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Background Estimated pulse-wave velocity (ePWV), a surrogate measure of arterial stiffness, was shown to independently predict morbidity and mortality from cardiovascular disease and other causes in both the general population and high-risk individuals. However, in people with type 2 diabetes, it is unknown whether ePWV adds prognostic information beyond the parameters used for calculating it. Aims To assess the independent association of ePWV with all-cause mortality in individuals with type 2 diabetes. Design Prospective cohort study that enrolled 15 773 patients in 19 Italian centres in 2006–08. Methods ePWV was calculated from a regression equation using age and mean blood pressure (BP). All-cause mortality was retrieved for 15 656 patients in 2015. Results Percentage and rate of deaths, Kaplan–Meier estimates and unadjusted hazard ratios increased from Quartile I to Quartile IV of ePWV. After adjustment for age, sex, BP levels and anti-hypertensive treatment, the strength of association decreased but mortality risk remained significantly higher for Quartiles II (+34%), III (+82%) and IV (+181%) vs. Quartile I and was virtually unchanged when further adjusting for other cardiovascular risk factors and complications/comorbidities. Each m·s− 1 increase in ePWV was associated with an increased adjusted risk of death in the whole cohort (+53%) and in participants with (+52%) and without (+65%) cardiorenal complications. Moreover, ePWV significantly improved prediction of mortality risk over cardiovascular risk factors and complications/comorbidities, though the net increase was modest. Conclusions These findings suggest that ePWV may represent a simple and inexpensive tool for providing prognostic information beyond traditional cardiovascular risk factors. Trial registration ClinicalTrials.gov , NCT00715481, https://clinicaltrials.gov/ct2/show/NCT00715481. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal/stem cells (MSCs) are a heterogeneous population of multipotent cells that can be obtained from various tissues, such as dental pulp, adipose tissue, bone marrow and placenta. MSCs have gained importance in the field of regenerative medicine because of their promising role in cell therapy and their regulatory abilities in tissue repair and regeneration. However, a better characterization of these cells and their products is necessary to further potentiate their clinical application. In this study, we used unbiased high-resolution mass spectrometry-based proteomic analysis to investigate the impact of distinct priming strategies, such as hypoxia and IFN-γ treatment, on the composition and therapeutic functionality of the secretome produced by MSCs derived from the amniotic membrane of the human placenta (hAMSCs). Our investigation revealed that both types of priming improved the therapeutic efficacy of hAMSCs, and these improvements were related to the secretion of functional factors present in the conditioned medium (CM) and exosomes (EXOs), which play crucial roles in mediating the paracrine effects of MSCs. In particular, hypoxia was able to induce a pro-angiogenic, innate immune response-activating, and tissue-regenerative hAMSC phenotype, as highlighted by the elevated production of regulatory factors such as VEGFA, PDGFRB, ANGPTL4, ENG, GRO-γ, IL8, and GRO-α. IFN-γ priming, instead, led to an immunosuppressive profile in hAMSCs, as indicated by increased levels of TGFB1, ANXA1, THBS1, HOMER2, GRN, TOLLIP and MCP-1. Functional assays validated the increased angiogenic properties of hypoxic hAMSCs and the enhanced immunosuppressive activity of IFN-γ-treated hAMSCs. This study extends beyond the direct priming effects on hAMSCs, demonstrating that hypoxia and IFN-γ can influence the functional characteristics of hAMSC-derived secretomes, which, in turn, orchestrate the production of functional factors by peripheral blood cells. This research provides valuable insights into the optimization of MSC-based therapies by systematically assessing and comparing the priming type-specific functional features of hAMSCs. These findings highlight new strategies for enhancing the therapeutic efficacy of MSCs, particularly in the context of multifactorial diseases, paving the way for the use of hAMSC-derived products in clinical practice.

