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Background To date, evidence on late-onset immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is limited to a small number of clinical cases. This study aimed to identify drug- and patient-related characteristics potentially associated with the reporting of late-onset irAEs with ICIs in VigiBase, the WHO global database of individual case safety reports (ICSRs).Methods Observational study comparing deduplicated ICSRs with ICIs reporting late-onset irAEs (occurred >90 days after ICI discontinuation) versus ICSRs with ICIs not reporting late-onset irAEs, collected in VigiBase from 2011 to December 31, 2022. Logistic regression was used to model the relationship between drug-related and patient-related characteristics of ICSRs and the reporting of late-onset irAEs. Significance was determined for variables with the lower bound of the 95% CI of the reporting OR (ROR) higher than 1 and a p value

Safety data on MET inhibitors in patients with advanced NSCLC harboring MET exon 14 mutation and treated with frontline immune checkpoint inhibitors (ICIs) are still limited. Here, we describe clinical characteristics, liver biopsy features, and management of liver injury of two patients with a diagnosis of MET exon 14-mutant NSCLC receiving capmatinib after ICI failure. On the basis of histologic findings and exclusion of other potential causes, a diagnosis of drug-induced liver injury (DILI) associated with portal fibrosis was made in both cases. The use of hepatoprotective drugs, in addition to oral ursodeoxycholic acid, resulted in liver blood tests normalization. To provide a global safety perspective, we queried the Food and Drug Administration Adverse Event Reporting System and detected a robust disproportionality signal. Out of the 918 total reports with capmatinib from the Food and Drug Administration Adverse Event Reporting System database, DILI was recorded in 43 cases (4.7%), mostly serious (93.0%) with hospitalization and death recorded in 25.6% and 16.3% of the cases, respectively. The median time to onset was 42 days, with discontinuation and positive dechallenge documented in 41.9% and 39.5% of the cases, respectively. Anti–programmed cell death protein-1 agents were coreported in 11 DILI cases. Only two cases of DILI out of 105 reports were found for tepotinib. Our data support a potential association between capmatinib and DILI in patients who have also been previously exposed to immunotherapy. Considering the potential implications for sequence strategy and timing of ICI and MET inhibitor, further investigation is warranted.

Background: Although endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) using lumen-apposing metal stents (LAMS) has become one of the treatments of choice for acute cholecystitis (AC) in fragile patients, scant data are available on real-life settings and long-term outcomes. Methods: We performed a multicenter retrospective study including EUS-guided GBD using LAMS for AC in 19 Italian centers from June 2014 to July 2020. The primary outcomes were technical and clinical success, and the secondary outcomes were the rate of adverse events (AE) and long-term follow-up. Results: In total, 116 patients (48.3% female) were included, with a mean age of 82.7 ± 11 years. LAMS were placed, transgastric in 44.8% of cases, transduodenal in 53.3% and transjejunal in 1.7%, in patients with altered anatomy. Technical success was achieved in 94% and clinical success in 87.1% of cases. The mean follow-up was 309 days. AEs occurred in 12/116 pts (10.3%); 8/12 were intraprocedural, while 1 was classified as early (15 days). According to the ASGE lexicon, two (16.7%) were mild, three (25%) were moderate, and seven (58.3%) were severe. No fatal AEs occurred. In subgroup analysis of 40 patients with a follow-up longer than one year, no recurrence of AC was observed. Conclusions: EUS-GBD had high technical and clinical success rates, despite the non-negligible rate of AEs, thus representing an effective treatment option for fragile patients.

Due to their aspecific macroscopic appearance, uncommon pancreatic cystic lesions (PCLs) are often misdiagnosed as mucinous lesions and improperly resected. We aimed to evaluate the endoscopic ultrasound (EUS)-guided through-the-needle biopsy (TTNB) capacity of the preoperative diagnosis of uncommon PCLs. Overall, 136 patients with PCLs who underwent EUS-TTNB between 2016 and 2022 were retrospectively identified. Common histotypes (e.g., IPMN, serous cystadenoma, and mucinous cystadenoma) were excluded and 26 (19.1%) patients (15 female, mean age 52.9 ± 10.4) were analyzed. The EUS findings, adverse events (AEs), and TTNB outcomes in uncommon PCLs were evaluated. The cysts histotype was accurately diagnosed by TTNB in 24/26 (92.3%) cases (seven cystic neuroendocrine tumors, four squamoid cysts, three acinar cells cystadenomas, two lymphoepithelial cysts, two mucinous non-neoplastic cysts, two bronchogenic cysts, two cystic lymphangiomas, one solid-pseudopapillary neoplasm, and one schwannoma). In the remaining two cases, lymphangioma was eventually diagnosed after resection. Surgery was performed in 15/26 (57.7%) patients. The mean follow-up of non-surgical patients was 32.5 months. One severe acute case of pancreatitis (3.8%) that required surgery occurred after EUS-TTNB. Uncommon pancreatic/peripancreatic lesions represent the 19.1% of PCLs in our series, with mainly benign histotypes. TTNB demonstrated a high diagnostic performance with a low rate of AEs in this setting, representing a reliable tool with which to avoid useless surgery.

