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Van-der Waals (vdW) atomically layered crystals can act as optical waveguides over a broad range of the electromagnetic spectrum ranging from Terahertz to visible. Unlike common Si-based waveguides, vdW semiconductors host strong excitonic resonances that may be controlled using non-thermal stimuli including electrostatic gating and photoexcitation. Here, we utilize waveguide modes to examine photo-induced changes of excitons in the prototypical vdW semiconductor, WSe2, prompted by femtosecond light pulses. Using time-resolved scanning near-field optical microscopy we visualize the electric field profiles of waveguide modes in real space and time and extract the temporal evolution of the optical constants following femtosecond photoexcitation. By monitoring the phase velocity of the waveguide modes, we detect incoherent A-exciton bleaching along with a coherent optical Stark shift in WSe2.

Background and aimA recently carried out randomized controlled trial showed the benefit of a novel 20-G fine-needle biopsy (FNB) over a 25-G fine-needle aspiration (FNA) needle. The current study evaluated the reproducibility of these findings among expert academic and non-academic pathologists.MethodsThis study was a side-study of the ASPRO (ASpiration versus PROcore) study. Five centers retrieved 74 (59%) consecutive FNB and 51 (41%) FNA samples from the ASPRO study according to randomization; 64 (51%) pancreatic and 61 (49%) lymph node specimens. Samples were re-reviewed by five expert academic and five non-academic pathologists and rated in terms of sample quality and diagnosis. Ratings were compared between needles, expert academic and non-academic pathologists, target lesions, and cytology versus histological specimens.ResultsBesides a higher diagnostic accuracy, FNB also provided for a better agreement on diagnosing malignancy (ĸ = 0.59 vs ĸ = 0.76, P

BackgroundWe evaluated apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) as a schwannoma tumor suppressor and explored its utilization in a schwannoma gene therapy strategy that may be translated to clinical use.MethodsASC protein expression and mRNA level were assessed in human schwannoma by immunohistochemistry and quantitative PCR, respectively. Methylation- specific PCR was used to assess ASC promoter methylation. The effect of ASC overexpression in schwannoma cells was evaluated through ATP-based viability, lactate dehydrogenase release, and apoptosis staining. Western blotting and colorimetric assay were used to test the effect of ASC overexpression on endogenous pro-apoptotic pathways. Bioluminescence imaging, behavioral testing, and immunohistochemistry in human xenograft and murine allograft schwannoma models were used to examine the efficacy and toxicity of intratumoral injection of adeno-associated virus (AAV) vector encoding ASC.ResultsASC expression was suppressed via promoter methylation in over 80% of the human schwannomas tested. ASC overexpression in schwannoma cells results in cell death and is associated with activation of endogenous caspase-9, caspase-3, and upregulation of BH3 interacting-domain death agonist. In a human xenograft schwannoma model, AAV1-mediated ASC delivery reduced tumor growth and resolved tumor-associated pain without detectable toxicity, and tumor control was associated with reduced Ki67 mitotic index and increased tumor-cell apoptosis. Efficacy of this schwannoma gene therapy strategy was confirmed in a murine schwannoma model.ConclusionWe have identified ASC as a putative schwannoma tumor suppressor with high potential clinical utility for schwannoma gene therapy and generated a vector that treats schwannomas via a novel mechanism that does not overlap with current treatments.

The neurofibromatoses are inherited, tumor suppressor disorders that are characterized by multiple, benign peripheral nerve sheath tumors and other nervous system tumors. Each disease is associated with a distinct genetic mutation and with a different pathogenesis and clinical course. Neurofibromatosis 1 (NF1) is common and epitomized by multiple neurofibromas with widespread complications. NF2 and schwannomatosis are rare diseases that are typified by multiple schwannomas that are particularly painful in people with schwannomatosis. Since 1985, the Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation) has hosted an international Neurofibromatosis Conference, bringing together international participants who are focused on NF research and clinical care. The 2017 Conference, held in Washington, DC, was among the largest gatherings of NF researchers to date and included presentations from clinicians and basic scientists, highlighting new data regarding the molecular and cellular mechanisms underlying each of these diseases as well as results from clinical studies and clinical trials. This article summarizes the findings presented at the meeting and represents the current state-of-the art for NF research.

