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Abstract Gut microbiota changes and brain-gut-axis (BGA) dysregulation are common in people with Parkinson’s Disease (PD). Probiotics and prebiotics are emerging as a potential therapeutic approach for PD patients. The aim of this paper was to assess the neurological and gastroenterological effects in PD patients with constipation after the administration of a synbiotic product, with a focus on behavioral and cognitive symptoms. We enrolled patients with stable PD who met diagnostic criteria for functional constipation and/or irritable bowel syndrome with constipation according to Rome IV Criteria. Patients received a synbiotic treatment (Enterolactis Duo, containing the probiotic strain Lacticaseibacillus paracasei DG and the prebiotic fiber inulin) for 12 weeks. A neurological and a gastroenterological evaluation were collected before and after the treatment. In addition, 16S rRNA gene profiling and short chain fatty acid quantification were performed to characterize the microbial ecosystem of fecal samples collected before (n = 22) and after (n = 9) the synbiotic administration. 30 patients were consecutively enrolled. After treatment, patients performed better in MDS-UPDRS part 1 (p = 0.000), SCOPA-AUT (p = 0.001), TAS-20 (p = 0.014), HAM-D (p = 0.026), DIFt (p = 0.003), PAS-A (p = 0.048). Gastroenterological evaluations showed improvements in PAC-SYM score (p

Abstract The use of monoclonal antibodies for the control of drug resistant nosocomial bacteria may alleviate a reliance on broad spectrum antimicrobials for treatment of infection. We identify monoclonal antibodies that may prevent infection caused by carbapenem resistant Acinetobacter baumannii. We use human immune repertoire mice (Kymouse platform mice) as a surrogate for human B cell interrogation to establish an unbiased strategy to probe the antibody-accessible target landscape of clinically relevant A. baumannii. After immunisation of the Kymouse platform mice with A. baumannii derived outer membrane vesicles (OMV) we identify 297 antibodies and analyse 26 of these for functional potential. These antibodies target lipooligosaccharide (OCL1), the Oxa-23 protein, and the KL49 capsular polysaccharide. We identify a single monoclonal antibody (mAb1416) recognising KL49 capsular polysaccharide to demonstrate prophylactic in vivo protection against a carbapenem resistant A. baumannii lineage associated with neonatal sepsis mortality in Asia. Our end-to-end approach identifies functional monoclonal antibodies with prophylactic potential against major lineages of drug resistant bacteria accounting for phylogenetic diversity and clinical relevance without existing knowledge of a specific target antigen. Such an approach might be scaled for a additional clinically important bacterial pathogens in the post-antimicrobial era.

Selected crystals of natural K-bearing tourmalines, extracted from a quartzofeldspathic rock from the Kumdy-Kol microdiamond deposit (an ultrahigh-pressure region of Kokchetav Massif, northern Kazakhstan), were characterized using a scanning electron microscope, an electron microprobe and single-crystal X-ray diffraction to investigate the impact of K uptake on the tourmaline structure. All the studied crystals belong to the maruyamaite–oxy-dravite/dravite compositional field, with K contents ranging from 0.03 to 0.47 apfu (atoms per formula unit), and contain a minor fluor-uvite component that increases towards oxy-dravite and dravite. The compositional variability of our samples can be expressed as a sequence of substitutions ranging from maruyamaite to oxy-dravite, dravite and fluor-uvite (or vice versa). Specifically, the substitutions that lead from maruyamaite to oxy-dravite to dravite are (1) XK + AlTOT + O1O ↔ XNa + MgTOT + O1O and (2) XNa + MgTOT + O1O ↔ XNa + MgTOT + O1OH, respectively. Conversely, the substitutions that lead from oxy-dravite to dravite to fluor-uvite are (1) XNa + MgTOT + O1O ↔ XNa + MgTOT + O1OH and (2) XNa + MgTOT + O1OH ↔ XCa + MgTOT + O1F, respectively. By analysing the difference between the bond valence sum and mean formal charge at the X site, we show that an increase in the K content (K > 0.21 apfu) results in the compression of X–O bonds (overbonded cation). Conversely, lower K contents lead to the stretching of the bonds (underbonded cation). Compared to the K-dominant analogues with ZFeO6 povondraite-type framework, K-bearing tourmalines with a smaller ZAlO6 framework such as maruyamaite should only be stable at higher-pressure conditions, as pressure is necessary to squeeze the relatively large K cation into the tighter X cavity. In both cases, the essential condition for the formation of K-dominant tourmalines is the extremely high K activity in the crystallization fluid. The K-tourmaline from the Kokchetav Massif may have crystallized under high-pressure (HP) conditions, with an upper limit between 3.5–7 GPa, during retrograde metamorphism following the ultrahigh-pressure (UHP) metamorphic peak.

