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The application and potential of energy sufficiency (ES) measures is examined in non-residential buildings occupied by small and medium-sized enterprises (SMEs). The hypothesis is whether integrating ES measures into energy audits could help disseminate these measures to SMEs. This is investigated in terms of the feasibility, challenges and opportunities for the actors involved. Standard ES measures are identified that could be implemented in SMEs, and their saving potential is evaluated. A mixed-methods approach is used incorporating interviews with experts from various backgrounds, a quantitative analysis of the database containing a list of ES measures and a questionnaire to SMEs. Results demonstrate that most ES measures are cost-effective and that certain measures can lead to substantial savings. Financial incentives need to be balanced with fostering a genuine commitment to the concept of sufficiency. By integrating ES with energy efficiency measures in energy audits, the paper advocates for a role for auditors in identifying ES opportunities, necessitating a blend of standardisation, flexibility and expert collaboration. Additionally, end-user preferences for indoor conditions significantly influence ES measure acceptance, highlighting the importance of involving users in ES measures related to thermal comfort. Policy relevance By establishing two categories of energy sufficiency (ES) measures based on differing levels of constraints, policymakers and programme designers can build experience by initially implementing widely accepted measures and subsequently aiming for more stringent measures that are closer to the essence of sufficiency. More fundamentally, implementing sufficiency in energy and climate policy requires a changed mindset related to production and consumption, for which the inclusion of ES in energy audits offers unexploited opportunities.

Abstract BackgroundTelemedicine and mobile health (mHealth) apps have emerged as powerful tools in health care, offering convenient access to services and empowering participants in managing their health. Among populations with chronic and progressive disease such as multiple sclerosis (MS), mHealth apps hold promise for enhancing self-management and care. To be used in clinical practice, the validity and usability of mHealth tools should be tested. The most commonly used method for assessing the usability of electronic technologies are questionnaires. ObjectiveThis study aimed to translate and validate the English version of the mHealth App Usability Questionnaire into Italian (ita-MAUQ) in a sample of people with MS. MethodsThe 18-item mHealth App Usability Questionnaire was forward- and back-translated from English into Italian by an expert panel, following scientific guidelines for translation and cross-cultural adaptation. The ita-MAUQ (patient version for stand-alone apps) comprises 3 subscales, which are ease of use, interface and satisfaction, and usefulness. After interacting with DIGICOG-MS (Digital Assessment of Cognitive Impairment in Multiple Sclerosis), a novel mHealth app for cognitive self-assessment in MS, people completed the ita-MAUQ and the System Usability Scale, included to test construct validity of the translated questionnaire. Confirmatory factor analysis, internal consistency, test-retest reliability, and construct validity were assessed. Known-groups validity was examined based on disability levels as indicated by the Expanded Disability Status Scale (EDSS) score and gender. ResultsIn total, 116 people with MS (female n=74; mean age 47.2, SD 14 years; mean EDSS 3.32, SD 1.72) were enrolled. The ita-MAUQ demonstrated acceptable model fit, good internal consistency (Cronbach αPPP ConclusionsThe ita-MAUQ demonstrated high reliability and validity and it might be used to evaluate the usability, utility, and acceptability of mHealth apps in people with MS.

