Search

This study assesses how partially sleep-deprived individuals learn regularities in a predictable yet uncertain environment and evaluates the impact of their expectations on inhibitory control performance. Participants were randomly assigned to undergo either an 8-hour (well-rested, WR, n=36) or a 4-hour (sleep-restriction, SR, n=32) sleep period before performing a Go/No-Go task in which we systematically varied the proportions of Go and No-Go trials (20%-80%, 80%-20%, 50%-50%). Preliminary results showed faster reaction times with increasing "Go" probability for both groups. The WR group showed a growing Go-Probability effect over time, unlike the SR group, suggesting potential differences in the underlying learning styles (e.g., meta- learning). As for accuracy, commission errors were more frequent as the probability of “Go” increased, irrespective of the group. To delve further into the effects of sleep deprivation on learning, a Bayesian model for individual learning under uncertainty will be implemented.

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by respiratory failure due to a vicious cycle of defective Cystic Fibrosis Transmembrane conductance Regulator (CFTR) function, chronic inflammation and recurrent bacterial and fungal infections. Although the recent introduction of CFTR correctors/potentiators has revolutionized the clinical management of CF patients, resurgence of inflammation and persistence of pathogens still posit a major concern and should be targeted contextually. On the background of a network-based selectivity that allows to target the same enzyme in the host and microbes with different outcomes, we focused on sphingosine-1-phosphate (S1P) lyase (SPL) of the sphingolipid metabolism as a potential candidate to uniquely induce anti-inflammatory and antifungal activities in CF. As a feasibility study, herein we show that interfering with S1P metabolism improved the immune response in a murine model of CF with aspergillosis while preventing germination of Aspergillus fumigatus conidia. In addition, in an early drug discovery process, we purified human and A. fumigatus SPL, characterized their biochemical and structural properties, and performed an in silico screening to identify potential dual species SPL inhibitors. We identified two hits behaving as competitive inhibitors of pathogen and host SPL, thus paving the way for hit-to-lead and translational studies for the development of drug candidates capable of restraining fungal growth and increasing antifungal resistance.

Abstract Background Low-income countries bear a growing and disproportionate burden of oral diseases. With the World Health Organization targeting universal oral health coverage by 2030, assessing the state of oral health coverage in these resource-limited nations becomes crucial. This research seeks to examine the political and resource commitments to oral health, along with the utilization rate of oral health services, across 27 low-income countries. Methods We investigated five aspects of oral health coverage in low-income countries, including the integration of oral health in national health policies, covered oral health services, utilization rates, expenditures, and the number of oral health professionals. A comprehensive search was conducted across seven bibliographic databases, three grey literature databases, and national governments’ and international organizations’ websites up to May 2023, with no linguistic restrictions. Countries were categorized into “full integration”, “partial integration”, or “no integration” based on the presence of dedicated oral health policies and the frequency of oral health mentions. Covered oral health services, utilization rates, expenditure trends, and the density of oral health professionals were analyzed using evidence from reviews and data from World Health Organization databases. Results A total of 4242 peer-reviewed and 3345 grey literature texts were screened, yielding 12 and 84 files respectively to be included in the final review. Nine countries belong to “full integration” and thirteen countries belong to “partial integration”, while five countries belong to “no integration”. Twelve countries collectively covered 26 types of oral health care services, with tooth extraction being the most prevalent service. Preventive and public health-based oral health interventions were scarce. Utilization rates remained low, with the primary motivation for seeking care being dental pain relief. Expenditures on oral health were minimal, predominantly relying on domestic private sources. On average, the 27 low-income countries had 0.51 dentists per 10,000 population, contrasting with 2.83 and 7.62 in middle-income and high-income countries. Conclusions Oral health care received little political and resource commitment toward achieving universal health coverage in low-income countries. Urgent action is needed to mobilize financial and human resources, and integrate preventive and public health-based interventions.