Introduction Machine learning (ML) approaches are a promising venue for identifying vocal markers of neuropsychiatric disorders, such as schizophrenia. While recent studies have shown that voice-based ML models can reliably predict diagnosis and clinical symptoms of schizophrenia, it is unclear to what extent such ML markers generalize to new speech samples collected using a different task or in a different language: the assessment of generalization performance is however crucial for testing their clinical applicability. Objectives In this research, we systematically assessed the generalizability of ML models across contexts and languages relying on a large cross-linguistic dataset of audio recordings of patients with schizophrenia and controls. Methods We trained ML models of vocal markers of schizophrenia on a large cross-linguistic dataset of audio recordings of 231 patients with schizophrenia and 238 matched controls (>4.000 recordings in Danish, German, Mandarin and Japanese). We developed a rigorous pipeline to minimize overfitting, including cross-validated training set and Mixture of Experts (MoE) models. We tested the generalizability of the ML models on: (i) different participants, speaking the same language (hold-out test set); (ii) different participants, speaking a different language. Finally, we compared the predictive performance of: (i) models trained on a single language (e.g., Danish) (ii) MoE models, i.e., ensemble of models (experts) trained on a single language whose predictions are combined using a weighted sum (iii) multi-language models trained on multiple languages (e.g., Danish and German). Results Model performance was comparable to state-of-the art findings (F1: 70%-80%) when trained and tested on participants speaking the same language (out-of-sample performance). Crucially, however, the ML models did not generalize well - showing a substantial decrease of performance (close to chance) - when trained in a language and tested on new languages (e.g., trained on Danish and tested on German). MoE and multi-language models showed a better increase of performance (F1: 55%-60%), but still far from those requested for achieving clinical applicability. Conclusions Our results show that the cross-linguistic generalizability of ML models of vocal markers of schizophrenia is very limited. This is an issue if our first goal is to translate these vocal markers into effective clinical applications. We argue that more emphasis needs to be placed on collecting large open datasets to test the generalizability of voice-based ML models, for example, across different speech tasks or across the heterogeneous clinical profiles that characterize schizophrenia spectrum disorder. Disclosure of Interest None Declared

The Romance tradition of a selected passage from the Gospel of John (XII-XVII) has long claimed scholarly attention, attracted by the exceptional nature of the individual manuscripts. This small but very interesting recensio has recently been associated with the BNF codex, fr. 2427. This study aims to enhance this new acquisition by offering a detailed technical description of it and tracing the fourteenth-century history of the Johannine text, in view of the edition that will follow this contribution in the next future.

Abstract Background The purpose of this study was to evaluate the palatal morphological changes in Anterior Open Bite (AOB) pre-pubertal subjects treated with Rapid Maxillary Expansion and Bite-Block (RME/BB) or Quad Helix with crib (QH/C) when compared with a Control Group (CG) by using Geometric Morphometric Analysis (GMM). Methods AOB group (AOBG) included 30 subjects (20 females, 10 males, mean age 8.1 ± 0.8ys) with dentoskeletal AOB. AOBG was divided in two subgroups according to the treatment strategy: RME/BB group (RME/BBg) included 15 subjects (10 females, 5 males, QH/C group (QH/Cg) comprised 15 subjects (10 females, 5 males). The two subgroups were compared with a CG of 15 subjects (10 females, 5 males) matched for sex, age, vertical pattern, and observation period. Digital upper dental casts were collected before treatment (T1) and at the end of the active treatment (T2). Landmarks and semilandmarks were digitized on dental casts and GMM was applied. Procrustes analysis and principal component analysis (PCA) were performed. Results At T2, RME/BBg when compared with QH/Cg evidenced no statistically significant differences. Instead, RME/BBg showed an increased maxillary transverse dimension and a decreased palatal depth when compared with CG. The comparison QH/Cg vs. CG demonstrated a slight transversal maxillary expansion. Conclusions RME/BBg showed significant changes in the transversal and vertical dimensions with a clear maxillary expansion and a decrease of the palatal depth when compared with QH/Cg and CG. QH/Cg showed a significant slight maxillary expansion and no variation in vertical and sagittal planes when compared with CG.

