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The paper illustrates the progress of Hadrian's Villa digital documentation with special emphasis on a series of modelling issues emerged while studying vaults and cupolas of the site. Together with the more general problem of giving scientific coherence to both active and passive sensor outputs – systematically gathered from 2013 – a methodological problem concerning data interpretation of complex opus caementicium vaults have become dramatically important for the interdisciplinary research team. A methodology for improving the understanding the original shapes of Hadrianic cupolas was designed to provide scholars and professionals operating at the Villa with reliable and easy to use outputs, for interpretation, restoration, maintenance practice. Sensors integration played a fundamental role since allowed researchers a global understanding of intrados and extrados surfaces using reverse modelling applications. Features and 2D primitives extracted from high-resolution models were analysed in order to create flexible procedural models of reconstruction hypothesis/completion of cupolas. Due to the very nature of these shapes (apparently irregular), but with a solid geometric conception, we applied the last achievements of Catmull-Clark bicubic surfaces in combination with Visual Programming Language (VPL). [ABSTRACT FROM AUTHOR]

The paper compares two workflows for the achievement of 3D models aimed at in-depth studies on the geometric features of Cultural Heritage artefacts and their dissemination. The purpose is the outlining of pros and cons of different techniques coming from entertainment and video games industry, starting from highly reliable 3D documentation of cultural assets, i.e. architectural/archaeological/urban sites. Two different possible applications are described: (i) procedural modelling used for understanding and visualising reconstruction hypotheses of the vaulted pavilions at Hadrian's Villa, Tivoli, Rome; (ii) optimisation of 3D high-detailed models, as input files, turned into visual reliable and highly portable assets for game-engines. The first case study is focussed on creating a flexible model for evalueting reconstruction hypotheses and supplying restorers with useful hints for shape completion of ruined pavilions. The second case study makes available detailed digital contents for storytelling historical and cultural events in an attractive way, as in the case of the urban explorative model of Chiuro, a small town in northern Italy. [ABSTRACT FROM AUTHOR]

The peculiar figurative friezes of the buildings with mixtilinear entablature have always fascinated collectors of antiquities since the Renaissance, determining their scattering in private collections and museums throughout Europe. Thanks to the application of digital surveying and reverse modelling techniques, increasingly adopted during the last years for the documentation and enhancement of Cultural Heritage, it has been possible to outline a specific methodology for the restoration works that concern the virtual anastylosis of the architectural order and the correct repositioning of the friezes, also not physically present on site. The master model, which shows the conditions of the Teatro Marittimo before the last restoration works (2017), is the result of several survey campaigns, carried out over the course of the last years, in collaboration with the Direction of the Villa. This model has become the basis for the hypothetical order reconstruction and the repositioning of the friezes, by considering their geometrical, morphological, stylistic, constructive, and figurative features. The ongoing research is in constant update, and it aims at providing methodological directions for virtual anastylosis and scientific tools, also preparatory to a real restoration work, starting from such a unique and delicate site as Villa Adriana. [ABSTRACT FROM AUTHOR]

The Maritime Theatre is one of the iconic buildings of Hadrian's Villa, Tivoli. The state of conservation of the theatre is not only the result of weathering over time, but also due to restoration work carried out during the Fifties of the past century. Although this anastylosis process had the virtue of partially restoring a few of the fragments of the compound's original image, it now reveals diverse inconsistencies and genuine errors in the reassembling of the fragments. This study aims at carrying out a digital reinterpretation of the restoration of the architectural fragments in relation to the architectural order, with particular reference to the miscellaneous decoration of the frieze of the Teatro Marittimo (vestibule and atrium). Over the course of the last few years the Teatro Marittimo has been the target of numerous surveying campaigns using digital methodology (laser scanner and photogrammetry SfM/MVS). Starting with the study of the remains of the opus caementicium on the ground, it is possible to identify surfaces which are then used in the model for subsequent cross sections, so as to achieve the best fitting circumferences to use as reference points to put the fragments back into place. [ABSTRACT FROM AUTHOR]

Image-based modelling tools based on SfM algorithms gained great popularity since several software houses provided applications able to achieve 3D textured models easily and automatically. The aim of this paper is to point out the importance of controlling models parameterization process, considering that automatic solutions included in these modelling tools can produce poor results in terms of texture utilization. In order to achieve a better quality of textured models from image-based modelling applications, this research presents a series of practical strategies aimed at providing a better balance between geometric resolution of models from passive sensors and their corresponding (u,v) map reference systems. This aspect is essential for the achievement of a high-quality 3D representation, since "apparent colour" is a fundamental aspect in the field of Cultural Heritage documentation. Complex meshes without native parameterization have to be "flatten" or "unwrapped" in the (u,v) parameter space, with the main objective to be mapped with a single image. This result can be obtained by using two different strategies: the former automatic and faster, while the latter manual and time-consuming. Reverse modelling applications provide automatic solutions based on splitting the models by means of different algorithms, that produce a sort of "atlas" of the original model in the parameter space, in many instances not adequate and negatively affecting the overall quality of representation. Using in synergy different solutions, ranging from semantic aware modelling techniques to quad-dominant meshes achieved using retopology tools, it is possible to obtain a complete control of the parameterization process. [ABSTRACT FROM AUTHOR]