Abstract Background A compromised cardiac autonomic function has been found in subjects with insulin resistance related disorders such as obesity, impaired glucose tolerance (IGT) and type 2 diabetes and confers an increased risk of adverse cardiovascular outcomes. Growing evidence indicate that 1 h plasma glucose levels (1hPG) during an oral glucose tolerance test (OGTT) ≥ 155 mg/dl identify amongst subjects with normal glucose tolerance (NGT) a new category of prediabetes (NGT 1 h-high), harboring an increased risk of cardiovascular organ damage. In this study we explored the relationship between 1 h post-load hyperglycemia and cardiac autonomic dysfunction. Methods Presence of cardiac autonomic neuropathy (CAN) defined by cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV), assessed by 24-h electrocardiography were evaluated in 88 non-diabetic subjects subdivided on the basis of OGTT data in: NGT with 1 h PG 50 ms (PNN50) and Triangular index. Univariate analyses showed that 1hPG, but not fasting and 2hPG, was inversely associated with all the explored HVR parameters and positively with CARTs determined presence of CAN. In multivariate regression analysis models including several confounders we found that 1hPG was an independent contributor of HRV and presence of CAN. Conclusion Subjects with 1hPG ≥ 155 mg/dl have an impaired cardiac autonomic function.

Abstract Elevated levels of the gut pro-hormone Proneurotensin (proNT) have been found to predict development of cardiovascular disease. However, it is still unknown whether higher proNT levels are associated with subclinical vascular damage. Herein, we investigated the relationship between higher proNT concentrations and augmented pulse pressure (PP) and carotid intima-media thickness (cIMT), indicators of increased arterial stiffness and subclinical atherosclerosis, respectively. Clinical characteristics, PP and cIMT were evaluated in 154 non-diabetic individuals stratified into tertiles according to fasting serum proNT concentrations. We found that, subjects with higher proNT levels exhibited a worse lipid profile and insulin sensitivity, increased C-reactive protein levels, along with higher values of PP and cIMT as compared to the lowest proNT tertile. Prevalence of elevated PP (≥ 60 mmHg) and subclinical carotid atherosclerosis (IMT > 0.9 mm) was increased in the highest tertile of proNT. In a logistic regression analysis adjusted for several confounders, subjects with higher proNT levels displayed a fivefold raised risk of having elevated PP values (OR 5.36; 95%CI 1.04–27.28; P = 0.05) and early carotid atherosclerosis (OR 4.81; 95%CI 1.39–16.57; P = 0.01) as compared to the lowest proNT tertile. In conclusion, higher circulating levels of proNT are a biomarker of subclinical vascular damage independent of other atherosclerotic risk factors.

The philosophical foundations of the veg(etari)an diet. Food choices as ethical choices Although recent decades have seen a substantial increase in talking about the moral value of nature, the discussion has not yet undermined the belief according to which we can use nature without restraint, as long as we respects other human beings. The food issue is a classic example: our very existence and survival within planet Earth implies a competition which implies our use and killing of other forms of life, not belonging to our moral community. However, is still really indisputable that only human beings, and no other non-human natural entities, are members of this community? The main aim of this paper is to explore the answers provided to this question by the best-known contemporary philosophers, who defend the need to adopt a vegetarian diet: Peter Singer and Tom Regan. The central assumption of both authors is that, even though there are undoubtedly differences between humans and other natural entities, the ethical principles that underlie relationships between human beings are based and justified on the possession of traits that are also possessed by a large part of the non-human animals. Thus, we do not have to overturn any of the assumptions of traditional ethic. In fact, we have to apply them correctly: if the ability to experience pleasure and pain and/or of being conscious have intrinsic value, as already widely supported by the Western moral tradition, then all the entities with sensitivity and/or cognition abilities have a moral status. Singer’s utilitarian ethics, however, focus on the sensitive analogies between humans and animals. Regan’s deontological ethics discuss cognitive analogies between all sentient beings. Both philosophers claim that the burden of ethically justify nutritional choices is not on veg(etari)ans, but on those whose eating habits produce the same quantity and quality of exploitation and death of non-human animals: habits that can no longer be defended by simply mentioning the pleasure (such as the good taste of meat) that some can derive from the slaughter of animals. The paper also explores critiques and alternative philosophical foundations for a less anthropomorphic, but still ethically bonding, veg(etari)anism. Contributions to debate offered by authors such as Midgley, Goopaster, Callicott, Taylor, Palmer, and Fox have indeed the merit to recognize the same moral value to different natural entities and still promote a more general veg(etarian) lifestyle which appears more aware of our being rooted in a nature made up of complex dynamic relationships whose energy flows are also food flows.

