Search

Shunt calcification is a known late sequela of ventriculoperitoneal (VP) shunt insertion and is associated with shunt malfunction. However, in some patients, while shunt functionality is preserved despite calcification of the catheters, they experience nociceptive symptoms. In this paper, the authors present their surgical experience in managing patients with a functional VP shunt and experiencing pain secondary to shunt calcification.We analysed outcomes of patients presenting with pain at the level of a calcified shunt who underwent surgical untethering of the calcified catheter from the soft tissues. This procedure was commenced by the senior author in 2015. Patients were collected prospectively from the databases of two institutions. Evidence of shunt calcification was confirmed on neuroimaging.Seven patients, two male and five female, were included. The mean age at untethering was 13.5 years. The mean time interval between primary shunt surgery and symptom onset was 12 years (range 6-16 years). The commonest site of tethering was the neck (50%) followed by abdomen and chest (both 25%). Six patients underwent untethering of the catheter from soft tissues. One patient had removal of a redundant segment of calcified shunt left in situ during a previous revision. All patients experienced pain relief following shunt untethering.Untethering of calcified VP shunt catheters from soft tissue can be considered an effective treatment of shunt site pain and offered to patients presenting with a functional VP shunt.

ERF mutation is one of the most recently identified genetic aberrations associated with syndromic craniosynostosis. Data on the pattern of craniosynostosis, surgical management of ERF-related craniosynostosis and outcomes is limited. We report on our single-centre experience in paediatric cohort of patients with syndromic craniosynostosis secondary to ERF mutation.A retrospective review of all paediatric craniofacial cases was performed over an 8-year period (2014-2022). All patients with genetically confirm ERF-related craniosynostosis were identified, and clinical parameters including, age, sex, pattern of craniosynostosis, associated tonsillar herniation and follow-up period were further analysed from electronic clinical and imaging systems. All patients were selected and discussed in multidisciplinary craniofacial meeting (composed of neurosurgical, maxillofacial, plastics and genetics teams) prior to any surgical intervention.Overall, 10 patients with ERF-related craniosynostosis were identified with a male-to-female ratio of 4:1 with mean age at the time of surgery of 21.6 months with a mean follow-up period of 5.2 years. ERF-confirmed cases led to variable craniosynostosis pattern with multi-sutural synostosis with concurrent sagittal and bilateral lambdoid involvement as the most common pattern (7/10). No patient pre-operatively had evidence of papilloedema on ophthalmological assessment. Eight out of 10 patients had associated low-lying tonsils/hind brain hernia pre-operatively. Eight out of 10 patients required surgery which included 2 fronto-orbital advancement, 3 calvarial remodelling, 2 posterior calvarial remodelling/release and 1 insertion of ventriculoperitoneal shunt.Involvement of sagittal and lambdoid sutures is the most common pattern of craniosynostosis. ERF-related craniosynostosis can have variable pattern of suture fusion, and management of each patient requires unique surgical planning and execution based on clinical needs for the optimal outcomes.

Career change of young talent aggravates human resource shortages in various industries and the analysis of vocational commitment during the educational phase becomes paramount. Knowledge transfer modes and dynamics in the education of young professionals can influence their vocation or “calling” in the sector they are specialising for. With the background of the knowledge-based view, the goal of this study is to identify knowledge transfer-related aspects of education that exert a relevant influence on apprentices’ vocational commitment. The findings of the study of 331 hospitality apprentices in Bavaria, Germany, reveal that both academic sources and firm sources in the apprenticeship-based, also called dual, educational system affect the vocational commitment of apprentices. Specifically, the satisfaction with the training in the educational centre, the existence of organisational mentorship, and a personalised training system in the firm significantly affect vocational commitment after the educational stage. Consequently, educators along with mentors and managers in the partner firms can help enhance their students’ vocational commitment and potentially decrease their likelihood of leaving a sector.