Background and study aims Endoscopic ultrasonography (EUS) is a reliable and efficient modality for detecting pancreatic tumors; however, plain EUS (P-EUS) is limited with respect to characterization of pancreatic tumors. Recently, the use of contrast-enhanced harmonic EUS (CH-EUS) has increased, and its utility for characterization of pancreatic tumors has been reported. This meta-analysis compares the diagnostic ability of P-EUS with that of CH-EUS for characterization of pancreatic tumors. Methods A systematic meta-analysis of all potentially relevant articles in PubMed, the Cochrane library, and Google Scholar databases was performed. Fixed effects or random effects models were used to investigate pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio, with 95 % confidence intervals (CIs). Results This meta-analysis included 719 patients who underwent CH-EUS and 723 who underwent P-EUS, from six eligible studies. The pooled estimates of sensitivity, specificity, and diagnostic odds ratio were 93 % (95 % CI, 0.90–0.95), 80 % (95 % CI, 0.75–0.85), and 57.9 (95 % CI, 25.9–130), respectively, for CH-EUS, and 86 % (95 % CI, 0.82–0.89), 59 % (95 % CI, 0.52–0.65), and 8.3 (95 % CI, 2.8–24.5) for P-EUS. The areas under the summary receiver operating characteristics curves for CH-EUS and P-EUS were 0.96 and 0.80, respectively. The diagnostic odds ratio for pancreatic cancer was 2.98 times higher on CH-EUS than on P-EUS (P = 0.03). Funnel plots demonstrated no publication bias. Conclusions This meta-analysis demonstrates that CH-EUS has higher diagnostic accuracy for pancreatic cancer than P-EUS, and is thus a valuable tool for characterization of pancreatic tumors.

Background/Aims: Endoscopic ultrasound (EUS)-guided tissue acquisition is widely utilized as a diagnostic modality for intra-abdominal masses, but there remains debate regarding which suction technique, slow pull (SP) or conventional suction (CS), is better. A meta-analysis of reported studies was conducted to compare the diagnostic yields of SP and CS during EUS-guided tissue acquisition. Methods: We conducted a systematic electronic search using MEDLINE/PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials to identify clinical studies comparing SP and CS. We meta-analyzed accuracy, sensitivity, blood contamination and cellularity using the random-effects model. Results: A total of 17 studies (seven randomized controlled trials, four prospective studies, and six retrospective studies) with 1,616 cases were included in the analysis. Compared to CS, there was a trend toward better accuracy (odds ratio [OR], 1.48; 95% confidence interval [CI], 0.97 to 2.27; p=0.07) and sensitivity (OR, 1.67; 95% CI, 0.95 to 2.93; p=0.08) with SP and a significantly lower rate of blood contamination (OR, 0.48; 95% CI, 0.33 to 0.69; p

Background and Aims: Pelvic fluid collections (PFCs) are frequent adverse events of abdominal surgery or inflammatory conditions. A percutaneous approach to deep PFCs could be challenging and result in a longer, painful recovery. The transvaginal approach has been considered easy but is limited by the difficulty of leaving a stent in place. The transrectal approach has been described, but issues related to fecal contamination were hypothesized. Data on EUS-guided transrectal drainage (EUS-TRD) with lumen-apposing metal stents (LAMSs) are few and suggest unsatisfactory outcomes. The aim of this study was to evaluate the safety and efficacy of EUS-TRD with LAMSs in patients with PFCs. Methods: A retrospective analysis of a prospectively maintained database on therapeutic EUS was conducted. All EUS-TRD procedures were included. Results: Five patients (2 male, age 44-89 years) were included. Four patients had postoperative PFCs, and 1 presented with a pelvic abscess complicating acute diverticulitis. Two of 5 had fecal diversion; the remaining 3 had unaltered large-bowel anatomy. One case had a concomitant abdominal collection, treated with percutaneous drainage in the same session. An electrocautery-enhanced LAMS delivery system (15 × 10 mm) was used in all cases. EUS-TRD was performed with the direct-puncture technique and lasted less than 10 minutes in 4 cases; in the remaining case, needle puncture and LAMS placement over a guidewire was required, and the procedure length was 14 minutes. The clinical success rate was 100%. LAMSs were removed after a median of 14 (range, 12-24) days. One patient reported partial proximal LAMS migration after 24 days (mild adverse event). No PFC recurrence was observed. Conclusion: EUS-TRD with LAMSs is a safe and effective technique for treatment of PFCs. The use of 15- × 10-mm LAMSs allows rapid PFC resolution. EUS-TRD could be performed not only in patients with fecal diversion but also in cases of unaltered anatomy.

Pancreatic neuroendocrine tumor (PNET) behavior assessment is a daily challenge for physicians. Modern PNET management varies from a watch-and-wait strategy to surgery depending on tumor aggressiveness. Therefore, the aggressiveness definition plays a pivotal role in the PNET work-up. The aggressiveness of PNETs is mainly based on the dimensions and histological grading, with sometimes a lack of specificity and sensibility. In the last twenty years, EUS has become a cornerstone in the diagnostic phase of PNET management for its high diagnostic yield and the possibility of obtaining a histological specimen. The number of EUS applications in the PNET work-up has been rapidly increasing with new and powerful possibilities. The application of contrast has led to an important step in PNET detection; in recent years, it has been gaining interesting applications in aggressiveness assessment. In this review, we underline the latest experiences and opportunities in the behavior assessment of PNETs using contact-enhanced EUS and contested enhanced harmonic EUS with a particular focus on the future application and possibility that these techniques could provide.

