A two-stages global sensitivity analysis by using the δ sensitivity index in presence of correlated inputs: application on a tumor growth inhibition model based on the dynamic energy budget theory.

Global sensitivity analysis (GSA) evaluates the impact of variability and/or uncertainty of the model parameters on given model outputs. GSA is useful for assessing the quality of Pharmacometric model inference. Indeed, model parameters can be affected by high (estimation) uncertainty due to the sparsity of data. Independence between model parameters is a common assumption of GSA methods. However, ignoring (known) correlations between parameters may alter model predictions and, then, GSA results. To address this issue, a novel two-stages GSA technique based on the δ index, which is well-defined also in presence of correlated parameters, is here proposed. In the first step, statistical dependencies are neglected to identify parameters exerting causal effects. Correlations are introduced in the second step to consider the real distribution of the model output and investigate also the 'indirect' effects due to the correlation structure. The proposed two-stages GSA strategy was applied, as case study, to a preclinical tumor-in-host-growth inhibition model based on the Dynamic Energy Budget theory. The aim is to evaluate the impact of the model parameter estimate uncertainty (including correlations) on key model-derived metrics: the drug threshold concentration for tumor eradication, the tumor volume doubling time and a new index evaluating the drug efficacy-toxicity trade-off. This approach allowed to rank parameters according to their impact on the output, discerning whether a parameter mainly exerts a causal or 'indirect' effect. Thus, it was possible to identify uncertainties that should be necessarily reduced to obtain robust predictions for the outputs of interest.

The moderating role of job resources in the relationship between job demands and interleukin-6 in an Italian healthcare organization.

In this study we examined the association between job demands (JD), job resources (JR), and serum levels of a possible biomarker of stress, the pro-inflammatory cytokine interleukin-6 (IL-6). According to the buffer hypothesis of the Job Demands-Resources (JD-R) model, we expected that job resources-defined as job autonomy and social support from supervisor-might buffer the relationship between job demands, defined as emotional demands and interpersonal conflict with colleagues, and IL-6. Data from 119 employees in an Italian public healthcare organization (acute care hospital) were analyzed using multiple regression. In predicting IL-6, the interactions between emotional demands and JR and between interpersonal conflict with colleagues and job autonomy (but not social support) were significant, after controlling for the effect of age and gender. The association between JD and IL-6 was stronger for individuals with low levels of JR, so that levels of IL-6 were highest when JD were high and JR were low. Overall, these results are consistent with the buffer hypothesis of the JD-R model and also extend previous research, showing that the exposure to stressful situations at work, measured as high JD and low JR, is associated with higher levels of IL-6 in hospital employees.

The mediating role of interpersonal conflict at work in the relationship between negative affectivity and biomarkers of stress.

This study examined the association between interpersonal conflict at work (ICW) and serum levels of three possible biomarkers of stress, namely the pro-inflammatory cytokines Interleukin 1 beta (IL-1ß), Interleukin 12 (IL-12), and Interleukin 17 (IL-17). Additionally, this study investigated the role of negative affectivity (NA) in the relationship between ICW and the pro-inflammatory cytokines. Data from 121 employees in an Italian healthcare organization were analyzed using structural equation modeling. Results showed that ICW was positively associated with IL-1ß, IL-12, and IL-17, after controlling for the effect of gender. Moreover, ICW completely mediated the relationship between NA and the pro-inflammatory cytokines IL-1ß, IL-12, and IL-17. This mediating effect was significant after controlling for the effect of gender. Overall, this study suggests that work-related stress may be associated with biomarkers of inflammation, and that negative affectivity may influence the stress process affecting the exposure to psychosocial stressors.

Reinforcement Learning and PK-PD Models Integration to Personalize the Adaptive Dosing Protocol of Erdafitinib in Patients with Metastatic Urothelial Carcinoma.

