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This study investigates the rain-initiated mixing and variability in the mixing ratio of selected trace gases in the atmosphere over the central Amazon rain forest. It builds on comprehensive data from the Amazon Tall Tower Observatory (ATTO), spanning from 2013 to 2020 and comprising the greenhouse gases (GHGs) carbon dioxide (CO2) and methane (CH4); the reactive trace gases carbon monoxide (CO), ozone (O3), nitric oxide (NO), and nitrogen dioxide (NO2); and selected volatile organic compounds (VOCs). Based on more than 1000 analyzed rainfall events, the study resolves the trace gas mixing ratio patterns before, during, and after the rain events, along with vertical mixing ratio gradients across the forest canopy. The assessment of the rainfall events was conducted independently for daytime and nighttime periods, which allows us to elucidate the influence of solar radiation. The mixing ratios of CO2, CO, and CH4 clearly declined during rainfall, which can be attributed to the downdraft-related entrainment of pristine air from higher altitudes into the boundary layer, a reduction of the photosynthetic activity under increased cloud cover, and changes in the surface fluxes. Notably, CO showed a faster reduction than CO2, and the vertical gradient of CO2 and CO is steeper than for CH4. Conversely, the O3 mixing ratio increased across all measurement heights in the course of the rain-related downdrafts. Following the O3 enhancement by up to a factor of 2, NO, NO2, and isoprene mixing ratios decreased. The temporal and vertical variability of the trace gases is intricately linked to the diverse sink and source processes, surface fluxes, and free-troposphere transport. Within the canopy, several interactions unfold among soil, atmosphere, and plants, shaping the overall dynamics. Also, the mixing ratio of biogenic VOCs (BVOCs) clearly varied with rainfall, driven by factors such as light, temperature, physical transport, and soil processes. Our results disentangle the patterns in the trace gas mixing ratio in the course of sudden and vigorous atmospheric mixing during rainfall events. By selectively uncovering processes that are not clearly detectable under undisturbed conditions, our results contribute to a better understanding of the trace gas life cycle and its interplay with meteorology, cloud dynamics, and rainfall in the Amazon.

This study investigates the rain-initiated mixing and variability in the concentration of selected trace gases in the atmosphere over the central Amazon rain forest. It builds on comprehensive data from the Amazon Tall Tower Observatory (ATTO), spanning from 2013 to 2020 and comprising the greenhouse gases (GHG) carbon dioxide (CO2) and methane (CH4), the reactive trace gases carbon monoxide (CO), ozone (O3), nitric oxide (NO), and nitrogen dioxide NO2 (NO2) as well as selected volatile organic compounds (VOC). Based on more than 1000 analyzed rainfall incidents, the study resolves the trace gas concentration patterns before, during, and after the rain events, along with its vertical concentration gradients across the forest canopy. The assessment of the rainfall events was conducted independently for daytime and nighttime periods, which allows us to elucidate the influence of solar radiation. The concentrations of CO2, CO, and CH4 clearly declined during rainfall, which can be attributed to the downdraft-related entrainment of pristine air from higher altitudes into the boundary layer, a reduction of the photosynthetic activity under increased cloud cover, as well as changes in the surface fluxes. Notably, CO showed a faster reduction than CO2, and the vertical gradient of CO2 and CO is steeper than for CH4. Conversely, the O3 concentration increased across all measurement heights in the course of the rain-related downdrafts. Following the O3 enhancement by up to a factor of two, NO and VOC concentrations decreased, whereas NO2 increased. The temporal and vertical variability of the trace gases is intricately linked to the diverse sink and source processes, surface fluxes, and free troposphere transport. Within the canopy, several interactions unfold among soil, atmosphere, and plants, shaping the overall dynamics. Also, the concentration of biogenic VOC (BVOC) clearly varied with rainfall, driven by factors such as light, temperature, physical transport, and soil processes. Our results disentangle the patterns in trace gas concentration in the course of the sudden and vigorous atmospheric mixing during rainfall events. By selectively uncovering processes that are not clearly detectable under undisturbed conditions, our results contribute to a better understanding of the trace gas life cycle and its interplay with meteorology, cloud dynamics, and rainfall in the Amazon and beyond. [ABSTRACT FROM AUTHOR]

7-methyl-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM2) have been shown to act as human (h) Cav3.1 voltage-gated calcium channel blockers with promising in vivo anti-absence activity, positioning them as potential antiepileptic drugs. The primary aim of this work was to develop cost-effective and environmentally friendly synthetic procedures for preparing 2-phenylimidazo[1,2-b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD-1 ICR mice after pentylenetetrazol administration and DBA/2 mice with seizures induced by audiogenic stimuli. Their neuroprotective effect against oxidative stress were assessed using C6 rat brain glioma cells. DM1 and DM2 exhibited potent anti-seizure effects in both animal models and demonstrated significant in vitro neuroprotective activity by reducing reactive oxygen species release. To lay the groundwork for the future rational optimization of this promising class of compounds, the molecular bases of DM1 and DM2 activity were investigated by modelling their interaction with hCav3.1 channels. The calculated binding modes of DM1 and DM2 to hCav3.1 channels partially mirrored that of the selective Cav3.1 blocker Z944, paving the way for future lead optimization., (© 2024 Wiley‐VCH GmbH.)

Background and Objectives: The incidence of ischemic stroke in young adults has increased substantially. There are limited data in the literature concerning the short-term clinical outcome in young adults with acute stroke after revascularization treatment. Due to the lack of available data on gender differences short-term clinical outcome, we designed the present study., Materials and Methods: We collected data from 127 patients aged 50 years or younger consecutively admitted to the Stroke-Unit of "Cardarelli" Hospital in Naples between August 2017 and September 2022 due to ischemic stroke. All of them underwent thrombolysis and/or endovascular treatment., Results and Conclusions: Smoking, hypertension, and dyslipidemia emerged as the most prevalent risk factors. A gender-based analysis revealed that the history of stroke was the only statistically significant factor more frequently observed in the female group. The leading stroke etiology was "cardioembolism," succeeded by strokes of "other determined origin", "undetermined etiology," "large-artery atherosclerosis," and "small-artery occlusion." Concerning reperfusion therapy, intravenous thrombolysis ranked as the most utilized treatment, followed by "bridging" therapy (combining intravenous thrombolytic therapy with thrombectomy) and primary mechanical thrombectomy. Notably, the average NIHSS scores 7 days post-revascularization were lower among females compared to males, constituting a statistically significant distinction. Nevertheless, no statistically significant correlation surfaced between gender and treatment type in NIHSS mean values at admission, 2 hours, 24 hours post-revascularization, or 7 days post-revascularization. This suggests that the observed disparity in mean NIHSS score between male and female groups after 7 days may potentially stem from other factors, such as endogenous estrogens., Competing Interests: Declarations Ethical approval None. Conflict of interest None. Informed consent None., (© 2024. Fondazione Società Italiana di Neurologia.)

