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This article uses the organisational trust repair model developed by Gillespie and Dietz to examine how the Royal Bank of Liverpool, which suspended payments during the commercial crisis in 1847, escaped liquidation and resumed business. This case study uses newspaper reports and selected corporate records to explore narratives of trust between bank management and different interest groups over the course of resuscitating the establishment. The case affords three distinct but interlaced conduits enabling analysis of the dynamics of trust repair: reassertion of credibility through appealing to its reputational past; reconciliation of competing expectations from different parties, and renegotiation of boundaries between directors’ powers and stakeholders’ rights. Exploring the professional standpoint, local attributes and moral discourses within which restoration of the bank was situated enables evaluation of the bank’s strategies for rebuilding trust and redeeming corporate legitimacy through a contemporary theoretical perspective, offering lessons for corporate trust repair in the twenty-first century.

Supplementary Data from Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors

Supplementary Legends - PDF file 80K, This file contains the legends to supplementary figures, supplementary movies and supplementary tables

Supplementary Tables - XLS file 163K. This file contains 6 supplementary tables

Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors.Significance:In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.

Supporting video 2 - MOV file 1047K, IMR32-NOTCH3IC cells cultured with doxycycline. Note the fast-moving presence of different cells.

Purpose: Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system with an often lethal outcome due to metastatic disease. Migration and epithelial–mesenchymal transitions have been implicated in metastasis but they are hardly investigated in neuroblastoma.Experimental Design: Cell migration of 16 neuroblastoma cell lines was quantified in Transwell migration assays. Gene expression profiling was used to derive a migration signature, which was applied to classify samples in a neuroblastoma tumor series. Differential expression of transcription factors was analyzed in the subsets. NOTCH3 was prioritized, and inducible transgene expression studies in cell lines were used to establish whether it functions as a master switch for motility.Results: We identified a 36-gene expression signature that predicts cell migration. This signature was used to analyse expression profiles of 88 neuroblastoma tumors and identified a group with distant metastases and a poor prognosis. This group also expressed a known mesenchymal gene signature established in glioblastoma. Neuroblastomas recognized by the motility and mesenchymal signatures strongly expressed genes of the NOTCH pathway. Inducible expression of a NOTCH intracellular (NOTCH3-IC) transgene conferred a highly motile phenotype to neuroblastoma cells. NOTCH3-IC strongly induced expression of motility- and mesenchymal marker genes. Many of these genes were significantly coexpressed with NOTCH3 in neuroblastoma, as well as colon, kidney, ovary, and breast tumor series.Conclusion: The NOTCH3 transcription factor is a master regulator of motility in neuroblastoma. A subset of neuroblastoma with high expression of NOTCH3 and its downstream-regulated genes has mesenchymal characteristics, increased incidence of metastases, and a poor prognosis. Clin Cancer Res; 19(13); 3485–94. ©2013 AACR.

Supplementary Figures - PDF file 2758K, This file contains supplementary figure 1-7

Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors. Significance: In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.

Elizabeth Crosby (1888-1983) is a beloved and well-respected titan of neuroanatomy. Her contributions to our understanding of neuroanatomy are rooted in her seminal text, The Comparative Anatomy of the Nervous System of Vertebrates, Including Man, published in 1936, which is a masterful and comprehensive account of comparative neuroanatomy. Her later texts, Correlative Neurosurgery and Correlative Anatomy of the Nervous System, are standard reference texts to this day. Her mentorship of graduate students, close work with the University of Michigan neurosurgery department, and the quality of her research and scientific publications were recognized with many awards, culminating in the National Medal of Science presented by President Carter in 1980.

To address the paucity of research investigating the implementation of multi-domain dementia prevention interventions, we implemented and evaluated a 24-week, bi-weekly multi-domain program for older adults at risk of cognitive impairment at neighborhood senior centres (SCs). It comprised dual-task exercises, cognitive training, and mobile application-based nutritional guidance. An RCT design informed by the Reach, Effectiveness, Adoption, Implementation, Maintenance framework was adopted. Outcome measures include cognition, quality of life, blood parameters, and physical performance. Implementation was evaluated through questionnaires administered to participants, implementers, SC managers, attendance lists, and observations. The program reached almost 50% of eligible participants, had an attrition rate of 22%, and was adopted by 8.7% of the SCs approached. It was implemented as intended; only the nutritional component was re-designed due to participants’ unfamiliarity with the mobile application. While there were no between-group differences in cognition, quality of life, and blood parameters, quality of life reduced in the control group and physical function improved in the intervention group after 24 weeks. The program was well-received by participants and SCs. Our findings show that a multi-domain program for at-risk older adults has benefits and can be implemented through neighborhood SCs. Areas of improvement are discussed.Trial registration: ClinicalTrials.gov NCT04440969 retrospectively registered on 22 June 2020.

