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Becker muscular dystrophy (BMD) is an X-linked disorder due to in-frame mutations in the DMD gene, leading to a less abundant and truncated dystrophin. BMD is less common and severe than Duchenne muscular dystrophy (DMD) as well as less investigated. To accelerate the search for innovative treatments, we developed a rat model of BMD by deleting the exons 45-47 of the Dmd gene. Here, we report a functional and histopathological evaluation of these rats during their first year of life, compared to DMD and control littermates. BMD rats exhibit moderate damage to locomotor and diaphragmatic muscles but suffer from a progressive cardiomyopathy. Single nuclei RNA-seq analysis of cardiac samples revealed shared transcriptomic abnormalities in BMD and DMD rats and highlighted an altered end-addressing of TMEM65 and Connexin-43 at the intercalated disc, along with electrocardiographic abnormalities. Our study documents the natural history of a translational preclinical model of BMD and reports a cellular mechanism for the cardiac dysfunction in BMD and DMD offering opportunities to further investigate the organization role of dystrophin in intercellular communication., (© 2024. The Author(s).)

Introduction: Surgical procedures, even under local anesthesia, can induce significant stress and anxiety in patients. Innovative approaches to alleviate anxiety are crucial for improving patient outcomes. Sedatives and anxiolytics may alleviate this discomfort, but they can also subject patients to undesirable side effects, diminishing their overall effectiveness, and, finally, delaying discharge. We present the first case series of a patients underwent inguinal hernia surgical repair under local anesthesia using VRH (HypnoVR) to avoid use of sedatives and anxiolytics., Methods: 12 consecutive patients were enrolled to undergo elective monolateral inguinal hernia repair surgery via an open approach using HypnoVR, at Colorectal Surgery Unit of Fondazione Policlinico Universitario Campus Bio-Medico di Roma. Vital signs (heart rate, SpO2, blood pressure) were detected for all patients before surgery, during local anesthesia, during the whole intervention and after surgery., Results: No intraoperative or postoperative complications have been recorded and only one postoperative complication occurred (seroma), which not required invasive treatment but only drug administration. All patient's vital parameters were recorded during all operative and perioperative phasis. No use of intraoperative analgesic, sedative or anxiolytic were needed. All patients were discharged no later than 3 h after surgery., Conclusion: Virtual Reality Hypnosis is a promising tool for anxiety management in surgical settings. Our series highlights the positive impact of HypnoVR in reduction and management of surgical patient anxiety and discomfort, allowing to perform inguinal hernia repair using only local anesthesia, with good patients' satisfaction., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Reduced TAPSE/sPAP ratio has recently emerged as a predictive parameter risk factor for PH, however its role in SSc has been poorly investigated. The aim of the study was to investigate the prognostic value of the TAPSE/sPAP ratio for the prediction of mortality and cardiovascular events in patients with SSc complicated by PH. A comparison between SSc patients with PAH (SSc-PAH) and those with PH and significant ILD (SSc-PH) was also carried out., Materials and Methods: A retrospective single-center study in which all patients having SSc-complicated by PH-referring to the Scleroderma-Unit of the AOU Policlinico of Modena, from October 2013 to October 2023 were evaluated. All SSc patients underwent recurrent clinical examination, routine blood chemistry analysis, functional, instrumental evaluation., Results: 61 SSc patients (F/M 52/9) were enrolled. During the follow-up, 60.1% of patients experienced at least one cardiovascular event and 62% died. The main causes of death were PH (39.4%) and other heart-related events (39.4%). The TAPSE/sPAP ratio was significantly lower in deceased patients compared to survivors (mm/mmHg 0.3 ± 0.12SD vs. 0.48 ± 0.17SD, p  < 0.001). Compared to the SSc-PAH subgroup, the SSc-PH patients had lower survival rates (55.3 ± 31.2 SD months vs. 25 ± 19 SD, p  = 0,05). At the multivariate analysis, TAPSE/sPAP ratio <0.32 mm/mmHg, male gender, and the presence of significant ILD were identified as independent predictors of mortality and cardiovascular events., Conclusion: Our work confirmed the predictive role of the TAPSE/sPAP ratio for mortality and cardiovascular events in patients with SSc complicated by PH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 de Pinto, Coppi, Spinella, Pagnoni, Morgante, Macripò, Boschini, Guerra, Tampieri, Secchi, Orlandi, Amati, Lumetti, Sandri, Rossi, Boriani, Mattioli, Ferri and Giuggioli.)

The prevailing methods to make large language models more powerful and amenable have been based on continuous scaling up (that is, increasing their size, data volume and computational resources 1 ) and bespoke shaping up (including post-filtering 2,3 , fine tuning or use of human feedback 4,5 ). However, larger and more instructable large language models may have become less reliable. By studying the relationship between difficulty concordance, task avoidance and prompting stability of several language model families, here we show that easy instances for human participants are also easy for the models, but scaled-up, shaped-up models do not secure areas of low difficulty in which either the model does not err or human supervision can spot the errors. We also find that early models often avoid user questions but scaled-up, shaped-up models tend to give an apparently sensible yet wrong answer much more often, including errors on difficult questions that human supervisors frequently overlook. Moreover, we observe that stability to different natural phrasings of the same question is improved by scaling-up and shaping-up interventions, but pockets of variability persist across difficulty levels. These findings highlight the need for a fundamental shift in the design and development of general-purpose artificial intelligence, particularly in high-stakes areas for which a predictable distribution of errors is paramount., (© 2024. The Author(s).)

Background: The mechanisms at the basis of depression are still matter of debate, but several studies in the literature suggest common pathways with dementia (genetic predispositions, metabolic and inflammatory mechanisms, neuropathological changes) and other geriatric syndromes., Aims: To evaluate the role of cortisol (as marker of the HPA, hypothalamus-pituitary-adrenal axis hyperactivity) in elderly subjects with depressive symptoms (by the means of the AGICO, AGIng and COrtisol, study), in relationship to the presence of the major geriatric syndromes., Methods: The AGICO study enrolled patients from ten Geriatric Units in Italy. Every subject received a comprehensive geriatric assessment or CGA (including the Mini Mental State Examination or MMSE, Geriatric Depression Scale or GDS and Cornell Scale for Depression in Dementia or CSDD), the neurological examination (with a computed tomography scan or magnetic resonance imaging of the brain), the assessment of the metabolic syndrome (MetS), the evaluation of the cortisol activity by two consecutive urine collections (diurnal and nocturnal), a CGA-derived frailty index (FI) and a modified measure of allostatic load (AL)., Results: The MMSE scores were significantly and inversely related to the values of GDS (p < 0.001) and CSDD (p < 0.05), respectively. The patients with depressive symptoms (GDS/CSDD > 8) showed significantly increased disability, MetS, inflammation, FI and AL and significantly reduced MMSE and renal function. The diurnal and nocturnal urinary cortisol levels in the patients with depressive symptoms (GDS/CSDD > 8) were higher with respects to controls (p < 0.05 for nocturnal difference)., Discussion: The AGICO study showed that the stress response is activated in the patients with depression., Conclusion: The depression in elderly patient should be reconsidered as a systemic disease, with coexisting major geriatric syndromes (disability, dementia, frailty) and combined pathogenetic mechanisms (metabolic syndrome, impaired renal function, low-grade inflammation, and allostatic load). Cortisol confirmed its role as principal mediator of the aging process in both dementia and metabolic syndrome., (© 2024. The Author(s).)

