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Abstract Aims Vericiguat is a soluble guanylate cyclase stimulator and improves survival in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and an increased risk of decompensation. As real‐world data on how many patients could be eligible for vericiguat therapy derive from outdated registries, we aimed to assess eligibility in a prospective cohort of patients with HF. Methods and results Data from consecutive HF patients undergoing an elective ambulatory visit at five university hospitals from 3 July to 28 July 2023 were collected. Independent investigators assessed which patients (i) met the eligibility criteria of the VICTORIA trial, (ii) complied with HF guideline recommendations, (iii) met regulatory agency criteria, or (iv) met criteria for refundability according to the Italian regulatory agency. Patients (n = 346, 72% men, median age 69 years) had HFrEF in 57% of cases, left ventricular ejection fraction

Background and objective: YouTube is an open online video platform that both patients and health care professionals use to access information. Our aim was to evaluate the quality of videos related to living-donor kidney transplantation (LDKT) on YouTube. Methods: Research was conducted using the keywords “living donor kidney transplant” and “kidney transplant”. We evaluated videos with more than 10 000 views and excluded those not in English. A total of 58 videos met the criteria for inclusion in the evaluation. We used the modified DISCERN tool, the Journal of the American Medical Association (JAMA) benchmark score, and the Global Quality Score (GQS) to evaluate the quality, accuracy, and educational value. Key findings and limitations: The quality of the videos was low, with a median DISCERN score of 1 (interquartile range [IQR] 1–2), JAMA score of 1 (IQR 1–2), and GQS of 2 (IQR 1–3). The majority of the videos were of North American origin (75.9%) and focused on the patient experience (51.7%). The scores for patient experience videos were significantly lower than for other videos according to all three scoring systems (p

Background Protection provided by seasonal influenza vaccination (SIV) may be measured against numerous outcomes, and their heterogeneity may hamper decision-making. The aim of this study was to explore outcomes used for estimation of SIV efficacy/effectiveness (VE) and obtain expert consensus on their importance.Research design and methods An umbrella review was first conducted to collect and map outcomes considered in systematic reviews of SIV VE. A Delphi study was then performed to reach expert convergence on the importance of single outcomes, measured on a 9-point Likert scale, in principal target groups, namely children, working-age adults, older adults, subjects with co-morbidities and pregnant women.Results The literature review identified 489 outcomes. Following data reduction, 20 outcomes were selected for the Delphi process. After two Delphi rounds and a final consensus meeting, convergence was reached. All 20 outcomes were judged to be important or critically important. More severe outcomes, such as influenza-related hospital encounters and mortality with or without laboratory confirmation, were generally top-ranked across all target groups (median scores ≥8 out of 9).Conclusions Rather than focusing on laboratory-confirmed infection per se, experimental and observational VE studies should include more severe influenza-related outcomes because they are expected to exercise a greater impact on decision-making.

Abstract Background Patient-reported outcome (PRO) measures are essential for evaluating disease-related quality of life. The International Hip Outcome Tool 12 (iHOT12) assesses various aspects of hip-related symptoms, function, sports participation, and social limitations. This study aimed to adapt and validate an Italian version of the iHOT12 according to COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines. Materials and methods A multicenter observational cohort study was conducted to translate and validate the iHOT-12 into Italian (iHOT-12-ita) and assess its psychometric properties. Following international guidelines, we translated and culturally adapted the iHOT-12-ita. Patients with hip pain included in the study completed the iHOT-12-ita and mHHS-ita questionnaires at three timepoints: initial consultation (T0), 10–20 days later (T1), and at least 2 months after treatment (T2): hip injection, hip arthroscopy or total hip replacement. The evaluation of the iHOT-12-ita psychometric properties was conducted following the COSMIN checklist, assessing its reliability, responsiveness, interpretability, and acceptability. Results Between May 2019 to September 2022, 104 patients were included, from two tertiary hip surgery referral center clinics, they completed both questionnaires and were available for data analysis. The psychometric evaluations revealed robust test–retest reliability on 27 patients at T1, with a Lin coefficient of 0.709 [95% confidence interval (CI) 0.553–0.888] and a high Pearson correlation coefficient of 0.745. At T2 after treatment, there was significant responsiveness (p

Abstract Background . The present study aimed at deriving regression-based reliable change indices (RCIs) for the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented Parkinson’s disease (PD) patients. Methods N = 33 consecutive, non-demented PD patients were followed-up at a 5-to-8-month interval (M = 6.6; SD = 0.6) with the MoCA. Practice effects and test-retest reliability were assessed via dependent-sample t-tests and intra-class correlation (ICC) coefficients, respectively. RCIs were derived separately for raw and demographically adjusted MoCA scores according to a standardized regression-based approach by accounting for both baseline confounders (i.e., demographics, disease duration and Unified Parkinson’s Disease Rating Scale scores) and retest interval. Results No practice effects were found (t(32) = 0.29; p = .778), with acceptable test-retest reliability being detected (ICC = 0.67). MoCA scores at T0 proved to be the only significant predictor of T1 MoCA performances within both the model addressing raw scores and that addressing adjusted scores (ps

The study aimed to test if Briganti’s 2012 nomogram could be associated with the risk of prostate cancer (PCa) progression in European Association of Urology (EAU) intermediate-risk patients treated with robotic surgery. From January 2013 to December 2021, 527 consecutive patients belonging to the EAU intermediate-risk class were selected. Briganti’s 2012 nomogram, which predicts the risk of pelvic lymph node invasion (PLNI), was assessed as a continuous and dichotomous variable that categorized up to the median of 3.0%. Disease progression defined as biochemical recurrence and/or metastatic progression was evaluated by Cox proportional hazards (univariate and multivariate analysis). After a median follow-up of 95.0 months (95% confidence interval [CI]: 78.5–111.4), PCa progression occurred in 108 (20.5%) patients who were more likely to present with an unfavorable nomogram risk score, independently by the occurrence of unfavorable pathology including tumor upgrading and upstaging as well as PLNI. Accordingly, as Briganti’s 2012 risk score increased, patients were more likely to experience disease progression (hazard ratio [HR] = 1.060; 95% CI: 1.021–1.100; P = 0.002); moreover, it also remained significant when dichotomized above a risk score of 3.0% (HR = 2.052; 95% CI: 1.298–3.243; P < 0.0001) after adjustment for clinical factors. In the studied risk population, PCa progression was independently predicted by Briganti’s 2012 nomogram. Specifically, we found that patients were more likely to experience disease progression as their risk score increased. Because of the significant association between risk score and tumor behavior, the nomogram can further stratify intermediate-risk PCa patients, who represent a heterogeneous risk category for which different treatment paradigms exist.

Abstract Background The thymus, responsible for T cell-mediated adaptive immune system, has a structural and functional complexity that is not yet fully understood. Until now, thymic anatomy has been studied using histological thin sections or confocal microscopy 3D reconstruction, necessarily for limited volumes. Methods We used Phase Contrast X-Ray Computed Tomography to address the lack of whole-organ volumetric information on the microarchitecture of its structural components. We scanned 15 human thymi (9 foetal and 6 postnatal) with synchrotron radiation, and repeated scans using a conventional laboratory x-ray system. We used histology, immunofluorescence and flow cytometry to validate the x-ray findings. Results Application to human thymi at pre- and post-natal stages allowed reliable tracking and quantification of the evolution of parameters such as size and distribution of Hassall’s Bodies and medulla-to-cortex ratio, whose changes reflect adaptation of thymic activity. We show that Hassall’s bodies can occupy 25% of the medulla volume, indicating they should be considered a third thymic compartment with possible implications on their role. Moreover, we demonstrate compatible results can be obtained with standard laboratory-based x-ray equipment, making this research tool accessible to a wider community. Conclusions Our study allows overcoming the resolution and/or volumetric limitations of existing approaches for the study of thymic disfunction in congenital and acquired disorders affecting the adaptive immune system.