Introduction: The analysis of pharmacovigilance databases is crucial for the safety profiling of new and repurposed drugs, especially in the COVID-19 era. Traditional pharmacovigilance analyses–based on disproportionality approaches–cannot usually account for the complexity of spontaneous reports often with multiple concomitant drugs and events. We propose a network-based approach on co-reported events to help assessing disproportionalities and to effectively and timely identify disease-, comorbidity- and drug-related syndromes, especially in a rapidly changing low-resources environment such as that of COVID-19.Materials and Methods: Reports on medications administered for COVID-19 were extracted from the FDA Adverse Event Reporting System quarterly data (January–September 2020) and queried for disproportionalities (Reporting Odds Ratio corrected for multiple comparisons). A network (the Adversome) was estimated considering events as nodes and conditional co-reporting as links. Communities of significantly co-reported events were identified. All data and scripts employed are available in a public repository.Results: Among the 7,082 COVID-19 reports extracted, the seven most frequently suspected drugs (remdesivir, hydroxychloroquine, azithromycin, tocilizumab, lopinavir/ritonavir, sarilumab, and ethanol) have shown disproportionalities with 54 events. Of interest, myasthenia gravis with hydroxychloroquine, and cerebrovascular vein thrombosis with azithromycin. Automatic clustering identified 13 communities, including a methanol-related neurotoxicity associated with alcohol-based hand-sanitizers and a long QT/hepatotoxicity cluster associated with azithromycin, hydroxychloroquine and lopinavir-ritonavir interactions.Conclusion: Findings from the Adversome detect plausible new signals and iatrogenic syndromes. Our network approach complements traditional pharmacovigilance analyses, and may represent a more effective signal detection technique to guide clinical recommendations by regulators and specific follow-up confirmatory studies.

Communication is increasingly taking place in Facebook Groups around the world. Yet, we have little scientific knowledge of Facebook Groups at scale, especially the extent to which general systemic gendering is a pattern in participation in such groups. This knowledge deficit is problematic for digitalized and data-driven democratic societies. Therefore, this article aims to investigate gender differences in open, closed, and secret Facebook Groups. The study relies on a unique large-scale Facebook Group dataset from a sample that reflects the gender of Facebook users and the Facebook Groups they belong to in both Denmark and South Korea. By applying Bayesian models and developing a notion of participation that consists of both structural and actual participation, the study finds that the relation between country, gender, and participation is strongly modulated by gender differences. Females are more engaged than males in Denmark, while the opposite is true for South Korea. In both countries, privacy affects females’ participation more than males’. This article contributes to the field by presenting new large-scale findings that explore gender differences on three levels of Facebook Group privacy settings (open, closed, and secret) in a hitherto understudied communication space and, by doing so, it highlights the importance of privacy and country in predicting systemic gendering.

Background and study aims Feasibility of EUS-guided choledochoduodenostomy (EUS-CDS) using available lumen-apposing stents (LAMS) is limited by the size of the common bile duct (CBD) (≤ 12 mm, cut-off for experts; 15 mm, cut-off for non-experts). We aimed to assess the prevalence and predictive factors associated with CBD size ≥ 12 and 15 mm in naïve patients with malignant distal biliary obstruction (MDBO). Patients and methods This was a prospective cohort study involving 22 centers with assessment of CBD diameter and subjective feasibility of the EUS-CDS performance in naïve jaundiced patients undergoing EUS evaluation for MDBO. Results A total of 491 patients (mean age 69 ± 12 years) with mean serum bilirubin of 12.7 ± 6.6 mg/dL entered the final analysis. Dilation of the CBD ≥ 12 and 15 mm was detected in 78.8 % and 51.9 % of cases, respectively. Subjective feasibility of EUS-CDS was expressed by endosonographers in 91.2 % for a CBD ≥ 12 mm and in 96.5 % for a CBD ≥ 15 mm. On multivariate analysis, age (P

Background: Developmental Defects of Enamel (DDE) represent an aesthetic, functional, and often psychological problem, especially in young patients. Infiltrative treatment with resin (Icon-DMG, Hamburg, Germany) is a minimally invasive technique based on the infiltration of high viscosity resin inside the hypomineralized enamel, modifying its optical properties. The aim of this paper is to evaluate the clinical efficacy of superficial infiltration in the treatment of white enamel defects of the anterior sector with pre-eruptive etiology and its stability over time. Methods: Thirty-three patients affected by DDE associated with mild and moderate Molar Incisor Hypomineralization (MIH), mild and moderate fluorosis, and post-traumatic hypomineralization treated with resin infiltration were retrospectively retrieved. Results: In all cases an improvement in aesthetic appearance was achieved, and the 24-month follow-up confirmed the stability of the results. However, in the cases of traumatic hypomineralization the results were not completely satisfactory. Conclusions: The superficial infiltration technique can be considered a valid minimally invasive alternative to traditional treatment of mild or moderate fluorosis and mild MIH.