Sex is an often overlooked, yet compulsory, biological variable when performing biomedical research. Periodontitis is a common yet progressively debilitating chronic inflammatory disorder affecting the tissues supporting teeth that ultimately leads to tooth loss if left untreated. The incidence of periodontitis is sex biased, with increased prevalence in males compared with females but with unknown etiology. We performed a sex-specific meta-analysis using publicly available oral microbiome data from different sampling sites of patients with periodontitis and periodontally healthy controls; sex balance was established for each periodontal health condition. Our results show sex-based diversity in oral biofilms of individuals with periodontitis but not in their saliva, with increased abundance of several periodontal pathogens in subgingival plaques from females compared with males. We devised a quantitative measure, uniquely defined as the Microsexome Index (MSI), which indicates that sexual dimorphism in subgingival bacterial composition is a distinct feature of reduced microbial diversity during periodontitis but not under healthy conditions. In addition, we found that smoking exacerbates microsexome diversity in supragingival biofilms, particularly during periodontitis. Taken together, we provide insights regarding sex-based diversity in periodontitis, a disease with multiorgan associations, and provide the rationale for further mechanistic, diagnostic, and therapeutic studies.

Introduction: Renovascular hypertension (RVH) remains underdiagnosed despite its significant cardiovascular and renal morbidity., Aim: This survey investigated screening and management practices for RVH among hypertensive patients in Italian hypertension centres in a real-life setting. Secondary, we analysed the current spread of renal denervation (RDN) and the criteria used for its eligibility., Methods: A 12 item-questionnaire was sent to hypertension centres belonging to the European Society of Hypertension and to the Italian Society of Hypertension (SIIA) in Italy. Data concerning the screening and management of RVH and of RDN were analysed according to the type of centre (excellence vs non-excellence centres), geographical area and medical specialty., Results: Eighty-two centres participated to the survey. The number of patients diagnosed in each centre with RVH and fibromuscular dysplasia during the last five years was 3 [1;6] and 1 [0;2], respectively. Despite higher rates of RVH diagnosis in excellence centres (p = 0.017), overall numbers remained unacceptably low, when compared to expected prevalence estimates. Screening rates were inadequate, particularly among young hypertensive patients, with only 28% of the centres screening for RVH in such population. Renal duplex ultrasound was underused, with computed tomographic angiography or magnetic resonance angiography reserved for confirming a RVH diagnosis (76.8%) rather than for screening (1.9-32.7%, according to patients' characteristics). Scepticism and logistical challenges limited RDN widespread adoption., Conclusions: These findings underscore the need for improving RVH screening strategies and for a wider use of related diagnostic tools. Enhanced awareness and adherence to guidelines are crucial to identifying renovascular hypertension and mitigating associated cardiovascular and renal risks., (© 2024. The Author(s).)

Background: The incidence of oral cancer has exhibited a rise within the young population. Considering that oral potentially malignant disorders (OPMDs) can precede the development of oral cancer, it is imperative to conduct studies in this particular younger population. This study aimed to evaluate the frequency and conduct a comparative analysis of the clinical-demographic characteristics of OPMDs in two distinct age groups., Material and Methods: A retrospective analysis was conducted with patients diagnosed with leukoplakia, erythroplakia, and leukoerythroplakia between 1965 and 2020. The individuals were categorized into two groups: those aged up to 40 years (Group Younger) and those aged 41 years and above (Group Older)., Results: A total of 640 lesions were subjected to analysis. Among these, patients aged up to 40 years constituted 10.63% of the sample, however, this proportion decreased significantly to 6.9% between 2010 and 2020. A predominant male representation was observed in both groups, with white lesions being the most common in both as well. However, the frequency of red or mixed lesions was significantly higher (p=0.034) in the older group, along with a higher prevalence of dysplastic lesions (26.9% versus 11.8%, p=0.01). Moreover, the older group exhibited a relatively higher percentage of smokers/ex-smokers (78.6%), compared to the younger group (61.5%, p=0.085) and alcohol consumers/ex-consumers (54.9% versus 22.7%, p=0.028). Elderly individuals exhibited an unfavorable progression (p=0.028). However, a logistic regression analysis identified as significant variables associated with malignant transformation, the presence of epithelial dysplasia, and red lesions diagnosed as erythroplakia., Conclusions: A declining frequency of OPMDs in young adults was observed over the years, whereas in older adults, these disorders exhibited an unfavorable progression.

Hypertension is often linked with metabolic risk factors that share common pathophysiological pathways. Despite wide-spread availability of multiple drug classes, optimal blood pressure (BP) control remains challenging. Increased central sympathetic outflow is frequently neglected as a critical regulator of both circulatory and metabolic pathways and often remains unopposed therapeutically. Selective imidazoline receptor agonists (SIRAs) effectively reduce BP with a favorable side effect profile compared with older centrally acting antihypertensive drugs. Hard outcome data in hypertension, such as prevention of stroke, heart and kidney diseases, are not available with SIRAs. However, in direct comparisons, SIRAs were as effective as angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers, and diuretics in lowering BP. Other beneficial effects on metabolic parameters in hypertensive patients with concomitant overweight and obesity have been documented with SIRAs. Here we review the existing evidence on the safety and efficacy of moxonidine, a widely available SIRA, compared with common antihypertensive agents and provide a consensus position statement based on inputs from 12 experts from Europe and Australia on SIRAs in hypertension management., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Screening of Cushing Syndrome (CS) and Mild Autonomous Cortisol Secretion (MACS) in hypertensive patients is crucial for proper treatment. The aim of the study was to investigate screening and management of hypercortisolism among patients with hypertension in Italy., Methods: A 10 item-questionnaire was delivered to referral centres of European and Italian Society of Hypertension (ESH and SIIA) in a nationwide survey. Data were analyzed according to type of centre (excellence vs non-excellence), geographical area, and medical specialty., Results: Within 14 Italian regions, 82 centres (30% excellence, 78.790 patients during the last year, average 600 patients/year) participated to the survey. Internal medicine (44%) and cardiology (31%) were the most prevalent medical specialty. CS and MACS were diagnosed in 313 and 490 patients during the previous 5 years. The highest number of diagnoses was reported by internal medicine and excellence centres. Screening for hypercortisolism was reported by 77% in the presence of specific features of CS, 61% in resistant hypertension, and 38% in patients with adrenal mass. Among screening tests, the 24 h urinary free cortisol was the most used (66%), followed by morning cortisol and ACTH (54%), 1 mg-dexamethasone suppression test (49%), adrenal CT or MRI scans (12%), and late night salivary cortisol (11%). Awareness of referral centres with expertise in management of CS was reported by 67% of the participants, which reduced to 44% among non-excellence centres., Conclusions: Current screening of hypercortisolism among hypertensive patients is unsatisfactory. Strategies tailored to different medical specialties and type of centres should be conceived., (© 2024. The Author(s).)