Objectives: to compare the adequacy of nutritional support in surgical, medical and geriatric wards, and to assess correlates and prognostic implications of inadequate caloric intake. Design: prospective observational study. Setting: an acute-care university hospital. Patients: 370 patients over 70 years of age consecutively admitted to general surgery (n = 86), general medicine (n = 149) and geriatric (n =135) wards. Method: a multidimensional assessment was performed on admission, and the average daily caloric intake was computed. The logistic regression analysis was used to characterize patients at risk of starvation, defined as a caloric intake below 40% of the estimated requirement, and of death. Results: the average daily caloric intake, expressed as mean +/- SD, was 63 +/- 40%, 63 +/- 31% and 69 +/- 34% of that required in surgical, medical and geriatric wards, respectively. Patients at risk of starvation were identified by body mass index <22 kg/cm2 on admission [odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.33-2.241 and pre-admission dependency in activities of daily living (OR = 1.34, 95% CI = 1.03-1.73). Mortality was independently predicted by an actual/required caloric intake ratio below 40% in the first 3 days of stay (OR = 1.87, 95% CI = 1.21-2.85), pre-admission dependency in at least one activity of daily living (OR = 1.91, 95% CI = 1.24-2.94), lymphocytes <1000/mm3 (OR = 1.71, CI = 1.11 -2.64), albumin <3.5 g/dl (OR = 1.69, 95% CI = 1.08- 2.66). Conclusions: nutritional support to geriatric patients is frequently inadequate in both surgical and medical and geriatric wards of the acute-care hospital. Malnourished and dependent patients are at high risk of in-hospital starvation. Inadequate caloric intake is a co-contributor to the risk of hospital mortality. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the TRT results in patients who did not complete the program, with particular reference to the timing and the reasons of their dropout. Design: retrospective case-control study with a telephone survey of 90 patients divided into three groups on the basis of the time of TRT program attendance. A group of control cases (CC) who completed with efficacy the whole TRT program was included.36 patients completed only the first phase of the TRT program (Missing group; M), 34 patients attended additional counseling for less than six months (Non-Compliant; NC), 20 patients attended counseling for more than six months but did not complete the TRT program (Compliant; C). 28 patients (CC) completed with efficacy the whole TRT program. Demographic factors and initial Tinnitus Handicap Inventory (THI) and tinnitus Visual Analogue Scale (VAS) for tinnitus score did not predict patients' dropout from the treatment. Telephonic THI and VAS were significantly lower than the initial ones in all the study groups, except for NC group. To have not shared the TRT program is a fundamental reason for TRT poor results. A single counselling can be effective also in the case the TRT program is not shared, but to follow a part of the TRT program with poor motivations and wrong expectations lead to not satisfactory results. [ABSTRACT FROM AUTHOR]

KEAP1 mutations have been associated with reduced survival in lung adenocarcinoma (LUAD) patients treated with immune checkpoint inhibitors (ICIs), particularly in the presence of STK11 / KRAS alterations. We hypothesized that, beyond co-occurring genomic events, clonality prediction may help identify deleterious KEAP1 mutations and their counterparts with retained sensitivity to ICIs. Beta-binomial modelling of sequencing read counts was used to infer KEAP1 clonal inactivation by combined somatic mutation and loss of heterozygosity (KEAP1 C-LOH) versus partial inactivation [ KEAP1 clonal diploid-subclonal (KEAP1 CD-SC)] in the Memorial Sloan Kettering Cancer Center (MSK) MetTropism cohort (N = 2550). Clonality/LOH prediction was compared to a streamlined clinical classifier that relies on variant allele frequencies (VAFs) and tumor purity (TP) (VAF/TP ratio). The impact of this classification on survival outcomes was tested in two independent cohorts of LUAD patients treated with immunotherapy (MSK/Rome N = 237; DFCI N = 461). Immune-related features were studied by exploiting RNA-sequencing data (TCGA) and multiplexed immunofluorescence (DFCI mIF cohort). Clonality/LOH inference in the MSK MetTropism cohort overlapped with a clinical classification model defined by the VAF/TP ratio. In the ICI-treated MSK/Rome discovery cohort, predicted KEAP1 C-LOH mutations were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAP1 wild-type cases (PFS log-rank P = 0.001; OS log-rank P < 0.001). Similar results were obtained in the DFCI validation cohort (PFS log-rank P = 0.006; OS log-rank P = 0.014). In both cohorts, we did not observe any significant difference in survival outcomes when comparing KEAP1 CD-SC and wild-type tumors. Immune deconvolution and multiplexed immunofluorescence revealed that KEAP1 C-LOH and KEAP1 CD-SC differed for immune-related features. KEAP1 C-LOH mutations are associated with an immune-excluded phenotype and worse clinical outcomes among advanced LUAD patients treated with ICIs. By contrast, survival outcomes of patients whose tumors harbored KEAP1 CD-SC mutations were similar to those with KEAP1 wild-type LUADs. • Variant allele frequency and tumor purity frame deleterious KEAP1 mutations in LUAD. • Clonal KEAP1 mutations with LOH (KEAP1 C-LOH) define a subset of LUAD patients unresponsive to immunotherapy. • Preserved immunotherapy efficacy was noticed in tumors with clonal diploid/subclonal KEAP1 mutations (KEAP1 CD-SC). • Immune-related pathways and markers were differentially represented across KEAP1 C-LOH, KEAP1 CD-SC, and wild-type tumors. [ABSTRACT FROM AUTHOR]

