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Background: This pilot study aimed to evaluate the effectiveness of digitally crafted customized healing abutments in stabilizing peri-implant soft tissues following tooth extraction and assess the preservation of peri-implant soft tissue architecture over 5 years. Material and Methods: Forty patients (age ≥ 25 years) were divided into test (n = 20) and control (n = 20) groups. The test group received dental implants with immediate loading after tooth extraction, along with customized healing abutments fabricated using CAD/CAM technology. The control group received dental implants with immediate loading without customized healing abutments. The primary outcome was the change in distance between the peri-implant soft tissue margin and implant fixture surface from baseline to 5 years post implantation. Results: In the test group, there was a significant decrease in the distance between the peri-implant soft tissue margin and fixture surface from baseline to 5 years (p < 0.001), with pairwise comparisons showing significant differences between multiple time points (p < 0.05). The control group showed less pronounced changes over time. Conclusions: Within the limitations of this pilot study, digitally fabricated customized healing abutments appear effective in stabilizing peri-implant soft tissues and preserving soft tissue architecture around dental implants over 5 years following immediate implant placement. Randomized controlled trials are needed to confirm these findings.

Systemic right ventricle (sRV) dysfunction is frequent in patients with congenitally corrected transposition of great arteries (cc-TGA) and those with dextro-transposition of great arteries (D-TGA) after Mustard/Senning operations. This condition should be identified promptly. We aimed to compare echocardiographic parameters with cardiac magnetic resonance (CMR)-derived parameters in patients with sRV and to evaluate their correlation with clinical variables and exercise capacity. Patients with cc-TGA and D-TGA after Mustard/Senning who underwent standard and advanced (speckle tracking and 3D) echocardiography and CMR (including feature-speckle tracking) were included. Clinical and imaging parameters were collected. Echocardiographic-derived right ventricle end-diastolic area and end-systolic area correlated with 3D echocardiographic-derived right ventricle end-diastolic and end-systolic volume (r=0.6, p=0.006 and r=0.8, p=0.002). 3D ejection fraction (EF) correlated with fractional area change and tricuspid annular plane systolic excursion (TAPSE) (r=0.8, p=0.001 and r=0.7, p=0.03). sRV global longitudinal strain correlated with systemic atrial strain (sAS) (r=-0.6, p=0.01). CMR-derived EF correlated with CMR-derived global longitudinal strain (GLS) both endocardial and myocardial (r=-0.7, p=0.007 and r=-0.6, p=0.005). sRV areas as assessed by echo correlated with CMR-derived volumes (r=0.9, p=0.0001 for diastole and r=0.8, p=0.0001 for systole). Similarly, a correlation was found between sRV echo-derived GLS and CMR-derived GLS, both endocardial and myocardial (r=0.8, p=0.001 and r=0.7, p=0.01). The only imaging parameter which correlated with peak V02 was sAS (r=0.55, p=0.04). When comparing cc-TGA and D-TGA, the former showed better GLS-derived values as assessed by CMR (CMR-derived right ventricle endocardial longitudinal strain -23.2% versus -17.2%, p=0.002; CMR-derived right ventricle myocardial longitudinal strain -21.2% versus -16.7%; p=0.05), bigger systemic atrial area (20.2 cm2/m2 versus 8.4 cm2/m2, p=0.005) and higher TAPSE values (16.2 mm versus 12.2 mm, p=0.04). Echocardiography is valid to screen for sRV dilatation and function and to guide the timing for CMR. The investigation of atrial deformation imaging may help to better understand diastolic function. Patients with cc-TGA show better cardiac function compared to patients after atrial switch. Further investigations are needed to identify imaging parameters linked to exercise capacity.

Summary: Background: Severe and prolonged mpox courses have been described during the 2022–2023 outbreak. Identifying predictors of severe evolution is crucial for improving management and therapeutic strategies. We explored the predictors of mpox severity and tested the association between mpox severity and viral load in biological fluids. We also analysed the predictors of disease duration and kinetics of inflammatory markers and described the viral presence and duration of shedding in biological fluids. Methods: This multicentre historical cohort study included adults diagnosed with laboratory-confirmed mpox diagnosis between May 2022 and September 2023 at 15 Italian centres. Patients were followed up from the day of diagnosis until clinical recovery. Biological fluids (blood, urine, saliva, and oropharyngeal and rectal swabs) were collected from each subgroup during the course of the disease and after healing. The primary outcomes were disease severity (presence of mucosal involvement, extended rash, or need for hospitalisation) and its association with the cycle threshold value (Ct-value, surrogate of viral load) in biological fluids, using standard linear and linear mixed-effect logistic regression models. Among the secondary outcomes, predictors of disease duration were assessed using a linear regression model. Findings: A total of 541 patients were enrolled, including four (0.74%) women, with a median age of 38 years (IQR 33–44). Among the 235 people living with HIV (PLWH) (43.44%), 22 (4.07%) had a CD4 count lower than 350 cells/μL. Severe mpox was reported in 215 patients (39.74%). No patient died. Multivariable analysis showed that, severe mpox was more likely among Caucasians (OR 1.82; 95% CI 1.14–2.90, p = 0.012) and patients who had an onset of fever (1.95; 1.27–2.99, p = 0.002), lymphadenopathy (2.30; 1.52–3.48, p

Abstract In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade. Trial registration: NCT02460224. Registered 02/06/2015.

Abstract In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability. Herein, we aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets. We identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. Principal Component Analysis was used to generate a HER2-low signature whose performance was evaluated in the independent INT3 (n = 95), and in the publicly available TCGA and GSE81538 datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by Kruskal–Wallis test with post hoc pair-wise comparisons. The HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic curve (AUC). Gene Ontology and KEGG analyses were performed to evaluate the HER2-low signature genes functional enrichment. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature values showed a bell-shaped distribution across IHC categories (low values in 0 and 3+; high values in 1+ and 2+), effectively distinguishing HER2-low from 0 (p

Abstract Drinking water infrastructures are systems of pipes which are generally networked. They play a crucial role in transporting and delivering clean water to people. The water quality analysis refers to the evaluation of the advective diffusion of any substance in drinking water infrastructures from source nodes. Such substances could be a contamination for the system or planned for the disinfection, e.g., chlorine. The water quality analysis is performed by integrating the differential equation in the pipes network domain using the kinetics of the substance decay and the Lagrangian scheme. The kinetics can be formulated using a specific reaction order depending on the substance characteristics. The basis for the integration is the pipes velocity field calculated by means of hydraulic analysis. The aim of the present work is to discover the intrinsic mechanism of the substance transport in drinking water infrastructures, i.e., their pipes network domain, using the symbolic machine learning, named Evolutionary Polynomial Regression, which provides “synthetic” models (symbolic formulas) from data. We demonstrated, using one real network and two test networks, that the concentration at each node of the network can be predicted using the travel time along the shortest path(s) between the source and each node. Additionally, the formula models provided by symbolic machine learning allowed discovering that a unique formula based on kinetic reaction model structure allows predicting the residual substance concentration at each node, given the source node concentration, surrogating with a good accuracy the integration of the differential equations.

