Search

PurposeConventional staging methods are inadequate to identify patients with stage II colon cancer (CC) who are at high risk of recurrence after surgery with curative intent. ColDx is a gene expression, microarray-based assay shown to be independently prognostic for recurrence-free interval (RFI) and overall survival in CC. The objective of this study was to further validate ColDx using formalin-fixed, paraffin-embedded specimens collected as part of the Alliance phase III trial, C9581.Patients and methodsC9581 evaluated edrecolomab versus observation in patients with stage II CC and reported no survival benefit. Under an initial case-cohort sampling design, a randomly selected subcohort (RS) comprised 514 patients from 901 eligible patients with available tissue. Forty-nine additional patients with recurrence events were included in the analysis. Final analysis comprised 393 patients: 360 RS (58 events) and 33 non-RS events. Risk status was determined for each patient by ColDx. The Self-Prentice method was used to test the association between the resulting ColDx risk score and RFI adjusting for standard prognostic variables.ResultsFifty-five percent of patients (216 of 393) were classified as high risk. After adjustment for prognostic variables that included mismatch repair (MMR) deficiency, ColDx high-risk patients exhibited significantly worse RFI (multivariable hazard ratio, 2.13; 95% CI, 1.3 to 3.5; P < .01). Age and MMR status were marginally significant. RFI at 5 years for patients classified as high risk was 82% (95% CI, 79% to 85%), compared with 91% (95% CI, 89% to 93%) for patients classified as low risk.ConclusionColDx is associated with RFI in the C9581 subsample in the presence of other prognostic factors, including MMR deficiency. ColDx could be incorporated with the traditional clinical markers of risk to refine patient prognosis.

Disciplines have emerged as an alternative administrative structure to departments or schools in Australian universities. We presently investigate the pattern of discipline use and by way of case study examine a role for distributed leadership in discipline management. Over forty per cent of Australian universities currently employ disciplines, especially within faculties of sciences, engineering and medicine. No trend is observed according to institutional age, state, or historical origins. Effective planning, retention of corporate knowledge and good communication are important during the transition period. Moreover, it is vital that professional staff continue to work closely alongside academics as extended members of the discipline. Distributed leadership encourages this interaction. The duties of a discipline leader can be similar to those faced by a head of department. Universities should therefore establish clear policies, position descriptions and appropriate remuneration packages in order to recruit, train and retain staff within this emerging academic management role.

Abstract Histological ‘phenotypic subtypes’ that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I–III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I–III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease‐free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II–III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893‐patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p

Abstract Background The University College Dublin (UCD) Public and Patient Invovlement (PPI) ignite program is focused on embedding PPI in health and social care related research, education and training, professional practice and administration. During a PPI knowledge sharing event challenges were noted during the pre-commencement stage of research projects. This stage includes the time before a research projects/partnership starts or when funding is being applied for. As a response, we agreed there was a need to spend time developing a values-based approach to be used from the pre-commencement of PPI projects and partnerships. Values are deeply held ideals that people consider to be important. They are vital in shaping our attitudes and motivating our choices and behaviours. Methods Using independent facilitators, we invited a diverse group of participants to a full-day workshop in February. During the workshop, the concept of a values statement and values-based approaches was introduced. The group via a majority consensus, agreed on a core set of values and a shared understanding of them. After the workshop, a draft was shared with participants for further comment and final agreement. Results The workshop had 22 people representing experts by experience, PPI charity partners, funders, academics and national PPI Ignite partners. The group via consensus identified four values of respect, openness, reciprocity and flexibility for the pre-commencement stage. A frequently reported experience of PPI partners was that some felt that the pre-commencement activities appeared at times like a performance; an act that had to be completed in order to move to the next stage rather than a genuine interest in a mutually beneficial partnership. Being open and transparent with all invovled that the funding application may not be successful was stressed. Another important feature related to ‘openness’ was the ‘spaces’ and ‘places’ in which meetings between partners could occur in an accessible and equitable way. The issue of ‘space’ is particularly critical for the involvement of seldom heard groups. The benefits of the research are often clear for academics, but for PPI partners, these are often less certain. To achieve reciprocity, academic and PPI partners need to engage in a timely, repeated and transparent dialogue to achieve beneficial outcomes for all stakeholders. Being open to new inputs and differing modes of knowledge and ideas was also stressed. For some, this will require a change in attitudes and behaviours and should result in more collective decision making. Several areas were identified using the four values. Conclusions This work via majority consensus identified four values of respect, openness, reciprocity, and flexibility for the pre-commencement stage. These values should be used to support inclusive, effective and collective PPI across all stages of involvement. We hope this work will stimulate further action in this area. In particular, we would welcome the evaluation of these values involving diverse PPI groups.