Objectives: The current knowledge about the role of comorbidities in systemic sclerosis (SSc) is limited. Therefore, the aim of this study was to evaluate the prevalence of comorbidities and their impact on disease activity and prognosis in the Systemic sclerosis PRogression INvestiGation (SPRING) registry., Methods: SSc patients from the SPRING registry, fulfilling the ACR/EULAR 2013 classification criteria, with complete data on baseline comorbidities were enrolled. The Charlson comorbidity index (CCI) was used to quantify the overall comorbidity burden. The disease activity was calculated using the revised EUSTAR activity index (AI). The impact of SSc features on CCI, the effect of CCI on SSc disease activity and mortality were tested with multivariable regression models., Results: Among 1910 SSc patients enrolled, 67.3 % had at least one comorbidity at baseline. The most frequent comorbidities were systemic arterial hypertension (23.7 %), osteoporosis (12.9 %) and dyslipidemia (11 %). The mean value of CCI score was 2.0 ± 1.8. When patients were grouped according to increasing levels of CCI, a clear separation in the distribution of SSc-related clinical features could be observed. Among over 900 patients with available follow-up, no association between baseline CCI and changes in disease activity was observed. Conversely, the risk of death over time was independently predicted by both CCI and AI., Conclusions: Comorbidities and disease activity independently impact on the prognosis of SSc patients. This suggests that the management of comorbidities, together with the reduction of disease activity, is fundamental to improve patient survival., Competing Interests: Declaration of competing interest Orlandi M, Bellando-Randone S, Ferri C, Foti R, Codullo V, De Angelis R, Cuomo G, Campochiaro C, Luca Magnani, Cacciapaglia F, Ariani A, Giuggioli D, and Guiducci S have no conflict of interest to declare. Matucci-Cerinic M received fees from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche. Bruni C received consulting fees and/or honoraria from Eli-Lilly, Boehringer Ingelheim, Research grants from Gruppo Italiano Lotta alla Sclerodermia (GILS), European Scleroderma Trials and Research Group (EUSTAR), Scleroderma Clinical Trials Consortium (SCTC), Scleroderma Research Foundation (SRF), Novartis foundation for biomedical research. Congress supports from Boehringer-Ingelheim. Educational grants from AbbVie and Wellcome Trust., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To review randomised controlled trials (RCT) investigating colchicine (COL) for cardiovascular (CV) prevention in patients at high to very high CV risk aiming to extract data that could be useful in rheumatology practice., Methods: A systematic search of multiple databases according to the PICO framework was performed from inception to April 3, 2023. Three researchers independently screened abstracts/titles and reviewed full texts reviewed. Data extraction was performed using a pilot-tested data extraction form., Results: A total of 14,096 references were retrieved by the search and 30 articles, describing 28 RCTs, were included in the review (Total number of patients 16,795, of which 8,463 randomised to COL; dose 0.5-2 mg/day, treatment duration 1day-29 months). Only one of the 28 RCTs provided clear information on whether patients with rheumatic diseases (more specifically gout) were enrolled in the study cohorts and previous use of COL was an exclusion criterion only in 14 (50 %) RCTs. Previous therapy with glucocorticoids and/or non-steroidal anti-inflammatory drugs and/or immune suppressive therapies was an exclusion criterion only in 9 (32 %) RCTs., Conclusion: Our results highlight the need to redefine the eligibility criteria as well as the reporting of results in future RCTs in order to minimise bias or previous exposure to COL and also obtain data that could be useful in rheumatology practice., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Introduction: Several observational studies have been conducted to assess the prevalence of cardiovascular risk factors in hypertensive patients; however, none has yet investigated prevalence, clustering, and current management of cardiovascular risk factors upon first referral to hypertension specialists, which is the aim of the present study., Methods: Consecutive adult outpatients with essential/secondary hypertension were included at the time of their first referral to hypertension specialists at 13 Italian centers in the period April 2022-2023 if they had at least one additional major cardiovascular risk factor among LDL-hypercholesterolemia, type 2 diabetes, and cigarette smoking. Prevalence, degree of control, and current management strategies of cardiovascular risk factors were assessed., Results: A total of 255 individuals were included, 40.2% women and 98.4% Caucasian. Mean age was 60.3±13.3 years and mean blood pressure [BP] was 140.3±17.9/84.8±12.3 mmHg). Most participants were smokers (55.3%), had a sedentary lifestyle (75.7%), suffered from overweight/obesity (51%) or high LDL-cholesterol (41.6%), had never adopted strategies to lose weight (55.7%), and were not on a low-salt diet (57.4%). Only a minority of patients reported receiving specialist counseling, and 27.9% had never received recommendations to correct unhealthy lifestyle habits. Nearly 90% of individuals with an estimated high/very high cardiovascular risk profile did not achieve recommended LDL-cholesterol targets., Conclusions: In patients with hypertension, both pharmacological and lifestyle therapeutic advice are yet to improve before referral to hypertension specialists. This should be considered in the primary care setting in order to optimize cardiovascular risk management strategies., (© 2024. The Author(s).)

Introduction: This study aimed to assess the percentage of patients treated according to the European Society for Medical Oncology (ESMO) 2018 guidelines for breakthrough cancer pain (BTcP) and the impact of guidelines adherence on patients' quality of life (QoL)., Methods: Adult opioid-tolerant patients diagnosed with BTcP and locally advanced or recurrent metastatic cancer with a life expectancy of >3 months prospectively were included. Patients were followed up for 28 days., Results: Of 127 patients included, 37 were excluded due to the impossibility to establish adherence to the ESMO guidelines. Among the evaluable patients [51.1% female; with mean (SD) age of 66.4 (11.8) years], all were adherent. BTcP was diagnosed by the Association for Palliative Medicine algorithm in 47.8% of patients and by clinical experience in 52.2% of patients. The mean number of daily BTcP episodes ranged between 1 and 8, with a mean (95% CI) severity of 7.3 (7.0; 7.6) at week 0 and 6.2 (5.8; 6.6) at week 4. Time to maximum pain intensity was 3-15 min in 52.2% of patients, and BTcP lasted 30-60 min in 14.4% of patients at week 0 and 4.4% of patients at week 4. Mean (95% CI) treatment effectiveness was 6.6 (6.1; 7.1) at week 0 and 7.4 (7.0; 7.8) at week 4. Median (Q1-Q3) patients' global impression of clinical condition was 4.0 (4.0-4.0) at week 0 and 3.0 (2.0-3.0) at week 4., Conclusion: A clear BTcP assessment and strict follow-up could be crucial to guidelines adherence and for patient's QoL., Competing Interests: PB reported participation to advisory board or conference honoraria for: Merck, Sanofi-Regeneron, Merck Sharp & Dohme, Sun Pharma, Angelini Pharma S.p.A., Nestlè, Elevar. CMF has received honoraria as speaker and consultant for Pfizer, Grunental, Asacpharma, Esteve and Ferrer. IM is employee of TFS Health Science. VT, SF, GDL, AC are full-time employees of Angelini Pharma S.p.A. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Bossi, Pietrzyńska, Margarit Ferri, Mansilla, Tellone, Fioravanti, Di Loreto and Comandini.)

The safety profile of baricitinib (BARI), a Janus kinase inhibitor broadly used for the treatment of rheumatoid arthritis (RA), includes asymptomatic laboratory abnormalities, such as an increase in creatine kinase (CK). Data from randomized controlled trials suggest that concomitant myalgia is rare in RA and does not lead to drug discontinuation. We describe the case of a 68-year-old Caucasian female with longstanding, multi-failure RA who started BARI and achieved disease remission. However, she developed a symptomatic CK increase, as well as a parallel increase in total cholesterol, low-density lipoprotein, and triglycerides. Dechallenge-rechallenge demonstrated a plausible relationship between the clinical/laboratory abnormalities and BARI. In fact, when the drug was withdrawn, CK returned to normal and myalgia disappeared, whereas symptoms returned and CK levels increased when BARI was restarted. BARI may be rarely associated with symptomatic CK elevation, and this may pose clinical challenges, particularly for patients with multi-failure RA who achieved good disease control with BARI but required drug discontinuation due to intolerance.

The objective of this study was to investigate the longitudinal association of metabolically healthy overweight/obese adults with major adverse cardiovascular events (MACE) and the effect of LDL-cholesterol levels on this association. This study was conducted with 15,904 participants from the URRAH study grouped according to BMI and metabolic status. Healthy metabolic status was identified with and without including LDL-cholesterol. The risk of MACE during 11.8 years of follow-up was evaluated with multivariable Cox regressions. Among the participants aged <70 years, high BMI was associated with an increased risk of MACE, whereas among the older subjects it was associated with lower risk. Compared to the group with normal weight/healthy metabolic status, the metabolically healthy participants aged <70 years who were overweight/obese had an increased risk of MACE with an adjusted hazard ratio of 3.81 (95% CI, 1.34-10.85, p = 0.012). However, when LDL-cholesterol < 130 mg/dL was included in the definition of healthy metabolic status, no increase in risk was found in the overweight/obese adults compared to the normal weight individuals (hazard ratio 0.70 (0.07-6.71, p = 0.75). The present data show that the risk of MACE is increased in metabolically healthy overweight/obese individuals identified according to standard criteria. However, when LDL-cholesterol is included in the definition, metabolically healthy individuals who are overweight/obese have no increase in risk.