BackgroundIn the United Kingdom a singing intervention for Postpartum Depression (PPD) titled “Music and Motherhood” was found to be effective. The World Health Organization Regional Office for Europe coordinated a study to assess the feasibility of implementing and adapting the intervention in other countries. In Italy, recent studies have highlighted the need to promote the availability of effective interventions for PPD in primary care.AimTo describe the implementation of “Music and Motherhood” within the Italian primary care services dedicated to pregnancy and postnatal care in three different geographical locations, thus providing an example of strategies for implementing an arts and health intervention in primary care that can improve health and well-being.MethodsA 10-week group singing intervention for mothers with PPD was conducted as part of a single arm feasibility study. Data were collected through one-to-one interviews, focus groups and questionnaires from the professionals involved in the implementation and selected participating mothers. A conceptual framework including acceptability, appropriateness, feasibility, fidelity, implementation process, costs and sustainability was adopted for analysis. Number of sessions attended by mothers and implementation outcome measures for acceptability, appropriateness and feasibility, each consisting of four items rated on a 5-point Likert scale were also gathered.ResultsThe intervention was found to be inclusive of women from different socio-cultural backgrounds and appropriate to the context. The group setting and the use of an arts-based intervention helped to de-medicalise the process of care maximising resources. Singing helped mothers to express their feelings and find strategies to improve interaction with their child. Attention to mothers’ needs and the co-presence of the professional singing leader and a health professional were among the key factors. The median number of sessions attended was nine out of 10. In terms of acceptability, almost 90% of the professionals were in complete agreement that they liked and approved the intervention.ConclusionOur study adds to the evidence that an arts and health intervention proven effective in one culture and linguistic context can be adapted to another. Collaboration among health professionals and artists in the implementation process and adequate funding are instrumental in moving from project to programme level.

Wildlife translocations are increasingly used to combat declining biodiversity worldwide. Successful translocation often hinges on coexistence between humans and wildlife, yet not all translocation efforts explicitly include human dimensions (e.g., economic incentives, education programs, and conflict reduction assistance). To evaluate the prevalence and associated outcomes of including human dimensions as objectives when planning translocations, we analyze 305 case studies from the IUCN's Global Re-Introduction Perspectives Series. We find that fewer than half of all projects included human dimension objectives (42%), but that projects including human dimension objectives were associated with improved wildlife population outcomes (i.e., higher probability of survival, reproduction, or population growth). Translocation efforts were more likely to include human dimension objectives if they involved mammals, species with a history of local human conflict, and local stakeholders. Our findings underscore the importance of incorporating objectives related to human dimensions in translocation planning efforts to improve conservation success.

Abstract Background Definitive local therapy with stereotactic ablative radiation therapy (SABR) for ultracentral lung lesions is associated with a high risk of toxicity, including treatment related death. Stereotactic MR-guided adaptive radiation therapy (SMART) can overcome many of the challenges associated with SABR treatment of ultracentral lesions. Methods We retrospectively identified 14 consecutive patients who received SMART to ultracentral lung lesions from 10/2019 to 01/2021. Patients had a median distance from the proximal bronchial tree (PBT) of 0.38 cm. Tumors were most often lung primary (64.3%) and HILUS group A (85.7%). A structure-specific rigid registration approach was used for cumulative dose analysis. Kaplan-Meier log-rank analysis was used for clinical outcome data and the Wilcoxon Signed Rank test was used for dosimetric data. Results Here we show that SMART dosimetric improvements in favor of delivered plans over predicted non-adapted plans for PBT, with improvements in proximal bronchial tree DMax of 5.7 Gy (p = 0.002) and gross tumor 100% prescription coverage of 7.3% (p = 0.002). The mean estimated follow-up is 17.2 months and 2-year local control and local failure free survival rates are 92.9% and 85.7%, respectively. There are no grade ≥ 3 toxicities. Conclusions SMART has dosimetric advantages and excellent clinical outcomes for ultracentral lung tumors. Daily plan adaptation reliably improves target coverage while simultaneously reducing doses to the proximal airways. These results further characterize the therapeutic window improvements for SMART. Structure-specific rigid dose accumulation dosimetric analysis provides insights that elucidate the dosimetric advantages of SMART more so than per fractional analysis alone.

