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In the present paper, double-diffusive convection, taking into account Coriolis effects, in a horizontal layer of Brinkman-anisotropic bi-disperse porous medium is analysed. Via linear instability analysis, we find that convection can set in through stationary or oscillatory motions and the critical Rayleigh numbers for the onset of stationary secondary flow (steady convection) and overstability (oscillatory convection) are determined.

Objectives to evaluate long-term effectiveness and safety of fluocinolone acetonide (FAc) implant used as second-line treatment in patients with persistent diabetic macular edema (DME).Methods retrospective data chart review of 241 pseudophakic eyes of 178 patients treated with FAc from July 2017 to December 2021 in 10 medical retinal units in Italy. The primary endpoint was the change of best-corrected visual acuity (BCVA) and central macular thickness (CMT) at 2 years. A Student's paired t-test was used. Additional therapies for DME and intraocular pressure (IOP)-related events were also evaluated.Results efficacy of FAc was assessed in a subset of 111 eyes with at least 24 months of follow-up. Mean BCVA increased at 2 years by 5.1 ETDRS letters (95%CI = 2.6–7.5; p< 0.001) while mean CMT decreased by 189 µm (95% CI 151–227; p< 0.001). Thirty-eight of these eyes (34.2%) needed additional intravitreal treatments, mainly anti-VEGF. Safety was evaluated on the entire cohort of 241 eyes treated with FAc. Overall, 66 eyes (27.4%) required emergent IOP-lowering medications (typically within the first-year post FAc) while 14 eyes (5.8%) underwent trabeculectomy, mostly during the second year of follow-up.Conclusion FAc implant provides a substantial long-term functional and anatomical benefit when used as second-line treatment in eyes with DME. IOP rise can be adequately managed with topical agents although some eyes may require IOP-lowering surgery.

ABSTRACTIntroductionPeople with severe mental illness have poor cardiometabolic health. Commonly used antidepressants and antipsychotics frequently lead to weight gain, which may further contribute to adverse cardiovascular outcomes.Areas coveredWe searched MEDLINE up to April 2023 for umbrella reviews, (network-)meta-analyses, trials and cohort studies on risk factors, prevention and treatment strategies of weight gain associated with antidepressants/antipsychotics. We developed 10 clinical recommendations.Expert opinionTo prevent, manage, and treat antidepressant/antipsychotic-related weight gain, we recommend i) assessing risk factors for obesity before treatment, ii) monitoring metabolic health at baseline and regularly during follow-up, iii) offering lifestyle interventions including regular exercise and healthy diet based on patient preference to optimize motivation, iv) considering first-line psychotherapy for mild-moderate depression and anxiety disorders, v)choosing medications based on medications’ and patient’s weight gain risk, vi) choosing medications based on acute vs long-term treatment, vii) using effective, tolerated medications, viii) switching to less weight-inducing antipsychotics/antidepressants where possible, ix) using early weight gain as a predictor of further weight gain to inform the timing of intervention/switch options, and x) considering adding metformin or glucagon-like peptide-1 receptor agonists, or topiramate(second-line due to potential adverse cognitive effects) to antipsychotics, or aripiprazole to clozapine or olanzapine.

Educational leaders are increasingly expected to use school climate data to improve outcomes and promote equity for all learners, including in California where school climate is included in state accountability policy. In this study, beliefs towards school climate assessment were explored in a sample (n=298) of California superintendents using a 37-item Likert-style instrument. Data were analyzed using an item response approach and latent class analysis. Findings showed variation in beliefs including three subgroups labeled “true believers” “still questioning” and “remains skeptical.” Findings suggest these groupings influence policy adoption and implementation. Education leaders are in a unique position to interpret and use school climate assessment data to facilitate change if they believe it is important, have the capacity, and trust the data. Implications for school and district improvement under the California continuous improvement model relies on stakeholders and local educational leaders believing in the value of school climate data and trusting its uses to effect change.