Abstract Background Mucosal Melanomas (MM) are highly aggressive neoplasms arising from mucosal melanocytes. Current treatments offer a limited survival benefit for patients with advanced MM; moreover, the lack of pre-clinical cellular systems has significantly limited the understanding of their immunobiology. Methods Five novel cell lines were obtained from patient-derived biopsies of MM arising in the sino-nasal mucosa and designated as SN-MM1-5. The morphology, ultrastructure and melanocytic identity of SN-MM cell lines were validated by transmission electron microscopy and immunohistochemistry. Moreover, in vivo tumorigenicity of SN-MM1-5 was tested by subcutaneous injection in NOD/SCID mice. Molecular characterization of SN-MM cell lines was performed by a mass-spectrometry proteomic approach, and their sensitivity to PI3K chemical inhibitor LY294002 was validated by Akt activation, measured by pAkt(Ser473) and pAkt(Thr308) in immunoblots, and MTS assay. Results This study reports the validation and functional characterization of five newly generated SN-MM cell lines. Compared to the normal counterpart, the proteomic profile of SN-MM is consistent with transformed melanocytes showing a heterogeneous degree of melanocytic differentiation and activation of cancer-related pathways. All SN-MM cell lines resulted tumorigenic in vivo and display recurrent structural variants according to aCGH analysis. Of relevance, the microscopic analysis of the corresponding xenotransplants allowed the identification of clusters of MITF-/CDH1-/CDH2 + /ZEB1 + /CD271 + cells, supporting the existence of melanoma-initiating cells also in MM, as confirmed in clinical samples. In vitro, SN-MM cell lines were sensitive to cisplatin, but not to temozolomide. Moreover, the proteomic analysis of SN-MM cell lines revealed that RICTOR, a subunit of mTORC2 complex, is the most significantly activated upstream regulator, suggesting a relevant role for the PI3K-Akt-mTOR pathway in these neoplasms. Consistently, phosphorylation of NDRG1 and Akt activation was observed in SN-MM, the latter being constitutive and sustained by PTEN loss in SN-MM2 and SN-MM3. The cell viability impairment induced by LY294002 confirmed a functional role for the PI3K-Akt-mTOR pathway in SN-MM cell lines. Conclusions Overall, these novel and unique cellular systems represent relevant experimental tools for a better understanding of the biology of these neoplasms and, as an extension, to MM from other sites.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease, whose main autoantigens are hemidesmosomal components BP180 and BP230. Although recent studies found no association between COVID-19 vaccines and BP, since mass vaccinations started, more than 90 vaccine-associated BP cases have been reported. To find an agreement among real-life clinical observations and recent epidemiologic data, we further investigated this topic. A total of 64 patients with BP onset in 2021 were demographically, clinically, and serologically characterized: 14 (21.9%) vaccine-associated patients (VA) developed BP within 5 weeks from the first/second vaccine dose. VA and vaccine-non-associated (VNA) patients had similar demographics and clinical and immunological characteristics. Noteworthy, the monthly distribution of BP onset during mass vaccinations paralleled vaccine administration to the elderly in the same catchment area. Additionally, in 2021, BP onsets in April–May and June–July significantly increased (p = 0.004) and declined (p = 0.027), respectively, compared to the three years before vaccination campaigns (2018–2020). Interestingly, VA and VNA patients showed statistically significant differences in the use of inhalers and diuretics. Our findings suggest that the COVID-19 vaccine may constitute an accelerating factor that, together with other triggering factors, could act in genetically predisposed individuals with possible sub-clinical autoreactivity against BP antigens, slightly accelerating BP onset.

The number for orthopedic implants and reconstructive joint replacements, including knee and hip implants, underwent a considerable increase, driven by the aging population and increasing prevalence of musculoskeletal disorders [...]

Total hip arthroplasties aim to improve quality of life and reduce pain in patients suffering from late-stage hip osteoarthritis. On the other hand, it may represent a risky surgical procedure in people who refuse blood products because of religious beliefs, such as Jehovah’s Witnesses (JW). Preoperative optimisation protocols of these patients allow medical professionals to perform arthroplasties in a safer manner, avoiding allogeneic blood transfusion. In our retrospective study, two groups of patients were evaluated. Group 1 included JW patients who underwent a preoperative Hb optimisation program; Group 2 included non-JW patients authorizing transfusion in case of necessity. Differences in Hb levels were as follows: before surgery (JW 14.24 ± 1.10 vs. non-JW 12.48 ± 1.00, p-value ≤ 0.05), and after surgery (day 1 Hb: JW 12.88 ± 0.90 vs. non-JW 10.04 ± 1.30, p-value ≤ 0.05; day 3 Hb: JW 14.65 ± 0.80 vs. non-JW 9.10 ± 0.90 p-value ≤ 0.05). Moreover, cost-effectiveness strategies were evaluated in both groups. Our findings support that patient blood management programs are a safe and good strategy in hip prosthetic surgery, decreasing risks and transfusion overuse.

Men who have sex with men (MSM) are disproportionately impacted by sexually transmitted infections (STIs), including HIV and those preventable through vaccination such as mpox, HPV, HAV, and HBV. A retrospective cohort study was conducted to evaluate the effectiveness of counseling provided during mpox vaccination on the uptake of other recommended vaccines (HPV, HAV, and HBV) and to identify associated factors. Relevant covariates such as nationality, age, HIV status, and use of PrEP were retrieved from electronic medical records. Vaccination status data were retrieved from the regional vaccination registry. Of the 330 participants, 98.8% were males and the mean age was 40.6 years (SD: 11.2). Following consultation, a statistically significant increase for both HPV (from 25.8% to 39.1%) and HAV (from 26.7% to 36.1%) was observed (p < 0.001). The multivariate analysis showed a significant negative association between the uptake of HPV and HBV vaccines and foreign nationality (aOR 0.25 (95%CI 0.08–0.69), p = 0.012; and aOR 0.31 (95%CI 0.11–0.81), p = 0.021). The HBV vaccine uptake was negatively associated with increasing age. Our results suggest that tailored counseling can effectively bridge the gap in vaccine acceptance among vulnerable populations, thereby improving overall public health outcomes.