Abstract Background Evidence has shown that women with type 2 diabetes (T2DM) have a higher excess risk for cardiovascular disease (CVD) than men with T2DM. Subjects with either T2DM or prediabetes exhibit myocardial insulin resistance, but it is still unsettled whether sex-related differences in myocardial insulin resistance occur in diabetic and prediabetic subjects. Methods We aimed to evaluate sex-related differences in myocardial glucose metabolic rate (MRGlu), assessed using dynamic PET with 18F-FDG combined with euglycemic-hyperinsulinemic clamp, in subjects with normal glucose tolerance (NGT; n = 20), prediabetes (n = 11), and T2DM (n = 26). Results Women with prediabetes or T2DM exhibited greater relative differences in myocardial MRGlu than men with prediabetes or T2DM when compared with their NGT counterparts. As compared with women with NGT, those with prediabetes exhibited an age-adjusted 35% lower myocardial MRGlu value (P = 0.04) and women with T2DM a 74% lower value (P = 0.006), respectively. Conversely, as compared with men with NGT, men with T2DM exhibited a 40% lower myocardial MRGlu value (P = 0.004), while no significant difference was observed between men with NGT and prediabetes. The statistical test for interaction between sex and glucose tolerance on myocardial MRGlu (P

The inaugural Pacific Ecological Security Conference (PESC) was held in October 2022, bringing together over 100 island leaders, policy-makers, natural resource managers and global and regional invasive species experts to prioritise the critical issue of invasive species in the Pacific Islands Region. Participants confirmed that invasive species are a major threat to building and maintaining climate resilience and adaptability of Pacific Island ecosystems, as well as food security, biodiversity, sustainable livelihoods and the protection of cultural resources and way of life. Three region-wide strategic action plans were developed to guide interventions focused on the topics of invasive ants, coconut rhinoceros beetle and the use of biological control as a pest and weed management tool. These plans were the major outcome of the PESC and, when implemented, will result in coordinated activities that take a “whole-of-Pacific” approach to invasive species biosecurity and management. Here, we briefly describe the background, planning and engagement process for the three plans, summarise any country- and territory-level data obtained through the process and detail what is planned to occur over the next few years. In addition to the adoption and implementation of the strategies as a result of this inaugural PESC, we anticipate that the PESC will become the premier regional conference aimed at reducing the entry and impacts of invasive species to improve sustainability of environments and peoples of the Pacific.

Abstract Background Platelets play an important role in the development of cardiovascular disease (CVD). Mean platelet volume (MPV) is considered as biological marker of platelets activity and function. The aim of the present study was to evaluate MPV values and its possible correlation with arterial stiffness and subclinical myocardial damage, in normal glucose tolerance patients (NGT), in newly diagnosed type 2 diabetic (T2DM) patients and in individuals with pre-diabetes. Methods We enrolled 400 newly diagnosed hypertensive patients. All patients underwent an Oral Glucose Tolerance test (OGTT). Arterial stiffness (AS) was evaluated with the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). Echocardiographic recordings were performed using an E-95 Pro ultrasound system. Results Among groups there was an increase in fasting plasma glucose (FPG) (p

Heart arrhythmia is caused by abnormal electrical conduction through the myocardium, which in some cases, can be treated with heat. One of the challenges is to reduce temperature peaks-by still guaranteeing an efficient treatment where desired-to avoid any healthy tissue damage or any electrical issues within the device employed. A solution might be employing pulsed heat, in which thermal dose is given to the tissue with a variation in time. In this work, pulsed heat is used to modulate induced temperature fields during radiofrequency cardiac ablation. A three-dimensional model of the myocardium, catheter and blood flow is developed. Porous media, heat conduction and Navier-Stokes equations are, respectively, employed for each of the investigated domains. For the electric field, solved via Laplace equation, it is assumed that the electrode is at a fixed voltage. Pulsed heating effects are considered with a cosine time-variable pulsed function for the fixed voltage by constraining the product between this variable and time. Different dimensionless frequencies are considered and applied for different blood flow velocity and sustained voltages. Results are presented for different pulsed conditions to establish if a reasonable ablation zone, known from the obtained temperature profiles, can be obtained without any undesired temperature peaks.

