Improving mental health outcomes: achieving equity through quality improvement

Objective. To investigate equity of patient outcomes in a psychological therapy service, following increased access achieved by a quality improvement (QI) initiative. Design. Retrospective service evaluation of health outcomes; data analysed by ANOVA, chi-squared and Statistical Process Control. Setting. A psychological therapy service in Westminster, London, UK. Participants. People living in the Borough of Westminster, London, attending the service (from either healthcare professional or self-referral) between February 2009 and May 2012. Intervention(s). Social marketing interventions were used to increase referrals, including the promotion of the service through local media and through existing social networks. Main Outcome Measure(s). (i) Severity of depression on entry using Patient Health Questionnaire-9 (PHQ9). (ii) Changes to severity of depression following treatment (ΔPHQ9). (iii) Changes in attainment of a meaningful improvement in condition assessed by a key performance indicator. Results. Patients from areas of high deprivation entered the service with more severe depression (M = 15.47, SD = 6.75), com-pared with patients from areas of low (M = 13.20, SD = 6.75) and medium (M = 14.44, SD = 6.64) deprivation. Patients in low

An Automated Process for 2D and 3D Finite Element Overclosure and Gap Adjustment using Radial Basis Function Networks

In biomechanics, geometries representing complicated organic structures are consistently segmented from sparse volumetric data or morphed from template geometries resulting in initial overclosure between adjacent geometries. In FEA, these overclosures result in numerical instability and inaccuracy as part of contact analysis. Several techniques exist to fix overclosures, but most suffer from several drawbacks. This work introduces a novel automated algorithm in an iterative process to remove overclosure and create a desired minimum gap for 2D and 3D finite element models. The RBF Network algorithm was introduced by its four major steps to remove the initial overclosure. Additionally, the algorithm was validated using two test cases against conventional nodal adjustment. The first case compared the ability of each algorithm to remove differing levels of overclosure between two deformable muscles and the effects on mesh quality. The second case used a non-deformable femur and deformable distal femoral cartilage geometry with initial overclosure to test both algorithms and observe the effects on the resulting contact FEA. The RBF Network in the first case study was successfully able to remove all overclosures. In the second case, the nodal adjustment method failed to create a usable FEA model, while the RBF Network had no such issue. This work proposed an algorithm to remove initial overclosures prior to FEA that has improved performance over conventional nodal adjustment, especially in complicated situations and those involving 3D elements. The work can be included in existing FEA modeling workflows to improve FEA results in situations involving sparse volumetric segmentation and mesh morphing. This algorithm has been implemented in MATLAB, and the source code is publicly available to download at the following GitHub repository: https://github.com/thor-andreassen/femorsComment: 26 Pages, 5 Figures, 2 Table

Cortical degeneration in chronic traumatic encephalopathy and Alzheimer's disease neuropathologic change

Objectives An observational study to compare the laminar distributions in frontal and temporal cortex of the tau-immunoreactive pathologies in chronic traumatic encephalopathy (CTE) and Alzheimer’s disease neuropathologic change (ADNC). Patients Post-mortem material of (1) four cases of CTE without ADNC, (2) seven cases of CTE with ADNC (CTE/ADNC), and (3) seven cases of ADNC alone. Results In CTE and CTE/ADNC, neurofibrillary tangles (NFT), neuropil threads (NT), and dot-like grains (DLG) were distributed either in upper cortex or across all layers. Low densities of astrocytic tangles (AT) and abnormally enlarged neurons (EN) were not localized to any specific layer. Surviving neurons exhibited peaks of density in both upper and lower cortex, and vacuole density was greatest in superficial layers. In ADNC, neuritic plaques (NP) were more frequent, AT rare, NFT and NT were more widely distributed, NT affected lower layers more frequently, and surviving neurons were less frequently bimodal than in CTE and CTE/ADNC. Conclusion Tau pathology in CTE and CTE/ADNC consistently affected the upper cortex but was more widely distributed in ADNC. The presence of CTE may encourage the development of ADNC pathology later in the course of the disease

