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Vitamin K-Antagonists (VKAs) are the treatment of choice in patients with indications other than atrial fibrillation and venous thromboembolism. Moreover, some patients still assume VKAs refusing to change their therapy when direct oral anticoagulants (DOACs) are properly indicated. The COVID-19 pandemic has completely changed our lives, nullifying inter-personal relationships to avoid contagion, making difficult the VKAs monitoring. We describe the re-organization of our thrombosis centre (TC) as an example on how to face the emergency due to the COVID-19 pandemic. In the first phase, to avoid overcrowding at the TC, we planned to increase the interval time between INRs checks and to encourage blood sampling at home, especially for elderly patients. Moreover, precise scheduled blood sampling was also organized while telephone and email counselling were guaranteed by two doctors of the TC. In the second phase, to reduce the number of patients who daily attended our TC a switch from VKAs to DOACs was carried out, if no contraindications were identified. In the third phase, to protect patients, healthcare staff and hospital from COVID-19 widespread, telemedicine was strengthened. We tried to extend self-testing at home by means of portable coagulometers to as more patients as possible. To avoid patients staying or coming back to the TC an ad hoc web platform for sending the therapeutic dose adjustment and the next scheduled appointment was developed. The TC re-organization allowed us to monitor anticoagulated patients respecting personal isolation and security measures to avoid possible COVID-19 contagion.

It is well known that tobacco smoking worsens asthma. Conversely, few data are currently available in the literature on the effects of vaping in asthmatic patients. This work aims to investigate the effects of vaping on asthmatic patients and in asthmatic patients that switched from tobacco smoking to electronic cigarette (e-cig), in particular focusing on quality of life, asthma control, and pulmonary function. We designed a two-group study. One group encompassed vapers with asthma selected through a web survey with questions on quality of life and symptoms worsening; the other group encompassed vapers that switched from tobacco smoking to e-cig, and that volunteered to undergo clinical visits at our outpatient clinic. 2787 people responded to the web survey, including 631 asthmatics. In the second group, 55 volunteers, including 15 asthmatics, were enrolled after a visit. The visit included physical examination and pulmonary function tests (PFT). Internationally validated questionnaires were administered to all subjects: Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), 36-Item Short Form Survey (SF-36) and Asthma Quality of Life Questionnaire (AQLQ). The 382 asthmatic vapers-only in the web survey were mainly males (86.9%), 31-65 years old. 90% of them declared that vaping did not worsen asthma symptoms and would recommend asthmatic smokers to switch to vaping (98.4%). There was worsening of asthma symptoms due to the actual asthma therapy used by the participants, while no relationship was found with other aspects analysed. In the second group, the analysis of variance in the questionnaires administered to the 10 asthmatics showed a significant improvement in ACQ, ACT and SF-36 for asthmatics that switched from tobacco to vaping, while PFT remained stable throughout the three visits. Almost all of the asthmatics who previously smoked would recommend switching to e-cig, and vaping did not worsen their asthma symptoms. Furthermore, switching from tobacco smoking to e-cigs showed a significant improvement in asthma control and quality of life, not showing, in the period studied, to affect pulmonary function tests.

Acutely ill hospitalized medical patients are at high risk of venous thromboembolism (VTE). Although thromboprophylaxis in these patients is recommended since 2004 by the American College of Chest Physicians, it is widely underused. The doubt as to whether or not to treat patients at high VTE risk after hospital discharge came from the knowledge that this risk may persist after the hospital admission period. Two meta-analyses comparing extended- versus short-duration prophylaxis are published. The results demonstrate an unfavorable balance between VTE prevention and incidence of major bleeding in patients assigned to extended-duration thromboprophylaxis. Only in the APEX study, betrixaban, a direct inhibitor of factor Xa, shows similar efficacy and safety compared to enoxaparin. However, while it is very promising, oral anticoagulant phase III studies and post-marketing registers are lacking. Moreover, betrixaban has a long half-life, an excretion in the gut by means of P-glycoprotein, and the lack of an antidote. These characteristics and the meta-analysis results prompt us to answer no to the extended thromboprophylaxis in hospitalized medical patients, at least now.

Direct oral anticoagulants (DOAC) possess high bioavailability, and their anticoagulant effect is more predictable than that of vitamin K antagonists, hence they do not require routine dose adjustment based on laboratory testing. However, there are circumstances when laboratory testing may be useful, including patients who need to undergo surgery or invasive procedures. Most guidelines state that patients on DOAC may safely undergo surgery/invasive procedures by stopping anticoagulation for a few days before intervention without testing if renal function is within normal limits. This review article discusses the pros and cons of measuring (or not measuring) DOAC levels before surgery/invasive procedures by a multidisciplinary team of experts with different background, including the thrombosis laboratory, clinical thrombosis, internal medicine, cardiology and nephrology. The conclusion is that measuring DOAC with dedicated tests before surgical or invasive procedures is important for patient safety. It provides the best and most direct evidence to rule in (or to rule out) clinically relevant concentrations of residual drugs. Regulatory agencies should urgently approve their use in clinical practice. Hospital administrators should make them available, and clinical laboratories should set up the relative methods and make them available to clinicians.