Background: Rosacea, a chronic inflammatory skin condition, is marked by enduring redness, visible blood vessels, and inflammatory eruptions in facial areas. Managing rosacea remains a persistent challenge for dermatologists, especially in cases unresponsive to conventional treatments. Injectable poly-d,l-lactic acid (PDLLA) has shown promise in treating erythema and telangiectasia associated with rosacea in addition to age-related concerns. Employing Mirajet, a laser-induced microjet system, for administering PDLLA is a novel and promising treatment for rosacea., Aims: We aimed to evaluate the efficacy and safety of injectable PDLLA delivered via a needle-free microjet system for managing rosacea., Methods: Four Korean women with persistent and refractory rosacea received five monthly sessions of PDLLA needle-free injections. Clinical assessments were conducted using the Clinician's Erythema Assessment and Patient's Self-Assessment (PSA) at baseline, 4 weeks post-treatment, and 22 weeks post-final treatment. Adverse events were monitored throughout the study period., Results: At 4 weeks post-treatment, both Clinician's Erythema Assessment and PSA scores indicated significant improvements in erythema that were sustained up to the 22-week follow-up. Patients reported high satisfaction with resolution of redness and improved skin texture. Mild swelling, redness, and petechiae were observed post-treatment but resolved spontaneously. No product-related adverse events were noted during the study period., Conclusion: Injectable PDLLA delivered via laser-induced microjet injection demonstrated promising efficacy in improving rosacea symptoms and skin quality for up to 22 weeks without significant adverse effects. Larger randomized controlled trials are needed to confirm these findings and evaluate long-term safety and sustainability of outcomes., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Sensitive skin is a highly prevalent problem. The objective of the study was to assess whether the tested products are effective and safe in terms of improving the symptoms of sensitive skin., Methods: A clinical randomized split-face study was carried out on 24 healthy female subjects. Three cosmetic combinations were tested versus vehicle: product A (Solía Thermal Spring Water-TSW-from Cantabria, Spain + diatom algae-P. tricornutum-extract), product B (Solía TSW + diatom algae extract + Annona cherimola Fruit Extract) and product C (Solía TSW + diatom algae extract + Annona cherimola Fruit Extract + niacinamide). Prior to each application of the study Product (A, B, or C)/vehicle, 10% of aqueous solution of capsaicin to induce skin irritation was applied, mimicking the symptoms of sensitive skin. Stinging and burning sensations were evaluated at different time points., Results: All three tested products A, B, and C showed to act better in calming the symptoms induced by capsaicin when compared to the vehicle., Conclusions: The tested products would be an interesting option for treating stinging and burning sensations in sensitive skin patients., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: The postprandial glucose response (PPGR), contributing to the glycemic variability (GV), is positively associated with cardiovascular risk in people without diabetes, and can thus represent a target for cardiometabolic prevention strategies., Objective: The study aimed to distinguish patterns of PPGR after a single non-standardized meal and to evaluate their relationship with the habitual diet and the daily glucose profile (DGP) in individuals at high-cardiometabolic risk., Methods: Baseline four-day continuous glucose monitoring (CGM) was performed in 159 adults recruited in the MEDGI-Carb trial. After a non-standardized breakfast, parameters of the PPGR were estimated by a mechanistic model: baseline glucose; amplitude - the magnitude of post-meal glucose concentrations; frequency - the velocity of post-meal glucose oscillations; damping - the rate of post-meal glucose decay. PPGR patterns were identified by cluster analysis. Differences between clusters and the relationship between PPGR parameters and individual features were explored by one-way ANOVA and correlation analysis, respectively., Results: Two patterns of PPGR emerged. Pattern A had higher baseline, amplitude, frequency, and damping than B. Individuals in cluster A compared to B had a higher energy (2,002±526 vs. 1,766±455 Kcal, p=0.025), protein (82±22 vs. 72±21 g, p=0.028) and fat (87±30 vs. 75±22 g, p=0.041), but not carbohydrate habitual intake. Pattern A associated with a higher average daily glucose (6.12±0.50 vs. 5.88±0.62 mmol/L, p=0.019) and lower GV (11.67±3.52 vs. 13.43±3.78%, p=0.010). Mean daily glucose correlated directly with baseline (r s =0.419, p<0.001) and amplitude (r s =0.189, p=0.022) of the PPGR, while DGP variability correlated directly with amplitude (r s =0.218, p=0.008), frequency (r s =-0.179, p=0.031) and damping (r s =-0.309, p<0.001)., Conclusions: Two PPGR patterns after a single non-standardized breakfast were identified in high-cardiometabolic risk individuals. The habitual diet was associated with the patterns and their dynamic parameters, which, in turn, could predict the individuals' DGP. Our findings could support the implementation of dietary strategies targeting the PPGR to ameliorate the cardiometabolic risk profile., Clinical Trial Id: NCT03410719., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gabriele Riccardi reports financial support was provided by Barilla International. Rikard Landberg reports financial support was provided by Barilla International. Wayne W Campbell reports financial support was provided by Barilla USA. Rikard Landberg reports a relationship with Barilla Center for Food and Nutrition Foundation that includes: funding grants. Rikard Landberg reports a relationship with Lantmännen Research Foundation that includes: funding grants. Gabriele Riccardi is member of the Health and Wellbeing Advisory Board of the Barilla G&R Fratelli Company: remuneration for this activity goes to his University Department.If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. G.R. is a member of the Scientific Advisory Board of the Nutrition Foundation of Italy and the Istituto Nutrizionale Carapelli Foundation; he is a member of the Health and Wellbeing Advisory Board of the Barilla G&R. Fratelli Company and Consultant for a Metabolic Health Masterclass sponsored by Nestlè. R.B. is currently employed by ADM; the research presented in this paper was conducted in a former role and has no connection with ADM. R.L. received funding grants from Barilla Center for Food and Nutrition Foundation and from Lantmännen Research Foundation. A.G., V.S., T.H., A.H., C.B, R.G., G.P., M.V., M.W., M.J. and W.W.C. report no conflict of interest., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Isolation mechanisms between mosquito species of the Anopheles gambiae complex, which includes major malaria vectors, remain poorly understood. In some cases, pre-zygotic barriers have been shown to limit gene flow between species of the complex, leading to a low level of hybridisation in nature. Post-zygotic mechanisms manifest with F 1 hybrid males fully sterile and F 1 hybrid females with reduced fertility. Genetic approaches combined with DNA sequencing techniques have highlighted the involvement of genomic regions in hybrid incompatibility with a predominant role of the X chromosome. In addition, differences in the phenotype of F 1 hybrid males have been identified depending on the directionality of the parental cross used to generate them. All these studies have focused on the interaction of nuclear DNA elements in hybrid individuals. Given the role that mitochondrial DNA plays in genetic incompatibilities within other organisms and its unique inheritance pattern, commonly maternal, we conducted a genetic study that relied on the introgression of mitochondrial DNA between Anopheles gambiae and Anopheles arabiensis. The findings indicate that the mitochondrial switch does not appear to restore the fertility of F 1 hybrid males, suggesting that mitochondrial DNA may not play a role in hybrid incompatibilities in these Anopheles species., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Diabetes is a chronic disease with a significant socio-economic burden. Recognizing its risk factors and gender differences within its physio-pathological mechanisms may allow early diagnosis. This review aims to summarize the current evidence on gender differences in terms of prevalence, risk factors and pathogenesis for Type 1 Diabetes (T1D), Type 2 Diabetes (T2D) and prediabetes., Methods: A comprehensive search of English-language articles was conducted in PubMed, EMBASE and Cochrane Library until July 2024. We selected all studies that assessed gender differences on risk factors for diabetes and prediabetes., Results: T1D is an autoimmune disease, with a multifactorial pathogenesis. Contrary to most autoimmune diseases, it has a male gender bias, with a male predominance incidence after puberty, for which the involvement of hormones has been hypothesized in addition to genetic predisposition. In T2D, the accumulation of visceral adipose tissue is recognized as the main predisposing factor for insulin resistance and consequent β-cells loss and dysfunction. Sex hormones influence fat disposition resulting in different body composition between males and females and different metabolic impact. Gender differences in dietary patterns and socio-cultural determinants also influence the risk of T2D. Also, a gender-related risk factor has been detected in prediabetes; indeed, females are at greater risk of impaired glucose tolerance than males., Conclusions: Evidence shows the existence of gender differences in risk factors for T1D, T2D and prediabetes. This suggests that gender should be considered in prevention and screening programs, with the goal of reducing incidence or making an early diagnosis., Competing Interests: Declarations. Conflict of interest: Nothing to declare., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Purpose: To determine, at 2 year follow-up, 3D spine growth for idiopathic early onset scoliosis (iEOS) patients treated with magnetically controlled growing rods (MCGR)., Methods: From an international EOS registry, patients with iEOS treated with MCGR were identified. Scoliosis, kyphosis, traditional coronal height, and 3D true spine length (3D-TSL) were measured pre-index surgery, post-index, and at 2 year follow-up., Results: 135 participants, mean age 8.1 years (2.7-15.6) were included. Scoliosis improved from 71° pre-index to 41° post-index (p < 0.001) and remained constant at 2 years (43°, p = 0.58). Kyphosis improved from 49° to 36° (p < 0.001); then increased by 2 years to 42° (p = 0.002). Traditional T1-S1 height, which reflects both spine growth and changes in deformity, increased from pre-index to post-index (274 mm vs. 310 mm; p < 0.001), and again at 2 years (332 mm, p < 0.001). As 3D-TSL reflects growth of the spine, independent of changes in deformity, as expected it did not change perioperatively (335 mm vs. 339 mm, p = 0.83), but significantly changed by 2 years (367 mm; p < 0.001). Participants < 5 years at surgery increased 22 mm (8.2%), 5-10 years increased 26 mm (7.8%), and > 10 increased 41 mm (11.0%). For instrumented levels, mean vertebral growth was 1.3 mm/level for < 5 years, 1.4 mm/level for 5-10 years, and 2.2 mm/level for > 10 years., Conclusions: As kyphosis increased over time, these out of the coronal plane changes justify the use of 3D-TSL for this cohort of patients. For idiopathic EOS patients treated with MCGR, 3D spine length increased by 28 mm during the 2 year post-operative period., Competing Interests: Declarations Conflict of interest Jennifer Hurry reports a research fellowship from Depuy Synthes. John-David Brown received the Dalhousie Medical Research Foundation Lalia B. Chase Studentship. Oheneba Boachie-Adjei reports personal fees from K2M, grants from K2M, board or editorial member with Scoliosis Research Society and Springer, other from WEIGAO and K2M, outside of submitted work. Michael Vitale reports grants from Childrens Spine Foundation, OREF, SRS, POSNA, and OSRF, personal fees from Biomet, Globus Medical, Nuvasive and Stryker, board or committee member for Childrens Spine Foundation, IPOS, Pediatric Orthopaedic Society of North America, Project for Safety in Spine Surgery, and other for FOX, Childrens Spine Foundation, and Biomet outside the submitted work. Joshua Pahys reports personal fees from DePuy, Nuvasive and Zimmer outside the submitted work. Scott Luhmann reports personal fees from Orthopaediatrics and Stryker, board or committee member for Pediatric Orthopaedic Society of North America and Scoliosis Research Society, editorial or governing board for Spine Deformity Journal, other from Globus Medical, Medtronic Sofamor Danek, Stryker, and Wolters Kluwer Health outside the submitted work. Pediatric Spine Study Group reports grants from DePuy Synthes Spine, grants from Medtronic, grants from NuVasive, grants from Globus Medical Inc., grants from OrthoPediatrics, grants from Zimmer Biomet, grants from Pediatric Spine Foundation, grants from Stryker, outside the submitted work. Ron El-Hawary reports personal fees from Depuy Synthes Spine, personal fees from Medtronic Spine, grants from Depuy Synthes Spine, grants from Medtronic Spine, personal fees from Orthopediatrics, other from Pediatric Spine Foundation, other from Scoliosis Research Society, outside the submitted work. The remaining authors have nothing to declare. Ethical approval This work is a sub-study of the Pediatric Spine Study Group Registry which was approved by the Research Ethics Board at the IWK Health Centre (#1002256) in accordance with the ethical standards outlined in the Tri-Council Policy Statement and the 1964 Declaration of Helsinki and its later amendments. Consent to participate All research participants or their legal guardians provided written consent to be a part of the registry and have the data collected be used in ongoing research on scoliosis. Consent for publication Not applicable., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Background: The impact of prolonged digital device exposure on physical and mental health in children has been widely investigated by the scientific community. Additionally, the lockdown periods due to the COVID-19 pandemic further exposed children to screen time for e-learning activities. The aim of this systematic review (PROSPERO Registration: CRD42022315596) was to evaluate the effect of digital device exposure on children's health. The impact of the COVID-19 pandemic was additionally explored to verify the further exposure of children due to the e-learning environment., Methods: Available online databases (PubMed, Google Scholar, Semantic Scholar, BASE, Scopus, Web of Science, and SPORTDiscus) were searched for study selection. The PICO model was followed by including a target population of children aged 2 to 12 years, exposed or not to any type of digital devices, while evaluating changes in both physical and mental health outcomes. The quality assessment was conducted by using the Joanna Briggs Institute (JBI) Critical Appraisal Tool. Synthesis without meta-analysis (SWiM) guidelines were followed to provide data synthesis., Results: Forty studies with a total sample of 75,540 children were included in this systematic review. The study design was mainly cross-sectional (n = 28) and of moderate quality (n = 33). Overall, the quality score was reduced due to recall, selection, and detection biases; blinding procedures influenced the quality score of controlled trials, and outcome validity reduced the quality score of cohort studies. Digital device exposure affected physical activity engagement and adiposity parameters; sleep and behavioral problems emerged in children overexposed to digital devices. Ocular conditions were also reported and associated with higher screen exposure. Home confinement during COVID-19 further increased digital device exposure with additional negative effects., Conclusions: The prolonged use of digital devices has a significant negative impact on children aged 2 to 12, leading to decreased physical activity, sleep disturbances, behavioral issues, lower academic performance, socioemotional challenges, and eye strain, particularly following extended online learning during lockdowns.