A small series of arylsulfonamide derivatives was designed and synthesized to study linear and cyclic inhibitors targeting human Carbonic Anhydrases (hCAs EC 4.2.1.1) as essential enzymes regulating (patho)-physiological processes. Particularly, the synthesis of these ten compounds was inspired to the well-known arylsulfonamides having flexible or constrained linkers able to maintain the two crucial moieties, anchoring zinc group and hydrophobic tail, in the optimized orientation within CA cavities of tumor-expressed isoforms hCA IX and hCA XII. The synthesized imine derivatives and related cyclic 1,3-thiazin-4-ones were screened in a stopped-flow carbon dioxide hydrase assay and proved to be effective inhibitors against hCA IX and hCA XII isoforms with K i values ranging of 3.7-215.7 nM and 5.7-415.0 nM, respectively. Molecular docking studies of both series of arylsulfonamides were conducted to propose their binding mode within hCA IX and hCA XII active sites thus highlighting their distinct ability to occupy the two catalytic cavities. Moreover, the 4-[(3-cyanophenyl)methylidene]aminobenzene-1-sulfonamide 7 proved to reduce the cell viability of breast carcinoma (MCF-7) and colon rectal carcinoma (HCT-116) human cell lines under the fixed doses of 10 μM. These results encouraged us to continue our efforts in developing potent and efficient arylsulfonamides targeting hCA IX and hCA XII isoforms., 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.)

Today, plastic pollution is a widespread problem in all ecosystems and has a particularly severe impact on marine ecosystems and external fertilisers such as the mussel Mytilus galloprovincialis. The present study aims to assess the toxicological reproductive health effects in this organism following exposure to two concentrations of polystyrene microplastics (PS-MPs) (0.5 and 1 μg/L), representative of conditions in the Mediterranean Sea. After exposure, the electrophoretic pattern of protamine-like (PL) proteins, the major basic protein component of Mytilus galloprovincialis sperm chromatin, was analysed. Compared to the unexposed condition, differences were observed by SDS-PAGE and an increased ability of PL to bind and protect DNA from oxidative damage was then measured, particularly for PL from mussels exposed to 1 μg/L PS-MPs. At this dose of PS-MPs, a reduced release of all PLs from the sperm nuclei was also observed, whereas the digestion by micrococcal nuclease did not show any significant differences between the exposed and the unexposed conditions. Finally, the possibility of poly(ADP)-ribosylation of the PLs was investigated. PL-II showed an increase in poly(ADP)-ribosylation after PS-MPs exposure, which may account for the difference in the ability of the PLs to bind DNA. In conclusion, while all the results might suggest a molecular mechanism of gametic plasticity occurring upon exposure of mussels to PS-MPs 1 μg/L, they also indicate that this dose of exposure could be extremely detrimental to the reproductive health of Mytilus galloprovincialis because it could prevent the release of basic nuclear proteins from the sperm DNA at fertilisation., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The phenomenon of suicide risk (SR) represents a psychiatric, social and environmental emergency. The acute psychiatric ward as the Italian Service for Psychiatric Diagnosis and Care (SPDC) represents the place where SR is high due to the acute and serious conditions of people hospitalized. The objective of this study was to evaluate the characteristics of subjects admitted to a SPDC over a 6-year period for SR represented by: suicidal ideation, attempted and failed suicide., Methods: With a retrospective single-center observational design, we collected hospitalizations from 01/01/2017 to 31/12/2022 in the SPDC of AUSL-Modena for SR, analyzed the modality of SR and compared the demographic and clinical variables of subjects with SR with those hospitalized for other clinical reasons in the same period. Data were statistically analyzed., Results: In the 6-year of study period, we collected 2,930 hospitalizations in the SPDC of AUSL- Modena and among them, 68% (n = 528) were carried out due to SR, which represented the second leading cause of hospitalization (18%), in particular among females (Pearson Chi2 = 17.41, p < 0.001). Individuals with SR were more frequently voluntary admitted (Pearson Chi2 = 215.41, p < 0.001) for a shorter period (7.36 ± 8.16 vs 11.66 ± 15.93, t = 6.03, t-test, p < 0.001) and less frequently repeated the hospitalization during the study period for the same reason (Pearson Chi2 = 6.0, p = 0.014). The most frequent psychiatric disorders associated with SR were depressive, personality and adjustment disorders, which represented the most common factor associated with SR (68%), followed by family/relationship problems (12%) and alcohol/substance abuse (8%). We highlighted three kinds of suicidal risk: suicidal ideation (40%), often associated with personality disorders and substance use disorders, drug ingestion (30%) concomitant with conflicting family relationships and use of violent means (30%) associated with depressive disorders (Pearson Chi2 = 42.83, p = 0.002)., Conclusions: Our study provides a real-world setting evaluation of subjects hospitalized for SR and, in accordance with literature, suggests that suicidal behavior is the product of many clinical and social factors' interaction, that occurred in a crucial moment of life in vulnerable individuals. The identification of subjects at SR represents the first step of preventive multi-professional interventions., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the Ethics Committee of the North Emilia Area Vasta (Prot. 306/2022/AOU) with subsequent amendment for extension of the period examined (Prot. 10826/2023) and authorized by the AUSL- Modena (Prot. no. 688; 27/4/2023). Consent for publication is not applicable. If the informed consent is waived, we would require full name of committee that waived the informed consent. As the study was conducted retrospectively, it was not possible to obtain written informed consent from the enrolled subjects, in accordance with the European GDPR 679/2016 and General Authorization n. 9/2016, extended by Provision n. 424/2018. Data access was granted to the study manager and collaborators, who were bound by confidentiality and data processing obligations under applicable regulations. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model. The β-arrestin assay on GPR109A and qPCR on TRPM7 were also carried out. CBDA and CBGA are effective on both acetyl- and butyryl-cholinesterases (AChE/BuChE), as well as on β-secretase-1 (BACE-1) enzymes in a low micromolar range, and they also prevent aggregation of β-amyloid fibrils. Computational studies provided a rationale for the competitive (AChE) vs. noncompetitive (BuChE) inhibitory profile of the two ligands. The repeated treatment with CBDA and CBGA (10 mg/kg, i.p.) improved the cognitive deficit induced by the β-amyloid peptide. A recovery of the long-term potentiation in the hippocampus was observed, where the treatment with CBGA and CBDA also restored the physiological expression level of TRPM7, a receptor channel involved in neurodegenerative diseases. We also showed that these compounds do not stimulate GPR109A in β-arrestin assay. Collectively, these data broaden the pharmacological profile of CBDA and CBGA and suggest their potential use as novel anti-AD MTDLs., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Chronic lipid overnutrition has been demonstrated to promote cardiac dysfunction resulting from metabolic derangement, inflammation, and fibrosis. Oleoylethanolamide (OEA), an endogenous peroxisome proliferator activating receptor (PPAR)-α agonist, has been extensively studied for its metabolic properties. The aim of this study was to determine if OEA has beneficial effects on high-fat diet (HFD)-induced cardiac disruption in obese mice, focusing on the underlying pathological mechanisms. OEA treatment restores the metabolic pattern, improving serum glycaemic and lipid profile. OEA also reduces heart weight and serum creatine kinase-myocardial band (CK-MB), a marker of cardiac damage. Accordingly, OEA modulates cardiac metabolism, increasing insulin signaling and reducing lipid accumulation. OEA increases AMPK and AKT phosphorylation, converging in the rise of AS160 activation and glucose transporter (GLUT)4 protein level. Moreover, OEA reduces the transcription of the cardiac fatty acid transporter CD36 and fatty acid synthase and increases PPAR-α mRNA levels. Adiponectin and meteorite-like protein transcription levels were significantly reduced by OEA in HFD mice, as well as those of inflammatory cytokines and pro-fibrotic markers. An increased autophagic process was also shown, contributing to OEA's cardioprotective effects. Metabolomic analyses of cardiac tissue revealed the modulation of different lipids, including triglycerides, glycerophospholipids and sphingomyelins by OEA treatment. In vitro experiments on HL-1 cardiomyocytes showed OEA's capability in reducing inflammation and fibrosis following palmitate challenge, demonstrating a direct activity of OEA on cardiac cells, mainly mediated by PPAR-α activation. Our results indicate OEA as a potential therapeutic to restrain cardiac damage associated with metabolic disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Aims/hypothesis: The diagnosis of type 2 diabetes is increasing in young people worldwide. This study evaluated the frequency and clinical characteristics of young people presenting with type 2 diabetes from the multinational SWEET e.V Registry 2012-2021, including the first years of the COVID-19 pandemic., Methods: This is a longitudinal observational study based on the SWEET Registry, which collects demographic and clinical data on children and adolescents with diabetes from centres worldwide, with the diagnosis and classification of diabetes provided locally by each centre according to International Society for Paediatric and Adolescent Diabetes definitions. By July 2022, the SWEET Registry included 96,931 individuals from 130 centres with a total of 1,154,555 visits. Data were analysed by region: Europe (EU), Australia and New Zealand (AU/NZ), South America (SA), North America (NA) and Asia/Middle East and Africa (AS/AF). Trends in proportions for the two-year periods, calculated as cases with type 2 diabetes diagnoses over all cases with diabetes diagnoses, were estimated using logistic regression models adjusted for age at onset and sex., Results: Overall, there were 2819 of 58,170 new cases (4.8%) with type 2 diabetes: 614 in EU, 293 in AU/NZ, 79 in SA, 1211 in NA and 622 in AS/AF. The proportion of type 2 diabetes increased from 3.2% to 6.0% from 2012/2013 to 2020/2021, a relative rate of increase of 9% per two-year period (95% CI 5.9, 12.3; p<0.001). In the two-year period of the COVID-19 pandemic, type 2 diabetes continued to follow the observed trend, with a proportion of 6.0% in 2020-2021 compared with 5.4% in 2018-2019. High variability in the proportion of type 2 diabetes was observed across regions, with the lowest values observed in EU and the highest in NA. A significant increase in the proportion of type 2 diabetes was observed in EU, AU/NZ and NA. The median HbA 1c was not uniform and was highest in AS/AF (85 mmol/mol [9.9%]; IQR 55-111 [7.2-12.3%]) and lowest in EU (63 mmol/mol [7.9%]; IQR 48-99 [6.5-11.2%]), and the difference between EU and NA (median value 73 mmol/mol [8.8%]; IQR 50-105 [6.7-11.8%]) was statistically significant (p=0.047). There was also a difference in BMI SD score by region: the lowest median BMI SD score was 2.2 (IQR 1.4-2.7) in AS/AF and the highest was 3.1 (IQR 2.5-3.6) in AU/NZ., Conclusions/interpretation: The multinational SWEET data from the years 2012 to 2021 inclusive support recent findings of a worldwide increase in type 2 diabetes in young people, albeit with regional differences. This increase highlights the need for ongoing preventive measures and available advanced treatment modalities worldwide., (© 2024. The Author(s).)