Purpose: Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models., Experimental Design: The Cancer Genome Atlas was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of patients with advanced NSCLC treated with immunotherapy and profiled by RNA sequencing (SU2C n = 153; OAK/POPLAR n = 439). The NSCLC TRACERx421 multiregion sequencing study (tumor regions, n = 947) was used to investigate evolutionary trajectories., Results: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of patients with NSCLC treated with immunotherapy (SU2C PFS P = 0.042, OS P = 0.008; OAK/POPLAR PFS P = 0.0014, OS P < 0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors., Conclusions: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in patients with NSCLC treated with immunotherapy., (©2024 American Association for Cancer Research.)

Background : this study aims to investigate the accuracy and completeness of ChatGPT in answering questions and solving clinical scenarios of interceptive orthodontics. Materials and Methods : ten specialized orthodontists from ten Italian postgraduate orthodontics schools developed 21 clinical open-ended questions encompassing all of the subspecialities of interceptive orthodontics and 7 comprehensive clinical cases. Questions and scenarios were inputted into ChatGPT4, and the resulting answers were evaluated by the researchers using predefined accuracy (range 1-6) and completeness (range 1-3) Likert scales. Results : For the open-ended questions, the overall median score was 4.9/6 for the accuracy and 2.4/3 for completeness. In addition, the reviewers rated the accuracy of open-ended answers as entirely correct (score 6 on Likert scale) in 40.5% of cases and completeness as entirely correct (score 3 n Likert scale) in 50.5% of cases. As for the clinical cases, the overall median score was 4.9/6 for accuracy and 2.5/3 for completeness. Overall, the reviewers rated the accuracy of clinical case answers as entirely correct in 46% of cases and the completeness of clinical case answers as entirely correct in 54.3% of cases. Conclusions : The results showed a high level of accuracy and completeness in AI responses and a great ability to solve difficult clinical cases, but the answers were not 100% accurate and complete. ChatGPT is not yet sophisticated enough to replace the intellectual work of human beings.

Turner syndrome (TS) is a genetic pathology that affects about 1/2500 newborn females. Turner's syndrome is characterized by highly variable genetic anomalies that consist in a partial or complete deletion of the X sexual chromosome; it can be present as a monosomy or as a mosaicism with two o three different cellular lines. 50% of the patients with Turner's syndrome has a 45 XO karyotype while the remaining cases have karyotypes with mosaicism or X isochromosome or with partial or whole Y chromosome. This pathology is characterized by multiple anomalies that involve physical and cognitive development and in particular endocrine, cardiovascular, reproductive, auditive and visual systems. Integrity of the X chromosome in essential for fertility. In TS is accelerated germ cells apoptosis. About 30% of TS girls have some pubertal development, 10-20% undergo menarche and 2-8% go through spontaneous pregnancy. Women with TS should be informed about the risk of premature menopause and should be referred, if possible, to a specialist evaluation with a doctor expert in assisted reproductive techniques. In adolescents and in adults, Premature Ovarian Insufficiency (POI) can be evaluated clinically and biochemically with the classic combination of amenorrhea and elevated FSH concentrations (hypergonadotropic hypogonadism). However, in postpubertal adolescents and adult women, reproductive hormones may remain within the normal range before POI is clinically evident, despite significant depletion of the ovarian reserve. Today, reproductive medicine offers the opportunity of fertility preservation in women with premature ovarian insufficiency (POI). Two techniques have been suggested such as ovarian cortex cryopreservation and oocytes cryopreservation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Porcu, Cipriani and Damiano.)

