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Abstract Background Cancer becomes lethal as it spreads from the primary site to the rest of the body. Circulating tumor cells (CTCs) are biomarkers of disease progression and have been associated with decreased overall survival. Blood filtration is a novel concept for removing CTCs from circulation to improve patient prognosis. Methods This study utilizes liquid biopsy to assess the efficacy of ExThera Medical’s Seraph® 100 Microbind® Affinity Blood Filter on the blood of patients with pancreatic ductal adenocarcinoma (PDAC) using the third generation high-definition single cell assay workflow. Blood samples from treatment-naïve PDAC patients were collected and analyzed to characterize the CTCs and other rare cells present before and after filtration. Results Examination of 6 paired portal vein blood (PoVB) samples demonstrated a statistically significant decrease in total rare cells, total cytokeratin (CK)+ cells, and CTCs across all patients due to filtration. Furthermore, analysis of 2 paired peripheral blood (PB) samples showed a decrease in total rare cells, total CK+ cells, and specific phenotypes of rare cells after filtration. Discussion These preliminary results demonstrate initial proof of concept that this filtration device can remove CTCs from circulation and may therefore be useful as a therapy or adjunct in PDAC patient care.

Due to the complexity of real-world deployments, a robot swarm is required to dynamically respond to tasks such as tracking multiple vehicles and continuously searching for victims. Frequent task assignments eliminate the need for system calibration time, but they also introduce uncertainty from previous tasks, which can undermine swarm performance. Therefore, responding to dynamic tasks presents a significant challenge for a robot swarm compared to handling tasks one at a time. In human–human cooperation, trust plays a crucial role in understanding each other’s performance expectations and adjusting one’s behavior for better cooperation. Taking inspiration from human trust, this paper introduces a trust-aware reflective control method called “Trust-R”. Trust-R, based on a weighted mean subsequence reduced algorithm (WMSR) and human trust modeling, enables a swarm to self-reflect on its performance from a human perspective. It proactively corrects faulty behaviors at an early stage before human intervention, mitigating the negative influence of uncertainty accumulated from dynamic tasks. Three typical task scenarios {Scenario 1: flocking to the assigned destination; Scenario 2: a transition between destinations; and Scenario 3: emergent response} were designed in the real-gravity simulation environment, and a human user study with 145 volunteers was conducted. Trust-R significantly improves both swarm performance and trust in dynamic task scenarios, marking a pivotal step forward in integrating trust dynamics into swarm robotics.

Abstract N‐methyl‐D‐aspartate receptor (NMDAR)‐positive allosteric modulators (PAMs) represent a potential therapeutic strategy for cognitive impairment in disorders associated with NMDAR hypofunction, including Huntington's disease (HD) and Alzheimer's disease. Dalzanemdor (SAGE‐718) is a novel, investigational NMDAR PAM being evaluated for the potential treatment of cognitive impairment in these disorders. We report first‐in‐human, phase I, double‐blind, dose‐finding studies to assess the safety, tolerability, and clinical pharmacology of dalzanemdor. A single‐ascending dose study (dalzanemdor 0.35, 0.75, 1.5, or 3.0 mg vs. placebo) was conducted in healthy participants and included food effects. A multiple‐ascending dose study (14 days) was conducted in healthy participants (dalzanemdor 0.5 or 1.0 mg vs. placebo) and HD participants (open‐label dalzanemdor 1.0 mg) and included exploratory pharmacodynamics on cognitive performance. Dalzanemdor was generally well tolerated with no adverse events leading to discontinuation. Dalzanemdor exhibited pharmacokinetic parameters appropriate for once‐daily dosing. Following single and multiple doses in healthy participants, median terminal half‐life was 8–118 h, and the median time to reach maximum plasma concentration was 4–7 h. Exposures were dose‐proportional after single dose (6–46 ng/mL) and more than dose‐proportional after multiple doses (6–41 ng/mL). With multiple dosing, a steady state was achieved after 11 days in healthy participants and 13 days in HD participants. Dalzanemdor exposure decreased slightly with food. In HD participants, results suggest that dalzanemdor may improve cognitive performance on tests of executive function. These results support continued clinical development of dalzanemdor for the potential treatment of cognitive impairment in disorders of NMDAR hypofunction.

