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As nanoparticles (NPs) can access the brain and impact on CNS function, novel in vitro models for the evaluation of NPs-induced neurotoxicity are advocated. Three-dimensional spheroids of primary neuron-like cells (hNLCs) of human origin have been generated, from differentiation of human umbilical cord mesenchymal stem cells (MSCs). The study evaluated Fe

Forensic handwriting examination involves the comparison of writing samples by forensic document examiners (FDEs) to determine whether or not they were written by the same person. Here we report the results of a large-scale study conducted to assess the accuracy and reliability of handwriting comparison conclusions. Eighty-six practicing FDEs each conducted up to 100 handwriting comparisons, resulting in 7,196 conclusions on 180 distinct comparison sets, using a five-level conclusion scale. Erroneous “written by” conclusions (false positives) were reached in 3.1% of the nonmated comparisons, while 1.1% of the mated comparisons yielded erroneous “not written by” conclusions (false negatives). False positive rates were markedly higher for nonmated samples written by twins (8.7%) compared to nontwins (2.5%). Notable associations between training and performance were observed: FDEs with less than 2 y of formal training generally had higher error rates, but they also had higher true positive and true negative rates because they tended to provide more definitive conclusions; FDEs with at least 2 y of formal training were less likely to make definitive conclusions, but those definitive conclusions they made were more likely to be correct (higher positive predictive and negative predictive values). We did not observe any association between writing style (cursive vs. printing) and rates of errors or incorrect conclusions. This report also provides details on the repeatability and reproducibility of conclusions, and reports how conclusions are affected by the quantity of writing and the similarity of content.

Trypanosoma cruzi, the protozoan agent of Chagas' disease, displays a complex population structure made up of multiple strains showing a diverse ecoepidemiological distribution. Parasite genetic variability may be associated with disease outcome, hence stressing the need to develop methods for T. cruzi typing in vivo. Serological typing methods that exploit the presence of host antibodies raised against polymorphic parasite antigens emerge as an appealing approach to address this issue. These techniques are robust, simple, cost-effective, and are not curtailed by methodological/biological limitations intrinsic to available genotyping methods. Here, we critically assess the progress towards T. cruzi serotyping and discuss the opportunity provided by high-throughput immunomics to improve this field.

A number of new psychoactive substances (NPS) have been released in the last decade, and the list of NPS continues to grow. This paper reports a retrospective evaluation of the toxicological analyses in 1,445 suspected intoxication cases by psychostimulant, hallucinogen, and dissociative NPS occurring in hospitals across Italy from 2011 to 2019. The objectives of the study were to contribute to the monitoring of the NPS diffusion based on analytically confirmed intoxications, and to evaluate the importance of the clinical toxicological laboratory in the diagnosis of NPS intoxication. For at least one NPS of the considered classes, 246 patients (17.0%) tested positive. Forty-four different NPS were detected and a consistent turnover was observed during the nine-year period, especially regarding cathinones. Among the positive cases, 47.2% tested positive for dissociative NPS, with particular regard to ketamine. Hallucinogens (30.9%) was the second most frequent NPS involved. Stimulants were found in 20% of the positive cases with a considerable presence of cathinones. Findings confirm the dynamism of the NPS phenomenon, underline the importance of awareness of this new public health threat among health care professionals, and highlight the need for analytical confirmation for the identification of the drugs in forensic contexts.

AIMS To study the predictive factors for the development of clinical manifestations in poisoning due to the erroneous taking of low-dose methotrexate (MTX). METHODS A retrospective observational study was performed. Only cases of erroneous administration in non-oncologic outpatients were included (July 2008-March 2020). RESULTS Forty-one cases were included. All patients were taking MTX for the first time. In 36 cases, patients took MTX daily instead of weekly. In the other five patients, MTX was sold instead of methylergometrine. Clinical manifestations were absent in 12/41 patients (29.3%). All 29 (70.7%) symptomatic patients recognized the medication error when they developed clinical manifestations: dermatological, haematological and gastrointestinal symptoms. Statistical results showed that symptomatic patients were older, received a higher amount of total dose and were treated for longer. Moreover, the probability of being symptomatic increases as a function of age and of total dose. Asymptomatic patients were treated with folinic acid (30 mg/m2 /day) for 5 days. Symptomatic patients were treated with folinic acid together with treatments for the specific clinical manifestations. No patients were treated with glucarpidase. All patients fully recovered. CONCLUSIONS When MTX is prescribed for the first time, it is important to clearly communicate with patients to avoid therapeutic errors. In our experience, age, total dose taken and number of days of assumption are predictive for the presence/absence of clinical manifestations. These parameters must be evaluated together to identify patients needing maximum starting treatment with folinic acid and closer monitoring.

We report on a photoelectrochemical (PEC) device to detect prostatic-specific antigen (PSA) under visible LED light irradiation within the point-of-care (POC) paradigm. The device consists of a 3D printed miniaturized photoelectrochemical system and a disposable PEC immunosensor made with screen-printed carbon electrodes (SPCEs). The SPCEs were coated with nickel single atoms anchored on graphitic carbon nitride (Ni-gC