Face mask usage has been hypothesized to reduce the rate of post-injection endophthalmitis. This research examined endophthalmitis rates before and during the coronavirus disease 2019 pandemic when face masking was mandated. This study suggests that face masking did not influence the incidence of post-injection endophthalmitis.

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A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO.

ABSTRACTBackgroundUstekinumab (UST) is an interleukin-12/interleukin-23 receptor antagonist recently approved for treating ulcerative colitis (UC) but with limited real-world data. Therefore, we evaluated the effectiveness and safety of UST in patients with UC in a real-world setting.Research design and methodsThis is a multicenter, retrospective, observational cohort study. The primary endpoints were the clinical remission rate (partial Mayo score, PMS, ≤1) and the safety of UST. Other endpoints were corticosteroid-free remission (CSFR) rate, clinical response rate (PMS reduction of at least 2 points), and fecal calprotectin (FC) reduction at week 24.ResultsWe included 256 consecutive patients with UC (M/F 139/117, median age 52). The clinical remission and clinical response rates at eight weeks were 18.7% (44/235) and 53.2% (125/235), respectively, and 27.6% (42/152) and 61.8% (94/152) at 24 weeks, respectively. At 24 weeks, CSFR was 20.3% (31/152), and FC significantly dropped at week 12 (p = 0.0004) and 24 (p = 0.038). At eight weeks, patients naïve or with one previous biologic treatment showed higher remission (p = 0.002) and clinical >response rates (p = 0.018) than patients previously treated with ≥ 2. Adverse events occurred in six patients (2.3%), whereas four patients (1.6%) underwent colectomy.ConclusionThis real-world study shows that UST effectively and safely treats patients with UC.

Background: Atypical-hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy often due to uncontrolled complement activation, characterized by high risk of end-stage kidney disease (ESKD). Eculizumab has improved the outcome, however, its efficacy varies among patients and its discontinuation is debated. Methods: To identify characteristics associated with treatment response, we analyzed 244 aHUS patients referred to our center. Patients were classified according to the presence/absence of complement abnormalities and/or triggers at onset in 4 categories: (1) primary (complement abnormality without trigger), (2) secondary (trigger without complement abnormality), (3) combined (trigger and complement abnormality), (4) idiopathic (no trigger, no complement abnormality). Response to treatment was evaluated by comparing the response to eculizumab with that of conventional therapy. Short- and long-term outcomes were evaluated with the relapse rate after discontinuation of C5-inhibition. Results: Patients had a better outcome with eculizumab compared to conventional treatment, with a response rate of 81.9% vs 56.9%, p&lt; 0.001 and a long-term cumulative incidence of ESKD of 5.8% vs 22.5% (hazard ratio 0.25, 95% confidence interval: 0.10–0.80). The excellent global response was driven by the primary and combined groups (89.8% vs 54.0% and 89.3% vs 54.2%, respectively). The relapse rate following discontinuation of the C5-inhibitor was as high as 66.7% in the primary group, 18.7% in the combined, and 0% in the secondary and idiopathic groups. Conclusions: Our data show a better outcome in aHUS patients treated with C5-inhibition, particularly in the primary and combined forms, which have a high risk of relapse after discontinuation that is not observed in the secondary and idiopathic forms. Graphical abstract:

In this paper, a predator–prey model with intraguild predation describing the evolution between three interacting species—namely prey, mesopredator and top predator—is investigated, with the aim to model a complete food web. In particular, the longtime behaviour of the solutions is analysed, proving the existence of an absorbing set, and the linear and nonlinear stability analyses of the coexistence equilibrium are performed.

