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Abstract Programmed death-ligand 1 (PD-L1) expression is currently used in the clinic to assess eligibility for immune-checkpoint inhibitors via the tumor proportion score (TPS), but its efficacy is limited by high interobserver variability. Multiple papers have presented systems for the automatic quantification of TPS, but none report on the task of determining cell-level PD-L1 expression and often reserve their evaluation to a single PD-L1 monoclonal antibody or clinical center. In this paper, we report on a deep learning algorithm for detecting PD-L1 negative and positive tumor cells at a cellular level and evaluate it on a cell-level reference standard established by six readers on a multi-centric, multi PD-L1 assay dataset. This reference standard also provides for the first time a benchmark for computer vision algorithms. In addition, in line with other papers, we also evaluate our algorithm at slide-level by measuring the agreement between the algorithm and six pathologists on TPS quantification. We find a moderately low interobserver agreement at cell-level level (mean reader-reader F1 score = 0.68) which our algorithm sits slightly under (mean reader-AI F1 score = 0.55), especially for cases from the clinical center not included in the training set. Despite this, we find good AI-pathologist agreement on quantifying TPS compared to the interobserver agreement (mean reader-reader Cohen’s kappa = 0.54, 95% CI 0.26–0.81, mean reader-AI kappa = 0.49, 95% CI 0.27—0.72). In conclusion, our deep learning algorithm demonstrates promise in detecting PD-L1 expression at a cellular level and exhibits favorable agreement with pathologists in quantifying the tumor proportion score (TPS). We publicly release our models for use via the Grand-Challenge platform.

This study presents a comprehensive life cycle assessment of the environmental impacts of dietary patterns in different cities, focusing on the correlation between food consumption and environmental impact. The functional unit was the food required to meet one person's yearly needs (1 Inh/year). To determine the quantity and type of food consumed, as well as the income level of the residents, 523 surveys were conducted in households in four cities in Chile (Iquique, Santiago, Temuco, and Coyhaique). Survey data were complemented with secondary information from national statistics and the Ecoinvent database. The environmental impact assessment was carried out using SimaPro, selecting the categories of global warming, terrestrial acidification, terrestrial ecotoxicity, freshwater ecotoxicity, freshwater eutrophication, land use, and fossil resource scarcity. The results show that higher-income households generate greater environmental impacts attributed to higher per capita food consumption. In the global warming category, the environmental impact can range from 1.08 kg CO2 eq/inh/year for the first quintile to 2.15 kg CO2 eq/inh/year for the fifth quintile in Santiago. In this category, the impacts in the highest quintiles can be up to 2.2 times greater than those in the lowest quintiles. Similarly, in acidification, this difference can reach 2.3 times. In the freshwater eutrophication category, the highest-income quintiles can double the environmental impacts compared to the lowest (I and II), mainly due to higher consumption of red meat and dairy products. The food production stage was the environmental hotspot across all evaluated impact categories, accounting for 45%–60% of the impacts in global warming, terrestrial ecotoxicity, and fossil resource scarcity; 74%–78% in terrestrial acidification, freshwater eutrophication, and land use; and 68%–71% in freshwater ecotoxicity. Meat was pinpointed as the primary environmental hotspot in global warming (44%), terrestrial acidification (56%), freshwater eutrophication (50%), land use (35%), and fossil resource scarcity (30%). Conversely, cereals are the primary environmental hotspot in terrestrial ecotoxicity (30%) and vegetables in freshwater ecotoxicity (18%). The geographical location of cities also influenced the environmental impacts of food consumption, primarily due to the types of available foods in regions near each city. Food availability conditions, diets, and quantities consumed, thus influencing environmental impacts. Finally, household incomes, the geographical location of cities, and the food production systems in each city determine the environmental impacts of food consumption. Different configurations of these variables create unique environmental impact profiles for each city. Despite this, typical environmental hotspots in food consumption were identified across all cities, enabling the implementation of strategies to minimize environmental impacts on a national scale. Thus, circular economy strategies linked to food production systems, as well as food loss and waste, could significantly reduce environmental impacts, presenting an intriguing opportunity for future research in this field.

Are children and adults sensitive to gaps in their knowledge, and do they actively elicit information to resolve such knowledge gaps? In a cross-situational word learning task, we asked 5-year-olds, 6- to 9-year-olds and adults to estimate their knowledge of newly learned word–object associations. We then examined whether participants preferentially sampled objects they reported not knowing the label in order to hear their labels again. We also examined whether such uncertainty-driven sampling behaviour led to improved learning. We found that all age groups were sensitive to gaps in their knowledge of the word–object associations, i.e. were more likely to say they had correctly indicated the label of an object when they were correct, relative to when they were incorrect. Furthermore, 6- to 9-year-olds and adults—but not 5-year-olds—were more likely to sample objects whose labels they reported not knowing. In other words, older children and adults displayed sampling behaviour directed at reducing knowledge gaps and uncertainty, while younger children did not. However, participants who displayed more uncertainty-driven sampling behaviour were not more accurate at test. Our findings underscore the role of uncertainty in driving 6- to 9-year-olds’ and adults’ sampling behaviour and speak to the mechanisms underlying previously reported performance boosts in active learning.