Introduction Participation in bowel cancer screening is lower in regions where there is high ethnic diversity and/or socioeconomic deprivation. Interventions, such as text message reminders and patient navigation (PN), have the potential to increase participation in these areas. As such, there is interest in the comparative effectiveness of these interventions to increase bowel cancer screening participation, as well as their relative cost-effectiveness.Methods and analysis This study will use a three-arm randomised controlled trial design to compare the effectiveness and cost-effectiveness of text message reminders and PN to increase the uptake of bowel cancer screening in London. Participants will be individuals who have not returned a completed faecal immunochemical test kit within 13 weeks of receiving a routine invitation from the London bowel cancer screening hub. Participants will be randomised (in a 1:1:1 ratio) to receive either (1) usual care (ie, ‘no intervention’), (2) a text message reminder at 13 weeks, followed by repeated text message reminders at 15, 17 and 19 weeks (in the event of non-response) or (3) a text message reminder at 13 weeks, followed by PN telephone calls at 15, 17 and 19 weeks in the event of non-response. The primary endpoint will be participation in bowel cancer screening, defined as ‘the return of a completed kit by week 24’. Statistical analysis will use multivariate logistic regression and will incorporate pairwise comparisons of all three groups, adjusted for multiple testing.Ethics and dissemination Approvals to conduct the research have been obtained from University College London’s Joint Research Office (Ref: 150666), the Screening Research, Innovation and Development Advisory Committee (‘RIDAC’, Ref: 2223 014 BCSP Kerrison), the Health Research Authority (Ref: 22/WM/0212) and the Confidentiality Advisory Group (Ref: 22/CAG/0140). Results will be conveyed to stakeholders, notably those managing the screening programme and published in peer-reviewed journals/presented at academic conferences.Trial registration number ISRCTN17245519

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of less than 10% due to its late diagnosis, rapid metastasis, and chemotherapeutic resistance. For a small proportion (10–20%) of early-stage patients however, surgical resection of the pancreatic tumor offers the best chance for survival but the effect of surgery on disease dissemination is unknown. The primary objective of this study was to characterize cellular and acellular blood-based analytes in portal and peripheral blood before pancreatic manipulation, during tumor dissection and immediately after surgical resection to determine the effects of the surgery. This study used the non-enriching third generation High-Definition Single Cell Assay (HDSCA3.0) workflow to investigate heterogeneous circulating rare cell population in the blood. Blood from both sites taken before surgical manipulation of the pancreas had significantly greater incidence of total rare cellular and acellular analytes than normal donor samples. Post-surgery portal and peripheral blood had significantly greater incidence of specific cellular and acellular subtypes compared to the matched pre- and during-surgery samples. Our results reveal that in patients with PDAC liquid biopsy analytes are increased in both the portal and peripheral blood; portal blood contains a higher frequency of analytes than in the peripheral blood; total analytes in the portal and peripheral blood samples were significantly associated with the tumor volume and pathological T stage; and the surgical procedure increased the blood levels of circulating cellular and acellular analytes, but not Epi.CTCs or Mes.CTCs. This study demonstrates liquid biopsy’s utility in monitoring patients with PDAC with surgically resectable disease.

Compound flooding (CF) events, driven by coincident/concurrent and mutually reinforcing factors such as heavy rainfall, storm surges, and river discharge, pose severe threats to coastal communities around the Globe. Moreover, the exacerbating influence of climate change and sea-level rise further amplifies these risks. This study delves into the complex and multifaceted issue of compound coastal flooding in two freshwater-influenced systems on the Gulf Coast of the United States – Southeast Texas and South Alabama. We first conduct a robust statistical analysis to evaluate the significance of non-stationarity, multi-dimensionality, and non-linearity of interactions among various drivers of CF. Second, to assess the extent to which current flood resilience policies and guidelines account for these characteristics of CF events, we perform a critical review of existing policy documents. The results of the statistical analysis reveal significant compounding and shifts in the statistics of flood drivers that emphasize the pressing need for a multi-mechanism, non-stationary approach to flood hazard assessment. We also found an evident lack of appropriate language/recommendation in policy documents of solid tools that systematically take non-stationarity, multi-dimensionality, and non-linearity of CF into account. By identifying the gaps between current policy measures and the detected complexities of CF, we seek to provide insights that can inform more effective flood resilience policies and design guidelines. Through this robust analysis, we aspire to bridge the divide between research and policy.