Abstract Advancing knowledge of the mineralogical composition of dust is key for understanding and predicting its climate and environmental impacts. The variability of dust mineralogy from one source to another and its evolution during atmospheric transport is not measured at large scale. In this study we use laboratory measurements to demonstrate that the extinction signature of suspended dust aerosols in the 740 − 1250 cm−1 atmospheric window can be used to derive dust mineralogy in terms of the main infrared − active minerals, namely quartz, clays, feldspars and calcite. Various spectral signatures in dust extinction enable to distinguish between multiple global sources with changing composition, whereas modifications of the dust extinction spectra with time inform on size − dependent particles mineralogy changes during transport. The present study confirms that spectral and hyperspectral infrared remote sensing observations offer great potential for elucidating the size − segregated mineralogy of airborne dust at regional and global scales.

Purpose The PRESTIGIO Registry was established in 2017 to collect clinical, virological and immunological monitoring data from people living with HIV (PLWH) with documented four-class drug resistance (4DR). Key research purposes include the evaluation of residual susceptibility to specific antiretrovirals and the validation of treatment and monitoring strategies in this population.Participants The PRESTIGIO Registry collects annual plasma and peripheral blood mononuclear cell samples and demographic, clinical, virological, treatment and laboratory data from PLWH followed at 39 Italian clinical centres and characterised by intermediate-to-high genotypic resistance to ≥1 nucleoside reverse transcriptase inhibitors, ≥1 non-nucleoside reverse transcriptase inhibitors, ≥1 protease inhibitors, plus either intermediate-to-high genotypic resistance to ≥1 integrase strand transfer inhibitors (INSTIs) or history of virological failure to an INSTI-containing regimen. To date, 229 people have been recorded in the cohort. Most of the data are collected from the date of the first evidence of 4DR (baseline), with some prebaseline information obtained retrospectively. Samples are collected from the date of enrollment in the registry.Findings to date The open-ended cohort has been used to assess (1) prognosis in terms of survival or development of AIDS-related or non-AIDS-related clinical events; (2) long-term efficacy and safety of different antiretroviral regimens and (3) virological and immunological factors predictive of clinical outcome and treatment efficacy, especially through analysis of plasma and cell samples.Future plans The registry can provide new knowledge on how to implement an integrated approach to study PLWH with documented resistance to the four main antiretroviral classes, a population with a limited number of individuals characterised by a high degree of frailty and complexity in therapeutic management. Given the scheduled annual updates of PLWH data, the researchers who collaborate in the registry can send study proposals at any time to the steering committee of the registry, which evaluates every 3 months whether the research studies can be conducted on data and biosamples from the registry and whether they are aimed at a better understanding of a specific health condition, the emergence of comorbidities or the effect of potential treatments or experimental drugs that may have an impact on disease progression and quality of life. Finally, the research studies should aim to be inclusive, innovative and in touch with the communities and society as a whole.Trial registration number NCT04098315.

AbstractBackground Candidemia is associated with a heavy burden of morbidity and mortality in hospitalized patients. The availability of blood culture results could require up to 48–72 h after blood draw; thus, early treatment decisions are made in the absence of a definite diagnosis.Methods In this retrospective study, we assessed the performance of different supervised machine learning algorithms for the early differential diagnosis of candidemia and bacteremia in adult patients on a large dataset automatically extracted within the AUTO-CAND project.Results Overall, 12,483 episodes of candidemia (1275; 10%) or bacteremia (11,208; 90%) were included in the analysis. A random forest classifier achieved the best diagnostic performance for candidemia, with sensitivity 0.98 and specificity 0.65 on the training set (true skill statistic [TSS] = 0.63) and sensitivity 0.74 and specificity 0.57 on the test set (TSS = 0.31). Then, the random classifier was trained in the subgroup of patients with available serum β-D-glucan (BDG) and procalcitonin (PCT) values by exploiting the feature ranking learned in the entire dataset. Although no statistically significant differences were observed from the performance measures obtained by employing BDG and PCT alone, the performance measures of the classifier that included the features selected in the entire dataset, plus BDG and PCT, were the highest in most cases.Conclusions Random forest classifiers trained on large datasets of automatically extracted data have the potential to improve current diagnostic algorithms for candidemia. However, further development through implementation of automatically extracted clinical features may be necessary to achieve crucial improvements.

AbstractBackground Hospitalized patients with coronavirus disease 2019 (COVID-19) can be classified into different clinical phenotypes based on their demographic, clinical, radiology, and laboratory features. We aimed to validate in an external cohort of hospitalized COVID-19 patients the prognostic value of a previously described phenotyping system (FEN-COVID-19) and to assess the reproducibility of phenotypes development as a secondary analysis.Methods Patients were classified in phenotypes A, B or C according to the severity of oxygenation impairment, inflammatory response, hemodynamic and laboratory tests according to the FEN-COVID-19 method.Results Overall, 992 patients were included in the study, and 181 (18%), 757 (76%) and 54 (6%) of them were assigned to the FEN-COVID-19 phenotypes A, B, and C, respectively. An association with mortality was observed for phenotype C vs. A (hazard ratio [HR] 3.10, 95% confidence interval [CI] 1.81–5.30, p

Abstract In this experimental study, we investigate the nonlinear dynamic response of nanocomposite beams composed of polybutylene terephthalate (PBT) and branched carbon nanotubes (bCNTs). By varying the weight fraction of bCNTs, we obtain frequency response curves for cantilever specimens under harmonic base excitations, measuring the tip displacement via 3D scanning laser vibrometry. Our findings reveal a surprising nonlinear softening trend in the steady-state response of the cantilevers, which gets switched into hardening for higher bCNT weight fractions and increasing oscillation amplitudes. The interaction of bCNTs with the thermoplastic hosting matrix results in stick-slip hysteresis, causing a softening nonlinearity that counteracts the geometric hardening associated with the nonlinear curvature of the first mode of the cantilever. However, when the weight fraction of bCNTs is greater than 1%, the bridging of the branched CNTs leads to the formation of a strong network that contributes to the hardening response at higher oscillation amplitudes. This mechanical behavior is detected by the trend of the nonlinear harmonic spectra and the equivalent damping ratio estimated using the half-power bandwidth method. To predict the observed unusual experimental behavior, we use a nonlinear mathematical model of the nanocomposite cantilever samples derived from a 3D mesoscale hysteretic model of the PBT/bCNT material. Our results suggest that the presence of bCNTs in a thermoplastic matrix is the main driver of the highly tunable nonlinear stiffness and damping capacity of the material. The reported experimental and modeling results provide valuable insights into the nonlinear dynamic behavior of PBT/bCNT nanocomposites and have potential applications in the design of advanced materials with tailored mechanical properties.