Background and Aims: Hypoalbuminemia, as defined by serum albumin (SA) levels ≤35 g/L, is associated to venous and arterial thrombosis in general population and in patients at risk of cardiovascular disease. It is unknown if SA ≤35 g/L is also associated to portal vein thrombosis (PVT) in cirrhosis. Methods: Cirrhotic patients enrolled in the Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry (PRO-LIVER) study (n = 753), were followed-up for 2 years to assess the risk of PVT, that was diagnosed by Doppler ultrasonography. Child-Pugh classes, Model for End-Stage Liver Disease score, presence of hepatocellular carcinoma and laboratory variables including SA, D-dimer, and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline. Results: SA ≤35 g/L was detected in 52% of patients. A logistic multivariate regression analysis showed that higher Child-Pugh class, hepatocellular carcinoma and thrombocytopenia were significantly associated to SA ≤35 g/L. In a subgroup of patients where data regarding hs-CRP and D-dimer were available, SA ≤35 g/L was inversely associated with hs-CRP and D-dimer. During the follow-up, a total of 61 patients experienced PVT. A Kaplan Meier survival analysis showed SA ≤35 g/L was associated to increased risk of PVT compared to SA >35 g/L (P = .005). A multivariate Cox proportional hazards regression analysis showed that male sex, lower platelet count, and SA ≤35 g/L remained associated to PVT after adjusting for confounding factors. Conclusion: Cirrhotic patients with SA ≤35 g/L are at higher risk of experiencing PVT compared to those with SA >35 g/L and could be considered as potential candidates to anticoagulant prophylaxis for PVT prevention.

Background and objectives: Subepithelial lesions (SELs) of the gastrointestinal (GI) tract present a diagnostic challenge due to their heterogeneous nature and varied clinical manifestations. Usually, SELs are small and asymptomatic; generally discovered during routine endoscopy or radiological examinations. Currently, endoscopic ultrasound (EUS) is the best tool to characterize gastric SELs. Materials and methods: For this review, the research and the study selection were conducted using the PubMed database. Articles in English language were reviewed from August 2019 to July 2024. Results: This review aims to summarize the international literature to examine and illustrate the progress in the last five years of endosonographic diagnostics and treatment of gastric SELs. Conclusions: Endoscopic ultrasound is the preferred option for the diagnosis of sub-epithelial lesions. In most of the cases, EUS-guided tissue sampling is mandatory; however, ancillary techniques (elastography, CEH-EUS, AI) may help in both diagnosis and prognostic assessment.

Background: In recent decades, there has been a startling rise in the number of cancer patients worldwide, which has led to an amazing upsurge in the development of novel anticancer treatment candidates. On a positive note, arylpiperazines have garnered attention in cancer research due to their potential as scaffolds for developing anticancer agents. These compounds exhibit a diverse array of biological activities, including cytotoxic effects against cancer cells. Indeed, one of the key advantages of arylpiperazines lies in their ability to interact with various molecular targets implicated in cancer pathogenesis. Aim: Here, we focus on the chemical structures of several arylpiperazine derivatives, highlighting their anti-proliferative activity in different tumor cell lines. The modular structure, diverse biological activities, and potential for combination therapies of arylpiperazine compounds make them valuable candidates for further preclinical and clinical investigations in the fight against cancer. Conclusion: This review, providing a careful analysis of different arylpiperazines and their biological applications, allows researchers to refine the chemical structures to improve potency, selectivity, and pharmacokinetic properties, thus advancing their therapeutic potential in oncology.