Background: Posterior fossa tumors (PFTs) are a morbid group of central nervous system tumors that most often present in childhood. While early diagnosis is critical to drive appropriate treatment, definitive diagnosis is currently only achievable through invasive tissue collection and histopathological analyses. Machine learning has been investigated as an alternative means of diagnosis. In this systematic review and meta-analysis, we evaluated the primary literature to identify all machine learning algorithms developed to classify and diagnose pediatric PFTs using imaging or molecular data. Methods: Of the 433 primary papers identified in PubMed, EMBASE, and Web of Science, 25 ultimately met the inclusion criteria. The included papers were extracted for algorithm architecture, study parameters, performance, strengths, and limitations. Results: The algorithms exhibited variable performance based on sample size, classifier(s) used, and individual tumor types being investigated. Ependymoma, medulloblastoma, and pilocytic astrocytoma were the most studied tumors with algorithm accuracies ranging from 37.5% to 94.5%. A minority of studies compared the developed algorithm to a trained neuroradiologist, with three imaging-based algorithms yielding superior performance. Common algorithm and study limitations included small sample sizes, uneven representation of individual tumor types, inconsistent performance reporting, and a lack of application in the clinical environment. Conclusions: Artificial intelligence has the potential to improve the speed and accuracy of diagnosis in this field if the right algorithm is applied to the right scenario. Work is needed to standardize outcome reporting and facilitate additional trials to allow for clinical uptake.

Neuroblastoma is a pediatric tumor of the adrenergic sympathetic lineage. Most high risk neuroblastoma go in complete clinical remission by chemotherapy, which is subsequently complemented by retinoic acid (RA) maintenance therapy. However, by unresolved mechanisms most tumors ultimately relapse as therapy-resistant disease. Neuroblastoma cell lines were recently found to include, besides lineage committed adrenergic (ADRN) tumor cells, also immature mesenchymal (MES) tumor cells. Here, we report that MES-type cells synthesize RA and require this metabolite for proliferation and motility. MES cells are even resistant to RA in vitro. MES cells appear to resemble Schwann Cell Precursors (SCP), which are motile precursors of the adrenergic lineage. MES and SCP cells express shared RA-synthesis and RA-target genes. Endogenous RA synthesis and RA resistance thus stem from normal programs of lineage precursors that are maintained in an immature tumor cell fraction. These cells are fully malignant in orthotopic patient-derived xenograft models and may mediate development of drug-resistant relapses.

Data from a drilling campaign in Malaysia reveal that mud loss severity is linked to the downhole mud weight exceeding the reactivation pressure of the faults penetrated.

We present a deep recurrent convolutional neural network (CNN) approach to solve the problem of hockey player identification in NHL broadcast videos. Player identification is a difficult computer vision problem mainly because of the players’ similar appearance, occlusion, and blurry facial and physical features. However, we can observe players’ jersey numbers over time by processing variable length image sequences of players (aka ‘tracklets’). We propose an end-to-end trainable ResNet+LSTM network, with a residual network (ResNet) base and a long short-term memory (LSTM) layer, to discover spatio-temporal features of jersey numbers over time and learn long-term dependencies. Additionally, we employ a secondary 1-dimensional convolutional neural network classifier as a late score-level fusion method to classify the output of the ResNet+LSTM network. For this work, we created a new hockey player tracklet dataset that contains sequences of hockey player bounding boxes. This achieves an overall player identification accuracy score over 87% on the test split of our new dataset.

Background The efficacy of multi-domain interventions for dementia prevention has been investigated in a few large randomized controlled trials (RCT). To link research to community action, we evaluated the implementation and effectiveness of a community-based multi-domain program for older adults at risk of cognitive impairment. Methods Three enterprises implemented a 24-week, bi-weekly, multi-domain program for older adults at risk of cognitive impairment through neighborhood senior centres (SCs). The program comprised a combination of dual-task group physical exercise, pen-and-paper cognitive games, computerised cognitive training, and mobile application-based personalized nutritional guidance. An effectiveness-implementation hybrid design using a RCT design and informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework was adopted to evaluate the program. Cognition and quality of life were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and EuroQol EQ-5D-5L (EQ-5D) respectively, at baseline and 24-weeks. Blood lipid panel and physical assessments were also conducted. Questionnaires on implementation outcomes were administered at the participants-, provider- and community-levels to participants, implementers, and SC managers. Program schedules and attendance were obtained from implementers and the research team conducted unannounced, random and non-intrusive observations of the program. Results The intervention program reached almost 50% of eligible participants, had an attrition rate of 22%, and was adopted by 8.7% of the SCs approached. The intervention was implemented as intended, except the nutritional component that was re-designed due to participants’ unfamiliarity with the application. There were no between-group differences in cognition, quality of life, and blood lipid panel, though there was a reduction in quality of life in the control group and improved physical function in the intervention group at 24-weeks. Intervention group participants reported improvement in their physical and cognitive functions. The program was well-received by participants and centre managers, who wanted the intervention to continue post-study. Conclusions A six-month multi-domain program for older adults at risk of cognitive impairment can be implemented through neighborhood SCs and elicit improvement in physical but not cognitive performance. Implementation evaluation highlight areas to improve on the uptake of such community-based interventions. Trial registration Trial registration: ClinicalTrials.gov NCT04440969. Registered 22 June 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04440969