The efficacy of Hylotelephium telephium (L.) H. Ohba (better known with its botanical synonym Sedum telephium L.) fresh leaf juice in the treatment of Herpes labialis wounds has been reported in traditional medicine in particular in Central regions of Italy; however, scientific insights are missing and the mechanism of action is not well understood. Aim of this study was to investigate the biological properties of S. telephium that underlie its ability to heal herpetic lesions. S. telephium fresh leaf juice (STJ) was analysed to obtain phytochemical information and tested in vitro to evaluate its antiviral activity against HSV-1 in Vero cells, then, according to computational predictions, immunomodulatory properties of STJ in human lympho-monocytes (PBMC), as well as its effect on cell viability in human keratinocytes (HaCaT cells), were also evaluated. Our results, at least in part, may explain the improvement of herpetic lesions empirically observed in patients treated with STJ: such improvement was not related to direct anti-viral effect of the juice but to its experimentally confirmed activity as cell viability booster and immunomodulatory agent.

Used since decades to produce pectin, citrus processing waste poor in lignin and rich in hemicellulose obtained from lemon and orange juice industrial manufacturing is ideally suited also as microcrystalline cellulose and nanocellulose raw material. The study merges the outcomes of chemistry and bioeconomy research between 2007 and early 2024 with technology and economic insight, to reach five conclusions that will hopefully inform practice-oriented work of researchers and bioeconomy company's managers interested in the sustainable manufacturing of these important biomaterials., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Direct oral anticoagulants (DOACs) are widely used for treatment and secondary prophylaxis of venous thromboembolism (VTE) and represent the gold standard for VTE secondary prophylaxis, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit widespread DOACs usage there are few literature data regarding their efficacy and safety in major thrombophilia carriers and almost no data is available for low intensity apixaban and rivaroxaban as secondary VTE prophylaxis in such patients. The aim of our study is to evaluate and confront the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis, in major thrombophilia carriers vs patients at high risk of VTE recurrence for other reasons. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily and that were screened for thrombophilia. The examined patients were 339. Baseline characteristics such as sex, age, obesity rate, smoking, number of previous VTEs and comorbidities (such as cardiovascular diseases, diabetes, mild CKD) were equally distributed in either group. The median low-dose DOACs administration time was 19.20 months (IQR 12.17-35.67). During low-dose DOACs treatment, 13 (3.8%) VTE recurrences were observed; 14 bleeding events were registered (4,1%), with no major bleeding (MB), 6 clinically relevant non major bleeding (CRNMB) (1.8%) and 8 minor bleeding (2.3%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between major thrombophilia carriers and non-major thrombophilia carriers. In multivariate analysis increased risk of VTE recurrence was found for patients with cardiovascular comorbidities (HR 4.00 - p = 0.034) and for patients with more than one previous VTE episode (HR 5.14 - p = 0.034). Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis for carriers of major thrombophilia with no increase in VTE recurrence and/or bleeding risk., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To develop and validate a questionnaire to evaluate missed nursing care (MNC) in a home care setting., Design: A new instrument was developed and tested performing a preliminary analysis of a multicenter cross-sectional study in Italy. Reporting was performed according to COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guidelines., Sample: Eight hundred out of a total of 2549 home care nurses enrolled in AIDOMUS-IT were considered for the validation of the Missed Nursing Care in Home Care (MNC&#95;HC)., Measurements: The MNC&#95;HC instrument was developed by a panel of experts and underwent content and face validation. Exploratory (EFA) and confirmatory factor analyses (CFA) were conducted., Results: EFA revealed a one-factor solution, explaining 56% of the total variance for MNC&#95;HC. CFA confirmed excellent structural validity, with a one-factor model showing an exceptional fit (χ 2 (27) = 141.39, p < .001, RMSEA = 0.04, SRMR = 0.04, CFI = 0.99, TLI = 0.99, factor loadings > 0.5). MNC&#95;HC also demonstrated high reliability (Cronbach's α = 0.92). The activity with the highest rate of missed care was the documentation of nursing care (77%), while activities related to nursing techniques (e.g., injections, dressings, etc.) were reported to be missed less (33.63%)., Conclusions: MNC&#95;HC is a quick-filling, valid, reliable, and psychometrically sound instrument for measuring MNC in home care useful for future research., (© 2024 The Author(s). Public Health Nursing published by Wiley Periodicals LLC.)