Background and objective: More than 10% of patients with negative clinical metastatic status (cN0M0) on conventional imaging for prostate cancer (PCa) harbor lymph node involvement (pN+) at final pathology following radical prostatectomy (RP) and lymphadenectomy. Our aim was to assess outcomes of initial observation for cN0M0 pN+ PCa and identify prognostic factors that may help in clinical decision-making. Methods: We performed a retrospective multicenter study of patients with cN0M0 PCa on conventional imaging (computed tomography and/or magnetic resonance imaging, and a bone scan) who were found to have pN+ disease at RP between 2000 and 2021. Biochemical recurrence (BCR) and systemic progression/recurrence were the primary outcomes. Kaplan-Meier curves and Cox proportional hazards model were used for survival and multivariate analysis. Key findings and limitations: A total of 469 men were included in this retrospective multicenter trial. Median prostate-specific antigen (PSA) was 10.1 ng/ml (interquartile range [IQR] 6.6–18.0). Among these patients, 56% had grade group ≥4, 53.7% had stage ≥pT3b, 42.6% had positive margins, and 19.6% had PSA persistence. The median number of positive nodes and of nodes removed were 1 (IQR 1–3) and 20 (14–28), respectively. At median follow-up of 41 mo, 48.5% experienced BCR. The 5-yr BCR-free survival rate was 31.7% (95% confidence interval [CI] 26.33–37.1%). Salvage treatments were needed in 211 patients and included radiotherapy (RT; n = 53), RT + androgen deprivation therapy (ADT; n = 88), ADT alone (n = 68), and salvage lymphadenectomy (n = 2). The 5-yr estimated survival rates were 66.3% (95% CI 60.4–72.1) for metastasis-free survival, 97.7% (95% CI 95.5–99.8%) for cancer-specific survival, and 95.3% (95% CI 92.4–98.1%) for overall survival. On multivariable analysis, PSA persistence was an independent predictor of BCR (odds ratio [OR] 51.8, 95% CI 12.2–219.2), exit from observation (OR 8.5, 95% CI 4.4–16.5), and systemic progression (OR 3.0, 95% CI 1.771–4.971). Conclusions: Initial observation in the management of pN+ cN0M0 PCa is feasible and has excellent survival rates in the intermediate term. Patients with worse disease features, especially PSA persistence, have a higher likelihood of recurrence and progression and may be candidates for more aggressive upfront management. Patient summary: We investigated the value of initial observation for men with prostate cancer with negative scan findings for metastasis who were then found to have positive lymph nodes after surgery to remove the prostate. Our results show that initial observation is a good option for patients with less aggressive prostate cancer features.

Abstract Background While immune checkpoint inhibitors (ICIs) are increasingly reshaping the therapeutic landscape of non‐small‐cell lung cancer (NSCLC), only a limited proportion of patients achieve a relevant and long‐lasting benefit with these treatments, calling for the identification of clinical and, ideally modifiable, predictors of efficacy. Body composition phenotypes may reflect aspects of patients' immunology and thereby their ability to respond to ICIs. This study aims to explore the possible association between pre‐treatment body composition phenotypes, tumour response, and clinical outcomes in patients receiving first‐line pembrolizumab monotherapy for advanced NSCLC. Methods A retrospective review of consecutive patients with treatment‐naïve NSCLC and PD‐L1 expression ≥50% undergoing pembrolizumab at three academic institutions was performed. Pre‐treatment body composition parameters were measured at the third lumbar vertebra level by computed tomography, defined using pre‐established cut‐offs. Primary endpoint was objective response rate (ORR), secondary endpoints progression‐free survival and overall survival (PFS and OS), compared through the log‐rank test and the Cox proportional hazards model. Results Data from 134 patients (93 males [69.4%] and 41 females [30.6%]) were collected. Median age was 69 years (range 36–85), with a median follow‐up of 12 months (range 1–131). The median body mass index (BMI) was 24.5 (IQR 21.5; 26.1) kg/m2. Overall, 59.0% and 51.5% of patients met established radiographic criteria for evidence of sarcopenia and myosteatosis, respectively, which occur across the BMI spectrum. Multivariate regression analysis, adjusted for co‐morbidities, revealed that sarcopenia (aOR 5.56, 95% CI. 2.46–12.6, P

Abstract Surgical repair of abdominal aortic aneurism (AAA) with horseshoe kidney (HK) is challenging because of several accessory renal arteries (RAs), variable in number, branches, and vascular territories, with subsequent variable renal damage. The identification of RAs and vascular territories could contribute to surgical planning. We developed a semiautomatic presurgical computed tomography angiography (CTA)-based model to measure the renal volume of each RA, validated on postsurgical CTA in patients with HK treated for AAA. Renal parenchyma volume was extracted on both CTAs (Vol_Totpre and Vol_Totpost) after labeling RAs ostia and vascular endpoints by two observers using a semiautomatic model by assigning each renal voxel to the closest vascular ending, obtaining volumes for each vascular territory. Number of RAs number was 4.0 ± 1.4 (mean ± standard deviation (SD)), Vol_Totpre 360 ± 76.5 cm3; kidney volume loss at surgery (KVLS) (Vol_Totpre minus Vol_Totpost) 51.9 ± 35.4 cm3; percentage of kidney loss 15.2 ± 11.6%. KVLS and predicted kidney volume loss on preoperative CTA (PKVL) were strongly correlated (r = 0.93; p = 0.023). Interobserver agreement was good (mean bias = 0.000001 ± 1.96 SD of 19.1 cm3). Presurgical semiautomatic segmentation of vascular territories in patients with HK and AAA is feasible. Relevance statement This software allowed the preoperative calculation of renal volume perfused by each renal artery in the challenging association of the horseshoe kidney and abdominal aortic aneurism. It helps to determine the feasibility of surgical resection of arteries, thereby improving surgical planning and reducing the risk of postoperative renal function deterioration. Key Points The association between horseshoe kidney and abdominal aortic aneurism is a challenging condition that may require renal vascular resection. A semiautomatic model measures renal volume perfused by each artery on preoperative computed tomography angiography with high accuracy. Customized use of this tool could improve surgical management by determining which arteries can be safely resected during surgery. Graphical Abstract

Abstract Low-cost sensors (LCS) for suspended particulate matter with an aerodynamic diameter less than or equal to 2.5 microns (PM2.5) have attracted worldwide attention for crowdsourcing air quality data. Here, we analyze one year’s worth of PM2.5 data from light-scattering LCS deployed in Monterrey, Mexico, one of the most polluted conurbations of Latin America. We also tested the Extreme Gradient Boosting (XGBoost) algorithm for classification and field calibration of the PM2.5 data derived from the LCS. Regression model performance increased from a low baseline (compared to other studies) of R 2 ≈ 0.3 to R 2 ≈ 0.5, with XGBoost outperforming the other machine learning algorithms tested. Differences in local climate and emission conditions emphasize the significance of considering regional distinctions when interpreting and comparing LCS responses and field calibration efforts. When using rank-level confusion matrices, True Positive air quality classification of predicted PM2.5 levels by XGBoost rated between 71% and 88%.