Background: Endothelial dysfunction is recognized as an early modification involved in the pathogenesis of vascular diseases. Evidence suggests that the Mediterranean Diet (MD) is associated with endothelial function improvement and, in turn, plays an important role in atherosclerosis development and progression., Objectives: To evaluate both acute and sustained effects of the MD on endothelial function in patients with high cardiometabolic risk., Methods: A total of 25 subjects were randomly assigned to either the MD group or the Control Diet (CD) group according to a single-blind, parallel-group study design. Endothelial function was evaluated through non-invasive flow-mediated dilation (FMD) measurements at baseline (T0) and after 8 weeks (Tw8) of the MD or CD intervention, under both 12 h fast condition (fasting) and 2 h post-meal resembling the assigned diet (2 h). Assessments were conducted by a blinded sonographer., Results: FMD at T0-fasting was similar between MD and CD groups (6.11% ± 0.67 vs. 7.90% ± 1.65; p = 0.266). A significant difference in FMD between MD and CD groups was observed at T0-2h (12.14% ± 1.93 vs. 4.01% ± 1.03; p = 0.004), T8w-fasting (9.76% ± 1.18 vs. 5.03% ± 0.89; p = 0.008), and T8w-2h (8.99% ± 1.22 vs. 3.86% ± 0.52; p = 0.003). Oral glucose insulin sensitivity (OGIS) at T0 correlated with FMD percent changes from T0-fasting to T0-2h (r = 0.414, p = 0.044). After adjusting for age, gender, and OGIS, MD was an independent predictor of percent changes in FMD from T0-fasting to T0-2h (β: -0.582, p = 0.003), from T0-fasting to T8w-fasting (β: -0.498, p = 0.013), and from T0-fasting to T8w-2h (β: -0.479, p = 0.018)., Conclusions: Adherence to the MD may improve endothelial function in both the short- and medium-term among patients at high cardiometabolic risk.

Background: Magnetic controlled growth rods (MCGR) are the most common type of implant used for operative treatment of patients with early-onset scoliosis (EOS). Rods can have either a 7-cm actuator, allowing 2.8 cm of potential expansion, or a 9-cm actuator which allows 4.8 cm potential expansion. We hypothesized that the rate of unplanned return to the operating room (UPROR) will be increased when the 9-cm actuator is implanted in smaller patients. In addition, we aimed to identify a cutoff for spine length between planned upper and lower instrumented MCGR levels that best differentiated between patients having a high versus low risk of UPROR., Methods: We identified 167 patients from a prospectively collected registry of EOS patients who began MCGR treatment at 9 years of age or younger, with greater than 1 year of follow-up, and had adequate radiographs. Demographic, clinical, and surgical characteristics were analyzed for 7-cm and 9-cm actuator patients. Chi-square tests and Student t tests were used to test for differences between the 2 actuator rod groups. A predictive model for UPROR within 2 years was developed based on variables significantly predictive of UPROR., Results: The average follow-up was 2.6 years (range, 1 to 5 y) in both the 7 cm (n=74) and 9 cm (n=93) groups. Twenty-five complications in 14 patients led to UPROR within 2 years of MCGR insertion, 8% incidence (95% CI, 4%-13%). Device-related complications (n=15) were the most common reason for UPROR, followed by wound complications (n=4), pain-related complications (n=3), junctional kyphosis (n=2), and incarcerated umbilical hernia (n=1). After adjusting for age, spine height, number of spine anchors, sex, and diagnosis, there was no significant difference in UPROR rates between groups. Fewer proximal anchors, smaller T1-S1 height, and more caudal mid-point of primary coronal curvature were significantly associated with UPROR in the predictive model., Conclusion: MCGR actuator size is not a significant factor in predicted UPROR. Smaller height, fewer anchors, and caudal apex increased UPROR risk., Level of Evidence: This is a retrospective, multicenter comparative cohort study (Level III therapeutic)., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Balneotherapy (BT) is a therapeutic approach that utilizes various forms of water-based treatments to promote health and well-being. BT possesses a rich historical heritage and has garnered recognition from esteemed institutions such as the World Health Organization (WHO). Recent scientific research enables the identification of relevant diseases (obesity, metabolic diseases, sleep disorders, mental health conditions, Long-COVID-19, and cancer rehabilitation) that could potentially benefit from balneo-therapeutic treatments, thereby presenting new avenues of opportunity for SPA ("Salus per Aquam") medicine. These conditions exemplify the potential benefits of BT for ailments beyond the traditional scope of treatment associated with BT (most commonly osteoarthritis, fibromyalgia, rheumatic back pain, and chronic inflammatory respiratory or skin disorders). Overall, the current scientific evidence suggests that BT holds significant potential for enhancing both individual wellbeing and public health. However, further high-quality clinical trials are essential to corroborate these preliminary findings and to provide critical insights into the therapeutic benefits of BT, paving the way for its broader integration into healthcare practices and public health initiatives., (© 2024. The Author(s) under exclusive licence to International Society of Biometeorology.)

Background: A Chronic Kidney Disease (CKD) Epidemiology Collaboration (EPI) formula not including a Black race coefficient has been recently developed and is now recommended in the US. The new (2021) equation was shown to yield higher estimated glomerular filtration rate (eGFR) values than the old (2009) one in a non-Black general population sample, thus reclassifying a significant number of individuals to a better eGFR category. However, reclassified individuals were previously shown to have a lower risk of progression to end-stage kidney disease, but higher adjusted risks for all-cause death and morbidity and mortality from cardiovascular disease than those not reclassified. This study evaluated the prognostic impact of switching from the 2009 to the 2021 CKD-EPI equation in non-Black individuals with type 2 diabetes., Methods: The Renal Insufficiency And Cardiovascular Events (RIACE) was a prospective cohort study enrolling 15,773 Caucasian patients in 19 Italian centers in 2006-2008. Cardiometabolic risk profile, treatments, complications, and comorbidities were assessed at baseline and eGFR was calculated with the two equations. Vital status was retrieved on 31 October 2015 for 15,656 participants (99.3%)., Results: With the 2021 equation, the eGFR value increased in all patients, except for 293 individuals with a 2009 eGFR ≥ 105 ml·min - 1 ·1.73 m - 2 . The median difference was 4.10 ml·min - 1 ·1.73 m - 2 and was higher in males, older individuals and those in the G2 category. Reclassification decreased the percentage of patients with reduced eGFR from 17.28 to 13.96% and with any CKD from 36.23 to 34.03%. Reclassified individuals had better cardiometabolic risk profile and lower prevalence of complications and use of medications than non-reclassified individuals. Risk of death versus the 2009 G1 category was lower for reclassified than non-reclassified participants in all eGFR categories and, particularly, in each 2009 eGFR category, though difference was significant only in the G4-G5 category. The Receiver Operator Characteristic curves were statistically, but not clinically different with the two equations., Conclusion: Changing from the 2009 to the 2021 CKD-EPI equation results in higher eGFR and lower CKD prevalence, with a lower risk of death in reclassified patients with an eGFR < 30 ml·min - 1 ·1.73 m - 2 , but virtually no impact on mortality prediction., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008., (© 2024. The Author(s).)