Background Biliary decompression can reduce symptoms and improve quality of life in patients with malignant biliary obstruction. Endoscopically placed stents have become the standard of care for biliary drainage with the aim of improving hepatic function, relieving jaundice, and reducing adverse effects of obstruction. The purpose of this study was to evaluate the performance characteristics of a newly-designed, uncovered metal biliary stent for the palliation of malignant biliary obstruction. Methods This post-market, prospective study included patients with biliary obstruction due to a malignant neoplasm treated with a single-type, commercially available uncovered self-expanding metal stent (SEMS). Stents were placed as clinically indicated for palliation of jaundice and to potentially facilitate neo-adjuvant chemotherapy. The main outcome measure was freedom from recurrent biliary obstruction (within the stent) requiring re-intervention within 1, 3, and 6 months of stent insertion. Secondary outcome measures included device-related adverse events and technical success of stent deployment. Results SEMS were placed in 113 patients (73 men; mean age, 69); a single stent was inserted in 106 patients, and 2 stents were placed in 7 patients. Forty-eight patients survived and/or completed the 6 month study protocol. Freedom from symptomatic recurrent biliary obstruction requiring re-intervention was achieved in 108 of 113 patients (95.6, 95%CI = 90.0–98.6%) at study exit for each patient. Per interval analysis yielded the absence of recurrent biliary obstruction in 99.0% of patients at 1 month (n = 99; 95%CI = 97.0–100%), 96.6% of patients at 3 months (n = 77; 95%CI = 92.7–100%), and 93.3% of patients at 6 months (n = 48; 95%CI = 86.8–99.9%). In total, only 5 patients (4.4%) were considered failures of the primary endpoint. Most of these failures (4/5) were due to stent occlusion from tumor ingrowth or overgrowth. Overall technical success rate of stent deployment was 99.2%. There were 2 cases of stent-related adverse events (1.8%). There were no cases of post-procedure stent migration, stent-related perforation, or stent-related deaths. Conclusions This newly designed and marketed biliary SEMS system appears to be effective at relieving biliary obstruction and preventing re-intervention within 6 months of insertion in the overwhelming majority of patients. The device has an excellent safety profile, and associated high technical success rate during deployment. Trial registration The study was registered on clinicaltrials.gov on 14 October 2013 and the study registration number is NCT01962168. University of Massachusetts Medical School did not participate in the study.

Tenosynovial giant cell tumour (TGCT) is a group of rare soft tissues neoplasia affecting synovial joints, bursae and tendon sheaths and is classified as localized type or diffuse type. The diffuse type (TGCT-D), also known as 'pigmented villonodular (teno)synovitis' is characterized by local aggressivity, with invasion and destruction of adjacent soft-tissue structures, and high local recurrence rate. Radical surgery remains the standard therapy while adjuvant radiotherapy may help to control local spread. Malignant TGCT is characterized by high rate of local recurrences and distant metastasis. Few cases of malignant TGCT and very few evidences on systemic therapies are described in the literature, so, to date, no systemic treatment is approved for this rare disease. We report the case of a malignant TGCT patient treated with many different systemic therapies, including chemotherapy and tyrosine-kinase inhibitors, and performed a review of the literature on the systemic treatment options of this rare tumour.

Coronavirus disease 2019 (COVID-19) patients may have varying degrees of hyperlipasemia. The aim was to compare outcomes among different levels of hyperlipasemia in patients with COVID-19.This is a retrospective study examining outcomes among hospitalized COVID-19 patients with a lipase3× upper limit of normal (ULN), asymptomatic hyperlipasemia (3× ULN), secondary pancreatitis (typical respiratory COVID-19 symptoms and found to have pancreatitis), and primary pancreatitis (presenting with pancreatitis).Of 11,883 patients admitted with COVID-19, 1560 patients were included: 1155 patients had normal serum lipase (control group), 270 had elevated lipase3× ULN, 46 patients had asymptomatic hyperlipasemia with lipase3× ULN, 57 patients had secondary pancreatitis, and 32 patients had primary pancreatitis. On adjusted multivariate analysis, the elevated lipase3× ULN and asymptomatic hyperlipasemia groups had worse outcomes with higher mortality (odds ratio [OR], 1.6 [95% confidence interval [CI], 1.2-2.2) and 1.1 [95% CI, 0.5-2.3], respectively), higher need for mechanical ventilation (OR, 2.8 [95% CI, 1.2-2.1] and 2.8 [95% CI, 1.5-5.2], respectively), and longer length of stay (OR, 1.5 [95% CI, 1.1-2.0] and 3.16 [95% CI, 1.5-6.5], respectively).Patients with COVID-19 with elevated lipase3× ULN and asymptomatic hyperlipasemia have generally worse outcomes than those with pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancies, with a 5-year survival rate

Background Long-lasting heavy alcohol intake has been progressively recognized as a leading cause of non-ischemic dilated cardiomyopathy, involving 10% of all people who use alcohol. It is of huge importance to identify the earliest markers of this dysfunction and it is known that the newest echocardiographic techniques such as speckle tracking may allow to do it. In this study we investigated if standard basal echocardiogram features allow to obtain predictors of asymptomatic cardiac dysfunction in alcoholics. Methods A population of 80 consecutive asymptomatic alcoholics was enrolled. None presented history, signs or symptoms of cardiovascular disease. All of them underwent a conventional transthoracic mono-bidimensional and doppler echocardiography. Results Our cohort did not present echocardiographic findings of increased left ventricular sizes, mass or relative wall thickness. Hence, a significant rate of systolic dysfunction was not found. Furthermore, statistical analysis displayed an inverse relationship between alcohol consumption and systolic pulmonary arterial pressure as well as between alcohol abuse and left atrium enlargement. This may be explained by a potential vasodilator mechanism occurring in the earliest stages of alcohol intake. On the contrary, a positive correlation with the E/A ratio was found, and this might be ascribed to state of high cardiac output determined by alcohol abuse. There were modes sex-related differences. Conclusions This study has demonstrated that standard echocardiography may allow to predict cardiac dysfunction in asymptomatic alcoholics, and sex-related differences may be identified in this regard. These data need to be confirmed by further studies involving larger population.