Background and study aims The poor flexibility of large-bore EUS needles often leads to technical failure when sampling from the duodenum. The aim of this study was to evaluate the technical and diagnostic performances of a new Menghini tip 19G nitinol EUS needle for sampling pancreatic solid lesions in the head and uncinate process. Patients and methods This was a European prospective multicenter single-arm study. A maximum of four passes were allowed. In case of failure, different needles were permitted. Results We included 75 patients (51 % males) with lesions in the head (n = 68; 91 %) and uncinate process (n = 7; 9 %) (mean size: 33 ± 12 mm; number of passes: 1.8 ± 0.9). Technical success was seen in 71 of 75 (94.7 %). Diagnostic rates were 89.3 % (67/75) and 94.4 % (67/71) in the intention-to-treat (ITT) and per-protocol (PP) analysis, respectively. In the eight cases with failure, diagnosis was obtained with another needle (n = 4), from another lesion (n = 3) or with follow-up (n = 1). A histological sample was obtained in 64 patients (ITT 85.3 % and PP 90 %) and immunohistochemistry was successfully performed in 13 of 15 lesions in which it was required. No differences between rapid on-site evaluation (ROSE) and non-ROSE groups were observed regarding diagnostic success (87.5 % vs 91 %, P = 0.582) and diagnosis at the first pass (70 % vs 81 %, P = 0.289). Number of passes was lower in the ROSE group (1.4 + 0.9 vs 2.2 + 0.7, P

Background and study aims The endoscopic report has a key role in quality improvement for gastrointestinal endoscopy. High quality standards have been set by the endoscopic societies in this field. Unlike other digestive endoscopy procedures, the quality of reporting in endoscopic ultrasound (EUS) has not been thoroughly evaluated and a reference standard is lacking. Methods We performed an international online survey concerning the attitudes of endosonographers towards EUS reports in order to understand the needs for standardization and quality improvement. Endosonographers from different countries and institutional setting, with varying case volume and experience were invited to take part to complete a structured questionnaire. Results We collected replies from 171 endosonographers. Overall analysis of results according to case volume, experience and working environment of respondents (academic, public hospital, private) are provided. In brief, everyone agreed on the need for standardization of EUS reporting. The use of minimal standard terminology and a structured tree with mandatory items was considered of primary importance. Image documentation was also deemed fundamental in complementing EUS reports both for patient documentation and research purposes. A strong demand for connection and consultation among endosonographers for clinical and training needs was also found. In this respect, a formal expert consultation network was advocated in order to improve the quality of reporting in EUS. Conclusions Our survey showed a strong agreement among endosonographers who expressed the need for a standardization in order to improve the report and, as a consequence, the quality of EUS.

Through this structured review of the published literature, we aimed to provide an up-to-date description of strategies (human-related) and tools (mainly from the digital field) facilitating the appropriateness of drug use in older adults. The evidence of each strategy and tool’s effectiveness and sustainability largely derives from local and heterogeneous experiences, with contrasting results. As a general framework, three main steps should be considered in implementing measures to improve appropriateness: prescription, acceptance by the patient, and continuous monitoring of adherence and risk-benefit profile. Each step needs efforts from specific actors (physicians, patients, caregivers, healthcare professionals) and dedicated supporting tools. Moreover, how to support the appropriateness also strictly depends on the particular setting of care (hospital, ambulatory or primary care, nursing home, long-term care) and available economic resources. Therefore, it is urgent assigning to each approach proposed in the literature the following characteristics: level of effectiveness, strength of evidence, setting of implementation, needed resources, and issues for its sustainability.