Differential gene expression in the cortical sulcus compared to the gyral crest within the early stages of chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative tauopathy found in individuals with a history of repetitive head impacts (RHI). Previous work has demonstrated that neuroinflammation is involved in CTE pathogenesis, however, the specific inflammatory mechanisms are still unclear. Here, using RNA-sequencing and gene set enrichment analysis (GSEA), we investigated the genetic changes found in tissue taken from the region CTE pathology is first found, the cortical sulcus, and compared it to neighboring gryal crest tissue to identify what pathways were directly related to initial hyperphosphorylated tau (p-tau) deposition. 21 cases were chosen for analysis: 6 cases had no exposure to RHI or presence of neurodegenerative disease (Control), 5 cases had exposure to RHI but no presence of neurodegenerative disease (RHI), and 10 cases had exposure to RHI and low stage CTE (CTE). Two sets of genes were identified: genes that changed in both the sulcus and crest and genes that changed specifically in the sulcus relative to the crest. When examining genes that changed in both the sulcus and crest, GSEA demonstrated an increase in immune related processes and a decrease in neuronal processes in RHI and CTE groups. Sulcal specific alterations were observed to be driven by three mechanisms: anatomy, RHI, or p-tau. First, we observed consistent sulcal specific alterations in immune, extracellular matrix, vascular, neuronal, and endocytosis/exocytosis categories across all groups, suggesting the sulcus has a unique molecular signature compared to the neighboring crest independent of pathology. Second, individuals with a history of RHI demonstrated impairment in metabolic and mitochondrial related processes. Finally, in individuals with CTE, we observed impairment of immune and phagocytic related processes. Overall, this work provides the first observation of biological processes specifically altered in the sulcus that could be directly implicated in CTE pathogenesis and provide novel targets for biomarkers and therapies

Floating stones off El Hierro, Canary Islands: xenoliths of pre-island sedimentary origin in the early products of the October 2011 eruption

The eruption that started off the south coast of El Hierro, Canary Islands, in October 2011 has emitted intriguing eruption products found floating in the sea. These specimens appeared as floating volcanic "bombs" that have in the meantime been termed "restingolites" (after the close-by village of La Restinga) and exhibit cores of white and porous pumice-like material. Currently the nature and origin of these "floating stones" is vigorously debated among researchers, with important implications for the interpretation of the hazard potential of the ongoing eruption. The "restingolites" have been proposed to be either (i) juvenile high-silica magma (e.g. rhyolite), (ii) remelted magmatic material (trachyte), (iii) altered volcanic rock, or (iv) reheated hyaloclastites or zeolite from the submarine slopes of El Hierro. Here, we provide evidence that supports yet a different conclusion. We have collected and analysed the structure and composition of samples and compared the results to previous work on similar rocks found in the archipelago. Based on their high silica content, the lack of igneous trace element signatures, and the presence of remnant quartz crystals, jasper fragments and carbonate relicts, we conclude that "restingolites" are in fact xenoliths from pre-island sedimentary rocks that were picked up and heated by the ascending magma causing them to partially melt and vesiculate. They hence represent messengers from depth that help us to understand the interaction between ascending magma and crustal lithologies in the Canary Islands as well as in similar Atlantic islands that rest on sediment/covered ocean crust (e.g. Cape Verdes, Azores). The occurrence of these "restingolites" does therefore not indicate the presence of an explosive high-silica magma that is involved in the ongoing eruption

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies

Downregulation of miR-342 is associated with tamoxifen resistant breast tumors

<p>Abstract</p> <p>Background</p> <p>Tumor resistance to the selective estrogen receptor modulator tamoxifen remains a serious clinical problem especially in patients with tumors that also overexpress HER2. We have recently demonstrated that the clinically important isoform of HER2, HERΔ16, promotes therapeutically refractory breast cancer including resistance to endocrine therapy. Likewise additional breast tumor cell models of tamoxifen resistance have been developed that do not involve HER2 overexpression. However, a unifying molecular mechanism of tamoxifen resistance has remained elusive.</p> <p>Results</p> <p>Here we analyzed multiple cell models of tamoxifen resistance derived from MCF-7 cells to examine the influence of microRNAs (miRNAs) on tamoxifen resistance. We compared miRNA expression profiles of tamoxifen sensitive MCF-7 cells and tamoxifen resistant MCF-7/HER2Δ16 cells. We observed significant and dramatic downregulation of miR-342 in the MCF-7/HER2Δ16 cell line as well as the HER2 negative but tamoxifen resistant MCF-7 variants TAMR1 and LCC2. Restoring miR-342 expression in the MCF-7/HER2Δ16 and TAMR1 cell lines sensitized these cells to tamoxifen-induced apoptosis with a dramatic reduction in cell growth. Expression of miR-342 was also reduced in a panel of tamoxifen refractory human breast tumors, underscoring the potential clinical importance of miR-342 downregulation. Towards the goal of identifying direct and indirect targets of miR-342 we restored miR-342 expression in MCF-7/HER2Δ16 cells and analyzed changes in global gene expression by microarray. The impact of miR-342 on gene expression in MCF-7/HER2Δ16 cells was not limited to miR-342 <it>in silica </it>predicted targets. Ingenuity Pathways Analysis of the dataset revealed a significant influence of miR-342 on multiple tumor cell cycle regulators.</p> <p>Conclusions</p> <p>Our findings suggest that miR-342 regulates tamoxifen response in breast tumor cell lines and our clinical data indicates a trend towards reduced miR-342 expression and tamoxifen resistance. In addition, our results suggest that miR-342 regulates expression of genes involved in tamoxifen mediated tumor cell apoptosis and cell cycle progression. Restoring miR-342 expression may represent a novel therapeutic approach to sensitizing and suppressing the growth of tamoxifen refractory breast tumors.</p