Background Chemoprevention of colorectal neoplasia with aspirin and statins is under-investigated in Black patients. Since Black patients suffer disproportionately from colon cancer incidence and mortality compared to other populations, we investigated the utility of aspirin and statin in reducing advanced adenomatous polyp (AAP) risk in Black patients. Methods We carried out a retrospective cohort study of screening colonoscopies performed at a large urban academic center from 1/1/2011 through 12/31/2019. We analyzed self-identified Black patients with > 1 colonoscopy and no personal history of either inflammatory bowel disease or colon cancer syndromes. Our primary endpoint was first AAP development after index colonoscopy among Black patients taking both aspirin and a statin compared to those taking one or neither medication. We used multivariate logistic regression modeling to investigate our outcomes. Results We found data on chemoprophylaxis use in 560 patients. The mean observation period between index colonoscopy and AAP identification was 4 years. AAP developed in 106/560 (19%) of our cohort. We found no difference in AAP risk among Black patients taking both chemoprevention medications compared to partial or no chemoprophylaxis (20% vs 18% respectively, p = 0.49). This finding remained after adjusting for age, body mass index, and tobacco use (odds ratio 1.04, 95% CI 0.65–1.67; p = 0.87). Conclusions Short-term aspirin-statin chemoprevention did not reduce the risk of AAP development in our cohort of Black patients. Larger and long-term prospective investigations are needed to investigate the utility of chemoprophylaxis in this population. Trial Registration: Not applicable.

Introduction Transseptal puncture (TSP) is widely used in clinical practice, but is negatively affected by a non-neglectable rate of complications and x-ray exposure. To address these problems, we investigated whether or not impedance mapping could correctly identify fossa ovalis (FO) and safely guide TSP. Methods and results Electro-anatomic mapping was performed with CARTO 3 system version 7 and a ThermoCool® SmartTouch® mapping catheter was employed. In each patient an impedance map and a bipolar voltage map of the whole interatrial septum were collected, acquiring at least 150 points with a contact force ≥ 2 grams and using the Pattern Matching filter. Thirty-five patients were enrolled. A low impedance area was clearly identified in 34 of them. In 30 patients (88%), the FO was located into the low impedance area. The map was obtained in sinus rhythm in 17 cases (50%); in 15 of these (88%), the TSP site, the PFO or the FO tenting area fell inside the low impedance area. The same numbers were observed when mapping during AF. Conclusion To the best of our knowledge, this is the first study that provides the reliability and reproducibility of impedance mapping in identifying FO, an affordable and feasible tool that could be potentially introduced into clinical practice. This article is protected by copyright. All rights reserved.

OBJECTIVES Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. METHODS All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. RESULTS Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%, respectively. CONCLUSIONS HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold.

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

Background Clinical assays for the assessment of the human epidermal growth factor receptor-2 (HER2) status in breast cancer include immunohistochemistry (IHC) and in situ hybridization (ISH), both of which have limitations. Recent studies have suggested that a more quantitative approach to the measurement of HER2 protein expression may improve specificity in selecting patients for HER-2 targeted therapy. In the current study, we have used HER2 expression in breast cancer cell lines and clinical samples as a model to explore the potential utility of a novel immunodetection technique, using streptavidin coated Phosphor Integrated Dot fluorescent nanoparticles (PID), which can be quantitatively measured using computer analysis. Methods The expression of HER2 protein in cell lines was evaluated with antibody-binding capacity using fluorescence-activated cell sorting (FACS) for comparison with PID measurements to test for correlations with existing quantitative protein analysis methodologies. Various other analytic validation tests were also performed, including accuracy, precision, sensitivity, robustness and reproducibility. A methods comparison study investigated correlations between PID versus IHC and ISH in clinical samples. Lastly, we measured HER2 protein expression using PID in the pretreatment biopsies from 34 HER2-positive carcinomas that had undergone neoadjuvant trastuzumab-based chemotherapy. Results In the analytic validation, PID HER2 measurements showed a strong linear correlation with FACS analysis in breast cell lines, and demonstrated significant correlations with all aspects of precision, sensitivity, robustness and reproducibility. PID also showed strong correlations with conventional HER2 testing methodologies (IHC and ISH). In the neoadjuvant study, patients with a pathologic complete response (pCR) had a significantly higher PID score compared with patients who did not achieve a pCR (p = 0.011), and was significantly correlated to residual cancer burden (RCB) class (p = 0.026, R2 = 0.9975). Conclusions Analytic testing of PID showed that it may be a viable testing methodology that could offer advantages over other experimental or conventional biomarker diagnostic methodologies. Our data also suggests that PID quantitation of HER2 protein may offer an improvement over conventional HER2 testing in the selection of patients who will be the most likely to benefit from HER2-targeted therapy. Further studies with a larger cohort are warranted.

Publications are an important component of academic careers.We investigated the financial costs to authors for submitting and publishing manuscripts in gastroenterology (GI) journals in the United States (US), United Kingdom (UK), and elsewhere.This was a cross-sectional study carried out from 11/1/2020 to 12/31/2020. We used the SCImago Journal and Country Rankings site to compile a list of gastroenterology and hepatology journals to analyze. We gathered information on the journals' Hirsch indices (h indices), SCImago Journal Rank (SJR), Impact Factor (IF), and base countries as of 2019, processing and publication fees, open access fees, time to first decision, and time from acceptance to publication. We used t-testing and linear regression modeling to evaluate the effect of geography and journal quality metrics on processing fees and times.We analyzed 97 GI journals, of which 51/97 (52.6%) were based in the US/UK while the other 46/97 (47.4%) were based elsewhere. The mean IF (5.67 vs 3.53, p = 0.08), h index (90.5 vs 41.8, p 0.001), and SJR (1.82 vs 0.83, p 0.001) for the US/UK journals were higher than those for non-US/UK journals. We also found that 11/51 (21.6%) of US/UK journals and 15/46 (32.6%) of non-US/UK journals had mandatory processing and publication fees. These tended to be significantly larger in the US/UK group than in the non-US/UK group (USD 2380 vs USD 1470, p = 0.04).Publication-related fees may preclude authors from smaller or socioeconomically disadvantaged institutions and countries from publishing and disseminating their work.