Osteoarthritis is a degenerative joint disease caused by the wear and tear of joint cartilage. The definitive and resolving treatment is prosthetic replacement of the articular surface, the demand of which is on the rise for patients with mild to moderate severity. However, a conservative strategy may be considered that aims to reduce and contain pain symptoms by postponing surgical treatment in the case of worsening that can no longer be otherwise controlled. Intra-articular infiltrations, like other therapeutic strategies, are not without complications, and among these the most feared is joint infection, especially in anticipation of future prosthetic replacement. Is important to avoid periprosthetic joint infections because they represent one of the third most common reasons for revision surgery. Using cases found in the literature, the aim of this article is to determine if there is a real correlation between the type of injections, the number of doses injected and the time between infiltrations and the surgical procedure.

Aim To report a novel surgical technique of capsular reconstruction of post-traumatic instability of the first metatarsophalangeal joint (MTPJ). Methods The clinical case is related to a 24-year-old male athlete whose clinical symptoms began with pain and spontaneous dislocation of the left first MTPJ during a kickboxing fight. He received conservative treatment (cryotherapy and rest) at first. Afterwards, he referred persistent hallux instability associated with moderate pain, despite normal anatomic alignment with no evidence of first ray deformity. Plain traditional x-rays of the left foot, magnetic resonance imaging (MRI), static and dynamic ultrasonography (US) and clinical tests were performed in order to diagnose capsular ligamentous structure lesions. Results The plain x-rays showed hallux abductus angle of 3°. The MRI and US demonstrated a rupture of the lateral capsular ligamentous structures and detachment of the abductor tendon. The pull out medium-lateral of the capsule with the abductor suture was performed as a treatment for dynamic hallux varus deformity. At six-month follow up, the patient walked without lameness with complete active and passive range of motion and with a stable first MTPJ. Conclusion The patient presented with the post traumatic instability of the first metatarsophalangeal joint treated with a novel surgical technique of capsular reconstruction. The patient returned to the full weight-bearing in only 2 months of rehab. To the best of our knowledge, the surgical correction proposed has not been previously described.

Abstract The expansion of the sheep model in research represents an attractive and economically beneficial academic reason for investigations in sheep echocardiography. The present study aimed to evaluate the clinical and echocardiographic parameters in Dorper lambs during the developmental period. Emphasis was placed on the use of the species in translational research for the echocardiographic diagnosis of congenital heart diseases, which can contribute to improvements in interventionist techniques. Ten Dorper lambs were evaluated at the following time points: 24 h after birth and 7, 14, 21, 30, 60, 90 and 120 days of age. Clinical parameters were compiled, and echocardiogram records were obtained without sedation. Rectal temperature was lower on the first day compared to the others. From 21 days of life, there was a reduction in HR, with differences between time points. Mean and systolic blood pressure differed, with the highest values at 90 and 120 days of age. The thickness of the interventricular septum in diastole (IVSd) increased as age progressed, with the highest value at 120 days of age, and the same occurred for LVIDd (left ventricle internal diameter in diastole), LVFWd (left ventricular free wall thickness in diastole), IVSs (interventricular septum thickness in systole), LVIDs (left ventricle internal diameter in systole) and LVFWs (left ventricular free wall thickness in systole). There were differences in the size of the LA, Ao and LA/Ao ratio, which were greater at 90 days and 120 days of age. Echocardiographic changes accompany the development of lambs, where changes in echocardiographic parameters are evident with advancing age. The echocardiographic measurements in lambs obtained in the present study are similar to those in newborns.

Poor knowledge of sexually transmitted infections (STIs) and HIV among people with HIV (PLHIV) could worsen life quality. We aimed to investigate their STI and HIV knowledge, disclosure and undetectable = untransmittable (U=U). We proposed an anonymous questionnaire regarding STI and HIV to PLHIV attending ten Italian outpatient infectious diseases clinics. Moreover, disclosure and U=U were investigated. The calculated sample size was 178 people. Considering a missing response of 10%, the final sample size was 196. We enrolled 200 PLHIV (73.5% males), with a median age of 52.5 (IQR 41–59) years. The mean score was 7.61 ± 1.22 with no difference by gender, education, and employment. Significant statistical difference was observed by sexual orientation; bisexuals and those who preferred not to answer had a lower score than heterosexuals and MSM (p = 0.0032). PLHIV showed poor knowledge about HIV transmission (25% appropriately answered). Nearly 30% responded that virologically suppressed PLHIV could transmit the infection. Finally, 137 (68.5%) and 158 (79.0%) disclosed to the general practitioner and family and friends, respectively. Nearly 52.0% knew the meaning of U=U, and 83.6% highlighted its positive rebound. In conclusion, important knowledge gaps are present among PLHIV regarding U=U, and its implications are little-known. Improving PLHIVs’ awareness will undermine self-stigma and enhance life quality.

Abstract Background Secreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carrying RSPO1-mutations. Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored. Our study was aimed at expanding the phenotypic, molecular and functional characterization of RSPO1-mutated skin and keratinocytes. Results Cultured primary keratinocytes from PPK skin of a RSPO1-mutated XX-sex reversed patient displayed highly impaired differentiation and epithelial-mesenchymal transition (EMT)-like phenotype. Interestingly, RSPO1-mutated PPK skin expressed markers of increased proliferation, dedifferentiation and altered cell–cell adhesion. Furthermore, all these signs were more evident in SCC specimens of the patient. Cultured PPK patient’s keratinocytes exhibited increased expression of cell‒matrix adhesion proteins and extracellular matrix remodeling enzymes. Moreover, they showed invasiveness properties in an organotypic skin model in presence of PPK fibroblasts, which behave like cancer-associated fibroblasts. However, the co-culture with normal fibroblasts or treatment with the recombinant RSPO1 protein did not revert or reduce the EMT-like phenotype and invasion capability of PPK keratinocytes. Notably, RSPO1-mutated PPK fibroblasts induced a hyperproliferative and dedifferentiated phenotype of age-matched normal control plantar keratinocytes. Wnt signaling has a key role in both PPK promotion and SCC development. Accordingly, Wnt mediators were differentially expressed in both PPK keratinocytes and skin specimens of RSPO1-mutated patient compared to control. Conclusions Altogether our data indicate that the absence of RSPO1 in patients with 46XX disorder of sexual development affects the skin microenvironment and epidermal integrity, thus contributing to the risk of SCC tumorigenesis in palmoplantar regions exposed to major frictional stresses.