Composite materials, particularly carbon fiber-reinforced polymers (CFRPs), have become a cornerstone in industries requiring high-performance materials due to their exceptional mechanical properties, such as high strength-to-weight ratios, and their inherent lightweight nature. These attributes make CFRPs highly desirable in aerospace, automotive, and other advanced engineering applications. However, the compressive behavior of CFRP structures remains a challenge, primarily due to the material sensitivity to structural instability, leading to matrix cracking and premature failure under compressive loads. Isogrid structures, characterized by their unique geometric patterns, have shown promise in enhancing the compressive behavior of CFRP panels by providing additional support that mitigates these issues. Traditionally, these structures are manufactured using automated techniques like automated fiber placement (AFP) and automated tape laying (ATL), which, despite their efficacy, are often cost-prohibitive for small-scale or custom applications. Recent advancements in 3D-printing technology, particularly those involving continuous fiber reinforcement, present a cost-effective and flexible alternative for producing complex CFRP structures. This study investigates the compressive behavior of 3D-printed isogrid structures, fabricated using continuous carbon fiber reinforcement via an Anisoprint Composer A3 printer equipped with towpreg coextrusion technology. A total of eight isogrid panels with varying infill percentages were produced and subjected to buckling tests to assess their performance. The experimental results indicate a direct correlation between infill density and buckling resistance, with higher infill densities leading to increased buckling loads. Additionally, the failure modes were observed to shift from local to global buckling as the infill density increased, suggesting a more uniform distribution of compressive stresses. Post-test analyses using optical microscopy and scanning electron microscopy (SEM) revealed the presence of voids within the 3D-printed structures, which were found to negatively impact the mechanical performance of the isogrid panels. The findings of this study demonstrate that 3D-printed isogrid CFRP structures can achieve significant buckling resistance, making them a viable option for high-performance applications. However, the presence of voids remains a critical issue, highlighting the need for process optimizations in 3D-printing techniques to enhance the overall performance and reliability of these structures.

Background: Kawasaki disease (KD) is a systemic vasculitis of medium arteries, particularly involving coronary arteries. Coronary artery lesions (CALs) is the most serious complication in the acute stage, potentially leading to ischemic cardiomyopathy, myocardial infarction and sudden death. Environmental factors and genetic background contribute to individual susceptibility to develop CALs. The aim of this study was to define the risk factors for CALs in an Italian cohort. Methods: Data of KD patients from 10 Italian sites were registered into a REDCap database where demographic and clinical data, laboratory findings and coronary status were recorded. KD was diagnosed according to AHA definition. We used multiple logistic regression analysis to identify independent risk factors for CALs. Results: A total of 517 patients were enrolled, mainly Caucasians (83.6%). Presentation was complete in 321 patients (62.8%) and IVIG responsiveness in 360 (70%). CALs developed in 136/517 (26.31%). Gender, age, ethnicity, clinical presentation, fever duration, non-coronary cardiac events, Hb, albumin and CRP were significantly different between patients with and without CALs, while seasonality was not. Male gender, age < 18 months, Asian ethnicity, incomplete presentation and fever > 10 days were independent risk factors for CALs. Conclusions: Age younger than 18 months, incomplete KD and longer fever duration are risk factors for CALs. Asian ethnicity also represents a risk factor in our Italian Cohort.

Background/ObjectivesGlucagon is important in the maintenance of glucose homeostasis, with also effects on lipids. In this study, we aimed to apply a recently developed model of glucagon kinetics to determine the sensitivity of glucagon variations (especially, glucagon inhibition) to insulin levels (“alpha-cell insulin sensitivity”), during oral glucose administration.Subjects/MethodsWe studied 50 participants (spanning from normal glucose tolerance to type 2 diabetes) undergoing frequently sampled 5-hr oral glucose tolerance test (OGTT). The alpha-cell insulin sensitivity and the glucagon kinetics were assessed by a mathematical model that we developed previously.ResultsThe alpha-cell insulin sensitivity parameter (named SGLUCA; “GLUCA”: “glucagon”) was remarkably variable among participants (CV=221%). SGLUCA was found inversely correlated with the mean glycemic values, as well as with 2-hr glycemia of the OGTT. When stratifying participants into two groups (normal glucose tolerance, NGT, N=28, and impaired glucose regulation/type 2 diabetes, IGR_T2D, N=22), we found that SGLUCA was lower in the latter (1.50 ± 0.50·10-2vs. 0.26 ± 0.14·10-2 ng·L-1GLUCA/pmol·L-1INS, in NGT and IGR_T2D, respectively, p=0.009; “INS”: “insulin”).ConclusionsThe alpha-cell insulin sensitivity is highly variable among subjects, and it is different in groups at different glucose tolerance. This may be relevant for defining personalized treatment schemes, in terms of dietary prescriptions but also for treatments with glucagon-related agents.

