Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis

Although immune checkpoint inhibitors (ICIs) are associated with different immune-related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug-event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD-1, PD-L1 and CTLA-4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause-effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines

Timescales of Massive Human Entrainment

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 concepts 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. 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 moments in the debate: Mentions in social media start within 5-10 seconds after the moment; 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.Comment: 20 pages, 7 figures, 6 tables, 4 supplementary figures. 2nd version revised according to peer reviewers' comments: more detailed explanation of the methods, and grounding of the hypothese

Methods for Drainage of Distal Malignant Biliary Obstruction after ERCP Failure: A Systematic Review and Network Meta‐Analysis

There is scarce evidence on the comparison between different methods for the drainage of distal malignant biliary obstruction (DMBO) after endoscopic retrograde cholangiopancreatography (ERCP) failure. Therefore, we performed a network meta‐analysis to compare the outcomes of these techniques. We searched main databases through September 2021 and identified five randomized controlled trials. The primary outcome was clinical success. The secondary outcomes were technical success, overall and serious adverse event rate. Percutaneous trans‐hepatic biliary drainage was found to be inferior to other interventions (PTBD: RR 1.01, 0.88– 1.17 with EUS‐choledochoduodenostomy (EUS‐CD); RR 1.03, 0.86–1.22 with EUS-hepaticogastrostomy (EUS‐HG); RR 1.42, 0.90–2.24 with surgical hepaticojejunostomy). The comparison between EUS‐HG and EUS‐CD was not significant (RR 1.01, 0.87–1.17). Surgery was not superior to other interventions (RR 1.40, 0.91–2.13 with EUS‐CD and RR 1.38, 0.88–2.16 with EUS‐HG). No difference in any of the comparisons concerning adverse event rate was detected, although PTBD showed a slightly poorer performance on ranking analysis (SUCRA score 0.13). In conclusion, all interventions seem to be effective for the drainage of DMBO, although PTBD showed a trend towards higher rates of adverse events

Endoscopic Ultrasound Guided Biliary Drainage in Malignant Distal Biliary Obstruction

Malignant biliary obstruction (MBO) is a challenging medical problem that often negatively impacts the patient’s quality of life (QoL), postoperative complications, and survival rates. Endoscopic approaches to biliary drainage are generally performed by ERCP or, in selected cases, with a percutaneous transhepatic biliary drainage (PTBD). Recent advances in therapeutic endoscopic ultrasound (EUS) allow drainage where previous methods have failed. EUS has evolved from a purely diagnostic technique to one that allows a therapeutic approach in the event of ERCP failure in distal MBO. Moreover, the introduction of dedicated accessories and prostheses for EUS-guided transmural biliary drainage (EUS-BD) made these procedures more successful with regard to technical success, clinical outcomes and reduction of adverse events (AEs). Finally, lumen-apposing metal stents (LAMS) have improved the therapeutic role of the EUS. Subsequently, the electrocautery enhanced tip of the LAMS (EC-LAMS) allows a direct access of the delivery system to the target lumen, thereby simplifying and reducing the EUS-BD procedure time. EUS-BD using LAMS and EC-LAMS has proven effective and safe with a low rate of AEs. This review aims to evaluate biliary drainage techniques in malignant obstruction, focusing on the role of EUS biliary drainage by LAMS

Endoscopic ultrasound fine-needle biopsy vs fine-needle aspiration for lymph nodes tissue acquisition: A systematic review and meta-Analysis

Background: Endoscopic ultrasound (EUS)-guided tissue acquisition represents the choice of methods for suspected lymph nodes (LNs) located next to the gastrointestinal tract. This study aimed to compare the pooled diagnostic performance of EUS-guided fine-needle biopsy (EUS-FNB) and fine-needle aspiration (EUS-FNA) for LNs sampling. Methods: We searched PubMed/MedLine and Embase databases through August 2021. Primary outcome was diagnostic accuracy; secondary outcomes were sensitivity, specificity, sample adequacy, optimal histological core procurement, number of passes, and adverse events. We performed a pairwise meta-Analysis using a random-effects model. The results are presented as odds ratio (OR) or mean difference along with 95% confidence interval (CI). Results: We identified nine studies (1,276 patients) in this meta-Analysis. Among these patients, 66.4% were male; the median age was 67 years. Diagnostic accuracy was not significantly different between the two approaches (OR, 1.31; 95% CI, 0.81-2.10; P = 0.270). The accuracy of EUS-FNB was significantly higher when being performed with newer end-cutting needles (OR, 1.87; 95% CI, 1.17-3.00; P = 0.009) and in abdominal LNs (OR, 2.48; 95% CI, 1.52-4.05; P < 0.001) than that of EUS-FNA. No difference in terms of sample adequacy was observed between the two approaches (OR, 1.40; 95% CI, 0.46-4.26; P = 0.550); however, histological core procurement and diagnostic sensitivity with EUS-FNB were significantly higher than those with EUS-FNA (OR, 6.15; 95% CI, 1.51-25.07; P = 0.010 and OR, 1.87; 95% CI, 1.27-2.74, P = 0.001). The number of needle passes needed was significantly lower in the EUS-FNB group than in the EUS-FNA group (mean difference,-0.54; 95% CI,-0.97 to-0.12; P = 0.010). Conclusions: EUS-FNA and EUS-FNB perform similarly in LN sampling; however, FNB performed with end-cutting needles outperformed FNA in terms of diagnostic accuracy