Alessandro Finzi,1 Simone Ottoboni,1 Mauro Cellini,1 Beniamino Corcioni,2 Caterina Gaudiano,2 Luigi Fontana1 1Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 2Department of Radiology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyCorrespondence: Alessandro Finzi, Ophthalmology Unit, Department of Experimental, Diagnostic and Specialty Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Pelagio Palagi 9, Bologna, 40138, Italy, Tel +39 051 2142831, Email finzialessandro@gmail.comPurpose: Age-related macular degeneration (AMD) presents a multifaceted etiopathogenesis involving ischemic, inflammatory, and genetic components. This study investigates the correlation between ocular hemodynamics, scleral rigidity (SR), and plasma endothelin-1 (ET1) levels in treatment-naive patients with asymmetrical AMD.Patients and Methods: This study included 20 treatment-naive patients (12 females and 8 males) with an average age of 76.4 ± 3.7 years, who presented with AMD with neovascular membrane formation (nAMD) in one eye, and intermediate grade 2 AMD (iAMD) in the other eye. The control group consisted of 20 healthy subjects (13 females and 7 males) with a mean age of 74.7 ± 3.9 years. All patients and healthy controls underwent color Doppler imaging (i) of the ophthalmic artery (OA), short posterior ciliary arteries (SPCAs), and central retinal artery (CRA); Plasma ET-1 levels were measured for all patients and healthy subjects. Corneal biomechanics were assessed using an Ocular Response Analyzer and two indices were obtained: corneal hysteresis (CH) and corneal resistance factor (CRF).Results: Results showed reduced blood flow velocities and increased resistance indices in AMD eyes, particularly affecting the short posterior ciliary arteries. According to mechanical theory, ARMD eyes exhibited elevated scleral rigidity and corneal resistance factor compared to controls, with a notable rise in SR in neovascular AMD (nAMD) eyes. As per the chronic subacute inflammation theory, plasma ET-1 levels were significantly higher in AMD patients, correlating with abnormal SPCAs blood flow and increased resistance indices.Conclusion: Findings suggest a multifactorial etiology of AMD involving an increase of ET-1 plasma levels with biomechanic damages of corneal and scleral tissue in nAMD.Keywords: AMD, endothelin-1, corneal biomechanics, scleral rigidity, hemodynamics

Abstract Background An equal distribution of hospital structures represents an important factor to achieve Universal Health Coverage. Generally, the most diffused approach to measure the potential availability to healthcare is the provider-to-population ratio based on the number of beds or professionals. However, this approach considers only the availability of resources provided at regional or local level ignoring the spatial accessibility of interregional facilities that are particularly accessed by patients living at the borders. Aim of this study is to outline the distribution of the intra and interregional services in Italy to capture the level of equity across the country. Moreover, it explores the impact of the accessibility to these resources on interregional patient’s mobility to receive care. Methods To compute spatial accessibility, we propose an alternative approach that applies the enhanced two-step floating catchment area (ESFCA) to capture the level of attraction of intra and interregional hospitals to a given population. Moreover, the adoption of process and outcome indices captured to what extent the quality of structures influenced patients in choosing services located inside or outside their region of residence. Results The study confirms that there is an unequal distribution of high-quality resources at regional and national level with a high level of inequality in the availability and accessibility of quality resources between the north and south part of Italy. This is particularly true considering the accessibility of intraregional resources in the southern part of the country that clearly influences patient choice and contribute to a significant cross border passive mobility to northern regions. This is confirmed by an econometric model that showed a significant effect of spatial accessibility with the propensity of patients of travel from the region of residence to receive care. Conclusions The analysis of intra and interregional components of spatial accessibility may contribute to identify to what extent patients are willing to travel outside their region of residence to access to care services. Moreover, it can contribute to gain a deeper understanding of the allocation of health resources providing input for policy makers on the basis of the principles of service accessibility in order to contain patient mobility.

