immune system. Literature described that females compared to males have greater inflammatory, antiviral, and humoral immune responses. In female, estrogen is a potential ally to alleviate SARS-COV-2 disease. In male, testosterone reduces vaccination response and depresses the cytokine response. In the older patients, and in particular, in female older patients, it has been reported a progressive functional decline in the immune systems. Differences by gender were reported in infection diseases, including SARS-CoV-2. These data should be confirmed by the other epidemiological studies.

The aim was to evaluate whether intra-hospital mortality from ischemic stroke is different in female patients. Methods. Studies were found in PubMed, Web of Science. We excluded 119 records because they did not include relevant reports or data. Studies were eligible for inclusion if enrolled adult patients with ischemic stroke and if the odds ratio (OR) of intra-hospital mortality in females compared to males is provided. Three retrospective cohort studies were eligible for inclusion criteria and so were included in the analysis. Findings: the random effect model showed a pooled significant higher risk of intra-hospital mortality [OR 1.34 (95% confidence interval 1.04, 1.74), P=0.026] in the female group compared to the male group. Our systematic review shows that intra-hospital mortality was significantly higher in female subjects compared to male.

In medicine, there is growing evidence that gender differences are important and lead to variations in the pathophysiology and treatment of many diseases with traits that appear to be particularly relevant in influencing the outcomes of many morbid forms. Today, the inclusion of gender in biomedical research, to improve the scientific quality and scientific relevance of knowledge, of technology is an increasingly present element precisely due to the practical implications that derive from it. Gender differences describe the biological variability between women and men, which is, in turn, related to differences in the information contained in sex chromosomes, the specific gene expression of autosomes linked to sex, the different number and quality of sex hormones, and their different effects on systems and organs, without neglecting the fact that each of the sexes has different target organs on which these hormones act. Additionally, both genders undergo metabolic changes throughout their lives, and this is especially true for women who show more dramatic changes due to their role in reproduction. Gender differences are not only the result of our genetic makeup but are also mixed with socio-cultural habits, behaviors, and lifestyles, differences between women and men, exposure to specific environmental influences, different food and lifestyle styles or stress, or different attitude in compliance with treatments and disease prevention campaigns. Gender differences also affect behavior throughout life, and physical changes can have implications for lifestyle, social roles, and mental health. Therefore, determinism and therapeutic outcome in chronic diseases are influenced by a complex combination of biological and environmental factors, not forgetting that there are many interactions of social and biological factors in women and men. This review will address the role of gender differences in the management of various forms of diabetes and its complications considering the different biological functions of hormones, the difference in body composition, physiological differences in glucose and fat metabolism, also considering the role of the microbiota. intestinal, as well as the description of gestational diabetes linked to possible pathophysiological events typical of reproduction.

Vaccination is one of the greatest achievements of public health. Vaccination programs have contributed to the decline in mortality and morbidity of various infectious diseases. This review aims to investigate the impact of sex/gender on the vaccine acceptance, responses, and outcomes. The studies were identified by using PubMed, until 30th June 2020. The search was performed by using the following keywords: SARS-CoV-2, COVID-19, gender, sex, vaccine, adverse reaction. Clinical trials, retrospective and prospective studies were included. Studies written in languages other than English were excluded. Studies were included if gender differences in response to vaccination trials were reported. All selected studies were qualitatively analyzed. Innate recognition and response to viruses, as well as, adaptive immune responses during viral infections, differ between females and males. Unfortunately, a majority of vaccine trials have focused on healthy people, with ages between 18 to 65 years, excluding the elderly, pregnant women, post-menopausal female and children. In conclusion, it is apparent that the design of vaccines and vaccine strategies should be sex-specific, to reduce adverse reactions in females and increase immunogenicity in males. It should be mandatory to examine sex-related variables in pre-clinical and clinical vaccine trials, such as their crucial role for successful prevention of pandemic COVID-19.