The uncanny valley describes the negative evaluation of near humanlike artificial entities. Previous research with synthetic and real voices failed to find an uncanny valley of voices. This may have been due to an incomplete selection of stimuli. In Experiment 1 (n = 50), synthetic, normal, and deviating voices (distorted and pathological) were rated on uncanniness and human likeness and categorized as human or non-human. Results showed a non-monotonic function when the uncanniness was plotted against human likeness indicative of an uncanny valley. However, the shape could be divided into two monotonic functions based on voice type (synthetic vs deviating). Categorization ambiguity could not predict voice uncanniness but moderated the effect of realism on uncanniness. Experiment 2 (n = 35) found that perceived organicness, animacy, and mind attribution of voices significantly moderated the effect of realism on uncanniness. Results indicate a vocal uncanny valley driven by deviations from typical human voices. While voices can fall into an uncanny valley, synthetic voices successfully escape it. Finally, the results support the account that uncanniness is caused by deviations from familiar categories, rather than categorical ambiguity or the misattribution of mind or animacy.

IntroductionSevere forms of short bowel syndrome (SBS) resulting in chronic intestinal failure (IF) have limited therapeutic options, all of which are associated with significant morbidities. Spring-mediated distraction enterogenesis (SMDE) uses an intraluminal self-expanding spring to generate mechanical force to induce intestinal stretching and sustained axial growth, providing a promising novel approach for patients with SBS. Previous studies have established this method to be safe and effective in small and large animal models. However, SMDE has previously not been implemented in a large, clinically relevant animal model.MethodsJuvenile mini-Yucatan pigs with 75% of their small intestine resected had intraluminal springs placed after an initial adaptive period. Morphological and histological assessments were performed on SMDE segments compared to the control region of the intestine undergoing normal adaptive responses to resection.ResultsWhile the initial histologic adaptive response observed following resection was attenuated after a month, the SMDE segments instead augmented these adaptive changes. Specifically, intestinal length increased 2-fold in SMDE segments, and the widths of the epithelial, muscularis, and serosal layers were enhanced in SMDE compared with control segments of the same animal. This data suggests that morphologic intestinal adaptation may be enhanced with SMDE in the setting of SBS.DiscussionHere we demonstrate the successful and reproducible implementation of SMDE in a large animal model in the setting of prior intestinal resection, making SMDE a viable and novel approach for SBS to be explored further.

Abstract Human-machine communication can be substantially enhanced by the inclusion of high-quality real-time recognition of spontaneous human emotional expressions. However, successful recognition of such expressions can be negatively impacted by factors such as sudden variations of lighting, or intentional obfuscation. Reliable recognition can be more substantively impeded due to the observation that the presentation and meaning of emotional expressions can vary significantly based on the culture of the expressor and the environment within which the emotions are expressed. As an example, an emotion recognition model trained on a regionally-specific database collected from North America might fail to recognize standard emotional expressions from another region, such as East Asia. To address the problem of regional and cultural bias in emotion recognition from facial expressions, we propose a meta-model that fuses multiple emotional cues and features. The proposed approach integrates image features, action level units, micro-expressions and macro-expressions into a multi-cues emotion model (MCAM). Each of the facial attributes incorporated into the model represents a specific category: fine-grained content-independent features, facial muscle movements, short-term facial expressions and high-level facial expressions. The results of the proposed meta-classifier (MCAM) approach show that a) the successful classification of regional facial expressions is based on non-sympathetic features b) learning the emotional facial expressions of some regional groups can confound the successful recognition of emotional expressions of other regional groups unless it is done from scratch and c) the identification of certain facial cues and features of the data-sets that serve to preclude the design of the perfect unbiased classifier. As a result of these observations we posit that to learn certain regional emotional expressions, other regional expressions first have to be “forgotten”.