Taking agent-based models to the data is still very challenging for researchers. In this paper we propose a new method to calibrate the model parameters based on indirect inference, which consists in minimizing the distance between real and artificial data. Basically, we first introduce a nonparametric regression meta-model to approximate the relationship between model parameters and distance. Then the meta-model is estimated by local polynomial regression estimation on a small sample of parameter vectors drawn from the parameter space of the ABM. Finally, once the distance has been estimated we can pick the parameter vector minimizing it. One innovative feature of the method is the sampling scheme, based on sampling at the same time both the parameter vectors and the seed of the random numbers generator in a random fashion, which permits to average out the effect of randomness without resorting to Monte Carlo simulations. A battery of simple calibration exercises performed on an agent-based macro model shows that the method allows to minimize the distance with good precision using relatively few simulations of the model.

For the solution of 2D exterior Dirichlet Poisson problems we propose the coupling of a Curved Virtual Element Method (CVEM) with a Boundary Element Method (BEM), by using decoupled approximation orders. We provide optimal convergence error estimates, in the energy and in the weaker $\textit{L}^\text{2}$-norm, in which the CVEM and BEM contributions to the error are separated. This allows taking advantage of the high order flexibility of the CVEM to retrieve an accurate discrete solution by using a low order BEM. The numerical results confirm the a priori estimates and show the effectiveness of the proposed approach., arXiv admin note: text overlap with arXiv:2107.04794

Background The long non-coding RNA (lncRNA), MALAT1, plays a key role in the development of different cancers, and its expression is associated with worse prognosis in patients. However, its mechanism of action and its regulation are not well known in prostate cancer (PCa). A general mechanism of action of lncRNAs is their interaction with other epigenetic regulators including microRNAs (miRNAs). Methods Using lentiviral stable miRNA transfection together with cell biology functional assays and gene expression/target analysis, we investigated the interaction between MALAT1 and miR-423-5p, defined as a target with in silico prediction analysis, in PCa. Results Through bioinformatic analysis of data available from TCGA, we have found that MALAT1 expression correlates with high Gleason grade, metastasis occurrence, and reduced survival in PCa patients. These findings were validated on a TMA of PCa showing a significant correlation between MALAT1 expression with both stage and grading. We report that, in PCa cells, MALAT1 expression and activity is regulated by miR-423-5p that binds MALAT1, downregulates its expression and inhibits its activity in promoting proliferation, migration, and invasion. Using NanoString analysis, we unraveled downstream cell pathways that were affected by miR-423-5p expression and MALAT1 downregulation and identified several alterations in genes that are involved in metastatic response and angiogenic pathways. In addition, we showed that the overexpression of miR-423-5p increases survival and decreases metastases formation in a xenograft mouse model. Conclusions We provide evidence on the role of MALAT1 in PCa tumorigenesis and progression. Also, we identify a direct interaction between miR-423-5p and MALAT1, which results in the suppression of MALAT1 action in PCa.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequently occurring condition involving type 2 inflammation. It has a global prevalence of approximately 4% and has a major effect on the quality of life of those affected by it. CRSwNP is a complex condition for otorhinolaryngologists to manage, since its precise pathogenic basis has not been established, treatment is challenging and the condition often recurs. It is common to find abnormalities in smelling in those with CRSwNP. This cross-sectional study enrolled patients suffering from CRS. Three groups were compared: 1812 patients with CRS, 571 with CRSwNP, and 120 with CRSwNP treated by FESS. The Sniffin’ Sticks® olfactory test was used to measure olfactory function in all patients. Olfactory dysfunction was a common symptom in patients with CRS, ranging in frequency from 56 to 74%. In patients with CRSwNP, impairment of sense of smell affected 64% of subjects (42% with anosmia, 10% with hyposmia, and 12% with cacosmia). After surgery, there was a significant improvement in the ability to smell normally. The present study confirms that impairment of smell is a common symptom in patients with chronic rhinosinusitis, mainly in subjects with nasal polyps. FESS reduces the prevalence of olfactory dysfunction.