Direct oral anticoagulants (DOACs) represent an innovation because they avoid periodic laboratory monitoring, and also reduce cerebral bleeding. An examination of the performance of DOACs versus warfarin in randomized clinical trials dedicated to atrial fibrillation would reveal the poor performance of warfarin because the percentage of major bleeding is always above 3%; however, the percentage of major bleeding is less than half of that when the management is done in anticoagulation clinics (ACs). Several years ago, a common opinion was that ACs would disappear as soon as DOACs enter the market. We proposed then that ACs could be transformed into thrombosis centres (TCs) because we envisaged many new activities in terms of diagnostic tools and therapeutic choices. After the introduction of DOACs, the role of the ACs has been re-evaluated because their role may be crucial in selecting both the most appropriate diagnostic approach and the best therapeutic option (including anti-vitamin K drugs) for the single patient. TCs can organize a regular follow-up to improve patient adherence to DOACs. Marketing might have a role in the decision making of the single doctor. Efforts should be made for limiting the relationships between doctors and pharmaceutical companies. It seems reasonable to better prepare doctors, during their university courses, for them to develop a greater scientific culture that would enable them to critically read clinical studies and acquire an independent opinion. Ideally, an expert in haemostasis and thrombosis should handle new and old anticoagulants.

Vitamin K antagonists (VKA) are the most widely used anticoagulants in the world. An appropriate management of treated patients is crucial for their efficacy and safety. The prospective, observational, multicenter, inception-cohort FCSA-START Register, a branch of START Register (NCT02219984) included VKA-treated patients managed by centers of Italian Federation of anticoagulation clinics (AC). Baseline patient characteristics and data during treatment were analyzed and compared with those of ISCOAT study, performed by the Federation and published in 1996/7. 5707 naïve patients [53% males, mean age 73.0 years (28.1% >80 years)], 61.6% treated for atrial fibrillation (AF), and 28.0% for venous thromboembolism were included. During the 8906 patient-years (pt-yrs) of observation, 123 patients had major bleeding (MB) (1.38% pt-yrs; fatal: 0.11% pt-yrs), while non-major clinically relevant bleeds were 144 (1.62% pt-yrs). Bleeding was more frequent in elderly (≥70 years; p = 0.04), and during initial 3-month therapy (p = 0.02). Bleeding rate was 2.5% pt-yrs for temporally related INR results <3.0, increasing to 12.5% for INR ≥ 4.5. Thrombotic events were 47 (0.53% pt-yrs; 4 fatal 0.04% pt-yrs). Compared with ISCOAT-1996/7 results, patients older than 80 y are increased from 8 to 28% (p < 0.01), and those treated for AF are increased from 17 to 61%. The quality of anticoagulation control and incidence of MB are not different. However, thrombotic complications fell drastically from 3.5 to 0.53% pt-yrs (p < 0.01), with lower mortality (p = 0.01). VKA-treated patients monitored in Italian AC have good clinical results, with low bleeding and thrombotic complications rates. Important changes in the treated population and improvement in thrombotic complications are detected compared with the ISCOAT-1996/7 study.

The aim of this study was to evaluate the number of patients with nonvalvular atrial fibrillation (NVAF), anticoagulated with vitamin K antagonists (VKA), and monitored in our Thrombosis Centre, who could replace VKA with direct oral anticoagulants (DOACs) based on the Italian Federation of Thrombosis Centres (FCSA) consensus criteria. A total of 525 NVAF patients treated with VKA were studied. Therapeutic range (TTR) assessment and a capillary test for serum creatinine measure were carried out. The patients' preference was evaluated through the administration of a dedicated questionnaire. A history of intracranial bleeding was also taken into account. DOACs would cover 29 % of the patients considering a TTR <70 %; the percentage falls to 10 % if a TTR <55 % is considered. Only 20 % of the patients would move from VKA to DOACs because of the lack of an antidote and laboratory checks during DOACs therapy. Thirty-three percent of patients were worried that they would forget to take the tablets twice a day. About 2 % of patients could not use DOACs since their glomerular filtration rate was less than 30 ml/min, while in 23.6 %, a reduction in the daily dose of DOACs would have been required due to renal failure. TTR assessment, renal function and a previous history of intracranial bleeding would reduce the percentage of patients who could switch from VKA to DOACs, but it is the patients' preference that strongly influences the percentage of those who would benefit from DOACs treatment. However, if laboratory controls were available, it would rise considerably.