Abstract Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we demonstrate that the transcriptional targets and proximal proteomes of GEMC1 and MCIDAS are highly similar. However, we identified distinct interactions with SWI/SNF subcomplexes; GEMC1 interacts primarily with the ARID1A containing BAF complex while MCIDAS interacts primarily with BRD9 containing ncBAF complexes. Treatment with a BRD9 inhibitor impaired MCIDAS-mediated activation of several target genes and compromised the MCC differentiation program in multiple cell based models. Our data suggest that the differential engagement of distinct SWI/SNF subcomplexes by GEMC1 and MCIDAS is required for MCC-specific transcriptional regulation and mediated by their distinct C-terminal domains.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

BackgroundInfective endocarditis (IE) is a rare, highly morbid condition with 17% in-hospital mortality. A total of 25–30% require surgery and there is ongoing debate with regard to markers predicting patient outcomes and guiding intervention. This systematic review aims to evaluate all IE risk scores currently available.MethodsStandard methodology (PRISMA guideline) was used. Papers with risk score analysis for IE patients were included, with attention to studies reporting area under the receiver-operating characteristic curve (AUC/ROC). Qualitative analysis was carried out, including assessment of validation processes and comparison of these results to original derivation cohorts where available. Risk-of-bias analysis illustrated according to PROBAST guidelines.ResultsOf 75 articles initially identified, 32 papers were analyzed for a total of 20 proposed scores (range 66–13,000 patients), 14 of which were specific for IE. The number of variables per score ranged from 3 to 14 with only 50% including microbiological variables and 15% including biomarkers. The following scores had good performance (AUC > 0.8) in studies proposing the score (often the derivation cohort); however fared poorly when applied to a new cohort: PALSUSE, DeFeo, ANCLA, RISK-E, EndoSCORE, MELD-XI, COSTA, and SHARPEN. DeFeo score demonstrated the largest discrepancy with initial AUC of 0.88, compared to 0.58 when applied to different cohorts. The inflammatory response in IE has been well documented and CRP has been found to be an independent predictor for worse outcomes. There is ongoing investigation on alternate inflammatory biomarkers which may assist in IE management. Of the scores identified in this review, only three have included a biomarker as a predictor.ConclusionDespite the variety of available scores, their development has been limited by small sample size, retrospective collection of data and short-term outcomes, with lack of external validation, limiting their transportability. Future population studies and large comprehensive registries are required to address this unmet clinical need.

The overwhelming increase in the prevalence of obesity and related disorders in recent years is one of the greatest threats to the global healthcare system since it generates immense healthcare costs. As the prevalence of obesity approaches epidemic proportions, the importance of elucidating the mechanisms regulating appetite, satiety, body metabolism, energy balance and adiposity has garnered significant attention. Currently, gastrointestinal (GI) bariatric surgery remains the only approach capable of achieving successful weight loss. Appetite, satiety, feeding behavior, energy intake and expenditure are regulated by central and peripheral neurohormonal mechanisms that have not been fully elucidated yet. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Vasoactive Intestinal Polypeptide (VIP) are members of a family of regulatory peptides that are widely distributed in parallel with their specific receptors, VPAC1R, VPAC2R and PAC1R, in the central nervous system (CNS) and in the periphery, such as in the gastrointestinal tract and its associated organs and immune cells. PACAP and VIP have been reported to play an important role in the regulation of body phenotype, metabolism and homeostatic functions. The purpose of this review is to present recent data on the effects of PACAP, VIP, VPAC1R, VPAC2R and PAC1R on the modulation of appetite, satiety, metabolism, calorie intake and fat accumulation, to evaluate their potential use as therapeutic targets for the treatment of obesity and metabolic syndrome.