Inadequate sampling of lymph nodes could lead to stage migration and indicate a poor prognosis for gastric cancer after curative surgery. Some emerging novel predictors and the application of a nomogram could increase the accuracy of survival prediction. An international database regarding gastric cancer was employed as the primary cohort. The patients with inadequate (

Conventional composites used in damping applications exhibit an undesirable tradeoff between stiffness and energy dissipation. Recent research demonstrates that it is possible to simultaneously achieve increased stiffness and energy dissipation for a configuration of a viscoelastic polymer matrix placed in parallel with a negative stiffness structure (NSS). This configuration resulted in energy dissipation equal to the sum of its components but is difficult to implement in practice. In this paper, an alternative configuration is investigated in which the NSS is embedded simultaneously in series and parallel with the matrix. The main objectives are to examine the tradeoff between the stiffness and energy dissipation of the composite and to identify the mechanisms for enhanced energy dissipation. To achieve this, FEA models were used to match the stiffness of a polymer matrix with that of a metallic NSS. Multiple specimens were manufactured and tested under quasi-static compressive loads to determine the force versus displacement curves and calculate the energy dissipation and stiffness. These tests demonstrate that the total energy dissipation of the composite can be greater than the sum of its components, while maintaining the benefit of increasing the stiffness and damping capacity simultaneously. The results also demonstrate that the applied strain rate plays a critical role in activating the NSS, which is essential to achieve the desired increase in energy dissipation. The results indicate that localized strain and strain rate at the interface between the NSS and polymer matrix are the main contributors to achieving energy dissipation beyond the sum of its components. Furthermore, it was demonstrated that the strain rate affects the activation of the NSS and therefore composites containing mechanically activated NSS must be designed for the strain rate of interest.

Because of their complexity, taking agent-based models to the data is still an unresolved issue. In this paper we propose a method to calibrate the model parameters on real data that is based on a novel global sensitivity analysis procedure. The innovative feature of this procedure is that it allows to estimate regression meta-models for the relationship between model parameters and model output without resorting to Monte Carlo simulations to eliminate the effect of randomness. This is achieved by sampling at the same time both the parameters and the seed of the random numbers generator in a random fashion. If correctly specified, the meta-models can be directly used to consistently estimate the average response of the ABM to any parameter vector input by the modeler and, as a consequence, also the distance between real and simulated data. The advantage of the proposed method is twofold: it is very parsimonious in terms of computational time and is relatively easy to implement, being it based on elementary econometric techniques.

Our translational research deals with the influence of microenvironment on the phenotype and colonization of bone metastases from breast carcinoma, and on pre-metastatic niche formation. The aim of the present study was to clarify the origin of hepatocyte growth factor (HGF), ligand of Met receptor, the control of the axis HGF/Met by DNA methylation, and its importance for the nexus supportive cells-metastatic cells and for metastasis outgrowth. In bone metastasis of the 1833-xenograft model, DNA methyltransferase blockade using the chemotherapic drug 5-aza-2′-deoxycytidine (decitabine) strongly reduced the expression of HGF/Met receptor axis and of E-cadherin, with decrease of metastasis wideness and osteolysis, prolonging mice survival. Thus, DNA methylation events acted as commanders of breast carcinoma cells metastatizing to bone influencing the epithelial phenotype. HGF emerged as a bone-marrow stimulus, and the exosomes seemed to furnish HGF to metastatic cells. In fact, decitabine treatment similarly affected some markers of these microvesicles and HGF, indicating that its supply to recipient cells was prevented. Notably, in bone metastasis the hypomethylation of HGF, Met and E-cadherin promoters did not appear responsible for their elevated expression, but we suggest the involvement of hypermethylated regulators and of Wwox oncosuppressor, the latter being affected by decitabine. Wwox expression increased under decitabine strongly localizing in nuclei of bone metastases. We hypothesize a role of Wwox in Met activity since in vitro Wwox overexpression downregulated the level of nuclear-Met protein fragment and Met stability, also under long exposure of 1833 cells to decitabine. HGF enhanced phosphoMet and the activity in nuclei, an effect partially prevented by decitabine. Altogether, the data indicated the importance to target the tumor microenvironment by blocking epigenetic mechanisms, which control critical events for colonization such as HGF/Met axis and Wwox, as therapy of bone metastasis.