BackgroundMobile health (mHealth) apps have proven useful for people with multiple sclerosis (MS). Thus, easy-to-use digital solutions are now strongly required to assess and monitor cognitive impairment, one of the most disturbing symptoms in MS that is experienced by almost 43% to 70% of people with MS. Therefore, we developed DIGICOG-MS (Digital assessment of Cognitive Impairment in Multiple Sclerosis), a smartphone- and tablet-based mHealth app to self-assess cognitive impairment in MS. ObjectiveThis study aimed to test the validity and usability of the novel mHealth app with a sample of people with MS. MethodsDIGICOG-MS includes 4 digital tests assumed to evaluate the most affected cognitive domains in MS (visuospatial memory [VSM], verbal memory [VM], semantic fluency [SF], and information processing speed [IPS]) and inspired by traditional paper-based tests that assess the same cognitive functions (10/36 Spatial Recall Test, Rey Auditory Verbal Learning Test, Word List Generation, Symbol Digit Modalities Test). Participants were asked to complete both digital and traditional assessments in 2 separate sessions. Convergent validity was analyzed using the Pearson correlation coefficient to determine the strength of the associations between digital and traditional tests. To test the app’s reliability, the agreement between 2 repeated measurements was assessed using intraclass correlation coefficients (ICCs). Usability of DIGICOG-MS was evaluated using the System Usability Scale (SUS) and mHealth App Usability Questionnaire (MAUQ) administered at the conclusion of the digital session. ResultsThe final sample consisted of 92 people with MS (60 women) followed as outpatients at the Italian Multiple Sclerosis Society (AISM) Rehabilitation Service of Genoa (Italy). They had a mean age of 51.38 (SD 11.36) years, education duration of 13.07 (SD 2.74) years, disease duration of 12.91 (SD 9.51) years, and a disability level (Expanded Disability Status Scale) of 3.58 (SD 1.75). Relapsing-remitting MS was most common (68/92, 74%), followed by secondary progressive (15/92, 16%) and primary progressive (9/92, 10%) courses. Pearson correlation analyses indicated significantly strong correlations for VSM, VM, SF, and IPS (all P0.90) for VM and IPS and good for VSM and SF (ICCs>0.80). Moreover, the SUS score averaged 84.5 (SD 13.34), and the mean total MAUQ score was 104.02 (SD 17.69), suggesting that DIGICOG-MS was highly usable and well appreciated. ConclusionsThe DIGICOG-MS tests were strongly correlated with traditional paper-based evaluations. Furthermore, people with MS positively evaluated DIGICOG-MS, finding it highly usable. Since cognitive impairment poses major limitations for people with MS, these findings open new paths to deploy digital cognitive tests for MS and further support the use of a novel mHealth app for cognitive self-assessment by people with MS in clinical practice.

Abstract Lymphedema (LD) is characterized by the accumulation of interstitial fluid, lipids and inflammatory cell infiltrate in the limb. Here, we find that LD tissues from women who developed LD after breast cancer exhibit an inflamed gene expression profile. Lipidomic analysis reveals decrease in specialized pro-resolving mediators (SPM) generated by the 15-lipoxygenase (15-LO) in LD. In mice, the loss of SPM is associated with an increase in apoptotic regulatory T (Treg) cell number. In addition, the selective depletion of 15-LO in the lymphatic endothelium induces an aggravation of LD that can be rescued by Treg cell adoptive transfer or ALOX15-expressing lentivector injections. Mechanistically, exogenous injections of the pro-resolving cytokine IFN−β restores both 15-LO expression and Treg cell number in a mouse model of LD. These results provide evidence that lymphatic 15-LO may represent a therapeutic target for LD by serving as a mediator of Treg cell populations to resolve inflammation.

Abstract Secondary lymphedema (LD) corresponds to a severe lymphatic dysfunction leading to the accumulation of fluid and fibrotic adipose tissue in a limb. Here, we identified apelin (APLN) as a powerful molecule for regenerating lymphatic function in LD. We identified the loss of APLN expression in the lymphedematous arm compared to the normal arm in patients. The role of APLN in LD was confirmed in APLN knockout mice, in which LD is increased and associated with fibrosis and dermal backflow. This was reversed by intradermal injection of APLN-lentivectors. Mechanistically, APLN stimulates lymphatic endothelial cell gene expression and induces the binding of E2F8 transcription factor to the promoter of CCBE1 that controls VEGF-C processing. In addition, APLN induces Akt and eNOS pathways to stimulate lymphatic collector pumping. Our results show that APLN represents a novel partner for VEGF-C to restore lymphatic function in both initial and collecting vessels. As LD appears after cancer treatment, we validated the APLN-VEGF-C combination using a novel class of nonintegrative RNA delivery LentiFlash® vector that will be evaluated for phase I/IIa clinical trial.

Abstract Autophagy receptor NDP52 triggers bacterial autophagy against infection. However, the ability of NDP52 to protect against viral infection has not been established. We show that NDP52 binds to envelope proteins of hepatitis B virus (HBV) and triggers a degradation process that promotes HBV clearance. Inactivating NDP52 in hepatocytes results in decreased targeting of viral envelopes in the lysosome and increased levels of viral replication. NDP52 inhibits HBV at both viral entry and late replication stages. In contrast to NDP52-mediated bacterial autophagy, lysosomal degradation of HBV envelopes is independent of galectin 8 and ATG5. NDP52 forms complex with Rab9 and viral envelope proteins and links HBV to Rab9-dependent lysosomal degradation pathway. These findings reveal that NDP52 acts as a sensor for HBV infection, which mediates a unique antiviral response to eliminate the virus. This work also suggests direct roles for autophagy receptors in other lysosomal degradation pathways than canonical autophagy.