Abstract Fibromyalgia is a musculoskeletal syndrome characterized by chronic widespread pain that is often associated with systemic manifestations. Since mitochondria are the main source of cellular energy, we hypothesized that fibromyalgia syndrome (FMS) could be linked to mitochondrial impairment. Aim was to study mitochondrial dysfunction in peripheral blood mononuclear cells isolated from 50 patients with primary FMS and 20 apparently healthy controls. Although no differences in mitochondrial basal respiration were observed between patients with primary FMS and healthy controls, a lower median bioenergetic health index (BHI; − 22.1%, p = 0.03), a proxy of mitochondrial function, was found in patients. According to fibromyalgia severity score (FSS), a composite of widespread pain index and symptom severity scale, a lower median BHI (− 18.7%) was found in patients with a FSS ≥ 20 compared to those with a FSS

Abstract Patients with carotid stenosis can receive indication for either carotid endarterectomy (CEA) or carotid artery stenting (CAS), with both techniques having an impact on the autonomic function and baroreflex control. Seventy carotid stenosis patients randomly assigned to CEA or CAS were enrolled. After exclusion of some recordings, 33 CEA (age 67.79 ± 5.32 yrs, 26 males) and 25 CAS (age 70.32 ± 3.63 yrs, 14 males) were admitted to analysis. Autonomic and baroreflex sensitivity markers were derived from the analysis of heart period and systolic arterial pressure spontaneous variability derived in supine position and during active standing (STAND), before (PRE) the intervention and after a 6 and 12-month follow-up (FU6, FU12). CEA had a preserved response of autonomic and baroreflex control to STAND in PRE and FU6, suggesting an early improvement. CAS had a similar response at PRE but a blunted one at the follow-ups. When directly compared, the two groups had a similar autonomic function, with CAS having a reduced baroreflex control in PRE and lower autonomic function at FU6. All the differences disappeared at the long-term follow-up, showing a similar long term effect of the surgical procedures, suggesting that CEA and CAS induced a similar long-term impairment of autonomic and baroreflex controls.

Abstract An interconnected system employing Kinect Azure and Fitbit Sense for continuous and non-intrusive data collection was used in the PRO-HOME protected discharge program, aiming at monitoring functional and clinical parameters in hospitalized older patients at different risks of frailty. The present study shows the findings on 30 older patients included in the PRO-HOME project. The Fitbit Sense recorded the mean daily and hourly number of steps, mean daily walked distance, and time spent inactive. Moreover, Kinect infrared camera captured gait speed and daily mean latero-lateral (body sway) and antero-posterior oscillations (lean-in). Patients underwent a standard Comprehensive Geriatric Assessment (CGA) to compute the Multidimensional Prognostic Index (MPI), including basic and instrumental activities of daily living (ADL, IADL), cognition (Short Portable Mental Status Questionnaire, SPMSQ) and nutrition, risk of pressure sores (Exton-Smith Scale, ESS), comorbidity, number of drugs and cohabitation status. Significant correlations between the mean hourly number of steps and MPI (p = 0.022), IADL (p = 0.013), SPMSQ (p = 0.006), ESS (p = 0.009), and both mean and maximum automated gait speed (p = 0.046 and p = 0.048) were found. Automated gait speed was also correlated with mean walked distance per day (p = 0.007) and lean-in (p = 0.047). Domotic technological monitoring through Fitbit Sense and Kinect Azure provides information on multidimensional frailty, including mobility and cognitive and functional status, in older people.

Abstract Background Despite adequate treatment, a subgroup of patients with inflammatory bowel disease (IBD), including Crohn`s disease and ulcerative colitis, have persistent gastrointestinal symptoms that are not always related to mucosal damage. Recently, two autoantibodies, anti-CdtB and anti-vinculin, were validated as post-infectious IBS (PI-IBS) markers, however there is limited evidence of its diagnostic role in IBD population. Methods Patients with more than 3 bowel movements/day and indication of colonoscopy were enrolled. Samples were collected at the time of colonoscopy for assessment of serum levels of anti-CdtB and anti-vinculin antibodies. Results A total of 160 subjects were included in 4 groups: active IBD (n = 44); quiescent IBD and chronic diarrhea IBD-IBS (n = 25); predominant-diarrhea IBS (n = 45) and controls (n = 46). The mean value of the optical density for anti-CdtB was 1.2 ± 0.65 in group 1, 1.27 ± 0.64 in group 2, 1.49 ± 0.47 in the group 3 and 1.6 ± 0.68 in group 4, p = 0.012. For anti-vinculin, optical densities were: 1.34 ± 0.78 in group 1, 1.46 ± 0.92 in group 2, 1.31 ± 0.79 in group 3 and 1.41 ± 0.86 for controls (p = 0.875). Using a cut-off of 1.56 for anti-CdtB, the positivity between groups was n = 10 (22.7%) in group 1, n = 9 (34.6%) in group 2, 19 (43.2%) in group 3, 21 (45.7%) in group 4 (p = 0.106). The positivity of anti-vinculin using a cut-off of 1.6 was n = 18 (40.9%) in group 1, n = 11 (42.3%), n = 15 (34.1%), n = 22 (47.8%) (p = 0.622). Conclusions Our findings show that anti-CdtB and anti-vinculin could not identify IBD-IBS patients or discriminate IBS-D from healthy controls.

Abstract Artificial intelligence (AI)-based drug discovery has not yet completely addressed the numerous and varied challenges posed by the inherent complexities and demands of achieving breakthroughs in drug discovery (DD). This review explores the promising role of advanced AI platforms in navigating the complex landscape of biopharmaceutical DD. A thorough examination of challenges, methodologies, and the pivotal role of AI outlines a vision for a more efficient, innovative, and transformative DD process. Using the cutting-edge Dompé Exscalate platform as a case study, this review describes how AI can address the diverse challenges that have long hampered progress in the field. By adopting a transformative approach in DD, the Exscalate platform exemplifies an AI-driven paradigm capable of not only streamlining the identification of promising molecular candidates but also improving prediction accuracy and the development of targeted therapeutics. Exploring the convergence of machine learning, deep learning, and high-performance computing, the article describes a landscape in which AI-integrated platforms blend technological and biological disciplines seamlessly. This synergy, encompassing physics-based simulations, generative modeling, and extensive molecular databases, has significant implications for both the scientific community and the pharmaceutical industry and will lead to notable improvements in both efficiency and innovation in biopharmaceutical DD.

Abstract Background In diagnosing chronic orthopedic implant infections culture of sonicate represents a supplement to tissue cultures. However, the extent to which biofilm forms on implant surfaces and the degree of dislodgement of bacteria by sonication remains unclear. In this in vivo study using a low bacterial inoculum, we aimed to determine whether a variable effect of sonication could be observed in a standardized in vivo model. Materials and Methods Seven Wistar rats underwent surgery with intramuscular implantation of two bone xenograft implants, each containing two steel plates. The grafts were inoculated with approximately 500 colony forming units (CFU) of Staphylococcus epidermidis ATCC 35984. After 20 days the rats were sacrificed, and the steel plates were removed from the bone grafts. Epifluorescence microscopy and scanning electron microscopy (SEM) were used to visualize biofilm formation and dislodgement on the plate surfaces. In addition to cultures of sonicate, a quantitative S. epidermidis specific PCR was developed for enumeration of bacteria. Results A chronic, low-grade implant infection was successfully established, with all animals remaining in good health. All infected bone graft implants yielded abundant growth of S. epidermidis, with a median of 3.25 (1.6–4.6) × 10⁷ CFU per/graft. We were unable to distinguish infected plates from negative controls using epifluorescence microscopy. On infected plates small colonies of staphylococci were identified by SEM. The number of bacteria detected in the sonicate was low with 500 (100–2400) CFU/plate and 475 (140–1821) copies/plate by qPCR. The difference in area covered by fluorescent material before and after sonication was 10.1 (5.7–12.3) %, p = 0.018. Conclusion Despite the pronounced infection in the surrounding tissue, only few bacteria were detected on the surface of the steel implants. This is evident from the minimal findings by SEM before sonication, as well as the very low CFU counts and DNA copies in the sonicate. Sonication did not show variable effectiveness, indicating it is a valuable addition to, but not a replacement for biopsy cultures in cases of implant-associated infections with low-virulence microorganisms.