Physicians are occasionally faced with difficult situations in the management of vitamin K antagonists (VKA) due to the lack of sound data available in controlled studies on certain conditions. In this review we would like to address some special but frequent conditions that can be encountered in daily clinical practice. These include the use of VKA in hemodialysis, thromboembolism in patients with liver cirrhosis and the thromboembolic risk in patients who bleed in the course of treatment with VKA. Moreover, two other conditions were examined: what the best way of expressing prothrombin time would be in patients with liver disease and how to behave when a patient treated with VKA shows a subtherapeutic INR. These topics were discussed by a panel of experts during a workshop recently held in Milan by the Italian Federation of Centres for the Diagnosis of Thrombosis and the Surveillance of Antithrombotic Therapies (FCSA). The main aim of the workshop was to provide helpful and practical advice to physicians in the daily management of VKA.

In this review, we present some different and special conditions that are generally being treated with anticoagulants such as cerebral vein thrombosis (CVT), mesenteric vein thrombosis (MVT), Budd-Chiari syndrome (BCS), and Pulmonary Hypertension (PH) despite the lack of controlled clinical trials. While either low molecular weight heparins (LMWHs) or unfractioned heparin (UFH) are used in the acute phase of the first three conditions, the potential chronic use of warfarin in PH is controversial. What is not completely known in the management of CVT, MTV, and BCS is whether (a) LMWHs are similar to UFH in terms of efficacy and safety, and (b) a fibrinolytic drug could be employed in the acute phase. The timing at which warfarin should be started, and the duration of its employment are two additional crucial points that deserve to be examined. In the course of PH, the role of warfarin is controversial, but it could be employed after a careful balance of the hemorrhagic and thromboembolic risk. In conclusion, we tried to simplify the approach to this sometimes problematic task considering the available literature with the aim of providing some practical skills to be used by physicians in their daily clinical practice. Since it is improbable that in the future controlled clinical trials will be designed to find the optimal anti-thrombotic management of these conditions, we believe that a physician should be aware of the lack of solid data in the field but at the same time should always exert clinical judgment when considering an aggressive anticoagulant approach. The duration of oral anticoagulant treatment is left to the clinical judgment of the balance between the hemorrhagic and thrombotic risks in any single patient.

Overt neoplasia is often the end result of a long biological process beginning with the appearance of focal lesions of altered tissue morphology. While the putative clonal nature of focal lesions has often been emphasized, increasing attention is being devoted to the possible role of an altered growth pattern in the evolution of carcinogenesis. Here we compare the growth patterns of normal and nodular hepatocytes in a transplantation system that allows their selective clonal proliferation in vivo. Rats were pre-treated with retrorsine, which blocks the growth of resident hepatocytes, and were then transplanted with hepatocytes isolated from either normal liver or hepatocyte nodules. Both cell types were able to proliferate extensively in the recipient liver, as expected. However, their growth pattern was remarkably different. Clusters of normal hepatocytes integrated in the host liver, displaying a normal histology; however, transplanted nodular hepatocytes formed new hepatocyte nodules, with altered morphology and sharp demarcation from surrounding host liver. Both the expression and distribution of proteins involved in cell polarity, cell communication, and cell adhesion, including connexin 32, E-cadherin, and matrix metalloproteinase-2, were altered in clusters of nodular hepatocytes. Furthermore, we were able to show that down-regulation of connexin 32 and E-cadherin in nodular hepatocyte clusters was independent of growth rate. These results support the concept that a dominant pathway towards neoplastic disease in several organs involves defect(s) in tissue pattern formation.

Hemorrhagic events due to production of antibodies directed against coagulation factors are rarely observed in systemic lupus erythematosus (SLE). We report the case of a patient with clinically quiescent SLE who developed factor VIII inhibitor in acquired hemophilia presenting as hemarthrosis. Initial treatment with FVII, FVIII and FIX plasma concentrate, metilprednisolone and immunoglobulins i.v. were started but new hemorrhagic manifestation occurred. Plasma exchange was also administered, but it was discontinued early due to partial efficacy. In addition, pulse cyclophosphamide 0.5 g/m(2) was started. Eight weeks later, FVIII and FIX activity returned within normal ranges, FVIII and FIX inhibitors decreased significantly and hemorrhagic manifestations disappeared. The rare occurrence of acquired hemophilia due to the presence of anti-factor VIII antibodies associated to SLE, which was reviewed, might explain the lack of therapeutic guide-lines; indeed therapeutic options are available but the outcome in each single patient is not predictable.

The aim of this paper is to briefly review some practical aspects of the relationship between thyroid function and several disorders of the hemostatic system in terms of bleeding and thrombosis. Thrombocytopenia, acquired hemophilia, hypercoagulability, cardioembolism and other biochemical coagulative and fibrinolytic abnormalities have been described in the past years both in hyper- and hypothyroidism. Since most of hyper- and hypothyroid conditions are the consequence of autoimmune thyroid disease (1), either deranged immune function, altered circulating thyroid hormone concentration, or both may concur in the pathogenesis of hemostatic disorders of potential crucial clinical impact. These aspects will be outlined and discussed in an attempt to give answers to some questions, often arising in the clinical approach.

