Clinically inapparent mpox virus (MPXV) infections among clients of three anonymous Community Based Voluntary Counselling and Testing centres in Berlin, Germany, 2022-2023.

INTRODUCTION: Since the mpox outbreak in 2022, it was unclear if and how often infections with mpox virus (MPXV) were clinically inapparent, i.e. not presenting to clinical care with mpox symptoms. Moreover, it was hypothesized that MPXV circulated in the affected communities before the outbreak was officially detected. METHODS: We retrospectively tested rectal and urethral swabs, and pooled samples for presence of MPXV. Samples were obtained from routine STI testing of three anonymous Community Based Voluntary Counselling and Testing (CBVCT) centres in Berlin, in 2022 and 2023. Testing results were linked to anonymously provided behavioural data. RESULTS: Overall, 9,053 samples from 6,600 client visits were included. Clinically inapparent MPXV infections were detectable in 1.1% of the samples. We did not find MPXV infections in the month before the first cases appeared in Berlin or between October 2022 and January 2023 when case numbers were low in Germany. However, during the outbreak period in 2022, we found clinically inapparent MPXV infections among 2.2% of the clients and during summer/autumn 2023 among 0.3%. The number of condomless anal/vaginal intercourse partners within the previous 6 months and PrEP use were identified as predictors of clinically inapparent MPXV infection. CONCLUSION: Clinically inapparent MPXV infections occurred during the mpox outbreak in Berlin in 2022 and post-outbreak in summer/autumn 2023. Unrecognized MPXV circulation in Berlin before the recognition of the outbreak in May 2022 appears unlikely. However, low-level sustained circulation of clinically inapparent MPXV infections need to be acknowledged in mpox prevention strategies.

Assessing between-officer variability in responses to a live-acted deadly force encounter as a window to the effectiveness of training and experience.

We aimed to infer the effectiveness of officers' training and experience by assessing consistency of behavioural responses between them. If officers facing the same scenario respond in similar ways, this implies their use of shared cognition, through acquired in-common tactical knowledge. Officers (n = 42) responded to a live-acted scenario in which an assailant ultimately discharged his weapon. Triangulated camera positions assessed their movement patterns, final positions, and weapon responses relative to when the assailant fired his weapon. We also assessed the officers' visual search and gathered information regarding their experience and rest. Our second aim was to examine sources of variability in the officers' responses. We found extensive variability in all aspects of the response. Experience did not impact spatial or temporal behavioural responses. However, longer hours awake and lower reported rest negatively impacted officers' responses. We conclude that officers had insufficient training and experience to demonstrate in-common knowledge.Practitioner summary: Police officers showed high spatial and temporal variability in response to the same scenario. This implies inadequate tactical training, and is supported by our finding that training and experience did not impact performance. Instead, the officers' variability was constrained by their visual search, and the hours awake before being tested.

Evaluation of a laboratory-developed test for simultaneous detection of norovirus and rotavirus by real-time RT-PCR on the Panther Fusion® system.

The Hologic Panther Fusion® Open Access™ functionality allows implementation of laboratory-developed tests (LDTs), with fully automated sample extraction, real-time PCR, and result interpretation. We report the development and validation of a multiplex LDT for norovirus G1, norovirus G2, and rotavirus from stool samples on this system. The LDT was optimized for primer and probe sequences, salt concentration, and PCR annealing temperature. Reproducibility of the PCR and extraction process was assessed. Performance of the multiplex LDT assay was evaluated with external quality assessment (EQA) samples and compared to a commercial multiplex assay (Allplex™ GI-Virus Assay, Seegene) in clinical samples. Salt concentrations and annealing/extension temperature were optimized to 4 mM MgCl2, 70 mM KCl, 20 mM Tris, and 60 °C, respectively. The user-prepared part of the LDT PCR mix (containing salts, probes, and primers) was stable for ≥ 11 days onboard the instrument. We observed reproducible results of PCR and the extraction process. The LDT had a sensitivity comparable to or greater than the commercial Allplex™ assay and showed excellent linearity. Forty-five EQA samples yielded the expected result with the LDT. There was 100% concordance between LDT and Allplex™ results in 160 clinical samples. Results from the suspension and direct swab stool sample preparation methods were highly concordant in the LDT. We report the successful development and validation of a multiplex PCR LDT for detection of norovirus G1, norovirus G2, and rotavirus from stool samples on the Panther Fusion® system.

DICOM Images Have Been Hacked! Now What?