Background Although pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates of all cancers, differences in survival exist between patients with clinically identical characteristics. The authors previously demonstrated that keratin 17 (K17) expression in PDAC, measured by RNA sequencing or immunohistochemistry (IHC), is an independent negative prognostic biomarker. Only 20% of cases are candidates for surgical resection, but most patients are diagnosed by needle aspiration biopsy (NAB). The aims of this study were to determine whether there was a correlation in K17 scores detected in matched NABs and surgical resection tissue sections and whether K17 IHC in NAB cell block specimens could be used as a negative prognostic biomarker in PDAC. Methods K17 IHC was performed for a cohort of 70 patients who had matched NAB cell block and surgical resection samples to analyze the correlation of K17 expression levels. K17 IHC was also performed in cell blocks from discovery and validation cohorts. Kaplan-Meier and Cox proportional hazards regression models were analyzed to determine survival differences in cases with different levels of K17 IHC expression. Results K17 IHC expression correlated in matched NABs and resection tissues. NAB samples were classified as high for K17 when ≥80% of tumor cells showed strong (2+) staining. High-K17 cases, including stage-matched cases, had shorter survival. Conclusions K17 has been identified as a robust and independent prognostic biomarker that stratifies clinical outcomes for cases that are diagnosed by NAB. Testing for K17 also has the potential to inform clinical decisions for optimization of chemotherapeutic interventions.

Acute kidney injury (AKI) may complicate transcatheter aortic valve replacement (TAVR) leading to higher mortality. The relationship between AKI, obesity, and mortality, however, is controversial. We sought to investigate the impact of body habitus on the prognostic value of AKI in TAVR.Among the 645 patients who underwent successful TAVR in a single high-volume centre, we retrospectively evaluated the association between AKI-TAVR and 30-day, 6-month, and 1-year mortality, and whether this relationship was affected by BMI. AKI was defined according to the Valve Academic Research Consortium-2 criteria. Patients were categorized into three groups by BMI: low-to-normal weight (25 kg/m2), overweight (25-30 kg/m2), obese (30.0 kg/m2).Three-hundred and twenty-four (50.2%) patients were low-to-normal weight, 223 (34.6%) overweight, and 98 (15.2%) obese. AKI occurred in 141 (21.9%), similarly across BMI groups. Thirty-day, 6-month, and 1-year mortality rates were 2.2, 3.7, and 7.9%, without differences across BMI groups. Among patients who developed AKI-TAVR, 30-day (8.7 vs. 2.0 vs. 0.0%), 6-month (13.0 vs. 6.1 vs. 4.3%), and 1-year (20.3 vs. 12.2 vs. 4.3%) mortality showed a decreasing trend across increasing BMI categories (all P 0.05); the same trend was not observed for patients without AKI-TAVR. In multivariate models, AKI was associated with 30-day [odds ratio (OR): 2.46, 95% confidence interval (CI): 1.70-8.67], 6-month (OR: 2.75, 95% CI: 1.32-7.59), and 1-year mortality (OR: 1.84, 95% CI: 1.22-3.71, all P 0.05). The interaction between AKI and BMI, when added to the models, was consistently significant (all P 0.05).Higher BMI is associated with better survival in TAVR patients who develop AKI.

ObjectivesIn Italy, the pandemic of COVID-19 resulted in congestion of hospitals and laboratories and probably determined an underestimation of the number of infected subjects, as the molecular diagnosis of SARS-CoV-2 infection was mainly performed on hospitalised patients. Therefore, limited data are available about the number of asymptomatic/paucisymptomatic subjects in the general population across time. To understand SARS-CoV-2 infection in the general population, we have developed a cross-sectional study (the ‘UNIversity against CORoNavirus study’) to investigate infection trends in asymptomatic/paucisymptomatic subjects in Milan (Italy), between March and June 2020.ParticipantsThe study population included 2023 subjects asymptomatic at the enrolment.Primary outcome measuresA nasal mid-turbinate swab for the detection of SARS-CoV-2 RNA and blood specimen for testing serum antibodies (immunoglobulin M (IgM) and IgG) were collected.ResultsSubjects showing positivity for the SARS-CoV-2 RNA and/or for anti-SARS-CoV-2 Ig is 237 (11.7%). Only 1.2% (n=25) of the total population had a positive nasal swab for SARS-CoV-2 and the large majority (21/25) of them were observed in March. A total of 226 subjects (11%) had IgM (n=19; 0.9%), IgG (n=155; 7.7%) or both (n=52; 2.6%) against SARS-CoV-2. Subjects with a present or past SARS-CoV-2 infection did not differ from other subjects as regards the number of cohabiting family members, travels, fever and upper and lower respiratory infection episodes.ConclusionsResults from the present study support the hypothesis that the actual spread of the virus in Lombardy was underestimated in the official records. However, as it is not known how long Ig persist, numbers should be taken cautiously.

