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The paper examines the Leopardian materials acquired and preserved by Loris Bononi at the library of the Centro Studi Umanistici Niccolò V in Castiglione del Terziere. The discourse opens by investigating the relationship between Bononi and Leopardi and the possible influences of the latter on the former's writing (both published and unpublished). The analysis of the Leopardi's sections begins with the ‘self-description’ the poet made of himself in a letter to Carlo Pepoli, which is part of this collection. The second part of the essay is devoted to the unpublished manuscripts of Giacomo’s sister, Paolina, and Carlo Leopardi’s wife, Teresa Teja: three letters allowing the reconstruction of the biographical context of two figures who contributed to keeping alive the first hand memory of Leopardi.

Background: Impairments in hamstring strength, flexibility, and morphology have been associated with altered knee biomechanics, pain, and function. Determining the presence of these impairments in individuals with gradual-onset knee disorders is important and may indicate targets for assessment and rehabilitation. This systematic review aimed to synthesize the literature to determine the presence of impairments in hamstring strength, flexibility, and morphology in individuals with gradual-onset knee disorders. Methods: Five databases (MEDLINE, Embase, CINAHL, SPORTDiscus, and Web of Science) were searched from inception to September 2022. Only studies comparing hamstring outcomes (e.g., strength, flexibility, and/or morphology) between individuals with gradual-onset knee disorders and their unaffected limbs or pain-free controls were included. Meta-analyses for each knee disorder were performed. Outcome-level certainty was assessed using the Grading of Recommendations Assessment, Development, and Evaluation, and evidence gap maps were created. Results: Seventy-nine studies across 4 different gradual-onset knee disorders (i.e., knee osteoarthritis (OA), patellofemoral pain (PFP), chondromalacia patellae, and patellar tendinopathy) were included. Individuals with knee OA presented with reduced hamstring strength compared to pain-free controls during isometric (standard mean difference (SMD) = –0.76, 95% confidence interval (95%CI) : –1.32 to –0.21) and concentric contractions (SMD = –0.97, 95%CI : –1.49 to –0.45). Individuals with PFP presented with reduced hamstring strength compared to pain-free controls during isometric (SMD = –0.48, 95%CI : –0.82 to –0.14), concentric (SMD = –1.07, 95%CI : –2.08 to –0.06), and eccentric contractions (SMD = –0.59, 95%CI : –0.97 to –0.21). No differences were observed in individuals with patellar tendinopathy. Individuals with PFP presented with reduced hamstring flexibility when compared to pain-free controls (SMD = –0.76, 95%CI : –1.15 to –0.36). Evidence gap maps identified insufficient evidence for chondromalacia patellae and hamstring morphology across all gradual-onset knee disorders. Conclusion: Our findings suggest that assessing and targeting impairments in hamstring strength and flexibility during rehabilitation may be recommended for individuals with knee OA or PFP.

This Phase I/IIa open-label, single-arm clinical trial addressing advanced, refractory, metastatic breast cancer was conducted at six medical centers in the United States. We repeated inoculations with irradiated SV-BR-1-GM, a breast cancer cell line with antigen-presenting activity engineered to release granulocyte-macrophage colony-stimulating factor (GM-CSF), with pre-dose low-dose cyclophosphamide and post-dose local interferon alpha. Twenty-six patients were enrolled; 23 (88.5%) were inoculated, receiving a total of 79 inoculations. There were six Grade 4 and one Grade 5 adverse events noted (judged unrelated to SV-BR-1-GM). Disease control (stable disease [SD]) occurred in 8 of 16 evaluable patients; 4 showed objective regression of metastases, including 1 patient with near-complete regressions in 20 of 20 pulmonary lesions. All patients with regressions had human leukocyte antigen (HLA) matches with SV-BR-1-GM; non-responders were equally divided between matching and nonmatching (p = .01, Chi-squared), and having ≥2 HLA matches with SV-BR-1-GM (n = 6) correlated with clinical benefit. Delayed-type hypersensitivity (DTH) testing to candida antigen and SV-BR-1-GM generated positive responses (≥5 mm) in 11 (42.3%) and 13 (50%) patients, respectively. Quantifying peripheral circulating tumor cells (CTCs) and cancer-associated macrophage-like cells (CAMLs) showed that a drop in CAMLs was significantly correlated with an improvement in progression-free survival (PFS; 4.1 months vs. 1.8 months, p = .0058). Eight of 10 patients significantly upregulated programmed cell death ligand 1 (PD-L1) on CTCs/CAMLs with treatment (p = .0012). These observations support the safety of the Bria-IMT regimen, demonstrate clinical regressions, imply a role for HLA matching, and identify a possible value for monitoring CAMLs in peripheral blood.