Primary cardiac angiosarcomas are rare malignant tumors with a very poor prognosis. We present a case of a 48-year-old man with no previous cardiac history who developed an incessant focal atrial tachycardia complicated by tachycardia-mediated cardiomyopathy as a consequence of cardiac angiosarcoma. (Level of Difficulty: Beginner.)

Bromodomain-containing protein 4 (BRD4) is an acetyl-lysine reader protein and transcriptional regulator implicated in chromatin dynamics and cancer development. Several BRD4 isoforms have been detected in humans with the long isoform (BRD4-L, aa 1-1,362) playing a tumor-suppressive role and a major short isoform (BRD4-S, aa 1-722) having oncogenic activity in breast cancer development. In vivo demonstration of the opposing functions of BRD4 protein isoforms requires development of mouse models, particularly transgenic mice conditionally expressing human BRD4-L or BRD4-S, which can be selectively induced in different mouse tissues in a spatiotemporal-specific manner. Here, we detail the procedures used to genotype transgenic mouse strains developed to define the effects of conditional human BRD4 isoform expression on polyomavirus middle T antigen (PyMT)-induced mouse mammary tumor growth, and the key steps for Western blot detection of BRD4 protein isoforms in those tumors and in cultured cells. With this protocol as a guide, interpretation of BRD4 isoform functions becomes more feasible and expandable to various biological settings. Adequate tracking of BRD4 isoform distributions in vivo and in vitro is key to understanding their biological roles, as well as avoiding misinterpretation of their functions due to improper use of experimental procedures that fail to detect their spatial and temporal distributions. Graphic abstract:

OBJECTIVES:. The Seraph100 Microbind Affinity Blood Filter (Seraph 100) (ExThera Medical, Martinez, CA) is an extracorporeal therapy that can remove pathogens from blood, including severe acute respiratory syndrome coronavirus 2. The aim of this study was to evaluate safety and efficacy of Seraph 100 treatment for COVID-19. DESIGN:. Retrospective cohort study. SETTING:. Nine participating ICUs. PATIENTS:. COVID-19 patients treated with Seraph 100 (n = 53) and control patients matched by study site (n = 53). INTERVENTION:. Treatment with Seraph 100. MEASUREMENTS AND MAIN RESULTS:. At baseline, there were no differences between the groups in terms of sex, race/ethnicity, body mass index, and need for mechanical ventilation. However, patients in the Seraph 100 group were younger (median age, 54 yr; interquartile range [IQR], 41–65) compared with controls (median age, 64 yr; IQR, 56–69; p = 0.009). Charlson comorbidity index scores were lower in the Seraph 100 group (2; IQR, 0–3) compared with the control group (3; IQR, 2–4; p = 0.006). Acute Physiology and Chronic Health Evaluation II scores were also lower in Seraph 100 subjects (12; IQR, 9–17) compared with controls (16; IQR, 12–21; p = 0.011). The Seraph 100 group had higher vasopressor-free days with an incidence rate ratio of 1.30 on univariate analysis. This difference was not significant after adjustment. Seraph 100-treated subjects were less likely to die compared with controls (32.1% vs 64.2%; p = 0.001), a difference that remained significant after adjustment. However, no difference in mortality was observed in a post hoc analysis utilizing an external control group. In the full cohort of 86 treated patients, there were 177 total treatments, in which only three serious adverse events were recorded. CONCLUSIONS:. Although this study did not demonstrate consistently significant clinical benefit across all endpoints and comparisons, the findings suggest that broad spectrum, pathogen agnostic, blood purification can be safely deployed to meet new pathogen threats while awaiting targeted therapies and vaccines.

Abstract Background Genome-wide association studies of Alzheimer’s disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. Methods We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. Results We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. Conclusion 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.