Abstract Background In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. Methods We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. Results Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. Conclusions Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

BackgroundPregnancy-associated breast cancer (PABC), with an incidence rate from 1:3,000 to 1:10,000 deliveries, is the most frequent cancer during pregnancy. PABC appropriate management must take into consideration both the maternal oncological safety and the fetal health, thus posing a challenge for the mother, the baby, and the clinicians. The treatment should adhere as closely as possible to the breast cancer (BC) guidelines. Therefore, surgery is a mainstay, and, when mastectomy is required, breast reconstruction (BR) is a topic of debate. To minimize the risks to the baby, most surgeons postpone BR to delivery. However, a delayed breast reconstruction (DBR) could affect the outcome. In the present case, we report cesarean section concurrent with mastectomy and immediate breast reconstruction (IBR).MethodsA 37-year-old patient, at the 36th week of pregnancy with PABC, underwent simultaneous cesarean delivery, nipple-sparing mastectomy, and IBR. To minimize risks for the newborn, cesarean was firstly performed under spinal anesthesia. Immediately after, breast surgery, including mastectomy and IBR, was performed under general anesthesia. Partial submuscular IBR with an acellular porcine dermal matrix concluded the surgical procedure. Lactation was inhibited, and adjuvant chemotherapy and hormone therapy were administered to the patient.ResultsIn a single surgical session, cesarean delivery, subcutaneous mastectomy, axillary dissection, and IBR were successfully carried out. No early or late postoperative complications were reported for both the patient and the newborn. Histopathological investigation reported a multifocal and multicentric infiltrating ductal carcinoma. After a 6-year follow-up, the patient is alive and well.ConclusionTo the best of our knowledge, this is the first reported case of concomitant cesarean delivery, PABC mastectomy, axillary dissection, and IBR. This surgical strategy allowed PABC treatment by the BC guideline, minimizing the newborn’s disadvantage and permitting, at the same time, the best final BR outcome.

While empirical studies on joint music-making have shed light on many aspects of ensemble performance in the past few decades, the role of auditory attention in such a context has remained strikingly understudied. We draw here on a self-annotation methodology to investigate musicians’ listening behaviors in freely improvised performances. Six trios of professional musicians were asked to freely improvise in a recording studio, hearing each other only through headphones. While they were playing, the loudness of each musician as sent to the other two musicians’ headphones was covertly increased/decreased during random periods of time in order to enhance its relative saliency within the musical scene. Immediately after each improvisation, musicians were asked to listen to the improvisation that they had just performed and to continuously indicate, using a specific application, where their listening focus was as they were performing. The results demonstrated that during periods of loudness manipulation, musicians’ attention was significantly drawn to the musician who had been made more salient. Two follow-up studies then investigated the extent to which joint auditory attention correlated with perceived togetherness, as well as whether improvisers’ auditory attention during the performance aligned with that of external listeners attending to the recording of the performance. Taken together, our results suggest that, beyond the effects of saliency, musicians also tend to strategically adapt their listening behavior to the specificities of the interactional context and that musicians’ collective listening behaviors have an impact on the performance, both at an acoustic level and at a perceptual level. By relying on attentional patterns that dynamically emerged from complex, ecological musical interactions, our studies provide a first attempt at assessing the effects of auditory attention on coordination and contribute to establishing sonic interactions as a promising setting for the study of the effects of joint attention.