Abstract Background This study represents the first Scottish retrospective analysis of the microbiology of diabetic foot infections (DFIs). The aims were to compare the microbiological profile of DFIs treated at a Scottish tertiary hospital to that in the literature, gather data regarding antimicrobial resistance and investigate potential trends between the microbiological results and nature or site of the clinical sample taken and age or gender of the patients. Methods A retrospective analysis of wound microbiology results was performed, data were obtained from one multidisciplinary outpatient foot clinic during the 12 months of the year 2017. Seventy-three patients and 200 microbiological investigations were included. In cases of soft tissue infection, the deepest part of a cleansed and debrided wound was sampled. In cases of osteomyelitis a bone biopsy was obtained. Factors influencing the pattern of microbial growth or prevalence of Staphylococcus aureus were investigated. Results Of the 200 microbiological investigations, 62% were culture positive, of which 37.9% were polymicrobial and 62.1% monomicrobial. Among the monomicrobial results (n = 77), most were Gram positive isolates (96.1%) and the most frequently isolated bacteria was S. aureus (84.4%). No methicillin-resistant S. aureus was reported. The prevalence of S. aureus in DFIs was associated with increasing age (p = 0.021), but no evidence of association with gender, anatomical sample site or sample material was found. Conclusion The microbiological profile of DFIs in Scotland resembles that reported elsewhere in the UK. In this context, Gram positive organisms, primarily S. aureus, are most frequently isolated from DFIs. The S. aureus isolates identified were largely susceptible to antibiotic therapy. An association between increasing patient age and the prevalence of S. aureus in DFIs was observed.

The primary motor cortex (M1) is known to be a critical site for movement initiation and motor learning. Surprisingly, it has also been shown to possess reward-related activity, presumably to facilitate reward-based learning of new movements. However, whether reward-related signals are represented among different cell types in M1, and whether their response properties change after cue–reward conditioning remains unclear. Here, we performed longitudinal in vivo two-photon Ca2+ imaging to monitor the activity of different neuronal cell types in M1 while mice engaged in a classical conditioning task. Our results demonstrate that most of the major neuronal cell types in M1 showed robust but differential responses to both the conditioned cue stimulus (CS) and reward, and their response properties undergo cell-type-specific modifications after associative learning. PV-INs’ responses became more reliable to the CS, while VIP-INs’ responses became more reliable to reward. Pyramidal neurons only showed robust responses to novel reward, and they habituated to it after associative learning. Lastly, SOM-INs’ responses emerged and became more reliable to both the CS and reward after conditioning. These observations suggest that cue- and reward-related signals are preferentially represented among different neuronal cell types in M1, and the distinct modifications they undergo during associative learning could be essential in triggering different aspects of local circuit reorganization in M1 during reward-based motor skill learning.