Abstract Connexins (Cxs) are fundamental in cell–cell communication, functioning as gap junction channels (GJCs) that facilitate solute exchange between adjacent cells and as hemichannels (HCs) that mediate solute exchange between the cytoplasm and the extracellular environment. Mutations in the GJB1 gene, which encodes Cx32, lead to X-linked Charcot-Marie-Tooth type 1 (CMTX1), a rare hereditary demyelinating disorder of the peripheral nervous system (PNS) without an effective cure or treatment. In Schwann cells, Cx32 HCs are thought to play a role in myelination by enhancing intracellular and intercellular Ca2+ signaling, which is crucial for proper PNS myelination. Single-point mutations (p.S85C, p.D178Y, p.F235C) generate pathological Cx32 HCs characterized by increased permeability (“leaky”) or excessive activity (“hyperactive”). We investigated the effects of abEC1.1-hIgG1, a fully human immunoglobulin G1 (hIgG1) monoclonal antibody, on wild-type (WT) and mutant Cx32D178Y HCs. Using HeLa DH cells conditionally co-expressing Cx and a genetically encoded Ca2+ biosensor (GCaMP6s), we demonstrated that mutant HCs facilitated 58% greater Ca2+ uptake in response to elevated extracellular Ca2+ concentrations ([Ca2+]ex) compared to WT HCs. abEC1.1-hIgG1 dose-dependently inhibited Ca2+ uptake, achieving a 50% inhibitory concentration (EC50) of ~ 10 nM for WT HCs and ~ 80 nM for mutant HCs. Additionally, the antibody suppressed DAPI uptake and ATP release. An atomistic computational model revealed that serine 56 (S56) of the antibody interacts with aspartate 178 (D178) of WT Cx32 HCs, contributing to binding affinity. Despite the p.D178Y mutation weakening this interaction, the antibody maintained binding to the mutant HC epitope at sub-micromolar concentrations. In conclusion, our study shows that abEC1.1-hIgG1 effectively inhibits both WT and mutant Cx32 HCs, highlighting its potential as a therapeutic approach for CMTX1. These findings expand the antibody’s applicability for treating diseases associated with Cx HCs and inform the rational design of next-generation antibodies with enhanced affinity and efficacy against mutant HCs.

Abstract Background Hemorrhoidal disease (HD) is associated with substantial economic burden and negative effects on health-related quality of life (HRQoL). The aCute HaemORrhoids treatment with MESoglycan (CHORMES) study aims to evaluate the effects of orally administered mesoglycan, a natural preparation of glycosaminoglycans with antithrombotic and profibrinolytic properties, as an acute treatment in patients with HD. Methods CHORMES is a phase 2, double-blind, randomized controlled trial being conducted at two centers in Italy. Adults aged 18–75 years with Grade I–III HD according to Goligher classification or external thrombosed hemorrhoids, and a Hemorrhoidal Disease Symptom Score (HDSS) of ≥ 5, will be randomly allocated in a 1:1 ratio to mesoglycan or placebo and will be treated for 40 days (two capsules for the first 5 days and one capsule for the subsequent 35 days twice daily [after breakfast and dinner], equivalent to 200 mg in the first 5 days and 100 mg subsequently). Concomitant use of analgesics is permitted in both treatment groups. The trial aims to enroll 50 patients, with 25 patients in each treatment group. The primary objective of the trial is to evaluate the efficacy of mesoglycan in reducing symptoms of HD, assessed via change in HDSS from baseline (day 0) to day 40 in the intention-to-treat population. Secondary objectives include changes in HRQoL from baseline to day 40 using the Short Health Scale for Hemorrhoidal Disease, safety (adverse effects, physical assessments, vital signs and laboratory parameters in the safety population), fecal continence assessed using the Vaizey score, bleeding assessed using the Bleeding score, the amount and type of analgesic taken, and pain. Patient enrolment began on 11 December 2023, and trial completion is expected by December 2024. Discussion The CHORMES trial will evaluate the efficacy and safety of mesoglycan, in addition to its impact on HRQoL, analgesic use and pain, in patients with HD. The results of the trial will assist clinicians in determining the most effective treatment for patients with HD. Trial registration ClinicalTrials.gov NCT06101992. Prospectively registered on 26 October 2023 at https://clinicaltrials.gov/ct2/show/NCT06101992 .

Background: The impact of behavioral habits such as exercise on the physical health of prostate cancer (PCa) patients is poorly understood. We aimed to investigate PCa patients' exercise habits and the association between exercise and self-reported physical health status. Methods: The 2016–2020 Behavioral Risk Factor Surveillance System (BRFSS) databases were used to identify men with a history of PCa. We identified patients with self-reported PCa diagnosis and excluded the non-male gender respondents in the self-reported PCa patients. We performed descriptive statistics and multivariable logistic regression analysis examining the association between exercise and poor physical health status. Our exposure of interest was the amount of physical exercise, and primary outcome was poor physical health status, defined as >14 self-reported days per month when patients felt “physical health is not good.” Covariates included age, body mass index (BMI), income, treatment, smoking, and exercise frequency. Results: From 2,193,981 weighted survey participants, we identified 3,952 men with a history of PCa. Of these, 75% of participants reported exercise within the last month. In adjusted analyses among men with a history of PCa, exercise (OR 0.50, 95% CI 0.40–0.64, P

Background: Pulmonary hypertension (PH) is a pathophysiological problem that may involve several clinical symptoms and be linked to various respiratory and cardiovascular illnesses. Its diagnosis is made invasively by Right Cardiac Catheterization (RHC), which is difficult to perform routinely. Aim of the current study was to develop a Machine Learning (ML) algorithm based on the analysis of anamnestic data to predict the presence of an invasively measured PH. Methods: 226 patients with clinical indication of RHC for suspected PH were enrolled between October 2017 and October 2020. All patients underwent a protocol of diagnostic techniques for PH according to the recommended guidelines. Machine learning (ML) approaches were considered to develop classifiers aiming to automatically detect patients affected by PH, based on the patient’s characteristics, anamnestic data, and non-invasive parameters, transthoracic echocardiography (TTE) results and spirometry outcomes. Results: Out of 51 variables of patients undergoing RHC collected, 12 resulted significantly different between patients who resulted positive and those who resulted negative at RHC. Among them 8 were selected and utilized to both train and validate an Elastic-Net Regularized Generalized Linear Model, from which a risk score was developed. The AUC of the identification model is of 83 % with an overall accuracy of 74 % [95 % CI (61 %, 84 %)], indicating very good discrimination between patients with and without the pathology. Conclusions: The PH-targeted ML models could streamline routine screening for PH, facilitating earlier identification and better RHC referrals.

