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Organic electrochemical transistors (OECTs) are important devices for the development of flexible and wearable sensors due to their flexibility, low power consumption, sensitivity, selectivity, ease of fabrication, and compatibility with other flexible materials. These features enable the creation of comfortable, versatile, and efficient portable devices that can monitor and detect a wide range of parameters for various applications. Herein, we present OECTs based on PEDOT-polyamine thin films for the selective monitoring of phosphate-containing compounds. Our findings reveal that supramolecular single phosphate–amino interaction induces higher changes in the OECT response compared to ATP–amino interactions, even at submillimolar concentrations. The steric character of binding anions plays a crucial role in OECT sensing, resulting in a smaller shift in maximum transconductance voltage and threshold voltage for bulkier binding species. The OECT response reflects not only the polymer/solution interface but also events within the conducting polymer film, where ion transport and concentration are affected by the ion size. Additionally, the investigation of enzyme immobilization reveals the influence of phosphate species on the assembly behavior of acetylcholinesterase (AchE) on PEDOT-PAH OECTs, with increasing phosphate concentrations leading to reduced enzyme anchoring. These findings contribute to the understanding of the mechanisms of OECT sensing and highlight the importance of careful design and optimization of the biosensor interface construction for diverse sensing applications.

Plastics accumulating in the environment are nowadays of great concern for aquatic systems and for the living organisms populating them. In this context, nanoplastics (NPs) are considered the major and most dangerous contaminants because of their small size and active surface, which allow them to interact with a variety of other molecules. Current methods used for the detection of NPs rely on bulky and expensive techniques such as spectroscopy. Here we propose, for the first time, a novel, fast, and easy-to-use sensor based on an electrolyte-gated field-effect transistor (EG-FET) with a carbon nanotube (CNT) semiconductor (EG-CNTFET) for the detection of NPs in aquatic environments, using polystyrene NPs (PS-NPs) as a model material. In particular, as a working mechanism for the EG-CNTFETs we exploited the ability of CNTs and PS to form noncovalent interactions. Indeed, in our EG-CNTFET devices, the interaction between NPs and CNTs caused a change in the electric double layers. A linear increase in the corrected on current (*ION) of the EG-CNTFETs, with a sensitivity of 9.68 μA/(1 mg/mL) and a linear range of detection from 0.025 to 0.25 mg/mL were observed. A π–π interaction was hypothesized to take place between the two materials, as indicated by an X-ray photoelectron spectroscopy analysis. Using artificial seawater as an electrolyte, to mimic a real-case scenario, a linear increase in *IONwas also observed, with a sensitivity of 6.19 μA/(1 mg/mL), proving the possibility to use the developed sensor in more complex solutions, as well as in low concentrations. This study offers a starting point for future exploitation of electrochemical sensors for NP detection and identification.

The International Collaboration on Cancer Reporting proposes histological tumour type, lymphovascular invasion, tumour grade, perineural invasion, extent, and dimensions of invasion as risk factors for lymph node metastases and tumour progression in completely endoscopically resected pT1 colorectal cancer (CRC). The aim of the study was to propose a predictive and reliable score to optimise the clinical management of endoscopically resected pT1 CRC patients. This multi‐centric, retrospective International Budding Consortium (IBC) study included an international pT1 CRC cohort of 565 patients. All cases were reviewed by eight expert gastrointestinal pathologists. All risk factors were reported according to international guidelines. Tumour budding and immune response (CD8+ T‐cells) were assessed with automated models using artificial intelligence. We used the information on risk factors and least absolute shrinkage and selection operator logistic regression to develop a prediction model and generate a score to predict the occurrence of lymph node metastasis or cancer recurrence. The IBC prediction score included the following parameters: lymphovascular invasion, tumour buds, infiltration depth and tumour grade. The score has an acceptable discrimination power (area under the curve of 0.68 [95% confidence intervals (CI) 0.61–0.75]; 0.64 [95% CI 0.57–0.71] after internal validation). At a cut‐off of 6.8 points to discriminate high‐and low‐risk patients, the score had a sensitivity and specificity of 0.9 [95% CI 0.8–0.95] and 0.26 [95% 0.22, 0.3], respectively. The IBC score is based on well‐established risk factors and is a promising tool with clinical utility to support the management of pT1 CRC patients.