Nowadays, total knee arthroplasty (TKA) is widely considered to be the gold standard for treatment of end-stage knee osteoarthritis. Although the optimal mode of fixation in TKA continues to be an important area of investigation, cementless fixation offers the possibility to gain biologic fixation, preserve bone stock and mineral density, and potentially improve survivorship. The purpose of this retrospective study was to evaluate the clinical results of a posterior-stabilized total knee arthroplasty with cementless tibial component in porous tantalum, comparing two groups: Group A (30 patients), TKA with a monoblock component and two pegs, and Group B (22 patients), with a modular component and three pegs. Knee Society Score (KSS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) were submitted to the patients, and radiographs were collected at the last follow-up. The mean follow-up was 26.32 (20–40) months. Significant differences were not detected between the postoperative KSS values in the two groups (p = 0.44). Evaluating KOOS outcomes, we found in Group A that the rating system showed a statistically significant improvement from a preoperative average rating of 51.4 (SD ± 15) to an average of 72.66 (SD ± 19) at final follow-up (p < 0.05). In Group B, the KOOS rating system showed a statistically significant improvement from a preoperative average rating of 48.3 (SD ± 18) to an average of 79.54 (SD ± 17) postoperatively (p < 0.05). Comparing KOOS final outcomes between groups, we found no statistically significant difference at the mean final follow-up (p = 0.20), with the exception of the sport-related section (p < 0.05). Radiological evaluation at the final follow-up did not show any sign of polyethylene wear, radiolucency, septic or aseptic loosening, or change in alignment in either group. The current study demonstrates an excellent survivorship of cementless tibial components in porous tantalum and the possibility of osseous integration, without significant differences between the two groups under investigation.

Abstract The molecular basis of the wide clinical heterogeneity of Coronavirus disease 2019 (COVID-19) is still unknown. Matrix metalloproteinases (MMPs) may have a role in the lung damage and regeneration that occur in severe patients. We studied serum MMP3 and MMP9 as potential biomarkers of COVID-19 severity, in 108 hospitalized patients with different World Health Organization (WHO) severity stage and in 48 controls. At hospital admission, serum MMP3 was increased in COVID-19 patients with a significant trend along the progression of the WHO stage, while serum levels of MMP9 were significantly increased in COVID-19 patients with no correlation with disease severity. At 1 week from hospitalization, MMP3 was reduced, suggesting an early pathogenic role of the protein in lung inflammation, while MMP9 levels were further increased, indicating a late role of the protein in the inflammatory process, specifically during the repairing phase. Furthermore, serum MMP9 was positively correlated with serum interleukin-6, myeloperoxidase, and circulating neutrophils and monocytes number. In conclusion, serum MMP3 may help to early predict the severity of COVID-19 and both proteins, MMP3 and MMP9, may contribute to define severe COVID-19 patients that may benefit from a targeted therapy on MMPs.

Abstract Background Coronavirus disease 2019 (COVID-19) pandemic had a 1st wave in Europe from March to May 2020 and a 2nd wave since September 2020. We previously studied 35 hospitalized COVID-19 patients of the 1st wave demonstrating a cytokine storm and the exhaustion of most lymphocyte subpopulations. Herein, we describe the results obtained from COVID-19 patients of the 2nd wave. Methods We analyzed interleukin (IL)-6 by human-specific enzyme-linked immunosorbent assay and a large set of lymphocyte subpopulations by flow cytometry in 274 COVID-19 patients hospitalized from September 2020 to May 2021. Results Patients of 2nd wave compared with those of 1st wave showed lower serum IL-6 levels and a higher number of B and most T lymphocyte subpopulations in advanced stages, in relation with the age and the gender. On the other hand, we observed in 2nd wave patients: (i) a reduction of most lymphocyte subpopulations at mild and moderate stages; (ii) a reduction of natural killer cells and T regulatory cells together with a higher number of activated T helper (TH) 17 lymphocytes in all stages, which were mainly related to steroid and azithromycin therapies before hospitalization. Conclusions COVID-19 had a less severe impact in patients of the 2nd wave in advanced stages, while the impact appeared more severe in patients of mild and moderate stages, as compared with 1st wave patients. This finding suggests that in COVID-19 patients with milder expression at diagnosis, steroid and azithromycin therapies appear to worsen the immune response against the virus. Furthermore, the cytometric profile may help to drive targeted therapies by monoclonal antibodies to modulate specific IL/lymphocyte inhibition or activation in COVID-19 patients.

Abstract Kienböck disease, also known as lunatomalacia, is a rare condition which can lead to progressive wrist pain and abnormal carpal motion. We present the case of a 30‐year‐old patient with Down syndrome who came to our observation for treatment of stage III C Kienböck disease. In September 2019, the patient reported wrist pain with limitation in movements and initially underwent conservative treatment without benefit. In October 2020, pain symptoms and difficult movements with reduced strength worsened and surgical treatment was proposed, but the patient and his family declined. Thereby the patient underwent conservative treatment with hyperbaric oxygen therapy (HBOT) 60 sessions, 100% oxygen at 2.5 absolute atmospheres (ATA), oxygen total time 60 min, once daily, five times per week. After 6 months, a positive clinical and radiological evolution were observed, with an improvement in the patterns of pain, motion, and strength and an almost complete involution of the process of aseptic necrosis of the semilunar. To the best of our knowledge, this is the first report of stage III C Kienböck's disease in Down's syndrome patient treated with HBOT.

Abstract The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for G NA 15, but not any other GNA gene. Demethylation of the 5′ GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11.

Abstract Emerging retrospective and prospective studies indicate that immune checkpoint inhibitors (ICIs) can be safe and effective cancer treatments among people living with human immunodeficiency virus (PLWH), however this high-cancer-risk population has often been excluded from groundbreaking cancer ICI trials. Our study aimed to characterize the current rate of exclusion and conditional inclusion of PLWH in cancer ICI trials by tumor type, trial phase, and year. ClinicalTrials.gov cancer ICI trials with planned starts between 1/1/2019 and 10/20/2020 were identified. Based on trial eligibility criteria, trials were categorized as “excluded” if PLWH could not enroll, “conditionally included” if only PLWH with adequate immune function were allowed, or “included/not specified” if HIV was not mentioned in the eligibility criteria. Trials from 2014 were separately collected for comparison over time. The number of trials excluding PLWH were compared to the included/not specified group using Fisher’s exact test. Of 809 trials analyzed from 2019 to 2020, 74.4% excluded, 6.9% conditionally included, and 18.7% included/did not specify PLWH. Early phase trials excluded PLWH more frequently than late phase trials. The 2019–2020 trial cohort showed no significant change in exclusion of PLWH compared to 2014. Despite increasing evidence for safe and effective ICI use for PLWH, most cancer ICI trials exclude PLWH and few studies permit PLWH to participate, even if HIV is well-controlled.