ABSTRACTCell-based therapeutic cancer vaccines use autologous patient-derived tumor cells, allogeneic cancer cell lines or autologous antigen presenting cells to mimic the natural immune process and stimulate an adaptive immune response against tumor antigens. The primary objective of this study is to perform a systematic literature review with an embedded meta-analysis of all published Phase 2 and 3 clinical trials of cell-based cancer vaccines in human subjects. The secondary objective of this study is to review trials demonstrating biological activity of cell-based cancer vaccines that could uncover additional hypotheses, which could be used in the design of future studies. We performed the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The final review included 36 studies − 16 single-arm studies, and 20 controlled trials. Our systematic review of the existing literature revealed largely negative trials and our meta-analysis did not show evidence of clinical benefit from cell-based cancer-vaccines. However, as we looked beyond the stringent inclusion criteria of our systematic review, we identified significant examples of biological activity of cell-based cancer vaccines that are worth highlighting. In conclusion, the existing literature on cell-based cancer vaccines is highly variable in terms of cancer type, vaccine therapies and the clinical setting with no overall statistically significant clinical benefit, but there are individual successes that represent the promise of this approach. As cell-based vaccine technology continues to evolve, future studies can perhaps fulfill the potential that this exciting field of anti-cancer therapy holds.

BACKGROUND: The associations of geographic atrophy (GA) progression with systemic health status and medication use are unclear. METHODS: We manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. We calculated GA perimeter-adjusted growth rate as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye (mean follow-up=5.3 years). Patients history of systemic health and medications was collected through questionnaires administered at study enrolment. We evaluated the associations between GA perimeter-adjusted growth rate and 27 systemic health factors using univariable and multivariable linear mixed-effects regression models. RESULTS: In the univariable model, GA perimeter-adjusted growth rate was associated with GA in the fellow eye at any visit (p=0.002), hypertension history (p=0.03), cholesterol-lowering medication use (p

Nell’affrontare la storia del rapporto di Cesare Pavese con la lingua e la cultura greca, il contributo si concentra sulle traduzioni private svolte durante il confino a Brancaleone calabro (1835-1836). Questo periodo segna un punto di svolta nell’apprendimento del greco, che influenzerà anche la sua successiva produzione creativa. Le particolarissime scelte di traduzione che l’autore compie sono analizzate nel contributo a partire dalla traduzione del Filottete sofocleo (vv. 1-169), di cui si fornisce l’edizione critica e il commento.

The Critical Raw Materials Act has been emanated to address perceived risks around supply chains for critical raw materials in light of expected demand growth [1]. Cobalt is one of the critical raw materials for the EU: it plays a central role in transition to a low-carbon economy and is crucial for batteries powering electric vehicles. The cobalt industry is important not only because of the green transition, it also creates employment opportunities as Europe is the third largest region for total global cobalt value chain employment [2]. The global market for battery electric vehicles (BEVs) is continuously increasing which results in higher material demand for the production of Li-ion batteries (LIBs). Especially Lithium nickel manganese cobalt (NMC) batteries are one of the leading types of batteries deployed on BEVs and recovering of materials from used batteries for producing new battery materials may mitigate the material supply risk [3,4]. The present survey concerns the creation and comparison of two datasets of patents concerning Cobalt recycling, respectively achieved without (dataset 1) and with (dataset 2) the addition of one specific ‘green’ CPC classification code to a huge list of classification codes concerning recycling. Namely, the CPC Y02P10/20 determines a significant improvement on the exhaustivity of the search regarding Cobalt recycling in dataset 2, on the other hand it might also generate issues evidenced by a subsequent selection of those records in principle focused on the recovery of NMC batteries and characterized by several false positives. Therefore, a refinement strategy is recommended, to make the accuracy of the NMC dataset comparable to that characterizing the NMC results from dataset 1 achieved without any refinement.