Proteins are broadly versatile biochemical materials, whose functionality is tightly related to their folding state. Native folding can be lost to yield misfolded conformations, often leading to formation of protein oligomers, aggregates, and biomolecular phase condensates. The fluorogenic hyaluronan HA-RB, a nonsulfonated glycosaminoglycan with a combination of polyanionic character and of hydrophobic spots due to rhodamine B dyes, binds to early aggregates of the model protein cytoplasmic glyceraldehyde-3-phosphate dehydrogenase 1 from Arabidopsis thaliana(AtGAPC1) since the very onset of the oligomeric phase, making them brightly fluorescent. This initial step of aggregation has, until now, remained elusive with other fluorescence- or scattering-based techniques. The information gathered from nanotracking (via light-sheet fluorescence microscopy) and from FCS in a confocal microscope converges to highlight the ability of HA-RB to bind protein aggregates from the very early steps of aggregation and with high affinity. Altogether, this fluorescence-based approach allows one to monitor and track individual early AtGAPC1 aggregates in the size range from 10 to 100 nm with high time (∼10–2 s) and space (∼250 nm) resolution.

CD8+T cells control tumors but inevitably become dysfunctional in the tumor microenvironment. Here, we show that sodium chloride (NaCl) counteracts T cell dysfunction to promote cancer regression. NaCl supplementation during CD8+T cell culture induced effector differentiation, IFN-γ production and cytotoxicity while maintaining the gene networks responsible for stem-like plasticity. Accordingly, adoptive transfer of tumor-specific T cells resulted in superior anti-tumor immunity in a humanized mouse model. In mice, a high-salt diet reduced the growth of experimental tumors in a CD8+T cell-dependent manner by inhibiting terminal differentiation and enhancing the effector potency of CD8+T cells. Mechanistically, NaCl enhanced glutamine consumption, which was critical for transcriptional, epigenetic and functional reprogramming. In humans, CD8+T cells undergoing antigen recognition in tumors and predicting favorable responses to checkpoint blockade immunotherapy resembled those induced by NaCl. Thus, NaCl metabolism is a regulator of CD8+T cell effector function, with potential implications for cancer immunotherapy.

Background: MicroBubbles Time test (MBT), consisting in the rapid infusion of saline with addition of air microbubbles, visualized by B-mode echocardiography, represents a potential alternative to Intracavitary ECG (IC-ECG) and chest X-ray for central venous catheters (CVCs) tip location. Even if promising, this technique lacks of standardization: a clear time cut-off between bubble infusion and their detection in heart’s right chambers hasn’t been yet established. At these regard, microbubbles could be also detected as microembolic signals (MES) with an alternative ultrasound technique: the pulse wave Doppler (PW).Objective and methods: The first aim of this pilot study is to establish agreement of MBT with PW test (MBT-PW) compared with reference standard IC-ECG and normal MBT for tip location on CVCs. Corrected tip’s position was established through reference standard IC-ECG, afterward MBT-PW was performed, with the sample volume placed at tricuspid valve to detect MES simultaneously with micro-bubbles injection in CVCs. The second aim was to evaluate inter-observer variability for MES detection and grading.Results: Eight patients were enrolled; we obtained three records for each patients (24 with MBT and 24 with MBT-PW, the two techniques were acquired simultaneously). Inter-methods agreement through reference standard IC-ECG versus MBT-PW and MBT versus MBT-PW methodic was satisfying (Cohen’s kappa value = 1). MBT-PW and MBT signals were recorded within the first heart beat after microbubble infusion in all patients. Mean time delay thorough MBT-PW and MBT was 0.76 ±0.07 and 0.78 ± 0.07 s respectively; Intraclass correlation coefficient was 0.992 (95% CI: 0.981–0.996) suggesting excellent correlation. Inter-observer variability for positive MBT-PW evaluation was optimal (Cohen’s kappa value was 1), while indicated substantial agreement for MES grade evaluation (Fleiss’ Kappa value was 0.704; 95% CI: 0.328–1.000).Conclusions: Our study supports agreement between MBT-PW and reference standard IC-ECG for tip location. Satisfactory agreement was observed also for MBT-PW and MBT.