Abstract Introduction School-based comprehensive sexuality education (CSE) is a powerful tool that provides young people with information on all aspects of sexuality and is aimed at protecting their sexual and reproductive health and well-being throughout their lives. Currently, CSE is not integrated within the schools’ curriculum in Italy. This study describes the co-construction, implementation, and evaluation of a CSE project piloted among students attending lower secondary schools, in four regions of Italy. Evidence-based evaluation will be helpful in promote the inclusion of CSE programs in the Italian schools’ curriculum. Methods The pilot scheme was co-constructed by a multidisciplinary curriculum development group through a Delphi process, including educators who conducted the activities. The evaluation followed three directions: the program (based on a literature review of CSE principles and recommended characteristics), implementation (assessing the execution of the program through the analysis of the reflection tools used by the educators), and short-term outcomes (assessing critical thinking and conscious behavioural choices through pre-post and satisfaction surveys). Results The main goal, learning modules and content were defined and structured in five interventions with the students, and two with families and teachers. A total of 638 students were involved in the activity, across 11 schools. Data analysis of pre/post surveys reported a significant increase in knowledge in 12 of the 15 items investigated (p

Abstract Purpose Social context and time are two dimensions within which our entire existence is embedded. Therefore, prompting a positive set of attitudes and beliefs towards these elements is fundamental for individuals’ psychological well-being. Currently, there is limited understanding regarding the interplay between the sense of community and time perspective in relation to psychological distress. The present study aims, at investigating the effects that the sense of community and time perspective have on the levels of anxiety, depression, and stress. Particular attention has been dedicated to testing whether the effect of sense of community on anxiety, depression, and stress is mediated by the deviation from a balanced time perspective. Methods To accomplish our purposes, we asked 352 participants to complete an online survey and respond to the Depression, Anxiety, Stress Scale (DASS-21), the Zimbardo Time Perspective Inventory (ZTPI), and the Multi-Dimensional Sense of Community Scale (MTSOCS). From these scales, we obtained the scores for anxiety, depression, and stress as well as a general score for the sense of community and the deviation from a balanced time perspective. We computed three General Linear Mediation Models, one for each scale of the DASS-21. Results The results showed that the relationship between sense of community and psychological distress was mediated by the deviation from a balanced time perspective extending previous findings and enriching the existing literature on time perspective. Conclusion The results described so far could be applied to build a series of interventions aimed at promoting psychological well-being in the general population. Considering our findings, we suggest that individuals’ health could be promoted by both improving their sense of community, which in turn would decrease their levels of stress, and by restructuring their time perspective when it became dysfunctional and unbalanced.

Abstract Depression is characterized by reduced physical activity and sleep-wake cycle disturbances, often considered important features of the disease. While a few studies have suggested that self-reported reduced physical activity and sleep-wake cycle disturbances might both be linked to depression vulnerability, actigraphy-based measures in vulnerable samples remain largely unexplored. This study relied on actigraphy-based parameters to test whether these disturbances characterize depression vulnerability. Seven-day actigraphy data were collected from 20 (13 female) university students with a high vulnerability to depression, which was determined by the presence of a family history of the condition but no current symptoms, and 32 (21 female) controls with neither a family history of depression nor current depressive symptoms. Daily physical activity, namely gross motor activity, was quantified as average daily acceleration and time spent engaging in moderate-vigorous physical activity (MVPA). The sleep-wake cycle and circadian rhythms were assessed as total sleep duration per night (in hours), sleep within sleep period time (in hours), sleep efficiency (%), and relative amplitude (i.e., the difference between the activity during the day and the night, which reflects circadian rhythms amplitude). Results showed that individuals with a familial risk for depression exhibited reduced daily acceleration and time spent in MVPA relative to the control group, particularly on the weekend during their free time away from scheduled activities. On the other hand, the two groups were comparable in terms of sleep estimates. Taken together, reduced physical activity, but not sleep-wake disturbances, seem to be associated with vulnerability to depression and might be a viable target for identification and prevention efforts.

Abstract Background Making timely moral decisions can save a life. However, literature on how moral decisions are made under time pressure reports conflicting results. Moreover, it is unclear whether and how moral choices under time pressure may be influenced by personality traits like impulsivity and sensitivity to reward and punishment. Methods To address these gaps, in this study we employed a moral dilemma task, manipulating decision time between participants: one group (N = 25) was subjected to time pressure (TP), with 8 s maximum time for response (including the reading time), the other (N = 28) was left free to take all the time to respond (noTP). We measured type of choice (utilitarian vs. non-utilitarian), decision times, self-reported unpleasantness and arousal during decision-making, and participants’ impulsivity and BIS-BAS sensitivity. Results We found no group effect on the type of choice, suggesting that time pressure per se did not influence moral decisions. However, impulsivity affected the impact of time pressure, in that individuals with higher cognitive instability showed slower response times under no time constraint. In addition, higher sensitivity to reward predicted a higher proportion of utilitarian choices regardless of the time available for decision. Conclusions Results are discussed within the dual-process theory of moral judgement, revealing that the impact of time pressure on moral decision-making might be more complex and multifaceted than expected, potentially interacting with a specific facet of attentional impulsivity.