High levels of serum uric acid (SUA) and triglycerides (TG) might promote high-cardiovascular-risk phenotypes, including subclinical atherosclerosis. An interaction between plaques xanthine oxidase (XO) expression, SUA, and HDL-C has been recently postulated. Subjects from the URic acid Right for heArt Health (URRAH) study with carotid ultrasound and without previous cardiovascular diseases (CVD) (n = 6209), followed over 20 years, were included in the analysis. Hypertriglyceridemia (hTG) was defined as TG ≥ 150 mg/dL. Higher levels of SUA (hSUA) were defined as ≥5.6 mg/dL in men and 5.1 mg/dL in women. A carotid plaque was identified in 1742 subjects (28%). SUA and TG predicted carotid plaque (HR 1.09 [1.04-1.27], p < 0.001 and HR 1.25 [1.09-1.45], p < 0.001) in the whole population, independently of age, sex, diabetes, systolic blood pressure, HDL and LDL cholesterol and treatment. Four different groups were identified (normal SUA and TG, hSUA and normal TG, normal SUA and hTG, hSUA and hTG). The prevalence of plaque was progressively greater in subjects with normal SUA and TG (23%), hSUA and normal TG (31%), normal SUA and hTG (34%), and hSUA and hTG (38%) (Chi-square, 0.0001). Logistic regression analysis showed that hSUA and normal TG [HR 1.159 (1.002 to 1.341); p = 0.001], normal SUA and hTG [HR 1.305 (1.057 to 1.611); p = 0.001], and the combination of hUA and hTG [HR 1.539 (1.274 to 1.859); p = 0.001] were associated with a higher risk of plaque. Our findings demonstrate that SUA is independently associated with the presence of carotid plaque and suggest that the combination of hyperuricemia and hypertriglyceridemia is a stronger determinant of carotid plaque than hSUA or hTG taken as single risk factors. The association between SUA and CVD events may be explained in part by a direct association of UA with carotid plaques.

(1) Background: The recent emphasis on sexual and gender diversity's impact on human health underscores the need for tailored diagnostic and therapeutic approaches in neurology. The aim of this article is to conduct a narrative review of the available scientific literature on sex differences in cerebrospinal fluid analysis. (2) Methods: The literature search encompassed PubMed databases, focusing on cerebrospinal fluid analysis and sex differences, considering parameters like cerebrospinal fluid protein content, cell count, albumin quotient (QAlb) and intrathecal IgG synthesis. (3) Results: Nine articles from the past two decades were identified, revealing limited research in this area. Males consistently exhibited higher cerebrospinal fluid protein content and albumin quotient values across various pathologies and age groups. Consequently, males more frequently manifested blood-cerebrospinal fluid barrier dysfunction than females. No significant sex differences were observed in cerebrospinal fluid leukocyte count or intrathecal IgG synthesis. (4) Conclusions: This review highlights the dearth of research on sex differences in cerebrospinal fluid analysis, despite consistent findings of higher protein content and albumin quotient values in males. Revisiting current diagnostic thresholds based on sex is crucial for accurate prognosis and personalised treatment strategies in neurological disorders. Moving towards sex-specific approaches in clinical practice is imperative for advancing personalised medicine.

Despite substantial progress in understanding the complex pathophysiology, hypertension remains a serious public health challenge affecting over 1.2 billion adults aged 30-79 years worldwide. Appropriate knowledge of the different pharmaceutical classes of antihypertensive agents and an understanding of the characteristics of individual molecules are essential to optimize clinical outcomes in patients with hypertension. We conducted a computer-assisted web interviewing (CAWI) quantitative survey in Italy, Poland, and Turkey to investigate physicians' prescriptions, knowledge, and perceptions of antihypertensive drugs with a focus on β-blockers, to assess antihypertensive usage patterns and the reasons underlying prescription choices. The survey findings show that β-blockers retain a pivotal role in the management of hypertension and are prescribed more often for patients with cardiovascular comorbidities than for patients with diabetic comorbidities. In all three countries, nebivolol is the only β-blocker among the ones analyzed which is consistently prescribed to 20% or more of patients and is overall the most prescribed one for the population with comorbid diabetes. In terms of specific β-blockers' features, this study revealed knowledge gaps that underline the need for educational activities focused on the differences among β-blockers, which are important in choosing the most suitable agent for individualized antihypertensive therapy., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Introduction: Hypertension is the main risk factor for cardiovascular diseases (CVD). Notably, only about half of hypertensive patients manage to achieve the recommended blood pressure (BP) control. Main reasons for the persistence of uncontrolled BP during treatment are lack of compliance on the patients' side, and therapeutic inertia on physicians' side., Methods: During the global BP screening campaign "May Measure Month" (MMM) (May 1st to July 31st, 2022), a nationwide, cross-sectional, opportunistic study endorsed by the Italian Society of Hypertension was conducted on volunteer adults ≥ 18 years to raise awareness of the health issues surrounding high BP. A questionnaire on demographic/clinical features and questions on the use of fixed-dose single-pills for the treatment of hypertension was administered. BP was measured with standard procedures., Results: A total of 1612 participants (mean age 60.0±15.41 years; 44.7% women) were enrolled. Their mean BP was 128.5±18.1/77.1±10.4 mmHg. About half of participants were sedentary, or overweight/obese, or hypertensive. 55.5% individuals with complete BP assessment had uncontrolled hypertension. Most were not on a fixed-dose combination of antihypertensive drugs and did not regularly measure BP at home. Self-reported adherence to BP medications was similar between individuals with controlled and uncontrolled BP (95% vs 95.5%)., Conclusions: This survey identified a remarkable degree of therapeutic inertia and poor patients' involvement in the therapeutic process and its monitoring in the examined population, underlining the importance of prevention campaigns to identify areas of unsatisfactory management of hypertension, to increase risk factors' awareness in the population with the final purpose of reducing cardiovascular risk., (© 2024. The Author(s).)

Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide with a high socioeconomic burden. Increasing evidence supports a convincing connection with increased cardiovascular risk of periodontal diseases (PD), a group of widespread, debilitating, and costly dysbiotic relapsing-remitting inflammatory diseases of the tissues supporting the teeth. Herein, we ensembled the best available evidence on the connection between CVDs and PD to review the recently emerging concept of the latter as a non-traditional risk factor for CVDs. We focused on oral dysbiosis, inflammation-associated molecular and cellular mechanisms, and epigenetic changes as potential causative links between PD and CVDs. The available evidence on the effects of periodontal treatment on cardiovascular risk factors and diseases was also described., Competing Interests: Conflict of interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

Evidence that psoriatic disease is burdened by an excess cardiovascular (CV) risk has accrued, however many questions remain unanswered. Although an interplay between traditional risk factors inflammation, disease activity and pharmacological therapies, as observed in rheumatoid arthritis (RA), may account for this increased risk, metabolic comorbidities rather than inflammation seem to have a leading role in psoriatic disease. Therefore, specific approaches, risk factors targeting and the importance of traditional risk factors and inflammation management need to be considered. The purpose of this review article is to discuss current data on CV risk in psoriatic disease, and to outline similarities and differences with RA in the light of international recommendations. Arguments in favour of developing specific guidance for CV prevention in psoriatic disease are discussed., Competing Interests: Declaration of competing interest AA: Grants from UCB, Astra Zeneca, BMS outside the submitted work. LG: Research grants: AbbVie, Biogen, Lilly, Novartis, UCB; consulting fees: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB; grants from AbbVie, Biogen, Lilly, Novartis, UCB; personal fees from AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB, non-financial support from AbbVie, Janssen, MSD, Novartis, Pfizer, UCB, Viatris outside the submitted work. FC, JRC, SD and CF have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

