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Recent advances in complex automated handwriting identification systems have led to a lack of understandability of these systems' computational processes and features by the forensic handwriting examiners that they are designed to support. To mitigate this issue, this research studied the relationship between two systems: FLASH ID® , an automated handwriting/black box system that uses measurements extracted from a static image of handwriting, and MovAlyzeR® , a system that captures kinematic features from pen strokes. For this study, 33 writers each wrote 60 phrases from the London Letter using cursive writing and handprinting, which led to thousands of sample pairs for analysis. The dissimilarities between pairs of samples were calculated using two score functions (one for each system). The observed results indicate that dissimilarity scores based on kinematic spatial-geometric pen stroke features (e.g., amplitude and slant) have a statistically significant relationship with dissimilarity scores obtained using static, graph-based features used by the FLASH ID® system. Similar relationships were observed for temporal features (e.g., duration and velocity) but not pen pressure, and for both handprinting and cursive samples. These results strongly imply that both the current implementation of FLASH ID® and MovAlyzeR® rely on similar features sets when measuring differences in pairs of handwritten samples. These results suggest that studies of biometric discrimination using MovAlyzeR® , specifically those based on the spatial-geometric feature set, support the validity of biometric matching algorithms based on FLASH ID® output.

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

BACKGROUND The Black/African Ancestry (AA) population has a higher prevalence of type 2 diabetes mellitus (T2DM) and a higher incidence and mortality rate for colorectal cancer (CRC) than all other races in the United States. T2DM has been shown to increase adenoma risk in predominantly white/European ancestry (EA) populations, but the effect of T2DM on adenoma risk in Black/AA individuals is less clear. We hypothesize that T2DM has a significant effect on adenoma risk in a predominantly Black/AA population. AIM To investigate the effect of T2DM and race on the adenoma detection rate (ADR) in screening colonoscopies in two disparate populations. METHODS A retrospective cohort study was conducted on ADR during index screening colonoscopies (age 45-75) performed at an urban public hospital serving a predominantly Black/AA population (92%) (2017-2018, n = 1606). Clinical metadata collected included basic demographics, insurance, body mass index (BMI), family history of CRC, smoking, diabetes diagnosis, and aspirin use. This dataset was combined with a recently reported parallel retrospective cohort data set collected at a suburban university hospital serving a predominantly White/EA population (87%) (2012-2015, n = 2882). RESULTS The ADR was higher in T2DM patients than in patients without T2DM or prediabetes (35.2% vs 27.9%, P = 0.0166, n = 981) at the urban public hospital. Multivariable analysis of the combined datasets showed that T2DM [odds ratio (OR) = 1.29, 95% confidence interval (CI): 1.08-1.55, P = 0.0049], smoking (current vs never OR = 1.47, 95%CI: 1.18-1.82, current vs past OR = 1.32, 95%CI: 1.02-1.70, P = 0.0026), older age (OR = 1.05 per year, 95%CI: 1.04-1.06, P < 0.0001), higher BMI (OR = 1.02 per unit, 95%CI: 1.01-1.03, P = 0.0003), and male sex (OR = 1.87, 95%CI: 1.62-2.15, P < 0.0001) were associated with increased ADR in the combined datasets, but race, aspirin use and insurance were not. CONCLUSION T2DM, but not race, is significantly associated with increased ADR on index screening colonoscopy while controlling for other factors.

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.

Background and study aims The coronavirus disease 2019 (COVID-19), and measures taken to mitigate its impact, have profoundly affected the clinical care of gastroenterology patients and the work of endoscopy units. We aimed to describe the clinical care delivered by gastroenterologists and the type of procedures performed during the early to peak period of the pandemic. Methods Endoscopy leaders in the New York region were invited to participate in an electronic survey describing operations and clinical service. Surveys were distributed on April 7, 2020 and responses were collected over the following week. A follow-up survey was distributed on April 20, 2020. Participants were asked to report procedure volumes and patient characteristics, as well protocols for staffing and testing for COVID-19. Results Eleven large academic endoscopy units in the New York City region responded to the survey, representing every major hospital system. COVID patients occupied an average of 54.5 % (18 – 84 %) of hospital beds at the time of survey completion, with 14.5 % (2 %-23 %) of COVID patients requiring intensive care. Endoscopy procedure volume and the number of physicians performing procedures declined by 90 % (66 %-98 %) and 84.5 % (50 %-97 %) respectively following introduction of restricted practice. During this period the most common procedures were EGDs (7.9/unit/week; 88 % for bleeding; the remainder for foreign body and feeding tube placement); ERCPs (5/unit/week; for cholangitis in 67 % and obstructive jaundice in 20 %); Colonoscopies (4/unit/week for bleeding in 77 % or colitis in 23 %) and least common were EUS (3/unit/week for tumor biopsies). Of the sites, 44 % performed pre-procedure COVID testing and the proportion of COVID-positive patients undergoing procedures was 4.6 % in the first 2 weeks and up to 19.6 % in the subsequent 2 weeks. The majority of COVID-positive patients undergoing procedures underwent EGD (30.6 % COVID +) and ERCP (10.2 % COVID +). Conclusions COVID-19 has profoundly impacted the operation of endoscopy units in the New York region. Our data show the impact of a restricted emergency practice on endoscopy volumes and the proportion of expected COVID positive cases during the peak time of the pandemic.