Most patients with Primary Mediastinal B-Cell Lymphoma (PMBCL) are cured by rituximab and doxorubicin-based immunochemotherapy, with or without radiotherapy. In cases with relapsed and refractory (RR) disease the prognosis was historically poor. Recently, immune checkpoint-based strategies have been shown to be highly effective in patients with RR-PMBCL. We report the case of a 23-year-old woman who, due to recurring episodes of symptomatic chemotherapy-induced sinus bradycardia, was unable to receive the planned six courses of immunochemotherapy, mediastinal radiotherapy, and autologous transplantation, leading to the early initiation of a chemo-free strategy. The patient maintains a continuous complete remission at a four-year follow-up after only two cycles of immunochemotherapy followed by nivolumab plus brentuximab vedotin (BV) and pembrolizumab consolidation. Beyond describing an underreported complication of anticancer treatments, the favorable clinical outcome suggests that in PMBCL, a minimal load of chemotherapy, integrated by early PD-1 blockade, with or without BV, may be sufficient to achieve long-term disease control and cure at least in some patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Tactile acuity is a somatosensory measure of the extent to which humans can discern tactile stimuli. It is influenced by how peripheral signals are processed centrally. In the oral cavity, Occlusal Tactile Acuity (OTA) is the ability to perceive minimal thicknesses between antagonist teeth. The aim of the current study was to assess the association between psychological traits and OTA of otherwise healthy individuals., Methods: Sixty-three volunteers (32 males; mean age ± SD: 24.6 ± 2.7 years) participated in this study. Somatosensory amplification, anxiety, depression, physical symptoms and pain catastrophizing were scored using questionnaires, and subgroups of severity were created per variable based on cut-offs. OTA was measured using 9 aluminium foils with thickness (ranging from 8 to 72 μm) and one sham test (without foil). Each thickness was tested 10 times in random order, the participants were instructed to report whether they felt the foil between their molars and the mean percentage of correct answers was computed. A linear mixed model was used with OTA as a dependent variable and psychological domain as an independent variable., Results: Significantly different OTA was observed among the anxiety subgroups (p = .003), supporting a decreased perception of thicknesses 24 and 32 μm (p = .018 and p < .001, respectively) in participants with moderate/severe anxiety compared to those with no/mild anxiety. Significantly different OTA was also observed among the pain catastrophizing subgroups (p = .008), showing decreased perception of thicknesses 32 and 40 μm (p < .001 and p = .007, respectively) in severe catastrophizing levels, compared to no/mild catastrophizing levels. No significant differences were observed for the other variables., Conclusions: Healthy adults with increased anxiety or pain catastrophizing levels show decreased interdental acuity as compared to participants with minor or no psychological impairment., (© 2024 The Author(s). Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Objective: The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers., Study Design: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period., Results: Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026)., Conclusions: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The aim of this study was to adapt the National Aeronautics and Space Administration Task Load Index (NASA-TLX) to the home care setting and translate and validate it in Italian. An online questionnaire containing the Italian version of the NASA-TLX adapted to the home care setting was administered to home care nurses to measure workload. Content Validity Index, Exploratory, and Confirmatory Factor Analyses were used to measure the psychometric characteristics of the modified NASA-TLX. The modified Italian version of NASA-TLX&#95;HC-IT showed good psychometric characteristics in measuring the workload of home care nurses, with excellent fit indices. The reliability, calculated with Cronbach's alpha, was 0.73, indicating adequate reliability. A negative correlation between workload and job satisfaction among home care nurses, as well as a positive association between high workload and intention to leave the workplace, was verified. The modified Italian version of the NASA-TLX&#95;HC-IT was confirmed to be a valid and reliable instrument to measure workload in home care nursing. Furthermore, the correlation between workload and the intention to leave the workplace among home care nurses was an important result that community nursing managers should consider preventing the shortage of home care nurses., (© 2024 The Author(s). Public Health Nursing published by Wiley Periodicals LLC.)

Introduction: Stroke negatively impacts both patients and their families, who must face multiple changes after the onset of the disease. Family caregivers must face new problems with a possible sense of inadequacy, stress and burden. Our retrospective study aimed to assess the burden of caregivers during the rehabilitation process of patients with Stroke., Material and Method: This study included patients with a diagnosis of stroke and their caregiver, who attended the Day Hospital of the IRCCS Neurolesi Center "Bonino-Pulejo", Messina, Italy, between January 2018 and October 2019, using electronic recovery system data. The final sample consisted of 30 patients and their caregivers., Results: Significant improvements were observed in patients' cognitive and mood scores, reflecting the efficacy of rehabilitation therapies. Additionally, a correlation emerged between patients' reported anxiety levels and caregivers' reported depression levels, highlighting a dynamic interaction between the emotional states of the two groups., Conclusion: The study highlights the intricate interplay between caregiver characteristics, patient outcomes, and family dynamics in the context of caregiving. Targeted interventions aimed at improving family resilience and coping mechanisms are crucial to optimizing the well-being of both caregivers and patients., (© 2024. The Author(s).)

