A RANDOMIZED, DOUBLE-BLIND, CROSS-OVER STUDY COMPARING A LEVOSULPIRIDE-BASED AND A METOCLOPRAMIDE-BASED COMBINATION IN THE PREVENTION OF PROMECE-CYTABOM-INDUCED EMESIS

Background. To test two different antiemetic regimens for preventing nausea and vomiting in patients with non-Hodgkin's lymphoma (NHL) undergoing systemic chemotherapy (CT) with ProMECE-CytaBOM (P-C). Patients and Methods. Twenty consecutive untreated adult outpatients with histologically confirmed NHL and scheduled to receive P-C chemotherapy were registered in a randomized, double-blind, cross-over study to compare the antiemetic efficacy of a levosulpiride (LS)-based and metoclopramide (MTC)-based regimen. Results. Complete protection from vomiting was recorded in 93% (62/67) of courses with the LS-regimen and in 89% (62/70) with the MTC-regimen (p = 0.428). No nausea was observed in 84% (56/67) of courses with the LS-regimen and in 74% (52/70) with the MTC-regimen (p = 0.183). No differences in prevention of emesis were recorded when patients crossed to the other regimen. Both regimens were well tolerated; however, on day 8 of chemotherapy, when both antiemetic regimens were administered at a higher dose, the LS-based combination showed significantly lower toxicity (p = 0.035). Conclusions. ProMECE-CytaBOM-induced emesis can be prevented in most cases with appropriate, specifically designed antiemetic therapy. Both the LS- and MTC-based combinations resulted in a high percentage of complete protection from emesis, but the higher incidence of side effects observed with MTC makes the LS-based regimen preferable for patients receiving P-C chemotherapy

PROTEUS: an immersive tool for exploring the world of cultural heritage across space and time scales

AbstractIn the field of digital humanities, it is increasingly necessary to develop and validate virtual reality tools that are capable of combining various scientific data in a virtualized context providing also access and user friendly consultation of online repositories. This paper reports the main aspects of the implementation of a virtual reality tool integrated with an online repository for storing 3D models, metadata and chemical analyses related to different sectors of digital humanities. The virtual reality software, developed for the Oculus Quest 2 hardware, is called PROTEUS and allows for seamless transition from the macroscopic world of digital humanities to the microscopic world of molecular sciences. The paper illustrates, by means of some case studies, the performances of this innovative tool that permits the researcher to understand and manipulate objects, to test hypotheses and to seek meaningful results, visualising the metadata while changing the parameters of the simulation in a dynamic and interactive way. This represents also a significant step forward in the democratisation of science, thanks to an user-friendly and immersive access to advanced scientific algorithms, which allow the natural perception of structural and topological features of the underlying molecular and supra-molecular systems. Graphical Abstrac

The Possible Role of Prescribing Medications, Including Central Nervous System Drugs, in Contributing to Male-Factor Infertility (MFI): Assessment of the Food and Drug Administration (FDA) Pharmacovigilance Database

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: A wide range of medications may have a possible role in the development of male-factor infertility (MFI), including various antineoplastic agents, testosterone/anabolic steroids, immunosuppressive drugs/immunomodulators, glucocorticosteroids, non-steroidal an-ti-inflammatory drugs, opiates, antiandrogenic drugs/5-alpha-reductase inhibitors, various antibi-otics, antidepressants, antipsychotics, antiepileptic agents and others. We aimed at investigating this issue from a pharmacovigilance-based perspective. Methods: The Food and Drug Administra-tion (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the drugs associated the most with MFI individual reports. Only those drugs being associated with more than 10 MFI reports were considered for the disproportionality analysis. Proportional Reporting Ratios (PRRs) and their confidence intervals were computed for all the drugs identified in this way in January 2023. Secondary, ‘unmasking’, dataset analyses were carried out as well. Results: Out of the whole database, 955 MFI reports were identified, 408 (42.7%) of which were associated with 20 medications ,which had more than 10 reports each. Within this group, finasteride, testosterone, valproate, diethylstilbestrol, mechloretamine, verapamil, lovastatin and nifedipine showed signif-icant levels of actual disproportionate reporting. Out of these, and before unmasking, the highest PRR values were identified for finasteride, diethylstilbestrol and mechloretamine, respectively, with values of 16.0 (12.7–20.3), 14.3 (9.1–22.4) and 58.7 (36.3–95.9). Conclusions: A variety of several medications, a number of which were already supposed to be potentially linked with MFI based on the existing evidence, were associated with significant PRR levels for MFI in this analysis. A number of agents which were previously hypothesized to be associated with MFI were not represented in this analysis, suggesting that drug-induced MFI is likely under-reported to regulatory agencies. Reproductive medicine specialists should put more effort into the detection and reporting of these adverse drug reactions.Peer reviewe