Acquired hemophilia due to autoantibody to Factor VIII coagulant (Factor VIIIc) is a rare event which may be observed in patients with different autoimmune diseases. To our knowledge, this association has been reported only once in patients with autoimmune thyroid disease. Here we describe a patient presenting with a severe hemorrhagic disorder due to Factor VIIIc antibody in whom biochemical screening for thyroid diseases led to a diagnosis of hyperthyroid Graves' disease not associated to overt clinical features. This case underlines the importance of carrying out a complete screening for autoimmunity, including thyroid autoimmune disease, in all patients with apparently isolated serum Factor VIIIc inhibitors.

Cellulite (CLT) is one of the commonly known lipodystrophy syndromes affecting post-adolescent women worldwide. It is topographically characterized by an orange-peel, dimpled skin appearance hence, it is an unacceptable cosmetic problem. CLT can be modulated by surgical procedures such as; liposuction and mesotherapy. But, these options are invasive, expensive and risky. For these reasons, topical CLT treatments are more preferred. Caffeine (CA), is a natural alkaloid that is well-known for its prominent anti-cellulite effects. However, its hydrophilicity hinders its cutaneous permeation. Therefore, in the present study CA was loaded into solid lipid nanoparticles (SLNs) by high shear homogenization/ultrasonication. CA-SLNs were prepared using Compritol® 888 ATO and stearic acid as solid lipids, and span 60 and brij™35, as lipid dispersion stabilizing agents. Formulation variables were adjusted to obtain entrapment efficiency (EE > 75%), particle size (PS < 350 nm), zeta potential (ZP < -25 mV) and polydispersity index (PDI < 0.5). CA-SLN-4 was selected and showed maximized EE (92.03 ± 0.16%), minimized PS (232.7 ± 1.90 nm), and optimum ZP (-25.15 ± 0.65 mV) and PDI values (0.24 ± 0.02). CA-SLN-4 showed superior CA release (99.44 ± 0.36%) compared to the rest CA-SLNs at 1 h. TEM analysis showed spherical, nanosized CA-SLN-4 vesicles. Con-LSM analysis showed successful CA-SLN-4 permeation transepidermally and via shunt diffusion. CA-SLN-4 incorporated into Noveon AA-1® hydrogel (CA-SLN-Ngel) showed accepted physical/rheological properties, and in vitro release profile. Histological studies showed that CA-SLN-Ngel significantly reduced mean subcutaneous fat tissue (SFT) thickness with 4.66 fold (p = 0.035) and 4.16 fold (p = 0.0001) compared to CA-gel, at 7th and 21st days, respectively. Also, significant mean SFT thickness reduction was observed compared to untreated group with 4.83 fold (p = 0.0005) and 3.83 fold (p = 0.0043), at 7th and 21st days, respectively. This study opened new avenue for CA skin delivery via advocating the importance of skin appendages. Hence, CA-SLN-Ngel could be a promising nanocosmeceutical gel for effective CLT treatment., (© 2024. The Author(s).)

Time-varying characteristics of particulate matter (PM) pollution play a crucial role in shaping atmospheric dynamics, which impact the health and welfare of urban commuters. Previously published studies on the diurnal patterns of PMs are not consistent, especially in the context of field experiments in central China, and most field studies have only focused on particles with a single particle size. This study conducted regional-scale studies across 72 street canyon sets in Wuhan, China, investigated diurnal and seasonal PM concentration variations while also evaluating various PM size and the key driving factors. During summer (July, August, and September), evergreen tree-lined street canyons maintained a stable linear trend for smaller d p particulates (i.e., PM 1 , PM 2.5 , and PM 4 ), while deciduous street canyons exhibited a bimodal distribution. In winter (January and February), fine particulates (i.e., PM 1 and PM 2.5 ) remained a linear trend in evergreen street canyons, while deciduous street canyons show a slightly wavy fluctuating pattern. Meanwhile, it exhibited quadrimodal-peak and triple-trough patterns in both PM 7 , PM 10 , and TSP concentrations. The lowest PM concentrations were observed between 14:00 and 16:00 for all particle sizes, with decreased summer pollution (7.81% lower in PM 2.5 , 53.47% lower in PM 10 , and 50.3% lower in TSP) noted in our seasonal analysis. Among the various meteorological factors, relative humidity (RH) was identified as the dominant influencing PM factor in both summer and winter. Results from this study will help us better understand field-based air pollutant dispersion processes within pedestrian spaces while laying the groundwork for future research into street PM experiments., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Skin cancer remains one of the most prominent types of cancer. Melanoma and non-melanoma skin cancer are commonly found together, with melanoma being the more deadly type. Skin cancer can be effectively treated with chemotherapy, which mostly uses small molecular medicines, phytoceuticals, and biomacromolecules. Topical delivery of these therapeutics is a non-invasive way that might be useful in effectively managing skin cancer. Different skin barriers, however, presented a major obstacle to topical cargo administration. Transferosomes have demonstrated significant potential in topical delivery by improving cargo penetration through the circumvention of diverse skin barriers. Additionally, the transferosome-based gel can prolong the residence of drug on the skin, lowering the frequency of doses and their associated side effects. However, the choice of appropriate transferosome compositions, such as phospholipids and edge activators, and fabrication technique are crucial for achieving improved entrapment efficiency, penetration, and regulated particle size. The present review discusses skin cancer overview, current treatment strategies for skin cancer and their drawbacks. Topical drug delivery against skin cancer is also covered, along with the difficulties associated with it and the importance of transferosomes in avoiding these difficulties. Additionally, a summary of transferosome compositions and fabrication methods is provided. Furthermore, topical delivery of small molecular drugs, phytoceuticals, and biomacromolecules using transferosomes and transferosomes-based gel in treating skin cancer is discussed. Thus, transferosomes can be a significant option in the topical delivery of drugs to manage skin cancer efficiently., (© 2024. Controlled Release Society.)