OBJECTIVE. As health care moves into a new era of increasing information vulnerability, radiologists should understand that they may be using systems that are exposed to altered data or data that contain malicious elements. This article explains the vulnerabilities of DICOM images and discusses requirements to properly secure these images from cyberattacks. CONCLUSION. There is an important need to properly secure DICOM images from attacks and tampering. The solutions described in this article will go a long way to achieving this goal.

DICOMweb™: Background and Application of the Web Standard for Medical Imaging.

This paper describes why and how DICOM, the standard that has been the basis for medical imaging interoperability around the world for several decades, has been extended into a full web technology-based standard, DICOMweb. At the turn of the century, healthcare embraced information technology, which created new problems and new opportunities for the medical imaging industry; at the same time, web technologies matured and began serving other domains well. This paper describes DICOMweb, how it extended the DICOM standard, and how DICOMweb can be applied to problems facing healthcare applications to address workflow and the changing healthcare climate.

Perspective: 4ß-hydroxycholesterol as an emerging endogenous biomarker of hepatic CYP3A.

A key goal in the clinical development of a new molecular entity is to quickly identify whether it has the potential for drug-drug interactions. In particular, confirmation of in vitro data in the early stage of clinical development would facilitate the decision making and inform future clinical pharmacology study designs. Plasma 4ß-hydroxycholesterol (4ß-HC) is considered as an emerging endogenous biomarker for cytochrome P450 3A (CYP3A), one of the major drug metabolizing enzymes. Although there are increasing reports of the use of 4ß-HC in academic- and industry-sponsored clinical studies, a thorough review, summary and consideration of the advantages and challenges of using 4ß-HC to evaluate changes in CYP3A activity has not been attempted. Herein, we review the biology of 4ß-HC, its response to treatment with CYP3A inducers, inhibitors and mixed inducer/inhibitors in healthy volunteers and patients, the association of 4ß-HC with other probes of CYP3A activity (e.g. midazolam, urinary cortisol ratios), and present predictive pharmacokinetic models. We provide recommendations for studying hepatic CYP3A activity in clinical pharmacology studies utilizing 4ß-HC at different stages of drug development.

Sequence-based identification of inositol monophosphatase-like histidinol-phosphate phosphatases (HisN) in Corynebacterium glutamicum, Actinobacteria, and beyond.

BACKGROUND: The eighth step of L-histidine biosynthesis is carried out by an enzyme called histidinol-phosphate phosphatase (HolPase). Three unrelated HolPase families are known so far. Two of them are well studied: HAD-type HolPases known from Gammaproteobacteria like Escherichia coli or Salmonella enterica and PHP-type HolPases known from yeast and Firmicutes like Bacillus subtilis. However, the third family of HolPases, the inositol monophosphatase (IMPase)-like HolPases, present in Actinobacteria like Corynebacterium glutamicum (HisN) and plants, are poorly characterized. Moreover, there exist several IMPase-like proteins in bacteria (e.g. CysQ, ImpA, and SuhB) which are very similar to HisN but most likely do not participate in L-histidine biosynthesis. RESULTS: Deletion of hisN, the gene encoding the IMPase-like HolPase in C. glutamicum, does not result in complete L-histidine auxotrophy. Out of four hisN homologs present in the genome of C. glutamicum (impA, suhB, cysQ, and cg0911), only cg0911 encodes an enzyme with HolPase activity. The enzymatic properties of HisN and Cg0911 were determined, delivering the first available kinetic data for IMPase-like HolPases. Additionally, we analyzed the amino acid sequences of potential HisN, ImpA, SuhB, CysQ and Cg0911 orthologs from bacteria and identified six conserved sequence motifs for each group of orthologs. Mutational studies confirmed the importance of a highly conserved aspartate residue accompanied by several aromatic amino acid residues present in motif 5 for HolPase activity. Several bacterial proteins containing all identified HolPase motifs, but showing only moderate sequence similarity to HisN from C. glutamicum, were experimentally confirmed as IMPase-like HolPases, demonstrating the value of the identified motifs. Based on the confirmed IMPase-like HolPases two profile Hidden Markov Models (HMMs) were build using an iterative approach. These HMMs allow the fast, reliable detection and differentiation of the two paralog groups from each other and other IMPases. CONCLUSION: The kinetic data obtained for HisN from C. glutamicum, as an example for an IMPase-like HolPases, shows remarkable differences in enzyme properties as compared to HAD- or PHP-type HolPases. The six sequence motifs and the HMMs presented in this study can be used to reliably differentiate between IMPase-like HolPases and IMPase-like proteins with no such activity, with the potential to enhance current and future genome annotations. A phylogenetic analysis reveals that IMPase-like HolPases are not only present in Actinobacteria and plant but can be found in further bacterial phyla, including, among others, Proteobacteria, Chlorobi and Planctomycetes.