Background and objective: Clinical practice guidelines for prostate cancer (PCa) are a valuable resource for everyday clinical practice. The clinical practice guidelines and recommendations produced by various societies should demonstrate a considerable level of consistency in terms of quality, regardless of the society that developed these given the common evidence base. However, to date, no study has assessed the quality of PCa clinical practice guidelines. As part of the Optimal Treatment for Patients with Solid Tumours in Europe Through Artificial intelligence (OPTIMA) project, we evaluated the quality of the most frequently used national and international clinical practice guidelines for PCa using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) tool. Methods: The quality of the identified clinical practice guidelines was assessed independently by two assessors using the AGREE II tool. The AGREE II tool comprises 23 different items organised into six domains, rated on a 7-point scale (1: strongly disagree to 7: strongly agree). The total score of the appraisal was the mean value of the two assessments. The agreement between assessors’ scores was calculated using the interclass correlation coefficient (ICC). Four key recommendations were compared among the included clinical practice guidelines to assess consistency. Key findings and limitations: Sixteen clinical practice guidelines were assessed using their latest available version (cut-off April 2024). The European Association of Urology, S3LL PCa, Belgian Health Care Knowledge Centre, National Comprehensive Cancer Network, and Prostatacancer—Nationellt vårdprogram guidelines received the highest overall scores with a mean domain score of 82.4% (range: 75.5–88.3%). The de l’Association Française d’Urologie (AFU), American Urological Association, and National Institute for Health and Care Excellence received a mean domain score of 77.6% (range: 73.7–84.0%). Below average were the European Society for Medical Oncology, localised (L) and systemic (S) CPPC American Society of Clinical Oncology, and Nederlandse Vereniging voor Urologie (NVU) with a mean domain score of 58.4% (range: 43.5–76.3%). The reasons for scoring below average included the following: inadequate information about the methodology applied, limited scope of the guideline, and limited patient engagement. The highest inter-rater variability was observed in NVU (ICC: 0.58) and the lowest in AFU-L (ICC: 0.84). When examining the scores of each domain, “clarity of presentation” (domain 4) achieved the highest score with a mean of 86.9% ± 12.6%. The domain with the lowest score was applicability (domain 5), with a mean of 48.3% ± 24.8%. The ICC was calculated to be 0.72 (±0.08). Conclusions and clinical implications: This is the first study in which a comprehensive quality assessment of the majority of international and national clinical practice guidelines was undertaken, and the key recommendations were compared to assess consistency. Our study shows that the majority of international and national clinical practice guidelines demonstrate high-quality standards when assessed using the AGREE II evaluation tool. The clinical practice guidelines that did not meet the expected standards could be improved by adopting several key recommendations outlined by our study. Patient summary: The OPTIMA project used the Appraisal of Guidelines for Research & Evaluation II (AGREE II) tool to evaluate the quality of 16 commonly used national and international clinical practice guidelines for prostate cancer. While some of these international and national clinical practice guidelines received the highest score, few guidelines scored below average due to methodological deficiencies and limited patient engagement. These findings highlight the need for a standardised process to ensure high-quality, consistent guidelines across practices.

We report a patient with lobomycosis caused by Paracoccidioides loboi fungi in the Andes-Amazon region of Bolivia. We examined clinical, epidemiologic, and phylogenetic data and describe potential transmission/environmental aspects of infection. Continued surveillance and identification of lobomycosis cases in South America are crucial to prevent the spread of this disease.

The tumor suppressor TP53 is frequently mutated in hormone receptor-negative, HER2-positive breast cancer (BC), contributing to tumor aggressiveness. Traditional ancillary methods like immunohistochemistry (IHC) to assess TP53 functionality face pre- and post-analytical challenges. This proof-of-concept study employed a deep learning (DL) algorithm to predict TP53 mutational status from H&E-stained whole slide images (WSIs) of BC tissue. Using a pre-trained convolutional neural network, the model identified tumor areas and predicted TP53 mutations with a Dice coefficient score of 0.82. Predictions were validated through IHC and next-generation sequencing (NGS), confirming TP53 aberrant expression in 92 % of the tumor area, closely matching IHC findings (90 %). The DL model exhibited high accuracy in tissue quantification and TP53 status prediction, outperforming traditional methods in terms of precision and efficiency. DL-based approaches offer significant promise for enhancing biomarker testing and precision oncology by reducing intra- and inter-observer variability, but further validation is required to optimize their integration into real-world clinical workflows. This study underscores the potential of DL algorithms to predict key genetic alterations, such as TP53 mutations, in BC. DL-based histopathological analysis represents a valuable tool for improving patient management and tailoring treatment approaches based on molecular biomarker status.

Soy contributes to the environmental impact of Italian pork production. This study aimed to evaluate the effect of a reduced soybean meal (SBM) and crude protein (CP) finishing diet on growth performance, health, behaviour and gut health of Italian heavy pigs. 1920 pigs (35.6 kg body weight; (BW)) balanced by sex and BW were assigned to the control diet (CO), or the treated diet (TRT) formulated by reducing SBM by 31%, 67% and 69% (replaced by pea and sunflower meal) in 3 feeding phases, respectively, and 1.2% CP in the third phase. 251 pigs were individually weighed at d11, d94 and d181. Feed intake (FI), behavioural indices and air gases at pen-level were monitored monthly. Faecal samples (20/pigs/group) for microbiota, ammonia and volatile fatty acids (VFAs) and hair for stress biomarkers were collected. Diet did not affect final BW, faecal ammonia, cortisol and dehydroepiandrosterone. From d11–d94, the CO group had higher gain to feed (G:F) (p = .007), favourable faecal VFAs profile and a lower environmental ammonia (p

Objectives: Correct identification and management of Developmental Defects of Enamel (DDEs) are essential to provide the best possible treatment. The present survey aims to investigate Italian dentists’ knowledge of DDEs, their ability to recognise the different clinical pictures, and to choose the most appropriate clinical approach. Methods: A cross-sectional survey was planned based on a questionnaire including 27 closed-ended questions, and that proposed 4 clinical pictures, molar incisor hypomineralisation (MIH), amelogenesis imperfecta (AI), dental fluorosis (DF), and an initial caries lesion (ICL). It was distributed by e-mail to all Italian dentists (N = 63,883) through the Italian Federation of Doctors and Dentists. Discrete variables were expressed as absolute and relative frequencies (%). A multivariate analysis assessed whether socio-demographic variables correlated with the answers’ truthfulness. Results: About 5017 questionnaires were included and analysed. Although 90.19% of the sample stated that they had received information on DDEs, a significant percentage did not recognise MIH (36.36%), AI (48.34%), DF (71.50%), and ICL (46.62%). Only 57.07% correctly classified enamel hypomineralisation as a qualitative defect, and even fewer, 54.45%, classified enamel hypoplasia as a quantitative defect. According to the logistic regressions, female dentists, dentists who treat mainly children and received information about DDEs, were more likely to recognise the 4 clinical pictures (P < .01). Conclusions: Italian dentists showed many knowledge gaps on DDEs that need to be filled; those who received formal training were more capable of correctly identifying the defects and were more likely to prescribe an appropriate management approach for the defects. Clinical significance: Increasing university courses and continuing education on diagnosing and managing DDEs seems reasonable to fill the knowledge gap on DDEs.