Cardiogenic shock (CS) is a complex and relatively rare disease. Whilst its mortality remains unacceptably high, a multidisciplinary approach based on pre-established and shared protocols may improve prognosis and ensure appropriate resource allocation. Comprehensive hemodynamic assessment and monitoring as well as tailored, goal-directed medical therapy are part of an optimal management. Moreover, mechanical support devices may be helpful as they sustain hemodynamics to a greater extent as compared to inotropes and vasopressors, while lacking their cardiotoxic effects. Therefore, they are increasingly used in CS patients. In 2019, a new protocol for the management of patients with CS was adopted at the Ospedale Policlinico San Martino (HSM) in Genoa, Italy. Following in the footsteps of similar international experiences, the HSM protocol aims at streamlining the management of these high-risk patients improving the cooperation among healthcare specialists, and also addressing the key issues of mechanical support device implantation and appropriate referral for palliative care.

Latent fingerprint examiners sometimes come to different conclusions when comparing fingerprints, and eye-gaze behavior may help explain these outcomes. missed identifications (missed IDs) are inconclusive, exclusion, or No Value determinations reached when the consensus of other examiners is an identification. To determine the relation between examiner behavior and missed IDs, we collected eye-gaze data from 121 latent print examiners as they completed a total 1444 difficult (latent-exemplar) comparisons. We extracted metrics from the gaze data that serve as proxies for underlying perceptual and cognitive capacities. We used these metrics to characterize potential mechanisms of missed IDs: Cursory Comparison and Mislocalization. We find that missed IDs are associated with shorter comparison times, fewer regions visited, and fewer attempted correspondences between the compared images. Latent print comparisons resulting in erroneous exclusions (a subset of missed IDs) are also more likely to have fixations in different regions and less accurate correspondence attempts than those comparisons resulting in identifications. We also use our derived metrics to describe one atypical examiner who made six erroneous identifications, four of which were on comparisons intended to be straightforward exclusions. The present work helps identify the degree to which missed IDs can be explained using eye-gaze behavior, and the extent to which missed IDs depend on cognitive and decision-making factors outside the domain of eye-tracking methodologies.

At the end of the 90s in Europe, the new psychoactive substances (NPS) phenomenon was limited to a small number of molecules created to mimic the actions and psychoactive effects of licensed medicines and existing drugs that are controlled by the United Nations drug conventions and therefore traded as their "legal" replacements. NPS were mostly circulating in rave parties and electronic music festivals. The globalization, the evolution of e-commerce and the growing popularity of NPS, facilitated the development of a wide illegal market in constant expansion. The dynamic nature of this phenomenon has led to an evolution in the prevention and monitoring of NPS trafficking within the European Union. The European legislative system has been amended with the aim of creating a faster and more effective regulatory system to tackle NPS diffusion and ban their sale and circulation. At the end of 2008, in compliance with the European Council Decision 2005/387/JHA, the Anti-Drug Policies Department of the Presidency of the Council of Ministers activated the National Early Warning System to promote a rapid exchange of information on NPS between Italy and the EU.

Red tides involving Karenia brevis expose humans to brevetoxins (PbTxs). Oral exposition triggers neurotoxic shellfish poisoning, whereas inhalation induces a respiratory syndrome and sensory disturbances. No curative treatment is available and the pathophysiology is not fully elucidated. Protease-activated receptor 2 (PAR2), cathepsin S (Cat-S) and substance P (SP) release are crucial mediators of the sensory effects of ciguatoxins (CTXs) which are PbTx analogs. This work explored the role of PAR2 and Cat-S in PbTx-1-induced sensory effects and deciphered the signaling pathway involved. We performed calcium imaging, PAR2 immunolocalization and SP release experiments in monocultured sensory neurons or co-cultured with keratinocytes treated with PbTx-1 or P-CTX-2. We demonstrated that PbTx-1-induced calcium increase and SP release involved Cat-S, PAR2 and transient receptor potential vanilloid 4 (TRPV4). The PbTx-1-induced signaling pathway included protein kinase A (PKA) and TRPV4, which are compatible with the PAR2 biased signaling induced by Cat-S. Internalization of PAR2 and protein kinase C (PKC), inositol triphosphate receptor and TRPV4 activation evoked by PbTx-1 are compatible with the PAR2 canonical signaling. Our results suggest that PbTx-1-induced sensory disturbances involve the PAR2-TRPV4 pathway. We identified PAR2, Cat-S, PKA, and PKC that are involved in TRPV4 sensitization induced by PbTx-1 in sensory neurons.

Several studies have compared EUS-guided FNA with fine-needle biopsy (FNB), but none have proven superiority. We performed a multicenter randomized controlled trial to compare the performance of a commonly used 25-gauge FNA needle with a newly designed 20-gauge FNB needle.Consecutive patients with a solid lesion were randomized in this international multicenter study between a 25-gauge FNA (EchoTip Ultra) or a 20-gauge FNB needle (ProCore). The primary endpoint was diagnostic accuracy for malignancy and the Bethesda classification (non-diagnostic, benign, atypical, malignant). Technical success, safety, and sample quality were also assessed. Multivariable and supplementary analyses were performed to adjust for confounders.A total of 608 patients were allocated to FNA (n = 306) or FNB (n = 302); 312 pancreatic lesions (51%), 147 lymph nodes (24%), and 149 other lesions (25%). Technical success rate was 100% for the 25-gauge FNA and 99% for the 20-gauge FNB needle (P = .043), with no differences in adverse events. The 20-gauge FNB needle outperformed 25-gauge FNA in terms of histologic yield (77% vs 44%, P .001), accuracy for malignancy (87% vs 78%, P = .002) and Bethesda classification (82% vs 72%, P = .002). This was robust when corrected for indication, lesion size, number of passes, and presence of an on-site pathologist (odds ratio, 3.53; 95% confidence interval, 1.55-8.56; P = .004), and did not differ among centers (P = .836).The 20-gauge FNB needle outperformed the 25-gauge FNA needle in terms of histologic yield and diagnostic accuracy. This benefit was irrespective of the indication and was consistent among participating centers, supporting the general applicability of our findings. (Clinical trial registration number: NCT02167074.).