Direct communication among vehicles, namely vehicle-to-vehicle (V2V), as part of vehicle-to-everything (V2X) system, will enable most of the upcoming Connected and Autonomous Vehicles (CAVs) applications. Nevertheless, the challenging requirements imposed by the vehicular environment necessitate advanced control mechanisms. Traditional Radio Access Networks (RANs) lack the necessary flexibility to address these control needs. The emerging Open RAN (O-RAN) concept offers a promising solution for orchestrating the V2X network. However, the seamless integration of these ecosystems remains an unresolved challenge. This article promotes a novel integration architecture that ensures the V2X control within O-RAN. We propose a novel architecture that establishes a low frequencies O-RAN-based control plane to ensure reliable and efficient multi-hops connectivity among CAVs at millimeter wave (mmWave). To examine and test the technological feasibility of this integrated architecture, we extend current Network Simulator 3 (ns-3) modules, leading to a simulation framework for experimenting with O-RAN-empowered V2X system. Such an integrated framework is used to show the benefits in a specific V2V challenge: link and relays selection. This case study serves as a practical example of a new O-RAN solution that effectively addresses the challenges of V2X communications. Numerical results showcase the improved reliability up to 60% of the proposed xApp-controlled V2V network, with low latency and negligible overhead, when compared to distributed and unmanaged solutions, supporting the viability of the proposed architecture.

BackgroundSeizures are reported to be more prevalent in individuals with multiple sclerosis (MS) compared with the general population. Existing data predominantly originate from population-based studies, which introduce variability in methodologies and are vulnerable to selection and reporting biases.MethodsThis meta-analysis aims to assess the incidence of seizures in patients participating in randomised clinical trials and to identify potential contributing factors. Data were extracted from 60 articles published from 1993 to 2022. The pooled effect size, representing the incidence rate of seizure events, was estimated using a random-effect model. Metaregression was employed to explore factors influencing the pooled effect size.ResultsThe meta-analysis included data from 53 535 patients and 120 seizure events in a median follow-up of 2 years. The pooled incidence rate of seizures was 68.0 per 100 000 patient-years, significantly higher than the general population rate of 34.6. Generalised tonic-clonic seizures were the most common type reported, although there was a high risk of misclassification for focal seizures with secondary generalisation. Disease progression, longer disease duration, higher disability levels and lower brain volume were associated with a higher incidence of seizures. Particularly, sphingosine-1-phosphate receptor (S1PR) modulators exhibited a 2.45-fold increased risk of seizures compared with placebo or comparators, with a risk difference of 20.5 events per 100 000 patient-years.ConclusionsPatients with MS face a nearly twofold higher seizure risk compared with the general population. This risk appears to be associated not only with disease burden but also with S1PR modulators. Our findings underscore epilepsy as a significant comorbidity in MS and emphasise the necessity for further research into its triggers, preventive measures and treatment strategies.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality in the world, and leads to a substantial burden on healthcare services. Effective and timely management of patients with COPD has been essential to alleviate COPD exacerbation, improve the quality of life, and consequently reduce the economic burden. To achieve this, we propose an innovative tele-medicine system based on Smart Breath Analyzer (SBA) device and devoted to the tele-monitoring of exhaled air in patients suffering chronic respiratory failure and home-assisted by mechanical ventilation. In this work the main characteristics of the developed tele-medicine system are presented together with preliminary pre-clinical test results. The preliminary tests demonstrated the effective possibility to enter the SBAs in medical practice in home-ventilo-therapy protocols by suitable interpretation of the monitored parameters from a physiological point of view. Thanks to a network composed by many SBA devices that send patients data to a remote server, the doctor can tele-monitor the status of patient in order to check any state of exacerbation of the disease and consequently improve quality of life in COPD.

In this short paper, some analytical results found in “Double-diffusive Soret convection phenomenon in porous media: effect of Vadasz inertia term” by F. Capone, R. De Luca, M. Vitiello, Ricerche Mat. 68, 581–595 (2019), are recalled in order to better explore the dynamic of thermosolutal convection in a horizontal porous layer with the influence of Vadasz and Soret terms.

The aim of this paper is to investigate the effect of a vertical constant throughflow on convective instabilities in a horizontal layer of fluid-saturated bi-disperse porous medium heated from below. Via linear instability and nonlinear stability analyses of the throughflow solution, the linear and nonlinear critical Rayleigh numbers for convective instabilities have been determined and studied as functions of the strength of the throughflow.