Effect of deuteration on metabolism and clearance of Nerispirdine (HP184) and AVE5638.

Replacing hydrogen with deuterium as a means of altering ADME properties of drug molecules has recently enjoyed a renaissance, such that at least two deuterated chemical entities are currently in clinical development. Although most research in this area aims to increase the metabolic stability, and hence half-life of the active species, experience has shown that prediction of the in vivo behaviour of deuterated molecules is difficult and depends on multiple factors including the complexity of the metabolic scheme, the enzymes involved and hence the mechanism of the rate-determining step in the biotransformation. In an effort to elucidate some of these factors we examined the metabolic behaviour of two molecules from the Sanofi portfolio in a range of in vitro and in vivo systems. Although some key metabolic reactions of the acetylcholine release stimulator HP184 4 were slowed in vitro and in vivo when deuterium was present at the sites of metabolism, this did not translate to an increase in overall metabolic stability. By contrast, the tryptase inhibitor AVE5638 13 was much more metabolically stable in vitro in its deuterated form than when unlabelled. These results indicate that it could be of value to concentrate efforts in this area to molecules which are metabolised by a major pathway that involves enzymes of the amine oxidase family or other low-capacity enzyme families.

Gaze Control and Tactical Decision-Making Under Stress in Active-Duty Police Officers During a Live Use-of-Force Response.

Police officers during dynamic and stressful encounters are required to make rapid decisions that rely on effective decision-making, experience, and intuition. Tactical decision-making is influenced by the officer's capability to recognize critical visual information and estimation of threat. The purpose of the current study is to investigate how visual search patterns using cluster analysis and factors that differentiate expertise (e.g., years of service, tactical training, related experiences) influence tactical decision-making in active-duty police officers (44 active-duty police officers) during high stress, high threat, realistic use of force scenario following a car accident and to examine the relationships between visual search patterns and physiological response (heart rate). A cluster analysis of visual search variables (fixation duration, fixation location difference score, and number of fixations) produced an Efficient Scan and an Inefficient Scan group. Specifically, the Efficient Scan group demonstrated longer total fixation duration and differences in area of interests (AOI) fixation duration compared to the Inefficient Scan group. Despite both groups exhibiting a rise in physiological stress response (HR) throughout the high-stress scenario, the Efficient Scan group had a history of tactical training, improved return fire performance, had higher sleep time total, and demonstrated increased processing efficiency and effective attentional control, due to having a background of increased tactical training.

Binding, Neutralization and Internalization of the Interleukin-13 Antibody, Lebrikizumab.

INTRODUCTION: IL-13 is the primary upregulated cytokine in atopic dermatitis (AD) skin and is the pathogenic mediator driving AD pathophysiology. Lebrikizumab, tralokinumab and cendakimab are therapeutic monoclonal antibodies (mAb) that target IL-13. METHODS: We undertook studies to compare in vitro binding affinities and cell-based functional activities of lebrikizumab, tralokinumab and cendakimab. RESULTS: Lebrikizumab bound IL-13 with higher affinity (as determined using surface plasma resonance) and slower off-rate. It was more potent in neutralizing IL-13-induced effects in STAT6 reporter and primary dermal fibroblast periostin secretion assays than either tralokinumab or cendakimab. Live imaging confocal microscopy was employed to determine the mAb effects on IL-13 internalization into cells via the decoy receptor IL-13Rα2, using A375 and HaCaT cells. The results showed that only the IL-13/lebrikizumab complex was internalized and co-localized with lysosomes, whereas IL-13/tralokinumab or IL-13/cendakimab complexes did not internalize. CONCLUSION: Lebrikizumab is a potent, neutralizing high-affinity antibody with a slow disassociation rate from IL-13. Additionally, lebrikizumab does not interfere with IL-13 clearance. Lebrikizumab has a different mode of action to both tralokinumab and cendakimab, possibly contributing to the clinical efficacy observed by lebrikizumab in Ph2b/3 AD studies.

Effects of omeprazole and genetic polymorphism of CYP2C19 on the clopidogrel active metabolite.

Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 µM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.

An unusual location of solitary fibrous tumor in heart-A case report and review of literature.