The aim of the article is to identify, on the basis of the phenomenological and ontological analysis of the experience of pain and the ways in which this experience is expressed in natural language, an ontological modelling of the language of pain and, at the same time, a revision of the traditional version of the McGill questionnaire. The purpose is to provide a different characterisation and an adequate evaluation of the phenomenon of pain, and, consequently, an effective measure of the actual experience of the suffering subject., (© 2023 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Background: Several methods with which to assess the risk of biomechanical overload of the upper limb are described in the literature., Methods: We retrospectively analysed the results of the risk assessment of the biomechanical overload of the upper limb in multiple settings by comparing the application of the Washington State Standard, the threshold limit values (TLV) proposed by the American Conference of Governmental Industrial Hygienists (ACGIH), based on hand-activity levels (HAL) and normalised peak force (PF), the Occupational Repetitive Actions (OCRA) checklist, the Rapid Upper-Limb Assessment (RULA), and the Strain Index and Outil de Repérage et d'Evaluation des Gestes of INRS (Institut National de Recherche et de Sécurité)., Results: Overall, 771 workstations were analysed for a total of 2509 risk assessments. The absence of risk demonstrated for the Washington CZCL, used as the screening method, was in good agreement with the other methods, with the sole exception of the OCRA CL, which showed at-risk conditions in a higher percentage of workstations. Differences in the assessment of the frequency of actions were observed among the methods, while their assessments of strength appeared to be more uniform. However, the greatest discrepancies were observed in the assessment of posture., Conclusions: The use of multiple assessment methods ensures a more adequate analysis of biomechanical risk, allowing researchers to investigate the factors and segments in which different methods show different specificities.

We investigated the spike IgG levels of HIV+ patients on antiretroviral therapy six months after they received their second dose (T2) and six months after the third dose (T3) of the BNT162b2 mRNA vaccine, as well as the influence of different levels of plasma HIV viremia of overall CD4+ cell count and nadir value on the humoral time course. One hundred eighty-four patients were enrolled. The median age was 55 years, the median CD4+ cell count was 639 cells/mm3 and the median nadir value was 258 cells/mm3. On the basis of all tests performed during the study period, persistently undetectable plasma HIV RNA (PUD) was found in 66 patients, low-level viremia (LLV) in 57 and ongoing viremia (OV) in 61. Serum levels of IgG antibodies against a trimeric S-protein antigen were tested with DiaSorin Liaison SARS-CoV-2 TrimericS IgG and the response was classified as optimal (>75th percentile), intermediate (50th−25th percentile) and low (<25th percentile). The frequencies of the three different patterns of plasma HIV viremia (PUD, LLV and OV) were comparable in patients with low, intermediate and optimal IgG response evaluated at T2, with no difference in overall CD4+ cell count or nadir count. At T3, 92.9% of patients achieved an optimal response: T2 response proved to be the most important factor in predicting T3 optimal response in patients with LLV and OV.A nadir value ≤ 330 cells/mm3 had 100% sensitivity in predicting a non-optimal response. In conclusion, we demonstrated the persistence of anti-spike IgG, with high serum levels occurring in most patients six months after the third dose of the BNT162b2 mRNA vaccine and a predictive role of humoral response at T2 in subjects with detectable plasma HIV viremia. Immunological alterations related to past immunodeficiency may persist despite immune reconstitution, and the nadir value could be a useful tool for elaborating personalized vaccine schedules.

Coronavirus disease 2019 (COVID-19) in hemodialysis patients (HD) is characterized by heterogeneity of clinical presentation and outcomes. To stratify patients, we collected clinical and laboratory data in two cohorts of HD patients at COVID-19 diagnosis and during the following 4 weeks. Baseline and longitudinal values were used to build a linear mixed effect model (LME) and define different clusters. The development of the LME model in the derivation cohort of 17 HD patients (66.7 ± 12.3 years, eight males) allowed the characterization of two clusters (cl1 and cl2). Patients in cl1 presented a prevalence of females, higher lymphocyte count, and lower levels of lactate dehydrogenase, C-reactive protein, and CD8 + T memory stem cells as a possible result of a milder inflammation. Then, this model was tested in an independent validation cohort of 30 HD patients (73.3 ± 16.3 years, 16 males) assigned to cl1 or cl2 (16 and 14 patients, respectively). The cluster comparison confirmed that cl1 presented a milder form of COVID-19 associated with reduced disease activity, hospitalization, mortality rate, and oxygen requirement. Clustering analysis on longitudinal data allowed patient stratification and identification of the patients at high risk of complications. This strategy could be suitable in different clinical settings.