Coronavirus Disease-2019 (COVID-19) is the worst worldwide pandemic with more than 12,000,000 cases and 560,000 deaths until 14th July 2020. Men were more infected by COVID-19 than women, and male subjects with underlying conditions, including diabetes, hypertension, and cardiovascular diseases developed a severe form of the affection, with increased mortality rate. Many factors can contribute to the disparity in disease outcomes, such as hormone-specific reaction and activity of X-linked genes, which modulate the innate and adaptive immune response to virus infection. Until now, only the Remdesivir was approved by FDA (Food Drug Administration) for COVID-19 treatment, although several clinical trials are ongoing worldwide also on other drugs. In this review, we analyzed published studies on several drugs (chloroquine or hydroxychloroquine, remdesivir, favipiravir, lopinavir-ritonavir in combination, tocilizumab, plasma, and immunoglobulins) with some efficacy to COVID-19 in humans, and evaluated if there were a gender analysis of the available data. In our opinion, it is essential to report data about COVID-19 disaggregated by sex, age, and race, because the knowledge of gender differences is fundamental to identify effective and customized treatments to reduce hospitalizations, admissions to intensive care units, and mortality.

As the main title ‘COVID-19 revolution: a new challenge for the internist’ states, the global coronavirus infection disease 2019 (COVID-19) pandemic represented a new challenge for the internists. This paper is part of a series of articles written during the difficult period of the ongoing global pandemic and published all together in this fourth issue of the Italian Journal of Medicine, with the aim of sharing the direct experiences of those who were the first to face this severe emergency, expressing each point of view in the management of COVID-19 in relation to other diseases. Each article is therefore the result of many efforts and a joint collaboration between many colleagues from the Departments of Internal Medicine or Emergency Medicine of several Italian hospitals, engaged in the front line during the pandemic. These preliminary studies therefore cover diagnostic tools available to health care personnel, epidemiological reflections, possible new therapeutic approaches, discharge and reintegration procedures to daily life, the involvement of the disease not only in the lung, aspects related to various comorbidities, such as: coagulopathies, vasculitis, vitamin D deficiency, gender differences, etc.. The goal is to offer a perspective, as broad as possible, of everything that has been done to initially face the pandemic in its first phase and provide the tools for an increasingly better approach, in the hope of not arriving unprepared to a possible second wave. This paper in particular deals with COVID-19 and gender differences.

(1) Background: In our previous study, acute ischemic stroke (AIS) patients showed increased levels of circulating miRNAs (-195-5p and -451a) involved in vascular endothelial growth factor A (VEGF-A) regulation. Here, we evaluated, for the first time, both circulating miRNAs in acute intracerebral hemorrhagic (ICH) patients. (2) Methods: Circulating miRNAs and serum VEGF-A were assessed by real-time PCR and ELISA in 20 acute ICH, 21 AIS patients, and 21 controls. These were evaluated at hospital admission (T0) and after 96 h (T96) from admission. (3) Results: At T0, circulating miRNAs were five-times up-regulated in AIS patients, tending to decrease at T96. By contrast, in the acute ICH group, circulating miRNAs were significantly increased at both T0 and T96. Moreover, a significant decrease was observed in serum VEGF-A levels at T0 in AIS patients, tending to increase at T96. Conversely, in acute ICH patients, the levels of VEGF-A were significantly decreased at both T0 and T96. (4) Conclusions: The absence of a reduction in circulating miRNAs (195-5p and -451a), reported in acute ICH subjects after 96 h from hospital admission, together with the absence of increment of serum VEGF-A, may represent useful biomarkers indicating the severe brain damage status that characterizes acute ICH patients.

We have evaluated gender-related differences in cardiovascular disease. In particular, in coronary heart disease, atrial fibrillation, arterial hypertension, venous thromboembolism and diabetes mellitus.

Background: Cardiomyopathies are a heterogeneous group of pathologies characterized by structural and functional alterations of the heart. Aims: The purpose of this narrative review is to focus on the most important cardiomyopathies and their epidemiology, diagnosis, and management. Methods: Clinical trials were identified by Pubmed until 30 March 2021. The search keywords were “cardiomyopathies, sudden cardiac arrest, dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy, arrhythmogenic cardiomyopathy (ARCV), takotsubo syndrome”. Results: Hypertrophic cardiomyopathy (HCM) is the most common primary cardiomyopathy, with a prevalence of 1:500 persons. Dilated cardiomyopathy (DCM) has a prevalence of 1:2500 and is the leading indication for heart transplantation. Restrictive cardiomyopathy (RCM) is the least common of the major cardiomyopathies, representing 2% to 5% of cases. Arrhythmogenic cardiomyopathy (ARCV) is a pathology characterized by the substitution of the myocardium by fibrofatty tissue. Takotsubo cardiomyopathy is defined as an abrupt onset of left ventricular dysfunction in response to severe emotional or physiologic stress. Conclusion: In particular, it has been reported that HCM is the most important cause of sudden death on the athletic field in the United States. It is needless to say how important it is to know which changes in the heart due to physical activity are normal, and when they are pathological.