Summary: Background: Despite the overall improvement in care, people with type 2 diabetes (T2D) experience an excess risk of end-stage kidney disease. We evaluated the long-term effectiveness of dapagliflozin on kidney function and albuminuria in patients with T2D. Methods: We included patients with T2D who initiated dapagliflozin or comparators from 2015 to 2020. Propensity score matching (PSM) was performed to balance the two groups. The primary endpoint was the change in estimated glomerular filtration rate (eGFR) from baseline to the end of observation. Secondary endpoints included changes in albuminuria and loss of kidney function. Findings: We analysed two matched groups of 6197 patients each. The comparator group included DPP-4 inhibitors (40%), GLP-1RA (22.3%), sulphonylureas (16.1%), pioglitazone (8%), metformin (5.8%), or acarbose (4%). Only 6.4% had baseline eGFR 30 mg/g. During a mean follow-up of 2.5 year, eGFR declined significantly less in the dapagliflozin vs comparator group by 1.81 ml/min/1.73 m2 (95% C.I. from 1.13 to 2.48; p

Abstract Background Uric acid (UA) is an independent prognostic factor for cardiovascular events, but there are no data demonstrating a different risk profile between women and men. Thus, we tested whether UA is associated with a possible sex-related difference in fatal and non-fatal cardiovascular events. Methods In this prospective population-based study we enrolled 1,650 never-treated Caucasian hypertensive outpatients referred to Catanzaro University Hospital (Italy). Inclusion criteria were newly diagnosed hypertensive patients, aged 20 years or more. Exclusion criteria were secondary form of hypertension, previous cardiovascular events, rheumatic and non-rheumatic valvular heart disease, prosthetic valves, cardiomyopathies, type-2 diabetes, chronic kidney disease, malignant diseases, gout arthritis and secondary forms of hyperuricemia, liver diseases, peripheral vascular diseases, and heart failure. Anthropometric, clinical, and biochemical parameters were measured. UA prognostic role was investigated by Cox regression analyses. Receiver-operating characteristic curve analyses and area under the curve were used to determine the predictive validity and the optimal cut-off point of UA. We investigated following endpoints: coronary events (fatal and nonfatal myocardial infarction, unstable angina, coronary revascularization procedures, coronary death); fatal and nonfatal stroke; all-cause mortality and major adverse cardiovascular events (MACE). Results We enrolled 830 males and 820 females aged 52.2 ± 11.3 years. During 9.5 ± 3.1 years follow-up, there were 424 new clinical events (2.71%): 250 coronary (1.59%), 118 (0.75%) cerebrovascular, and 56 (0.40%) deaths. Comparison between groups demonstrated a higher and significant difference in incidence rate in females for MACE (3.08 vs 2.33%, P = 0.001), coronary (1.82 vs 1.36%, P = 0.014) and cerebrovascular events (0.93 vs 0.57%, P = 0.006). UA at multiple Cox regression analysis resulted a strong and significant predictor of coronary events (HR = 1.493;95% CI 1.375–1.621), cerebrovascular events (HR = 1.256;95% CI 1.109–1.423), MACE (HR = 1.415;95% CI 1.328- 53 1.508), and all-cause mortality (HR = 1.469;95% CI 1.237–1.745) in the whole population and in both groups with a HR higher in females. The best estimated cut-off values of uric acid for males and females predicted these endpoints equally well, but it was always lower in females than males. Conclusions We demonstrate, that UA operates with a sex-related impact and best cut-off value in predicting cardiovascular outcomes and all-cause mortality, reflecting a possible sex difference in disease pathophysiology.

Abstract The incidence and prevalence of Parkinson’s disease (PD) is expected to raise dramatically over the next decades. Gender-related differences are not yet widely recognized, particularly regarding the response to dopaminergic medications. To analyse gender differences in the clinical effects of safinamide, compared to placebo, in Chinese PD patients of the pivotal XINDI trial. The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Patients were followed for 16 weeks receiving safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson’s Disease Rating Scale and Parkinson's Disease Questionnaire-39 items. A post-hoc analysis was performed to describe the efficacy of safinamide in both genders on motor symptoms, motor fluctuations and quality of life. 128 (42%) out of 305 patients enrolled were women and 177 (58%) men. Our additional analyses of the XINDI study have shown that safinamide, compared to placebo, was associated with improvements in motor symptoms, motor fluctuations and quality of life in both genders, with some differences in the response that did not reach statistical significance, possibly due to sample size limitation and post-hoc design of the study. The changes from baseline at week 16 were > 50% higher in the females compared to males for the total daily OFF time (− 1.149 h vs − 0.764 h in males), the total daily ON time (1.283 h vs 0.441 h in males), the UPDRS total score (− 8.300 points vs − 5.253 points in males) and the UPDRS part II score (− 2.574 points vs − 1.016 points in males). The changes from baseline at week 16 were higher in the females compared to males in the “ADL” domain (− 6.965 points vs − 5.772 points in males), the “Emotional well-being” domain (− 6.243 points vs − 4.203 in males), the “Stigma” domain (− 6.185 points vs − 4.913 points in males) and the “Bodily discomfort” domain (− 5.196 points vs 1.099 points in males), while were higher in males in the “Mobility” score (− 6.523 points vs − 4.961 points in females) and the “Communication” score (− 3.863 points vs − 1.564 points in females). Safinamide was shown to improve PD symptoms and quality of life in both male and female Chinese patients. Possible differences in the response between genders need to be further studied in larger and different ethnic populations.