Abstract In the context of continuous emergence of SARS-CoV-2 variants of concern (VOCs), one strategy to prevent the severe outcomes of COVID-19 is developing safe and effective broad-spectrum vaccines. Here, we present preclinical studies of a RBD vaccine derived from the Gamma SARS-CoV-2 variant adjuvanted with Alum. The Gamma-adapted RBD vaccine is more immunogenic than the Ancestral RBD vaccine in terms of inducing broader neutralizing antibodies. The Gamma RBD presents more immunogenic B-cell restricted epitopes and induces a higher proportion of specific-B cells and plasmablasts than the Ancestral RBD version. The Gamma-adapted vaccine induces antigen specific T cell immune responses and confers protection against Ancestral and Omicron BA.5 SARS-CoV-2 challenge in mice. Moreover, the Gamma RBD vaccine induces higher and broader neutralizing antibody activity than homologous booster vaccination in mice previously primed with different SARS-CoV-2 vaccine platforms. Our study indicates that the adjuvanted Gamma RBD vaccine is highly immunogenic and a broad-spectrum vaccine candidate.

Abstract Introduction Intravascular catheters are crucial devices in medical practice that increase the risk of healthcare-associated infections (HAIs), and related health-economic adverse outcomes. This scoping review aims to provide a comprehensive overview of published automated algorithms for surveillance of catheter-related bloodstream infections (CRBSI) and central line-associated bloodstream infections (CLABSI). Methods We performed a scoping review based on a systematic search of the literature in PubMed and EMBASE from 1 January 2000 to 31 December 2021. Studies were included if they evaluated predictive performance of automated surveillance algorithms for CLABSI/CRBSI detection and used manually collected surveillance data as reference. We assessed the design of the automated systems, including the definitions used to develop algorithms (CLABSI versus CRBSI), the datasets and denominators used, and the algorithms evaluated in each of the studies. Results We screened 586 studies based on title and abstract, and 99 were assessed based on full text. Nine studies were included in the scoping review. Most studies were monocentric (n = 5), and they identified CLABSI (n = 7) as an outcome. The majority of the studies used administrative and microbiological data (n = 9) and five studies included the presence of a vascular central line in their automated system. Six studies explained the denominator they selected, five of which chose central line-days. The most common rules and steps used in the algorithms were categorized as hospital-acquired rules, infection rules (infection versus contamination), deduplication, episode grouping, secondary BSI rules (secondary versus primary BSI), and catheter-associated rules. Conclusion The automated surveillance systems that we identified were heterogeneous in terms of definitions, datasets and denominators used, with a combination of rules in each algorithm. Further guidelines and studies are needed to develop and implement algorithms to detect CLABSI/CRBSI, with standardized definitions, appropriate data sources and suitable denominators.

A rising demand for prosthetic-driven jaw reconstruction is encountered in maxillo-facial surgery. The free scapula flap is a workhorse of cervico-facial reconstructions, but an implant-based prosthetic rehabilitation on this flap is a debated topic. A systematic review of the papers on this subject has been conducted on Embase, MEDLINE, and Cochrane libraries following PRISMA guidelines, in order to analyze the results described in the literature. A total of nine papers were eligible for inclusion, with 83 scapula flaps overall being used for an implant-based prosthetic rehabilitation. The mandible was the reconstructed jaw in 58.0% of the cases. Overall, 249 implants were positioned (mean 3.0 implant per flap) with a 3.6% implant failure rate. In 95.2% of the cases, delayed rehabilitation was performed. Radiotherapy and the timing of implant placement did not seem to influence implant failure. Only two papers analyzed the quality of life following the rehabilitation, highlighting a functional improvement. Scapula-based implant-prosthetic rehabilitation is a feasible technique that can also benefit from the new CAD/CAM technologies and digital workflows. Nonetheless, further studies focused on this topic and on its impact on the quality of life are needed in order to analyze risk factors and to optimize the outcomes.

PurposeThe purpose of this study was to demonstrate that the organized formation of subretinal drusenoid deposits (SDDs) may be a Turing pattern.MethodsA Java-based computational model of an inferred reaction-diffusion system using paired partial differential equations was used to create topographic images. Reaction kinetics were varied to illustrate a spectrum of pattern development, which were then compared to dot-like, reticular, and confluent SDD patterns observed clinically.ResultsA reaction-diffusion system using two agents, one an "activator" that increases its own production, and the other an "inhibitor" that decreases the activator's production, can create patterns that match the spectrum of topographic appearance of organized SDD. By varying a single parameter, the strength of the activator, the full spectrum of clinically observed SDD patterns can be generated. A new pattern, confluence with holes, is predicted and identified in one case example.ConclusionsThe formation of clinically significant SDD and its different patterns can be explained using Turing patterns obtained by simulating a two-component reaction-diffusion system.Translational relevanceThis model may be able to guide future risk stratification for patients with SDD, and provide mechanistic insights into the cause of the disease.