International audience; BACKGROUND:FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) is an option for fit patients with metastatic (MPC) and locally advanced unresectable (LAPC) pancreatic cancer. However, no criteria reliably identify patients with better outcomes.PATIENTS AND METHODS:We investigated putative prognostic factors among 137 MPC/LAPC patients treated with triplet chemotherapy. Association with 6-month survival status (primary endpoint) was assessed by multivariate logistic regression models. A nomogram predicting the risk of death at 6 months was built by assigning a numeric score to each identified variable, weighted on its level of association with survival. External validation was performed in an independent data set of 206 patients. The study was registered at ClinicalTrials.gov (NCT03590275).RESULTS:Four variables (performance status, liver metastases, baseline carbohydrate antigen 19-9 level, and neutrophil-to-lymphocyte ratio) were found to be associated with 6-month survival by multivariate analysis or had sufficient clinical plausibility to be included in the nomogram. Accuracy was confirmed in the validation cohort (C index = 0.762; 95% confidence interval, 0.713-0.825). After grouping all cases, 4 subsets with different outcomes were identified by 0, 1, 2, or > 2 poor prognostic features (P < .0001).CONCLUSION:The nomogram we constructed accurately predicts the risk of death in the first 6 months after initiation of FOLFIRINOX in MPC/LAPC patients. This tool could be useful to guide communication about prognosis, and to inform the design and interpretation of clinical trials.

Visceral artery aneurysms represent a very rare condition. The affected patients usually present as emergency secondary to the sudden rupture of the aneurysm or as an incidental finding on imaging. In this setting, gastric and gastroepiploic aneurysms account for only about 4% of all the splancnic aneurysms. Since ruptured visceral aneurysms present a high mortality, a prompt and adequate (surgical or radiological interventional) treatment is mandatory. Due to the difficulty in achieving an adequate transcatheter access in some cases the emergency laparotomy may represent the only chance for the recover of the affected patients. We report two cases of ruptured left gastroepiploic aneurysms occurred in two young male patients, treated respectively with emergency laparotomy and laparoscopy.

Encapsulating peritoneal sclerosis (EPS) is a rare clinical syndrome characterized by an acquired, inflammatory fibrocollagenous membrane encasing the small intestine, resulting in symptoms of bowel obstruction. It is still unclear whether early surgical intervention has an advantage over conservative management, but, in most reviewed case reports, it is preferred to preserve the surgical management in patients not responding to conservative measures, or when bowel ischaemia is occurring. We report a case of a 58-year old patients, affected by chronic renal failure, on treatment with peritoneal dialysis, in which a late diagnosis of encapsulating peritoneal sclerosis was made, and where surgical intervention was not sufficient to guarantee survival due to the late diagnosis.

The intracellular Ca

Botulinum neurotoxins (BoNTs) produced by Clostridia species are the most potent identified natural toxins. Classically, the toxic neurological syndrome is characterized by an (afebrile) acute symmetric descending flaccid paralysis. The most know typical clinical syndrome of botulism refers to the foodborne form. All different forms are characterized by the same symptoms, caused by toxin-induced neuromuscular paralysis. The diagnosis of botulism is essentially clinical, as well as the decision to apply the specific antidotal treatment. The role of the laboratory is mandatory to confirm the clinical suspicion in relation to regulatory agencies, to identify the BoNTs involved and the source of intoxication. The laboratory diagnosis of foodborne botulism is based on the detection of BoNTs in clinical specimens/food samples and the isolation of BoNT from stools. Foodborne botulism intoxication is often underdiagnosed; the initial symptoms can be confused with more common clinical conditions (i.e., stroke, myasthenia gravis, Guillain–Barré syndrome—Miller–Fisher variant, Eaton–Lambert syndrome, tick paralysis and shellfish or tetrodotoxin poisoning). The treatment includes procedures for decontamination, antidote administration and, when required, support of respiratory function; few differences are related to the different way of exposure.

Since deregulation of intracellular Ca

Introduction: Scientific evidence on subjects treated with statin or other lipid-lowering treatments has established that treatments aiming to lower low-density lipoprotein cholesterol (LDL-C) can reduce atherosclerosis. PCSK9 inhibitors (PCSK9-i), thanks to their efficacy in reducing LDL-C constitute a further step in the treatment of dyslipidemia and cardiovascular (CV) diseases.Areas covered: The purpose of this narrative review is to summarize the current knowledge of PCSK9-i, with particular regard to pharmacodynamic, pharmacokinetic, and clinical data on evolocumab and alirocumab.Expert opinion: PCSK9-I are effective in reducing atherosclerotic events through their significant LDL-C-lowering action similarly to statins. Furthermore, these drugs can be considered safe and well-tolerated. However, some controversies remain with regard to their efficacy in reducing mortality and the paucity of data on both pleiotropic effects and long-term safety of these drugs. However, future studies will focus on understanding the effects of very low cholesterol levels on health. At present, we know that the genetic model of PCSK9 deficiency is characterized by very low LDL-C levels without particular health problems. Yet, we do not know the effect of prolonged PCSK9 inhibition induced by antibody action during the lifetime of normal subjects.