Ischemic heart disease, the leading cause of death, is extremely diffuse among patients hospitalized in Internal Medicine ward so that Internist should be able to manage correctly this disease. The following review revises the most recent literature and offers a practical clinical guide to be confident on this topic. After having emphasized that clinical overview remains essential, it briefly mentions advantages and limits of different investigations, reminds readers of possible alternative etiopathogeneses of ischemic heart disease (cardiac syndrome X), reports the most appropriate medical therapy, and gives the opportunity to understand appropriateness of specialist strategies such as coronary artery by-pass grafting and percutaneous coronary intervention. Finally, it illustrates a rational and evidence-based follow-up of these patients, considering that only a small part of them should be followed by a Cardiologist. The aim of a correct management of ischemic heart disease remains to reduce mortality and improve the quality of life.

Pericarditis is an inflammatory syndrome involving pericardium, which is a double-walled sac consisting of two leaves, a serous visceral layer in contact with the myocardium (pericardium) and a parietal fibrous one, delimiting a cavity (pericardial cavity) containing pericardial fluid. Pericarditis may occur isolated or as a manifestation of a systemic disorder. Diagnosis and correct management of pericarditis can be difficult and its natural history is often characterized by a lot of relapses. Treatment of acute pericarditis should target the underlying etiology. The diagnosis is based on characteristic clinical findings, electrocardiogram, and echocardiography. The goals of treatment are relief of pain, resolution of inflammation (and, if present, pericardial effusion), and prevention of recurrence. Despite a significant impairment of the quality of life, pericarditis usually has good long-term outcomes.

Thrombotic manifestations are common in cancer patients and increase morbidity and mortality. They can affect large or small, venous or arterial vessels. Thrombosis of large arteries and veins is much more studied than that of small vessels. Nevertheless, thrombotic micro-angiopathies - a group of disorders characterized by microvascular thrombosis, thrombocytopenia, and ischemic organ failure - represent a severe and often fatal complication of cancer natural history, as their diagnosis is not always prompt and easy, and treatment controversial or ineffective. Herein, we report a case of sub-acute/acute cor pulmonale in a patient with advanced gastric cancer, treated with mitomycin C, as a good model for differential diagnosis of cancer-related thrombotic micro-angiopathies.

Background: The global active prevalence of migraines is approximately 14.7%. Oxygen therapy may reduce the use of non-steroidal anti-inflammatory drugs (NSAIDs) which often have various negative side effects. The purpose of this systematic review is to analyze the literature on the efficacy of high flow oxygen for the management of headache disorders, compared to placebo treatment. Methods: Studies were identified by PubMed, Web of Science and Scopus database from 1980 to the 30 October 2020. The search included the following terms: “oxygen therapy” and “headache” and “migraine”. Studies were included if high flow oxygen was used in the treatment of headache disorders. All selected studies were qualitatively analyzed. Results: Our literature search identified 71 studies, of which 65 were discarded and 6 were included in the meta-analysis. The random effect model did not show a pooled significant resolution of headache disorders (OR 2.08 (95% CI 0.92–4.70), p < 0.0001) in the oxygen therapy group compared to the placebo group. Conclusion: In our systematic review of six studies, there were no significant differences between high flow oxygen and placebo treatment groups.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. This analysis aimed to determine the sex-gender differences in patients with AF enrolled in the observational AntiThrombotic Agents in Atrial Fibrillation (ATA-AF) study. The study was conducted in 360 centers in Italy. During a 4-week period, all consecutive inpatients and outpatients aged ≥18 years, with a documented primary or secondary diagnosis of AF, were included. A total of 7148 patients (47% females) were enrolled. Females were significantly older, they more frequently needed assistance and were affected by severe cognitive impairment. The preferred anti-arrhythmic strategy in both genders was heart rate control (females: 54.7%, males: 48.4%, P2DS2-VASc ≥2 (96.1% vs 80.7%; P2 ≥2 (68.2% vs 60.4%; Pvs 26.1%; Pvs 59.2%; Pi.e., severe cognitive and functional impairment) may at least partly explain this trend towards gender-related under-prescription of OAC.