Background/Aims: The endoscopic step-up approach is accepted as the preferred treatment for complicated or symptomatic walled-off necrosis (WON). Direct endoscopic necrosectomy (DEN) is an effective therapeutic option, but few reports describe long-term follow-up in this patient population. Thus, we aim to assess the long-term outcomes of DEN following severe necrotizing pancreatitis. Methods: The data of all acute pancreatitis patients who underwent DEN following endoscopic transmural drainage from six referral centers between 2007 and 2017 were retrospectively collected. Results: Sixty patients (76.7% male, mean age 48.3 years) underwent a median of 4 sessions of DEN starting at a median of 45.5 days after the onset of acute pancreatitis. Clinical success was achieved in 51 patients (85%), with a 35% complication rate and a 5% mortality rate. Using multivariate analysis, the risk factor associated with DEN failure or major DEN complications requiring intervention or surgery was an identified bacterial/fungal WON infection (odds ratio, 19.3; 95% confidence interval, 1.5 to 261.7). During the median follow-up period of 27 months, complicated WON recurrence was observed in 5.3% of patients, and long-term complications occurred in 24.6% of patients (four exocrine insufficiency, nine newly developed diabetes mellitus, one recurrent small bowel obstruction, one chylous ascites). Conclusions: Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously while minimizing damage to the viable pancreatic parenchyma with adequate antibiotic escalation.

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration’s Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15–7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis.

Theories of vocal signalling in humans typically only consider communication within the interactive group and ignore intergroup dynamics. Recent work has found that colaughter generated between pairs of people in conversation can afford accurate judgements of affiliation across widely disparate cultures, and the acoustic features that listeners use to make these judgements are linked to speaker arousal. But to what extent does colaughter inform third party listeners beyond other dynamic information between interlocutors such as overlapping talk? We presented listeners with short segments (1–3 s) of colaughter and simultaneous speech (i.e. cospeech) taken from natural conversations between established friends and newly acquainted strangers. Participants judged whether the pairs of interactants in the segments were friends or strangers. Colaughter afforded more accurate judgements of affiliation than did cospeech, despite cospeech being over twice in duration relative to colaughter on average. Sped-up versions of colaughter and cospeech (proxies of speaker arousal) did not improve accuracy for either identifying friends or strangers, but faster versions of both modes increased the likelihood of tokens being judged as being between friends. Overall, results are consistent with research showing that laughter is well suited to transmit rich information about social relationships to third party overhearers—a signal that works between, and not just within conversational groups.

BackgroundEstimating the morbidity of a population is strategic for health systems to improve healthcare. In recent years administrative databases have been increasingly used to predict health outcomes. In 1992, Von Korff proposed a Chronic Disease Score (CDS) to predict 1-year mortality by only using drug prescription data. Because pharmacotherapy underwent many changes over the last 3 decades, the original version of the CDS has limitations. The aim of this paper is to report on the development of the modified version of the CDS.MethodsThe modified CDS (M-CDS) was developed using 33 variables (from drug prescriptions within two-year before 01/01/2018) to predict one-year mortality in Bologna residents aged ≥50 years. The population was split into training and testing sets for internal validation. Score weights were estimated in the training set using Cox regression model with LASSO procedure for variables selection. The external validation was carried out on the Imola population. The predictive ability of M-CDS was assessed using ROC analysis and compared with that of the Charlson Comorbidity Index (CCI), that is based on hospital data only, and of the Multisource Comorbidity Score (MCS), which uses hospital and pharmaceutical data.ResultsThe predictive ability of M-CDS was similar in the training and testing sets (AUC 95% CI: training [0.760-0.770] vs. testing [0.750-0.772]) and in the external population (Imola AUC 95% CI [0.756-0.781]). M-CDS was significantly better than CCI (M-CDS AUC = 0.761, 95% CI [0.750-0.772] vs. CCI-AUC = 0.696, 95% CI [0.681-0.711]). No significant difference was found between M-CDS and MCS (MCS AUC = 0.762, 95% CI [0.749-0.775]).ConclusionsM-CDS, using only drug prescriptions, has a better performance than the CCI score in predicting 1-year mortality, and is not inferior to the multisource comorbidity score. M-CDS can be used for population risk stratification, for risk-adjustment in association studies and to predict the individual risk of death.

Endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and stone extraction is the treatment of choice for choledocholithiasis, reaching a successful clearance of the common bile duct (CBD) in up to 90% of the cases. Endoscopic ultrasound (EUS) has the best diagnostic accuracy for CBD stones, its sensitivity and specificity range being 89–94% and 94–95%, respectively. Traditionally seen as two separate entities, the two worlds of EUS and ERCP have recently come together under the new discipline of bilio-pancreatic endoscopy. Nevertheless, the complexity of both EUS and ERCP led the European Society of Gastrointestinal Endoscopy to identify quality in endoscopy as a top priority in its recent EUS and ERCP curriculum recommendations. The clinical benefits of performing EUS and ERCP in the same session are several, such as benefiting from real-time information from EUS, having one single sedation for both the diagnosis and the treatment of biliary stones, reducing the risk of cholangitis/acute pancreatitis while waiting for ERCP after the EUS diagnosis, and ultimately shortening the hospital stay and costs while preserving patients’ outcomes. Potential candidates for the same session approach include patients at high risk for CBD stones, symptomatic individuals with status post-cholecystectomy, pregnant women, and those unfit for surgery. This narrative review discusses the main technical aspects and evidence from the literature about EUS and ERCP in the management of choledocholithiasis.