Pilot trial of paclitaxel-trastuzumab adjuvant therapy for early stage breast cancer: a trial of the ECOG-ACRIN cancer research group (E2198)

BACKGROUND: Blockade of human epidermal growth factor receptor type 2 (HER2) has dramatically improved outcome for patients with HER2-positive breast cancer. Trastuzumab, an anti-HER2 monoclonal antibody, has previously demonstrated improvement in overall survival (OS) in patients with metastatic and early stage HER2-positive breast cancer. However, trastuzumab can cause congestive heart failure (CHF) with an increased frequency for patients who have also received an anthracycline. The current trial was designed to evaluate the impact of the duration of trastuzumab on CHF. METHODS: E2198 included 227 eligible women with histologically confirmed stage II or IIIA HER2-positive breast cancer. The patients were randomised to receive 12 weeks of paclitaxel and trastuzumab followed by four cycles of doxorubicin and cyclophosphamide (abbreviated Arm) or the aforementioned treatment with additional 1 year of trastuzumab (conventional Arm). The primary end point was to evaluate the safety of this variable duration of trastuzumab therapy, particularly cardiac toxicity defined as CHF or left ventricular ejection fraction decrease >10%. Secondary end points included disease-free survival (DFS) and OS. RESULTS: Compared with 12-week treatment with trastuzumab, 1 year of trastuzumab-based therapy did not increase the frequency or severity of cardiac toxicity: three patients on the abbreviated Arm and four on the conventional Arm experienced CHF. The 5-year DFS was 76% and 73% for the abbreviated and conventional Arms, respectively, with a hazard ratio (HR) of 1.3 (95% CI: 0.8-2.1; P=0.3). There was also no statistically significance difference in OS (HR, 1.4; P=0.3). CONCLUSIONS: Compared with 12 weeks of treatment, 1 year of treatment with trastuzumab did not significantly increase the risk of cardiac toxicity. Although not powered for efficacy comparisons, the longer duration of trastuzumab therapy did not demonstrate a signal for marked superiority

Energy is required for maximal adherence of Neisseria gonorrhoeae to phagocytic and nonphagocytic cells.

The possibility that gonococcal energy might play a role in the interaction of Neisseria gonorrhoeae with both phagocytic and nonphagocytic cells was examined. Respiratory chain inhibitors including KCN and amobarbital resulted in reduction in gonococcal association with human neutrophils. Similar results were seen with HeLa cells and the human promyelocytic (HL-60) cell line. Identical conditions did not affect the opsonindependent association of Staphylococcus aureus with the same cell types. New protein synthesis by gonococci did not account for the observed reduction in association. These results suggest that energy is needed for maximal opsonin-independent association of gonococci with mammalian cells

Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football

IMPORTANCE: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). OBJECTIVE: To determine the neuropathological and clinical features of deceased football players with CTE. DESIGN, SETTING, AND PARTICIPANTS: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. EXPOSURES: Participation in American football at any level of play. MAIN OUTCOMES AND MEASURES: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. RESULTS: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. CONCLUSIONS AND RELEVANCE: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.This study received support from NINDS (grants U01 NS086659, R01 NS078337, R56 NS078337, U01 NS093334, and F32 NS096803), the National Institute on Aging (grants K23 AG046377, P30AG13846 and supplement 0572063345-5, R01 AG1649), the US Department of Defense (grant W81XWH-13-2-0064), the US Department of Veterans Affairs (I01 CX001038), the Veterans Affairs Biorepository (CSP 501), the Veterans Affairs Rehabilitation Research and Development Traumatic Brain Injury Center of Excellence (grant B6796-C), the Department of Defense Peer Reviewed Alzheimer’s Research Program (grant 13267017), the National Operating Committee on Standards for Athletic Equipment, the Alzheimer’s Association (grants NIRG-15-362697 and NIRG-305779), the Concussion Legacy Foundation, the Andlinger Family Foundation, the WWE, and the NFL