Urban seismic networks are considered very useful tools for the management of seismic emergencies. In this work, a study of the first urban seismic network in central Italy is presented. The urban seismic network, built using MEMS sensors, was implemented in the urban district of Camerino, one of the cities in central Italy with the greatest seismic vulnerability. The technological choices adopted in developing this system as well as the implemented algorithms are shown in the context of their application to the first seismic event recorded by this innovative monitoring infrastructure. This monitoring network is innovative because it implements a distributed computing and statistical earthquake detection algorithm. As such, it is not based on the traces received by the stations from the central server; rather, each station carries out the necessary checks on the signal in real time, sending brief reports to the server in case of anomalies. This approach attempts to shorten the time between event detection and alert, effectively removing the dead times in the systems currently used in the Italian national network. The only limit for an instant alarm is the latency in the tcp/ip packages used to send the short reports to the server. The presented work shows the infrastructure created; however, there is not enough data to draw conclusions on this new early warning approach in the field, as it is currently in the data collection phase.

Objective: To evaluate the information collected from workers infected with severe acute respiratory coronavirus virus 2 (SARS-CoV-2) or close contacts using a digital data gathering system (DDGS) developed at the onset of the coronavirus disease 2019 (COVID-19) pandemic to better manage the spread of infection at our hospital., Design: Observational retrospective study., Setting: Tertiary University Hospital "Spedali Civili" Hospital, Brescia, Italy., Participants: Workers (most of whom are healthcare workers) employed at the hospital., Methods: The information collected by the DDGS was transferred to the IBM SPSS statistical software package and then statistically analyzed., Results: Overall, ∼16% of the hospital workforce was infected by SARS-CoV-2 in the first pandemic wave. Nurses were the professional category with the highest infection rate (∼15%). The asymptomatic rate of infection was between 31% and 62%. Positive molecular swabs were significantly more frequent in workers undergoing the test after sending a signaling form to our DDGS. Among workers sending the signaling forms, the information about symptoms was more predictive in terms of risk, compared to the close-contact information. The concordance between molecular swabs and subsequent serological testing was significantly higher in workers signaling their at-risk condition through the DDGS., Conclusions: Overall, our data demonstrate the advantages of a digital system to gather information from workers, which is useful for managing emergencies such as the COVID-19 pandemic. This holds particularly true for large organizations such as hospitals., (© The Author(s) 2022.)

The preservation of fertility in cancer patients is a crucial aspect of modern reproductive medicine. Amenorrhea and infertility often occur after cancer therapy, worsening the quality of life. Cryopreservation of oocytes in young cancer patients is a therapeutic option for preserving fertility. A prospective study was conducted on 508 cancer patients who underwent oocyte cryopreservation to preserve fertility between 1996 and 2021 including the COVID-19 pandemic period. Patients underwent ovarian stimulation, followed by egg retrieval, and oocytes were cryopreserved by slow freezing or vitrification. Sixty-four thawing/warming cycles were performed. Survival, fertilization, pregnancy, and birth rate over the thawing/warming cycles were obtained. The data were compared with those from a group of 1042 nononcological patients who cryopreserved supernumerary oocytes. An average of 8.8 ± 6.9 oocytes were retrieved per cycle, and 6.1 ± 4.2 oocytes were cryopreserved. With their own stored oocytes, 44 patients returned to attempt pregnancy. From a total of 194 thawed/warmed oocytes, 157 survived (80%). In total, 100 embryos were transferred in 57 transfer/cycles, and 18 pregnancies were achieved. The pregnancy rate per transfer and pregnancy rate per patient were 31% and 41%, respectively. No statistically significant differences were observed between oncological patients and nononcological patients. A total of 15 babies were born from oncological patients. Children born showed normal growth and development. One minor malformation was detected.

Uterine sarcomas are rare cancers, sometimes diagnosed in women of childbearing age. Hysterectomy is the standard treatment in early stages. The option of lesion removal to save fertility is described in the literature, but it is still considered experimental. The objective of this systematic review is to report on the available evidence on the reproductive and oncological outcomes of fertility-sparing treatment in women with uterine sarcomas. PubMed, Scopus and Cochrane Central Register of Controlled Trials were searched between 1 January 2011 and 21 June 2021 for publications in English about women with uterine sarcoma treated with a fertility-sparing intervention. Thirty-seven studies were included for a total of 210 patients: 63 low-grade endometrial stromal sarcomas, 35 embryonal rhabdomyosarcomas of the cervix, 19 adenosarcomas, 7 leiomyosarcomas and 2 uterine tumors resembling an ovarian sex cord. Conservative treatment ensured pregnancy in 32% of cases. In terms of oncological outcomes, relapse was related to histology and the worst prognosis was reported for leiomyosarcoma, followed by low-grade endometrial stromal sarcoma, which relapsed in 71% and 54% of cases, respectively. The highest death rate was associated with leiomyosarcoma (57.1%). This study demonstrated that fertility-sparing treatments may be employed in selected cases of early stage uterine sarcoma.