Background: During coronavirus disease 2019 (COVID-19) pandemic, Helmet Continuous Positive Airway Pressure (h-CPAP) has been widely used to treat Acute Hypoxemic Respiratory Failure (AHRF). In COVID-19 patients undergoing h-CPAP a simple short peripheral catheter could be insufficient. According to the European Recommendations for Proper Indication and Use of Peripheral venous access consensus, a stable peripheral Vascular Access Device is indicated for intravenous treatment compatible with the peripheral route scheduled for more than 1 week.Objective: The aim of this prospective study was to evaluate the performance and the potential complications of superficial femoral midline catheters (SFMC) inserted in the Superficial Femoral Vein by direct Seldinger technique with peripheral tip (Arrow®, Teleflex; 20 cm length four FR single lumen and seven FR dual lumen) in AHRF COVID-19 patient. Complications were divided in early (accidental puncture of superficial femoral artery (APSFA); accidental saphenous nerve puncture (ASNP); bleeding) and late (Catheter Related Thrombosis (CRT); Catheter-Related Bloodstream Infections (CRBSI); Accidental Removal (AR); persistent withdrawal occlusion (PWO)).Methods: From 1stOctober 2020 to 30thJune 2021 we conducted a prospective observational study in COVID-19 sub-intensive wards at Luigi Sacco Hospital (Milan).Results: Hundred seventy five SFMC (mean dwell time 11.1 ± 9.8 days) were implanted in COVID-19 patients, 107 (61.1%) during h-CPAP treatment (10.5 ± 8.9 days), the remaining 68 (38.9%) in patients with severe disease. We recorded two minor immediate/early complications (APSFA without sequelae) and no major complications. The long-term follow-up registered four CRBSI (2.3%–2.5/1000 catheters days (CD)), five CRT (2.9%: 2.6/1000 CD), 22 AR (12.6%; 11.4/1000 CD), 38 PWO (36.5%), 34 of which occurred due to fibroblastic sleeve (32.7%).Conclusions: SFMC proved to be safe, easy and time-saving. It could be implemented, after a careful benefits and risks evaluation, in particular settings such as h-CPAP, delirium, bleeding risk factors and palliative care patients.

In this work, we present a novel, sensitive, easy-to-fabricate, flexible amperometric sensor constituted by screen-printed silver (Ag) electrodes functionalized with a copper (Cu) film electrodeposited on top of a spray coated network of single-walled carbon nanotubes (SWCNTs). The Cu/SWCNTs/Ag electrode showed excellent catalytic activity towards the electro-reduction of nitrate ions at neutral pHwith a significant increasein cathodicpeak currents incomparison with the electrode without SWCNTs (Cu/Ag). The developed Cu/SWCNTs/Ag sensor showed a wide linear detection range from $0.5~ \mu \rm{M}$ to 6.0 mM (0.31 mg/l to 372.02 mg/l) with good sensitivity (18.39 $\mu$ A/mM) and a calculated limit of detection (LOD) of 0.166 nM(10.29 $\mu$ g/l). It also showed a good selectivity (maximum standard deviation (SD) was 3.25 $\mu$ A) towards different interfering ions (Fe2+, Na+, Cu2+, SO2−4, CH3COO−, Cl−, NO−2 and HCO−3), as well as good reproducibility,mechanical durability, time and temperature stability. In real sample analysis (tap and river water), the sensor exhibited good agreement with the compared outcome of high-performance liquid chromatography (HPLC) measurements, proving to be a promising analytical tool for the detection of nitrate in water.