Background and objective: In the literature, no studies correlate the effects of mandibular advancement devices (MADs) with different titration systems to periodontitis. Through a finite element analysis (FEA), this study investigates the effects generated on periodontal ligaments (PDLs) and teeth by four commercial MADs in periodontal health and with 15% bone resorption. Methods: Four MADs (Somnodent Flex™, Somnodent Avant™, Orthoapnea™, and Herbst™) were digitalised starting from the impressions of a patient's dental arches. A force of 11.18 N, representing an advancement of 9.5 mm, was applied, and a FEA was subsequently performed. After measuring the stresses and displacements on the PDLs and teeth in healthy periodontal conditions, the vertical dimension of the alveolar bone was reduced by 15%, and measurements were repeated. Results: In terms of PDL stress, Herbst™ is the device which guarantees a more uniform increment in case of the first stage of periodontitis (+7% for mandibular and maxillary PDLs compared to the healthy condition). For Somnodent™ devices, the PDLs stress increment is almost null for mandibular PDLs but much higher than Herbst™ for maxillary PDLs (+17% and +21% for Flex™ and Avant™). Orthoapnea™ determines a PDL stress augmentation between the other devices (+16% and +7%, respectively, for maxillary and mandibular PDLs). Concerning teeth movement, Herbst™ and Orthoapnea™ determine a lower and more uniform displacement than Somnodent devices. Conclusions: The stress distribution and teeth displacement are strictly related to MAD geometry. Since its minor effects on teeth and PDLs, the Herbst™ could be more appropriate in patients with periodontitis.

Data on acute coronary syndrome (ACS) is lacking in Africa where cases of premature ACS seem to be on the rise. Africa would benefit from an epidemiological assessment of premature ACS to determine its risk factors and management in this demographic to inform guidelines and practice. The European Atherosclerosis Society recognised this urgency and formed a growing network across 11 African countries to create the Lipid Registry of Africa (EAS-LIPRA). This article is based on the EAS-LIPRA protocol and presents the aims, concept and methodological considerations, and the operations and collaborative governance structure of this project. EAS-LIPRA aims to report risk factors and outcomes of premature ACS in Africa to further understand its prevalence and management via collating and pooling multinational prospective data on premature ACS across multiple sites in Africa into a standardised registry. Data will be stratified into subgroups based on country-level income as defined by the World Bank, and within country residence of urban versus rural areas. Valid statistical procedures will be employed to compare and observe trends in the pooled data based on demographics, clinical and laboratory variables, and disparities in its management. Being the first multinational lipid registry in Africa, it is envisaged that the network will expand to other African countries and sites yet to participate, facilitate other epidemiological studies in preventive cardiology, and set a precedent for other developing countries and regions.

Efficient design, production, and optimization of new safe and sustainable by design materials for various industrial sectors is an on-going challenge for our society, poised to escalate in the future. Wood-based composite materials offer an attractive sustainable alternative to high impact materials such as glass and polymers and have been the focus of experimental research and development for years. Computational and AI-based materials design provides significant speed-up the development of these materials compared to traditional methods of development. However, reliable numerical models are essential for achieving this goal. The AI-TranspWood project, recently funded by the European Commission, has the ambition to develop such computational and AI-based tools in the context of transparent wood (TW), a promising composite with potential applications in various industrial fields. In this project we advance the development specifically by using an Artificial Intelligence (AI)-driven multiscale methodology.

The consequences of climate change are becoming a relevant issue also for the livestock industry in temperate countries. Transgenerational studies outlined the effect of the ancestors’ calving season, considered as an indicator of the period during which pregnancy occurs, on their female progeny performance. The aim of this study was to evaluate the effect of great granddam (F0) calving month on their great granddaughters (F3) Test Day (TD) records for milk production. A total of 414,069 TD records of milk, fat, and protein yields from 27,224 Italian Simmental F3 cows was analysed with a mixed linear model with year of calving, parity, age at parity, F0 calving month, days in milk class, the interactions between DIM and F0 calving month and between parity and F0 calving month, F3 calving date and the random effects of herd-test date and animal. The F0 calving month significantly influenced F3 performance for the three considered traits; largest F3 TD records were obtained for F0 calvings occurring in October, smallest for February. The largest milk production of F3 cows were observed when their F1 conceptions occurred in winter. Results were confirmed by a further analysis considering the calving seasons of F0, F1 and F2. The effect of F0 calving month (associated with the conception of F1) on milk production decreased as F3 parity increased. Results of this study suggest that the period of ancestor pregnancy and conception affects milk production traits of further generations also in temperate climates.

Background: Nitrous oxide (N2O) use in recreational settings has been increasing in Sweden and Europe and consequently, the related injuries are also increasing. We aimed to investigate the incidence, management, and surgical outcomes of frostbite injury (FI) related to N2O use. Material and Method: All patients in a 22-month period from 2021 to 2022 presenting with FI related to N2O abuse from 2 plastic surgery clinics (1 national burn center) were identified. Data regarding patient comorbidity, mechanism of injury, initial management, treatment, and follow-up were investigated. Complications following surgery were categorized into minor (treated in outpatient setting) and major (requiring reoperation) complications. Results: In total, 9 patients were identified; among them, 5 patients provided consent and were included in the study. Direct contact with the gas canister was the most common injury mechanism (n = 4). All but 1 patient contracted full-thickness injuries, and these 4 patients later required surgery. The medial thigh was the most common area of injury. Outpatient clinic visits were common (mean 4.8 visits/patient). Surgical complications were common and all operated patients were diagnosed with minor complications and half of them with major complications (wound dehiscence and scar contracture). Conclusion: Frostbite injuries arising from recreational N2O use are complex and often require surgical intervention that may lead to complications. With the increasing incidence of N2O abuse in Sweden, further research is crucial to address this emerging public health concerns and optimize treatment strategies for these distinctive injuries.

The fact that lipoprotein(a) levels should be regarded as a causal residual risk factor in the atherosclerotic cardiovascular diseases (ASCVD) is now a no-brainer. This review article aims to summarize the latest evidence supporting the causal role of lipoprotein(a) in ASCVD and the potential strategies to reduce the lipoprotein(a) burden until clinical trial results are available. Epidemiological and genetic data demonstrate the causal link between lipoprotein(a) and increased ASCVD risk. That being said, a specific question comes to mind: “must we wait for outcome trials in order to take action?”. Given that lipoprotein(a) levels predict incident ASCVD in both primary and secondary prevention contexts, with a linear risk gradient across its distribution, measuring lipoprotein(a) can unequivocally help identify patients who may later benefit from specific lipoprotein(a)-lowering therapies. This understanding has led various National Societies to recommend dosing lipoprotein(a) in high-risk individuals and to support the recommendation of measuring lipoprotein(a) levels at least once in every adult for risk stratification.

This study aimed to evaluate the influence of different plant species widespread in alpine pastures on in vitro rumen fermentation parameters and methane kinetic production. A total of 11 plant species were sampled at the beginning of the grazing season and used as substrates in an in vitro batch fermentation system. After 24h of fermentation, plants affected volatile fatty acids profiles, ammonia yield, and dry matter (DM) digestibilities. Carum carvi, Ranunculus. acris and Festuca rubra showed the highest total production of methane per unit of digested DM while Potentilla erecta was the species that produced less methane. In terms of methane as a percentage of the total gas, F. rubra had the highest value (28.9%) while R. acris had the lowest (24.2%). Total gas and methane production were monitored continuously and the percentage of methane in total gas was fitted with the Gompertz model. Plants differed significantly (p < .01) in methane production kinetics, including production rate decline (A), asymptotic methane concentration (B), time to maximum fermentation rate (TMFR), and maximum fermentation rate (MFR). C. carvi, Prunella grandiflora, and R. acris showed high values of MFR and the top values in the production rate decline (A > 0.9). The two grasses (F. rubra and Poa alpina) together with Hypericum maculatum showed an opposite behaviour with low values in MFR, A and a longer TMFR. The results of the methane production kinetics allow for an in-depth evaluation of plant species, adding further information to those registered at the end of fermentation.