In the present study, in order to expand the knowledge on the distribution of parasites of the genus Eustrongylides in never investigated Italian lacustrine areas of Tuscany and Latium, fish specimens from four Tuscan lakes (Bilancino, Chiusi, Montedoglio and San Cipriano) and two Latium lakes (Bolsena and Bracciano) were collected and analyzed. The parasitological analysis, consisting of a visual inspection followed by a chloro-peptic digestion, was performed on 1650 specimens belonging to 17 species: European perch (Perca fluviatilis), Pumpkinseed (Lepomis gibbosus), Pike-perch (Sander lucioperca), Largemouth black bass (Micropterus salmoides), Pike (Esox lucius), Big-scale sand smelt (Atherina boyeri), Tench (Tinca), European Whitefish (Coregonus lavaretus), Channel catfish (Ictalurus punctatus), Chub (Squalius cephalus), Rudd (Scardinius erythrophthalmus), Common bleak (Alburnus alborella), South European roach (Sarmarutilus rubilio), South European nase (Protochondrostoma genei), Italian riffle dace (Telestes muticellus), Goldfish (Carassius auratus), and Freshwater bream (Abramis brama). Eustrongylides spp. larvae were only found in one specimen of European perch caught in Bracciano Lake and purchased from a local fishmonger (P = 3.3%; MI = 1; MA = 0.03). The only isolated Eustrongylides spp. larva was submitted to molecular analysis of the ITS gene region and identified as E. excisus. This finding adds Bracciano Lake to the list of the several Italian lakes in which nematodes belonging to this genus have been reported. Even if the observed prevalence is currently low, the presence of the parasite in this local freshwater fish supply chain requires FBOs to adopt risk management measures to prevent contaminated products from reaching final consumer. Moreover, future investigations will show if the parasite expands in these areas.

Background. Breast cancer with about 2.3 million diagnoses and 685,000 deaths globally is the most frequent malignancy in the female population. Continuous research has led to oncological and reconstructive advances in the management of breast cancer, thus improving outcomes and decreasing patient morbidity. Nowadays, the submuscular expander and prosthesis (E/P) implant-based breast reconstruction (IBR) accounts for 73% of all reconstructions. Despite its widely accepted efficacy, the technique is not free from complications and up to 28% of cases require revision surgery for mechanical complications such as capsular contracture, implant displacement/rotation, and implant rupture. With this study, the authors report their experience in the management of E/P IBR revision surgery through the technique of Selective Capsulotomies (SCs) and Partial Capsulectomy (PC). Methods. A retrospective study was conducted on patients who had previously undergone E/P IBR and presented for revision reconstruction between January 2013 and May 2023 at the Department of Plastic Surgery of the University of Siena, Italy. Reasons for revision included capsular contracture, implant displacement/rotation, and implant rupture. Revision reconstructions involved SC and PC with implant replacement. Fat grafting was also considered. The complication rate was evaluated by analysis of patients’ medical records. Patients’ satisfaction with the treatment was assessed through a specific questionnaire. Results. 32 patients underwent revision surgeries. No early complication occurred. Recurrence rate was assessed at 19% with average follow-up of 59 months (range: 13–114 months). The average time between revision surgery and recurrence was 3 years (range: 1–6 years). 23 patients answered the questionnaire and were overall satisfied with the treatments (8.29/10). Conclusions. SC possibly associated to PC is a valuable option for E/P IBR revision surgery with minimal complications, reduced surgical trauma, short operating time, and relatively low recurrence risk. In addition, treated patients are overall satisfied with the results over time.

ABSTRACTThis paper presents a 1:20,000 scale Geoarchaeological map of the Cornia river coastal plain in southern Tuscany. The Geoarchaeological map integrates a comprehensive dataset of geomorphological and archaeological features. The spatial relationships between landforms and archaeological records show that the settlement pattern from the VII century BC to the V century AD was mostly influenced by the presence of several depositional landforms which formed before the period under consideration. Integrating the outputs of geomorphological and topographical analyses with archaeological databases is also helpful for land planning, especially in areas where present-day anthropic exploitation needs predictive and valid tools to assess the archaeological hazard.

Abstract Attention allows the listener to select relevant information from their environment, and disregard what is irrelevant. However, irrelevant stimuli sometimes manage to capture it and stand out from a scene because of bottom-up processes driven by salient stimuli. This attentional capture effect was observed using an implicit approach based on the additional singleton paradigm. In the auditory domain, it was shown that sound attributes such as intensity and frequency tend to capture attention during auditory search (cost to performance) for targets defined on a different dimension such as duration. In the present study, the authors examined whether a similar phenomenon occurs for attributes of timbre such as brightness (related to the spectral centroid) and roughness (related the amplitude modulation depth). More specifically, we revealed the relationship between the variations of these attributes and the magnitude of the attentional capture effect. In experiment 1, the occurrence of a brighter sound (higher spectral centroid) embedded in sequences of successive tones produced significant search costs. In experiments 2 and 3, different values of brightness and roughness confirmed that attention capture is monotonically driven by the sound features. In experiment 4, the effect was found to be symmetrical: positive or negative, the same difference in brightness had the same negative effect on performance. Experiment 5 suggested that the effect produced by the variations of the two attributes is additive. This work provides a methodology for quantifying the bottom-up component of attention and brings new insights on attention capture and auditory salience.