(1) Background: Cerebrospinal fluid (CSF)/serum albumin quotient (QAlb) and CSF total protein (TP) are more elevated in males than females, and this has been hypothesised to be due to anthropometric differences between the sexes. This study aimed to investigate QAlb and CSF TP as a function of body height, weight, and body mass index (BMI). (2) Methods: A total of 207 patients were included in the study and analysed blinded to clinical diagnosis. (3) Results: Multivariable linear regressions were run to predict log-transformed Qalb and log-transformed CSF TP value from age, sex, weight, and height (first model) or from age, sex, and BMI (second model). In both models, age (β = 0.004, 95% CI = 0.002 to 0.006) and sex (β = -0.095, 95% CI = -0.169 to -0.021, and β = -0.135, 95% CI = -0.191 to -0.079) were significant predictors for QAlb, but weight, height, and BMI were not. Similarly, age (β = 0.004, 95% CI = 0.003 to 0.006) and sex (β = -0.077, 95% CI = -0.142 to -0.013, and β = -0.109, 95% CI = -0.157 to -0.060) were significant predictors for CSF TP, while anthropometric characteristics were not. No differences in QAlb and CSF TP were found when grouping males and females by BMI status. (4) Conclusions: Our data suggest that anthropometric characteristics could not explain the sex-related differences in QAlb and CSF TP.

Several studies have detected a direct association between serum uric acid (SUA) and cardiovascular (CV) risk. In consideration that SUA largely depends on kidney function, some studies explored the role of the serum creatinine (sCr)-normalized SUA (SUA/sCr) ratio in different settings. Previously, the URRAH (URic acid Right for heArt Health) Study has identified a cut-off value of this index to predict CV mortality at 5.35 Units. Therefore, given that no SUA/sCr ratio threshold for CV risk has been identified for patients with diabetes, we aimed to assess the relationship between this index and CV mortality and to validate this threshold in the URRAH subpopulation with diabetes; the URRAH participants with diabetes were studied ( n = 2230). The risk of CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis. During a median follow-up of 9.2 years, 380 CV deaths occurred. A non-linear inverse association between baseline SUA/sCr ratio and risk of CV mortality was detected. In the whole sample, SUA/sCr ratio > 5.35 Units was not a significant predictor of CV mortality in diabetic patients. However, after stratification by kidney function, values > 5.35 Units were associated with a significantly higher mortality rate only in normal kidney function, while, in participants with overt kidney dysfunction, values of SUA/sCr ratio > 7.50 Units were associated with higher CV mortality. The SUA/sCr ratio threshold, previously proposed by the URRAH Study Group, is predictive of an increased risk of CV mortality in people with diabetes and preserved kidney function. While, in consideration of the strong association among kidney function, SUA, and CV mortality, a different cut-point was detected for diabetics with impaired kidney function. These data highlight the different predictive roles of SUA (and its interaction with kidney function) in CV risk, pointing out the difference in metabolic- and kidney-dependent SUA levels also in diabetic individuals.

Purpose: Recently, a novel index (triglyceride-glucose index-TyG) was considered a surrogate marker of insulin resistance (IR); in addition, it was estimated to be a better expression of IR than widely used tools. Few and heterogeneous data are available on the relationship between this index and mortality risk in non-Asian populations. Therefore, we estimated the predictive role of baseline TyG on the incidence of all-cause and cardiovascular (CV) mortality in a large sample of the general population. Moreover, in consideration of the well-recognized role of serum uric acid (SUA) on CV risk and the close correlation between SUA and IR, we also evaluated the combined effect of TyG and SUA on mortality risk., Methods: The analysis included 16,649 participants from the URRAH cohort. The risk of all-cause and CV mortality was evaluated by the Kaplan-Meier estimator and Cox multivariate analysis., Results: During a median follow-up of 144 months, 2569 deaths occurred. We stratified the sample by the optimal cut-off point for all-cause (4.62) and CV mortality (4.53). In the multivariate Cox regression analyses, participants with TyG above cut-off had a significantly higher risk of all-cause and CV mortality, than those with TyG below the cut-off. Moreover, the simultaneous presence of high levels of TyG and SUA was associated with a higher mortality risk than none or only one of the two factors., Conclusions: The results of this study indicate that these TyG (a low-cost and simple non-invasive marker) thresholds are predictive of an increased risk of mortality in a large and homogeneous general population. In addition, these results show a synergic effect of TyG and SUA on the risk of mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Management following endoscopic submucosal dissection (ESD) of pT1b esophageal adenocarcinoma (EAC) remains controversial. This study compared pathological and survival outcomes of patients after endoscopic resection (ER) of pT1b EAC followed by either en bloc esophagectomy or observation., Methods: From 1/12 to 12/22, all patients with pT1b EAC treated with ER were identified from a prospectively maintained departmental database. ESD was curative (all of: Submucosal invasion < 500 μm; G1/2, LVI/PNI-; deep margin-) or non-curative (one or more of Submucosal invasion ≥ 500 μm; G3; LVI/PNI+; deep margin+). Patients were allocated to observation (OBS) or esophagectomy (SURG) based on patient factors/preference and pathological variables., Results: 56/171 ERs met the inclusion criteria. ER was curative in 8/56 (14%) and non-curative in 48/56 (86%). OBS was undertaken after 8/27 (30%) curative and 19/27 (70%) non-curative resections. All 29 SURG patients had non-curative ERs and were younger, had lower Charlson comorbidity scores and had more deep margin + lesions than OBS patients. Post-esophagectomy, 15/29 (52%) had no residual disease within the surgical specimen while pT+N-/pT-N+/pT+N+ occurred in 5/3/6 (17%/10%/21%) patients. Of those with residual disease in the surgical specimen, 12/14 (86%) had deep margin + ERs; however, only ESD instead of EMR was independently associated with a lower risk of residual disease (OR 0.431, 95% CI - 0.016 to 1.234, p = 0.045). OBS and SURG patients had equivalent overall survival outcomes and recurrence was low in both groups even following non-curative ER. Follow-up was 28 months (0-102) and 30 months (0-97), respectively., Conclusion: In select patients, including some of those with a non-curative ESD resection of pT1B EAC, surveillance alone may be appropriate. Alternatives beyond traditional pathological features is needed to direct patient care more accurately., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of Competing Interest (The authors declare they have no conflict of interest.)

Chronic Myeloid Leukemia (CML) is a hematological malignancy characterized by the presence of the BCR::ABL1 fusion gene, which leads to uncontrolled cell growth and survival. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, but a significant proportion of patients develop resistance or lose response to these drugs. Understanding the molecular mechanisms underlying treatment response and resistance is crucial for improving patient outcomes. This study aimed to analyze the expression patterns of genes involved in treatment response and resistance in CML patients receiving TKI therapy. The expression levels of MET, FOXO3, p15, p16, HCK, and FYN genes were examined in CML patients and compared to healthy donors. Gene expression levels were compared between optimal responders (OR) and resistant patients (R) vs. healthy donors (HD). The MET and FOXO3 OR group showed significant differences compared with the HD, (p < 0.0001) and (p = 0.0003), respectively. p15 expression showed significant differences between OR and HD groups (p = 0.0078), while no significant differences were found in p16 expression between the HD groups. FYN showed a statistically significant difference between R vs. HD (p = 0.0157). The results of HCK expression analysis revealed significant differences between OR and HD (p = 0.0041) and between R and HD (p = 0.0026). When we analyzed OR patients with undetectable BCR::ABL1 transcripts, a greater expression of HCK was observed in the R group. These findings suggest that monitoring the expression levels of MET and FOXO3 genes could be valuable in predicting treatment response and relapse in CML patients. Our study provides important insights into the potential use of gene expression analysis as a tool for predicting treatment response and guiding treatment decisions in CML patients. This knowledge may ultimately contribute to the development of personalized treatment strategies to improve patient outcomes in CML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the association between diabetes and cognitive performance in a nationally representative study in Brazil. We also aimed to investigate the interaction between frailty and diabetes on cognitive performance. A cross-sectional analysis of the Brazilian Longitudinal Study of Aging (ELSI-Brazil) baseline data that included adults aged 50 years and older was conducted. Linear regression models were used to study the association between diabetes and cognitive performance. A total of 8,149 participants were included, and a subgroup analysis was performed in 1,768 with hemoglobin A1c data. Diabetes and hemoglobin A1c levels were not associated with cognitive performance. Interaction of hemoglobin A1c levels with frailty status was found on global cognitive z-score (P-value for interaction=0.038). These results suggested an association between higher hemoglobin A1c levels and lower cognitive performance only in non-frail participants. Additionally, undiagnosed diabetes with higher hemoglobin A1c levels was associated with both poor global cognitive (β=-0.36; 95%CI: -0.62; -0.10, P=0.008) and semantic verbal fluency performance (β=-0.47; 95%CI: -0.73; -0.21, P=0.001). In conclusion, higher hemoglobin A1c levels were associated with lower cognitive performance among non-frail participants. Higher hemoglobin A1c levels without a previous diagnosis of diabetes were also related to poor cognitive performance. Future longitudinal analyses of the ELSI-Brazil study will provide further information on the role of frailty in the association of diabetes and glycemic control with cognitive decline.