The main objective of this review is to examine the impact of balneotherapy on serum and salivary cortisol concentrations. A systematic search was conducted in PubMed, Scopus, Web of Science, PEDro, and Google Scholar. The databases were screened from inception up until April 2024. After screening the scientific literature, 845 articles were retrieved and 17 studies, involving a total of 765 participants, were eventually included in the review. Among them, four were randomized controlled trials, five were non-randomized studies, and eight were pre-post studies with no control group. The evidence gathered in this review indicates a significant short-term reduction in cortisol levels in healthy individuals undergoing balneotherapy, particularly those experiencing high levels of stress. Conversely, in patients with rheumatic conditions (especially if elderly), increases in cortisol levels induced by balneotherapy can act as beneficial hormetic stress, reducing inflammatory mediators and improving pain and functional quality of life. The meta-analysis shows an overall trend of reduction in stress hormone levels, more pronounced in the intervention group undergoing mud-balneotherapy compared to the control group, a finding that, however, does not reach statistical significance (g=-0.11 [95% CI: -0.30; 0.08]; p > 0.05). Current scientific evidence demonstrates that balneotherapy has a positive impact on the regulation of cortisol levels. The regulation of the hypothalamic-pituitary-adrenal axis and the beneficial effects observed on health parameters and quality of life allow mud-balneotherapy to be classified as eustressful stimuli useful in preventing stress-related pathologies in healthy individuals and in alleviating symptoms in patients with chronic conditions. Future research on the topic is advised., (© 2024. The Author(s) under exclusive licence to International Society of Biometeorology.)

Aims: To assess whether and to what extent excess risk of all-cause death is reduced in individuals with type 2 diabetes by achieving optimal control of traditional cardiovascular risk factors., Methods: This observational, prospective, cohort study enrolled 15,773 Caucasian patients in 19 Italian centres in 2006-2008. Participants were stratified according to the number of the following risk factors outside target: haemoglobin A 1c , blood pressure, micro/macroalbuminuria, current smoking, LDL cholesterol, and triglycerides. All-cause mortality was retrieved for 15,656 patients (99.3 %) on 31 October 2015., Results: Age-adjusted mortality rates and hazard ratios were significantly higher in the whole RIACE cohort (by ∼20 %) and in patients with (by ∼100 %) but not in those without prior cardiovascular disease (CVD), as compared with the coeval Italian general population. In all patients and in those without prior CVD, the relationship with mortality according to the number of risk factors outside target was J-shaped, an effect that was attenuated after either excluding "overtreated " patients, i.e., those with haemoglobin A 1c ≤6.0 % on anti-hyperglycaemic agents causing hypoglycaemia and/or systolic blood pressure ≤120 mmHg on anti-hypertensive agents, or adjusting for "overtreatment". Conversely, in patients with prior CVD, mortality remained higher than in the general population in all categories and increased progressively from +70 % to +314 %, without J-effect., Conclusions: In patients with type 2 diabetes, optimal treatment of traditional cardiovascular risk factors completely eliminated the excess mortality risk versus the general population, provided that they were not "overtreated". However, this effect was observed only in participants without history of CVD., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July 2008., Competing Interests: Declaration of Competing Interest Monia Garofolo: consultant fees from Eli Lilly, and lecture fees from Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk. Giuseppe Penno: consultant fees from Bayer and Eli Lilly, and lecture fees from AstraZeneca, Boerhinger Ingelheim, Eli-Lilly, Merck Sharp & Dohme, Mundipharma, Novo Nordisk, and Takeda. Anna Solini: consultant fees from Axxam, Bayer, and Novo Nordisk, and lecture fees from Eli Lilly, Novo Nordisk, and Sanofi-Aventis. Emanuela Orsi: consultant fees from Eli Lilly and Novo Nordisk, and lecture fees from Astellas. Martina Vitale: lecture fees from MundiPharma and Novo Nordisk. Veronica Resi: lecture fees from Astra-Zeneca, Eli Lilly, and Sanofi-Aventis. Enzo Bonora: consultant fees from Abbott, Bayer, Becton Dickinson, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, and Novo Nordisk. Cecilia Fondelli: lecture fees from Abbot, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Merck Sharp & Dohme, Mundipharma, and Theras Lifetech. Roberto Trevisan: consultant fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, and Sanofi-Aventis, and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. Monica Vedovato: lecture fees from Lifescan and Novo Nordisk. Antonio Nicolucci: consultant fees from AstraZeneca, lecture fees from Eli Lilly, Medtronic, and Novo Nordisk, and grant support from AlfaSigma, Novo Nordisk, Pikdare, Sanofi, Shionogi, SOBI, and Theras. Giuseppe Pugliese: consultant fees from Abbot, Bayer, and Novo Nordisk, and lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Mundipharma, and Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Context: Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). The definition of predictive factors of survival is incomplete., Objective: To identify pre- and posttreatment survival predictors in a real-life cohort of RR-DTC treated with lenvatinib., Design: Multicenter, retrospective, cohort study., Setting: 3 Italian thyroid cancer referral centers., Participants: 55 RR-DTC treated with lenvatinib., Main Outcome Measures: Progression-free survival (PFS) and overall survival (OS)., Results: Lenvatinib was the first-line kinase-inhibitor in 96.4% of subjects. Median follow-up was 48 months. Median PFS and OS were 26 [95% confidence interval (CI) 19.06-32.93] and 70 months (95% CI 36-111.99), respectively. Pretreatment setting: Eastern Cooperative Oncology Group (ECOG) performance status was independently related to PFS [P < .001; hazard ratio (HR) 18.82; 95% CI 3.65-97.08: score 0-1 as reference] and OS (P = .001; HR 6.20; 95% CI 2.11-18.20; score 0-1 as reference); radioactive iodine (RAI) avidity was independently related to PFS (P = .047; HR 3.74; 95% CI 1.01-13.76; avid disease as reference). Patients with good ECOG status (0-1) and RAI-avid disease obtained objective response in 100% of cases and achieved a median PFS of 45 months without any death upon a median follow-up of 81 months. Posttreatment setting: the best radiological response independently predicted PFS (P = .001; HR 4.6; 95% CI 1.89-11.18; partial/complete response as reference) and OS (P = .013; HR 2.94; 95% CI 1.25-6.89; partial/complete response as reference)., Conclusion: RR-DTC with good performance status and RAI-avid disease obtains the highest clinical benefit from lenvatinib. After treatment initiation, objective response was the only independent survival predictor., (© 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.)

Aims: It is unclear whether type 2 diabetes diagnosed in young adulthood is associated with increased severity than that occurring later in life beyond longer lifetime exposure to hyperglycemia. This study aimed at assessing the independent association of age at type 2 diabetes diagnosis with all-cause mortality., Methods: This prospective cohort study enrolled 15,773 Caucasian patients with type 2 diabetes in 19 Italian centers in 2006-2008. Cardiometabolic risk profile and presence of complications and comorbidities were assessed at baseline and participants were stratified by quartiles of age at diabetes diagnosis. All-cause mortality was verified on 31 October 2015., Results: Valid information on vital status was retrieved for 15,656 participants (99.3%). Patients in the lowest quartile had the longest diabetes duration, the worst glycemic control and the highest prevalence of insulin treatment, obesity, atherogenic dyslipidemia, and smoking habits. All complications were inversely associated with age at diabetes diagnosis after adjustment for age and sex, but not after further adjustment for diabetes duration. Percentages of death, Kaplan-Meier estimates, and unadjusted hazard ratios and mortality rates increased from the lowest to the highest quartile. In contrast, when adjusting for age and sex, participants falling in the lowest quartile, showed the highest mortality risk [hazard ratio 1.321 (95% confidence interval 1.196-1.460), P < 0.0001]. However, differences among quartiles disappeared after adjustment for diabetes duration, complications/comorbidities, or other cardiovascular risk factors., Conclusions: Type 2 diabetes onset in young adulthood is associated with increased mortality that is mainly driven by longer diabetes duration favoring the development of complications., Trial Registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008., (© 2024. The Author(s).)