B cell-targeting strategies such as rituximab are widely used in B cell hematologic malignancies, rheumatologic and musculoskeletal diseases and a variety of autoimmune disorders. The purpose of this paper is to illustrate how exposure to anti-CD20 treatment profoundly affects B cell functions involved in anti-SARS-CoV-2 immunity and significantly impacts on the clinical and serological course of SARS-CoV-2 infection, long term immunity and vaccine responses. The data presented here suggest that the effects of B cell-depleting agents on adaptive immunity should be taken into account for the proper selection and interpretation of SARS-CoV-2 diagnostics and to guide appropriate therapeutic approaches and protective measures. Combination therapeutic strategies including immunotherapy in association with prolonged antiviral treatment may play a decisive role in the setting of B cell immune deficiencies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Furlan, Forner, Cipriani, Vian, Rigoli, Gherlinzoni and Scotton.)

Objective: To examine the magnitude and the predictors of emotional reactions to an infertility diagnosis, comparing women and men who were clinically diagnosed with an anatomical cause of infertility or non-anatomical cause of infertility., Study Design: Cross-sectional study involving a total of 133 adults waiting for infertility treatment at the IVF and Infertility Unit of the S. Orsola University Hospital in Bologna (Italy). Of these, 107 patients (55 with anatomical causes of infertility and 52 with non-anatomical causes of infertility; response rate: 80%) took part to the study. After providing informed written consent, each participant was asked to complete the Infertility Self-efficacy Scale, the Fertility Quality of Life, and the Brief Coping Orientation to Problem Experienced, which they returned at their second access to the Unit. Differences between the groups were analyzed through a series of univariate ANOVA, whereas a multiple regression analysis was used to jointly examine the predictors of fertility quality of life., Results: Results showed both gender related and diagnosis related differences. Women had statistically significant lower scores than men on the Infertility Self-Efficacy Scale and on the global, emotional, and mind-body subscales of the Fertility Quality of Life, while they scored significantly higher on the emotion focused and socially supported subscales of the Coping Orientation to Problem Experienced. Independently of gender, patients with non-anatomical causes of infertility scored poorly than patients with anatomical causes of infertility on the relational subscale of the Fertility Quality of Life and on the Avoidant scale of the Brief Coping Orientation to Problem Experienced. Hierarchical multiple regression analyses revealed that higher levels of self-efficacy and a lower use of avoidant coping strategies predicted a more positive quality of life over and above gender and cause of infertility., Conclusion: This study partly confirms data on gender differences in experiencing the psychological burden of infertility and adds some new information, particularly with respect to the prediction of quality of life indicators over and above infertility cause., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

Objectives: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes., Methods: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques., Results: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months., Conclusions: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN., Trial Registration: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115)., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Sexual abstinence is considered one of the several factors that influence sperm quality. Recent studies show that a shortening of the abstinence period could be beneficial mostly in oligoasthenoteratozoospermic (OAT) patients., Objective: Retrospective study to verify the efficacy of a second semen sample after a short abstinence to treat severe OAT infertile patients., Materials and Methods: 127 couples treated between May 2014 and May 2018 were divided into two groups. Study Group 1 (75 cycles): severe OAT characteristics: count <0.2 × 10 6 /mL no progressive motility; count ≥0.2 × 10 6 /mL and no total or progressive motility; 0% normal morphology; a second semen sample was requested after abstinence of 2 h. Control Group 0 (52 cycles): normozoospermic or mild OAT; only one sample was requested. Intracytoplasmic sperm injection was utilized in all cases., Results: All semen parameters were significantly different between Group 0 vs both samples of Group 1 (p < 0.001), excluding volume between Group 0 and 1st sample of Group 1 (p = 0.682). The comparison between 1st and 2nd samples from Group 1 showed significant differences in volume, total and progressive motility and morphology (p < 0.001, p < 0.001, p < 0.020) but not in total sperm count (p = 0.970). Fertilization, pregnancy rate/transfer, implantation and miscarriage rates were 85.9% and 61.1% (p < 0.001), 30.6% and 35.8% (p = 0.700), 17.5% and 24.0 (p = 0.292), 20.0% and 25.0% (p = 0.017) in Group 0 and Group 1 respectively., Discussion and Conclusion: The results show that a short abstinence in severe OAT patients allows us to obtain spermatozoa with better motility. The request for a second semen sample in couples with extreme semen parameters is a valid and simple strategy that helps to achieve the same probability of pregnancy compared to a Control Group. Furthermore, it allows us to utilize fresh spermatozoa avoiding the need to resort to cryopreserved reserves or testicular surgery., (© 2021 American Society of Andrology and European Academy of Andrology.)