Background: Despite longstanding epidemiologic data on the association between increased serum triglycerides and cardiovascular events, the exact level at which risk begins to rise is unclear. The Working Group on Uric Acid and Cardiovascular Risk of the Italian Society of Hypertension has conceived a protocol aimed at searching for the prognostic cutoff value of triglycerides in predicting cardiovascular events in a large regional-based Italian cohort., Methods and Results: Among 14 189 subjects aged 18 to 95 years followed-up for 11.2 (5.3-13.2) years, the prognostic cutoff value of triglycerides, able to discriminate combined cardiovascular events, was identified by means of receiver operating characteristic curve. The conventional (150 mg/dL) and the prognostic cutoff values of triglycerides were used as independent predictors in separate multivariable Cox regression models adjusted for age, sex, body mass index, total and high-density lipoprotein cholesterol, serum uric acid, arterial hypertension, diabetes, chronic renal disease, smoking habit, and use of antihypertensive and lipid-lowering drugs. During 139 375 person-years of follow-up, 1601 participants experienced cardiovascular events. Receiver operating characteristic curve showed that 89 mg/dL (95% CI, 75.8-103.3, sensitivity 76.6, specificity 34.1, P <0.0001) was the prognostic cutoff value for cardiovascular events. Both cutoff values of triglycerides, the conventional and the newly identified, were accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.211 (95% CI, 1.063-1.378, P =0.004) and 1.150 (95% CI, 1.021-1.295, P =0.02), respectively., Conclusions: Lower (89 mg/dL) than conventional (150 mg/dL) prognostic cutoff value of triglycerides for cardiovascular events does exist and is associated with increased cardiovascular risk in an Italian cohort.

Multimorbidity-the coexistence of at least two chronic health conditions within the same individual-is an important global health challenge. In high-income countries (HICs), multimorbidity is dominated by non-communicable diseases (NCDs); whereas, the situation may be different in low- and middle-income countries (LMICs), where chronic communicable diseases remain prominent. The aim of this systematic review was to identify determinants (including risk and protective factors) and potential mechanisms underlying multimorbidity from published longitudinal studies across diverse population-based or community-dwelling populations in LMICs. We systematically searched three electronic databases (Medline, Embase, and Global Health) using pre-defined search terms and selection criteria, complemented by hand-searching. All titles, abstracts, and full texts were independently screened by two reviewers from a pool of four researchers. Data extraction and reporting were according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Methodological quality and risk of bias assessment was performed using the Newcastle-Ottawa Scale for cohort studies. Data were summarized using narrative synthesis. The search yielded 1782 records. Of the 52 full-text articles included for review, 8 longitudinal population-based studies were included for final data synthesis. Almost all studies were conducted in Asia, with only one from South America and none from Africa. All studies were published in the last decade, with half published in the year 2021. The definitions used for multimorbidity were heterogeneous, including 3-16 chronic conditions per study. The leading chronic conditions were heart disease, stroke, and diabetes, and there was a lack of consideration of mental health conditions (MHCs), infectious diseases, and undernutrition. Prospectively evaluated determinants included socio-economic status, markers of social inequities, childhood adversity, lifestyle behaviors, obesity, dyslipidemia, and disability. This review revealed a paucity of evidence from LMICs and a geographical bias in the distribution of multimorbidity research. Longitudinal research into epidemiological aspects of multimorbidity is warranted to build up scientific evidence in regions beyond Asia. Such evidence can provide a detailed picture of disease development, with important implications for community, clinical, and interventions in LMICs. The heterogeneity in study designs, exposures, outcomes, and statistical methods observed in the present review calls for greater methodological standardisation while conducting epidemiological studies on multimorbidity. The limited evidence for MHCs, infectious diseases, and undernutrition as components of multimorbidity calls for a more comprehensive definition of multimorbidity globally., (© 2023 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34 + cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34 + cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34 + cells infused and younger age at GT affected positively the plateau of CD3 + transduced cells, lymphocytes and CD4 + CD45RA + naive T cells, whereas the cell dose positively influenced the final plateau of CD15 + transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Intravenous iloprost has been widely used for the treatment of systemic sclerosis peripheral vasculopathy. No agreement has been found on the regimen and the dosage of intravenous iloprost in different scleroderma subset conditions. This study aimed to evaluate the modalities of intravenous iloprost administration within a large cohort of systemic sclerosis patients from the SPRING Registry and to identify any associated clinical-demographic, instrumental or therapeutic data., Patients and Methods: Data of systemic sclerosis patients treated with intravenous iloprost for at least 1 year (case group) were retrospectively analyzed, including different timing and duration of intravenous iloprost session, and compared with those of untreated patients (control group)., Results: Out of 1895 analyzed patients, 937 (49%) received intravenous iloprost treatment, while 958 (51%) were assigned to the control group. Among cases, about 70% were treated every 4 weeks, 24% with an interval of more than 4 weeks, and only 6% of less than 4 weeks. Most patients receiving the treatment every 4 weeks, or less, underwent infusion cycle for 1 day only, while if it was scheduled with an interval of more than 4 weeks, a total number of 5 consecutive days of infusions was the preferred regimen. The comparison between the two groups revealed that patients treated with intravenous iloprost had a higher frequency of DUs (p < 0.001), pitting scars (p < 0.001), diffuse cutaneous involvement (p < 0.001), interstitial lung disease (p < 0.002), as well as higher rates of anti-topoisomerase I, " late " scleroderma pattern at nailfold videocapillaroscopy. These findings were confirmed by multivariate analysis., Conclusion: Our data provide a picture on the Italian use of intravenous iloprost among systemic sclerosis patients and showed that it was usually employed in patients with a more aggressive spectrum of the disease. The disparity of intravenous iloprost treatment strategies in the different centers suggests the need of a rational therapeutical approach based on the clinical characteristics of different patients' subsets., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Rationale: Immune system deregulation, including AAV, is a key event that may potentially evolve into ESRD. Abnormal activation of the cAP is also a cardinal feature of TMA, particularly aHUS. The kidney is the most frequently involved organ, and renal-limited forms of TMA are often encountered in clinical practice. Isolated case reports described the occurrence of renal TMA in AAV patients. Some cases of both de novo and relapses of AAV and/or TMAs after anti-SARS-CoV2 vaccination have been reported. We reported, for the 1st time, a case of patients with new-onset MPA and aHUS occurring 3 weeks after the third dose of mRNA-1273 vaccine anti-SARS-CoV2., Patient Concerns: We present a 67-year-old man, affected by arterial hypertension, reported, after mRNA-1273 vaccine anti-SARS-CoV2, anuria, fatigue, anorexia and nausea. Laboratory data revealed acute renal failure., Diagnosis: Positivity of MPO-ANCA was observed. 7 days after admission, we observed a worsening of anemia and thrombocytopenia with haptoglobin reduction, LDH increase and presence of schistocytes. Plasma levels of ADAMTS-13 were normal. A renal biopsy was performed, and findings were consistent with microscopic polyangiitis, with features of micro-thrombotic glomerulopathy. Genetic tests revealed absence of hybrid genes associated with the increased risk of aHUS., Interventions and Outcomes: We started renal replacement treatment, including hemodialysis, and pulsed methylprednisolone, with no improvement of laboratory parameters. Then, plasma exchange was performed leading to partial haematological response. Only with Eculizumab, a human C5 inhibitor, we observed a normalization of haptoglobin levels and platelets' count. However, three months after discharge, the patient still required hemodialysis., Lessons: To our knowledge we observed the first case aHUS, without genetic predisposition, associated with MPA occurring after the third dose of anti-SARS-CoV2 vaccine. This case report highlights the potential link between anti-SARS-CoV2 vaccine as a trigger of MPA and aHUS. This systematic review offers additional perspectives. It is plausible to hypothesize that the vaccine was the trigger for the development of these 2 diseases.Solid evidence on the mechanisms of interaction between vaccine and immune system, the role of genetic predisposition, and other variables, will shed additional light on the controversial link between anti-SARS-CoV2 vaccine and autoimmunity., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