Background Traumatic abdominal herniation with or without evisceration occurs with some regularity in dogs and cats, usually secondary to blunt force trauma or penetrating injuries. Sporadic peer-reviewed case reports have described herniorrhaphies in reptiles and amphibians, but none have described successful repair of acute traumatic eviscerations in companion lizards with long-term follow-up. Case descriptions One crested gecko (Correlophus ciliatus) and two leopard geckos (Eublepharis macularius) were presented for evaluation of traumatic coelomic eviscerations. Two of the animals were attacked by cats, while the third was presumptively attacked by its conspecific cagemate. Two animals eviscerated segments of their small intestines, while one animal eviscerated small intestines, stomach, spleen, and parts of a liver lobe and a fat pad. All eviscerated organs in all animals appeared viable at the time of their respective surgeries. All three animals had uncomplicated herniorrhaphies, recovered without complications, and were discharged alive from the hospital within 24 hours of their surgeries. Two of the animals were confirmed to be alive and doing well at the time of submission of this manuscript in June 2020 (one at approximately six months after surgery and one at approximately four years after surgery), whereas the final case was known to have survived at least three months postoperatively before being lost to follow-up. Conclusions and case relevance While limited to three cases, this case series demonstrates that coelomic herniorrhaphy can be a viable procedure in companion geckos to correct acute traumatic coelomic evisceration.

A 19-year-old female chimpanzee (Pan troglodytes) presented for cachexia, acute weakness, hyporexia, icterus, and polyuria. The animal was diagnosed with a hyperglycemic hyperosmolar state, which is a well-recognized syndrome in diabetic humans that is rarely diagnosed in animals. This case documents an important and likely under-reported syndrome in non-human primates.

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.

Objectives 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). Background Coronary obstruction following TAVR is a life-threatening complication with high procedural and short-term mortality. Methods Data were collected retrospectively from a multicenter international registry between April 2011 and February 2019. Results 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 Conclusions 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.

A class of computationally efficient approximations to a set of natural U-statistics and related U-processes that arise in forensic and biometric comparisons have been developed. This paper details...

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

Aluminum (Al) powder is commonly encountered in improvised explosive devices (IEDs) as a metallic fuel due to its availability and low cost. Although available commercially in powder form, amateur bomb-makers also produce their own Al powder via simple methods found online. In order to provide investigative leads and forensic intelligence, it is important to evaluate not only the composition of homemade devices, but also to distinguish between the various forms of Al powder they contain. To achieve this goal, a method using automated microscopy in combination with statistical techniques has been demonstrated to have the potential to provide source discrimination and investigative leads in source attribution of Al powders in IEDs. The present research refined this method and investigated 59 industrially and amateurly produced Al powder sources with seven subsamples per source using two traditional linear discriminant analyses (LDA), one with a standard data split for training and testing, and another using leave-one-out cross-validation. Averaging the classification accuracies for the two LDA-based analyses, LDA has the ability to correctly classify 59.26%, 83.35%, and 80.69% of the samples based on their powder source, type, and production method, respectively. This classification accuracy represents a 3407%, 317%, and 61.38% increase in accuracy from random class assignment, respectively. Further, in most instances of incorrect data attribution to a particular source, the subsample has been misidentified with another sample of the same powder type or production method.

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.