IntroductionThe identification of baseline prognostic factors in Classical Hodgkin Lymphoma could help in tailoring a risk-based approach as the therapeutic landscape expands. Currently, the International Prognostic Score (IPS) represents the most used prediction tool in clinical practice, but other potential baseline risk predictors have been identified.MethodsWe performed a retrospective analysis in a cohort of 274 patients treated with 18FDG-PET/CT-guided ABVD to assess the prognostic significance of the IPS risk factors, and to validate the impact of the peripheral blood lymphocyte to monocyte (LMR) and neutrophil to lymphocyte (NLR) ratios on prognosis definition.ResultsAmong the considered risk factors, stage IV disease (HR 1.83), leukocytosis (HR 2.28), anemia (HR 3.23) and low LMR (HR 2.01) significantly predicted PFS, whereas male sex (HR 2.93), stage IV disease (HR 3.00) and lymphopenia (HR 7.84) significantly predicted OS. A 4 variable and a 3 variable prognostic system was subsequently proposed for PFS and OS, respectively. In both cases, a stark decrease in the survival probability was documented as the score increased. Moreover, by selecting only the significant IPS items and considering a more recently proposed prognostic factor (LMR) we were able to better identify patients at higher risk of relapsing after PET/CT-guided ABVD.DiscussionAlthough the IPS was still able to identify a subgroup of high-risk patients within our cohort of individuals treated with PET/CT-guided ABVD, not all the risk factors that it considers were found to have an impact on survival times. Moreover, by selecting only the significant IPS items and considering a more recently proposed prognostic factor (LMR) we were able to better identify patients at higher risk of relapse, in an effort to contribute to the building of a modern risk prediction tool that can help guide treatment choices.

Abstract Background Oligo-progression or further recurrence is an open issue in the multi-integrated management of oligometastatic disease (OMD). Re-irradiation with stereotactic body radiotherapy (re-SBRT) technique could represent a valuable treatment option to improve OMD clinical outcomes. MRI-guided allows real-time visualization of the target volumes and online adaptive radiotherapy (oART). The aim of this retrospective study is to evaluate the efficacy and toxicity profile of MRI-guided repeated SBRT (MRIg-reSBRT) in the OMD setting and propose a re-SBRT classification. Methods We retrospectively analyzed patients (pts) with recurrent liver metastases or abdominal metastatic lesions between 1 and 5 centimeters from liver candidate to MRIg-reSBRT showing geometric overlap between the different SBRT courses and assessing whether they were in field (type 1) or not (type 2). Results Eighteen pts completed MRIg-reSBRT course for 25 metastatic hepatic/perihepatic lesions from July 2019 to January 2020. A total of 20 SBRT courses: 15 Type 1 re-SBRT (75%) and 5 Type 2 re-SBRT (25%) was delivered. Mean interval between the first SBRT and MRIg-reSBRT was 8,6 months. Mean prescribed dose for the first treatment was 43 Gy (range 24–50 Gy, mean BEDα/β10=93), while 41 Gy (range 16–50 Gy, mean BEDα/β10=92) for MRIg-reSBRT. Average liver dose was 3,9 Gy (range 1–10 Gy) and 3,7 Gy (range 1,6–8 Gy) for the first SBRT and MRIg-reSBRT, respectively. No acute or late toxicities were reported at a median follow-up of 10,7 months. The 1-year OS and PFS was 73,08% and 50%, respectively. Overall Clinical Benefit was 54%. Conclusions MRIg-reSBRT could be considered an effective and safe option in the multi-integrated treatment of OMD.