CASE A 63-year-old woman with a history of a malunited distal radius fracture presented with left hand pain and inability to flex her thumb, index, and middle fingers. Anterior interosseous neuropathy was suggested because of abnormal electromyography findings. However, magnetic resonance imaging later revealed flexor tendon ruptures. A distal radius corrective osteotomy with autograft and volar fixation was performed with tendon transfers and carpal tunnel release. CONCLUSIONS Attritional flexor tendon rupture after a nonoperatively managed distal radius fracture is rare but remains an important differential diagnosis in patients with signs and symptoms of anterior interosseous nerve paralysis.

Surgical site infection (SSI) following spine surgery causes major morbidity and greatly impedes functional recovery. In the modern era of advanced operative techniques and improved perioperative care, SSI remains a problematic complication that may be reduced with institutional practices. The objectives of this study were to 1) characterize the SSI rate and microbial etiology following spine surgery for various thoracolumbar diseases, and 2) identify risk factors that were associated with SSI despite current perioperative management.All patients treated with thoracic or lumbar spine operations on the neurosurgery service at the University of California, San Francisco from April 2012 to April 2016 were formally reviewed for SSI using the National Healthcare Safety Network (NHSN) guidelines. Preoperative risk variables included age, sex, BMI, smoking, diabetes mellitus (DM), coronary artery disease (CAD), ambulatory status, history of malignancy, use of preoperative chlorhexidine gluconate (CHG) showers, and the American Society of Anesthesiologists (ASA) classification. Operative variables included surgical pathology, resident involvement, spine level and surgical technique, instrumentation, antibiotic and steroid use, estimated blood loss (EBL), and operative time. Multivariable logistic regression was used to evaluate predictors for SSI. Odds ratios and 95% confidence intervals were reported.In total, 2252 consecutive patients underwent thoracolumbar spine surgery. The mean patient age was 58.6 ± 13.8 years and 49.6% were male. The mean hospital length of stay was 6.6 ± 7.4 days. Sixty percent of patients had degenerative conditions, and 51.9% underwent fusions. Sixty percent of patients utilized presurgery CHG showers. The mean operative duration was 3.7 ± 2 hours, and the mean EBL was 467 ± 829 ml. Compared to nonfusion patients, fusion patients were older (mean 60.1 ± 12.7 vs 57.1 ± 14.7 years, p0.001), were more likely to have an ASA classificationII (48.0% vs 36.0%, p0.001), and experienced longer operative times (252.3 ± 120.9 minutes vs 191.1 ± 110.2 minutes, p0.001). Eleven patients had deep SSI (0.49%), and the most common causative organisms were methicillin-sensitive Staphylococcus aureus and methicillin-resistant S. aureus. Patients with CAD (p = 0.003) or DM (p = 0.050), and those who were male (p = 0.006), were predictors of increased odds of SSI, and presurgery CHG showers (p = 0.001) were associated with decreased odds of SSI.This institutional experience over a 4-year period revealed that the overall rate of SSI by the NHSN criteria was low at 0.49% following thoracolumbar surgery. This was attributable to the implementation of presurgery optimization, and intraoperative and postoperative measures to prevent SSI across the authors’ institution. Despite prevention measures, having a history of CAD or DM, and being male, were risk factors associated with increased SSI, and presurgery CHG shower utilization decreased SSI risk in patients.ASA = American Society of Anesthesiologists; CAD = coronary artery disease; CHG = chlorhexidine gluconate; CI = confidence interval; DM = diabetes mellitus; EBL = estimated blood loss; LOS = length of stay; MIS = minimally invasive surgery; MRSA = methicillin-resistant Staphylococcus aureus; MRSE = methicillin-resistant Staphylococcus epidermidis; MSSA = methicillin-sensitive S. aureus; MSSE = methicillin-sensitive S. epidermidis; NHSN = National Healthcare Safety Network; OR = odds ratio; SSI = surgical site infection.

Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states., Neuroblastoma includes adrenergic and mesenchymal cell types that can interconvert. Here, the authors show that this transdifferentiation is driven by a NOTCH feedforward loop that allows a swift transition between two semi-stable cellular states.