Electron and hole transport characteristics were evaluated for perylene-based and pyrene-based compounds using electron-only and hole-only devices. The perylene presented a columnar hexagonal liquid crystal phase at room temperature with strong molecular π-stacking inside the columns. The pyrene crystallizes bellow 166 °C, preserving the close-packed columnar rectangular structure of the mesophase. Photophysical analysis and numerical calculations assisted the interpretation of positive and negative charge carrier mobilities obtained from fitting the space charge limited regime of current vs voltage curves. The pyrene-based material demonstrated an electron mobility two orders of magnitude higher than the perylene one, indicating the potential of this class of materials as electron transporting layer.

How do individuals select which of multiple sources of information to attend to, and which events and entities in their environment to solicit more information about? This studyaims at understanding whether adults actively solicit information that they are missing to fill gaps in their knowledge of recently learned novel word-object associations. In otherwords, we ask whether adults actively solicit the labels of objects they are not confident about. Furthermore, given the role of confidence on the influence of feedback on word learning, we ask whether the beneficial effects of feedback on errors vary as a result of the confidence learners have in their knowledge of newly learned novel word-object associations. We will also compare the findings of this study to the results of a study with the same design that was conducted with preschoolers.

Abstract Introduction Type 2 diabetes mellitus (T2DM) is a non-communicable disease representing one of the most serious public health challenges of the twenty-first century. Its incidence continues to rise in both developed and developing countries, causing the death of 1.5 million people every year. The use of technology (e.g. smartphone application—App) in the health field has progressively increased as it has been proved to be effective in helping individuals manage their long-term diseases. Therefore, it has the potential to reduce the use of health service and its related costs. The objective of this study is to evaluate the impact of using a digital platform called “TreC Diabete” embedded into a novel organisational asset targeting poorly controlled T2DM individuals in the Autonomous Province of Trento (PAT), Italy. Methods This trial was designed as a multi-centre, open-label, randomised, superiority study with two parallel groups and a 1:1 allocation ratio. Individuals regularly attending outpatient diabetes clinics, providing informed consent, are randomised to be prescribed TreC Diabete platform as part of their personalised care plan. Healthcare staff members will remotely assess the data shared by the participants through the App by using a dedicated online medical dashboard. The primary end-point is the evaluation of the Hb1Ac level at 12-month post-randomisation. Data will be analysed on an intention-to-treat (ITT) basis. Discussion This trial is the first conducted in the PAT area for the use of an App specifically designed for individuals with poorly controlled T2DM. If the effects of introducing this specific App within a new organisational asset are positive, the digital platform will represent a possible way for people diagnosed with T2DM to better manage their health in the future. Results will be disseminated through conferences and peer-reviewed journals once the study is completed. Trial registration ClinicalTrials.gov NCT05629221. Registered on November 29, 2022, prior start of inclusion.

BackgroundCladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed.AimTo estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine.MethodsForty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The ‘no evidence of disease activity’ (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs.ResultsThree patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91).ConclusionsCSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug’s effect on chronic macrophage and microglia activation deserves further evaluation.

ObjectiveWe investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies.MethodsWe prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10.ResultsIn the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases.ConclusionsELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk.

Background: Enteric-type adenocarcinoma of the lung (lung-ETAC) is a rare form of lung cancer with histologic similarities to colorectal cancer, with aggressive behavior and unfavorable prognosis. Case Presentation: An 81-year-old man presented with discolored skin lesions on the chest and abdomen. After comprehensive evaluation, including skin biopsy and molecular profiling, the patient was diagnosed with having lung-ETAC with a BRAF p.V600E mutation. Treatment with dabrafenib and trametinib initially resulted in positive results, with improvement in skin lesions and overall clinical condition. Nevertheless, approximately 6 months after, the disease had progression with new skin lesions reappearing. Conclusions: We reported a unique case of a patient with BRAF p.V600E-mutant lung-ETAC with metastatic skin lesions achieving complete cutaneous response after targeted treatment with dabrafenib and trametinib, highlighting the potential for targeted therapy in patients with lung-ETAC harboring a BRAF p.V600E mutation.

Second opinion consultation is a well-established practice in different clinical settings of diagnostic medicine. However, little is known about second opinion consultation activity in transplantation, and even less is known about it concerning donor assessment. The consultations provided by the second opinion service led to the safer and homogeneous management of donors with a history of malignancy or ongoing neoplasm by transplant centers. Indeed, two of the most important aspects are the reduction of semantic differences in cancer reporting and the standardization of procedures, which are mainly due to the different settings and logistics of different pathology services. This article aims to discuss the role and the future of the second opinion in Italy during organ procurement, highlighting the critical issues and areas for improvement.