The integration of pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulations with artificial intelligence/machine learning algorithms is one of the most attractive areas of the pharmacometric research. These hybrid techniques are currently under investigation to perform several tasks, among which precision dosing. In this scenario, this paper presents and evaluates a new framework embedding PK-PD models into a reinforcement learning (RL) algorithm, Q-learning (QL), to personalize pharmacological treatment. Each patient is represented with a set of PK-PD parameters and has a personal QL agent which optimizes the individual treatment. In the training phase, leveraging PK-PD simulations, the QL agent assesses different actions, defined consistently with the clinical knowledge to consider only plausible dose-adjustments, in order to find the optimal rules. The proposed framework was evaluated to optimize the erdafitinib treatment in patients with metastatic urothelial carcinoma. This drug was approved by the US Food and Drug Administration (FDA) with a dose-adaptive protocol based on monitoring the levels of serum phosphate, which represent a biomarker of both treatment efficacy and toxicity. To evaluate the flexibility of the methodology, a heterogeneous virtual population of 141 patients was generated using an erdafitinib population PK (PopPK)-PD literature model. For each patient, treatment response was simulated by using both QL-optimized protocol and the clinical one. QL agents outperform the approved dose-adaptive rules, increasing more than 10% the efficacy and the safety of treatment at each end point. Results confirm the great potentialities of the integration of PopPK-PD models and RL algorithms to optimize precision dosing tasks.

Predicting ADMET Properties from Molecule SMILE: A Bottom-Up Approach Using Attention-Based Graph Neural Networks.

Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline.

Breaking the maternity mold: navigating the return to work and challenging rigid maternal beliefs through an online psychological intervention.

Working mothers must often balance work and family responsibilities which can be affected by rigid and irrational beliefs about motherhood. The present study had two aims: (a) to provide psychometric evidence for a shortened Italian version of the Rigid Maternal Beliefs Scale (RMBS) and (b) to facilitate mothers' return to work after maternity leave by reducing perceptions of anxiety and stress related to rigid maternal beliefs (i.e., perceptions and societal expectations of mothers, maternal confidence, maternal dichotomy) and by teaching specific recovery strategies (e.g., relaxation, mastery experiences) to manage anxiety and stress through an online psychological intervention. Results replicated the three-factor structure of the original RMBS and showed good psychometric properties. The online psychological intervention resulted in decrease in the rigidity of maternal beliefs, perceived anxiety and stress, and increase in recovery strategies. These initial results are promising and encourage further investigation into online psychological interventions for improving the well-being of working mothers.

In silico trial for the assessment of givinostat dose adjustment rules based on the management of key hematological parameters in polycythemia vera patients.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by excessive levels of platelets (PLT), white blood cells (WBC), and hematocrit (HCT). Givinostat (ITF2357) is a potent histone-deacetylase inhibitor that showed a good safety/efficacy profile in PV patients during phase I/II studies. A phase III clinical trial had been planned and an adaptive dosing protocol had been proposed where givinostat dose is iteratively adjusted every 28 days (one cycle) based on PLT, WBC, and HCT. As support, a simulation platform to evaluate and refine the proposed givinostat dose adjustment rules was developed. A population pharmacokinetic/pharmacodynamic model predicting the givinostat effects on PLT, WBC, and HCT in PV patients was developed and integrated with a control algorithm implementing the adaptive dosing protocol. Ten in silico trials in ten virtual PV patient populations were simulated 500 times. Considering an eight-treatment cycle horizon, reducing/increasing the givinostat daily dose by 25 mg/day step resulted in a higher percentage of patients with a complete hematological response (CHR), that is, PLT ≤400 × 109 /L, WBC ≤10 × 109 /L, and HCT < 45% without phlebotomies in the last three cycles, and a lower percentage of patients with grade II toxicity events compared with 50 mg/day adjustment steps. After the eighth cycle, 85% of patients were predicted to receive a dose ≥100 mg/day and 40.90% (95% prediction interval = [34, 48.05]) to show a CHR. These results were confirmed at the end of 12th, 18th, and 24th cycles, showing a stability of the response between the eighth and 24th cycles.