Association between pancreatic intraductal papillary mucinous neoplasms and extrapancreatic malignancies: A systematic review with meta-analysis

Background: It is unclear whether patients with intraductal papillary mucinous neoplasia harbor a higher risk of developing extrapancreatic malignancies. Aims: We performed a pooled estimate of the incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasia, with a particular focus on the comparison to the general population. Methods: Computerized bibliographic search of main databases was performed through February 2021. The primary endpoint was the pooled incidence of extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasms. Additional outcome was the comparison between intraductal papillary mucinous neoplasia patients and the general population, expressed in terms of standardized incidence ratio along with 95% confidence intervals. Results: Eighteen studies with 8709 patients were included. The pooled rate of metachronous extrapancreatic malignancies was 10 (6e13)/1000 persons-year. No difference was observed according to intraductal papillary mucinous neoplasia histology and sex, whereas a significantly superior incidence of extrapancreatic malignancies was observed in patients with main-duct (36.7%, 25.4ä8%) as compared to branch-duct intraductal papillary mucinous neoplasia (26.2%, 17.6ã4.8%; p 1⁄4 0.03). Pooled standardized incidence ratio comparing expected rates in the general population was 1.01 (0.79e1.29); no difference was observed concerning rates of metachronous gastric cancer (standardized incidence ratio 1.60, 0.72e3.54) and colorectal cancer (1.29, 0.92e1.18), whereas biliary cancer was observed more frequently in intraductal papillary mucinous neoplasia patients (2.29, 1.07e4.93). Conclusion: Patients with intraductal papillary mucinous neoplasia harbor an overall rate of extrapancreatic malignancies as high as 27.3%. The rate of metachronous extrapancreatic malignancies is not superior to the general population

What failure in collective decision-making tells us about metacognition

Condorcet (1785) proposed that a majority vote drawn from individual, independent and fallible (but not totally uninformed) opinions provides near-perfect accuracy if the number of voters is adequately large. Research in social psychology has since then repeatedly demonstrated that collectives can and do fail more often than expected by Condorcet. Since human collective decisions often follow from exchange of opinions, these failures provide an exquisite opportunity to understand human communication of metacognitive confidence. This question can be addressed by recasting collective decision-making as an information-integration problem similar to multisensory (cross-modal) perception. Previous research in systems neuroscience shows that one brain can integrate information from multiple senses nearly optimally. Inverting the question, we ask: under what conditions can two brains integrate information about one sensory modality optimally? We review recent work that has taken this approach and report discoveries about the quantitative limits of collective perceptual decision-making, and the role of the mode of communication and feedback in collective decision-making. We propose that shared metacognitive confidence conveys the strength of an individual's opinion and its reliability inseparably. We further suggest that a functional role of shared metacognition is to provide substitute signals in situations where outcome is necessary for learning but unavailable or impossible to establish

Distinguishing Oneself from Others: Spontaneous Perspective- Taking in First Episode Schizophrenia and its relation to Mentalizing and Psychotic Symptoms

Characteristic symptoms of schizophrenia such as thought broadcasting, verbal hallucinations and delusions of being controlled suggest a failure in distinguishing between oneself and others. In addition, patients frequently experience mentalizing deficits, which could be related to such a failure. Here we investigated the tendency to distinguish self and other with a visual perspective-taking task that measures to what extent individuals spontaneously take another’s perspective when having to process their own (altercentric intrusion) or vice versa (egocentric intrusion). This was done in 22 patients with first episode schizophrenia and 23 matched healthy controls. We assessed whether patients displayed altered altercentric or egocentric intrusion and whether such alterations are related to mentalizing deficits – as measured with the Animated Triangles Task (ATT) and The Awareness of Social Inference Task (TASIT) – and/or specific psychotic symptoms, suggestive of problems with self-other distinction. The results showed that patients display similar egocentric intrusion and increased altercentric intrusion compared to controls. Degree of altercentric intrusion was associated with severity of delusions and hallucinations that have been tied to problems with self-other distinction but not with unrelated delusions and hallucinations or negative symptom severity. Higher altercentric intrusion was also associated with better TASIT performance in both patients and controls; suggesting that it may also be beneficial. In conclusion, patients display difficulties inhibiting representations of the other when having to process self-relevant information. A failure to control or distinguish the two representations could give rise to the experience that others have access to and control of your thoughts and actions

Is spoken language all-or-nothing? Implications for future speech-based human-machine interaction

Recent years have seen significant market penetration for voice-based personal assistants such as Apple’s Siri. However, despite this success, user take-up is frustratingly low. This article argues that there is a habitability gap caused by the inevitablemismatch between the capabilities and expectations of human users and the features and benefits provided by contemporary technology. Suggestions aremade as to how such problems might be mitigated, but a more worrisome question emerges: “is spoken language all-or-nothing”? The answer, based on contemporary views on the special nature of (spoken) language, is that there may indeed be a fundamental limit to the interaction that can take place between mismatched interlocutors (such as humans and machines). However, it is concluded that interactions between native and non-native speakers, or between adults and children, or even between humans and dogs, might provide critical inspiration for the design of future speech-based human-machine interaction