Plasma concentration of fibrinogen and B beta 15-42, a specific product of fibrinogen metabolism induced by plasmin, were measured in a group of patients with untreated hyperthyroidism and in controls. Significantly increased plasma levels of both parameters were observed in hyperthyroid patients. The restoration of euthyroidism either by antithyroid drug or by radioiodine caused a significant decrease of fibrinogen and B beta 15-42. These data indicate that hyperthyroidism is another clinical condition associated with increased concentration of fibrinogen and B beta 15-42.

Ferroptosis is a unique form of cell death reliant on iron and lipid peroxidation. It disrupts redox balance, causing cell death by damaging the plasma membrane, with inducers acting through enzymatic pathways or transport systems. In cancer treatment, suppressing ferroptosis or circumventing it holds significant promise. Beyond cancer, ferroptosis affects aging, organs, metabolism, and nervous system. Understanding ferroptosis mechanisms holds promise for uncovering novel therapeutic strategies across a spectrum of diseases. However, detection and regulation of this regulated cell death are still mired with challenges. The dearth of cell, tissue, or organ-specific biomarkers muted the pharmacological use of ferroptosis. This review covers recent studies on ferroptosis, detailing its properties, key genes, metabolic pathways, and regulatory networks, emphasizing the interaction between cellular signaling and ferroptotic cell death. It also summarizes recent findings on ferroptosis inducers, inhibitors, and regulators, highlighting their potential therapeutic applications across diseases. The review addresses challenges in utilizing ferroptosis therapeutically and explores the use of machine learning to uncover complex patterns in ferroptosis-related data, aiding in the discovery of biomarkers, predictive models, and therapeutic targets. Finally, it discusses emerging research areas and the importance of continued investigation to harness the full therapeutic potential of targeting ferroptosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Direct oral anticoagulants (DOACs) are widely used for the treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (AF). However, evidence in obese and underweight patients is limited. We assessed the safety and effectiveness of DOACs and vitamin K antagonists (VKAs) in patients  ≥ 120 kg or ≤ 50 kg enrolled in an observational prospective cohort study, the START-Register., Methods: Adult patients started on anticoagulant therapy were followed up for a median of 1.5 years (IQR 0.6-2.8). Primary efficacy outcome was the occurrence of VTE recurrence, stroke and systemic embolism. Primary safety outcome was major bleeding (MB)., Results: 10,080 AF and VTE patients were enrolled between March 2011 and June 2021, 295 patients weighted  ≤ 50 kg and 82 patients ≥ 120 kg. Obese patients were significantly younger than underweight patients. Rates of thrombotic events were low and similar between DOACs and VKAs in underweight patients (1 event on DOACs therapy [0.9% 95% CI 0.11-5.39] and 2 on VKAs [1.1% 95% CI 0.01-47.68]) and in overweight patients (0 events on DOACs, 1 on VKAs [1.6%, 95% CI 0.11-5.79]. Two MB events occurred on DOACs (1.9%, 95% CI 0.38-6.00) and 3 on VKAs (1.6%, 95% CI 0.04-22.06) in the underweight group; 1 MB on DOACs (5.3% 95% CI 0.33-16.68) and 2 on VKAs (3.3%, 95% CI 0.02-130.77) in the overweight group., Conclusions: DOACs seem to be effective and safe also for the treatment of patients with extreme body weights, both underweight and overweight. Further prospective studies are needed to support these findings., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