Abstract Rhabdoid tumor predisposition syndrome 1 (RTPS1) results from inactivation of the tumor-suppressor SMARCB1, a core component of the BAF (hSWI/SNF) complex. Rhabdoid tumors (RTs) are a highly malignant group of neoplasms that usually occur in children less than 2 years of age, which have no effective medical treatment. We discovered that the myelin protein zero (P0) gene serves as a lineage marker to trace the developmental origin of RT neoplastic cells. Ablating Smarcb1 in the P0+early neural crest lineage was necessary and sufficient to initiate tumorigenesis in cranial nerves and meninges, faithfully recapitulating histological features and molecular profiles of human RTs. About 65% of P0-CreC;Smarcb1flox/floxmice developed tumors between 1.5 and 5 months of age with an overall median survival of 3.2 months. These mice developed aggressive tumors emanating from cranial nerves, meninges, with variable extent of brain invasion, and spinal nerve roots. This genetically engineered mouse model opens the doors for deciphering the origin and evolution of RTs to identify effective therapies.

BackgroundNeurofibromatosis type 2 (NF2) is a genetic tumor-predisposition disorder caused by NF2/merlin tumor suppressor gene inactivation. The hallmark of NF2 is formation of bilateral vestibular schwannomas (VS). Because merlin modulates activity of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, we investigated repurposing drugs targeting MEK1 and/or MEK2 as a treatment for NF2-associated schwannomas.MethodsMouse and human merlin-deficient Schwann cell lines (MD-MSC/HSC) were screened against 6 MEK1/2 inhibitors. Efficacious drugs were tested in orthotopic allograft and NF2 transgenic mouse models. Pathway and proteome analyses were conducted. Drug efficacy was examined in primary human VS cells with NF2 mutations and correlated with DNA methylation patterns.ResultsTrametinib, PD0325901, and cobimetinib were most effective in reducing MD-MSC/HSC viability. Each decreased phosphorylated pERK1/2 and cyclin D1, increased p27, and induced caspase-3 cleavage in MD-MSCs. Proteomic analysis confirmed cell cycle arrest and activation of pro-apoptotic pathways in trametinib-treated MD-MSCs. The 3 inhibitors slowed allograft growth; however, decreased pERK1/2, cyclin D1, and Ki-67 levels were observed only in PD0325901 and cobimetinib-treated grafts. Tumor burden and average tumor size were reduced in trametinib-treated NF2 transgenic mice; however, tumors did not exhibit reduced pERK1/2 levels. Trametinib and PD0325901 modestly reduced viability of several primary human VS cell cultures with NF2 mutations. DNA methylation analysis of PD0325901-resistant versus -susceptible VS identified genes that could contribute to drug resistance.ConclusionMEK inhibitors exhibited differences in antitumor efficacy resistance in schwannoma models with possible emergence of trametinib resistance. The results support further investigation of MEK inhibitors in combination with other targeted drugs for NF2 schwannomas.

Abstract Background Stroke, the incidence of which increases with age, has a negative impact on motor and cognitive performance, quality of life, and the independence of the person and his or her family, leading to a number of direct and indirect costs. Motor recovery is essential, especially in elderly patients, to enable the patient to be independent in activities of daily living and to prevent falls. Several studies have shown how robotic training associated with physical therapy influenced functional and motor outcomes of walking after stroke by improving endurance and walking strategies. Considering data from previous studies and patients’ needs in gait and balance control, we hypothesized that robot-assisted balance treatment associated with physical therapy may be more effective than usual therapy performed by a physical therapist in terms of improving static, dynamic balance and gait, on fatigue and cognitive performance. Methods This is an interventional, single-blinded, preliminary randomized control trial. Twenty-four patients of both sexes will be recruited, evaluated, and treated at the UOC Rehabilitation and Physical Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome from January to December 2022. Patients will be randomized into two groups: the experimental group will perform specific rehabilitation for balance disorder using the Hunova® robotic platform (Movendo Technology srl, Genoa, IT) for 3 times a week, for 4 weeks (12 total sessions), and for 45 min of treatment, in addition to conventional treatment, while the conventional group (GC) will perform only conventional treatment as per daily routine. All patients will undergo clinical and instrumental evaluation at the beginning and end of the 4 weeks of treatment. Conclusions The study aims to evaluate the improvement in balance, fatigue, quality of life, and motor and cognitive performance after combined conventional and robotic balance treatment with Hunova® (Movendo Technology srl, Genoa, IT) compared with conventional therapy alone. Robotic assessment to identify the most appropriate and individualized rehabilitation treatment may allow reducing disability and improving quality of life in the frail population. This would reduce direct and indirect social costs of care and treatment for the National Health Service and caregivers. Trial registration ClinicalTrials.gov NCT05280587. Registered on March 15, 2022.