Background: A healthy eating pattern such as the Mediterranean-style healthy eating pattern (MED-HEP) is associated with favorable effects on both cardiometabolic risk markers and self-reported health outcomes. Limited evidence exists regarding the influence of the glycemic index (GI) of carbohydrate foods consumed within a healthy eating pattern on self-reported health status and sleep., Objectives: To investigate the effects of a low- compared with high-GI MED-HEP on changes in health-related quality of life (HRQoL) and sleep., Methods: The MEDGICarb-intervention trial is a 12-wk randomized, controlled, parallel multi-center trial in adults with ≥2 features of the metabolic syndrome. Participants consumed an eu-energetic diet profiled as a MED-HEP with either low GI (experimental) or high GI (control). HRQoL and sleep were measured with Medical Outcomes Study 36-item short-form health survey version 2, Pittsburgh sleep quality index, and Epworth Sleepiness Scale at baseline and postintervention., Results: One hundred and sixty adults with ≥2 features of the metabolic syndrome completed the intervention [53% females, age 56 ± 10 y, body mass index (kg/m 2 ) 31.0 ± 3.1]. Low- compared with high-GI MED-HEP resulted in differential changes between the groups in the HRQoL domains role physical [5.6 ± 2.2 arbitrary units (AU) compared with -2.5 ± 2.5 AU) and vitality (6.9 ± 1.7 AU compared with 0.0 ± 1.8 AU] (P < 0.05), which were driven mostly by improvements in the low-GI group. There were no significant differences between the MED-HEPs for changes in aggregated physical or mental components or for the other individual domains of HRQoL (physical functioning, bodily pain, general health, social functioning, role emotional, and mental health) or for sleep quality or daytime sleepiness., Conclusions: Low compared to high GI in the context of a MED-HEP resulted in modest improvements in some, but not all, health domains of HRQoL. No major differences were seen between the groups for measures of sleep. This trial was registered at clinicaltrials.gov as NCT03410719., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Adherence to dietary recommendations is a critical component in the management of type 1 diabetes (T1D). Taste and flavor significantly influence food choices. The aim of this study was to investigate taste sensitivity and flavor recognition ability in adults with T1D compared to healthy individuals., Subjects/methods: Seventy-two people with T1D and 72 matched healthy controls participated in the study. Participants underwent the gustometry test for sweet, sour, salty, and bitter tastes and the flavor test, which consisted of oral administration of aqueous aromatic solutions identifying 21 different compounds., Results: Participants with T1D had significantly lower flavor scores and gustometry scores than controls (p < 0.0001 and p = 0.0063, respectively). T1D individuals showed a lower perception of sour, bitter and salty tastes than controls, while the perception of sweet taste was similar. The sex differences and age-related decline in flavor perception observed in controls were not present in the participants with T1D. Neither BMI nor disease-related parameters such as fasting blood glucose on the day of the study, glycosylated hemoglobin, age at onset of diabetes, duration of diabetes, or type of insulin treatment (insulin pump or multiple daily injections) correlated with flavor and taste perception in the T1D participants., Conclusions: Flavor and taste perception are impaired in adults with T1D, potentially affecting dietary adherence and food choices. This highlights the need for further research into the mechanisms underlying sensory changes in T1D and emphasizes the importance of targeted dietary interventions to improve health outcomes and quality of life in this population., (© 2024. The Author(s).)

Context: Growth hormone (GH) deficiency in a child with short stature is diagnosed by GH secretion provocative tests. When the test response is considered adequate, the short stature is considered idiopathic (ISS)., Objective: To determine the effect of GH provocative tests on the growth rate in children with idiopathic short stature., Design: Children with short stature with a normal response to at least one GH provocative test were enrolled. Height and growth velocity were measured prior to and after stimulus tests during the follow-up., Methods: Height, mid-parental height, body weight, and body mass index were measured. The height and growth rate were converted to percentiles and Standard Deviation Scores (SDS) using reference ranges standardized by age and sex. GH provocative tests employed arginine or clonidine as secretagogues., Results: Fourty-six children of both genders were enrolled. In thirty-six children, height was measured at the time of testing and on an average time prior to and after the tests of 210 days and 180 days respectively. After testing the children displayed a 3.4-fold increase in their estimated 90-day growth rate. The median (inter-quartile range, IQR) 90 days growth of children pre-and post-tests were 0.7 (0.2-1.0) cm and 2.4 (1.7-3.1) cm respectively with a mean 3,4-fold increase (p < 0.0001). The median (IQR) 90 days growth of children pre- and post-tests calculated as standard deviation scores (SDS) were -4.0 (-5.4--2.1) SDS and 0.1 (-1.9-1.4) SDS respectively (p < 0.0001). Ten children with ISS were observed for about 5 months before the GH provocative tests. A small increase in the growth rate was seen only in 2 out of 10 children before testing while it increased in all of them after the tests. The difference in the median growth rate at the first and the second observation was not significant (p = 0.219)., Conclusions: Two sequential somatotropic axis provocative tests increase the growth rate in children with idiopathic short stature. The duration of this effect is yet to be determined., (© 2024. The Author(s).)

The long story of NK cells started about 50 y ago with the first demonstration of a natural cytotoxic activity within an undefined subset of circulating leukocytes, has involved an ever-growing number of researchers, fascinated by the apparently easy-to-reach aim of getting a "universal anti-tumor immune tool". In fact, in spite of the impressive progress obtained in the first decades, these cells proved far more complex than expected and, paradoxically, the accumulating findings have continuously moved forward the attainment of a complete control of their function for immunotherapy. The refined studies of these latter years have indicated that NK cells can epigenetically calibrate their functional potential, in response to specific environmental contexts, giving rise to extraordinarily variegated subpopulations, comprehensive of memory-like cells, tissue-resident cells, or cells in various differentiation stages, or distinct functional states. In addition, NK cells can adapt their activity in response to a complex body of signals, spanning from the interaction with either suppressive or stimulating cells (myeloid-derived suppressor cells or dendritic cells, respectively) to the engagement of various receptors (specific for immune checkpoints, cytokines, tumor/viral ligands, or mediating antibody-dependent cell-mediated cytotoxicity). According to this picture, the idea of an easy and generalized exploitation of NK cells is changing, and the way is opening toward new carefully designed, combined and personalized therapeutic strategies, also based on the use of genetically modified NK cells and stimuli capable of strengthening and redirecting their effector functions against cancer., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background and Aims: Sleep disorders are bidirectionally linked with eating behaviors and glucose metabolism, which could be clinically relevant in type 1 diabetes (T1D). We investigated the relationship between dietary habits and sleep quality in individuals with T1D on insulin pumps and continuous glucose monitoring (CGM)., Methods and Results: In a cross-sectional study, dietary habits (7-day food diary, EPIC questionnaire) and sleep quality (Pittsburgh Sleep Quality Index questionnaire) were assessed in 59 men and 58 women with T1D, aged 19-79 years, using CGM and insulin pump. Differences in dietary habits and blood glucose after dinner (6 h) between participants differing in sleep quality, sleep duration, and sleep onset latency were evaluated. Bad Sleepers (n = 81) were twice as prevalent as Good Sleepers (n = 36) and had a significantly higher intake of fat than Good Sleepers (dinner: 30.7 ± 10.7 vs. 24.0 ± 10.5 g, p = 0.004). Short sleepers had a significantly higher usual intake (g/1000 kcal) of coffee and tea (90.4 ± 71.7 vs. 62.0 ± 35.6), alcoholic (47.8 ± 51.1 vs. 28.9 ± 31.5) and carbonated beverages (21.8 ± 38.1 vs. 9.3 ± 17.2) (p < 0.05 for all) than Long Sleepers. Long Sleep Onset Latency was associated with a significantly higher fat intake at dinner (41.8 ± 7.4 vs. 38.1 ± 9.1 % total energy, p = 0.029) than Short Sleep Onset Latency. No significant differences in post-dinner blood glucose levels were detected between participants with good or bad sleep quality., Conclusion: Sleep disruption is common in T1D and is associated with unhealthy dietary choices, especially at dinner, independently of post-dinner blood glucose control., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Estimated pulse-wave velocity (ePWV), a surrogate measure of arterial stiffness, was shown to independently predict morbidity and mortality from cardiovascular disease and other causes in both the general population and high-risk individuals. However, in people with type 2 diabetes, it is unknown whether ePWV adds prognostic information beyond the parameters used for calculating it., Aims: To assess the independent association of ePWV with all-cause mortality in individuals with type 2 diabetes., Design: Prospective cohort study that enrolled 15 773 patients in 19 Italian centres in 2006-08., Methods: ePWV was calculated from a regression equation using age and mean blood pressure (BP). All-cause mortality was retrieved for 15 656 patients in 2015., Results: Percentage and rate of deaths, Kaplan-Meier estimates and unadjusted hazard ratios increased from Quartile I to Quartile IV of ePWV. After adjustment for age, sex, BP levels and anti-hypertensive treatment, the strength of association decreased but mortality risk remained significantly higher for Quartiles II (+34%), III (+82%) and IV (+181%) vs. Quartile I and was virtually unchanged when further adjusting for other cardiovascular risk factors and complications/comorbidities. Each m·s- 1 increase in ePWV was associated with an increased adjusted risk of death in the whole cohort (+53%) and in participants with (+52%) and without (+65%) cardiorenal complications. Moreover, ePWV significantly improved prediction of mortality risk over cardiovascular risk factors and complications/comorbidities, though the net increase was modest., Conclusions: These findings suggest that ePWV may represent a simple and inexpensive tool for providing prognostic information beyond traditional cardiovascular risk factors., Trial Registration: ClinicalTrials.gov, NCT00715481, https://clinicaltrials.gov/ct2/show/NCT00715481., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study aimed to describe the spinopelvic alignment of a cohort of young ambulatory individuals with cerebral palsy (CP) and compare it to published spinopelvic alignment data for the typically developing adolescents., Methods: Thirty-seven adolescents (18 females) with CP at GMFCS I-III were included in this retrospective case series. Lumbar lordosis and pelvic incidence were measured, and their mismatch was calculated. A model that calculates predicted lumbar lordosis based on pelvic incidence in normative data was utilized to calculate a predicted lumbar lordosis in this cohort with cerebral palsy., Results: At imaging, ages were mean and standard deviation 13.5 ± 3.0 years. Pelvic incidence was 46.2° ± 12.9°, pelvic tilt was 2.8° ± 9.4°, sacral slope was 43.6° ± 10.8°, and measured lumbar lordosis was 59.4° ± 11.6°. There were no differences in pelvic incidence or lumbar lordosis among the GMFCS levels; however, pelvic incidence was higher in females. Pelvic incidence-lumbar lordosis mismatch greater than 10° was found in 67% of the cohort. Mean predicted lumbar lordosis based on the model was 54.7° ± 8.5°, averaging 8° less than measured lordosis., Conclusion: PI-LL mismatch was identified in 67% of this cohort of ambulatory adolescents with CP, in part due to greater lordosis than predicted by a model based on data from adolescents without CP. The implications of this finding, such as the correlation between sagittal spinopelvic alignment and quality of life in this population, should be assessed further in ambulatory patients with cerebral palsy., Level of Evidence: Level IV-retrospective cohort study and literature comparison., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