The strong genetic association between HLA-B*27 and spondyloarthritis (SpA) accounts for about 90% of the susceptibility to axial SpA (axSpA), and the presence of HLA-B*27 is helpful in classifying patients according to the Assessment of SpondyloArthritis International Society (ASAS) classification criteria. However, over the years, other HLA-B alleles have been associated with an increased risk of developing SpA; on this basis, the aim of our study was to describe the demographic, clinical, and radiological characteristics of a cohort of SpA patients who were negative for HLA-B*27. We identified 85 patients with a clinical diagnosis of SpA displaying HLA-B alleles other than HLA-B*27; HLA-B*51 emerged as the most prevalent allele (N = 33, 39%), regardless of the fulfilment of either the axial or the peripheral ASAS criteria. The second most prevalent allele in the full cohort (N = 16, 19%) and in the patients fulfilling either the axial or the peripheral criteria was HLA-B*35. The third most prevalent allele in the full cohort was HLA-B*18 (N = 12, 15%), which was also the second most prevalent allele in the patients fulfilling neither of the two sets of criteria. Overall, the clinical picture was similar across the subgroups fulfilling the different sets of ASAS criteria; however, the patients not fulfilling any ASAS criteria had a higher likelihood of having arthritis compared to the patients fulfilling the axial criteria, whereas the Bath Ankylosing Spondylitis Functional Index was significantly higher in those patients fulfilling the axial criteria compared to those who did not fulfill any criteria. Our results indicate that other HLA alleles, beyond HLA-B*27, could be useful in facilitating SpA diagnosis, particularly in patients with a clinical picture which is consistent with SpA but does not fulfill the ASAS classification criteria.

Chronic kidney disease (CKD) is a severe condition and a significant public health issue worldwide, carrying the burden of an increased risk of cardiovascular events and mortality. The traditional factors that promote the onset and progression of CKD are cardiometabolic risk factors like hypertension and diabetes, but non-traditional contributors are escalating. Moreover, gut dysbiosis, inflammation, and an impaired immune response are emerging as crucial mechanisms in the disease pathology. The gut microbiome and kidney disease exert a reciprocal influence commonly referred to as "the gut-kidney axis" through the induction of metabolic, immunological, and endocrine alterations. Periodontal diseases are strictly involved in the gut-kidney axis for their impact on the gut microbiota composition and for the metabolic and immunological alterations occurring in and reciprocally affecting both conditions. This review aims to provide an overview of the dynamic biological interconnections between oral health status, gut, and renal pathophysiology, spotlighting the dynamic oral-gut-kidney axis and raising whether periodontal diseases and gut microbiota can be disease modifiers in CKD. By doing so, we try to offer new insights into therapeutic strategies that may enhance the clinical trajectory of CKD patients, ultimately advancing our quest for improved patient outcomes and well-being.

Background: Bempedoic acid (BA) is a small-molecule first-in-class of inhibitor of ATP citrate lyase that significantly lowers low-density lipoproteins cholesterol (LDL-c) in statin-intolerant and inadequate responders. Increased serum uric acid (SUA) levels and gout incidence have been described in BA-treated patients. The aim of this systematic review was to investigate the safety of BA regarding SUA levels and gout in randomised controlled trials (RCTs)., Methods: A search on 7 databases was performed from inception to May 4, 2023. RCTs of BA monotherapy or combination with other lipid-lowering treatment (LLT) in patients with increased LDL-c were included. Dual data extraction was performed with disagreements resolved through consensus. Due to the methodological purpose of this review risk-of-bias assessment of studies was not performed., Results: 6 Phase 3 RCTs ( N  = 17,975 patients of which 9,635 received BA) 9 Phase 2 RCTs ( N  = 362 patients of which 170 received BA) and an open-label extension of a Phase 3 RCT were included. Gout and/or hyperuricemia were not mentioned as exclusion criteria, previous/current use of urate-lowering therapies (ULT) and/or colchicine and/or dietary patterns were not reported. Phase 3 RCTs: 2 studies specified the number of patients experiencing hyperuricemia over the study period (BA: 4.9%-11%; placebo: 1.9%-5.6%) and the effect size was significant only in 1 study (OR = 2.0, 95% CI 1.8-2.3). Four RCTs reported a higher incidence of gout in the BA arm however, when we calculated the effect size, it was small and often not significant. Two studies reported 0 cases of gout. The paucity of information about SUA levels at baseline and/or at the end of follow-up do not allow us to quantify the effect sizes for BA-induced SUA elevation. Data on gout from Phase 2 RCTs is scant., Conclusions: Data from phase 2 and 3 RCTs do not allow for confirming a clear association between BA and gout. It is conceivable that a careful assessment of SUA levels/history of gout at baseline and the concomitant use of urate-lowering agents may be instrumental to minimise the risk of new-onset gout/gout flares in patients treated with BA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Alunno, Carubbi, Campanozzi, Bellisario, Schoones, Mariani, Di Ruscio, Altieri and Ferri.)