The objective of this work is to assess the 5-year outcomes of patients undergoing conization for high-grade cervical lesions that simultaneously present as risk factors in the persistence of HPV infection and the positivity of surgical resection margins. This is a retrospective study evaluating patients undergoing conization for high-grade cervical lesions. All patients included had both positive surgical margins and experienced HPV persistence at 6 months. Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR). The charts of 2966 patients undergoing conization were reviewed. Among the whole population, 163 (5.5%) patients met the inclusion criteria, being at high risk due to the presence of positive surgical margins and experiencing HPV persistence. Of 163 patients included, 17 (10.4%) patients developed a CIN2+ recurrence during the 5-year follow-up. Via univariate analyses, diagnosis of CIN3 instead of CIN2 (HR: 4.88 (95%CI: 1.10, 12.41); p = 0.035) and positive endocervical instead of ectocervical margins (HR: 6.44 (95%CI: 2.80, 9.65); p < 0.001) were associated with increased risk of persistence/recurrence. Via multivariate analyses, only positive endocervical instead of ectocervical margins (HR: 4.56 (95%CI: 1.23, 7.95); p = 0.021) were associated with worse outcomes. In this high-risk group, positive endocervical margins is the main risk factor predicting 5-year recurrence.

Nowadays total hip arthroplasty (THA) is widely considered the operation of the century in orthopedic and traumatological fields. Despite this fact, instability and dislocation after THA are a common reason for revision surgery. The purpose of this prospective study is to evaluate the preliminary clinical and radiological results of a novel dual mobility cup. We evaluated 32 consecutive cases of patients who underwent THA using a novel dual mobility cup—with holes in the cup, a modular metallic inlay and a crosslinked polyethylene. All of them were considered at risk of instability of the implant due to primary or concomitant diagnosis. The preoperative Harris hip score was 54.7 on average. At a minimum 2 years follow-up, the mean HHS raised up to a mean value of 88.4; this improvement was statistically significant (p < 0.0001). None of the patients enrolled in this study sustained a postoperative dislocation at a mean follow-up of 39.6 months. Furthermore, no patients sustained modular liner dissociation or an intraprosthetic dislocation. As such, survivorship free from dislocation was 100% at both 2 and 5 years. This study demonstrates that the modular dual mobility (DM) socket provides dual articulation, larger jump distance, and greater range of motion before impingement, which significantly reduce the rate of dislocation.

Abstract The role played by the right ventricular (RV) dysfunction has long been underestimated in clinical practice. Recent findings are progressively confirming that when the RV efficiency deteriorates both the right and the left circulation is (significantly) affected, but studies dedicated to a detailed description of RV hemodynamic role still lack. In response to such a gap in knowledge, this work proposes a numerical model that for the first time evaluates the effect of isolated RV dysfunction on the whole circulation. Lumped parameter modelling was applied to represent the physio-pathological hemodynamics. Different grades of impairment were simulated for three dysfunctions i.e., systolic, diastolic, and combined systolic and diastolic. Hemodynamic alterations (i.e., of blood pressure, flow, global hemodynamic parameters), arising from the dysfunctions, are calculated and analysed. Results well accord with clinical observations, showing that RV dysfunction significantly affects both the pulmonary and systemic hemodynamics. Successful verification against in vivo data proved the clinical potentiality of the model i.e., the capability of identifying the degree of RV impairment for given hemodynamic conditions. This study aims at contributing to the improvement of RV dysfunction recognition and treatment, and to the development of tools for the clinical management of pathologies involving the right heart.

Abstract Salvage surgery in recurrent head and neck squamous cell carcinoma has a poor outcome, both in terms of survival and quality of life. Therefore, the identification of pre-operative prognostic factors to improve the selection of patients who could benefit the most from salvage surgery is clinically relevant. The present study is a single-center retrospective analysis of 164 patients treated with salvage surgery after recurrence of head and neck cancer. Progression free survival and overall survival were calculated through Kaplan–Meier method. Hazard risk (HR) and corresponding confidence intervals (CI) were estimated through Cox proportional hazard model, adjusting for potential confounders. Significant predictors were combined into a prognostic score, attributing one point to each factor. Progression-free survival and overall survival were respectively 50.3% and 56.5% at 2 years, and 36.6% and 44.2% at 5 years. Four pre-operative factors were independently associated with poor prognosis: age > 70 years (HR = 2.18; 95% CI 1.27–3.73), initial stage IV (HR = 2.37; 95% CI 1.18–4.76), disease free interval 70 years, initial stage IV, disease-free interval

BACKGROUND: In Switzerland, SARS-CoV-2 vaccination campaigns started in early 2021. Vaccine coverage reached 65% of the population in December 2021, mostly with mRNA vaccines from Moderna and Pfizer-BioNtech. Simultaneously, the proportion of vaccinated among COVID-19-related hospitalisations and deaths rose, creating some confusion in the general population. We aimed to assess vaccine effectiveness against severe forms of SARS-CoV-2 infection using routine surveillance data on the vaccination status of COVID-19-related hospitalisations and deaths, and data on vaccine coverage in Switzerland. METHODS: We considered all routine surveillance data on COVID-19-related hospitalisations and deaths received at the Swiss Federal Office of Public Health from 1 July to 1 December 2021. We estimated the relative risk of COVID-19-related hospitalisation or death for not fully vaccinated compared with fully vaccinated individuals, adjusted for the dynamics of vaccine coverage over time, by age and location. We stratified the analysis by age group and by calendar month. We assessed variations in the relative risk of hospitalisation associated with the time since vaccination. RESULTS: We included a total of 5948 COVID-19-related hospitalisations of which 1245 (21%) were fully vaccinated patients, and a total of 739 deaths of which 259 (35%) were fully vaccinated. We found that the relative risk of COVID-19 related hospitalisation was 12.5 (95% confidence interval [CI] 11.7–13.4) times higher for not fully vaccinated than for fully vaccinated individuals. This translates into a vaccine effectiveness against hospitalisation of 92.0% (95% CI 91.4–92.5%). Vaccine effectiveness against death was estimated to be 90.3% (95% CI 88.6–91.8%). Effectiveness appeared to be comparatively lower in age groups over 70 and during the months of October and November 2021. We also found evidence of a decrease in vaccine effectiveness against hospitalisation for individuals vaccinated for 25 weeks or more, but this decrease appeared only in age groups below 70. CONCLUSIONS: The observed proportions of vaccinated among COVD-19-related hospitalisations and deaths in Switzerland were compatible with a high effectiveness of mRNA vaccines from Moderna and Pfizer-BioNtech against hospitalisation and death in all age groups. Effectiveness appears comparatively lower in older age groups, suggesting the importance of booster vaccinations. We found inconclusive evidence that vaccine effectiveness wanes over time. Repeated analyses will be able to better assess waning and the effect of boosters.