The objective is to perform a multimodal ophthalmological evaluation, including optical coherence angiography (OCTA), asymptomatic APS secondary to SLE (APS/SLE), and compare to SLE patients and control group (CG). We performed a complete structural/functional ophthalmological evaluation using OCTA/microperimetry exam in all participants. One hundred fifty eyes/75 asymptomatic subjects [APS/SLE (n = 25), SLE (n = 25), and CG (n = 25)] were included. Ophthalmologic abnormalities occurred in 9 (36%) APS/SLE, 11 (44%) SLE, and none of CG (p < 0.001). The most common retinal finding was Drusen-like deposits (DLDs) exclusively in APS/SLE and SLE (16% vs. 24%, p = 0.75) whereas severe changes occurred solely in APS/SLE [2 paracentral acute middle maculopathy (PAMM) and 1 homonymous quadrantanopsia]. A trend of higher frequency of antiphospholipid antibody (aPL) triple positivity (100% vs. 16%, p = 0.05) and higher mean values of adjusted Global Antiphospholipid Syndrome Score (aGAPSS) (14 ± 0 vs. 9.69 ± 3.44, p = 0.09) was observed in APS/SLE with PAMM vs. those without this complication. We identified that ophthalmologic retinal abnormalities occurred in more than 1/4 of asymptomatic APS/SLE and SLE. DLDs are the most frequent with similar frequencies in both conditions whereas PAMM occurred exclusively in APS/SLE patients. The possible association of the latter condition with aPL triple positivity and high aGAPSS suggests these two conditions may underlie the retinal maculopathy. Our findings in asymptomatic patients reinforce the need for early surveillance in these patients. Key Points • Retinal abnormalities occur in more than 1/4 of asymptomatic APS/SLE and SLE patients. • The occurrence of PAMM is possibly associated with APS and DLDs with SLE. • Presence of aPL triple positivity and high aGAPSS seem to be risk factors for PAMM., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Purpose: The effects of calorie restriction (CR) on gut microbiota and the mechanism of CR ameliorating hyperglycemia in streptozotocin (STZ)-induced T2DM model rats were explored., Methods: High-fat diet and STZ injection were applied to induce T2DM model rats. Rats were divided into the following three groups: the control-diet ad libitum group, the T2DM model group fed with ad libitum diet, and the T2DM group fed with 30% restriction diet. 16S rRNA sequencing was used to determine the bacterial communities. Lipopolysaccharide (LPS)-binding protein (LBP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured., Results: Glucose tolerance and insulin sensitivity were improved by CR, as well as the levels of fasting and random plasma glucose. Besides, CR not only modulated the overall structure of gut microbiota but also had selective enrichment in anti-inflammatory bacteria such as Lachnospiraceae&#95;NK4A136&#95;group, Ruminococcaceae&#95;9, Allobaculum, Alistipes, and Oscillibacter, and decreased pro-inflammatory pathogenic bacteria such as Bacteroides, Lachnoclostridium, and Bifidobacterium. Tax4Fun indicated that CR could regulate related functional pathways such as lipopolysaccharide biosynthesis, and the plasma levels of LBP, IL-6, and TNF-α were markedly reduced by CR, suggesting the mechanism of CR ameliorating hyperglycemia may associate with the modulation of disordered gut microbiota and the reduction of metabolic endotoxemia and inflammation., Conclusion: CR could ameliorate hyperglycemia, the mechanism of which may associate with the alteration of the overall structure of gut microbiota, restoration of disordered microbiota function, and the downregulation of metabolic endotoxemia and inflammation in diabetic rats., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: The number of recognised distinct autoimmune diseases (AIDs) has progressively increased over the years with more than 100 being reported today. The natural history of AIDs is characterized by progression from latent and subclinical to clinical stages and is associated with the presence of the specific circulating autoantibodies. Once presented, AIDs are generally chronic conditions. AIDs have the tendency to cluster and co-occur in a single patient. Autoimmune thyroid diseases (AITD) are the most prevalent of AIDs in the world population, and about one-third of the AITD patients also present with a non-thyroid AID during their life-span. Furthermore, patient with non-thyroid AIDs often presents with a form of AITD as a concurrent condition. Many of the clusters of AIDs are well characterized as distinctive syndromes, while some are infrequent and only described in case reports., Purpose: In this review, we describe the wide spectrum of the combinations and the intricate relationships between AITD and the other AIDs, excluding Addison's disease. These combinations are collectively termed type 3 Autoimmune Polyglandular Syndrome (APS-3), also called type 3 Multiple Autoimmune Syndrome (MAS-3), and represent the most frequent APS in the world populations., Conclusions: Numerous associations of AITD with various AIDs could be viewed as if the other AIDs were gravitating like satellites around AITD located in the center of a progressively expanding galaxy of autoimmunity., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Impaired reproductive health is a worldwide problem that affects the psychological well-being of a society. Despite the technological developments to treat infertility, the global infertility rate is increasing significantly. Many infertility conditions are currently treated using various advanced clinical approaches such as intrauterine semination (IUI), in vitro fertilization (IVF), and intracytoplasmic injection (ICSI). Nonetheless, clinical management of some conditions such as dysfunctional endometrium, premature ovarian failure, and ovarian physiological aging still pose significant challenges. Stem cells based therapeutic strategies have a long-standing history to treat many infertility conditions, but ethical restrictions do not allow the broad-scale utilization of adult mesenchymal stromal/stem cells (MSCs). Easily accessible, placental derived or amniotic stem cells present an invaluable alternative source of non-immunogenic and non-tumorigenic stem cells that possess multilineage potential. Given these characteristics, placental or amniotic stem cells (ASCs) have been investigated for therapeutic purposes to address infertility in the last decade. This study aims to summarize the current standing and progress of human amniotic epithelial stem cells (hAECs), amniotic mesenchymal stem cells (hAMSCs), and amniotic fluid stem cells (hAFSCs) in the field of reproductive medicine. The therapeutic potential of these cells to restore or enhance normal ovarian function and pregnancy outcomes are highlighted in this study., (© 2022. The Author(s).)