Abstract The Extremely Brilliant Source (EBS) is the experimental implementation of the novel Hybrid Multi Bend Achromat (HMBA) storage ring magnetic lattice concept, which has been realised at European Synchrotron Radiation Facility. We present its successful commissioning and first operation. We highlight the strengths of the HMBA design and compare them to the previous designs, on which most operational synchrotron X-ray sources are based. We report on the EBS storage ring’s significantly improved horizontal electron beam emittance and other key beam parameters. EBS extends the reach of synchrotron X-ray science confirming the HMBA concept for future facility upgrades and new constructions.

Abstract Communication between sound and music experts is based on the shared understanding of a metaphorical vocabulary derived from other sensory modalities. Yet, the impact of sound expertise on the mental representation of these sound concepts remains blurry. To address this issue, we investigated the acoustic portraits of four metaphorical sound concepts (brightness, warmth, roundness, and roughness) in three groups of participants (sound engineers, conductors, and non-experts). Participants (N = 24) rated a corpus of orchestral instrument sounds (N = 520) using Best–Worst Scaling. With this data-driven method, we sorted the sound corpus for each concept and population. We compared the population ratings and ran machine learning algorithms to unveil the acoustic portraits of each concept. Overall, the results revealed that sound engineers were the most consistent. We found that roughness is widely shared while brightness is expertise dependent. The frequent use of brightness by expert populations suggests that its meaning got specified through sound expertise. As for roundness and warmth, it seems that the importance of pitch and noise in their acoustic definition is the key to distinguishing them. These results provide crucial information on the mental representations of a metaphorical vocabulary of sound and whether it is shared or refined by sound expertise.

Background Despite the promising efficacy of immune checkpoint blockers (ICB), tumor resistance and immune-related adverse events hinder their success in cancer treatment. To address these challenges, intratumoral delivery of immunotherapies has emerged as a potential solution, aiming to mitigate side effects through reduced systemic exposure while increasing effectiveness by enhancing local bioavailability. However, a comprehensive understanding of the local and systemic distribution of ICBs following intratumoral administration, as well as their impact on distant tumors, remains crucial for optimizing their therapeutic potential.To comprehensively investigate the distribution patterns following the intratumoral and intravenous administration of radiolabeled anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and to assess its corresponding efficacy in both injected and non-injected tumors, we conducted an immunoPET imaging study.Methods CT26 and MC38 syngeneic colorectal tumor cells were implanted subcutaneously on both flanks of Balb/c and C57Bl/6 mice, respectively. Hamster anti-mouse CTLA-4 antibody (9H10) labeled with zirconium-89 ([89Zr]9H10) was intratumorally or intravenously administered. Whole-body distribution of the antibody was monitored by immunoPET imaging (n=12 CT26 Balb/c mice, n=10 MC38 C57Bl/6 mice). Tumorous responses to injected doses (1–10 mg/kg) were correlated with specific uptake of [89Zr]9H10 (n=24). Impacts on the tumor microenvironment were assessed by immunofluorescence and flow cytometry.Results Half of the dose was cleared into the blood 1 hour after intratumoral administration. Despite this, 7 days post-injection, 6–8% of the dose remained in the intratumoral-injected tumors. CT26 tumors with prolonged ICB exposure demonstrated complete responses. Seven days post-injection, the contralateral non-injected tumor uptake of the ICB was comparable to the one achieved through intravenous administration (7.5±1.7% ID.cm–3 and 7.6±2.1% ID.cm–3, respectively) at the same dose in the CT26 model. This observation was confirmed in the MC38 model. Consistent intratumoral pharmacodynamic effects were observed in both intratumoral and intravenous treatment groups, as evidenced by a notable increase in CD8+T cells within the CT26 tumors following treatment.Conclusions ImmunoPET-derived pharmacokinetics supports intratumoral injection of ICBs to decrease systemic exposure while maintaining efficacy compared with intravenous. Intratumoral-ICBs lead to high local drug exposure while maintaining significant therapeutic exposure in non-injected tumors. This immunoPET approach is applicable for clinical practice to support evidence-based drug development.