JCV-specific T-cells producing IFN-gamma are differently associated with PmL occurrence in HIV patients and liver transplant recipients

Aim of this work was to investigate a possible correlation between the frequency of JCV-specific T-cells and PML occurrence in HIV-infected subjects and in liver transplant recipients. A significant decrease of JCV-specific T-cells was observed in HIV-PML subjects, highlighting a close relation between JCV-specific T-cell immune impairment and PML occurrence in HIV-subjects. Interestingly, liver-transplant recipients (LTR) showed a low frequency of JCV-specific T-cells, similar to HIV-PML subjects. Nevertheless, none of the enrolled LTR developed PML, suggesting the existence of different immunological mechanisms involved in the maintenance of a protective immune response in LT

BacArena: Individual-Based Metabolic Modeling of Heterogeneous Microbes in Complex Communities

Recent advances focusing on the metabolic interactions within and between cellular populations, have emphasized the importance of microbial communities for human health. Constraint-based modeling, with flux balance analysis in particular, has been established as a key approach for studying microbial metabolism, whereas individual-based modeling has been commonly used to study complex dynamics between interacting organisms. In this study, we combine both techniques into the R package BacArena (https://cran.r-project.org/package=BacArena), to generate novel biological insights into Pseudomonas aeruginosa biofilm formation as well as a seven species model community of the human gut. For our P. aeruginosa model, we found that cross-feeding of fermentation products cause a spatial differentiation of emerging metabolic phenotypes in the biofilm over time. In the human gut model community, we found that spatial gradients of mucus glycans are important for niche formations, which shape the overall community structure. Additionally, we could provide novel hypothesis concerning the metabolic interactions between the microbes. These results demonstrate the importance of spatial and temporal multi-scale modeling approaches such as BacArena

Accuracy of automated 3D cephalometric landmarks by deep learning algorithms: systematic review and meta-analysis

Objectives The aim of the present systematic review and meta-analysis is to assess the accuracy of automated landmarking using deep learning in comparison with manual tracing for cephalometric analysis of 3D medical images. Methods PubMed/Medline, IEEE Xplore, Scopus and ArXiv electronic databases were searched. Selection criteria were: ex vivo and in vivo volumetric data images suitable for 3D landmarking (Problem), a minimum of five automated landmarking performed by deep learning method (Intervention), manual landmarking (Comparison), and mean accuracy, in mm, between manual and automated landmarking (Outcome). QUADAS-2 was adapted for quality analysis. Meta-analysis was performed on studies that reported as outcome mean values and standard deviation of the difference (error) between manual and automated landmarking. Linear regression plots were used to analyze correlations between mean accuracy and year of publication. Results The initial electronic screening yielded 252 papers published between 2020 and 2022. A total of 15 studies were included for the qualitative synthesis, whereas 11 studies were used for the meta-analysis. Overall random effect model revealed a mean value of 2.44 mm, with a high heterogeneity (I-2 = 98.13%, tau(2) = 1.018, p-value < 0.001); risk of bias was high due to the presence of issues for several domains per study. Meta-regression indicated a significant relation between mean error and year of publication (p value = 0.012). Conclusion Deep learning algorithms showed an excellent accuracy for automated 3D cephalometric landmarking. In the last two years promising algorithms have been developed and improvements in landmarks annotation accuracy have been done

Temporal lobe connects regression and macrocephaly to autism spectrum disorders

Interictal electroencephalogram (EEG) abnormalities are frequently associated with autism spectrum disorders (ASD), although their relationship with the clinical features of ASD, particularly the regressive onset, remains controversial. The aim of this study was to investigate whether the characteristics of interictal EEG abnormalities might help to distinguish and predict definite phenotypes within the heterogeneity of ASD. We reviewed the awake and sleep interictal EEGs of 220 individuals with idiopathic ASD, either with or without a history of seizures. EEG findings were analyzed with respect to a set of clinical variables to explore significant associations. A brain morphometry study was also carried out on a subgroup of patients. EEG abnormalities were seen in 154/220 individuals (70 %) and were mostly focal (p < 0.01) with an anterior localization (p < 0.001). They were detected more frequently during sleep (p < 0.01), and were associated with a regressive onset of ASD (p < 0.05), particularly in individuals with focal temporal localization (p < 0.05). This association was also stronger in regressive patients with concurrent macrocephaly, together with a relative volumetric reduction of the right temporal cortex (p < 0.05). Indeed, concurrence of temporal EEG abnormalities, regression and macrocephaly might possibly define a distinct endophenotype of ASD. EEG-based endophenotypes could be useful to untangle the complexity of ASD, helping to establish anatomic or pathophysiologic subtypes of the disorder

Validation of the international prognostic index in working formulation group a low-grade non-Hodgkin's lymphoma: retrospective analysis of 137 patients from the Gruppo Italiano per lo studio dei linfomi registry.