Introduction: The impact of COVID-19 pandemic represents a serious challenge for 'frail' patients' populations with inflammatory autoimmune systemic diseases such as systemic sclerosis (SSc). We investigated the prevalence and severity of COVID-19, as well the effects of COVID-19 vaccination campaign in a large series of SSc patients followed for the entire period (first 38 months) of pandemic., Patients and Method: This prospective survey study included 1755 unselected SSc patients (186 M, 1,569F; mean age 58.7 ± 13.4SD years, mean disease duration 8.8 ± 7.3SD years) recruited in part by telephone survey at 37 referral centers from February 2020 to April 2023. The following parameters were carefully evaluated: i. demographic, clinical, serological, and therapeutical features; ii. prevalence and severity of COVID-19; and iii. safety, immunogenicity, and efficacy of COVID-19 vaccines., Results: The prevalence of COVID-19 recorded during the whole pandemic was significantly higher compared to Italian general population (47.3 % vs 43.3 %, p < 0.000), as well the COVID-19-related mortality (1.91 % vs 0.72 %, p < 0.001). As regards the putative prognostic factors of worse outcome, COVID-19 positive patients with SSc-related interstitial lung involvement showed significantly higher percentage of COVID-19-related hospitalization compared to those without (5.85 % vs 1.73 %; p < 0.0001), as well as of mortality rate (2.01 % vs 0.4 %; p = 0.002). Over half of patients (56.3 %) received the first two plus one booster dose of vaccine; while a fourth dose was administered to 35.6 %, and only few of them (1.99 %) had five or more doses of vaccine. Of note, an impaired seroconversion was recorded in 25.6 % of individuals after the first 2 doses of vaccine, and in 8.4 % of patients also after the booster dose. Furthermore, the absence of T-cell immunoreactivity was observed in 3/7 patients tested by QuantiFERON® SARSCoV-2 Starter Set (Qiagen). The efficacy of vaccines, evaluated by comparing the COVID-19-related death rate recorded during pre- and post-vaccination pandemic periods, revealed a quite stable outcome in SSc patients ( death rate from 2.54 % to 1.76 %; p = ns), despite the significant drop of mortality observed in the Italian general population (from 2.95 % to 0.29 %; p < 0.0001)., Conclusions: An increased COVID-19 prevalence and mortality rate was recorded in SSc patients; moreover, the efficacy of vaccines in term of improved outcomes was less evident in SSc compared to Italian general population. This discrepancy might be explained by concomitant adverse prognostic factors: increased rate of non-responders to vaccine in SSc series, low percentage of individuals with four or more doses of vaccine, ongoing immunomodulating treatments, disease-related interstitial lung disease, and/or reduced preventive measures in the second half of pandemic. A careful monitoring of response to COVID-19 vaccines together with adequate preventive/therapeutical strategies are highly recommendable in the near course of pandemic in this frail patients' population., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Alessandro Antonelli reports financial support was provided by Italian 10.13039/100009647Ministry of Health, Ricerca Finalizzata (RF-2021-12374986) Destinatario istituzionale: Regione Toscana. Unità Operative:U.O.1: Azienda Ospedaliero-Universitaria Pisana; U.O.2: Azienda Ospedaliero-Universitaria Aldo Moro Bari; U.O.3: Azienda Ospedaliero-Universitaria Modena, CUP Master: D55E22000670001., (© 2023 Published by Elsevier B.V.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological culprit of COronaVIrus Disease 19 (COVID-19), can enter the cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which has been found in several tissues including in endocrine organs, such as the ovaries, testes, pancreas, and thyroid. Several thyroid disorders have been associated with SARS-CoV-2 infection [subacute thyroiditis (SAT), thyrotoxicosis, and non-thyroidal illness syndrome (NTIS)] and, in part, they are believed to be secondary to the local virus replication within the gland cells. However, as documented for other viruses, SARS-CoV-2 seems to interfere with several aspects of the immune system, inducing the synthesis of autoantibodies and triggering latent or new onset autoimmune disease (AID), including autoimmune thyroid disease (AITD), such as Hashimoto Thyroiditis (HT) and Graves' disease (GD). Several mechanisms have been hypothesized to explain this induction of autoimmunity by SARS-CoV-2 infection: the immune system hyper-stimulation, the molecular mimicry between the self-antigens of the host and the virus, neutrophils extracellular traps, and finally, the virus induced transcriptional changes in the immune genes; nonetheless, more evidence is needed especially from large, long-term cohort studies involving COVID-19 patients, to establish or reject this pathogenetic relationship.

Nephroangiosclerosis (NAS) associated with hypertension continues to be one of the most causes of end stage renal diseases in Europe, but it is still poorly studied. The prevalence of NAS shows a large variability due to the difference among different countries regarding clinical presentations and the indication to perform renal biopsy. The study aimed to investigate the prevalence in biopsy-proven NAS patients and the association with hypertension and/or glomerulonephritis (GN). We included all patients referred for native kidney biopsy between 2003-2021 at Policlinic Umberto I of Rome. From 837 patients who underwent renal biopsy NAS was diagnosed in 80 (10.5%) patients. Serum creatinine was significantly higher in NAS [2.07 mg/dl (IQR 1.13-5.2) vs 1.1 mg/dl (IQR 0.8-2.1), p < 0.001] compared to patients without NAS. Hypertension was present in 45% of patients with NAS. Proteinuria was significantly higher in patients with mild-moderate NAS compared to patients with severe NAS [2.6 g/die (IQR 1-5) vs 1.5 g/die (IQR 0.86-2.3), p < 0.05]. We did not find any significant differences, including histological features, between NAS patients with hypertension and NAS patients without hypertension (p > 0.05). IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy were the most frequent GN associated. In conclusion no specific histological features are reported in NAS with and without hypertension. More information on the phenotype, clinical presentation and markers are needed to improve histological and clinical diagnostics., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The term spondyloarthritis (SpA) encompasses a group of interrelated disorders characterised by the involvement of the musculoskeletal system as well as extra-articular manifestations like acute anterior uveitis, psoriasis and inflammatory bowel diseases (IBD). Likewise, IBD may present with various extra-intestinal manifestations among which those involving the musculoskeletal system, namely peripheral and axial SpA are the most common. The identification of patients with both SpA and IBD is of paramount importance in clinical practice since the coexistence of these two entities has been associated with great disability and decreased quality of life. In order to achieve an early diagnosis of IBD-SpA it is instrumental that rheumatologists seek for gastrointestinal symptoms in SpA patients and likewise that gastroenterologists seek for inflammatory musculoskeletal symptoms in patients with IBD. This narrative review aims at critically appraising the available evidence about SpA occurring in IBD patients versus IBD occurring in patients with SpA and at highlighting similarities and differences between the two scenarios., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The black-box nature of most artificial intelligence (AI) models encourages the development of explainability methods to engender trust into the AI decision-making process. Such methods can be broadly categorized into two main types: post hoc explanations and inherently interpretable algorithms. We aimed at analyzing the possible associations between COVID-19 and the push of explainable AI (XAI) to the forefront of biomedical research. We automatically extracted from the PubMed database biomedical XAI studies related to concepts of causality or explainability and manually labeled 1,603 papers with respect to XAI categories. To compare the trends pre- and post-COVID-19, we fit a change point detection model and evaluated significant changes in publication rates. We show that the advent of COVID-19 in the beginning of 2020 could be the driving factor behind an increased focus concerning XAI, playing a crucial role in accelerating an already evolving trend. Finally, we present a discussion with future societal use and impact of XAI technologies and potential future directions for those who pursue fostering clinical trust with interpretable machine learning models., Competing Interests: M.R.-Z. and V.B. are employees of IBM Research, Haifa, Israel. F.M. is an employee of Philips Research, Eindhoven, the Netherlands. I.S. has received funding from multiple funding agencies through a collaborative funding program and declares no support from any organization for the submitted work. P.J.N. receives funding from the Dutch Research Council (DWO) for the grant “Mobile Support Systems for Behavior Change,” of which he is the principal investigator (P.I.). M.L. is funded by the EU-Commission grant no. 101057497-EDIAQI., (© 2023 The Authors.)

The relationship between Serum Uric Acid (UA) and Cardiovascular (CV) diseases has already been extensively evaluated, and it was found to be an independent predictor of all-cause and cardiovascular mortality but also acute coronary syndrome, stroke and heart failure. Similarly, also many papers have been published on the association between UA and kidney function, while less is known on the role of UA in metabolic derangement and, particularly, in metabolic syndrome. Despite the substantial number of publications on the topic, there are still some elements of doubt: (1) the better cut-off to be used to refine CV risk (also called CV cut-off); (2) the needing for a correction of UA values for kidney function; and (3) the better definition of its role in metabolic syndrome: is UA simply a marker, a bystander or a key pathological element of metabolic dysregulation?. The Uric acid Right for heArt Health (URRAH) project was designed by the Working Group on uric acid and CV risk of the Italian Society of Hypertension to answer the first question. After the first papers that individuates specific cut-off for different CV disease, subsequent articles have been published responding to the other relevant questions. This review will summarise most of the results obtained so far from the URRAH research project., (© 2023. The Author(s).)