The β2-Adrenergic receptor (β2-AR) is a G protein-coupled receptor (GPCR), involved in the development of many cancers, among which HNSCC. In this contest, β2-AR signaling interacts with different pathways, such as PI3K and MAPK, commonly activated by TK receptors. For this reason, TK blockade is one of the most adopted therapeutic strategies in HNSCC patients. In our study we investigated the effects of the β2-AR blocking in HNSCC cell lines, using the selective inhibitor ICI118,551 (ICI), in combination with the MAPK inhibitor U0126. We found that ICI leads to the blocking of p38 and NF-kB oncogenic pathways, strongly affecting also the ERK and PI3K pathways. Cotreatment with U0126 displays a synergic effect on cell viability and pathway alteration. Interestingly, we found that the β2-AR blockade affects Nrf2-Keap1 stability and its nuclear translocation leading to a drastic ROS increase and oxidative stress. Our results are confirmed by a TCGA dataset analysis, showing that NFE2L2 gene is commonly overexpressed in HNSC, and correlated with a lower survival rate. In our system, the PI3K pathway inhibition culminated in the blocking of pro-survival autophagy, a mechanism normally adopted by cancer cells to became less responsive to the therapies. The mTOR expression, commonly upregulated in HNSC, was reduced in patients with disease-recurrence. It is well known that mTOR has a strong autophagy inhibition effect, therefore its downregulation promoted pro-survival autophagy, with a related increase recurrence rate. Our findings highlight for the first time the key role of β2-AR and related pathway in HNSCC cell proliferation and drug resistance, proposing it as a valuable therapeutic molecular target. The β2-Adrenergic receptor (β2-AR) is a G protein-coupled receptor (GPCR), involved in the development of many cancers, among which HNSCC. In this contest, β2-AR signaling interacts with different pathways, such as PI3K and MAPK, commonly activated by TK receptors. For this reason, TK blockade is one of the most adopted therapeutic strategies in HNSCC patients. In our study we investigated the effects of the β2-AR blocking in HNSCC cell lines, using the selective inhibitor ICI118,551 (ICI), in combination with the MAPK inhibitor U0126. We found that ICI leads to the blocking of p38 and NF-kB oncogenic pathways, strongly affecting also the ERK and PI3K pathways. Cotreatment with U0126 displays a synergic effect on cell viability and pathway alteration. Interestingly, we found that the β2-AR blockade affects Nrf2-Keap1 stability and its nuclear translocation leading to a drastic ROS increase and oxidative stress. Our results are confirmed by a TCGA dataset analysis, showing that NFE2L2 gene is commonly overexpressed in HNSC, and correlated with a lower survival rate. In our system, the PI3K pathway inhibition culminated in the blocking of pro-survival autophagy, a mechanism normally adopted by cancer cells to became less responsive to the therapies. The mTOR expression, commonly upregulated in HNSC, was reduced in patients with disease-recurrence. It is well known that mTOR has a strong autophagy inhibition effect, therefore its downregulation promoted pro-survival autophagy, with a related increase recurrence rate. Our findings highlight for the first time the key role of β2-AR and related pathway in HNSCC cell proliferation and drug resistance, proposing it as a valuable therapeutic molecular target.

Gustatory perception has been poorly explored in Parkinson's disease (PD). Aim of this study was to assess the flavor ability in PD patients, using the "flavor test" (FT), a new standardized and validated tool to examine the flavor perception. Thirty-eight patients (17 F and 21 M) and 36 control subjects (15 F and 21 M) comparable for age and gender were enrolled. All the subjects underwent the flavor test (FT), the Sniffin' Sticks test (SST), and the gustometry test (GT), based on the basic four tastants ("salty," "sour," "sweet," and "bitter"). PD patients presented a FT score significantly lower than controls (p