The Antisecretory Factor (AF) is a protein that can reduce intestinal hypersecretion and various inflammation disorders in vivo. Discovered in many mammalian tissues and plasma, its mechanism of action remains unknown. Interestingly, its induction has been found to counteract vertigo in patients with Méniere's disease. This suggests an inherent ability to control body balance and posture, an activity that may play a role in cerebellar function. Therefore, it may be worthwhile to investigate whether this activity can inhibit neuronal cells involved in cerebellar circuitries and its potential action on enteric nervous system ganglia, which could explain its antisecretory effect in the intestine.Previously, we studied the role of AF on GABAA receptors in cerebellar granule cells, taking advantage of electrophysiology and evaluating the effects of the administration of AF-16, an AF peptide. Treatment with AF-16 increased GABAA receptor responses, especially those containing the α6 subunit. Here, we performed immunofluorescence experiments by staining α1 and α6 subunits before and after incubation with AF-16, analyzed super-resolved images comparing pre- and post-treatment maps and critically examined these experimental results with our previous electrophysiological data to shed light on the mechanisms of action of AF protein on GABAA receptor subpopulations, specifically the ''fast'' receptors of αn β2/3 γ2 composition that contain either the α1 or the α6 subunit.The results indicate that the α6 subunit is redistributed, with a decrease in neurites and an increase in soma. Conversely, the α1 subunit shows opposite results, with an increase in neurites and a decrease in soma.

The Anglo-Arabian horse breed (AA) is the result of crossing between Thoroughbred and Arabian horses renowned for versatility in show-jumping and racing. Southwest France and Sardinia in Italy are considered the historical nucleus of European AA breeding. Since little is known on genetic variability in the AA breed, especially those bred in the Sardinia region, this study investigates: i) inbreeding levels via pedigree and SNP genotyping; ii) runs of homozygosity (ROH) and selection signatures; iii) effective population size; and iv) distinctiveness of AA compared to Arabian and Thoroughbred horses. The ROH revealed an excessive amount of homozygosity, with a high kurtosis value observed in several chromosomes and an average inbreeding based on ROH of 21.1%. This latter value is higher compared to what was found based on pedigree data, highlighting the importance of complete pedigree records when estimating inbreeding based on genealogical data. The genomic inbreeding in AA horses was higher compared to other Italian horse breeds but lower than what was found in pure Thoroughbred and Arabian horses. This result suggests that the selection process for AA horses, may have prioritised racing ability over breed preservation which is the main goal in most local Italian breeds. The reduction in effective population size found in the latest 20 generations corroborates the potential presence of genetic diversity reduction due to selection in the AA breed. Remarkably, a large ROH island was identified on ECA17, which overlapped with two QTLs associated with racing performance.

Gut microbiota is recognized nowadays as one of the key players in the development of several gastro-intestinal diseases. The first studies focused mainly on healthy subjects with staining of main bacterial species via culture-based techniques. Subsequently, lots of studies tried to focus on principal esophageal disease enlarged the knowledge on esophageal microbial environment and its role in pathogenesis. Gastro Esophageal Reflux Disease (GERD), the most widespread esophageal condition, seems related to a certain degree of mucosal inflammation, via interleukin (IL) 8 potentially enhanced by bacterial components, lipopolysaccharide (LPS) above all. Gram- bacteria, producing LPS), such as Campylobacter genus, have been found associated with GERD. Barrett esophagus (BE) seems characterized by a Gram- and microaerophils-shaped microbiota. Esophageal cancer (EC) development leads to an overturn in the esophageal environment with the shift from an oral-like microbiome to a prevalently low-abundant and low-diverse Gram--shaped microbiome. Although underinvestigated, also changes in the esophageal microbiome are associated with rare chronic inflammatory or neuropathic disease pathogenesis. The paucity of knowledge about the microbiota-driven mechanisms in esophageal disease pathogenesis is mainly due to the scarce sensitivity of sequencing technology and culture methods applied so far to study commensals in the esophagus. However, the recent advances in molecular techniques, especially with the advent of non-culture-based genomic sequencing tools and the implementation of multi-omics approaches, have revolutionized the microbiome field, with promises of implementing the current knowledge, discovering more mechanisms underneath, and giving insights into the development of novel therapies aimed to re-establish the microbial equilibrium for ameliorating esophageal diseases..

Cortisol is the primary biomarker associated with the hypothalamic–pituitary–adrenal (HPA) axis. This research aimed at assessing the predictive potential and the relationship of cortisol concentrations in four media (blood, milk, whey and hair) with parity, lactation stage and productive classes. Multiparous (n = 30) and primiparous (n = 38) Italian Mediterranean buffaloes were used and assigned to four productive classes (based on percentiles of mature equivalent milk yield (EMY) and mature equivalent energy corrected milk (eECM)), and cortisol concentrations were measured using a in house radioimmunoassay (RIA) method. Parity did not show a significant effect on cortisol concentrations of the four media. The catabolic stage of lactation (up to 90 d in milk (DIM)) was characterised by higher cortisol concentrations compared to the second anabolic stage (beyond 150 DIM) in milk formulations. The plasmatic concentrations of cortisol were higher at the catabolic and the first anabolic stage (91–150 DIM) compared to the second anabolic (p = 0.022 and p = 0.009, respectively). Buffaloes beyond 150 DIM differed from those below 90 DIM (p

ABSTRACTInfectious prions are resistant to degradation and remain infectious in the environment for several years. Chronic wasting disease (CWD) has been detected in cervids inhabiting North America, the Nordic countries, and South Korea. CWD-prion spread is partially attributed to carcass transport and disposal. We employed a forensic approach to investigate an illegal carcass dump site connected with a CWD-positive herd. We integrated anatomic, genetic, and prion amplification methods to discover CWD-positive remains from six white-tailed deer (Odocoileus virginianus) and, using microsatellite markers, confirmed a portion originated from the CWD-infected herd. This approach provides a foundation for future studies of carcass prion transmission risk.

Introduction Different COVID-19 vaccines are being utilized as boosters. This systematic review and meta-analysis aims to evaluate the reactogenicity of COVID-19 vaccines given as booster doses, according to vaccine type, dose, timing, participant characteristics and primary immunization regimen received.Methods Four databases (MEDLINE, Embase, Web of Science and CENTRAL) were searched for randomized controlled trials between 1 January 2020 and 1 January 2023 according to predetermined criteria.Results Twenty-eight studies describing 19 vaccines of four different types (viral vector, inactivated, mRNA and protein sub-unit) were identified. BNT162b2 vaccine (Pfizer-BioNTech) was selected as the control as it was most often compared with other vaccines. Fever, fatigue, headache, injection-site pain, redness, and swelling were the most frequently reported solicited events. mRNA vaccines were the most reactogenic, followed by viral vector vaccines and protein sub-unit vaccines, while inactivated vaccines were the least reactogenic. Full-dose vaccines were more reactogenic than half-dose vaccines. Heterologous BNT162b2 boosters were more reactogenic than boosters with the same vaccine used for primary immunization.Conclusions COVID-19 vaccine booster schedules have distinct reactogenicity profiles, dependent on dose and vaccine type, which may allow targeted recommendations and provide choice for specific populations. Greater standardization of adverse event reporting will aid future studies.