Humanlike entities deviating from the norm of human appearance are perceived as strange or uncanny. Explanations for the eeriness of deviating humanlike entities include ideas specific to human or animal stimuli like mate selection, avoidance of threat or disease, or dehumanization; however, deviation from highly familiar categories may provide a better explanation. Here it is tested whether experts and novices in a novel (greeble) category show different patterns of abnormality, attractiveness, and uncanniness responses to distorted and averaged greebles. Greeble-trained participants assessed the abnormality, attractiveness, uncanniness of normal, averaged, and distorted greebles and their responses were compared to participants who had not previously seen greebles. The data show that distorted greebles were more uncanny than normal greebles only in the training condition, and distorted greebles were more uncanny in the training compared to the control condition. In addition, averaged greebles were not more attractive than normal greebles regardless of condition. The results suggest uncanniness is elicited by deviations from stimulus categories of expertise rather than being a purely biological human- or animal-specific response.

Background: Standalone thoracoscopic surgical ablation may be more effective than catheter ablation in patients with long-standing persistent atrial fibrillation. Objectives: To determine whether or not surgical ablation is clinically superior to catheter ablation as the first-line treatment strategy in long-standing persistent atrial fibrillation. Design: This was a prospective, multicentre, randomised control trial. Setting: Four NHS tertiary centres in England. Participants: Adults with long-standing persistent atrial fibrillation, who had European Heart Rhythm Association symptom scores > 2 and who were naive to previous catheter ablation or thoracic/cardiac surgery. Interventions: Minimally invasive thoracoscopic surgical ablation and conventional catheter ablation (control intervention). Main outcome measures: The primary outcome was freedom from atrial fibrillation/tachycardia ≥ 30 seconds after a single procedure without antiarrhythmic drugs (class 1C/3) at 1 year, excluding a 3-month blanking period. The secondary outcomes include the intervention-related major complication rate; clinical success (≥ 75% reduction in arrhythmia burden); and changes in symptoms, quality of life and cost-effectiveness. Methods: Patients (n = 120) were randomised to surgical ablation (n = 60) or catheter ablation (n = 60). An implanted loop recorder provided continuous cardiac monitoring following ablation. Follow-up visits were at 3, 6, 9 and 12 months. Loop recorder data were reviewed monthly by a physiologist who was blinded to the randomisation outcome. Results: The study treatment was received by 55 patients in the surgical ablation arm and 60 patients in the catheter ablation arm; five patients withdrew from surgical ablation before treatment. Data from randomised and treated patients were analysed as per intention to treat. Patients had a mean age of 62.3 (standard deviation 9.6) years, were predominantly male (74%), had a mean left atrial diameter of 44.6 mm (standard deviation 6 mm) and were in continuous atrial fibrillation for 22 months (range 16–31 months). At 12 months, 26% of patients in the surgical ablation arm (14/54) and 28% of patients in the catheter ablation arm (17/60) were free from atrial arrhythmias after a single procedure without antiarrhythmic drugs (odds ratio 1.13, 95% confidence interval 0.46 to 2.83; p = 0.84). An arrhythmia burden reduction of ≥ 75% was seen in 36 out of 54 (67%) patients in the surgical ablation arm, compared with 46 out of 60 (77%) patients in the catheter ablation arm (odds ratio 1.64, 95% confidence interval 0.67 to 4.08; p = 0.3). Procedure-related serious complications within 30 days of the intervention occurred in 15% (8/55) of patients in the surgical ablation arm (including one death) compared with 10% (6/60) of patients in the catheter ablation arm (p = 0.46). Surgical ablation was associated with significantly higher costs (£23,221 vs. £18,186; p = 0.02) and fewer quality-adjusted life-years than catheter ablation (0.76 vs. 0.83; p = 0.02). Limitations: This study was conducted in four highly specialised cardiology centres that have substantial experience in both treatment modalities; therefore, the results may not be widely generalisable. The study was not powered to detect small differences in efficacy. Conclusions: We found no evidence to suggest that standalone thoracoscopic surgical ablation outcomes were superior to catheter ablation outcomes in achieving freedom from atrial arrhythmia after a single procedure without antiarrhythmic drugs. Moreover, surgical ablation is associated with a longer hospital stay, smaller improvements in quality of life and higher health-care costs than catheter ablation (standard care therapy). Future work: Evaluation of the impact of ablation treatments on sinus rhythm maintenance and quality of life with extended follow-up to 3 years. Model-based economic analysis to estimate long-term benefits, harms and costs of surgical and catheter ablation compared with antiarrhythmic drug therapy in long-standing persistent atrial fibrillation patients. Trial registration: Current Controlled Trials ISRCTN18250790 and ClinicalTrials.gov NCT02755688. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This study was supported by the UK Clinical Research Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR Evaluation, Trials and Studies Coordinating Centre. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 18. See the NIHR Journals Library website for further project information.