Objectives: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis., Methods: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques., Results: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions., Conclusion: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients., Trial Registration: The Zeus study was registered at https://clinicaltrials.gov, NCT02403115., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The canalith repositioning manoeuvre (CRM) described by Epley remains a grade A recommended treatment for Benign Paroxysmal Positional Vertigo (BPPV) of the posterior semicircular canal (PSC). However, significant variability in the efficacy of Epley CRM has been reported., Aims: To compare the treatment efficacy of different combinations of the Epley CRM and Dix-Hallpike retest., Material and Methods: Patients with PSC BPPV were divided into one of the following three treatment groups. Manoeuvre group (M): patients underwent a single Epley CRM without subsequent Dix-Hallpike retesting. Manoeuvre-Control group (MC): patients underwent up to three Epley CRM followed by Dix-Hallpike retesting until nystagmus resolution. Manoeuvre-Control-Manoeuvre group (MCM): A similar procedure to that used in the MC group except that, after the negative Dix-Hallpike retest, there was an additional CRM., Results: A more favourable tendency for recovery was observed in the MCM group. There was a positive odds ratio of 1.1 between groups M and MC at the first control, 2.7 between groups M and MCM, and 2.5 between groups MC and MCM., Conclusions and Significance: Close repetition of a single Epley CRM after the first effective one would allow a positional retest to be combined with a reduction in the risk of persistent/recurrent BPPV.

Uncontrolled inflammation plays a relevant role in the pathogenesis of coronavirus disease-19 (COVID-19). Here, we studied the time trend of inflammatory markers in a population of hemodialysis (HD) patients affected by COVID-19, undergoing two different dialysis approaches. In a prospective study, thirty-one maintenance HD patients with COVID-19 were randomized to expanded HD (HDx), performed using a medium cut-off membrane, or standard treatment using a protein-leaking dialyzer (PLD). Circulating levels of interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TLR4 (sTLR4), and interferon-gamma (IFN-γ), were collected at diagnosis, and one and two weeks after. Compared with 14 non-infected HD patients, COVID-19 patients showed lymphopenia and higher ferritin and lactate dehydrogenase levels. Moreover, COVID-19 patients had higher levels of IL-10 (15.2 (12.5) vs. 1.2 (1.4) pg/mL, p = 0.02). Twenty-nine patients were randomized to HDx (n = 15) or PLD (n = 14). After a single treatment, IL-8 showed a significant reduction in both groups, whereas IL-10 decreased only in HDx. All over the study, there were no significant modifications in circulating cytokine levels between the two groups, except for a parallel increase of IL-8 and IL-10 at one week control in the HDx group. No correlations were found between cytokine levels and clinical outcomes. In maintenance HD patients, COVID-19 is not related to a sustained inflammatory response. Therefore, modulation of inflammation seems not to be a suitable therapeutic target in this specific population.

Purpose: The main purpose and research question of the study are to compare the efficacy of high-security closed versus open devices for human oocytes' vitrification., Methods: A prospective randomized study was conducted. A total of 737 patients attending the Infertility and IVF Unit at S.Orsola University Hospital (Italy) between October 2015 and April 2020 were randomly assigned to two groups. A total of 368 patients were assigned to group 1 (High-Security Vitrification™ - HSV) and 369 to group 2 (Cryotop® open system). Oocyte survival, fertilization, cleavage, pregnancy, implantation, and miscarriage rate were compared between the two groups., Results: No statistically significant differences were observed on survival rate (70.3% vs. 73.3%), fertilization rate (70.8% vs. 74.9%), cleavage rate (90.6% vs. 90.3%), pregnancy/transfer ratio (32.0% vs. 31.8%), implantation rate (19.7% vs. 19.9%), nor miscarriage rates (22.1% vs. 21.5%) between the two groups. Women's mean age in group 1 (36.18 ± 3.92) and group 2 (35.88 ± 3.88) was not significantly different (P = .297). A total of 4029 oocytes were vitrified (1980 and 2049 in groups 1 and 2 respectively). A total of 2564 were warmed (1469 and 1095 in groups 1 and 2 respectively). A total of 1386 morphologically eligible oocytes were inseminated by intracytoplasmic sperm injection (792 and 594 respectively, P = .304)., Conclusions: The present study shows that the replacement of the open vitrification system by a closed one has no impact on in vitro and in vivo survival, development, pregnancy and implantation rate. Furthermore, to ensure safety, especially during the current COVID-19 pandemic, the use of the closed device eliminates the potential samples' contamination during vitrification and storage.