Two theoretical perspectives have been proffered to explain changes in alcohol use during the pandemic: the 'affordability-availability' mechanism (i.e., drinking decreases due to changes in physical availability and/or reduced disposable income) and the 'psychological-coping' mechanism (i.e., drinking increases as adults attempt to cope with pandemic-related distress). We tested these alternative perspectives via longitudinal analyses of the COVID-19 Psychological Consortium (C19PRC) Study data (spanning three timepoints during March to July 2020). Respondents provided data on psychological measures (e.g., anxiety, depression, posttraumatic stress, paranoia, extraversion, neuroticism, death anxiety, COVID-19 anxiety, intolerance of uncertainty, resilience), changes in socio-economic circumstances (e.g., income loss, reduced working hours), drinking motives, solitary drinking, and 'at-risk' drinking (assessed using a modified version of the AUDIT-C). Structural equation modelling was used to determine (i) whether 'at-risk' drinking during the pandemic differed from that recalled before the pandemic, (ii) dimensions of drinking motives and the psychosocial correlates of these dimensions, (iii) if increased alcohol consumption was predicted by drinking motives, solitary drinking, and socio-economic changes. The proportion of adults who recalled engaging in 'at-risk' drinking decreased significantly from 35.9% pre-pandemic to 32.0% during the pandemic. Drinking to cope was uniquely predicted by experiences of anxiety and/or depression and low resilience levels. Income loss or reduced working hours were not associated with coping, social enhancement, or conformity drinking motives, nor changes in drinking during lockdown. In the earliest stage of the pandemic, psychological-coping mechanisms may have been a stronger driver to changes in adults' alcohol use than 'affordability-availability' alone.

Nanomedicine is currently focused on the design and development of nanocarriers that enhance drug delivery to the brain to address unmet clinical needs for treating neuropsychiatric disorders and neurological diseases. Polymer and lipid-based drug carriers are advantageous for delivery to the central nervous system (CNS) due to their safety profiles, drug-loading capacity, and controlled-release properties. Polymer and lipid-based nanoparticles (NPs) are reported to penetrate the blood–brain barrier (BBB) and have been extensively assessed in in vitro and animal models of glioblastoma, epilepsy, and neurodegenerative disease. Since approval by the Food and Drug Administration (FDA) of intranasal esketamine for treatment of major depressive disorder, intranasal administration has emerged as an attractive route to bypass the BBB for drug delivery to the CNS. NPs can be specifically designed for intranasal administration by tailoring their size and coating with mucoadhesive agents or other moieties that promote transport across the nasal mucosa. In this review, unique characteristics of polymeric and lipid-based nanocarriers desirable for drug delivery to the brain are explored in addition to their potential for drug repurposing for the treatment of CNS disorders. Progress in intranasal drug delivery using polymeric and lipid-based nanostructures for the development of treatments of various neurological diseases are also described.

Abstract Background Interleukin-33 (IL-33) belongs to the IL-1 cytokine family and resides in the nuclei of various cell types. In the neural retina, IL-33 is predominately expressed in Müller cells although its role in health and disease is ill-defined. Müller cell gliosis is a critical response during the acute phase of retinal detachment (RD), and in this study, we investigated if IL-33 was modulatory in the inflammatory and neurodegenerative pathology which is characteristic of this important clinical condition. Methods RD was induced by subretinal injection of sodium hyaluronate into C57BL/6 J (WT) and IL-33 −/− mice and confirmed by fundus imaging and optical coherence tomography (OCT). The expression of inflammatory cytokines, complement components and growth factors was examined by RT-PCR. Retinal neurodegeneration, Müller cell activation and immune cell infiltration were assessed using immunohistochemistry. The expression of inflammatory cytokines in primary Müller cells and bone marrow-derived macrophages (BM-DMs) was assessed by RT-PCR and Cytometric Bead Array. Results RD persisted for at least 28 days after the injection of sodium hyaluronate, accompanied by significant cone photoreceptor degeneration. The mRNA levels of CCL2, C1ra, C1s, IL-18, IL-1β, TNFα, IL-33 and glial fibrillary acidic protein (GFAP) were significantly increased at day 1 post-RD, reduced gradually and, with the exception of GFAP and C1ra, returned to the basal levels by day 28 in WT mice. In IL-33 −/− mice, RD induced an exacerbated inflammatory response with significantly higher levels of CCL2, IL-1β and GFAP when compared to WT. Sustained GFAP activation and immune cell infiltration was detected at day 28 post-RD in IL-33 −/− mice. Electroretinography revealed a lower A-wave amplitude at day 28 post-RD in IL-33 −/− mice compared to that in WT RD mice. IL-33 −/− mice subjected to RD also had significantly more severe cone photoreceptor degeneration compared to WT counterparts. Surprisingly, Müller cells from IL-33 −/− mice expressed significantly lower levels of CCL2 and IL-6 compared with those from WT mice, particularly under hypoxic conditions, whereas IL-33 −/− bone marrow-derived macrophages expressed higher levels of inducible nitric oxide synthase, TNFα, IL-1β and CCL2 after LPS + IFNγ stimulation compared to WT macrophages. Conclusion IL-33 deficiency enhanced retinal degeneration and gliosis following RD which was related to sustained subretinal inflammation from infiltrating macrophages. IL-33 may provide a previously unrecognised protective response by negatively regulating macrophage activation following retinal detachment.