The development and application of functional feed ingredients represents a great opportunity to advance fish growth and health, boost the immune system, and induce physiological benefits beyond those provided by traditional feeds. In the present study, we looked at the feasibility of in vitro methods for screening the qualities of functional feed ingredients using the fish cell line RTgill-W1, which has never been used in fish nutrition, and the culture of Paramoeba perurans. Five functional feed ingredients (arginine, β-glucan, vitamin C, and two phytogenic feed additives) were selected to investigate their effects on cell viability and reactive oxygen species production. Three of the selected ingredients (arginine and two phytogenic feed additives) were additionally tested to assess their potential amoebicidal activity. As these functional ingredients are the core of a commercially available feed (Protec Gill, Skretting AS), their beneficial effects were further assessed in a field trial in fish affected by complex gill disease. Here, the analyzed parameters included the evaluation of macroscopic and histopathological gill conditions, pathogen detections, and analyses of plasma parameters. RTgill-W1 cell line assays were a good tool for screening functional ingredients and provided information about the optimal ingredient concentration ranges, which can be helpful for adjusting the concentrations in future feed diets. Through the culture of P. perurans, the tested ingredients showed a clear amoebicidal activity, suggesting that their inclusions in dietary supplements could be a viable way to prevent microbial infections. A three-week period of feeding Protec Gill slowed the disease progression, by reducing the pathogen load and significantly improving gill tissue conditions, as revealed by histological evaluation. The use of diets containing selected functional ingredients may be a feasible strategy for preventing or mitigating the increasingly common gill diseases, particularly in cases of complex gill disease, as documented in this study., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vitale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions., (© 2024 Orsi et al.)

Despite efforts to explore the genome of the malaria vector Anopheles gambiae, the Y chromosome of this species remains enigmatic. The large number of repetitive and heterochromatic DNA sequences makes the Y chromosome exceptionally difficult to fully assemble, hampering the progress of gene editing techniques and functional studies for this chromosome. In this study, we made use of a bioinformatic platform to identify Y-specific repetitive DNA sequences that served as a target site for a CRISPR/Cas9 system. The activity of Cas9 in the reproductive organs of males caused damage to Y-bearing sperm without affecting their fertility, leading to a strong female bias in the progeny. Cytological investigation allowed us to identify meiotic defects and investigate sperm selection in this new synthetic sex ratio distorter system. In addition, alternative promoters enable us to target the Y chromosome in specific tissues and developmental stages of male mosquitoes, enabling studies that shed light on the role of this chromosome in male gametogenesis. This work paves the way for further insight into the poorly characterised Y chromosome of Anopheles gambiae. Moreover, the sex distorter strain we have generated promises to be a valuable tool for the advancement of studies in the field of developmental biology, with the potential to support the progress of genetic strategies aimed at controlling malaria mosquitoes and other pest species., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vitale et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Current guidelines for nonalcoholic fatty liver disease (NAFLD) recommend high volumes and/or intensities of physical activity (PA), the achievement of which generally requires participation in supervised exercise training programs that however are difficult to implement in routine clinical practice. Conversely, counselling interventions may be more suitable, but result in only modest increases in moderate-to-vigorous-intensity PA (MVPA). This study assessed whether a counseling intervention for increasing PA and decreasing sedentary time (SED-time) is effective in improving NAFLD markers in people with type 2 diabetes., Methods: Three-hundred physically inactive and sedentary patients were randomized 1:1 to receive one-month theoretical and practical counseling once-a-year (intervention group) or standard care (control group) for 3 years. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltranspeptidase (γGT) levels were measured and fatty liver index (FLI), hepatic steatosis index (HSI), and visceral adiposity index (VAI) were calculated. Total PA volume, light-intensity PA (LPA), moderate-to-vigorous-intensity PA (MVPA), and SED-time were objectively measured by an accelerometer., Results: Throughout the 3-year period, NAFLD markers did not change in the control group, whereas ALT, γGT, FLI, and HSI decreased in the intervention group, with significant between-group differences, despite modest MVPA increases, which however were associated with larger decrements in SED-time and reciprocal increments in LPA. Mean changes in NAFLD markers varied according to quartiles of (and correlated with) changes in MVPA (all markers) and SED-time, LPA, and PA volume (ALT, γGT, and HSI). Mean changes in MVPA or PA volume were independent predictors of changes in NAFLD markers. When included in the models, change in cardiorespiratory fitness and lower body muscle strength were independently associated with some NAFLD markers., Conclusion: A behavior change involving all domains of PA lifestyle, even if insufficient to achieve the recommended MVPA target, may provide beneficial effects on NAFLD markers in people with type 2 diabetes., Competing Interests: SZ is an employee of Technogym. AN reported grant from Artsana, Astra-Zeneca, Eli Lilly, Novo Nordisk, and Sanofi Aventis and personal fees from Eli Lilly and Novo Nordisk. SB reported personal fees from Astra-Zeneca, Eli Lilly, Novo Nordisk, and Takeda. GP reported personal fees from Astra-Zeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dome, Mylan, Sigma-Tau, and Takeda. The remaining 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. 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., (Copyright © 2024 Haxhi, Vitale, Mattia, Giuliani, Sacchetti, Orlando, Iacobini, Menini, Zanuso, Nicolucci, Balducci and Pugliese.)

Lightning strikes, a prominent meteorological event, pose a significant risk of triggering technological disruptions within the process industry. To better understand this phenomenon, an analysis focused on past lightning-triggered events was carried out, examining open-source industrial-accident databases to compile a new NaTech-driven dataset of 689 records. First, an overall quantitative analysis revealed that over 80 % of these events involved incidents or loss of containment. Notably, 83.3 % of them occurred during the spring and summer, indicating a seasonal pattern. Based on the frequency of functional attributes, the chemical and petrochemical macro-sector was the most vulnerable, followed by storage and warehousing. About 40 % of all classifiable events happened on storage equipment, while 21 % happened on electric and electronic devices. Given the lack of valuable information for the principal source of data (NRC), the technological scenarios triggered were characterized using a refined subset of 127 observations, obtained considering the "other sources" of data. Fire scenarios predominated at 56 %; coincidentally, roughly 70 % of all scenarios involved hazardous substances classified as physical hazards. Estimated losses for the available information underscored the adverse consequences of lightning-triggered NaTech events, highlighting their major impact on both safety and the environment. An analysis of the event tree showed the logical path from the lightning strike to the final ignition scenarios (considering a subset of 107 records). This path accounted for 36 % of the classifiable records that directly affected the structure, while more than 50 % of them did not. Bayesian network structures made it possible to get conditional probabilities from the event tree and improved the model by adding attributes for vulnerable equipment and macro-sectors. In order to deal with the uncertain data, algorithms were used to generalize the models that were obtained from smaller subsets of data with more accurate information to the whole dataset. It provides an important additional view of unclassifiable data that otherwise remained in the dark. This novel insight contributes to increase the vulnerability awareness of industrial assets against lightning strikes., Competing Interests: 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., (© 2024 The Authors.)