(1) Background: Circulating micro-RNAs (miRNAs) modulate the expression of molecules in diabetes. We evaluated the expression of serum miRNA-195-5p and -451a in diabetic patients with ischemic stroke and correlated them with two markers of brain tissue integrity. (2) Methods: Seventy-eight subjects with acute ischemic stroke (AIS) or transient ischemic attack (TIA) (40 with diabetes) were enrolled. Serum miRNA levels, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF-A) were assessed at admission and 24 and 72 h after a post-ischemic stroke, and were compared to 20 controls. (3) Results: Both circulating miRNAs were two-fold up-regulated in diabetic AIS and TIA patients compared to non-diabetics. Their levels progressively decreased at 24 and 72 h in both AIS and TIA patients. Interestingly, in the non-diabetic TIA group, both circulating miRNAs, although higher than the controls, tended to achieve a complete decay after 72 h. Furthermore, miRNA-195-5p and miRNA-451a levels inversely correlated with both BDNF and VEGF-A serum levels. (4) Conclusions: These data show a different profile of both micro-RNAs in diabetic versus non-diabetic patients after acute ischemic stroke, suggesting their pivotal role in cerebrovascular ischemic attack.

Introduction: Early detection is crucial for prompt management of acute kidney injury (AKI) patients in emergency department (ED). This study aimed to investigate the usefulness of hyperchloremic metabolic acidosis (HCMA) levels in this regard. Methods: In this retrospective observational study, > 18 years old critically ill patients presenting to ED of Marcianise Hospital, Italy, were divided into non-AKI and AKI group according to KDIGO guideline. The level of HCMA ((arterial pH x bicarbonate)/chloride) was compared between groups and correlation of HCMA with estimated glomerular filtration rate (e-GFR) in ARF patients was evaluated. Results: 134 patients with the mean age of 76.5 ± 3.1 years were enrolled (64 non-AKI and 70 AKI; 64% female). Two groups were similar regarding mean age (p = 0.251), sex (p = 0.091), APACHII score (p = 0.215), Charlson Comorbidity Index (p= 0.187), and body mass index (p = 0.129). The mean HCMA level was 1.98 ± 0.09 in the non-AKI group and 1.56 ± 0.07 in the AKI group (p=0.039). There was a positive correlation between HCMA and e-GFR levels in AKI group (r: 0.467, p=0.0092). Conclusions: If confirmed and validated in a future study, ABG derived formula for HCMA may be a useful tool for early detection of AKI patients in emergency department.

Women get sick more, use more health services, take more drugs, and have a higher frequency of serious adverse reactions. Despite this, the drugs we use are little studied in women: both clinical studies and pre-clinical experiments are carried out predominantly in males and the young. Before 1990, no more than 26-30% of women were usually enrolled in a trial, so we lacked the statistical power of showing the efficacy and safety of the drugs being studied in the whole population. The gender blindness (transposition of the male studies in female populations) resulted in a lack of awareness of the differences between males and females, and this prevented both genders from receiving the best possible care. This gender bias also, to a lower degree, hurts men: depression, migraines, osteoporosis have not been studied properly in males. Although the process is slow, the scientific community has begun to pay more attention to direct and indirect influences that gender exercise on biological mechanisms, and this includes both internal and external cultural and environmental factors. Therefore, the differences between the old, the young, children, and pregnant women (considered the third gender group) will become increasingly more important as care becomes more personalized. The first course of gender medicine was established only in 2002 at Columbia University, New York, USA. The World Health Organization has incorporated gender medicine into the Equity Act. This implies that the treatment given must be the most appropriate and best suited the individual patient’s gender. The Committee on Women’s Health of the Ministry of Health in Italy was established in 2007. Institutions now pay great attention to the importance of this clinical perspective and are sensitive to the need for change. This review focuses on specific open questions regarding gender: pharmacology, clinical trial recruitment, cardiovascular prevention, stroke, osteoporosis, chronic obstructive pulmonary disease, depression, and discusses presentations made to the 1st course of gender medicine organized as part of the 18th National Congress of the Federation of Associations of Hospital Doctors on Internal Medicine (FADOI), 2012.