BACKGROUND: Solitary fibrous tumor (SFT) are rare spindle cell tumors originating from the mesenchymal cells mostly from the visceral pleura. SFT was first described as a distinct entity in 1931 by Klemperer et al. Until now, we have limited data regarding the manifestation and behavior of extra pleural forms such as cardiac SFT. Here we present a case of SFT involving the pericardium where the diagnosis was made by imaging followed by biopsy findings. We also review the literature of SFT involving the heart and the management approaches. CASE PRESENTATION: An 81-year-old male presented with progressive dyspnea. Computed tomography (CT) of the chest showed a 6.2 × 5.3 cm soft tissue mass in the anterior mediastinum. Further imaging with CT angiogram showed a stalk-like connection to the pericardium. A biopsy of the mass showed spindle cells positive for BCL-2, CD34, and STAT 6, indicative of a solitary fibrous tumor. A surveillance approach was adopted for the patient. CONCLUSION: Primary pericardial tumors are exceedingly rare, with a prevalence rate of 0.001%-0.007%. Diagnosing a SFT requires a positive CD34 and BCL-2 marker. The current recommendation is resection of localized disease which has been documented to be curative in cases of benign disease however our patient was put on surveillance.

Gender harmony: improved standards to support affirmative care of gender-marginalized people through inclusive gender and sex representation.

OBJECTIVE: Accurate representation of clinical sex and gender identity in interoperable clinical systems is a major challenge for organizations intent on improving outcomes for sex- and gender-marginalized people. Improved data collection has been hindered by the historical approach that presumed a single, often binary, datum was sufficient. We describe the Health Level Seven International (HL7) Gender Harmony logical model that proposes an improved approach. MATERIALS AND METHODS: The proposed solution was developed via an American National Standards Institute (ANSI)-certified collaborative balloted process. As an HL7 Informative Document, it is an HL7 International-balloted consensus on the subject of representing sex and representing gender in clinical systems based on work of the gender harmony project led by the HL7 Vocabulary Work Group. RESULTS: The Gender Harmony Model is a logical model that provides a standardized approach that is both backwards-compatible and an improvement to the meaningful capture of gender identity, recorded sex or recorded gender, a sex for clinical use, the name to use, and pronouns that are affirmative and inclusive of gender-marginalized people. CONCLUSION: Most clinical systems and current standards in health care do not meaningfully address, nor do they consistently represent, sex and gender diversity, which has impeded interoperability and led to suboptimal health care. The Gender Harmony Project was formed to create more inclusive health information exchange standards to enable a safer, higher-quality, and embracing healthcare experience. The Gender Harmony Model provides the informative guidance for standards developers to implement a more thorough technical design that improves the narrow binary design used in many legacy clinical systems.

Overall Survival in Phase 3 Clinical Trials and the Surveillance, Epidemiology, and End Results Database in Patients With Metastatic Colorectal Cancer, 1986-2016: A Systematic Review.

Importance: Phase 3 trials for patients with metastatic colorectal cancer (mCRC) have been conducted with varying designs and often with surrogate end points for overall survival (OS). Objectives: To critically examine the factors associated with clinically relevant improvement in OS (defined as ≥2 months) in these trials and to evaluate their association with outcomes reflected in Surveillance, Epidemiology, and End Results (SEER) registry data. Evidence Review: Medline, EMBASE, Cochrane, Web of Science, ClinicalTrials.gov, EU Clinical Trials Register, and the International Clinical Trials Registry Platform were searched for phase 3 trials of systemic therapy for patients with mCRC by decade (1986-1996, 1997-2006, and 2007-2016), excluding early or pilot studies, studies that did not involve an anticancer drug, studies on cancer screening and prevention, reports of pooled data from multiple trials, and studies with nonpharmaceutical approaches. The association of drug development with OS outside the clinical trial setting was evaluated using data from the SEER registry, including adult patients with a primary cancer site in the colon or rectum, including adenocarcinoma, mucinous adenocarcinoma, or signet ring cell carcinoma; a distant stage; and receipt of chemotherapy as first-line therapy. Kaplan-Meier curves and log-rank tests were used to assess OS. Findings: The literature search identified 150 phase III clinical trials with 77 494 total enrollments, and 67 126 patients with mCRC were identified from the SEER database. Significant increases in survival were noted over time, best reflected in the experimental arm of first-line therapy (OS increased by 5.7 months per 10 years; 95% CI, 4.7-6.6 months; progression-free survival increased by 1.4 months per 10 years; 95% CI, 0.7-2.1 months). Although 69 of 148 trials (46.6%) met their predefined primary end point (including 20 of 44 trials [45.5%] with OS as the primary end point), only 35 of 132 trials (26.5%) resulted in improvement in OS by 2 months or more (including 13 of 42 trials [31.0%] with OS as the primary end point). Multivariable logistic regression showed that third-line therapies or later (odds ratio, 0.57; 95% CI, 0.51-0.63) and funding by pharmaceutical companies (odds ratio, 0.57; 95% CI, 0.54-0.60) were less often associated with improvement in OS. Furthermore, there was a decrease in the novelty of targets and agents over time, with trials that evaluated regimens composed entirely of previously approved drugs for mCRC increasing from 28% to 50%. Data from the SEER database showed that median OS increased from 12 months (95% CI, 12-13 months) (1986-1996) to 21 months (95% CI, 21-22 months) (2007-2015) (P < .001), but the 5-year OS continued to be low at 12.2% in 2011. Conclusions and Relevance: In this systematic review, OS for patients with mCRC appeared to improve significantly in trials, translating into meaningful benefits outside the clinical trial setting; however, these advances, although significant cumulatively, are largely incremental individually. These data should be a call to aim for larger gains from future trials with novel drugs, building on the increasing understanding of the biology of mCRC and sophisticated translational research tools.