IntroductionNeutropenic enterocolitis (NEC) is a life-threatening complication reported in patients with acute myeloid leukemia (AML) following chemotherapy (CHT). Intensive induction and consolidation CHT may damage intestinal mucosa leading to a NEC episode (NECe). NEC reported mortality may be up to 30-60%. Early US-guided bed-side diagnosis and prompt treatment may substantially improve the survival. An emerging worldwide concern is the intestinal colonization by multi-drug-resistant bacteria especially when patients are exposed to chemotherapy regimens potentially correlated to mucosal damage. MethodsIn our study we prospectively enrolled all AML patients admitted in our leukemia unit to receive intensive induction and consolidation chemotherapy and experiencing chemotherapy-induced-neutropenia (CHTN). Results and discussionOverall, we enrolled N=213 patients from 2007 to March 2023. We recorded N=465 CHTN, and N=42 NECe (9.0% incidence). The aim of our study was to assess which chemotherapy regimens are more associated with NEC. We found that ALM1310, followed by 7 + 3 (daunorubicin), 7 + 3 (idarubicin), 5 + 3 + 3 (cytarabine, etoposide, idarubicin), and AML1310 (consolidation) were associated with a statistically higher incidence of NEC. We did not detect NEC episodes in patients treated with CPX-351, 5 + 2 (cytarabine, idarubicine), and high-dose cytarabine. Thus, we found that cytarabine could determine mucosal damage when associated with an anthracycline but not if delivered either alone or as dual-drug liposomal encapsulation of daunorubicin/cytarabine. We also describe NEC mortality, symptoms at diagnosis, intestinal sites involvement, and prognostic significance of bowel wall thickening.

Background:. Capsular contracture (CC) is the most relevant complication of both aesthetic and reconstructive breast implant surgery. For many years, experimental and clinical trials have attempted to analyze CC risk factors, clinical features, and appropriate management strategies. It is commonly accepted that a multifactorial etiology promotes CC development. However, the heterogeneity in patients, implants and surgical techniques make it difficult to suitably compare or analyze specific factors. As a consequence, discordant data are present in literature, and a true systematic review is often limited in its conclusions. Hence, we decided to present a comprehensive review of current theories on prevention and management strategies, rather than a specific “solution” to this complication. Methods:. The PubMed database was searched for literature regarding CC prevention and management strategies. Pertinent articles in English, published before December 1, 2022, were compared with selection criteria and eventually included in this review. Results:. Through the initial search, 97 articles were identified, of which 38 were included in the final study. Several articles explored different medical and surgical preventive and therapeutic strategies, showing numerous controversies on appropriate CC management. Conclusions:. This review provides a clear overview of the complexity of CC. The wide variety of clinical situations in term of patients, implants, and surgical techniques prevent the standardization of CC management strategies. By contrast, a patient-customized approach should be preferred, and different strategies should be considered depending on the specific case. Further research is desirable to better ascertain evidence-based protocols with regard to CC prevention and treatment.

Microplastics (MPs) (0.1 µm–5 mm particles) have been documented in oceans and seas. Bivalve molluscs (BMs) can accumulate MPs and transfer to humans through the food chain. BMs (especially mussels) are used to assess MPs’ contamination, but the genus Donax has not been thoroughly investigated. The aim of this study was to detect and characterize MPs in D. trunculus specimens collected along the Tuscan coast (Italy), and to assess the potential risk for consumers. The samples (~10 g of tissue and intervalval liquid from 35 specimens) were digested using a solution of 10% KOH, subjected to NaCl density separation, and filtered through 5 μm pore-size filters. All items were morphologically classified and measured, and their mean abundance (MA) was calculated. Furthermore, 20% of them were analyzed by Raman spectroscopy and, based on the obtained results, the MA was recalculated (corrected MA) and the annual human exposure was estimated. In the 39 samples analyzed, 85 items fibers (n = 45; 52.94%) and fragments (n = 40; 47.06%) were found. The MA was 0.23 ± 0.17 items/grww. Additionally, 83.33% of the items were confirmed as MPs (polyethylene and polyethylene terephthalate). Based on the correct MA (0.18 MPs/grww), D. trunculus consumers could be exposed to 19.2 MPs/per capita/year. The health risk level of MPs was classified as level III (moderate).