Immunohistochemical analysis of matrix metalloproteinase-9, vascular endothelial growth factor, bone sialoprotein and i-nitric oxide synthase in calvaria vs. iliac crest bone grafts.

OBJECTIVES: The aim of this study was to investigate, in parallel to clinical and histological modifications, the expression of specific proteins involved in different extraoral autologous bone grafts integration in humans. MATERIAL AND METHODS: Patients needing oral rehabilitation of posterior maxilla, with inadequate bone volume for implant placement, received bone grafts from calvaria (Group 1) and iliac crest (Group 2), respectively. From five patients from each group, with a total of 10 subjects, bone biopsy specimens were collected at two different experimental time points: at bone blocks withdrawal for grafting (T0), from donor sites, and after 4 months, from reconstructed sites. Samples were processed for light microscope and immunohistochemical analyses to evaluate MMP9, VEGF, BSP, iNOS expression. RESULTS: Morphological analysis of T0 calvaria evidenced areas of extracellular matrix, uniformly stained and organized in concentric mineralized lamellae edging few vascular canals, while T0 iliac crest showed greater cellularity compared to calvaria, with rare mineralized areas, surrounding wide bone marrow lacunae. In T1, Group 1 samples showed large areas of extracellular matrix, uniformly stained, at the same time as Group 2 samples disclosed few areas of mineralized tissue. Although no significant differences were found in proteins expression among calvaria and iliac crest T0 samples, MMP9, VEGF and BSP expression at T1 were discovered higher in Group 1 samples than in Group 2 ones, while iNOS expression increased in Group 2 samples compared to the others. In any group, molecules expression increased passing from T0 to T1. CONCLUSION: These findings suggested that, even though clinically both extraoral sources of autologous bone could be considered suitable for grafting in case of large oral rehabilitation, some differences might be detected microscopically and biologically. Calvaria bone graft seemed to enhance not only the quantity of bone tissue at the defect site, but also its quality, better than iliac crest bone do. Then, while both grafts appeared to promote a suitable neoangiogenesis, as showed by morphological analysis and by MMP9 and VEGF expression, in terms of new bone formation and lack of occurrence of inflammatory events, calvaria could be considered a more suitable donor site for bone grafts.

Laparoscopic versus open total mesorectal excision for stage I-III mid and low rectal cancer: a retrospective 5 years analysis.

INTRODUCTION: Total mesorectal excision (TME) is the cornerstone of a correct surgical therapy for extraperitoneal rectal cancer. Aim of the study is to evaluate our 5 years experience confronting retrospectively laparoscopic (lap) TME in respect to its laparotomic (open) counterpart. PATIENTS AND METHODS: 30 patients were treated laparoscopically for stage I-III extraperitoneal rectal cancer and retrospectively compared to a homogeneous group, stratified for sex, age, comorbidities and stage of disease. RESULTS: 30 days mortality was zero for both groups, while morbidity was 20% for the lap group and 36.6% for the open group. Mean lymph nodes harvested was 24 ± 12 for the lap group, 26 ± 14 for the open group (p > 0.05). Five years overall and disease free survival was respectively 82.2% and 81.4% in the lap group, 79.9% and 79.6% in the open group, without statistical significance (p>0.05). Discussion. Minimally invasive TME resulted a safe, effective and oncologically adequate procedure when retrospectively compared to its laparotomic counterpart, with 5 years overall survival and disease free survival reaching no statistical significance compared to the open approach, but with all the advantages of the laparoscopy such as less pain and blood loss, faster recovery, less morbidity and better cosmetics. CONCLUSIONS: Our study has retrospectively demonstrated that laparoscopic TME is feasible and oncologically effective, even if it remains a complex minimally invasive procedure, requiring adequate skill. More prospective, randomized studies are necessary to define such a procedure as the new gold standard in treatment of stage I-III extraperitoneal rectal cancer.