Aims: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA)., Materials and Methods: Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD1 16  = palmitoleic acid/palmitic acid and SCD1 18  = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated., Results: Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD1 16, SCD1 18 , ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005)., Conclusions: High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes., Registration Number Trial: ID NCT00700856 https://clinicaltrials.gov., (© 2024 John Wiley & Sons Ltd.)

Abstract: Ambrosini, L, Presta, V, Vitale, M, Menegatti, E, Guarnieri, A, Bianchi, V, De Munari, I, Condello, G, and Gobbi, G. A higher kick frequency swimming training program optimizes swim-to-cycle transition in triathlon. J Strength Cond Res 38(5): 976-984, 2024-The purpose of this study was to evaluate the effect of an 8-week swimming training program on biomechanical and physiological responses during a swim-to-cycle simulation. Fifteen triathletes were randomly allocated to 3 groups: a 6-beat-kick group (K6), a 4-beat-kick group (K4), and a control group (CG). Biomechanical and physiological parameters were evaluated during a 400-m swim and a 10-minute cycle segment before (Pretraining) and after (Posttraining) the program. A lower stroke frequency ( p = 0.004) and a higher stroke length ( p = 0.002) was found in K6 compared with CG at Posttraining. A reduction in the K6 emerged between Pretraining and Posttraining during cycling for heart rate ( p = 0.005), V̇O 2 ( p = 0.014), and energy expenditure ( p = 0.008). A positive association emerged between swim kick index and cycling cadence in the K6 group. The improvement in stroke frequency and length observed in the K6 group could be explained as an improvement in swimming technique. Similarly, the reduction in energy expenditure during cycling at Posttraining for the K6 group suggests an improvement in the working economy. Triathlon coaches and athletes should consider the inclusion of high swim kick into their training programs to enhance swim and cycling performance, which can ultimately lead to an improvement in the swim-to-cycle transition and the overall triathlon performance., (Copyright © 2024 National Strength and Conditioning Association.)

Endometrial cancer (EC) incidence and mortality rates have been increasing, particularly among young females. Although more than 90% of ECs are sporadic, 5-10% are hereditary, a majority of which occurs within Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) or Lynch syndrome. The traditional histopathological classification differentiates EC between two main groups: type I (or endometrioid) and type II (including all other histopathological subtypes). However, this classification lacks reproducibility and does not account for the emerging molecular heterogeneity. In 2013, The Cancer Genome Atlas (TCGA) project proposed EC molecular classification defining four groups with different prognostic and predictive values and the current international guidelines are progressively establishing EC risk stratification and treatment based on both histopathological and molecular criteria. Our manuscript aims to summarize the current state of EC molecular characterizations, including germline alterations at the basis of hereditary EC predisposition, to discuss their clinical utility as prognostic and predictive markers., 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 © 2024 Elsevier Ltd. All rights reserved.)

Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the β-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The role of dietary Glycemic Index (GI), independently of fiber intake, in modulating cardiovascular disease (CVD) risk among non-diabetic individuals has not been fully elucidated., Objective: To evaluate the effects of a low- versus a high-GI diet, based on a Mediterranean dietary pattern, on cardiometabolic risk factors in individuals at high CVD risk, participating in the MEDGI-Carb intervention study., Subjects and Methods: 160 individuals, aged 30-69 years, BMI 25-37 kg/m 2 , with a waist circumference >102 cm (males) or >88 cm (females) and one feature of the metabolic syndrome, participated in a multi-national (Italy, Sweden, USA) randomized controlled parallel group trial. Participants were assigned to a low GI (< 55) or high-GI MedDiet ( > 70) for 12 weeks. The diets were isoenergetic and similar for available carbohydrate (270 g/d) and fiber (35 g/d) content. Fasting metabolic parameters were evaluated in the whole cohort, while an 8-h triglyceride profile (after standard breakfast and lunch) was evaluated only in the Italian cohort., Results: Blood pressure and most fasting metabolic parameters improved at the end of the dietary intervention (time effect, p < 0.05 for all); however, no differences were observed between the low- and the high-GI MedDiet groups (time x group effect; p > 0.05 for all). Conversely, the low-GI diet, compared with high-GI diet, significantly reduced the 8-h triglyceride profile (p < 0.017, time*group effect) that was measured only in the Italian cohort. However, it induced a reduction of plasma triglycerides after lunch (tAUC) that was of only borderline statistically significance (p = 0.065)., Conclusions: Consuming a low-GI in comparison with a high-GI MedDiet does not differentially affect the major cardiometabolic risk factors at fasting in individuals at increased cardiometabolic risk. Conversely, it could reduce postprandial plasma triglycerides., Clinical Trial Registry Number: NCT03410719, ( https://clinicaltrials.gov )., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.

Background: Idiopathic pulmonary fibrosis (IPF) is a debilitating and progressive lung disease of unknown aetiology, characterized by the relentless deposition of fibrotic tissue. Biomarkers may play a pivotal role as indicators of disease presence, progression, and treatment response. Sirtuins, a family of enzymes with ADP ribosyltransferase or deacetylase activity, have been implicated in several diseases, including pulmonary fibrosis., Methods: A cross-sectional, prospective, observational single-center study was conducted to investigate the potential role of serum SIRTs levels as biomarkers in patients with IPF. Demographic, clinical, and functional data and serological samples were collected from 34 patients with IPF followed at the Interstital Lung and Rare Diseases Outpatient Clinic of the Vanvitelli Pneumology Clinic, Monaldi Hospital, Naples, Italy and from 19 age-matched controls., Results: Serum SIRT-1 levels were significantly reduced in IPF patients compared to controls (median IPF 667 [435-858] pg/mL versus controls 925 [794-1173] pg/mL; p < 0.001 ). In contrast, serum SIRT-3 levels were significantly increased in IPF patients compared to controls (median IPF 338 [230-500] pg/mL versus controls 154 [99.8-246] pg/mL; p < 0.001). There were no statistically significant differences in serum SIRT-6 and SIRT-7 levels between IPF and controls. In addition, we found a significant positive correlation between SIRT-1 and lung function parameters such as FEV 1 % (ϱ=0.417;p = 0.016), FVC% (ϱ=0.449;p = 0.009) and DL CO % (ϱ=0.393;p = 0.024), while a significant negative correlation was demonstrated between SIR-1 and GAP score, demonstrating a significant reduction in SIRT-1 in advanced Gender-Age-Physiology (GAP) stages 2-3 compared to GAP stage 1 (p = 0.008)., Conclusions: This prospective, cross-sectional study showed that SIRT-1 was associated with lung function and IPF severity and that both SIRT-1 and SIRT-3 could be considered as potential biomarkers of IPF, whereas SIRT-6 and SIRT-7 were not associated with IPF., (© 2024. The Author(s).)

The influenza A(H1N1) pdm09 virus, which emerged in 2009, has been circulating seasonally since then. In this study, we conducted a comprehensive genome-based investigation to gain a detailed understanding of the genetic and evolutionary characteristics of the hemagglutinin (HA) and neuraminidase (NA) surface proteins of A/H1N1pdm09 strains circulating in Italy over a fourteen-year period from 2009 to 2023 in relation to global strains. Phylogenetic analysis revealed rapid transmission and diversification of viral variants during the early pandemic that clustered in clade 6B.1. In contrast, limited genetic diversity was observed during the 2023 season, probably due to the genetic drift, which provides the virus with a constant adaptability to the host; furthermore, all isolates were split into two main groups representing two clades, i.e., 6B.1A.5a.2a and its descendant 6B.1A.5a.2a.1. The HA gene showed a faster rate of evolution compared to the NA gene. Using FUBAR, we identified positively selected sites 41 and 177 for HA and 248, 286, and 455 for NA in 2009, as well as sites 22, 123, and 513 for HA and 339 for NA in 2023, all of which may be important sites related to the host immune response. Changes in glycosylation acquisition/loss at prominent sites, i.e., 177 in HA and 248 in NA, should be considered as a predictive tool for early warning signs of emerging pandemics, and for vaccine and drug development.