Background: Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition., Methods: We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 -related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed., Results: The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 -related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds., Conclusions: Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contributes to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction., Clinical Perspective: What is Known:Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia.What the Study Adds:The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

We developed a flow cytometry (FC) assay enabling the rapid and accurate identification of bacterial and viral infections using whole blood samples. The streamlined flow cytometry assay is designed to be user-friendly, making it accessible even for operators with limited experience in FC techniques. The key components of the assay focus on the expression levels of specific surface markers-CD64 on polymorphonuclear neutrophils (PMN) as a marker for bacterial infection, and CD169 on monocytes (MO) for viral infection. The strong performance indicated by an area under the receiver operating characteristic (ROC) curve of 0.94 for both PMN CD64 positive predictive value (PPV) 97.96% and negative predictive value (NPV) 76.67%, and MO CD169 PPV 82.6% and NPV 86.9%, highlight the assay's robustness in differentiating between bacterial and viral infections accurately. The FC assay includes the assessment of immune system status through HLA-DR and IL-1R2 modulation in MO, providing a useful insight into the patients' immune response. The significant increase in the frequency of MO exhibiting reduced HLA-DR expression and elevated IL-1R2 levels in infected patients (compared to healthy controls) underscores the potential of these markers as indicators of infection severity. Although the overall correlation between HLA-DR and IL-1R2 expression levels was not significant across all patients, there was a trend in patients with more severe disease suggesting that these markers may have the potential to assist in stratifying patient risk. The present FC assay has the potential to become routine in the clinical microbiology laboratory community and to be helpful in guiding clinical decision making.

IgG4-related disease is a rare fibroinflammatory condition. Prompt recognition is fundamental to initiate treatment and to prevent organ damage. Diagnostic and classification criteria are primarily intended for use by clinicians with established expertise in IgG4-related disease. Absence of disease awareness among primary care physicians and specialists without expertise in IgG4-related disease remains the main cause of diagnostic delay. We aimed to identify red flags that might increase the suspicion of IgG4-related disease in primary and secondary care settings. A task force of experts in IgG4-related disease from the European Reference Network for Rare Connective Tissue Diseases (ERN-ReCONNET), patient representatives, and primary care physicians derived potential red flags for IgG4-related disease through a systematic literature search and a level of agreement exercise. Five red flags reached 100% agreement among experts: swelling in one or more organ system; pancreatic and biliary tree involvement; increased serum IgG4; IgG4 + plasma cell tissue infiltration; and obliterative phlebitis. Red flags for IgG4-related disease are intended for use in primary and secondary care to improve referral to centres of expertise and prompt early diagnosis., Competing Interests: Declaration of interests GPG received funding from The European Commission within the contract SANTE/2018/B3/030-SI2·813822 to support collaboration with European Reference Network (ERN) ReCONNET as a methodologist in the systematic review on red flags for IgG4-related disease. FF received honoraria from GSK for lectures and plenary presentations at educational events. TA received travel grants from AbbVie and Neovil; declares study support from Janssen; and received honoraria from AbbVie, Amgen, AstraZeneca, GSK, and Neovil for lectures and plenary presentations at educational events. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Prolonged treatment with anti-CD20 antibodies can lead to hypogammaglobulinemia and increased infection risk in multiple sclerosis (MS). We investigated switch from anti-CD20 to cladribine as a strategy to prevent immunoglobulin reduction while preserving efficacy. We prospectively analysed serum IgG, IgM, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in 44 patients, 14 who were switched from anti-CD20 to cladribine and 30 continuing anti-CD20. Over 1 year, serum IgG, IgM, NfL and GFAP remained stable after switch and similar to patients continuing anti-CD20. More than 90 % of patients remained free of disease activity. Cladribine should be further explored as de-escalating agent from anti-CD20 in MS., Competing Interests: Declaration of competing interest The employer (Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland) receives financial support from Abbvie, Biogen Idec, Lundbeck, Merck, Novartis Roche, Sanofi, Teva. The submitted work is not related to these agreements., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Autism Spectrum Disorder (ASD) involves challenges in social communication and daily functioning. Emerging research highlights that virtual reality (VR) interventions can significantly improve social skills in adults with ASD by providing immersive, controlled practice environments. This systematic review will assess the effectiveness of VR-based interventions for improving social skills in adults with ASD. Materials and Methods: Studies were identified from an online search of PubMed, Web of Science, Cochrane Library, and Embase databases without any search time range. This review was registered on Open OSF ( n ) P4SM5. Results: Recent studies show that VR interventions significantly enhance job interview skills, social abilities, and practical tasks in adults with ASD, with improvements in confidence, social understanding, and everyday skills. VR has been shown to be user-friendly and effective in providing immersive, adaptable training experiences. Conclusions: The review highlights VR's promising role in improving social skills, job interview abilities, and daily functioning in adults with ASD. It emphasizes the need for broader studies, standardized interventions, and exploration of VR's integration with other therapies to enhance long-term effectiveness and address comorbidities like anxiety and depression.

Temporomandibular disorders (TMDs) are a common musculoskeletal condition, presenting treatment challenges due to their non-specific nature. Categorizing patients with TMDs into clusters based on neurobiological pain mechanisms could provide a promising approach to facilitate targeted treatments. This observational study (1) used a network analysis (NA) to explore the complexity of TMDs by investigating relationships among biopsychosocial variables, and (2) validated potential TMD subgroups based on mechanism-specific pain categories. One hundred and two patients with TMD were included. Biopsychosocial variables covered: general health, psychosocial features, TMD pain, and TMD characteristics. A NA evaluated the associations between variables and determined the role of each feature within the network. Hierarchical clustering was used to identify TMD subgroups. The NA revealed significant correlations primarily within the same feature domains, indicating a strong interplay between symptoms and psychological factors. Cluster analysis identified two subgroups driven by nociceptive and nociplastic pain mechanisms; the nociplastic group exhibited higher levels of anxiety, depression, pain catastrophization, central sensitization, pain duration, and more pain locations, along with poorer sleep quality, quality of life, and health status. In contrast, the nociceptive group exhibited restricted maximal mouth opening (MMO), heightened pain during TMJ palpation and mouth opening, and a greater positive response to manual therapy. Across all features, psychological factors, pain locations, and MMO primarily contributed to the separation of subgroups. By adopting a data-driven approach, these results support the significant role of considering the neurobiological basis of pain to improve patient classification. This knowledge may facilitate clinical reasoning and personalized treatments. PERSPECTIVE: This study used a network analysis to explore the complex biopsychosocial interactions present in people with TMDs, identifying important variables such as the Central Sensitization Inventory and pain-free maximal mouth opening. The findings distinguish potential nociceptive and nociplastic pain subgroups, offering important insights for targeted therapeutic strategies., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors., Methods: In a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague-Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration., Results: Both doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP., Conclusions: The findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine., (© 2024. The Author(s).)