Simple Summary Lung cancer (LC) is the most common malignancy and the leading cause of cancer deaths in the world. Limitations of current screening approaches, such as substantial cost, radiation exposure, and high-false positive rates as well as increasing numbers of LC diagnoses in people without known risk factors, indicate the need for the development of new screening strategies. The aim of our study was to evaluate the utility of differential scanning calorimetry (DSC) for LC patients’ diagnosis. We found that DSC curves could be useful in differentiation of LC patients from control individuals and some changes were subtype or/and stage-dependent. Moreover, some DSC curve features correlated with patients’ overall/progression-free survival. Although the utility of the DSC technique still needs to be confirmed in a clinical setting, with further optimization and development of the classification method, this technique could provide an accurate, non-invasive, radiation-free strategy for LC screening and diagnosis. Abstract Early detection of lung cancer (LC) significantly increases the likelihood of successful treatment and improves LC survival rates. Currently, screening (mainly low-dose CT scans) is recommended for individuals at high risk. However, the recent increase in the number of LC cases unrelated to the well-known risk factors, and the high false-positive rate of low-dose CT, indicate a need to develop new, non-invasive methods for LC detection. Therefore, we evaluated the use of differential scanning calorimetry (DSC) for LC patients’ diagnosis and predicted survival. Additionally, by applying mass spectrometry, we investigated whether changes in O- and N-glycosylation of plasma proteins could be an underlying mechanism responsible for observed differences in DSC curves of LC and control subjects. Our results indicate selected DSC curve features could be useful for differentiation of LC patients from controls with some capable of distinction between subtypes and stages of LC. DSC curve features also correlate with LC patients’ overall/progression free survival. Moreover, the development of classification models combining patients’ DSC curves with selected plasma protein glycosylation levels that changed in the presence of LC could improve the sensitivity and specificity of the detection of LC. With further optimization and development of the classification method, DSC could provide an accurate, non-invasive, radiation-free strategy for LC screening and diagnosis.

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.

Ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning syndromes are induced by the consumption of seafood contaminated by ciguatoxins and brevetoxins. Both toxins cause sensory symptoms such as paresthesia, cold dysesthesia and painful disorders. An intense pruritus, which may become chronic, occurs also in CFP. No curative treatment is available and the pathophysiology is not fully elucidated. Here we conducted single-cell calcium video-imaging experiments in sensory neurons from newborn rats to study in vitro the ability of Pacific-ciguatoxin-2 (P-CTX-2) and brevetoxin-1 (PbTx-1) to sensitize receptors and ion channels, (i.e., to increase the percentage of responding cells and/or the response amplitude to their pharmacological agonists). In addition, we studied the neurotrophin release in sensory neurons co-cultured with keratinocytes after exposure to P-CTX-2. Our results show that P-CTX-2 induced the sensitization of TRPA1, TRPV4, PAR2, MrgprC, MrgprA and TTX-r NaV channels in sensory neurons. P-CTX-2 increased the release of nerve growth factor and brain-derived neurotrophic factor in the co-culture supernatant, suggesting that those neurotrophins could contribute to the sensitization of the aforementioned receptors and channels. Our results suggest the potential role of sensitization of sensory receptors/ion channels in the induction or persistence of sensory disturbances in CFP syndrome.

Until now, reports about pulmonary function in previously hospitalised subjects for COVID-19 are at discharge [1] or at 3–4 months [2–4]. The first study at 6 months is that of Huang et al . [5], enrolling 1733 discharged subjects, 349 of them underwent a pulmonary function study. Footnotes This manuscript has recently been accepted for publication in the ERJ Open Research . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article. Conflict of interest: Dr. MILANESE has nothing to disclose. Conflict of interest: Dr. ANSELMO has nothing to disclose. Conflict of interest: Dr. BUSCAGLIA has nothing to disclose. Conflict of interest: Dr. GARRA has nothing to disclose. Conflict of interest: Dr. GORETTI has nothing to disclose. Conflict of interest: Dr. PARODI has nothing to disclose. Conflict of interest: Dr. RICCIO has nothing to disclose. Conflict of interest: Dr. TASSARA has nothing to disclose. Conflict of interest: Dr. GNERRE has nothing to disclose.