Serum hepatitis B core-related antigen (HBcrAg) was shown to predict the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients undergoing treatment. We investigated the longitudinal profile of HBcrAg in entecavir (ETV)-treated CHB patients with subsequent HCC development. We identified HCC cases diagnosed at ≥1 year after ETV initiation. CHB patients without HCC (matched for age, sex, cirrhosis status, baseline hepatitis B virus [HBV] DNA level, and ETV treatment duration) were identified as controls at an HCC:non-HCC ratio of 1:2. Serum samples were retrieved at baseline (ETV initiation) and at 3 and 5 years of ETV therapy for HBcrAg measurement (log IU/mL). In total, 180 patients (60 HCC patients matched with 120 CHB patients without HCC; median age, 56.5 years; 80.6% male; baseline HBV DNA, 5.9 log IU/mL; median follow-up, 6.8 years) were recruited. The median time from ETV initiation to HCC development was 3.2 years. HBcrAg levels were higher in HCC cases than in controls at all three time points: 5.69 log IU/ mL versus 5.02 log IU/mL (p=0.025), 4.23 log IU/mL versus 3.36 log IU/mL (p=0.007), and 3.86 log IU/mL versus 3.36 log IU/mL (p=0.009), respectively. ETV led to similar rates of decline in HBcrAg from baseline to 3 years in both groups (0.34 log IU/mL/year vs 0.39 log IU/mL/year, p=0.774), although the decline from 3 to 5 years was slower in the non- HCC group (0.05 log IU/mL/year) than in the HCC group (0.09 log IU/mL/year, p=0.055). ETV time-dependently reduced HBcrAg in HCC and non-HCC patients. HBcrAg interpretation should consider the antiviral treatment duration.

In a view of language as part of embodied and situated cognition, reduction of its meaning to individual mental representations ceases to be sufficient. Language relies on and at the same time enables distributed cognition thus the key aspects of meaning are in the interaction of individuals within their world. This special issue is an outcome of a workshop, which gathered representatives of several disciplines in a common effort to find appropriate theoretical concepts for the characterization of those aspects of meaning that lie in the mutual constraining between language and collective practice. The emerging picture is complex, involving multimodal participatory construction of meaning in multiple systems and on multiple timescales. The Authors, however propose also several innovative methods to navigate this complexity. In this short introduction we aim at placing the works contained in this issue on a broader map of ongoing efforts to understand language as a proper part of human ecology.

Background The differential diagnosis between benign and malignant lymph nodes (LNs) is crucial for patient management and clinical outcome. The use of contrast-enhanced endoscopic ultrasound (EUS) has been evaluated in several studies with diverse results. The aim of this meta-analysis was to evaluate the pooled diagnostic accuracy of contrast-enhanced EUS (CE-EUS) and contrast-enhanced harmonic EUS (CH-EUS) in this setting. Methods A systematic electronic search was performed, including all original papers dealing with assessment of the nature of the LNs using CE-EUS or CH-EUS. A meta-analysis was performed to obtain pooled sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio. The Summary Receiver Operating Characteristic (ROC) Curve method was used to calculate the area under the curve. Statistical analysis was carried out using Meta-Disc V.1.4, Stata V.12.0 and Review Manager V.5.2. Results Among 210 pertinent studies, four (336 patients) were included in the analysis. The pooled sensitivity was 82.1 % (75.1 – 87.7 %) and pooled specificity was 90.7 % (85.9 – 94.3 %) with significant heterogeneity found in sensitivity; the positive-likelihood ratio (LR) was 7.77 (5.09 – 11.85) and the negative-LR was 0.15 (0.05 – 0.46); the pooled diagnostic odds ratio (DOR) was 54 (15 – 190). Subgroup analysis including studies performed using CH-EUS (two studies, 177 LNs) showed a pooled sensitivity of 87.7 % (77.0 – 93.9 %) and a pooled specificity of 91.8 % (84.5 % – 96.4 %) with no significant heterogeneity; the pooled positive-LR was 9.51 (4.95 – 18.28) and the pooled negative-LR was 0.14 (0.06 – 0.35); pooled DOR was 68.42 (15.5 – 301.4). Conclusions From these data, CE-EUS is not recommended due to inadequate sensitivity. On the other hand, CH-EUS studies showed optimal accuracy (pooled sensitivity 87.7 % and specificity 91.8 %), comparable to elastography and even EUS-guided fine needle aspiration (EUS-FNA), suggesting a role in the diagnostic algorithm.