BACKGROUND AND OBJECTIVE: The subset of non-follicular non-Hodgkin's lymphoma (NHL) includes patients with varied prognoses, thus suitable for different therapeutic approaches. The International Prognostic Index (IPI), originally proposed for aggressive NHL, has been demonstrated to be of prognostic relevance also in follicular NHL. The main aim of the study was to validate the IPI in this histologic category; in addition, the specific prognostic classification, currently employed in the Gruppo Italiano per lo Studio dei Linfomi (GISL) prospective therapeutic trials and based on different features, more similar to those applied to chronic lymphocytic leukemia, was analyzed. DESIGN AND METHODS: The present series consists of 137 evaluable patients affected by Working Formulation group A NHL out of 256 cases referred to the GISL Registry. The retrospective prognostic study included the evaluation by both univariate and multivariate analyses of overall survival, response to therapy and response duration. The IPI was applied as originally proposed. The GISL definition of indolent and aggressive disease at diagnosis was based on the presence of B symptoms, bulky disease, anemia and thrombocytopenia. RESULTS: The distribution of patients in IPI risk groups was rather unbalanced with 18%, 47%, 28% and 7% of cases classified as low (L), intermediate-low (IL), intermediate-high (IH) and high (H) risk, respectively. The median overall survival was not reached in either L or IL risk groups, and was 84.1 and 7.4 months for IH and H risk groups, respectively (p=0. 0005). A simplified IPI model was designed merging patients in both intermediate risk groups and the statistical difference of survival retained its significance. GISL prognostic stratification was demonstrated to have a significant association with survival, with a median survival of 71.3 months in aggressive disease and a median survival not reached at 152 months in indolent disease. Both the simplified IPI model and the GISL risk definition retained their significance in multivariate analysis for overall survival, while for response to therapy only the simplified IPI model resulted to be of statistical significance. In addition, the GISL prognostic stratification identified patients with different outcomes within the IPI intermediate risk group, with a median survival of 70.2 months for patients with aggressive disease wheras the median survival for those with indolent disease was not reached. Finally, a prognostic score resulting from the integration of the simplified IPI and the GISL system was statistically validated. INTERPRETATION AND CONCLUSIONS: The retrospective analysis of this series demonstrates the validity of the IPI in non-follicular indolent NHL and the usefulness of integrating the IPI parameters with disease specific prognostic variables

The Microbiome Modeling Toolbox: from microbial interactions to personalized microbial communities

The application of constraint-based modeling to functionally analyze metagenomic data has been limited so far, partially due to the absence of suitable toolboxes. To address this gap, we created a comprehensive toolbox to model i) microbe-microbe and host-microbe metabolic interactions, and ii) microbial communities using microbial genome-scale metabolic reconstructions and metagenomic data. The Microbiome Modeling Toolbox extends the functionality of the COBRA Toolbox. The Microbiome Modeling Toolbox and the tutorials at https://git.io/microbiomeModelingToolbox

Absolute monocyte count at diagnosis could improve the prognostic role of early FDG-PET in classical Hodgkin lymphoma patients