A major question in clinical science is how to study the natural course of a chronic disease from inception to end, which is challenging because it is impractical to follow patients over decades. Here, we developed BETR (Bayesian entry time realignment), a hierarchical Bayesian method for investigating the long-term natural history of diseases using data from patients followed over short durations. A simulation study shows that BETR outperforms an existing method that ignores patient-level variation in progression rates. BETR, when combined with a common Bayesian model comparison tool, can identify the correct disease progression function nearly 100% of the time, with high accuracy in estimating the individual disease durations and progression rates. Application of BETR in patients with geographic atrophy, a disease with a known natural history model, shows that it can identify the correct disease progression model. Applying BETR in patients with Huntington's disease demonstrates that the progression of motor symptoms follows a second order function over approximately 20 years.

PurposeTo use empirical data to develop a model of cell loss in choroideremia that predicts the known exponential rate of RPE loss and central, scalloped preservation pattern seen in this disease.MethodsA computational model of RPE loss was created in Python 3.7, which constructed an array of RPE cells clusters, binarized as either live or atrophic. Two rules were applied to this model: the background effect gave each cell a chance of dying defined by a background function, and the neighbor effect increased the chance of RPE cell death if a neighbor were dead. The known anatomic distribution of rods, RPE, choriocapillaris density, amacrine, ganglion, and cone cells were derived from the literature and applied to this model. Atrophy growth rates were measured over arbitrary time units and fit to the known exponential decay model. The main outcome measures: included topography of atrophy over time and fit of simulated residual RPE area to exponential decay.ResultsA background effect alone can simulate exponential decay, but does not simulate the central island preservation seen in choroideremia. An additive neighbor effect alone does not simulate exponential decay. When the neighbor effect multiplies the background effect using the rod density function, our model follows an exponential decay, similar to previous observations. Also, our model predicts a residual island of RPE that resembles the topographic distribution of residual RPE seen in choroideremia.ConclusionsThe pattern of RPE loss in choroideremia can be predicted by applying simple rules. The RPE preservation pattern typically seen in choroideremia may be related to the underlying pattern of rod density. Further studies are needed to validate these findings.

PurposeTo assess the influence of lesion morphology and location on geographic atrophy (GA) growth rate.MethodsWe manually delineated GA on color fundus photographs of 237 eyes in the Age-Related Eye Disease Study. We calculated local border expansion rate (BER) as the linear distance that a point on the GA border traveled over 1 year based on a Euclidean distance map. Eye-specific BER was defined as the mean local BER of all points on the GA border in an eye. The percentage area affected by GA was defined as the GA area divided by the total retinal area in the region.ResultsGA enlarged 1.51 ± 1.96 mm2 in area and 0.13 ± 0.11 mm in distance over 1 year. The GA area growth rate (mm2/y) was associated with the baseline GA area (P < 0.001), perimeter (P < 0.001), lesion number (P < 0.001), and circularity index (P < 0.001); in contrast, eye-specific BER (mm/y) was not significantly associated with any of these factors. As the retinal eccentricity increased from 0 to 3.5 mm, the local BER increased from 0.10 to 0.24 mm/y (P < 0.001); in contrast, the percentage of area affected by GA decreased from 49.3% to 2.3%.ConclusionsUsing distance-based measurements allows GA progression evaluation without significant confounding effects from baseline GA morphology. Local GA progression rates increased as a function of retinal eccentricity within the macula which is opposite of the trend for GA distribution, suggesting that GA initiation and enlargement may be mediated by different biological processes.

PurposeTo establish a continuous topography of retinal vessel density in normal eyes using optical coherence tomography angiography (OCTA).MethodsA retrospective chart review was performed, and 8-mm × 8-mm OCTA images from 22 normal eyes were analyzed. Vessel density was plotted as a continuous function of distance from the foveal center (radial vessel density) and directional meridians (directional vessel density) for the superficial capillary plexus and deep capillary plexus.ResultsContinuous radial and directional vessel density plots for the superficial and deep capillary plexus were generated. Radial vessel density analysis revealed transition points at 657 microns (95% confidence interval [CI], 619-696) and 950 microns (95% CI, 903-997) from the foveal center for the superficial plexus and deep plexus, respectively. Directional vessel density analysis demonstrated significant vessel density variations in these vascular layers and provided greater detail compared to traditional quadrant analysis.ConclusionsThere are significant topographic variations of retinal vessel density in normal eyes. Continuous vessel density analysis offers greater sensitivity in detecting topographic vessel density changes compared to traditional methods of analysis.Translational relevanceThis study establishes a normative continuous vessel density topography that may help elucidate the role of the vascular bed in different chorioretinal diseases.