Background: There is a compelling evidence from animal models that early exposure to clinically relevant general anesthetics (GAs) interferes with brain development, resulting in long-lasting cognitive impairments. Human studies have been inconclusive and are challenging due to numerous confounding factors. Here, we employed primary human neural cells to analyze ketamine neurotoxic effects focusing on the role of glial cells and their activation state. We also explored the roles of astrocyte-derived extracellular vesicles (EVs) and different components of the brain-derived neurotrophic factor (BDNF) pathway.Methods: Ketamine effects on cell death were analyzed using live/dead assay, caspase 3 activity and PARP-1 cleavage. Astrocytic and microglial cell differentiation was determined using RT-PCR, ELISA and phagocytosis assay. The impact of the neuron-glial cell interactions in the neurotoxic effects of ketamine was analyzed using transwell cultures. In addition, the role of isolated and secreted EVs in this cross-talk were studied. The expression and function of different components of the BDNF pathway were analyzed using ELISA, RT-PCR and gene silencing.Results: Ketamine induced neuronal and oligodendrocytic cell apoptosis and promoted pro-inflammatory astrocyte (A1) and microglia (M1) phenotypes. Astrocytes and microglia enhanced the neurotoxic effects of ketamine on neuronal cells, whereas neurons increased oligodendrocyte cell death. Ketamine modulated different components in the BDNF pathway: decreasing BDNF secretion in neurons and astrocytes while increasing the expression of p75 in neurons and that of BDNF-AS and pro-BDNF secretion in both neurons and astrocytes. We demonstrated an important role of EVs secreted by ketamine-treated astrocytes in neuronal cell death and a role for EV-associated BDNF-AS in this effect.Conclusions: Ketamine exerted a neurotoxic effect on neural cells by impacting both neuronal and non-neuronal cells. The BDNF pathway and astrocyte-derived EVs represent important mediators of ketamine effects. These results contribute to a better understanding of ketamine neurotoxic effects in humans and to the development of potential approaches to decrease its neurodevelopmental impact.

Negotiation teams are well established within tactical policing. Police agencies select and train personnel they deem suitable to act as negotiators during critical incidents. Consultants, such as forensic psychologists, have been considered as a means of increasing success during critical incidents through the specialist advice they are able to provide. However, there remains little research on the effectiveness of the advisor role and whether it is perceived by policing colleagues to be of benefit to the negotiation process. This will be discussed whilst also considering the consultancy process and how the forensic psychologist’s skill set may benefit negotiation teams. This manuscript will focus predominantly on hostage-taking as an example, as this is where a significant portion of the literature originated.

Abstract Background The treatment paradigm for metastatic hormone-sensitive prostate cancer (mHSPC) patients is evolving. PET/CT now offers improved sensitivity and accuracy in staging. Recent randomized trial data supports escalated hormone therapy, local primary tumor therapy, and metastasis-directed therapy. The impact of combining such therapies into a multimodal approach is unknown. This Phase II single-arm clinical trial sponsored and funded by Veterans Affairs combines local, metastasis-directed, and systemic therapies to durably render patients free of detectable disease off active therapy. Methods Patients with newly-diagnosed M1a/b prostate cancer (PSMA PET/CT staging is permitted) and 1–5 radiographically visible metastases (excluding pelvic lymph nodes) are undergoing local treatment with radical prostatectomy, limited duration systemic therapy for a total of six months (leuprolide, abiraterone acetate with prednisone, and apalutamide), metastasis-directed stereotactic body radiotherapy (SBRT), and post-operative fractionated radiotherapy if pT ≥ 3a, N1, or positive margins are present. The primary endpoint is the percent of patients achieving a serum PSA of