Accumulating clinical evidence shows that psychedelic therapy, by synergistically combining psychopharmacology and psychological support, offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and/or maladaptive habitual patterns of emotion, cognition and behavior, notably, depression (MDD), treatment resistant depression (TRD) and addiction disorders, but perhaps also anxiety disorders, obsessive-compulsive disorder (OCD), Post-Traumatic Stress Disorder (PTSD) and eating disorders. Despite the emergent transdiagnostic evidence, the specific clinical dimensions that psychedelics are efficacious for, and associated underlying neurobiological pathways, remain to be well-characterized. To this end, this review focuses on pre-clinical and clinical evidence of the acute and sustained therapeutic potential of psychedelic therapy in the context of a transdiagnostic dimensional systems framework. Focusing on the Research Domain Criteria (RDoC) as a template, we will describe the multimodal mechanisms underlying the transdiagnostic therapeutic effects of psychedelic therapy, traversing molecular, cellular and network levels. These levels will be mapped to the RDoC constructs of negative and positive valence systems, arousal regulation, social processing, cognitive and sensorimotor systems. In summarizing this literature and framing it transdiagnostically, we hope we can assist the field in moving toward a mechanistic understanding of how psychedelics work for patients and eventually toward a precise-personalized psychedelic therapy paradigm.

This article is an auto-ethnography detailing the lived experience of the mainstreaming, Regular Education Initiative, and inclusion movements from the teacher and administrator perspectives. The article illustrates the challenges of integrating students with disabilities in general education and the sociopolitical contexts within which this occurred. A number of factors are necessary to successfully facilitate inclusion and inclusive schooling. These include an understanding of schools as social systems, institutional and administrative authorization and leadership, collaboration and partnerships, and professional development. The implications of institutional and administrative authorization and inclusive practices have significant implications for teacher education and inclusive schooling.

Background Electric scooters (e-scooters) have become a widespread method of transportation due to convenience and affordability. However, the financial impact of medical care for sustained injuries is currently unknown. The purpose of this study is to characterize total billing charges associated with medical care of e-scooter injuries.Methods A retrospective review of patients with e-scooter injuries presenting to the trauma bay, emergency department or outpatient clinics at an urban level 1 trauma center was conducted from November 2017 to March 2020. Demographic and clinical data were collected. Primary outcomes of interest were total billing charges and billing to insurance (hospital and professional). Multivariable models were used to identify preventable risk factors associated with higher total billing charges.Results A total of 63 patients were identified consisting of 42 (66.7%) males, average age 40.19 (SD 13.29) years and 3.2% rate of helmet use. Patients sustained orthopedic (29%, n=18), facial (48%, n=30) and cranial (23%, n=15) injuries. The average total billing charges for e-scooter clinical encounters was $95 710 (SD $138 215). Average billing to insurance was $86 376 (SD $125 438) for hospital charges and $9 334 (SD $14 711) for professional charges. There were no significant differences in charges between injury categories. On multivariable regression, modifiable risk factors independently associated with higher total billing charges included any intoxication prior to injury ($231 377 increase, p=0.02), intracranial bleeds ($75 528, p=0.04) and TBI ($360 898, p=0.006).Discussion Many patients sustain high-energy injuries during e-scooter accidents with significant medical and financial consequences. Further studies may continue expanding the financial impact of e-scooter injuries on both patients and the healthcare system.Level of evidence III