Long-term evaluation of maxillary reconstruction by iliac bone graft.

The aim of this study was to analyze histologic and immunohistochemical modifications taking place in maxillary sites reconstructed by iliac crest bone grafts, 4 months (T1) and 10 years (T2) after grafting, in comparison to native iliac crest bone (T0).By light microscopy, T1 samples showed well-organized osteoblasts and extracellular matrix (ECM), and surrounding areas of connective tissue where a discrete number of blood vessels can be distinguished. Samples obtained from reconstructed areas after a long period of follow-up (T2) were characterized by uniform mineralized ECM with cavities containing osteocytes, whereas T0 samples disclosed both mineralized matrix and bone marrow. Matrix metalloproteinase 2 (MMP-2), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and bone sialoprotein (BSP) expressions were investigated by immunohistochemical analysis. Both MMP-2 and VEGF showed significantly increased expression in T1, with respect to T0, and lowered in T2. Otherwise, BSP expression, which was elevated in native iliac crest bone (T0), was deeply decreased in T1 and T2 samples. Moreover, changes in iNOS expression and in apoptotic cell nuclei percentages (TUNEL analysis) seemed to have a similar trend, increasing in T1 and lowering in T2.After a period of 4 months, iliac crest bone graft-reconstructed sites show mineralizing nuclei not strongly represented, as suggested by BSP lower expression, whereas new blood vessel proliferation and active remodeling phenomena are developing. After a long period from the grafting (T2), BSP expression decreases along with MMP-2, VEGF, and iNOS, suggesting the presence of only weak arrangement phenomena of the graft.

Positive Supervisor Behaviors and Employee Performance: The Serial Mediation of Workplace Spirituality and Work Engagement.

Organizational research has highlighted the crucial role of supervisors in promoting employee well-being and performance. According to the motivational approach, supervisors positively influence employees' outcomes by enhancing their positive feelings. In this study, we examine how positive supervisor behaviors may improve employee performance through the serial mediation of workplace spirituality and work engagement. Data were collected from 330 Italian employees. Results showed that supervisor integrity and responsible behaviors have a positive effect on employee performance directly; moreover, positive supervisor behaviors influence performance indirectly, through both the partial mediation of work engagement and the serial mediation of workplace spirituality and work engagement. The present study highlighted that supervisors should behave responsively and honestly to trigger a virtuous motivational process in their employees, which leads to boost their performance. The practical implications of these findings are discussed.

Employee burnout and positive dimensions of well-being: A latent workplace spirituality profile analysis.

In recent years, a new and promising construct has attracted the attention of organizational research: Workplace spirituality. To investigate the role of workplace spirituality in organizational contexts, two studies were carried out. Study 1 explored the mediation role of workplace spirituality in the relationship between positive supervisor behaviors and employee burnout. Results showed that workplace spirituality strongly contributes to reduce burnout and mediates the effect of supervisor integrity in reducing this threat. Study 2 considered the relationships of workplace spirituality with positive affectivity, resilience, self-efficacy, and work engagement. In particular, workplace spirituality profiles were investigated through latent profile analysis (LPA). Findings showed that workplace spirituality is related to higher positive affectivity, resilience, self-efficacy, and work engagement. In contrast, a workplace spirituality profile characterized by a low-intensity spiritual experience is associated with higher negative feelings. The practical implications of these findings are discussed.

An Opportunity to Grow or a Label? Performance Appraisal Justice and Performance Appraisal Satisfaction to Increase Teachers' Well-Being.