Kawasaki disease (KD) is an acute vasculitis that mainly affects children under 5 years of age, leading to coronary artery alterations (CAAs) in 25% of untreated patients. Macrophage activation syndrome (MAS) is a secondary hemophagocytic lymphohistiocytosis (HLH) that can complicate the acute, subacute, and chronic phases of KD. We retrospectively reviewed three cases of children affected by KD complicated with MAS hospitalized in two pediatric units in Emilia Romagna, a northern region of Italy. Case 1: a previously healthy 23-month-old female with full clinical criteria of KD and a hemorrhagic rash due to MAS during the acute phase of the illness. This patient responded promptly to a high dose of intravenous immune globulin (IVIG) and three pulses of high doses of methylprednisolone (MPD) with improvement in clinical signs and laboratory tests without the development of CAA at any phase of illness. Case 2: a previously healthy 10-month-old female with incomplete KD with persistent fever and maculopapular rash. This patient did not respond to IVIG and developed MAS during the subacute phase, characterized by persistent fever, hypertransaminasemia, hyperferritinemia, and hypofibrinogenemia after two high doses of IVIG and boluses of MPD. The patient responded to the addition of IL-1 blocker and anakinra and did not present CAA alterations during any phase of the illness. Case 3: a previously healthy 26-month-old male with incomplete KD with fever, maculopapular rash, cheilitis, and hyperemic conjunctivitis. This patient developed gallbladder hydrops and CAA in the acute phase and did not respond to two high doses of IVIG and a high dose of MPD. In the subacute phase, this patient was complicated with MAS and responded to intravenous anakinra. During the subacute phase, the patient developed transient aneurysms that regressed during the chronic phase. These cases reiterate that prompt diagnosis and aggressive immunomodulatory treatment can limit the most severe complications of MAS complicating KD. High doses of IVIG and MPD may result in a favorable outcome or more aggressive adjunctive treatment may be needed. Anakinra, cyclosporine, monoclonal antibodies, and plasmapheresis can be used as adjunctive treatment in the case of unresponsive MAS in KD. Notably, MAS, present during the subacute phase in cases 2 and 3, promptly responded to anakinra, an IL-1 blocker, without the use of cyclosporine. Our experience confirms that the IL-1 blocker can be considered an optimal choice after non-response to IVIG and MPD in KD complicating with MAS, avoiding over-treatment with cytotoxic drugs.

Tourmaline crystals from the island of Elba commonly display a sharp transition to dark colors at the analogous termination due to the incorporation of Fe and/or Mn during the latest stages of crystallization in pegmatites. The formation of such color anomalies is related to a dramatic physicochemical change in the crystallization environment as a consequence of an opening of the geochemical system. However, mechanisms that may lead to the availability of Fe and/or Mn in the residual cavity fluids have been unclear. On the basis of chemical and spectroscopic investigations, combined with structural and paragenetic observations of the cavities, we propose a general genetic model in which, as a consequence of a pocket rupture event, chemical alteration of Fe- and Mn-rich minerals that formed early in the pegmatitic rock surrounding the cavities occurred through leaching processes, produced by the action of the highly reactive late-stage cavity fluids. Such processes were responsible for the release of Fe and Mn in the geochemical system, allowing the formation of the late-stage dark-colored terminations in the tourmaline crystals. In some cavities, a high availability of Mn and/or Fe determined the evolution of the crystals from an initial elbaite/fluor-elbaite composition to celleriite, foitite or schorl. This compositional evolution trend can be described by the following general chemical substitution: XNa+ + Y(Li1.5 + Al0.5)3+ + WF− ↔ X□ + 2Y(Fe,Mn)2+ + WOH−.