ALK5 inhibitors represent an attractive therapeutic approach for the treatment of a variety of pathologies, including cancer and fibrosis. Herein, we report the design and in vitro characterization of a novel series of ALK5 modulators featuring a 4,6-disubstituted pyridazine core. A knowledge-based scaffold-hopping exploration was initially conducted on a restricted set of heteroaromatic cores using available ligand- and structure-based information. The most potent structurally novel hit compound 2A was subsequently subjected to a preliminary optimization for the inhaled delivery, applying physicochemical criteria aimed at minimizing systemic exposure to limit the risk of adverse side effects. The resulting inhibitors showed a marked boost in potency against ALK5 and in vitro ADME properties, potentially favoring lung retention. The optimized hits 20 and 23 might thus be considered promising starting points for the development of novel inhaled ALK5 inhibitors., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Background: this study was performed under the umbrella of the Health Extended Alliance for Innovative Therapies, Advanced Lab Research, and Integrated Approaches of Precision Medicine (HEAL ITALIA) partnership and funded under the National Recovery and Resilience Plan, Mission 4 Component 2 Investment 1.3, and by the European Union., Objectives: the overall objective of the HEAL project is to identify innovative and effective therapeutic approaches to reduce disease burden. The present research falls within Spoke 7: Prevention Strategies: Integrated and gender medicine approaches for prevention strategies based on environmental, lifestyle, and clinical biometric data. Obesity represents a primary risk factor worldwide for the onset of numerous life-threatening diseases, including metabolic, cardiovascular, and neurological diseases. Environmental and gender-related factors influence obesity development. However, the molecular mechanisms underlying the effects of those agents on different organs of the human body are not fully understood yet., Methods: here, we present a study protocol aimed at shedding light on (i) the complex interplays among adipose tissue, brain and gut in obesity, and (ii) the effects of specific dietary components and environmental metabolism-disrupting compounds on those interactions. To this purpose, we combined ex vivo, in vitro, and in vivo approaches to gain additional knowledge about the molecular mechanisms underlying connections between organs., Conclusions: the data provided by this study will contribute to defining new targets for therapeutic and/or preventive interventions, thereby allowing more personalized approaches to nutrition.

Bifidobacteria are recognized as health-promoting bacteria that reside in the human gut, helping in the digestion of fiber, preventing infections, and producing essential compounds like vitamins. To date, Bifidobacterium animalis subsp. lactis , together with Bifidobacterium adolescentis , Bifidobacterium bifidum , Bifidobacterium breve, and Bifidobacterium longum , represents one of the species that are used as probiotic bacteria. Despite the extensive and detailed scientific research conducted on this microbial taxon, the molecular mechanisms by which B. animalis subsp. lactis exerts health benefits to its host are still largely unknown. Thus, we dissected the genetic repertoire and phylogenetic relationship of 162 strains of B. animalis subsp. lactis to select a representative reference strain of this taxon suitable for investigating its interaction with the host. The B. animalis subsp. lactis PRL2013 strain, which was isolated by a mucosal sample of a healthy adult, was chosen as the reference of the monophyletic cluster of human origin and revealed a greater adhesion index than that observed for another B. animalis subsp. lactis strain used in the industry as a probiotic supplement. Transcriptomics analyses of PRL2013 strain, when exposed to human cell monolayers, revealed 291 significantly upregulated genes, among which were found genes predicted to encode extracellular structures that may directly interact with human cells, such as extracellular polymeric substances, wall teichoic acids, and pili., Importance: To date, many Bifidobacterium animalis subsp. lactis strains have been isolated from human fecal samples. However, their presence in these samples does not necessarily suggest an ability to colonize the human gut. Furthermore, probiotics of non-human origin may not effectively interact with the gut epithelium, resulting in transient bacteria of the gut microbiota. In vitro experiments with human cells revealed that B. animalis subsp. lactis PRL2013, an autochthonous member of the human gut, shows colonization capability, leading to future applications in functional foods., Competing Interests: The authors declare no conflict of interest.

Objective: To evaluate the impact of coadministering statins with direct oral anticoagulants (DOACs) on the risk of major bleeding events in patients with venous thromboembolism (VTE)., Design: Observational cohort analysis based on a multicentre international registry., Setting: Data were extracted from the Registro Informatizado de Enfermedad TromboEmbolica Registry, which involves 205 centres across 27 countries., Participants: A total of 73 659 patients diagnosed with VTE were classified based on their anticoagulant therapy (DOACs) versus low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs) and concurrent use of statins., Methods: Multivariable Cox proportional hazards models adjusted for confounding variables to assess the risk of major bleeding events stratified by the type of anticoagulant use and statin use., Results: From October 2013 to February 2023, 73 659 patients were recruited: 2573 were statin users on DOACs, 14 090 were statin users on LMWH or VKA therapy, 10 088 were non-statin users on DOACs and 46 908 were non-statin users on LMWH or VKA therapy. Statin users were 10 years older and more likely to have hypertension, diabetes, renal failure or prior artery disease. During anticoagulation (median, 187 days), 1917 patients (2.6%) suffered major bleeding. Rates of major bleeding per 100 patient-years were 2.33 (95% CI 1.72 to 3.09), 3.75 (95% CI 3.43 to 4.10), 1.39 (95% CI 1.13 to 1.69) and 3.10 (95% CI 2.93 to 3.27), respectively. On multivariable analysis, patients treated with DOACs had a significantly lower risk of major bleeding compared with those on LMWH or VKA therapy (adjusted HR 0.59; 95% CI 0.48 to 0.74). The adjusted HR in statin users versus non-users was 1.03 (95% CI 0.92 to 1.14), while in statin users on DOACs versus the rest of patients, it was 1.18 (95% CI 0.79 to 1.76)., Conclusions: In patients with VTE receiving statins, long-term anticoagulation with DOACs was associated with a reduced risk of major bleeding, regardless of the statin use. These findings support the safety profile of DOACs over VKAs or LMWH in the management of VTE in patients requiring statins., 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.)

Introduction: Perampanel is a selective non-competitive antagonist of AMPA receptors, and the first agent of this class to become available for the treatment of epilepsy. It could be a useful tool for treatment of refractory status epilepticus (RSE)., Methods: We describe a series of eight RSE cases treated with Perampanel., Results: Perampanel was successful in terminating SE in all the described cases. Only in one patient a severe psychomotor agitation occurred, but without needing PER discontinuation. No other adverse events were observed., Conslusion: Our case series of eight patients, albeit small, broadens the clinical experiences on the efficacy and safety of PER as a treatment for RSE. It may also support the early use of PER, considering the role of AMPA receptors in sustaining epileptic firing in SE. Further studies are warranted to clarify the potential of Perampanel in the treatment of status epilepticus and, in particular, in RSE., (© 2024. Fondazione Società Italiana di Neurologia.)