Performance management is a key factor to enhance professional development and improve teaching quality. This process is successful only if teachers perceive it as fair, clear, and effective: namely, if it is satisfying. Carefully considering teachers' attributions in the performance appraisal process is fundamental to better clarify the relations between performance management and positive individual outcomes. Therefore, this study aims to investigate the effects of perceived performance appraisal justice on teachers' well-being, in terms of job performance, job satisfaction, and life satisfaction, hypothesizing the mediation role of performance appraisal satisfaction. Data from a sample of Italian teachers were analyzed through structural equation modeling. Results confirm the mediation role of performance appraisal satisfaction. In particular, perceived performance appraisal justice was positively associated to performance appraisal satisfaction, which, in turn, was positively associated with job performance, job satisfaction, life satisfaction. Consequently, performance appraisal satisfaction totally mediated the relations between performance appraisal justice and the outcomes considered. Findings are relevant for two reasons. First, they contribute to better understanding the performance management process in educational settings - an issue requiring further attention. Second, they contribute to highlighting the importance of performance management efficacy, which is essential not only to improve individual well-being but also to enhance teaching quality.

When Does Work Interfere With Teachers' Private Life? An Application of the Job Demands-Resources Model.

The purpose of this study is to examine the relationship between contextual work-related factors on the one hand, in terms of job demands (i.e., risk factors) and job resources (i.e., protective factors), and work-family conflict (WFC) in teachers on the other. Building on the Job Demands-Resources (JD-R) model, we hypothesized that job demands, namely qualitative, and quantitative workload, are positively associated with WFC in teachers. Moreover, in line with the buffer hypothesis of the JD-R, we expected job resources, in terms of support from supervisor (SS), job autonomy (JA), and participation in decision making (PDM), to affect this association, which is expected to be stronger when job resources are low. The study was conducted in an Italian secondary school. Overall, 122 teachers completed a self-report questionnaire aimed at determining WFC, as well as job demands and resources. The hypothesized relationships were tested using moderated multiple regression. The results of this study largely support our predictions. First, both aspects of workload were positively associated with WFC. Secondly, job resources, including SS and PDM, buffered this association, which was stronger when resources were low. On the contrary, JA did not buffer the association between workload and WFC. Overall, the results of this study are consistent with the JD-R model and contribute to the understanding of work-family conflict among teachers. More specifically, our study suggests that teachers with high levels of job resources, namely SS and PDM, can effectively cope with job demands, in terms of both qualitative and quantitative workload, thus preventing negative consequences such as conflict between work and family domains. Interventions aimed at preventing WFC among teachers should encourage organizations to optimize the balance between job demands and resources, as well as the identification and training of the workers at risk of WFC.

Ethical Leadership as Antecedent of Job Satisfaction, Affective Organizational Commitment and Intention to Stay Among Volunteers of Non-profit Organizations.

The aim of this paper is to investigate among a group of non-profit organizations: (a) the effect of ethical leadership (EL) on volunteers' satisfaction, affective organizational commitment and intention to stay in the same organization; (b) the role played by job satisfaction as a mediator in the relationship between EL and volunteers' intentions to stay in the same organization, as well as between EL and affective commitment. An anonymous questionnaire was individually administered to 198 Italian volunteers of different non-profit organizations. The questionnaire contained the Ethical Leadership Scale, the Volunteers Satisfaction Index, the Affective organization Scale, as well as questions regarding the participants' age, sex, type of work, level of education, length of their volunteer works, intention to volunteer in the following months in the same organization. The construct as well the effects of EL on volunteers is approached in light of the Social Exchange Theory and the Social Learning Theory. Structural equation models were used to test hypothesized relationships. The results confirm the role of mediation of volunteer satisfaction in the relationships between the variables studied. In particular, EL was found to be positively associated both with volunteers' intention of staying and with their affective commitment. In the first case this relationship is fully explained by the mediation of the volunteers' satisfaction, while the latter is explained by both direct and indirect factors. To the authors' knowledge, this the first attempt to understand the role played by EL on volunteers' behavior and, more in general, in the management of non-profit organizations. Findings are relevant both for practitioners and managers of non-profit organization, since they suggest the relevance of the perception of EL by volunteers, as well as for scholars, since they further deepen the knowledge on EL and its effects on the followers. Limits of the study: the questionnaire was administered only among a group of non-statistical sample of volunteers. Furthermore, the study reached only volunteers from Italian non-profit organization.