Electrochemical biosensors are widely investigated as they represent attractive analytical tools for detection of a broad range of bio-molecules, thanks to their simplicity, high sensitivity and short response time. Especially, biosensors employing an electrolyte-gated field-effect transistors (EG-FETs) as electrochemical transduction element have gained increasing interest, due to the signal amplification and the intrinsic low voltage range of operation. In this work we report the fabrication of flexible EG-FETs using spray-deposited semiconducting carbon nanotubes (CNTs), with a specific focus on the optimization of the CNT channel to optimize the performance of the resulting CNT-based EG-FET (EG-CNTFET). The transfer and the output characteristic of different devices with varying spraying parameters were tested, finding out that only devices with source-drain resistance of about ≤10 $\text{k}\Omega $ showed proper EG-CNTFET operation: for these devices we recorded a typical p-type behavior with an on–off ratio of 214 A/A up to 469 A/A (depending on number of the spray-deposited CNT layers). The fabricated EG-CNTFETs were functionalized with anti-spermidine antibodies to detect polyamine spermidine - a well-known chemical indicator of food quality. To ensure controlled immobilization and at the same time to preserve the electrical properties of the nanotubes, the spray-deposited films were modified with a bifunctional molecule, which attaches to the CNT via non-covalent ${\pi -\pi }$ interactions and leaves a free NHS-ester group for amide coupling of the antibodies. The fabricated EG-CNTFET-based immunosensors showed a linear detection range for spermidine from 10−3 to 102 nM, with the sensitivities ranging from −1.03 to $- 2.45\,\,\mu \text{A}/$ decade.

•Infusions of donor memory T-cells after haplo-HSCT lead to engraftment, persistence, and prominent expansion of selected T-cell clones.•Infused patients harbor highly functional CMV-specific T-cells and their expansion correlates with their frequency in the donor.

ABSTRACTHumans have this extraordinary cognitive ability: They imagine inexistent objects, they treat them as if they were real, and by doing so they make them real. They thus give rise to a shared institutional reality that enables them to cooperate in ways that would be impossible otherwise. In this paper, we would like to revisit the account that HLA Hart gives of the practice of collective acceptance that makes a legal system possible. We try to provide an explanation of what Hart calls the ‘internal point of view’, on the basis of experiments on institutional concepts, drawing on the paradigm known as ‘embodied cognition’. Experts and non-experts in law rated the role of several cognitive dimensions for a list of words referring to two kinds of abstract concepts (institutional and theoretical/scientific) and two kinds of concrete ones (food and artifact). Institutional concepts were distinguished into pure-institutional (e.g., ‘contract’, ‘state’, ‘property’) and meta-institutional (e.g., ‘norm’, ‘duty’, ‘justice’). The results provide an empirical account of how our way of thinking about institutions changes as we acquire expertise in the legal field, thus shading light on the cognitive underpinnings of the ‘internal point of view’.

Background: Contrast enhanced ultrasound (CEUS) through MicroBubbles Time (MBT) (time from infusion of saline with addition of micro-bubbles of air to visualization of first bubbles in right atrium (RA), visualized by subxiphoid or apical echocardiography) is an alternative to Intracavitary ECG and chest X-ray in evaluation of tip location in central venous catheters.Objective: To evaluate feasibility and variability of CEUS in peripheral catheters (Midline-MC) in a cohort of patients and in a subgroup where tip location was also performed through chest X-ray. Secondary outcomes were verifying the correlation between MBT and distance between tip of MC and RA (anthropometric and radiological measures), body mass index (BMI), vein diameter at point of insertion.Methods: Patients with insertion of MC were enrolled in this prospective cohort. After catheter insertion, CEUS was performed recording MBT.Results: One hundred thirty-two MCs were inserted, 45 performed Chest X-ray. MBT wasn’t feasible in 7 (5%) because of low quality echocardiographic images. Subcostal view was available in 114 patients (91.2%), while 11 patients (8.8%) were examined through apical four-chamber view. Mean MBT in the whole population was 2.3 ± 0.8 s. Significant correlation between anthropometric and radiological measures, BMI and MBT was found. 32.8% of MC had a MBT ⩽2 s.Conclusions: CEUS could be useful to estimate tip position. Our study showed how 2 s is not a suitable cutoff to confirm central catheter’s tip.

Computational pathology (CPath) algorithms detect, segment or classify cancer in whole slide images, approaching or even exceeding the accuracy of pathologists. Challenges have to be overcome before these algorithms can be used in practice. We therefore aim to explore international perspectives on the future role of CPath in oncological pathology by focusing on opinions and first experiences regarding barriers and facilitators. We conducted an international explorative eSurvey and semi-structured interviews with pathologists utilizing an implementation framework to classify potential influencing factors. The eSurvey results showed remarkable variation in opinions regarding attitude, understandability and validation of CPath. Interview results showed that barriers focused on the quality of available evidence, while most facilitators concerned strengths of CPath. A lack of consensus was present for multiple factors, such as the determination of sufficient validation using CPath, the preferred function of CPath within the digital workflow and the timing of CPath introduction in pathology education. The diversity in opinions illustrates variety in influencing factors in CPath adoption. A next step would be to quantitatively determine important factors for adoption and initiate validation studies. Both should include clear case descriptions and be conducted among a more homogenous panel of pathologists based on sub specialization.