In aquaculture, Lactococcus garvieae is a common fish pathogen that can cause significant economic losses in several fresh and saltwater species. Despite the extensive range of hosts, L. garvieae infection in sea bass (Dicentrarchus labrax) has rarely been reported. During the summer of 2023, an outbreak occurred in an inland farm in the Gulf of Follonica (Tuscany, Italy). Fish of various sizes were affected, showing apathy, inappetence, erratic swimming and eye lesions, while the mortality was low (2–3% per month). Anatomopathological examinations suggested a septicaemic infection characterised by melanosis, diffuse redness (skin and fins), paleness (gills and internal organs), haemorrhages and splenomegaly. Seventy swabs from the viscera of 14 subjects were collected and colonies similar to Streptococcus spp. grew from all the samples. Lactococcus garvieae was identified via the biochemical tests, API20STREP, MALDI-TOF, 16S rDNA and whole genome sequencing. Genetical characterisation revealed remarkable differences between this isolate and the strains previously isolated in Italian fish farms. Feed treatments with flumequine and erythromycin were ineffective. Considering the limited effects of antimicrobials, preventive measures, such as vaccination and biosecurity, should be implemented.

Abstract Background We aimed to determine the safety and efficacy of nintedanib, an oral anti-angiogenic tyrosine kinase inhibitor, in combination with pembrolizumab, an anti-PD1 immunotherapy, in patients with advanced solid tumors (PEMBIB trial; NCT02856425). Methods In this monocentric phase Ib dose escalation cohort, we evaluated escalating doses of nintedanib (Dose level 1 (DL1) = 150 mg bid [bis in die, as twice a day]; DL2 = 200 mg bid, oral delivery) in combination with pembrolizumab (200 mg Q3W, IV). Patients received a 1-week lead-in dose of nintedanib monotherapy prior starting pembrolizumab. The primary objective was to establish the maximum tolerated dose (MTD) of the combination based on dose limiting toxicity (DLT) occurrence during the first 4 weeks. Secondary objectives were to assess the anti-tumor efficacy and to identify the associated immune and angiogenic parameters in order to establish the recommended nintedanib dose for expansion cohorts. Flow cytometry (FC), Immuno-Histo-Chemistry (IHC) and electrochemiluminescence multi-arrays were prospectively performed on baseline & on-treatment tumor and blood samples to identify immune correlates of efficacy. Results A total of 12/13 patients enrolled were evaluable for DLT (1 patient withdrew consent prior receiving pembrolizumab). Three patients at 200 mg bid experienced a DLT (grade 3 liver enzymes increase). Four patients developed grade 1–2 immune related adverse events (irAE). Eight patients died because of cancer progression. Median follow-up was 23.7 months (95%CI: 5.55–40.5). Three patients developed a partial response (PR) (ORR = 25%) and five patients (42%) had durable clinical benefit (DCB), defined as PR or stable disease (SD) ≥ 6 months. At baseline, patients with DCB had higher plasma levels of Tie2, CXCL10, CCL22 and circulating CD4+ PD1+ OX40+ T cells than patients without DCB. Patients with DCB presented also with more DC-LAMP+ dendritic cells, CD3+ T cells and FOXP3+ Tregs in baseline tumor biopsies. For DCB patients, the nintedanib lead-in monotherapy resulted in higher blood CCL3, Tregs and CCR4+ CXCR3+ CXCR5− memory CD4 T cells. After the first pembrolizumab infusion, patients with DCB showed lower IL-6, IL-8, IL-27 plasma levels. Conclusion Nintedanib 150 mg bid is the recommended dose for combination with pembrolizumab and is currently investigated in multiple expansion cohorts. Early tumoral and circulating immune factors were associated with cancer outcome under nintedanib & pembrolizumab therapy. Trial registration ClinicalTrials.gov, NCT02856425 . Registered August 4, 2016 — Prospectively registered.