Introduction: Parkinson's disease (PD) is one the most common neurodegenerative movement disorder, leading to motor and non-motor symptoms, including deficits in executive functions (EF), memory, visuospatial abilities, and psychomotor speed. Current treatments are primarily symptomatic, involving pharmacological, surgical strategies. Neurologic Music Therapy (NMT) has gained recognition for its effectiveness in neurorehabilitation of PD patients and improving motor and cognitive domains, such as EF. This study combines NMT with the virtual reality (VR) platform Computer-Assisted Rehabilitation Environment (CAREN), offering customizable environments for rhythmic cue practice to provide an innovative approach to Parkinson's rehabilitation., Methods: In our single-blind quasi-randomized controlled trial, forty patients were assigned to either an experimental group (EG = 20) or a control group (CG = 20). Both groups underwent two months of training with CAREN scenarios (three times a week for 24 sessions). The experimental group additionally received NMT applied to the selected scenarios. Participants were evaluated by a neuropsychologist at baseline and immediately after training., Results: Intra-group analysis showed significant improvements in the EG for MOCA (p = 0.007), FAB (p = 0.008), Stroop Error (p = 0.003), Stroop Time (p < 0.001), and Visual Search (p < 0.001). The CG showed a significant difference only in Stroop Error (p = 0.02)., Conclusions: This pilot study is the first to combine NMT with CAREN in PD patients. Our findings suggest that NMT, within an immersive VR environment, effectively improves cognitive and EF in PD. Music structured within NMT techniques, coupled with advanced audio-visual feedback from VR, offers an innovative and potentially more effective approach for managing cognitive and executive deficits associated with PD., Competing Interests: The authors declare no conflicts of interest regarding the research, authorship, or publication of this article., (© 2024 The Author(s).)

Background/Objectives : Empowerment in medicine and psychiatry involves patients gaining control over health-related decisions, improving treatment adherence, outcomes, and satisfaction. This concept is especially significant in psychiatric care due to the complex challenges of mental health conditions, including stigma and impairment of emotional and cognitive functioning. We aim to investigate the correlations between patient trust, decision-making involvement, symptom severity, and perceived empowerment among individuals with Major Depression. Methods : Patients with Major Depressive Disorder were recruited in the "Policlinico G. Rodolico" psychiatry outpatient clinic from November 2022 to June 2023. Inclusion criteria: ages 18-65, ability to consent, stable condition, psychiatric medication history, and recent consultation. Exclusion criteria: psychotic features, bipolar disorder, substance abuse, high suicide risk, and severe comorbidities. Measures included the User Scale for Measuring Empowerment in Mental Health Services (SESM), Trust in Oncologist Scale (TiOS), Clinical Decision-Making Style for Patients (CDMS-P), and Hamilton Depression Rating Scale (HAM-D). Analysis used Kendall's Tau correlation and Two-One-Sided Tests procedure. Results : Seventy-three patients completed the study. No relationship was found between decision-making involvement and perceived empowerment (τ = -0.0625; p = 0.448), or between trust in psychiatrists and empowerment (τ = 0.0747; p = 0.364). An inverse correlation existed between patient involvement in therapy management and trust (τ = -0.2505; p = 0.002). Depression severity inversely correlated with empowerment (τ = -0.2762; p = <.001), but not with trust or decision-making involvement. Conclusions : The lack of significant correlations suggests that decision-making involvement and trust alone may not suffice to enhance empowerment. Trust may encourage patient passivity, while skepticism might drive active involvement. Higher empowerment is associated with less depressive symptoms, highlighting its potential connection with patient outcomes.

Objectives: The COVID-19 pandemic has negatively impacted child and adolescent mental health. The study outcome was the evaluation of the pandemic impact on adolescents' hospitalizations in an acute psychiatric ward., Methods: With an observational and retrospective design, we collected selected variables among adolescents hospitalized in an acute psychiatric ward from 01/07/2017 to 30/06/2022. Data were statistically processed., Results: Our sample consisted of 118 minors with an average age of 15.7 ± 1.2 SD, mostly represented by females (61 %) and Italians (60.2 %), who made 204 hospitalizations in the study period. The admissions by years drastically decreased in 2020 concomitantly with the lockdown and increased in the first half of 2022. The admission rate was higher in winter and spring, except in 2020 when all admissions decreased (p=0.000). Females more frequently were hospitalized for suicidal behavior and acute anxiety (p=0.000) and were discharged with acute stress reactions, eating disorders, and mood disorder diagnoses (p=0.000). Differently, males more frequently were hospitalized for aggressive behavior (p=0.000) and discharged with ADHD diagnosis (p=0.000). At multiple linear regression, the duration of hospitalization (dependent variable) was negatively associated with "the pandemic period" (p=0.017) and "absent aggressive behavior" (p=0.003), and positively with "autism" diagnosis (p=0.000)., Conclusions: We highlighted the more stressful impact of COVID-19 pandemic on female adolescents, who required more frequently psychiatric hospitalizations due to suicidal behavior, anxiety and mood disorders., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

This study investigates P. ostreatus and A. bisporus biodegradation capacity of low density polyethylene (LDPE) oxidised to simulate environmental weathering. Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM) were used to analyse the degradation of LDPE treated with fungal cultures. Molecular implications of LDPE degradation by P. ostreatus and A. bisporus were evaluated by Reverse transcription followed by quantitative PCR (qRT-PCR) of lac, mnp and lip genes expression. After 90 days of incubation, FT-IR analysis showed, for both fungal treatments, an increasing in the intensity of peaks related to the asymmetric C-C-O stretching (1160 to 1000 cm -1 ) and the -OH stretching (3700 to 3200 cm -1 ) due to the formation of alcohols and carboxylic acid, indicating depolymerisation of LDPE. This was confirmed by the SEM analysis, where a widespread alteration of the surface morphology was observed for treated LDPE fragments. Results revealed that the exposure of P. ostreatus to oxidised LDPE treatment led to a significant increase in the expression of the lac6, lac7, lac9, lac10 and mnp2 genes, while A. bisporus showed an over-expression in lac2 and lac12 genes. The obtained results offer new perspectives for a biotechnological use of P. ostreatus and A. bisporus for plastic bioremediation., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

In the aging process, skin morphology might be affected by wrinkle formation due to the loss of elasticity and resilience of connective tissues linked to the cleavage of elastin by the enzymatic activity of elastase. Little information is available about the structural requirements to efficiently inhibit elastase 1 (EC 3.4.21.36) expressed in skin keratinocytes. In this study, a structure-based approach led to the identification to the pharmacophoric hypotheses that described the main structural requirements for binding to porcine pancreatic elastase as a valuable tool for the development of skin therapeutic agents due to its similarity with human elastase 1. The obtained models were subsequently refined through the application of computational alanine-scanning mutagenesis to evaluate the effect of single residues on the binding affinity and protein stability; in turn, molecular dynamic simulations were carried out; these procedures led to a simplified model bearing few essential features, enabling a reliable collection of chemical features for their interactions with elastase. Then, a virtual screening campaign on the in-house library of synthetic compounds led to the identification of a nonpeptide-based inhibitor (IC 50 = 60.4 µM) belonging to the class of N -substituted-1 H -benzimidazol-2-yl]thio]acetamides, which might be further exploited to obtain more efficient ligands of elastase for therapeutic applications.