The aim of this study was to investigate the safety and efficacy of coronary protection by preventive coronary wiring and stenting across the coronary ostia in patients at high risk for coronary obstruction after transcatheter aortic valve replacement (TAVR).Coronary obstruction following TAVR is a life-threatening complication with high procedural and short-term mortality.Data were collected retrospectively from a multicenter international registry between April 2011 and February 2019.Among 236 patients undergoing coronary protection with preventive coronary wiring, 143 had eventually stents implanted across the coronary ostia after valve deployment. At 3-year follow-up, rates of cardiac death were 7.8% in patients receiving stents and 15.7% in those not receiving stents (adjusted hazard ratio: 0.42; 95% confidence interval: 0.14 to 1.28; p = 0.13). There were 2 definite stent thromboses (0.9%) in patients receiving stents, both occurring after TAVR in "valve-in-valve" procedures. In patients not receiving stents, there were 4 delayed coronary occlusions (DCOs) (4.3%), occurring from 5 min to 6 h after wire removal. Three cases occurred in valve-in-valve procedures and 1 in a native aortic valve procedure. Distance between the virtual transcatheter valve and the protected coronary ostia 4 mm was present in 75.0% of patients with DCO compared with 30.4% of patients without DCO (p = 0.19).In patients undergoing TAVR at high risk for coronary obstruction, preventive stent implantation across the coronary ostia is associated with good mid-term survival rates and low rates of stent thrombosis. Patients undergoing coronary protection with wire only have a considerable risk for DCO.

The past two decades have witnessed rapid and remarkable technical improvement of multidetector computed tomography (CT) in both image quality and diagnostic accuracy. These improvements include higher temporal resolution, high-definition and wider detectors, the introduction of dual-source and dual-energy scanners, and advanced postprocessing. Current new generation multidetector row (≥64 slices) CT systems allow an accurate and reliable assessment of both coronary epicardial stenosis and myocardial CT perfusion (CTP) imaging at rest and during pharmacologic stress in the same examination. This novel application makes CT the unique noninvasive “one-stop-shop” method for a comprehensive assessment of both anatomical coronary atherosclerosis and its physiological consequences. Myocardial CTP imaging can be performed with different approaches such as static arterial first-pass imaging, and dynamic CTP imaging, with their own advantages and disadvantages. Static CTP can be performed using single-energy or dual-energy CT, employing qualitative or semiquantitative analysis. In addition, dynamic CTP can obtain quantitative data of myocardial blood flow and coronary flow reserve. The purpose of this review was to summarize all available evidence about the emerging role of myocardial CTP to identify ischemia-associated lesions, focusing on technical considerations, clinical applications, strengths, limitations, and the more promising future fields of interest in the broad spectra of ischemic heart disease.

Immunotherapy is associated with different response patterns compared with chemotherapy and targeted therapy, including delayed response and stabilization after progression (pseudoprogression). According to new immuno-based response criteria, immunotherapy can be continued after radiological progression when a clinical benefit is observed. We report a case of an advanced renal cell carcinoma patient treated with nivolumab, who developed clinical benefit and delayed radiological response after initial progression. We performed a review of the literature on immunotherapy beyond progression in advanced solid tumors. 12 clinical trials were identified and showed that selected patients have subsequent response and survival benefit receiving immunotherapy beyond progression. Future studies are needed to optimize timing and duration of immunotherapy and to define patient selection criteria for treatment beyond progression.

Background Dysregulation in calcium (Ca2+) signaling is a hallmark of chronic lymphocytic leukemia (CLL). While the role of the B cell receptor (BCR) Ca2+ pathway has been associated with disease progression, the importance of the newly described constitutive Ca2+ entry (CE) pathway is less clear. In addition, we hypothesized that these differences reflect modifications of the CE pathway and Ca2+ actors such as Orai1, transient receptor potential canonical (TRPC) 1, and stromal interaction molecule 1 (STIM1), the latter being the focus of this study. Methods An extensive analysis of the Ca2+ entry (CE) pathway in CLL B cells was performed including constitutive Ca2+ entry, basal Ca2+ levels, and store operated Ca2+ entry (SOCE) activated following B cell receptor engagement or using Thapsigargin. The molecular characterization of the calcium channels Orai1 and TRPC1 and to their partner STIM1 was performed by flow cytometry and/or Western blotting. Specific siRNAs for Orai1, TRPC1 and STIM1 plus the Orai1 channel blocker Synta66 were used. CLL B cell viability was tested in the presence of an anti-STIM1 monoclonal antibody (mAb, clone GOK) coupled or not with an anti-CD20 mAb, rituximab. The Cox regression model was used to determine the optimal threshold and to stratify patients. Results Seeking to explore the CE pathway, we found in untreated CLL patients that an abnormal CE pathway was (i) highly associated with the disease outcome; (ii) positively correlated with basal Ca2+ concentrations; (iii) independent from the BCR-PLCγ2-InsP3R (SOCE) Ca2+ signaling pathway; (iv) supported by Orai1 and TRPC1 channels; (v) regulated by the pool of STIM1 located in the plasma membrane (STIM1PM); and (vi) blocked when using a mAb targeting STIM1PM. Next, we further established an association between an elevated expression of STIM1PM and clinical outcome. In addition, combining an anti-STIM1 mAb with rituximab significantly reduced in vitro CLL B cell viability within the high STIM1PM CLL subgroup. Conclusions These data establish the critical role of a newly discovered BCR independent Ca2+ entry in CLL evolution, provide new insights into CLL pathophysiology, and support innovative therapeutic perspectives such as targeting STIM1 located at the plasma membrane. Electronic supplementary material The online version of this article (10.1186/s40425-019-0591-3) contains supplementary material, which is available to authorized users.