Small opportunities are often the beginning of great enterprises: The role of work engagement in support of people through the recovery process and in preventing relapse in drug and alcohol abuse.

BACKGROUND: This study, carried out in five Therapeutic Communities (TCs), aims to evaluate the relationship between social support and sense of community for people with pathological addictions and the personal and professional dimensions of hope, resilience, work engagement, future time perspective, and job performance. Support to the person is attained through social support at work by the supervisor and the person's sense of belonging to the community. OBJECTIVE: The purpose of this article is to analyze the relationship between social support, sense of community, hope, resilience, work engagement, future time perspective, and job performance. METHODS: In order to verify the relations between those variables, structural equation models with observed variables (path analysis) were estimated using LISREL 8.80. RESULTS: The results show a direct relationship between social support at work by the supervisor and hope, as well as between sense of community and resilience at work, while work engagement plays a mediating role between the two antecedents and the personal and professional variables investigated - hope, resilience, future time perspective and performance at work. Performance was measured through both people's self-perceptions and their supervisors' evaluations. A positive correlation exists between the two assessments. CONCLUSIONS: The positive consequences of the research entail both theoretical and practical aspects.

Characterizing scientific production of Italian Oral Surgery professionals through evaluation of bibliometric indices.

The aim of this study was to characterize the scientific production of Italian Oral Surgery professionals by evaluating different bibliometric indices. The bibliometric evaluation was conducted on the Scopus Database upon all the Active Members joining three important Italian scientific societies in Oral Surgery (SIdCO, SIO, and SICOI). The scientific production was analysed by considering the number of total publications, number of total citations, h-index, and hc-index. Moreover, the overall sample was divided into two groups (Academics and Not Academics), according to the fact the professionals had or not a university position, and then into sub-groups according to the different career lengths. Statistical analyses were performed to compare the scientific productivity amongst groups. For all the considered parameters a lack of homogeneity between groups was reported, and significantly greater mean values were recorded for the Academics compared to the Not Academics Group. Moreover, the h-index values increased more regularly as the career length progressed than the hc-index values, even if the last seemed to be less variable. h- and hc-indices are both stable bibliometric parameters, but as the hc-index values are related not only to the number of citation but also to their age, it seems to be less influenced by the authors' career length. Bibliometric analysis of the scientific production in dentistry may facilitate the recognition of factors that may further enhance research activity and clinical performance and be useful for a comparative assessment of authors or research groups in terms of quality and quantity of the scientific production.

Macroscopic and microscopic evaluation of a new implant design supporting immediately loaded full arch rehabilitation.

The purpose of this study is to evaluate macroscopic and microscopic appearance of a new implant design, with particular emphasis given to the type of prosthesis connection. Two dental implants of the same type (Torque Type(®), WinSix(®), BioSAFin. S.r.l. - Ancona, Italy), with sandblasted and acid etched surfaces (Micro Rough Surface(®)), but differing from each other for the prosthesis connection system, were examined by scanning electron microscope (SEM) analysis at different magnifications: TTI implant, with a hexagonal internal connection, and TTX implant, with a hexagonal external connection. SEM analysis showed that the Torque Type(®) implant is characterized by a truncated cone shape with tapered tips. The implant body showed a double loop thread and double pitch with blunt tips. For both types of connection, the implant neck was 0.7 mm in height with a 3% taper. This implant design may be able to guarantee osteotomic properties at the time of insertion in a surgical site suitably prepared, a facilitated screwing, thanks to the thread pitch and to the broad and deep draining grooves, thereby ensuring a good primary stability. The different connection design appears defined and precise, in order to ensure a good interface between the fixture and the prosthetic components. Therefore, this design appears to be particularly suitable in cases where a good primary stability is necessary and a precise coupling between endosseous and prosthetic components, as it allows an easy insertion of the fixture even in conditions of reduced bone availability, and in cases of immediately loaded full-arch rehabilitations.