Loss of function of the neurofibromatosis type 2 (NF2) tumor suppressor gene leads to the formation of schwannomas, meningiomas, and ependymomas, comprising ∼50% of all sporadic cases of primary nervous system tumors. NF2 syndrome is an autosomal dominant condition, with bi-allelic inactivation of germline and somatic alleles resulting in loss of function of the encoded protein merlin and activation of mammalian target of rapamycin (mTOR) pathway signaling in NF2-deficient cells. Here we describe a gene replacement approach through direct intratumoral injection of an adeno-associated virus vector expressing merlin in a novel human schwannoma model in nude mice. In culture, the introduction of an AAV1 vector encoding merlin into CRISPR-modified human NF2-null arachnoidal cells (ACs) or Schwann cells (SCs) was associated with decreased size and mTORC1 pathway activation consistent with restored merlin activity. In vivo, a single injection of AAV1-merlin directly into human NF2-null SC-derived tumors growing in the sciatic nerve of nude mice led to regression of tumors over a 10-week period, associated with a decrease in dividing cells and an increase in apoptosis, in comparison with vehicle. These studies establish that merlin re-expression via gene replacement in NF2-null schwannomas is sufficient to cause tumor regression, thereby potentially providing an effective treatment for NF2.

Abstract According to the common wisdom, between a fraction of the mHz and few Hz the spectral energy density of the inflationary gravitons can be safely disregarded even assuming the most optimistic sensitivities of the space-borne detectors. In this analysis we show that this conclusion is evaded if, prior to nucleosynthesis, the post-inflationary evolution includes a sequence of stages expanding either faster or slower than radiation. As a consequence, contrary to the conventional lore, it is shown that below a fraction of the Hz the spectral energy density of the relic gravitons may exceed (even by eight orders of magnitude) the signal obtained under the hypothesis of radiation dominance throughout the whole expansion history prior to the formation of light nuclei. Since the slopes and the amplitudes of the spectra specifically reflect both the inflationary dynamics and the subsequent decelerated evolution, it is possible to disentangle the contribution of the relic gravitons from other (late-time) bursts of gravitational radiation associated, for instance, with a putative strongly first-order phase transition at the TeV scale. Hence, any limit on the spectral energy density of the relic gravitons in the mHz range simultaneously constrains the post-inflationary expansion history and the inflationary initial data.

Hypertension and diabetes are modifiable cardiovascular disease (CVD) risk factors that contribute to nearly one-third of all deaths in the Americas Region each year (2.3 million deaths). Despite advances in the detection and clinical management of hypertension and diabetes, there are substantial gaps in their implementation globally and in the Region. The considerable overlap in risk factors, prognosis, and treatment of hypertension and diabetes creates a unique opportunity for a unified implementation model for management at the population level. This report highlights one such high-profile effort, the Pan American Health Organization’s “HEARTS in the Americas” program, based on the World Health Organization’s HEARTS Technical Package for Cardiovascular Disease Management in Primary Health Care. The HEARTS program aims to improve the implementation of preventive CVD care in primary health systems using six evidence-based, pragmatic components: Healthy-lifestyle counseling, Evidence-based protocols, Access to essential medicines and technology, Risk-based CVD management, Team-based care, and Systems for monitoring. To date, HEARTS implementation projects have focused primarily on hypertension given that it is the leading modifiable CVD risk factor and can be treated cost-effectively. The objective of this report is to describe opportunities for integration of diabetes clinical care and policy within the HEARTS hypertension framework. A substantial global burden of disease could be averted with integrated primary care management of these conditions. Thus, there is an urgency in applying lessons from HEARTS to close these implementation gaps and improve the integrated detection, treatment, and control of diabetes and hypertension.