Recently published international guidelines suggested that positron emission tomography (PET)-computed tomography (CT) could be utilized for response assessment using the Deauville criteria in fluorodeoxyglucose (FDG)-avid lym- phomas (Meignan et al, 2012). Interim PET (I-PET) scan- ning seems highly predictive of treatment failure in Hodgkin Lymphoma (HL) patients. We recently showed that the absolute monocyte count (AMC) has prognostic value in patients with classical HL (cHL) (Tadmor et al, 2015). Here, we show that the com- bined use of I-PET and AMC at diagnosis enables a more accurate projection of patient outcome in cHL. The present study is an ancillary branch of the analysis reported by Tadmor et al, (2015). Patients with histopatho- logical diagnosis of cHL previously enrolled in the Gruppo Italiano Studio Linfomi trials were eligible if data on all clini- cal and laboratory features and treatments, reported I-PET results, treatment response and follow-up were available. Response was defined according to the revised International Working Group guidelines (Cheson et al, 1999). An absolute lymphocyte count <06 9 10 9 /l and AMC > 075 9 10 9 /l were used as cut-off points. I-PET was performed after 2 cycles of treatment. A positive or negative I-PET was defined by the local investigators’ interpretation of the nuclear physi- cian’s scan report, which was based on a visual qualitative assessment. The principal end-point of the study was the impact of I-PET and AMC on progression-free survival (PFS); their impact on overall survival (OS) was the secondary end-point. Survival functions were estimated using the Kaplan–Meier method. Statistical comparisons between curves were per- formed with log-rank test, and the effect of the covariate was reported as hazard ratios (HR), from Cox regression. All patients had a diagnosis of cHL; 76% of cases had the nodular sclerosis (NS) subtype. Seventy-six patients (64%) were treated with classical ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), and 23 (19%) and 19 (16%) with the more intensive BEACOPP (bleomycin, etoposide, doxoru- bicin, cyclophosphamide, vincristine, procarbazine, pred- nisone) and COPPEBVCAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, bleomycin) regimens (Federico et al, 2009), respectively. Of the entire cohort, 104 patients (88%) achieved complete remission. Twenty-six patients had a positive I-PET (22%) and 28 (24%) had AMC > 075 9 10 9 /l at diagnosis. The median follow-up of the entire cohort was 88 months (range 5–142 months). The estimated 5-year OS was 91% (95% confidence interval [CI]: 84–95%). The 5-year PFS was 80% (95% CI: 71–86%). Patients with positive I-PET showed a worse PFS compared to patients with negative I-PET (51% and 88%, respectively; HR 587 [95% CI: 256–135]). Patients with AMC > 075 9 10 9 /l at diagnosis had a worse PFS compared to patients with AMC ≤ 075 9 10 9 /l (58% and 87%, respectively; HR 373 [95% CI: 161–864]). Multi- ple Cox proportional hazards (PH) regression, adjusted for International Prognostic Score 3–7, confirmed the prognostic role of I-PET (HR 532 [95% CI: 230–123]; P < 0001) and AMC >075 9 10 9 /l (HR 319 [95% CI: 132–768]; P = 0010). Figure 1A, B shows the PFS for I-PET and AMC, and Table I shows the uni- and multivariate Cox PH regres- sion for PFS. The prognostic role of I-PET and AMC on OS was also confirmed. Given the strong predictive value of both I-PET and AMC, we stratified patients by positive or negative I-PET and AMC > 075 9 10 9 /l or ≤075 9 10 9 /l into 3 groups with different levels of risk. The low risk level (negative I- PET and AMC ≤ 075 9 10 9 /l; n = 73, 62%) had a 5-year PFS of 90% (95% CI: 80–96%), the intermediate level (I-PET positive or AMC > 075 9 10 9 /l; n = 36, 51%) had a 5-year PFS of 73% (95% CI: 55–85%), and the high risk level (I-PET positive and AMC > 075 9 10 9 /l; n = 9, 8%) had a 5-year PFS of 17% (95% CI: 1–49%). The log-rank test between the intermediate and low levels and between the high and intermediate levels were significant (P = 0 007, P = 0001, respectively). For OS, the difference between the intermediate and low risk levels tended to narrow (P = 0232), while the difference between the high and inter- mediate levels was significantly different (P < 0001). Fig- ure 1C, D shows the PFS and OS stratified by risk group. The test for trend in PFS and OS was significant (P < 0001). The rationale for using AMC as a prognostic parameter in cHL is relevant because immunohistochemical and molecular data, including the gene expression profile, have identified a key role for monocytes and macrophages in the biology of cHL (Steidl et al, 2010; Porrata et al, 2012; Tan et al, 2012; Koh et al , 2015; Tadmor et al, 2015). It might therefore bepossible that AMC is associated with the number of tumour- associated macrophages (TAMs) in the microenvironment. If so, then it could be considered as a biomarker of reactive cells that is easily detectable in peripheral blood. The FDG- PET scan is currently considered the most precise staging method and may also be used to provide an early prediction of treatment efficacy There is a strong suggestion that reactive cells are respon- sible for the increased FDG uptake at baseline, as they account for 99% of Hodgkin tumours (Gallamini, 2010). Furthermore, early responses to treatment have been sug- gested to demonstrate the elimination of reactive cells, or at least the disappearance of their activity, and are indirect surrogates of tumour chemo-sensitivity (Gallamini & Kostakoglu, 2012). Thus, the FDG-PET scan could be considered a biomarker of the extent and activity of the tumour microenvironment. However, in clinical practice, patients with negative I-PET can rapidly progress during induction treatment, while other patients with positive I-PET may eventually achieve a CR. Therefore, there is a need to further improve the predictive power of I-PET. By combining the AMC at diagnosis with the I-PET results, we showed that it is possible to increase the discriminatory power of I-PET alone in identifying cHL patients with poor PFS and OS. We are fully aware that our study has many weaknesses, such as its retrospective nature, the small number of patients and the lack of use of the Deauville criteria. However, our results suggest that it is pos- sible to further improve the already high predictive power of PET by combining it with a simple and inexpensive surrogate biomarker of reactive cells that are easily detectable in peripheral blood