The productivity of rainforests growing on highly weathered tropical soils is expected to be limited by phosphorus availability1. Yet, controlled fertilization experiments have been unable to demonstrate a dominant role for phosphorus in controlling tropical forest net primary productivity. Recent syntheses have demonstrated that responses to nitrogen addition are as large as to phosphorus2, and adaptations to low phosphorus availability appear to enable net primary productivity to be maintained across major soil phosphorus gradients3. Thus, the extent to which phosphorus availability limits tropical forest productivity is highly uncertain. The majority of the Amazonia, however, is characterized by soils that are more depleted in phosphorus than those in which most tropical fertilization experiments have taken place2. Thus, we established a phosphorus, nitrogen and base cation addition experiment in an old growth Amazon rainforest, with a low soil phosphorus content that is representative of approximately 60% of the Amazon basin. Here we show that net primary productivity increased exclusively with phosphorus addition. After 2 years, strong responses were observed in fine root (+29%) and canopy productivity (+19%), but not stem growth. The direct evidence of phosphorus limitation of net primary productivity suggests that phosphorus availability may restrict Amazon forest responses to CO2fertilization4, with major implications for future carbon sequestration and forest resilience to climate change.

ABSTRACTThis study extends the examination of the difference between abstract concepts to the Chinese language and its peculiar characteristics in word formation, where components with different semantic content might be aggregated within a word. Native Chinese speakers categorised abstract and concrete words by moving the computer mouse towards their choice. Stimuli with a “semantically simple structure” (i.e. abstract-abstract/concrete-concrete) were compared with those with a “mixed structure” (i.e. abstract-concrete/concrete-abstract) to test for an effect of the conceptual content of the stimulus’s components on its overall processing. Response time and kinematic parameters revealed that: a) the semantic content of the components affected the processing of abstract but not concrete concepts, b) concepts differed when they have a semantically mixed structure, not a simple one. We extend the concreteness effect to logographic script and provide evidence that the presence of a concrete component within an abstract concept is elaborated and affects its processing.

Background: Venous Access Devices (VADs) are the most used devices in COVID-19 patients.Objective: Identify VADs implanted, catheter related thrombosis (CRT), catheter-related bloodstream infection (CRBSI), and accidental remove of VADs in both COVID-19 positive and COVID-19 free patients. Successive analysis was conducted comparing COVID-19 positive patients with COVID-19 free with inverse probability propensity score weights using simple regression to account for these two confounders (peripheral tip as central/peripheral and hospitalization as no/yes).Methods: This multicenter, retrospective cohort study collected data from seven hospitals in Lombardy during the pandemic period from February 21st to May 31st 2020.Results: A total of 2206 VADs were evaluated, 1107 (50.2%) of which were inserted in COVID-19 patients. In COVID-19 cohort the first choice was Long Peripheral Cannula in 388 patients (35.1%) followed by Midline Catheter in 385 (34.8%). The number of “central tip” VADs inserted in COVID-free inpatients and COVID-19 positive were similar (307 vs 334). We recorded 42 (1.9%) CRT; 32 (79.2%) were observed in COVID-19 patients. A total of 19 CRBSI were diagnosed; 15 (78.95%) were observed in COVID-19. Accidental removals were the more represented complication with 123 cases, 85 (69.1%) of them were in COVID-19. COVID-19 significantly predicted occurrence of CRT (OR = 2.00(1.85–5.03); p< 0.001), CRSB (OR = 3.82(1.82–8.97); p< 0.001), and Accidental Removal (OR = 2.39(1.80–3.20); p< 0.001) in our propensity score weighted models.Conclusions: CRT, CRBSI, and accidental removal are significantly more frequent in COVID-19 patients. Accidental removals are the principal complication, for this reason, the use of subcutaneously anchored securement is recommended for a shorter period than usual.