Abstract Background Chemotherapy is a primary treatment for cancer, but its efficacy is often limited by cancer-associated bacteria (CAB) that impair tumor suppressor functions. Our previous research found that Mycoplasma fermentans DnaK, a chaperone protein, impairs p53 activities, which are essential for most anti-cancer chemotherapeutic responses. Methods To investigate the role of DnaK in chemotherapy, we treated cancer cell lines with M. fermentans DnaK and then with commonly used p53-dependent anti-cancer drugs (cisplatin and 5FU). We evaluated the cells’ survival in the presence or absence of a DnaK-binding peptide (ARV-1502). We also validated our findings using primary tumor cells from a novel DnaK knock-in mouse model. To provide a broader context for the clinical significance of these findings, we investigated human primary cancer sequencing datasets from The Cancer Genome Atlas (TCGA). We identified F. nucleatum as a CAB carrying DnaK with an amino acid composition highly similar to M. fermentans DnaK. Therefore, we investigated the effect of F. nucleatum DnaK on the anti-cancer activity of cisplatin and 5FU. Results Our results show that both M. fermentans and F. nucleatum DnaKs reduce the effectiveness of cisplatin and 5FU. However, the use of ARV-1502 effectively restored the drugs' anti-cancer efficacy. Conclusions Our findings offer a practical framework for designing and implementing novel personalized anti-cancer strategies by targeting specific bacterial DnaKs in patients with poor response to chemotherapy, underscoring the potential for microbiome-based personalized cancer therapies.

Abstract The bin packing is a well-known NP-Hard problem in the domain of artificial intelligence, posing significant challenges in finding efficient solutions. Conversely, recent advancements in quantum technologies have shown promising potential for achieving substantial computational speedup, particularly in certain problem classes, such as combinatorial optimization. In this study, we introduce QAL-BP, a novel Quadratic Unconstrained Binary Optimization (QUBO) formulation designed specifically for bin packing and suitable for quantum computation. QAL-BP utilizes the Augmented Lagrangian method to incorporate the bin packing constraints into the objective function while also facilitating an analytical estimation of heuristic, but empirically robust, penalty multipliers. This approach leads to a more versatile and generalizable model that eliminates the need for empirically calculating instance-dependent Lagrangian coefficients, a requirement commonly encountered in alternative QUBO formulations for similar problems. To assess the effectiveness of our proposed approach, we conduct experiments on a set of bin packing instances using a real Quantum Annealing device. Additionally, we compare the results with those obtained from two different classical solvers, namely simulated annealing and Gurobi. The experimental findings not only confirm the correctness of the proposed formulation, but also demonstrate the potential of quantum computation in effectively solving the bin packing problem, particularly as more reliable quantum technology becomes available.

Abstract Effective String Theory (EST) represents a powerful non-perturbative approach to describe confinement in Yang-Mills theory that models the confining flux tube as a thin vibrating string. EST calculations are usually performed using the zeta-function regularization: however there are situations (for instance the study of the shape of the flux tube or of the higher order corrections beyond the Nambu-Goto EST) which involve observables that are too complex to be addressed in this way. In this paper we propose a numerical approach based on recent advances in machine learning methods to circumvent this problem. Using as a laboratory the Nambu-Goto string, we show that by using a new class of deep generative models called Continuous Normalizing Flows it is possible to obtain reliable numerical estimates of EST predictions.

Abstract Background Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. Methods Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. Results Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as “very high priority”, that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient’s tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. Conclusions PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

IntroductionIn classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (β) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies.Methods and resultsBiochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2β compared to normal B lymphocytes. Mechanistically, CK2β was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin.ConclusionsOur data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2β has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL

We draw on administrative data from the country of Colombia to assess differences in student learning in online and traditional on-campus college programs. The Colombian context is uniquely suited to study this topic, as students take a compulsory exit examination at the end of their studies. We can therefore directly compare the performance on the exit exam for students in online and on-campus programs both across and within institutions, degrees, and majors. Using inverse probability weighting methods based on a rich set of background characteristics coupled with institution--degree--major fixed effects, our results suggest that bachelor's degree students in online programs perform worse on nearly all test score measures (including math, reading, writing, and English) relative to their counterparts in on-campus programs. Results for shorter technical certificates are more mixed. While online students perform significantly worse than on-campus students on exit exams in private institutions, they perform better in SENA--the main public vocational institution in the country.