In this work, antistatic, high-performance composites of poly (ether ether ketone) (PEEK) and concentrations of 0.5–7 vol% expanded graphite (EG) were fabricated via twin-screw extrusion and injection moulding at mould temperatures of 200°C. The morphological, electrical, rheological, thermal, mechanical, and wear properties of the composites were investigated. Scanning electron microscope (SEM) images indicate that distribution and dispersion of EG platelets in the PEEK matrix are enhanced at higher EG loadings. The electrical conductivity of the composites with 5 vol% of EG exhibits a sharp rise in the electrical conductivity range of antistatic materials because of the formation of conductive paths. The formation of a three-dimensional EG network led to a rapid increase in the storage modulus of the melt of the 2 vol% of EG-loaded composite at a frequency of 0.1 rad/s and temperature of 370°C. The neat PEEK and composites containing 0.5–5 vol% EG indicated a cold-crystallisation peak in the first heating scan of a non-isothermal differential scan calorimetry (DSC) test and their crystallinity degrees changed slightly. However, after removing their thermal and stress histories, the EG platelets promoted nucleation and increased the PEEK crystallinity remarkably, indicating that annealing of the PEEK composites can improve their mechanical performance. The neat PEEK exhibits the standard tensile and flexural stress-strain behaviour of thermoplastics, and the composites exhibit elastic behaviour initially followed by a weak plastic deformation before fracture. The addition of 5 vol% of EG to PEEK increased the tensile and flexural modulus from 3.84 and 3.55 GPa to 4.15 and 4.40 GPa, decreased the strength from 96.73 and 156.41 MPa to 62 and 118.19 MPa, and the elongation at break from 27.09 and 12.9% to 4 and 4.6%, respectively. The wear resistance of the composite containing 3 vol% EG was enhanced by 37% compared with the neat PEEK.

In this study, PEEK nanocomposites with 0, 0.5, 1, and 2wt% IF-WS2 were manufactured by injection moulding and Fused Deposition Modelling (FDM). To compare the impact of the two processing methods and the incorporated nanoparticles on the morphology, crystallization and final mechanical properties of the nanocomposites, SEM, DSC and tensile testing were performed. In general, a good distribution of nanoparticles was observed in PEEK, although larger agglomerates were visible at 2 wt% IF-WS2. The crystallization degree of PEEK increased with increasing loading of IF-WS2 nanoparticles up to 1wt% and then declined at 2 wt%, due to lower level of particle dispersion in this sample. The 3D printed samples showed slightly higher crystallinity at each IF-WS2 loading in relation to the injection moulded samples and extruded filaments, because of multiple reheating effect from subsequent layer deposition during FDM, causing recrystallization. In general, incorporation of IF-WS2 nanoparticles increased the mechanical properties of pure PEEK in both 3D printed and injection moulded samples. However, this increment was more noticeable in the 3D-printed nanocomposite samples, resulting in smaller gap between the mechanical properties of the 3D-printed samples and the injection moulded counterparts, in respect to pure PEEK, particularly at 1 wt% IF-WS2. This effect is ascribed to the increased inter-layer bonding of PEEK in the presence of IF-WS2 nanoparticles in FDM. In general, the lower mechanical properties of the 3D printed samples compared with the injection moulded ones are ascribed to poor interlayer bonding between the deposited layers and the presence of voids. However, addition of just 1 wt% of IF-WS2 nanoparticles into PEEK increased the tensile strength and Young’s modulus of the FDM PEEK materials to similar levels to those achieved for unfilled injection moulded PEEK. Therefore, incorporation of IF-WS2 nanoparticles into PEEK is a useful strategy to improve the mechanical performance of FDM PEEK.