Abstract Background Intravascular catheter infections are associated with adverse clinical outcomes. However, a significant proportion of these infections are preventable. Evaluations of the performance of automated surveillance systems for adequate monitoring of central-line associated bloodstream infection (CLABSI) or catheter-related bloodstream infection (CRBSI) are limited. Objectives We evaluated the predictive performance of automated algorithms for CLABSI/CRBSI detection, and investigated which parameters included in automated algorithms provide the greatest accuracy for CLABSI/CRBSI detection. Methods We performed a meta-analysis based on a systematic search of published studies in PubMed and EMBASE from 1 January 2000 to 31 December 2021. We included studies that evaluated predictive performance of automated surveillance algorithms for CLABSI/CRBSI detection and used manually collected surveillance data as reference. We estimated the pooled sensitivity and specificity of algorithms for accuracy and performed a univariable meta-regression of the different parameters used across algorithms. Results The search identified five full text studies and 32 different algorithms or study populations were included in the meta-analysis. All studies analysed central venous catheters and identified CLABSI or CRBSI as an outcome. Pooled sensitivity and specificity of automated surveillance algorithm were 0.88 [95%CI 0.84–0.91] and 0.86 [95%CI 0.79–0.92] with significant heterogeneity (I 2 = 91.9, p

Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7-80.1); doubling-time 6.2 months (range 1.4-36.6) and baseline testosterone 319.1 ng/ml (range 2.5-913.7). Median duration of therapy was 6.5 months (2.6-14.0). CTCs (median 48.5 cells/4 ml (range 15-268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of

Abstract Background Patellofemoral pain (PFP) is a common knee disorder that causes persistent pain, lower self-reported function and quality of life. People with PFP also present with altered psychological factors, which are associated with higher levels of pain and dysfunction. Mindfulness-based interventions (MBI) generally consist of meditative practices developed to provide a holistic approach to chronic conditions. However, the effects of MBI on clinical and psychological outcomes for people with PFP remains understudied. Methods This assessor-blinded, parallel, two-arm randomized clinical trial aims to investigate the effects of adding an 8-week online MBI program to exercise therapy and patient education on clinical and psychological factors for people with PFP. We also aim to investigate whether psychological factors mediate changes in pain and function. Sixty-two participants with PFP will be recruited and randomized into one of two treatment groups (Mindfulness or Control group). Both groups will receive an 8-week intervention involving exercise therapy and education delivered through an online platform. The Mindfulness group will additionally receive a MBI component including formal and informal practices. Outcomes will be assessed online at baseline, intervention endpoint (follow-up 1) and 12 months after intervention completion (follow-up 2). Comparisons between groups will be performed at all time points with linear mixed models. A mediation analysis will be performed using a 3-variable framework. Discussion Exercise therapy and patient education are considered the “best management” options for PFP. However, unsatisfactory long-term prognosis remains an issue. It is known that people with PFP present with altered psychological factors, which should be considered during the evaluation and treatment of people with PFP. Adding a MBI to the current best treatment for PFP may improve short and long-term effects by addressing the underlying psychological factors. Trial registration Registro Brasileiro de Ensaios Clínicos (ReBEC) RBR-4yhbqwk, registered in April 6, 2021.

Abstract Expanded CAG/CTG repeats are sites of DNA damage, leading to repeat length changes. Homologous recombination (HR) is one cause of repeat instability and we hypothesized that gap filling was a driver of repeat instability during HR. To test this, we developed an assay such that resection and ssDNA gap fill-in would occur across a (CAG)70 or (CTG)70 repeat tract. When the ssDNA template was a CTG sequence, there were increased repeat contractions and a fragile site was created leading to large-scale deletions. When the CTG sequence was on the resected strand, resection was inhibited, resulting in repeat expansions. Increased nucleolytic processing by deletion of Rad9, the ortholog of 53BP1, rescued repeat instability and chromosome breakage. Loss of Rad51 increased contractions implicating a protective role for Rad51 on ssDNA. Together, our work implicates structure-forming repeats as an impediment to resection and gap-filling which can lead to mutations and large-scale deletions.