Metaphor is essential to human cognition and central to teaching and learning. In this case study, the author documents the use of metaphor in a senior-level course as a strategy to build community, provide a sense of direction, and unite the class around a shared experience. Students who experienced the metaphor as a teaching tool were invited to share their memories and reflect on the impact (N= 395). Through content analysis, three themes were identified in the responses: (1) Appreciating the Journey, (2) Building and Supporting a Classroom Community, and (3) Finding Motivation, Purpose, and Willingness to Face the Unknown. Overall, most respondents remembered and valued the metaphor immediately and, in the months, and years following the course. The use of metaphors is recommended in public health teaching and learning.

The development of quantum simulators, artificial platforms where the predictions of many-body theories of correlated quantum materials can be tested in a controllable and tunable way, is one of the main challenges of condensed matter physics. Here we introduce artificial lattices made of lead halide perovskite nanocubes as a new platform to simulate and investigate the physics of correlated quantum materials. We demonstrate that optical injection of quantum confined excitons in this system realizes the two main features that ubiquitously pervade the phase diagram of many quantum materials: collective phenomena, in which long-range orders emerge from incoherent fluctuations, and the excitonic Mott transition, which has one-to-one correspondence with the insulator-to-metal transition described by the repulsive Hubbard model in a magnetic field. Our results demonstrate that time-resolved experiments provide a quantum simulator that is able to span a parameter range relevant for a broad class of phenomena, such as superconductivity and charge-density waves.

The impact of cavitation and inflow perturbation by an upstream support structure on the performance of a horizontal-axis tidal turbine has been studied by experiments at model scale in a depressurized water channel at CNR-INM. Measurements of turbine generated power and thrust have been carried out at varying channel flow speed, tip-speed ratio, and cavitation number. The visualization of cavitation patterns has been associated with the performance measurements to identify the role played by different cavitation types on turbine behavior. Radiated noise measurement were also performed to assess the impact of cavitation phenomena on turbine induced acoustic signature.

Introduction: During the last few years it has been shown that an anaplastic T cell lymphoma can develop as a rare and late sequelae of implant-based breast reconstruction. This malignancy was recognized in the 2017 by WHO and named breast implant associated anaplastic large T cell lymphoma (BIA-ALCL). BIA-ALCL usually presents as abundant effusion around the implant, thus, in addition to cytology smears, its diagnosis also requires immunohistochemistry, T cells clonality and cytometry. Due to the increasing attention of clinicians, it is likely that the number of the BIA-ALCL suspected cases will grow in the future, implying the necessity of a reliable and cost-effective diagnostic procedure.Methods: To achieve this goal, we retrospectively analyzed the results of laboratory investigations performed at our Institute (Fondazione IRCCS Istituto Nazionale dei Tumori Milan, Italy) on 44 effusions obtained from 31 women suspected for BIA-ALCL.Results: Through cytology, eight out of 44 effusions showed the presence of BIA-ALCL cells. Lymphoma cells were than confirmed in seven samples by immunohistochemistry and/or T cell clonality and/or cytometry. Overall, cytology showed 100% sensitivity, 97% specificity and positive and negative predictive values of 87.5% and 100% respectively. Further analyses were particularly useful in effusions showing small percentages of BIA-ALCL cells. Moreover, an extended cytometric profile that can be applied when fast confirmation of the cytologic result is required was also identified.Conclusions: Our results evidenced a central role of cytopathology in the management of BIA-ALCL suspected effusions and suggested that further laboratory investigations might be applied only in cases showing atypical/activated lymphoid cells through cytology.

Accelerating Clinical Trials in the EU (ACT EU) is an initiative developed by the European Commission, Heads of Medicines Agencies and the European Medicines Agency to transform the clinical trials landscape in the European Union. It aims to foster regulatory, technological and process innovation to support better, faster and optimized clinical trials.