IntroductionWorldwide, COVID-19 pandemic lead to a large fall in the number of newly reported TB cases. In sub-Saharan Africa, microbiological diagnosis of TB is generally based on smear microscopy and Xpert MTB/RIF on sputum samples, but good quality sputum samples are often difficult to obtain, leading clinicians to rely on more invasive procedures for diagnosis. Aim of this study was to investigate pooled sensitivity and specificity of Xpert MTB/RIF on stool samples compared to respiratory microbiological reference standards in African countries.MethodsFour investigators independently searched PubMed, SCOPUS, and Web of Science until 12th October 2022, then screened titles and abstracts of all potentially eligible articles. The authors applied the eligibility criteria, considered the full texts. All the studies reported the data regarding true positive (TP), true negative (TN), false positive (FP) and false negative (FN). Risk of bias and applicability concerns were assessed with the Quadas-2 tool.Resultsoverall, among 130 papers initially screened, we evaluated 47 works, finally including 13 papers for a total of 2,352 participants, mainly children. The mean percentage of females was 49.6%, whilst the mean percentage of patients reporting HIV was 27.7%. Pooled sensitivity for Xpert MTB/RIF assay for detecting pulmonary tuberculosis was 68.2% (95%CI: 61.1–74.7%) even if characterized by a high heterogeneity (I2=53.7%). Specificity was almost 100% (99%, 95%CI: 97–100%; I2 = 45.7%). When divided for reference standard, in the six studies using sputum and nasogastric aspirate the accuracy was optimal (AUC = 0.99, SE = 0.02), whilst in the studies using only sputum for tuberculosis detection the AUC was 0.85 (with a SE = 0.16). The most common source of bias was exclusion of enrolled patients in the analysis.ConclusionsOur study confirms that, in Africa, stool Xpert MTB/RIF may be a useful rule-in test for children above and below 5 years of age under evaluation for pulmonary tuberculosis. Sensitivity increased substantially when using both sputum and nasogastric aspirate as reference samples.

Thigh lift, first described by Lewis in 1957, consists of thigh recontouring by various strategies. In post-bariatric thigh lift (PBTL), the technical details become fundamental due to both patient comorbidities and increased risk of complications. Moreover, post-bariatric weight loss affects the thighs, resulting in significant tissue redundancy, inner excess, lower thigh deformity, later excess, and buttocks ptosis. With the present paper, a systematic review of PBTL procedures is reported and a comprehensive classification system is proposed, aiming to improve their medical and surgical management. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) systematic review was carried out by searching the PubMed (MEDLINE) database from May 2004 to May 2024 using the search string "thighplasty OR thigh lift OR post-bariatric thighplasty OR (thigh lift AND weight loss) OR (thigh lift AND liposuction)". Original studies discussing PBTL with a minimum of three clinical cases were eligible for inclusion. The final synthesis included 17 articles and 496 patients. The articles were published in the last 20 years. Several papers discussed significant PBTL surgical strategies and technical measures. PBTL is challenging because of both technical factors and complex comorbidities of post-bariatric patients. This comprehensive assessment of PBTL may help in choosing the appropriate treatment based on a patient's individual needs. Liposuction-assisted inner thigh lift with combined horizontal-vertical scars and skin-only excision is effective and versatile for most patients. However, select cases may benefit from alternative and more invasive strategies. Artificial intelligence is a topic of growing interest, and it will probably become increasingly relevant in PBTL. [ABSTRACT FROM AUTHOR]

Internal ribosome entry sites (IRESs) drive translation initiation during stress. In response to hypoxia, (lymph)angiogenic factors responsible for tissue revascularization in ischemic diseases are induced by the IRES-dependent mechanism. Here, we searched for IRES trans-acting factors (ITAFs) active in early hypoxia in mouse cardiomyocytes. Using knock-down and proteomics approaches, we show a link between a stressed-induced nuclear body, the paraspeckle, and IRES-dependent translation. Furthermore, smiFISH experiments demonstrate the recruitment of IRES-containing mRNA into paraspeckle during hypoxia. Our data reveal that the long non-coding RNA Neat1, an essential paraspeckle component, is a key translational regulator, active on IRESs of (lymph)angiogenic and cardioprotective factor mRNAs. In addition, paraspeckle proteins p54nrb and PSPC1 as well as nucleolin and RPS2, two p54nrb-interacting proteins identified by mass spectrometry, are ITAFs for IRES subgroups. Paraspeckle thus appears as a platform to recruit IRES-containing mRNAs and possibly host IRESome assembly. Polysome PCR array shows that Neat1 isoforms regulate IRES-dependent translation and, more widely, translation of mRNAs involved in stress response.