Purpose: We aimed to evaluate the results of Tinnitus Retraining Therapy (TRT) in patients who did not complete the program. Methods: We divided 90 patients who failed to complete the TRT program were into 3 groups: 36 patients who only completed the first phase of the TRT program (Missing group; M), 34 patients who attended counselling for less than 6 months (Noncompliant group; NC) and 20 patients who attended counselling for more than 6 months but did not complete the TRT program (Compliant group; C). The Tinnitus Handicap Inventory (THI), tinnitus Visual Analogue Scales (VAS) and a questionnaire regarding the reasons for dropout were obtained through a telephone survey. Results: Telephonic THI and VAS scores were significantly lower than the initial scores in the M and C groups but not in the NC group. Patients who were unsure about the effectiveness of TRT were prevalent in the NC group, and the poorest long-term THI results were registered in those patients. Conclusions: A fundamental cause of very poor TRT results was when patients were unsure about TRT. On the other hand, a single counselling session could be effective in reducing tinnitus annoyance in patients who accepted the TRT approach and trusted its efficacy.

Hyperkalemia may cause life-threatening cardiac and neuromuscular alterations, and it is associated with high mortality rates. Its treatment includes a multifaceted approach, guided by potassium levels and clinical presentation. In general, treatment of hyperkalemia may be directed towards stabilizing cell membrane potential, promoting transcellular potassium shift and lowering total K + body content. The latter can be obtained by dialysis, or by increasing potassium elimination by urine or the gastrointestinal tract. Until recently, the only therapeutic option for increasing fecal K + excretion was represented by the cation-exchanging resin sodium polystyrene sulfonate. However, despite its common use, the efficacy of this drug has been poorly studied in controlled studies, and concerns about its safety have been reported. Interestingly, new drugs, namely patiromer and sodium zirconium cyclosilicate, have been developed to treat hyperkalemia by increasing gastrointestinal potassium elimination. These medications have proved their efficacy and safety in large clinical trials, involving subjects at high risk of hyperkalemia, such as patients with heart failure and chronic kidney disease. In this review, we discuss the mechanisms of action and the updated data of patiromer and sodium zirconium cyclosilicate, considering that the availability of these new treatment options offers the possibility of improving the management of both acute and chronic hyperkalemia.

Purpose: To determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcome. The main purpose and research question of the study is to determine the impact of BRCA1 and BRCA2 mutations on ovarian reserve and fertility preservation outcomes., Methods: Prospective study: 67 breast cancer patients between 18 and 40 years old, undergoing a fertility preservation by means of oocyte storage were considered. Inclusions criteria for the study were age between 18 and 40 years old, BMI between 18 and 28, breast cancer neoplasm stage I and II according to American Joint Committee on Cancer classification (2017) and no metastasis., Exclusion Criteria: age over 40 years old, BMI < 18 and > 28, breast cancer neoplasm stage III and IV and do not performed the BRCA test. A total of 21 patients had not performed the test and were excluded. Patients were divided into four groups: Group A was composed by 11 breast cancer patients with BRCA 1 mutations, Group B was composed by 11 breast cancer patients with BRCA 2 mutations, Group C was composed by 24 women with breast cancer without BRCA mutations, and Group D (control) was composed by 181 normal women., Results: Group A showed significant lower AMH levels compared to Group C and D (1.2 ± 1.1 vs 4.5 ± 4.1 p < 0.05 and 1.2 ± 1.1 vs 3.8 ± 2.5 p < 0.05). BRCA1 mutated patients showed a significant lower rate of mature oocytes (MII) compared to Group C (3.1 ± 2.3 vs 7.2 ± 4.4 p < 0,05) and Group D (3.1 ± 2.3 vs 7.3 ± 3.4; p < 0,05). Breast cancer patients needed a higher dose of gonadotropins compared to controls (Group A 2206 ± 1392 Group B2047.5 ± 829.9 Group C 2106 ± 1336 Group D 1597 ± 709 p < 0,05). No significant differences were found among the groups considering basal FSH levels, duration of stimulation, number of developed follicles, and number of total retrieved oocytes. Regarding BRCA2 mutation, no effect on fertility was shown in this study., Conclusions: The study showed that BRCA1 patients had a higher risk of premature ovarian insufficiency (POI) confirmed by a diminished ovarian reserve and a lower number of mature oocytes suitable for cryopreservation.

Background: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown., Methods: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up., Results: Cell senescence (p16INK4A, SA-β-galactosidase [SA-β-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05-0.01). Tubular SA-β-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-β-Gal and p16INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16INK4A, but not SA-β-Gal, contributed significantly to the prediction of eGFR loss., Conclusions: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS., (© 2021 S. Karger AG, Basel.)