Virus-specific CD8+T cells that differentiate in the context of resolved versus persisting infections exhibit divergent phenotypic and functional characteristics, which suggests that their differentiation trajectories are governed by distinct cellular dynamics, developmental pathways and molecular mechanisms. For acute infection, it is long known that antigen-specific T cell populations contain terminally differentiated effector T cells, known as short-lived effector T cells, and proliferation-competent and differentiation-competent memory precursor T cells. More recently, it was identified that a similar functional segregation occurs in chronic infections. A failure to generate proliferation-competent precursor cells in chronic infections and tumors results in the collapse of the T cell response. Thus, these precursor cells are major therapeutic and prophylactic targets of immune interventions. These observations suggest substantial commonality between T cell responses in acute and chronic infections but there are also critical differences. We are therefore reviewing the common features and peculiarities of precursor cells in acute infections, different types of persistent infection and cancer.

Purpose: The differences between Big audit firms (BigN) and non BigN (nBigN) have been discussed at the international level from various points of view, focusing in particular on issues regarding the different quality of the services offered. This study aims to analyze the impact of digitalization on audit firms in the Italian context, seeking to understand how this phenomenon has influenced the quality differences already studied in the scientific literature. Design/methodology/approach: The research adopts a qualitative approach, using semi-structured interviews. A total of 16 professionals working in the legal audit world were interviewed. The firms involved were PricewaterhouseCoopers, KPMG, Ernst and Young and Deloitte in the BigN category and BDO Italia Spa, MooreAxis Srl and Analisi Spa in the non Big class. The data collected via the interviews underwent thematic analysis. This analysis allowed the identification of three topics, on which the presentation of the results concentrated. Findings: The findings of this research reveal that the digitalization of companies has widened the quality gap between Big and non BigN. BigN have been better able to exploit the benefits of the new digital technologies due to their greater investment capacity. At the same time, stakeholders’ expectations of the audit process in terms of quality have increased sharply, also in relation to nBigN. Originality/value: This study’s main contribution is its analysis of the impact of digitalization on the audit quality of BigN and nBigN. This paper contributes to the existing literature by studying the consequences of digitalization on nBigN, a topic previously unexplored in the scientific literature (Manita et al., 2020), and the impact of new technologies in the context of audit firms in general.

The backbone of all colorectal cancer classifications including the consensus molecular subtypes (CMS) highlights microsatellite instability (MSI) as a key molecular pathway. Although mucinous histology (generally defined as >50% extracellular mucin-to-tumor area) is a “typical” feature of MSI, it is not limited to this subgroup. Here, we investigate the association of CMS classification and mucin-to-tumor area quantified using a deep learning algorithm, and  the expression of specific mucins in predicting CMS groups and clinical outcome. A weakly supervised segmentation method was developed to quantify extracellular mucin-to-tumor area in H&E images. Performance was compared to two pathologists' scores, then applied to two cohorts: (1) TCGA (n= 871 slides/412 patients) used for mucin-CMS group correlation and (2) Bern (n= 775 slides/517 patients) for histopathological correlations and next-generation Tissue Microarray construction. TCGA and CPTAC (n= 85 patients) were used to further validate mucin detection and CMS classification by gene and protein expression analysis for MUC2, MUC4, MUC5ACand MUC5B. An excellent inter-observer agreement between pathologists' scores and the algorithm was obtained (ICC = 0.92). In TCGA, mucinous tumors were predominantly CMS1 (25.7%), CMS3 (24.6%) and CMS4 (16.2%). Average mucin in CMS2 was 1.8%, indicating negligible amounts. RNA and protein expression of MUC2, MUC4, MUC5ACand MUC5Bwere low-to-absent in CMS2. MUC5AC protein expression correlated with aggressive tumor features (e.g., distant metastases (p= 0.0334), BRAFmutation (p< 0.0001), mismatch repair-deficiency (p< 0.0001), and unfavorable 5-year overall survival (44% versus 65% for positive/negative staining). MUC2 expression showed the opposite trend, correlating with less lymphatic (p= 0.0096) and venous vessel invasion (p= 0.0023), no impact on survival.