Abstract Background Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Video Abstract Graphical Abstract

Background Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. Methods We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. Results We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67–82]), than encephalopathy (54% [42–65]). Intensive care use was high (38% [35–41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27–32]. The hazard of death was comparatively lower for patients in the WHO European region. Interpretation Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission.

Early treatment with antivirals against SARS-CoV-2 infection can prevent the onset of severe COVID-19 in fragile and immunocompromised patients. In this real-life, prospective, observational study, we evaluated efficacy and safety of a 3-day early treatment with remdesivir in adult and fragile patients with a diagnosis of SARS-CoV-2 infection who referred to the COVID-19 early treatment service of Infectious Diseases Unit of University of Naples Federico from 10 January 2022 to 31 March 2022. The included patients could be treated with either remdesivir alone or with remdesivir plus a monoclonal antibody with activity against SARS-CoV-2. Among the 62 included patients, we showed low rates of hospitalization (8%), increase in oxygen supplementation (3.2%), ICU admission (1.6%) and death (1.6%). The rate of disease progression was 8% and it was similar in patients treated with remdesivir alone or in combination with monoclonal antibodies (6.7% and 9.4%, respectively; p = 0.531). The rate of adverse drug reaction was low and similar in the two groups (13.3% in patients treated with remdesivir, 15.6% in patients treated with the combination; p = 0.543). Most common adverse events were headache and fever. In conclusion, in our cohort of patients at a high risk of worse COVID-19 outcomes, an early course of remdesivir showed low rates of disease progression and adverse drug reactions.

Aim: This study aims to investigate any modification of serological FSCN1 in prostate cancer patients compared with patients without neoplasia. Material & methods: Clinical data and blood specimens from patients with and without prostate cancer were obtained. A quantitative sandwich ELISA method was used to determine serological values of FSCN1. Results: Although serum values of FSCN1 were dissimilar in the two cohorts of patients (6.90 vs 7.33 ng/ml), the difference was not statistically significant (p = 0.20). Serum values of FSCN1 stratified for Gleason score groups were not significantly distinguishable (p = 0.65). A negative correlation (rho = -0.331; p = 0.009) was reported between FSCN1 and age. Conclusion: Further studies are required to evaluate a possible diagnostic role of FSCN1 in prostate cancer.

We evaluated the role of CRP and other laboratory parameters in predicting the worsening of clinical conditions during hospitalization, ICU admission, and fatal outcome among patients with COVID-19. Consecutive adult inpatients with SARS-CoV-2 infection and respiratory symptoms treated in three different COVID centres were enrolled, and they were tested for laboratory parameters within 48 h from admission. Three-hundred ninety patients were enrolled. Age, baseline CRP, and LDH were associated with a P/F ratio < 200 during hospitalization. Male gender and CRP > 60 mg/L were shown to be independently associated with ICU admission. Lymphocytes < 1000 cell/μL were associated with the worst P/F ratio. CRP > 60 mg/L predicted exitus. We subsequently devised an 11-points numeric ordinary scoring system based on age, sex, CRP, and LDH at admission (ASCL score). Patients with an ASCL score of 0 or 2 were shown to be protected against a P/F ratio < 200, while patients with an ASCL score of 6 to 8 were shown to be at risk for P/F ratio < 200. Patients with an ASCL score ≥ 7 had a significantly increased probability of death during hospitalization. In conclusion, patients with elevated CRP and LDH and an ASCL score > 6 at admission should be prioritized for careful respiratory function monitoring and early treatment to prevent a progression of the disease.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a significant threat to public health. However, among the Coronaviridae family members, there are other viruses that can also cause infections in humans. Among these, severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV) have posed significant threats to human health in the past. Other human pathogenic coronaviruses have been identified, and they are known to cause respiratory diseases with manifestations ranging from mild to severe. In this study, we evaluated the performance of a multiplex RT-rPCR specific to seven human pathogenic coronaviruses in mainly detecting SARS-CoV-2 directly from nasopharyngeal swabs obtained from suspected COVID-19 infected patients, while simultaneously detecting different human pathogenic coronaviruses in case these were also present. We tested 1195 clinical samples suspected of COVID-19 infection. The assay identified that 69% of the samples tested positive for SARS-CoV-2 (1195), which was confirmed using another SARS-CoV-2 RT-PCR kit available in our laboratory. None of these clinical samples were positive for SARS-CoV, MERS-CoV or HCoV. This means that during the endemic phase of COVID-19, infection with other human pathogenic coronaviruses, even the common cold coronavirus (HCoV), is very uncommon. Our study also confirmed that the multiplex RT-rPCR is a sensitive assay for detecting SARS-CoV-2 regardless of differences among the variants. This multiplex RT-rPCR is also time- and cost-saving and very easy to apply in the diagnostic laboratory due to its simple procedure and its stability in storage after preparation. These features make the assay a valuable approach in screening procedures for the rapid detection of SARS-CoV-2 and other human pathogenic coronaviruses that could affect public health.

Periprosthetic joint infections are some of the leading causes of revision prosthetic surgery, accounting for 25% of failed total knee replacements and 15% of failed total hip replacements. The search for a biomarker that, together with clinical and radiological findings, could improve the management of such patients is currently a significant challenge for orthopaedic surgeons. Synovial fluid is a viscous and mucinous substance produced by the synovium, a specialized connective tissue that lines diarthrodial joints. Synovial fluid is an ultrafiltrate of plasma but also contains proteins secreted from the surrounding tissues, including the articular cartilage and synovium. Therefore, synovial fluid represents a source of disease-related proteins that could be used as potential biomarkers in several articular diseases. Based on these findings, the study of synovial fluid has been gaining increasing importance in recent years. This review aims to assess the accuracy and the limitations of the most promising synovial fluid biomarkers—i.e., Alpha-Defensin, Leukocyte Esterase, C-Reactive Protein, Interleukin-6, Calprotectin, Presepsin and Neopterin—in the diagnosis of PJI. Special attention will be given to emerging synovial biomarkers, which could soon be important in diagnosing PJIs.