O objetivo foi avaliar o comportamento alimentar, satisfação com o peso corporal e questões relacionadas à saúde mental de alunos de um Colégio de Aplicação de uma universidade Federal , antes e durante a pandemia. Aplicou-se um questionário online semiestruturado via Google Forms, contendo informações sobre hábitos e comportamentos alimentares, satisfação com peso corporal, prática de atividade física e questões referentes à saúde mental, antes e durante o período da pandemia de COVID-19. Avaliou-se 88 alunos, 54,5% do sexo feminino, com mediana de idade de 16,5 anos. Durante o cenário crítico imposto pela pandemia do SARS-CoV-2, ocorreram mudanças positivas nos hábitos alimentares dos adolescentes e no padrão de atividade física, principalmente por estarem morando com os pais, contudo, foram observados importantes impactos negativos na saúde mental.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer associated with an early age of onset, greater propensity towards metastasis, and poorer clinical outcomes. It accounts for 10% to 20% of newly diagnosed breast cancer cases and disproportionately affects individuals from the African American race. While TNBC is sensitive to chemotherapy, it is also prone to relapse. This is because chemotherapy successfully targets the primary TNBC tumor cell but often fails to target the subpopulation of TNBC stem cells. TNBC stem cells display cancerous traits such as cell cycle progression, survival, proliferation, apoptosis inhibition, and epithelial-mesenchymal transition. To study the cancer initiating behavior of the TNBC stem cells, we studied their underlying signaling pathways using Boolean networks(BN). BNs are effective in capturing the causal interactions taking place in signaling pathways. We built the BN from the pathway literature and used it to evaluate the efficacies of eleven targeted inhibitory drugs in suppressing cancer-promoting genes. We simulated the BN when the pathways had single or multiple mutations, with a maximum of three mutations at a time. Our findings indicated that STAT3, GLI, and NF- $\kappa $ B are the most optimal targets for inhibition. These genes are known regulators of the cancer-promoting genes in the pathway,hence our model agrees with the existing biological literature. Therefore inhibiting these three genes has the potential to prevent TNBC relapse. Additionally, our studies found that drug efficacies decreased as mutations increased in the pathway. Furthermore, we noticed that combinations of drugs performed better than single drugs.

The real-time reconstruction of the displacement field of a structure from a network of in situ strain sensors is commonly referred to as “shape sensing”. The inverse finite element method (iFEM) stands out as a highly effective and promising approach to perform this task. In the current investigation, this technique is employed to monitor different plate structures experiencing flexural and torsional deformation fields. In order to reduce the number of installed sensors and obtain more accurate results, the iFEM is applied in synergy with smoothing element analysis (SEA), which allows the pre-extrapolation of the strain field over the entire structure from a limited number of measurement points. For the SEA extrapolation to be effective for a multitude of load cases, it is necessary to position the strain sensors appropriately. In this study, an innovative sensor placement strategy that relies on a multi-objective genetic algorithm (NSGA-II) is proposed. This approach aims to minimize the root mean square error of the pre-extrapolated strain field across a set of mode shapes for the examined plate structures. The optimized strain reconstruction is subsequently utilized as input for the iFEM technique. Comparisons are drawn between the displacement field reconstructions obtained using the proposed methodology and the conventional iFEM. In order to validate such methodology, two different numerical case studies, one involving a rectangular cantilevered plate and the other encompassing a square plate clamped at the edges, are investigated. For the considered case studies, the results obtained by the proposed approach reveal a significant improvement in the monitoring capabilities over the basic iFEM algorithm with the same number of sensors.

The Immune Tolerance Network ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n = 77) or maintenance (n = 18) 1- to 2-years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; ≤Stage 2 Ishak fibrosis; and absence of rejection on biopsy. Immunosuppression withdrawal followed an 8-step reduction algorithm with ≥8 weeks per level. Fifty-two of 77 subjects (67.5%) reduced to ≤50% of baseline dose, and 10 of 77 (13.0%) discontinued all immunosuppression for ≥1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage ≥3; or >25% decrease in glomerular filtration rate within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.

Abstract Estrogen receptor alpha (ERα) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of an ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(−) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.

The recognition and dating of corrective stratigraphies, in the study of manuscript writings, is fundamental in the preparation of critical editions, for author philology and variant criticism, and in cases of authorship. The analysis of the different "corrective campaigns" of a text can now be carried out with some imaging techniques, from RTI, to interferometers, to photometric stereo, which allow to reconstruct the third dimension: "z", that of time: a technology widely used in cultural heritage, but still not very widespread in the study of texts. The contribution illustrates some cases of 3D reconstruction of manuscripts, from Dante to Leopardi, and proposes a protocol for sharing digital reproduction standards.