Performance of the Sofia SARS-CoV-2 rapid antigen test as frontline test in a university hospital, Germany.

The rapid and reliable detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of high importance for individual patient care and hospital infection prevention. We aimed to evaluate the performance of the Sofia SARS-CoV-2 antigen rapid diagnostic test (Ag-RDT) in comparison to real-time reverse-transcription polymerase chain reaction (RT-PCR). We conducted a prospective, monocentric cross-sectional study in an emergency department of a German university hospital from November 2020 to March 2021. We tested all samples using both Sofia SARS-CoV-2 Ag-RDT and real-time RT-PCR. A total of 7877 patients were included. Overall sensitivity of the Ag-RDT was 62.9% and specificity was 99.4%. Sensitivity varied across study months, whereas specificity remained high. Sensitivity increased to 94.2% in samples with a cycle threshold (Ct)-value ≤25. The Sofia Ag-RDT proved to be a rapid tool to detect samples with high viral loads (Ct-value ≤25) and might thus help to identify infectious patients.

Cdk1 activity is required for mitotic activation of aurora A during G2/M transition of human cells.

In mammalian cells entry into and progression through mitosis are regulated by multiple mitotic kinases. How mitotic kinases interact with each other and coordinately regulate mitosis remains to be fully understood. Here we employed a chemical biology approach using selective small molecule kinase inhibitors to dissect the relationship between Cdk1 and Aurora A kinases during G(2)/M transition. We find that activation of Aurora A first occurs at centrosomes at late G(2) and is required for centrosome separation independently of Cdk1 activity. Upon entry into mitosis, Aurora A then becomes fully activated downstream of Cdk1 activation. Inactivation of Aurora A or Plk1 individually during a synchronized cell cycle shows no significant effect on Cdk1 activation and entry into mitosis. However, simultaneous inactivation of both Aurora A and Plk1 markedly delays Cdk1 activation and entry into mitosis, suggesting that Aurora A and Plk1 have redundant functions in the feedback activation of Cdk1. Together, our data suggest that Cdk1, Aurora A, and Plk1 mitotic kinases participate in a feedback activation loop and that activation of Cdk1 initiates the feedback loop activity, leading to rapid and timely entry into mitosis in human cells. In addition, live cell imaging reveals that the nuclear cycle of cells becomes uncoupled from cytokinesis upon inactivation of both Aurora A and Aurora B kinases and continues to oscillate in a Cdk1-dependent manner in the absence of cytokinesis, resulting in multinucleated, polyploidy cells.

Chicago neoliberalism versus Cowles planning: perspectives on patents and public goods in Cold War economic thought.

In post-Sputnik America, when many policymakers and social scientists feared the Soviet Union had a technological advantage over the United States, assessing the relative importance of patents for inventive activity and examining whether scientific research constituted a public good were paramount concerns. The neoliberals of the University of Chicago and the planners of the Cowles Commission both spoke to these issues. This paper sheds light on their views on patents and public goods in the late 1950s and early 1960s by examining representatives of Cowles and Chicago, Kenneth Arrow and Ronald Coase, respectively. Furthermore, it evaluates whether their views on patents and public goods clashed with the interests of RAND, at which both Arrow and Coase worked at some point during this time period. The paper argues that the Chicago-neoliberal position of Coase undermined the interests of RAND, while the Cowles-planning conclusions of Arrow furthered those interests.