Background: Over-expression of Human Epidermal Growth Factor receptor-2 (HER2) in breast cancer is associated with an aggressive clinical course and poor prognosis. Targeting HER2 over-expression has been shown to be a remarkably effective therapeutic modality in the metastatic, adjuvant and neoadjuvant setting and the pathologic response to neoadjuvant treatment in HER2-positive breast cancer has been shown to be an excellent surrogate for a good outcome. The stromal tumor microenvironment is implicated in fostering tumor growth, facilitating cell migration and ultimately resulting in metastatic disease. Specifically, the collagenous extracellular matrix, which includes fibrillar collagen, has been suggested to play a role in the migration of malignant breast epithelial cells within the surrounding stroma. We have developed a novel methodology which uses an intrinsic optical signature to quantitatively evaluate fibrillar collagen (Burke et al. BMC Cancer 15 (2015): 929). Here, we evaluate the ability of this quantitative methodology to predict the pathologic response after neoadjuvant HER2-targeted treatment as assessed by the Residual Cancer Burden score/class (RCB). This quantitative evaluation in pre-treatment biopsies is then correlated with the pathologic response to treatment in the post-therapy resection. Material and Methods: Clinical pathologic variables for 29 cases of HER2-positive breast cancer that had undergone neoadjuvant chemotherapy plus HER2-targeted therapy were retrieved from the medical record database at URMC, including the post-treatment RCB score and ER/PR/HER2 status. Second harmonic generation (SHG) is an intrinsic optical signal produced by fibrillar collagen. To quantify collagen microstructure in the pre-treatment core biopsy, we used SHG imaging to determine the average forward to backward-light scattering ratio (F/B). The F/B ratio is sensitive to structural properties of collagen fibers. Results: Logistic regression was used to assess the association between F/B and the binary response variable RCB class (0/1 or 2/3). A likelihood ratio test was used to calculate the p-value to test whether the regression coefficient for F/B was zero (i.e. no effect) in the tumor-stromal interface. The average F/B ratio at the leading edge of the tumor stratified by RCB class is shown in Table 1. When evaluated in the bulk of the tumor tissue, F/B was not correlated with RCB status; however, when evaluated at the leading edge of the tumor stromal interface, F/B was significantly correlated with RCB status (p=0.035). Table 1:RCB class and average F/BRCB class (n)Average F/B ± SEM0/1 (19)16.95 ± 1.062/3 (10)12.32 ± 1.84 Conclusions: We have previously shown that the measurement of F/B in the primary tumor after resection is an independent prognostic indicator of metastasis-free survival in breast cancer. Our results in the current study furthers these observations and suggests that the evaluations of the microstructure of collagen fibers by F/B measurement from the pre-treatment biopsy, specifically at the leading edge of the tumor-stroma interface, may be useful for predicting pathologic response to trastuzumab-based neoadjuvant therapy. Further studies in a larger patient cohort are warranted. Citation Format: Desa DE, Turner BM, Buscaglia B, Hill RL, Strawderman RL, Hicks DG, Brown EB. Using multiphoton laser scanning microscopy to assess neoadjuvant therapy outcome in core needle biopsies: A novel methodology [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-12.

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.

Background and AimsCOVID-19 patients may have asymptomatic hyperlipasemia without abdominal imaging findings or abdominal pain. In addition, primary and secondary pancreatitis have been described in COVID-19 patients. There is limited information on how the groups compare in outcomes. The aim is to compare outcomes among these groups.MethodsThis is a retrospective study from 12 hospitals within one healthcare system examining outcomes between hospitalized COVID-19 patients with a lipase 3x ULN), secondary pancreatitis (typical respiratory COVID-19 symptoms and found to have pancreatitis), and primary pancreatitis (presenting with pancreatitis).ResultsOf 11,883 patients admitted with COVID-19, 1,560 patients were included: 1,155 COVID-19 patients with a normal serum lipase (control group), 270 with an elevated lipase ConclusionCOVID-19 patients with an elevated lipase< 3x ULN and asymptomatic hyperlipasemia have generally worse outcomes than those with pancreatitis. This could be attributed to extrapancreatic causes (liver failure, renal failure, enteritis, etc), which may signify a more severe course of clinical disease.

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.

Herein, the properties of broadband dielectric spectra up to THz-infrared range of the (1 - x)BaTiO3-xBaZrO(3) (BZT-x) solid solution are reviewed and complemented. This includes the proper ferroelectric (x = 0), diffuse ferroelectrics (0 < x 0.8), and the normal dielectric (x = 1). The spectra are characterized by an overdamped central mode in the microwave range which weakens on cooling. Except for BaTiO3, the soft mode and central mode do not soften appreciably and do not contribute substantially to the low-frequency permittivity maximum. The most important dielectric contribution is brought by Cole-Cole relaxation assigned to hopping of Ti ions in the BaTiO3 clusters, which obeys the Arrhenius law with a common activation energy for the whole relaxor range of E (a) approximate to 181 +/- 17 meV and broadens on cooling as described by a temperature-independent distribution of activation energies. It follows that the polar nanoregions within the BaTiO3 clusters remain very small with temperature-independent size and frozen boundaries, even if the Ti ions inside them are hopping. This differs from the usual lead-containing relaxors, in which the polar nanoregions grow on cooling and follow the glass-like freezing.