This study evaluated the effect of resveratrol (RES) on the prevention of medication-related osteonecrosis of the jaws (MRONJ) in ovariectomized (OVX) rats treated with zoledronate (ZOL). Fifty rats were distributed in five groups: SHAM (n = 10): non-ovariectomy + placebo; OVX (n = 10):ovariectomy + placebo; OVX + RES (n = 10):ovariectomy + resveratrol; OVX + ZOL (n = 10):ovariectomy + placebo + zoledronate; and OVX + RES + ZOL (n = 10):ovariectomy + resveratrol + zoledronate. The mandibles left sides were analyzed with micro-CT, histomorphometry, and immunohistochemistry. On the right side, bone markers gene expression was analyzed by qPCR. ZOL increased the percentage of necrotic bone and reduced the neo-formed bone compared to groups not receiving ZOL (p < 0.05). RES impacted the tissue healing pattern in OVX + ZOL + RES, reduced inflammatory cell infiltrate, and improved bone formation in the extraction site. Osteoblasts, alkaline phosphatase (ALP)-, and osteocalcin (OCN)-immunoreactive cells were lower in OVX-ZOL than in SHAM, OVX, and OVX-RES. The OXV-ZOL-RES had fewer osteoblasts and ALP- and OCN-cells than the SHAM and OVX-RES. The tartrate-resistant acid phosphatase (TRAP)-positive cells were reduced in the presence of ZOL (p < 0.05), while the TRAP mRNA levels increased with ZOL treatment, with or without resveratrol, compared with the other groups (p < 0.05). RES alone increased superoxide dismutase levels compared to OVX + ZOL and OVX + ZOL + RES (p < 0.05). In conclusion, resveratrol reduced the tissue impairment severity induced by ZOL; however, it could not prevent the occurrence of MRONJ., (© 2023 Wiley Periodicals LLC.)

Background: Epithelial to mesenchymal transition (EMT) endows cancer cells with pro-metastatic properties, which appear most effective when cells enter an intermediate hybrid (H) state, characterized by integrated mesenchymal (M) and epithelial (E) traits. The reasons for this advantage are poorly known and, especially, it is totally unexplored whether the interplay between H-cells and NK cells could have a role. Here we characterize the pro-metastatic mechanics of non-small cell lung cancer (NSCLC) H-cells and their subset of cancer-initiating cells (CICs), dissecting crucial interactions with NK cells., Methods: Human lung cancer cell lines and sublines representative of E, M, or H states, assessed by proteomics, were analyzed in vivo for their tumor-forming and disseminating capabilities. Interactions with NK cells were investigated in vitro using migration assays, cytotoxic degranulation assays, and evaluation of CD133+ CICs modulation after coculture, and validated in vivo through NK cell neutralization assays. Correlation between EMT status, NK cell infiltration, and survival data, was evaluated in a cohort of surgically resected NSCLC cases (n=79)., Results: We demonstrated that H-cells, have limited dissemination capability but show the highest potential to initiate metastases in vivo. This property was related to their ability to escape NK cell surveillance. Mechanistically, H-cells expressed low levels of NK-attracting chemokines (CXCL1 and CXCL8), generating poorly infiltrated metastases. Accordingly, proteomics and GO enrichment analysis of E, H, M cell lines showed that the related secretory processes could change during EMT.Furthermore, H-CICs uniquely expressed high levels of the inhibitory ligand B7-H3, which protected H-CIC from NK cell-mediated clearance. In vivo neutralization assays confirmed that, indeed, the pro-metastatic properties of H-cells are poorly controlled by NK cells.Finally, the analysis of patients revealed that detection of hybrid phenotypes associated with low NK infiltration in NSCLC clinical specimens could identify a subset of patients with poor prognosis., Conclusions: Our study demonstrates that H-cells play a central role in the metastatic spread in NSCLC. Such pro-metastatic advantage of H-cells is supported by their altered interaction with NK cells and by the critical role of B7-H3 in preserving their H-CIC component, indicating B7-H3 as a potential target in combined NK-based therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Improving the composition of circulating fatty acids (FA) leads to a reduction in cardiovascular diseases (CVD) in high-risk individuals. The membrane fluidity of red blood cells (RBC), which reflects circulating FA status, may be a valid biomarker of cardiovascular (CV) risk in type 2 diabetes (T2D)., Methods: Red blood cell membrane fluidity, quantified as general polarization (GP), was assessed in 234 subjects with T2D, 86 with prior major CVD. Based on GP distribution, a cut-off of .445 was used to divide the study cohort into two groups: the first with higher GP, called GEL, and the second, defined as lower GP (LGP). Lipidomic analysis was performed to evaluate FA composition of RBC membranes., Results: Although with comparable CV risk factors, the LGP group had a greater percentage of patients with major CVD than the GEL group (40% vs 24%, respectively, p < .05). Moreover, in a logistic regression analysis, a lower GP value was independently associated with the presence of macrovascular complications. Lipidomic analysis showed a clear shift of LGP membranes towards a pro-inflammatory condition due to higher content of arachidonic acid and increased omega 6/omega 3 index., Conclusions: Increased membrane fluidity is associated with a higher CV risk in subjects with T2D. If confirmed in prospective studies, membrane fluidity could be a new biomarker for residual CV risk assessment in T2D., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Study Design: Systematic Review., Objective: 3DP technology use has become increasingly more common in the field of medicine and is notable for its growing utility in spine surgery applications. Many studies have evaluated the use of pedicle screw placement guides and spine models in adult spine patients, but there is little evidence assessing its efficacy in pediatric spine patient populations. This systematic review identifies and evaluates the current applications and surgical outcomes of 3-Dimensional Printing (3DP) technology in pediatric spinal surgery., Methods: A search of publications was conducted using literature databases and relevant keywords in concordance with PRISMA guidelines. Inclusion criteria consisted of original studies, and studies focusing on the use of 3DP technology in pediatric spinal surgery. Studies with a focus on adult populations, non-deformity surgery, animal subjects, systematic or literature reviews, editorials, or non-English studies were excluded from further analysis., Results: After application of inclusion/exclusion criteria, we identified 25 studies with 3DP applications in pediatric spinal surgery. Overall, the studies found significantly improved screw placement accuracy using 3DP pedicle screw placement guides but did not identify significant differences in operative time or blood loss. All studies that utilized 3D spine models in preoperative planning found it helpful and noted an increased screw placement accuracy rate of 89.9%., Conclusions: 3DP applications and techniques are currently used in pre-operative planning using pedicle screw drill guides and spine models to improve patient outcomes in pediatric spinal deformity patients., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Prerana Katiyar, Venkat Boddapati, Josephine Coury, and Benjamine Roye have no financial interests. Michael Vitale receives royalties from Zimmer Biomet, is a consultant for NuVasive and Stryker, is on the board of directors for Children’s Spine Foundation and Pediatric Orthopedic Society of North America, and has current grant/research support from Scoliosis Research Society, Children’s Spine Foundation and Pediatric Orthopedic Society of North America, and the Orthopedic Scientific Research Foundation. Lawrence Lenke has received royalties from Medtronic, consulting fees from Medtronic and Acuity Surgical, and is a reviewer for the following journals: Spine, The Spine Journal, European Spine Journal, AO Spine Deformity Knowledge Forum, JBJS, GSJ, ISSG, Spine Deformity.

Bovine tuberculosis and paratuberculosis are endemic in many areas worldwide. This work aims to study cytokines production and gene expression profiles of bovine macrophages infected with Mycobacterium bovis and Mycobacterium paratuberculosis subsp. avium (MAP) strains to identify potential diagnostic biomarkers. Bovine bone marrow stem cells were differentiated into macrophages and subsequently infected in vitro with different spoligotypes of M. bovis and MAP field strains (as single infections and coinfections), using different multiplicity of infection. Supernatant and cell pellets were collected 24 h, 48 h, and one week post-infection. Preliminarily, gene expression on cell pellets of IL-1β, IL-2, INFγ, IL-6, IL-10, IL-12, and TNFα was assessed by qRT-PCR one week p.i. Subsequently, IL-1β and IL-6 were measured by ELISA and qRT-PCR to investigated their production retrospectively 24 h and 48 h p.i. A variability in macrophages response related to the concentration of mycobacteria, the coinfection with MAP, and M. bovis spoligotypes was identified. An early and constant IL-6 increase was observed in the M. bovis infection. A lower increase in IL-1β was also detected at the highest concentration of the two M. bovis spoligotypes one week post-infection. IL-6 and IL-1 β production was reduced and differently expressed in the MAP infection. IL-6 appeared to be the earliest cytokines produced by bovine macrophages infected with M. bovis .