Tumor cells evolve through space and time, generating genetically and phenotypically diverse cancer cell populations that are continually subjected to the selection pressures of their microenvironment and cancer treatment., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease, and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years., (© 2021. The Author(s).)

The International Normalized Ratio (INR) monitoring is an essential component to manage thrombotic disease therapy. This study presents a semi-empirical model of INR as a function of time and assigned therapy (Warfarin, k-vitamin). With respect to other methodologies, this model is able to describe the INR using a limited number of parameters and is able to describe the time variation of INR described in the literature. The presented methodology showed great accuracy in model calibration [(trueness (precision)]: 0.2% (0.1%) to 1.2% (0.3%) for coagulation factors, from 5% (9%) to 9.7% (12%) for Warfarin-related parameters and 38% (40%) for K-vitamin-related parameters. The latter value was considered acceptable given the assumptions made in the model. It has two other important results: the first is that it was able to correctly estimate INR with respect to daily therapy doses taken from the literature. The second is that it introduces a single numeric semi-empirical parameter that is able to correlate INR/dose response to physiological and environmental condition of patients., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Drugs are referred to as drug nanocrystals when they exist as nanoscale crystal structures. This kind of nanocarrier has been widely utilized to increase the solubility and absorption for poorly aqueous soluble drugs after oral administration, or prolong the drug circulation when intravenous administration. The systemic cytotoxicity caused by antitumor drugs usually come from the nonspecific drug distribution. To solve the disadvantage of poor targetability, drug nanocrystals for tumor targeted delivery have been developed in recent years. In this review, the targeting mechanisms of various surface modified drug nanocrystals are introduced with the focus on passive targeting, active targeting and stimuli-responsive targeting in details. Function and application of common surface modified materials are also discussed., (© 2021. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Preliminary evidence supports the notion that COVID-19 patients may have an increased susceptibility to develop venous thromboembolism (VTE). However, the magnitude of this association still needs to be defined. Furthermore, clinical predictors of thrombogenesis, and the relationship with the inflammatory status are currently unknown. On this basis, we conducted a retrospective, observational study on 259 consecutive COVID-19 patients admitted to an academic tertiary referral hospital in Northern Italy between March 19th and April 6th, 2020. Records of COVID-19 patients with a definite VTE event were reviewed for demographic information, co-morbidities, risk factors for VTE, laboratory tests, and anticoagulation treatment. Twenty-five cases among 259 COVID-19 patients developed VTE (9.6%), all of them having a Padua score > 4, although being under standard anticoagulation prophylaxis since hospital admission. In the VTE subcohort, we found a significant positive correlation between platelet count (PLT) and either C reactive protein (CRP) (p < 0.0001) or lactate dehydrogenase (LDH) (p = 0.0013), while a significant inverse correlation was observed between PLT and mean platelet volume (p < 0.0001). Platelet-to-lymphocyte ratio significantly correlated with CRP (p < 0.0001). The majority of VTE patients was male and younger compared to non-VTE patients (p = 0.002 and p = 0.005, respectively). No significant difference was found in D-dimer levels between VTE and non VTE patients, while significantly higher levels of LDH (p = 0.04) and IL-6 (p = 0.04) were observed in VTE patients in comparison to non-VTE patients. In conclusion, our findings showed a quite high prevalence of VTE in COVID-19 patients. Raised inflammatory indexes and increased serum levels of pro-inflammatory cytokines should raise the clinical suspicion of VTE., (© 2020. The Author(s).)