AbstractCandida antarcticaLipase B (CALB) is a paradigm for the family of lipases. At pH 7, the optimal pH for catalysis, the protonation state of an aspartic acid of the active site (Asp134) could not be conclusively assigned. In fact, the pKaestimate provided by a widely used computational tool, namely PropKa, that predicts pKavalues of ionizable groups in proteins based on the crystallographic structure, is only slightly above 7 (pKa = 7.25). This, along with the lack of an experimental evaluation, makes the assignment of its protonation state at neutral pH challenging. Here, we calculate the pKaof Asp134 by means of a fully atomistic multiscale computational approach based on classical molecular dynamics (MD) simulation and the perturbed matrix method (PMM), namely the MD-PMM approach. MD-PMM is able to take into account the dynamics of the system and, at the same time, to treat the deprotonation step at the quantum level. The calculations provide a pKavalue of 8.9 ± 1.1, hence suggesting that Asp134 in CALB should be protonated at neutral, and even at slightly basic, pH.Communicated by Ramaswamy H. Sarma

Abstract:Philanthropy has the ability to advance social justice, but it also has the potential to thwart it. This potential stems from the power dynamics experienced in philanthropy, such as one party (i.e., donors) allocating the resources that another party (e.g., individuals, communities, and organizations) needs for its very existence. Frontline fundraisers play an important role in shaping donors’ understanding of the relationship between philanthropy and societal issues, including the potential for power imbalances and the use of critical theories to mitigate those power dynamics. Despite this opportunity, there are not yet widely established guidelines or methodologies for frontline fundraisers. This paper uses a composite case study to illustrate ways frontline fundraisers can facilitate philanthropy while being mindful of the power dynamics, ultimately helping donors to achieve their intended goals of enfranchising individuals and communities.

Galectin-3 binding protein (Gal-3BP) is a glycoprotein that is overexpressed and secreted by several cancers and has been implicated as a marker of both tumor progression and poor prognosis in melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and breast cancer. The expression of Gal-3BP by a variety of neoplasms makes it an enticing target for both diagnostics and therapeutics, including immuno-positron emission tomography (immunoPET) probes and antibody-drug conjugates (ADCs). Herein, we report the development, in vitrocharacterization, and in vivoevaluation of a pair of Gal-3BP-targeting radioimmunoconjugates for 89Zr-immunoPET. A humanized anti-Gal-3BP antibody, 1959, and its corresponding ADC, 1959-sss/DM4 (DM4 = ravtansine), were modified with desferrioxamine (DFO) to yield DFO-1959 and DFO-1959-sss/DM4 immunoconjugates bearing 1–2 DFO/monoclonal antibody. Both DFO-modified immunoconjugates retained their affinity for Gal-3BP in enzyme-linked immunosorbent assay experiments. The chelator-bearing antibodies were radiolabeled with zirconium-89 (t1/2≈ 3.3 d) to produce radioimmunoconjugates ─ [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 ─ with high specific activity (>444 MBq/mg, >12 mCi/mg) and stability (>80% intact after 168 h in human serum at 37 °C). In mice bearing subcutaneous Gal-3BP-secreting A375-MA1 xenografts, [89Zr]Zr-DFO-1959 clearly delineated tumor tissue, reaching a maximum tumoral activity concentration (54.8 ± 15.8%ID/g) and tumor-to-background contrast (tumor-to-blood = 8.0 ± 4.6) at 120 h post-injection. The administration of [89Zr]Zr-DFO-1959 to mice bearing subcutaneous Gal-3BP-expressing melanoma patient-derived xenografts produced similarly promising results. [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 exhibited nearly identical pharmacokinetic profiles in the mice bearing A375-MA1 tumors, though the latter produced higher uptake in the spleen and kidneys. Both [89Zr]Zr-DFO-1959 and [89Zr]Zr-DFO-1959-sss/DM4 effectively visualized Gal-3BP-secreting tumors in murine models of melanoma. These results suggest that both probes could play a role in the clinical imaging of Gal-3BP-expressing malignancies, particularly as companion theranostics for the identification of patients likely to respond to Gal-3BP-targeted therapeutics such as 1959-sss/DM4.