Despite the lightning-fast advances in the management of SARS-CoV after 2 years of pandemic, COVID-19 continues to pose a challenge for fragile patients, who could benefit from early administration of monoclonal antibodies (mAbs) to reduce the risk of severe disease progression. We conducted a prospective study to evaluate the effectiveness of mAbs against SARS-CoV-2 among patients at risk for severe disease progression, namely elderly and those with comorbidities, before the omicron variant surge. Patients were treated with either casirivimab/imdevimab, sotrovimab, or bamlanivimab/etesevimab. The rates and risk factors for clinical worsening, hospitalization, ICU admission and death (unfavorable outcomes) were evaluated. A stratified analysis according to the presence of SARS-CoV-2 IgG was also performed. Among 185 included patients, we showed low rates of unfavorable outcomes (9.2%), which were more frequent in patients with chronic kidney disease (aOR: 10.44, 95% CI: 1.73–63.03; p < 0.05) and basal D-dimer serum concentrations > 600 ng/mL (aOR 21.74, 95% CI: 1.18–397.70; p < 0.05). Patients with negative SARS-CoV-2 serology at baseline showed higher C-reactive protein values compared with patients with positive serology (p < 0.05) and a trend toward a higher admission rate to SICU and ICU compared with patients with positive serology. Our results thus showed, in a real-life setting, the efficacy of mAbs against SARS-CoV-2 before an Omicron surge when the available mabs become not effective.

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

Molnupiravir and nirmatrelvir were the first available oral antivirals (OAs) active against SARS-CoV-2. Trials evaluating the efficacy of OAs involved patients unvaccinated and infected with variants different from those currently circulating. We conducted a retrospective study on patients with confirmed SARS-CoV-2 infection treated with OAs during the omicron surge in Italy in order to provide real-life data on the efficacy and safety of OAs during the omicron surge of the COVID-19 pandemic. Among 257 patients, 56.8% received molnupiravir, while 43.2% received nirmatrelvir/ritonavir. Patients in the molnupiravir group were older, had a lower body mass index, and had a higher rate of chronic heart disease than those treated with nirmatrelvir/ritonavir. Three hospitalizations were recorded in the molnupiravir (2.1%) group and one in the nirmatrelvir/ritonavir (0.9%) group. One patient treated with molnupiravir died. The median time to negativity was 8 days in the nirmatrelvir/ritonavir group vs. 10 days in the molnupiravir group, p < 0.01. We recorded 37 ADRs (mainly dysgeusia, diarrhea, and nausea) in 31 individuals (12.1%). Only two patients (0.8%) treated with molnupiravir terminated treatment due to ADRs. In conclusion, in a population of mostly vaccinated patients treated with OAs, we observed a low rate of hospitalization, death, and adverse drug reactions. These rates were lower than those reported in pivotal trials.

Aim: To investigate the prognostic role of neutrophil percentage-to-albumin ratio (NPAR) in muscle-invasive bladder cancer (MIBC) patients treated with neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Patients & methods: 213 patients were included. Inclusion criteria: Nonmetastatic, MIBC (cT2-T4aN0M0), at least three cycles of NAC, undergone RC and with blood count within 30 days before NAC. Results: Five-years overall survival (OS) with NPAR >18 was 34.06% (95% CI: 18.3–50.5) and 65.37% (95% CI: 52.4–75.6) with NPAR 18 was 42.9% (95% CI: 23.9–60.7) and 74.5% (95% CI: 62.6–83.1) with NPAR

Abstract In 2017, the WHO classification of tumours of the endocrine organs established the criteria for a NIFTP diagnosis. The present paper considers some aspects that are still debated or unresolved: the real incidence and clinical meaning of multifocal/multinodular lesions, the biological behaviour of micro-NIFTP, the sprinkling phenomenon and the corresponding modifications to the FNA reporting systems based on changes to the ROM. Moreover, the paper suggests possible scenarios for the clinical-pathological management of this entity. From the initial 1470 cases, a group of 68 NIFTPs was recruited in a 9 year-long period. The average age at diagnosis was 55 years. The average diameter of the lesion was 1.7 cm (0.1 cm–10 cm). In 41 cases (60.1%), the lesion was inserted in the context of a multinodular background. In 12 cases, the diagnosis was incidental and the pre- operative FNA was performed on a different target. In 10 out of 68 cases, there was a multifocal NIFTP; in 14.7% of patients, PTC-like nuclear features showed sprinkling phenomenon. The cytological revision allocated 21 cases (49%) to the SIAPEC TIR3 indeterminate class and a nuclear score 2 or 3 were identified in 25 smears. Multifocality is part of the spectrum of NIFTPs, that can arise in a multinodular background with variable sizes from microscopic lesions to very large ones. Cytopathological criteria such as an evaluation of the nuclear score may help the pathologists in promoting a NIFTP diagnosis in the preoperative setting.

Background: Ponticlus Posticus (PP) is a rare anomaly of the first cervical vertebra easily identifiable in lateral cephalometric radiograph and typically required for orthodontic diagnosis. The aim of this study is to evaluate the PP prevalence in lateral Cephalograms in a cohort of orthodontic patients treated at the Dental School of the University of Bari ‘Aldo Moro’, Italy, and to find possible connection between PP and other dental anomalies, as well as the patient’s cephalometric characteristics. Methods: A total of 150 panoramic radiographs and 150 lateral Cephalograms, obtained for orthodontic use only, were evaluated. No patients were referred to for congenital syndromes or disease, or a history of previously occurred maxillofacial trauma. A detailed cephalometric study was performed for each patient, and the whole cohort was divided according to the common three dental malocclusion classes. The values obtained were analyzed using the Chi-Square Test. Results: PP prevalence was 8% (12 of 150 cases), where the complete and partial forms observed 4.7% and 3.3%, respectively. Although females were more affected (9.6%), no statistically significant sex-related difference was found. Furthermore, no statistically significant relationship regarding age or dental anomalies (dental agenesis/palatal impacted canines) among the groups was observed either. Cephalometric analyses revealed that half of the subjects with PP were sagittal skeletal class I and had vertical hyper-divergence. Conclusions: PP is a frequent anatomical variation of the cervical vertebra, apparently unrelated to the skeletal malocclusion type or dental anomalies. The current study needs to further confirm the congenital hypothesis of PP’s origin already reported in literature.

Information on the efficacy and safety of molnupiravir in daily clinical practice is very scarce. We aimed to describe the clinical characteristics and outcomes of fully vaccinated patients with mild to moderate breakthrough COVID-19 treated with molnupiravir between January 2022 and February 2022. Overall, 145 patients were enrolled. Their median age was 71.0 years, and 60.7% were males. The most common underlying condition was a severe cardiovascular disease (37.2%), followed by primary or acquired immunodeficiency (22.8%), and oncological/onco-hematological disease in the active phase (22.1%). At 30 days after breakthrough COVID-19 diagnosis, only 4 out of 145 patients (2.7%) required hospital admission. No patients developed severe COVID-19, were admitted to the ICU, or died during the follow-up period. Adverse events, mild in intensity, occurred in 2 patients (1.4%). Our results support the current evidence establishing positive clinical and safety outcomes of molnupiravir in fully vaccinated patients with mild or moderate breakthrough COVID-19.