Mucositis is one of the most adverse effects of 5-fluorouracil (5-FU) and had no standard drug for treatment. Melatonin is a neurohormone, and can ameliorate radiotherapy-induced small intestinal mucositis. Melatonin encapsulated in niosomes improved its poor bioavailability. Succinyl melatonin, a melatonin derivative, showed prolonged release compared with melatonin. This study investigated the efficacy of melatonin niosome gel (MNG) and succinyl melatonin niosome gel (SNG) in 5-FU-induced small intestinal mucositis treatment in mice. MNG and SNG with particle sizes of 293 and 270 nm were shown to have mucoadhesive potentials. The effect of a daily oral application of MNG, SNG, or fluocinolone acetonide gel (FAG, positive control) was compared to that of the normal group. The body weight, food consumption, histology, Fourier transform infrared (FTIR) spectroscopy, inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β), and malondialdehyde (MDA) in the small intestine were monitored. The results showed decreased %body weight and food consumption in all 5-FU-injected groups compared with the normal group. The MNG and SNG treatments maintained the food consumption and the normal integrity of the small intestines, as evidenced by villus length and crypt depth, similar to the observations in the normal groups. The FTIR spectra showed no change in lipids of the MNG and SNG groups compared with the normal group. Moreover, SNG could reduce IL-1β content to a level that was not different from the level in the normal groups. Therefore, the oral application of MNG and SNG could protect against 5-FU-induced small intestinal mucositis in mice.

Rhein (RH), an anthraquinone derivative, has proven to be a promising molecule for treating several skin disorders thanks to its pleiotropic pharmacological activities like antimicrobial, antifungal, antioxidant, and anticancer. However, RH's low water and oil solubility and poor skin permeability halted its topical delivery. This is the first work to investigate the expediency of tailoring a rhein-phospholipid complex (RH-PLC) to improve RH challenging physicochemical and skin permeability properties. The phospholipid complex was prepared by employing different methods and different RH/PL molar ratios. RH-PLC was successfully developed at a stoichiometric ratio of 1:1 using a novel pH-dependent method where at a certain pH, it exhibits the highest complexation efficiency (95%). RH-PLC formation was confirmed using FTIR, DSC, and XRPD analysis. RH-PLC showed a significant increase in water and n-octanol solubility. RH-PLC was self-assembled upon dispersion into water forming nano-sized particles (196.6 ± 1.6 nm) with high negatively charged surface (- 29.7 ± 2.45 mV). RH-PLC exhibited a significant 3.3- and 2.46-fold increase in ex vivo and in vivo skin permeability when compared with RH suspension, respectively. Confocal microscopy study confirmed the ability of RH-PLC to penetrate deeply into rat skin. Besides, skin irritation test on healthy rats indicated compatibility and safety of RH-PLC. Conclusively, phospholipid complex might be a suitable approach to improve permeability of RH and other promising abandoned poor-permeable drugs. The proposed RH-PLC is expected to be a major progressive step toward the development of a topical RH formulation. Graphical abstract.

Nanocrystals can enhance skin penetration of drug by increased saturation solubility, dissolution rate and adhesion on the skin. Apremilast is 'difficult-to-deliver' in viable layers (epidermis, dermis) and stratum corneum (SC) owing to its poor aqueous solubility and modest lipophilicity, respectively. Apremilast is currently available as oral tablet formulation for the indication of psoriasis but its effectiveness is limited by systemic side effects. Therefore, the present study aimed to develop novel nanocrystal-based formulations of apremilast for improved topical delivery. Nanosuspension was prepared using wet media milling and exhibited a mean particle size of 200 nm. The saturation solubility of nanocrystals was improved by 2-fold than micronized apremilast and showed significant advantage during dissolution study. Nanosuspension and micronized apremilast was incorporated into gel and cream and characterized for rheological properties. Skin permeation and ex vivo dermatokinetic study of topical formulations were performed on pig ear skin at a dose of 1% w/w using Franz diffusion cells. Skin permeation studies indicated that non-detectable amount of apremilast permeated through pig ear skin during exposure of formulations. Nanosuspension showed 2.6- and 3.2-fold drug penetration in SC and viable layers, respectively, over microsuspension. Nanogel showed 2.7- and 2.4-fold drug penetration in SC and viable layers, respectively, over microgel. Nanocream showed 1.2- and 2.8-fold drug penetration in SC and viable layers, respectively, over microcream. Thus, nanocrystal-based formulations of apremilast aid in selective delivery into viable layers by crossing the SC barrier. This is of paramount importance in enhancing therapeutic effectiveness utilizing localized delivery and provides an alternative delivery approach for the treatment of psoriasis. Graphical abstract.

Liver disease has been long considered as a risk factor for bleeding for the presence of prolongation of global tests of clotting activation and low platelet count. For this reason, the use of anticoagulants in patients with liver disease and an indication to anticoagulation, such as atrial fibrillation of venous thrombosis, has been poorly considered. Furthermore, recent studies underscored the fact that patients with chronic liver disease may experience thrombosis in portal as well as systemic circulation and treatment with anticoagulants should be considered. The introduction of direct oral anticoagulants has increased therapeutic options for thromboprophylaxis; however, evidence on their safety and efficacy in specific populations, such as patients with liver disease, is still scarce and needs further investigation. Thus, atrial fibrillation patients with coexistent liver disease have been excluded from clinical trials with direct oral anticoagulants. Here, we provide an overview on mechanisms of thrombosis in patients with advanced chronic liver disease and a summary of evidence on the use of oral anticoagulants in patients with liver disease and portal vein thrombosis or atrial fibrillation.