Michele Lorenzon,1 Erica Spina,1 Francesco Tulipano Di Franco,1 Ivan Giovannini,2 Salvatore De Vita,2 Alen Zabotti2 1Institute of Radiology, Department of Medicine, University of Udine, Udine, Italy; 2Rheumatology Clinic, Department of Medical and Biological Sciences, Azienda Sanitaria Universitaria Friuli Centrale c/o University of Udine, Udine, ItalyCorrespondence: Michele Lorenzon, Institute of Radiology, Department of Medicine, University of Udine, Udine, Italy, Tel +39 0432 559232, Email michele.lorenzon@gmail.comAbstract: Salivary gland ultrasound (SGUS) is the imaging modality of choice for the assessment of parotid and submandibular gland parenchyma. Being highly effective, non-invasive and easy to perform, SGUS has become increasingly popular among specialists in assessing salivary gland (SG) abnormalities, including those commonly found in primary Sjögren’s syndrome (pSS). SGUS may be useful in the assessment of pSS and its complications, the most serious being the development of non-Hodgkin’s lymphoma (NHL). SGUS may also be useful in the characterization and differential diagnosis of diffuse and focal abnormalities commonly associated with pSS, and may act as a guide for core-needle biopsy (CNB), an established, safe, and feasible technique, which provides enough viable tissue for the diagnosis and assessment of lymphoproliferative diseases of the SG. The combination of SGUS with other tools, such as sonoelastography and artificial intelligence (AI), could further improve the usefulness of SGUS in the management of pSS. In this perspective, we summarize current and future applications of SGUS in pSS.Keywords: primary Sjögren’s syndrome, major salivary glands, ultrasound, lymphoma, core needle biopsy

The large-scale magnetic fields arising from the quantum mechanical fluctuations of the hypercharge are investigated when the evolution of the gauge coupling is combined with a sufficiently long inflationary stage. In this framework the travelling waves associated with the quantum mechanical initial conditions turn asymptotically into standing waves which are the gauge analog of the Sakharov oscillations. Even if the rate of dilution of the hypermagnetic and hyperelectric fields seems to be superficially smaller than expected from the covariant conservation of the energy-momentum tensor, the standard evolution for wavelengths larger than the Hubble radius fully accounts for this anomalous scaling which is anyway unable to increase the amplitude of the magnetic power spectra after symmetry breaking. An effective amplification of the gauge power spectra may instead occur when the post-inflationary expansion rate is slower than radiation. We stress that the modulations of the gauge power spectra freeze as soon as the relevant wavelengths reenter the Hubble radius and not at the end of inflation. After the Mpc scale crosses the comoving Hubble radius the scaling of the magnetic power spectrum follows from the dominance of the conductivity. From these two observations the late-time values of the magnetic power spectra are accurately computed in the case of a nearly scale-invariant slope and contrasted with the situation where the phases of Sakharov oscillations are not evaluated at horizon crossing but at the end of inflation, i.e. when all the wavelengths relevant for magnetogenesis are still larger than the comoving horizon.

Multiple sclerosis (MS) primarily affects adult females. However, in the last decades, rising incidence and prevalence have been observed for demographic extremes, such as pediatric-onset MS (POMS; occurring before 18 years of age) and late-onset MS (corresponding to an onset above 50 years). These categories show peculiar clinical-pathogenetic characteristics, aging processes and disease courses, therapeutic options, and unmet needs. Nonetheless, several open questions are still pending. POMS patients display an important contribution of multiple genetic and environmental factors such as EBV, while in LOMS, hormonal changes and pollution may represent disease triggers. In both categories, immunosenescence emerges as a pathogenic driver of the disease, particularly for LOMS. In both populations, patient and caregiver engagement are essential from the diagnosis communication to early treatment of disease-modifying therapy (DMTs), which in the elderly population appears more complex and less proven in terms of efficacy and safety. Digital technologies (e.g., exergames and e-training) have recently emerged with promising results, particularly in treating and following motor and cognitive deficits. However, this offer seems more feasible for POMS, being LOMS less familiar with digital technology. In this narrative review, we discuss how the aging process influences the pathogenesis, disease course, and therapeutic options of both POMS and LOMS. Finally, we evaluate the impact of new digital communication tools, which greatly interest the current and future management of POMS and LOMS patients.