Testing during the COVID-19 pandemic has been crucial to public health surveillance and clinical care. Supply chain constraints—spanning limitations in testing kits, reagents, pipet tips, and swabs availability—have challenged the ability to scale COVID-19 testing. During the early months, sample collection kits shortages constrained planned testing expansions. In response, the University of Vermont Medical Center, University of Vermont College of Medicine, Vermont Department of Health Laboratory, Aspenti Health, and providers across Vermont including 16 area hospitals partnered to surmount these barriers. The primary objectives were to increase supply availability and manage utilization. Within the first month of Vermont’s stay-at-home order, the University of Vermont Medical Center laboratory partnered with College of Medicine to create in-house collection kits, producing 5000 per week. University of Vermont Medical Center reassigned 4 phlebotomists, laboratory educators, and other laboratory staff, who had reduced workloads, to participate (requiring a total of 5.3-7.6 full-time equivalent (FTE) during the period of study). By August, automation at a local commercial laboratory produced 22,000 vials of media in one week (reducing the required personnel by 1.2 FTE). A multisite, cross-institutional approach was used to manage specimen collection kit utilization across Vermont. Hospital laboratory directors, managers, and providers agreed to order only as needed to avoid supply stockpiles and supported operational constraints through ongoing validations and kit assembly. Throughout this pandemic, Vermont has ranked highly in number of tests per million people, demonstrating the value of local collaboration to surmount obstacles during disease outbreaks and the importance of creative allocation of resources to address statewide needs.

Researchers are beginning to transition from studying human–automation interaction to human–autonomy teaming. This distinction has been highlighted in recent literature, and theoretical reasons why the psychological experience of humans interacting with autonomy may vary and affect subsequent collaboration outcomes are beginning to emerge (de Visser et al., 2018; Wynne and Lyons, 2018). In this review, we do a deep dive into human–autonomy teams (HATs) by explaining the differences between automation and autonomy and by reviewing the domain of human–human teaming to make inferences for HATs. We examine the domain of human–human teaming to extrapolate a few core factors that could have relevance for HATs. Notably, these factors involve critical social elements within teams that are central (as argued in this review) for HATs. We conclude by highlighting some research gaps that researchers should strive toward answering, which will ultimately facilitate a more nuanced and complete understanding of HATs in a variety of real-world contexts.

Background Social and ecological differences in early SARS-CoV-2 pandemic screening and outcomes have been documented, but the means by which these differences have arisen are not well understood. Objective To characterize socioeconomic and chronic disease-related mechanisms underlying these differences. Design Observational cohort study. Setting Outpatient and emergency care. Patients 12900 Cleveland Clinic Health System patients referred for SARS-CoV-2 testing between March 17 and April 15, 2020. Interventions Nasopharyngeal PCR test for SARS-CoV-2 infection. Measurements Test location (emergency department, ED, vs. outpatient care), COVID-19 symptoms, test positivity and hospitalization among positive cases. Results We identified six classes of symptoms, ranging in test positivity from 3.4% to 23%. Non-Hispanic Black race/ethnicity was disproportionately represented in the group with highest positivity rates. Non-Hispanic Black patients ranged from 1.81 [95% confidence interval: 0.91–3.59] times (at age 20) to 2.37 [1.54–3.65] times (at age 80) more likely to test positive for the SARS-CoV-2 virus than non-Hispanic White patients, while test positivity was not significantly different across the neighborhood income spectrum. Testing in the emergency department (OR: 5.4 [3.9, 7.5]) and cardiovascular disease (OR: 2.5 [1.7, 3.8]) were related to increased risk of hospitalization among the 1247 patients who tested positive. Limitations Constraints on availability of test kits forced providers to selectively test for SARS-Cov-2. Conclusion Non-Hispanic Black patients and patients from low-income neighborhoods tended toward more severe and prolonged symptom profiles and increased comorbidity burden. These factors were associated with higher rates of testing in the ED. Non-Hispanic Black patients also had higher test positivity rates.