Organoids are three-dimensional in vitro models of human disease developed from benign and malignant gastrointestinal tissues with tremendous potential for personalized medicine applications. We sought to determine whether gastric cancer patient-derived organoids (PDOs) could be safely established from endoscopic biopsies for rapid drug screening. Patients underwent esophagogastroduodenoscopy (EGD) for surveillance or staging and had additional forceps biopsies taken for PDO creation. Cancer tissues from operative specimens were also used to create PDOs. To address potential tumor heterogeneity, we performed low-coverage whole-genome sequencing of endoscopic-derived PDOs with paired surgical PDOs and whole-tumor lysates. The stability of genomic alterations in endoscopic organoids was assessed by next-generation sequencing and nested polymerase chain reaction (PCR) assay. The feasibility and potential accuracy of drug sensitivity screening with endoscopic-derived PDOs were also evaluated. Gastric cancer PDOs (n = 15) were successfully established from EGD forceps biopsies (n = 8) and surgical tissues (n = 7) from five patients with gastric adenocarcinoma. Low-coverage whole-genomic profiling of paired EGD and surgical PDOs along with whole-tumor lysates demonstrated absence of tumor heterogeneity. Nested PCR assay identified similar KRAS alterations in primary tumor and paired organoids. Drug sensitivity testing of endoscopic-derived PDOs displayed standard dose–response curves to current gastric cancer cytotoxic therapies. Our study results demonstrate the feasibility of developing gastric cancer PDOs from EGD biopsies. These results also indicate that endoscopic-derived PDOs are accurate surrogates of the primary tumor and have the potential for drug sensitivity screening and personalized medicine applications.

Background and Aims Pancreatic cancer organoids are tumor models of individualized human pancreatic ductal adenocarcinoma (PDA), created from surgical specimens and used for personalized treatment strategies. Unfortunately, most patients with PDA are not operative candidates. Creation of human PDA organoids at the time of initial tumor diagnosis is therefore critical. Our aim was to assess the feasibility of creating human PDA organoids by EUS fine-needle biopsy (EUS-FNB) sampling in patients with PDA. Methods In this prospective clinical trial in patients referred to evaluate a pancreatic mass, EUS-FNA was performed for initial onsite diagnosis. Two additional needle passes were performed with a 22-gauge FNB needle for organoid creation. Primary outcome was successful isolation of organoids within 2 weeks of EUS-FNB sampling (P0, no passages), confirmed by organoid morphology and positive genotyping. Results Thirty-seven patients with 38 PDA tumors were enrolled. Successful isolation of organoids (P0) was achieved in 33 of 38 tumors (87%). Establishment of PDA organoid lines for ≥5 passages of growth (P5, five passages) was reached in 25 of 38 tumors (66%). In the single patient with successful P5 FNB sampling–derived and P5 surgically derived organoids, there was identical matching of specimens. There were no serious adverse events. Two patients developed bleeding at the EUS-FNB puncture site requiring hemostasis clips. Conclusions Pancreatic cancer organoids can be successfully and rapidly created by means of EUS-FNB sampling using a 22-gauge needle at the time of initial diagnosis. Successful organoid generation is essential for precision medicine in patients with pancreatic cancer in whom most are not surgically resectable. (Clinical trial registration number: NCT03140592.)

Exclusion is the determination by a latent print examiner that two friction ridge impressions did not originate from the same source. The concept and terminology of exclusion vary among agencies. Much of the literature on latent print examination focuses on individualization, and much less attention has been paid to exclusion. This experimental study assesses the associations between a variety of factors and exclusion determinations. Although erroneous exclusions are more likely to occur on some images and for some examiners, they were widely distributed among images and examiners. Measurable factors found to be associated with exclusion rates include the quality of the latent, value determinations, analysis minutia count, comparison difficulty, and the presence of cores or deltas. An understanding of these associations will help explain the circumstances under which errors are more likely to occur and when determinations are less likely to be reproduced by other examiners; the results should also lead to improved effectiveness and efficiency of training and casework quality assurance. This research is intended to assist examiners in improving the examination process and provide information to the broader community regarding the accuracy, reliability, and implications of exclusion decisions.

International audience; Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically, calcium levels are kept at less than 100 nM in the nucleus and cytosol, but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intracellular calcium-dependent functions. Stromal interacting molecule 1 (STIM1) plays a critical role in early sensing of changes in the ER's calcium level, especially when there is a sudden release of stored calcium from the ER. Inactive STIM1, which has a bound calcium ion, is activated upon ion release. Following activation of STIM1, there is STIM1-assisted initiation of extracellular calcium entry through channels in the cell membrane. This extracellular calcium entering the cell then amplifies intracellular calcium-dependent actions. At the end of the process, ER levels of stored calcium are reestablished. The main focus of this work was to study the conformational changes accompanying homo- or heterodimerization of STIM1. For this purpose, the ER luminal portion of STIM1 (residues 58-236), which includes the sterile alpha motif (SAM) domain plus the calcium-binding EF-hand domains 1 and 2 attached to the STIM1 transmembrane region (TM), was modeled and embedded in a virtual membrane. Next, molecular dynamics simulations were performed to study the conformational changes that take place during STIM1 activation and subsequent protein-protein interactions. Indeed, the simulations revealed exposure of residues in the EF-hand domains, which may be important for dimerization steps. Altogether, understanding conformational changes in STIM1 can help in drug discovery when targeting this key protein in intracellular calcium functions.