PurposeThe aim of this systematic review is to evaluate the perception of the patient, the chairside time, and the reliability and/or reproducibility of intraoral scanners for full arch in pediatric patients.MethodsA data search was performed in four databases (Medline-Pubmed, Scopus, ProQuest and Web of Science) in accordance with the PRISMA 2020 statements. Studies were classified in three categories (patient perception, scanning or impression time and reliability and/or reproducibility). The resources, the data extraction and the quality assessment were carried out independently by two operators. The variables recorded were population characteristics, material and methods aspects and included country, study design and main conclusion. A quality assessment of the selected studies was performed with QUADAS-2 tool, and Kappa-Cohen Index was calculated to analyze examiner agreement.ResultsThe initial search obtained 681 publications, and finally four studies matching inclusion criteria were selected. The distribution of the studies in the categories was three for the analysis of the patient's perception and scanning or impression time; and two items to assess the reliability and/or reproducibility of intraoral scans. All included studies have a repeated measures–transversal design. The sample size ranged between 26 and 59 children with a mean age. The intraoral scanners evaluated were Lava C.O.S, Cerec Omnicam, TRIOS Classic, TRIOS 3-Cart and TRIOS Ortho. The quality assessment of the studies using QUADAS-2 tool revealed a low risk of bias while evaluating patient perception, but an unclear risk of bias in the analysis of accuracy or chairside time. In relation to the applicability concerns, the patient selection was of high risk of bias. All studies agreed that the patient perception and comfort is better with intraoral scanners in comparison with the conventional method. The accuracy or reliability of the digital procedure is not clear, being clinically acceptable. In relation with the chairside time, it depends on the intraoral scanner, with contradictory data in the different analyzed studies.ConclusionThe use of intraoral scanners in children is a favorable option, finding a significantly higher patient perception and comfort with intraoral scanners compared to the conventional impression method. The evidence for reliability or reproducibility is not strong to date, however, the differences between the intraoral measurements and the digital models would be clinically acceptable.

Il seguente articolo si propone di analizzare l’acquisizione delle espressioni idiomatiche nell’apprendimento dell’italiano L2/LS e di ipotizzare una possibile attività didattica che permetta di indagare questa acquisizione in apprendenti francofoni. Dopo una prima sezione teorica in cui si espone una dettagliata analisi di questo tipo di locuzioni e del loro ruolo nell’apprendimento globale della L2/LS, si focalizza l’attenzione sull’analisi di un recente caso di studio, il lavoro della ricercatrice Vicky Mazoua Megni Tchio su apprendenti camerunensi di italiano L2/LS e si propone un materiale didattico che possa stimolare gli studenti a un uso consapevole dell’influsso interlinguistico per arrivare a risolvere gli esercizi proposti. The role of idiomatic expressions in learning L2/LS. Operational proposal for francophone learners of Italian This article aims to analyze the acquisition of idiomatic expressions when learning Italian as a foreign or second language and hypothesizes a possible teaching activity that allows the examination of this acquisition process by French native speaker learners. In the first section, a detailed analysis of this kind of locution and its role in the global learning of a foreign or second language is performed. Afterward, the article examines a recent case study, the work of Vicky Mazoua Megni Tchio about Cameroonian learners of Italian. The article concludes by proposing educational material that should stimulate students to a conscious use of the interlingual influence to solve the introduced exercises.

Abstract This editorial introduces the contributions to the Special Issue ‘Atmospheric processes and applications in urban, coastal, and mountainous terrain’ of the journal Meteorological Applications. The scientific background and motivation for this Special Issue are described and followed by a brief summary of the 15 articles of this Special Issue. The conclusions of this Editorial summarise the approaches taken and address future developments expected in process‐oriented studies and for the development of applications in complex terrain.

Las empresas familiares tienen enorme importancia económica social en Argentina y en particular las agropecuarias EFA, sin embargo éstas trabajan con importantes ineficiencias económicas, pocas superan traspasos generacionales y cuando se disuelven pierden patrimonio y lazos familiares, entre otras razones, por sus particulares formas de gestión. Tras el propósito de generar evidencias sobre el estado de situación actual de particularidades de las gestiones de EFA para uso académico científico se llevó a cabo un estudio exploratorio basado en interpretación de respuestas obtenidas de encuestas realizadas en el año 2019 a responsables de veintisiete EFA localizadas en cinco provincias de Argentina diversificadas y especializadas en rubros productivos y con diferente patrimonio. En este grupo de EFA los resultados mostraron, más allá de las diferencias en localización, tipos de producción y escalas, importantes debilidades en sus gestiones tales como la informalidad, la escasa profesionalización, organizaciones poco participativas y democráticas muy influenciadas por culturas conservadoras y la falta de incorporación de conocimientos disponibles para fortalecer las gestiones por desconocimiento o considerar problemas que afectan la eficiencia productiva y económica de la empresa, la duración de las EFA y la integridad de las familias propietarias como poco importantes.