Background and study aims Carbon dioxide (CO2) is being increasingly used for insufflation during endoscopy for safety and better tolerance. The role of CO2 during endoscopic ultrasonography (EUS) has not been studied yet. Our main aim was to compare the effects of CO2 vs. air insufflation on abdominal discomfort in patients undergoing EUS. Our secondary outcomes were to ascertain the effects of CO2 insufflation on image quality/visual artifacts and on the amount of sedation. Patients and methods This was a prospective, controlled, single-blind, observational study. Abdominal discomfort was assessed before diagnostic EUS, and 1 and 3 hours post-procedure and recorded as a visual analogue scale. Image quality was also recorded as a 4-point scale from optimal to poor at four different scanning sites (esophagus, stomach, duodenal bulb and second portion). Results A total of 198 patients were enrolled. We observed that CO2 resulted in less abdominal discomfort than air insufflation that was statistically significant at 3 hours (P = 0.048) but not at 1 hour after EUS (P = 0.112), probably due to the ongoing effects of sedation at the latter stage. On the other hand, no differences were found in the dose of sedation administered in the two groups. Image quality was significantly better in the CO2 group compared to the air group at all four different scanning sites (P

This study investigates the presence of dynamical patterns of interpersonal coordination in extended deceptive conversations across multimodal channels of behavior. Using a novel "devil's advocate" paradigm, we experimentally elicited deception and truth across topics in which conversational partners either agreed or disagreed, and where one partner was surreptitiously asked to argue an opinion opposite of what he or she really believed. We focus on interpersonal coordination as an emergent behavioral signal that captures interdependencies between conversational partners, both as the coupling of head movements over the span of milliseconds, measured via a windowed lagged cross correlation (WLCC) technique, and more global temporal dependencies across speech rate, using cross recurrence quantification analysis (CRQA). Moreover, we considered how interpersonal coordination might be shaped by strategic, adaptive conversational goals associated with deception. We found that deceptive conversations displayed more structured speech rate and higher head movement coordination, the latter with a peak in deceptive disagreement conversations. Together the results allow us to posit an adaptive account, whereby interpersonal coordination is not beholden to any single functional explanation, but can strategically adapt to diverse conversational demands.

Most of our perceptions of and engagements with the world are shaped by our immersion in socialinteractions, cultural traditions, tools and linguistic categories. In this study we experimentallyinvestigate the impact of two types of language-based coordination on the recognition anddescription of complex sensory stimuli: that of red wine. Participants were asked to taste,remember and successively recognize samples of wines within a larger set in a two-by-twoexperimental design: 1) either individually or in pairs, and 2) with or without the support of asommelier card – a cultural linguistic tool designed for wine description. Both effectiveness ofrecognition and the kinds of errors in the four conditions were analyzed. While our experimentalmanipulations did not impact recognition accuracy, bias-variance decomposition of error revealsnon-trivial differences in how participants solved the task. Pairs generally displayed reduced biasand increased variance compared to individuals, however the variance dropped significantly whenthey used the sommelier card. The effect of card reducing the variance was observed only inpairs, individuals did not seem to benefit from the cultural linguistic tool. Subsequent analysis ofdescriptions generated with the aid of card by individuals and pairs showed that they were moreconsistent and discriminative in the case of pairs. The findings are discussed in terms of globalproperties and dynamics of collective systems when constrained by different types of culturalpractices.

The past two decades have seen an upsurge of interest in the collective behaviors of complex systems composed of many agents entrained to each other and to external events. In this paper, we extend the concept of entrainment to the dynamics of human collective attention. We conducted a detailed investigation of the unfolding of human entrainment--as expressed by the content and patterns of hundreds of thousands of messages on Twitter--during the 2012 US presidential debates. By time-locking these data sources, we quantify the impact of the unfolding debate on human attention at three time scales. We show that collective social behavior covaries second-by-second to the interactional dynamics of the debates: A candidate speaking induces rapid increases in mentions of his name on social media and decreases in mentions of the other candidate. Moreover, interruptions by an interlocutor increase the attention received. We also highlight a distinct time scale for the impact of salient content during the debates: Across well-known remarks in each debate, mentions in social media start within 5-10 seconds after it occurs; peak at approximately one minute; and slowly decay in a consistent fashion across well-known events during the debates. Finally, we show that public attention after an initial burst slowly decays through the course of the debates. Thus we demonstrate that large-scale human entrainment may hold across a number of distinct scales, in an exquisitely time-locked fashion. The methods and results pave the way for careful study of the dynamics and mechanisms of large-scale human entrainment.

Several treatment options are available to treat esophageal cancer. Ideally, treatment should be individualized, based on the projected treatment outcome for that individual. Accurate staging of the extent of the disease at the time of diagnosis offers the most rational attempt at stratifying patients into categories that can be used to affect treatment choices. Endoscopic ultrasonography (EUS) is the most accurate nonoperative technique for determining the depth of tumour infiltration and thus is accurate in predicting which patients will be able to undergo complete resection. EUS is also being used for tumour staging in order to guide treatment decisions in patients with esophageal cancer.