Introduction: Evidence from randomised controlled trials on anti-tumour necrosis factor (TNF) agents in patients with Behçet's syndrome (BS) is low., Method: We conducted a phase 3, multicentre, prospective, randomised, active-controlled, parallel-group study to evaluate the efficacy and safety of either infliximab (IFX) or adalimumab (ADA) in patients with BS. Adults patients with BS presenting with active mucocutaneous manifestations, occurring while on therapy with either azathioprine or cyclosporine for at least 3 months prior to study entry, were eligible. Participants were randomly assigned (1:1) to receive IFX or ADA for 6 months. The primary study outcome was the time to response of manifestations over 6-month anti-TNF alpha agents' treatment., Results: 42 patients underwent screening visits, of whom 40 were randomly assigned to the IFX group (n=22) or to the ADA group (n=18). All patients at the time of randomisation had active mucocutaneous manifestations and a smaller proportion had concomitant vital organ involvement (ie, six and three patients with ocular and neurological involvement, respectively). A total of 14 (64%) responders in the IFX group and 17 (94%) in the ADA group were observed. Retention on treatment was 95% and 94% in the IFX and in the ADA group, respectively. Quality of life resulted to be significantly improved in both groups from baseline, as well as Behçet's Disease Current Activity Form assessment. We registered two adverse events (one serious) in the ADA group and three non-serious adverse events in the IFX group., Discussion: The overall results of this study confirm the effectiveness of both IFX and ADA in achieving remission in patients with BS affected by mucocutaneous involvement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ on behalf of EULAR.)

Introduction: The impact of ETI therapy on pulmonary function and nutritional status has been widely studied; the literature on the possible outcomes on glycemic control and insulin requirement in patients affected by CFRD is controversial., Aim: The main objective of our study was to evaluate HbA1c levels in patients with cystic fibrosis-related diabetes (CFRD) after one year of therapy with elexacaftor/tezacaftor/ivacaftor (ETI). The secondary objective was to study the changes in the total daily insulin dose (TDD), pulmonary function and metabolism in this population., Materials and Methods: A retrospective single-center observational study was conducted at the Regional Cystic Fibrosis Centre and Diabetology Centre of IRCCS Istituto Giannina Gaslini. The observation period was divided into four different time points: initiation (T0), 3 months (T 3mo ), 6 months (T 6mo ) and 12 months (T 12mo ) of ETI therapy. Demographic and clinical data were collected. The results were then stratified by genotype (homozygous or heterozygous F508del)., Results: Twenty-eight patients with CFRD undergoing insulin therapy were included. TDD (IU) significantly decreased at T 3mo and T 6mo , but not at T 12mo , whereas HbA1c decreased significantly at all three times. The number of hospitalizations and pulmonary exacerbations decreased significantly., Conclusion: We demonstrated both improvement in glycemic control (by means of HbA1c) and insulin requirement in insulin-dependent CFRD patients after one year of ETI treatment.

A simple and sustainable propylphosphonic anhydride (T3P)-assisted methodology for the synthesis of N -acyl tryptamines, an interesting class of gut microbiota-derived endocannabinoid-like lipid mediators, was proposed. This protocol is characterized by great operational simplicity, and all products were obtained at room temperature, without the use of an inert atmosphere and by using limited amounts of non-halogenated solvents. Finally, the possibility to realize the reaction under mechanochemical conditions was explored with interesting results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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 Villano and Di Marzo.)

Objective: To optimise the organisation of care and encourage the adoption of good clinical practices, the RarERN Path © methodology was designed within ERN ReCONNET. The aim of our work was to report the application of RarERN Path © on systemic sclerosis within the ERN ReCONNET centres, providing a feasible and flexible organisational reference model for optimising the systemic sclerosis care pathway in different countries., Methods: RarERN Path © is a six-phase methodology which enables the creation of a reference organisational model co-designed on the basis of the expertise of different stakeholders. It foresees six phases, ranging from the map of existing patients' care pathways and patients' stories, to the consensus on a common organisational patient care pathways, and its key performance indicators definition., Results: The agreed reference model highlights the importance of having an organisational flow for referrals that foresees how patients may access directly the specialised unit from the different referrals. Specific specialised visits were considered as mandatory to be organised and they included cardiologist, pneumologist, gastroenterologist, psychologist, nephrologist, dermatologist, wound care specialist/nurses and other healthcare professionals (such as nurses, social workers and nutritional counselling). Moreover, specific services related to therapy were highlighted as strongly recommended to be organised, mainly represented by infusion therapy and wound care, as well as occupation therapy and physiotherapy., Conclusion: The organisational model emerged from our investigation emphasises that the organisation of specific services for systemic sclerosis treatment should be organised as a solid support for implementing the existing recommendations on systemic sclerosis management in real life., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

The present study describes a small library of peptides derived from a potent and selective CXCR4 antagonist (3), wherein the native disulfide bond is replaced using a side-chain to tail macrolactamization technique to vary ring size and amino acid composition. The peptides were preliminary assessed for their ability to interfere with the interaction between the receptor and anti-CXCR4 PE-conjugated antibody clone 12G5. Two promising candidates (13 and 17) were identified and further evaluated in a 125 I-CXCL12 competition binding assay, exhibiting IC 50 in the low-nanomolar range. Furthermore, both candidates displayed high selectivity towards CXCR4 with respect to the cognate receptor CXCR7, ability to block CXCL12-dependent cancer cell migration, and receptor internalization, albeit at a higher concentration compared to 3. Molecular modeling studies on 13 and 17 produced a theoretical model that may serve as a guide for future modifications, aiding in the development of analogs with improved affinity. Finally, the study provides valuable insights into developing therapeutic agents targeting CXCR4-mediated processes, demonstrating the adaptability of our lead peptide 3 to alternative cyclization approaches and offering prospects for comprehensive investigations into the receptor region's interaction with its C-terminal region., Competing Interests: Declaration of competing interest On behalf of all the authors of the manuscript titled “Disulfide Bond Replacement with Non-Reducible Side Chain to Tail Macrolactamization for the Development of Potent and Selective CXCR4 Peptide Antagonists Endowed with Flanking Binding Sites,” I confirm that A. M. T. and S. S. declare a conflict of interest as they hold a patent on one of the compounds mentioned in the article (compound 3) (WO2021130329A1). The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Cardiovascular diseases are a major cause of death worldwide. Advanced in vitro models can be the key stone for a better understanding of the mechanisms at the basis of the different pathologies, supporting the development of novel therapeutic protocols. In particular, the implementation of induced pluripotent stem cell (iPSC) technology allows for the generation of a patient-specific pluripotent cell line that is able to differentiate in several organ-specific cell subsets while retaining the patient genetic background, thus putting the basis for personalized in vitro modeling toward personalized medicine. The design of iPSC-based models able to recapitulate the complexity of the cardiac environment is a critical goal. Here, we review some of the published efforts to exploit three dimensional (3D) iPSC-based methods to recapitulate the relevant cardiomyopathies, including genetically and non-genetically determined cardiomyopathies and cardiotoxicity studies. Finally, we discuss the actual method limitations and the future perspectives in the field.