The identification of mechanisms capable of modifying genetic information by the addition of covalent RNA modifications distinguishes a level of complexity in gene expression which challenges key long-standing concepts of RNA biology. One of the current challenges of molecular biology is to properly understand the molecular functions of these RNA modifications, with more than 170 different ones having been identified so far. However, it has not been possible to map specific RNA modifications at a single-cell resolution until very recently. This review will highlight the technological advances in single-cell methodologies aimed at assessing and testing the biological function of certain RNA modifications, focusing on m6A. These advances have allowed for the development of novel strategies that enable the study of the ‘epitranscriptome’. Nevertheless, despite all these improvements, many challenges and difficulties still need fixing for these techniques to work efficiently.

The study investigated the effects of housing conditions and temperature-humidity index (THI) during the dry period on total bacteria counts of bedding material, animal cleanliness, and teat bacterial contamination on 212 cows from three farms. Additionally, milk yield, quality, total somatic cells, and leucocyte fractions were evaluated in the subsequent lactation on a subgroup of 119 cows. The results showed a relationship between persistent high THI, teat bacterial contamination, and pathogens on teat skin. Somatic cell count (SCC) in milk at the beginning of the next lactation was not affected by THI during the dry period. Multiple correlation analysis revealed a relationship among high milk SCC, high percentage of neutrophils, high bacterial count of bedding during the dry period, and high milk production at dry-off. The study confirms that critical environmental conditions, such as high THI and poor bedding hygiene, during the dry period, can affect teat bacterial contamination and increase the risks for high SCC in the next lactation. High milk production at dry-off may be another risk factor.

Abstract Human milk proteins, a mixture of whey proteins including caseins, milk fat globule membrane (MFGM) proteins, various peptides, and their amino acids, play a crucial role in infant growth and development, as do non-nutritional bioactive components. The extracellular nicotinamide phosphoribosyltransferase (eNAMPT) or visfatin is a conserved cytokine/enzyme released by many mammalian cells, related to multiple metabolic and immune processes. Few investigations have been reported about detecting visfatin in skimmed milk and the hypothesis of its potential role in regulating infant adiposity through breast milk. Milk samples from a donated human milk bank were analyzed. After milk fractionation by centrifugation, skimmed milk and MFGM were analyzed by SDS-PAGE, MALDI-TOF mass spectrometry ELISA and/or Western blot. The ELISA assay showed a higher visfatin content in raw skimmed milk than in pasteurized samples. Meanwhile, MFGMs revealed higher visfatin levels in pasteurized samples. This is the first time visfatin has been identified associated with MFGM, and these results could suggest an affinity of this molecule for a lipidic environment.

Abstract X-ray photon-counting computed tomography (PCCT) has garnered considerable interest owing to its low-dose administration, high-quality imaging, and material decomposition characteristics. Current commercial PCCT systems employ compound semiconductor photon-counting X-ray detectors, which offer good energy resolution. However, the choice of materials is limited, and cadmium telluride or cadmium zinc telluride is mostly used. Although indirect radiation detectors can be used as alternatives to compound semiconductor detectors, implementing fine-pitch segmentation in such detectors is challenging. Here we designed an indirect fine-pitch X-ray photon-counting detector by combining miniaturized silicon photomultiplier arrays and fast scintillation crystals, with a pixel size of 250 µm, for future indirect PCCT. The fabricated array detector has the potential to discriminate photon energies with a 27% resolution at 122 keV, 296 µm spatial resolution, and charge-sharing inhibition ability.

Abstract Microbial growth is central to soil carbon cycling. However, how microbial communities grow under climate change is still largely unexplored. Here we use a unique field experiment simulating future climate conditions (increased atmospheric CO2 and temperature) and drought concomitantly and investigate impacts on soil microbial activity. We trace 2H or 18O applied via water-vapor exchange into membrane (and storage) fatty acids or DNA, respectively, to assess community- and group-level adjustments in soil microbial physiology (replication, storage product synthesis, and carbon use efficiency). We show that, while bacterial growth decreases by half during drought, fungal growth remains stable, demonstrating a remarkable resistance against soil moisture changes. In addition, fungal investment into storage triglycerides increases more than five-fold under drought. Community-level carbon use efficiency (the balance between anabolism and catabolism) is unaffected by drought but decreases in future climate conditions, favoring catabolism. Our results highlight that accounting for different microbial growth strategies can foster our understanding of soil microbial contributions to carbon cycling and feedback on the climate system.

Abstract Interfaces between twisted 2D materials host a wealth of physical phenomena originating from the long-scale periodicity associated with the resulting moiré structure. Besides twisting, an alternative route to create structures with comparably long—or even longer—periodicities is inducing a differential strain between adjacent layers in a van der Waals (vdW) material. Despite recent theoretical efforts analyzing its benefits, this route has not yet been implemented experimentally. Here we report evidence for the simultaneous presence of ferromagnetic and antiferromagnetic regions in CrBr3—a hallmark of moiré magnetism—from the observation of an unexpected magnetoconductance in CrBr3 tunnel barriers with ferromagnetic Fe3GeTe2 and graphene electrodes. The observed magnetoconductance evolves with temperature and magnetic field as the magnetoconductance measured in small-angle CrBr3 twisted junctions, in which moiré magnetism occurs. Consistent with Raman measurements and theoretical modeling, we attribute the phenomenon to the presence of a differential strain in the CrBr3 multilayer, which locally modifies the stacking and the interlayer exchange between adjacent CrBr3 layers, resulting in spatially modulated spin textures. Our conclusions indicate that inducing differential strain in vdW multilayers is a viable strategy to create moiré-like superlattices, which in the future may offer in-situ continuous tunability even at low temperatures.

Abstract Hemoglobin (Hb) performs its physiological function within the erythrocyte. Extracellular Hb has prooxidative and proinflammatory properties and is therefore sequestered by haptoglobin and bound by the CD163 receptor on macrophages. In the present study, we demonstrate a novel process of Hb uptake by macrophages independent of haptoglobin and CD163. Unexpectedly, macrophages do not degrade the entire Hb, but instead transfer it to neighboring cells. We have shown that the phenomenon of Hb transfer from macrophages to other cells is mainly mediated by extracellular vesicles. In contrast to the canonical Hb degradation pathway by macrophages, Hb transfer has not been reported before. In addition, we have used the process of Hb transfer in anticancer therapy, where macrophages are loaded with a Hb-anticancer drug conjugate and act as cellular drug carriers. Both mouse and human macrophages loaded with Hb-monomethyl auristatin E (MMAE) effectively killed cancer cells when co-cultured in vitro.

Abstract Background Glaesserella parasuis (G. parasuis) is the primary agent of Glässer’s disease, significantly affecting nursery and early fattening piglets. Current prophylactic measures, mainly serovar-specific bacterins administered to sows, are limited by maternal immunity, which can interfere with active immunization in piglets. Subunit vaccines containing G. parasuis-specific antigenic molecules show promise but are not yet commercially available. Transferrin-binding proteins (Tbp), which enable G. parasuis to acquire iron in low-iron environments like mucosal surfaces, have been proposed as potential vaccine antigens. The mucosal administration of a TbpB-based subunit vaccine could provide a promising solution to overcome the limitations posed by maternal immunity, offering an effective approach to control the disease in weaning piglets. This study, conducted in two phases, primarily evaluates (days 0–45) the immunogenicity of a two-dose oral mucosal TbpB-based subunit vaccine (TbpBY167A) administered to colostrum-deprived piglets, and subsequently (days 45–52), its heterologous protection by challenging these piglets with four G. parasuis clinical isolates from different TbpB clusters (I, III) and serovars (SV1, SV4, SV5, SV7) recovered from Spanish pig farms. Results The oral mucosal administration of the two-dose TbpB-based vaccine induced a robust humoral immune response in immunized colostrum-deprived piglets, significantly increasing IgA and IgM concentration 15 days after the second dose (p