Approximate Target Pre-Cueing Reduces Programming Quiet Eye and Movement Preparation Time: Evidence for Parameter Pre-Programming?

Purpose: We examined the effect of target pre-cues on quiet eye duration (QED). If quiet eye (QE) represents the initial and only period for the programming of movement parameters, then the precision of target pre-cues should not affect QED. In contrast, shorter QED after pre-cueing of targets implies some initial programming process to have occurred before QE. Method: Sixteen participants threw darts at targets projected onto a soft screen. We manipulated the precision of target pre-cues by highlighting an area within which the target would appear. These pre-cued areas were either the full screen (i.e., no cue), any half, quarter, or sixteenth of the screen. Participants threw eight times in each condition. Dependent measures included QED (programming and online segments), movement preparation time (MPT; from target presentation to initiation of movement), and radial error (cm). Results: Analysis revealed that programming QE was shorter when the target was pre-cued in the most precise sixteenth condition, compared to the no cue condition. Also, MPT was shorter when pre-cued in the sixteenth condition than in either the no cue or half screen conditions. Target pre-cueing conditions did not affect the other dependent variables. Conclusions: Shorter PQE following the most precise target pre-cueing implies that some pre-programming occurred before QE, perhaps through inhibition, but only when the pre-cue was specific enough to make pre-programming possible.

Outcomes of patients with metastatic renal cell carcinoma with sarcomatoid dedifferentiation to immune checkpoint inhibitors.

INTRODUCTION: Metastatic renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with poor survival outcomes. We aimed to analyze the efficacy and safety of immune checkpoint inhibitors (ICI) in patients with sRCC comparing clear-cell (sccRCC) to non-clear cell epithelial histology (snccRCC). METHODS: We performed retrospective analysis of sRCC patients who received ICI at MD Anderson Cancer Center (n = 48, 41 with ccRCC and 7 with nccRCC) to determine the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Additionally, we performed a prespecified multivariable Cox regression comparing survival outcomes between sccRCC and snccRCC. RESULTS: The ORR for the entire cohort was 35.4% (95% confidence interval [CI]: 23.4%, 49.6%), including 8 (16.7%) patients (95% CI: 8.7%, 29.6%) who achieved a complete remission. The disease control rate was 52% (95% CI: 38.3%, 65.5%). In patients with sccRCC, the ORR was 39% (95% CI: 25.7%, 54.3%) and disease control rate 58.5% (43.4%, 72.2%). Among 7 snccRCC patients, only one (14.3%) achieved an objective partial response. At a median follow-up of 51.1 months, the median PFS was 4.9 months (95% CI: 2.7, 16.3) and the median OS was 28.4 months (95% CI: 15.8, NA) for the entire cohort. For patients with sccRCC, the median PFS was 8.9 months, with median OS of 30.1 months, compared with median PFS of 2.3 months (HR 0.25 [95% CI: 0.08, 0.78]; P= 0.0145) and median OS of 6.7 months (HR 0.13 [95% CI 0.04, 0.44]; P=0.0009) for patients with snccRCC. CONCLUSION: ICIs appear to be effective in sccRCC while the treatment of snccRCC remains challenging.

The role of narrative in collaborative reasoning and intelligence analysis: A case study.

This paper explores the significance of narrative in collaborative reasoning using a qualitative case study of two teams of intelligence analysts who took part in an exercise using an online collaborative platform. Digital ethnographic methods were used to analyze the chat transcripts of analysts as they reasoned with evidence provided in a difficult, fictional intelligence-type problem and produced a final intelligence report. These chat transcripts provided a powerful "microscope" into the reasoning processes and interactions involved in complex, collaborative reasoning. We found that Individuals and teams used narrative to solve the kinds of complex problems organizations and intelligence agencies face daily. We observed that team members generated what we term "micro-narratives", which provided a means for testing, assessing and weighing alternative hypotheses through mental simulation in the context of collaborative reasoning. The creation of micro-narratives assisted in the teams' reasoning with evidence, an integral part of collaborative reasoning and intelligence analysis. Micro-narratives were combined into, and compared with, an ideal or 'virtual' narrative which informed the judgements the team came to in their final intelligence report. The case study developed in this paper provides evidence that narrative thought processes play an important role in complex collaborative problem-solving, reasoning with evidence and problem-solving. This is contrary to a widespread perception that narrative thinking is fundamentally distinct from formal, logical reasoning.