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.

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.

We report on genosensors to detect an ssDNA sequence from the SARS-CoV-2 genome, which mimics the GU280 gp10 gene (coding the viral nucleocapsid phosphoprotein), using four distinct principles of detection and treating the data with information visualization and machine learning techniques. Genosensors were fabricated on either gold (Au) interdigitated electrodes for electrical and electrochemical measurements or on Au nanoparticles on a glass slide for optical measurements. They contained a matrix of 11-mercaptoundecanoic acid (11-MUA) self-assembled monolayer (SAM) onto which a layer of capture probe (cpDNA) sequence was immobilized. Detection was performed using electrical and electrochemical impedance spectroscopies and localized surface plasmon resonance (LSPR). The highest sensitivity was reached with impedance spectroscopy, including using a low-cost (US$ 100) homemade impedance analyzer. Complementary ssDNA sequences were detected with a detection limit of 0.5 aM (0.3 copy per µL). This performance may be attributed to the high sensitivity of the electrical impedance technique combined with an appropriate arrangement of the sequences on the electrodes and hybridization between the complementary sequences, as inferred from polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS). The selectivity of the genosensor was confirmed by plotting the impedance spectroscopy data with a multidimensional projection technique (interactive document mapping, IDMAP), where a clear separation was observed among the samples of the complementary DNA sequence at various concentrations and from buffer samples containing a non-complementary sequence and other DNA biomarkers. The diagnosis of SARS-CoV-2 mimicking sequences was also achieved with machine learning techniques applied to scanning electron microscope images taken from genosensors exposed to distinct concentrations of the complementary ssDNA sequences. In summary, the genosensors proposed here are promising for detecting SARS-CoV-2 genetic material (RNA) in biological fluids in point-of-care settings., The authors are thankful to CAPES (88887.510657/2020-00 and 88887.364257/2019-00), São Paulo Research Foundation (FAPESP) (2013/14262, 2016/01919-6, 2018/18953-8, 2018/19750-3, 2018/22214-6, 2019/00101-8, 2019/13514-9, 2016/23763-8, 2019/07811-0, 2020/02938-0), INEO, INCTBio grants (FAPESP 2014/50867-3) and CNPq (423952/2018-8, 465389/2014-7, and 401256/2020-0) for the financial support. The authors are grateful to Angelo Luiz Gobbi and Maria Helena de Oliveira Piazzetta (LMF/LNNano/CNPEM) for producing the Au electrodes.

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.

A 21-year-old male southern rockhopper penguin (Eudyptes chrysocome) was presented with a chronic history of intermittently decreased appetite, lethargy, and regurgitation. On the external physical examination, the bird was determined to be in fair-to-thin body condition with the complete blood count and plasma chemistry panel being largely unremarkable. Full-body radiographic images were considered normal, and gastroscopy showed only mild gastritis and duodenitis. The penguin was euthanatized shortly thereafter due to acute onset of respiratory distress. During the gross necropsy examination, the bird had severe airsacculitis with thick, yellow-to-tan, moist granular plaques adhering to the surface of many air sacs, as well as regional contiguous pneumonia. Intralesional acid-fast bacilli were observed in histologic sections of air sac tissue, and polymerase chain reaction of the affected air sacs was positive for Mycobacterium fortuitum. This clinical case study describes mycobacteriosis in a sub-Antarctic penguin and to the best of the authors' knowledge, the first reported isolation of M fortuitum from a penguin.

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.

Three captive macropods comprising three different species sustained unilateral antebrachial fractures. All fractures were assumed to be trauma related, although the specific circumstances surrounding each case was unknown. Each fracture was surgically repaired with type Ia (unilateral, monoplanar) external skeletal fixators, which were all removed approximately 3 mo postoperatively. Although each animal experienced at least one complication, all animals showed adequate bridging and remodeling at the fracture sites and had good-to-excellent return to normal function after fixator removal. This case series is the first to describe the successful repair of antebrachial fractures using external skeletal fixation in captive macropods and details some of the complications that can occur with postoperative management of captive animals.

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 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.

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.)