Abstract To disguise man-made communications as natural signals, underwater transceivers have the option to pre-record animal vocalizations, and play them back in a way that carries meaningful information for a trained receiver. This operation, known as biomimicking, has been used to perform covert communications and to emit broadband signals for localization, either by playing pre-recorded animal sounds back into the environment, or by designing artificial waveforms whose spectrum is close to that of bioacoustic sounds.However, organic sound-emitting body structures in animals have very different trans-characteristics with respect to electro-acoustic transducers used in underwater acoustic transceivers. In this paper, we observe the distortion induced by transmitting pre-recorded animal vocalization through a transducer’s front-end, and argue that such distortion can be detected via appropriate entropy metrics. We test ten different metrics for this purpose, both via emulated transmission and in two field experiments. Our result indicate which signals and entropy metrics lead to the highest probability of detecting transducer-originated distortions, thus exposing ongoing covert communications. Our research emphasizes the limitations that man-made equipment incurs when reproducing bioacoustic sounds, and prompts for the choice of biomimicking signals that are possibly suboptimal for communications or localization, but help avoid exposing disguised transmissions.

Objective Digital pathology (DP) is currently in the spotlight and is rapidly gaining ground, even though the history of this field spans decades. Despite great technological progress, the adoption of DP for routine clinical diagnostic use remains limited. Methods A systematic search was conducted in the electronic databases Pubmed-MEDLINE and Embase. Inclusion criteria were all published studies that encompassed any application of DP. Results Of 4888 articles retrieved, 4041 were included. Relevant articles were categorized as “diagnostic” (147/4041, 4%) where DP was utilized for routine diagnostic workflow and “non-diagnostic” (3894/4041, 96%) for all other applications. The “non-diagnostic” articles were further categorized according to DP application including “artificial intelligence” (33%), “education” (5%), “narrative” (17%) for reviews and editorials, and “technical” (45%) for pure research publications. Conclusion This manuscript provided temporal and geographical insight into the global adoption of DP by analyzing the published scientific literature.

Objectives Workers in the construction industry have been exposed to asbestos in various occupations. In Italy, a National Mesothelioma Registry has been implemented more than 20 years ago. Using cases selected from this registry and exploiting existing control data sets, we estimated relative risks for pleural mesothelioma (PM) among construction workers.Design Case–control study.Setting Cases from the National Mesothelioma Registry (2000–2018), controls from three previous case–control studies.Methods We selected male PM incident cases diagnosed in 2000–2018. Population controls were taken from three studies performed in six Italian regions within two periods (2002–2004 and 2012–2016). Age-adjusted and period-adjusted unconditional logistic regression models were fitted to estimate odds ratios (OR) for occupations in the construction industry. We followed two approaches, one (primary) excluding and the other (secondary) including subjects employed in other non-construction blue collar occupations for >5 years. For both approaches, we performed an overall analysis including all cases and, given the incomplete temporal and geographic overlap of cases and controls, three time or/and space restricted sensitivity analyses.Results The whole data set included 15 592 cases and 2210 controls. With the primary approach (4797 cases and 1085 controls), OR was 3.64 (2181 cases) for subjects ever employed in construction. We found elevated risks for blue-collar occupations (1993 cases, OR 4.52), including bricklayers (988 cases, OR 7.05), general construction workers (320 cases, OR 4.66), plumbers and pipe fitters (305 cases, OR 9.13), painters (104 cases, OR 2.17) and several others. Sensitivity analyses yielded very similar findings. Using the secondary approach, we observed similar patterns, but ORs were remarkably lower.Conclusions We found markedly increased PM risks for most occupations in the construction industry. These findings are relevant for compensation of subjects affected with mesothelioma in the construction industry.

Kidney transplantation is the best treatment for end-stage renal disease since it offers the greatest survival benefit compared to dialysis. The gap between the number of renal transplants performed and the number of patients awaiting renal transplants leads to a steadily increasing pressure on the scientific community. Kidney preimplantation biopsy is used as a component of the evaluation of organ quality before acceptance for transplantation. However, the reliability and predictive value of biopsy data are controversial. Most of the previously proposed predictive models were not associated with graft survival, but what has to be reaffirmed is that histologic examination of kidney tissue can provide an objective window on the state of the organ that cannot be deduced from clinical records and renal functional studies. The balance of evidence indicates that reliable decisions about donor suitability must be made based on the overall picture. This work discusses recent trends that can reduce diagnostic timing and variability among players in the decision-making process that lead to kidney transplants, from the pathologist’s perspective.