bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving capacity and consent to treatment recording in psychiatric inpatient wards: A multi-centre quality improvement project
Authors: Li Ching , Stellman Judith , Patel Nitisha , Dalton Florence 
Published: December 2016

Assessment of mental capacity provides an ethical and legal framework for care which values patients' autonomy whilst recognising the instances where it is appropriate to act in patients' best interests.Existing medical literature indicates that mental capacity is poorly documented in psychiatric inpatient settings. The aim of the project was to examine the frequency of capacity and consent to treatment documentation with a view to creating changes in practice by raising awareness about the importance of assessing and documenting mental capacity.A multi-centre quality improvement project was conducted in September 2014 across all general adult psychiatric inpatient wards in the North Central London Training Scheme. The frequency of documentation of capacity and consent to treatment for all adult psychiatric inpatient wards across North Central London was measured.Electronic patient notes were audited retrospectively to ascertain whether capacity and consent to treatment on admission, and within the preceding seven days of data collection, was recorded. Data was collected across three successive time points during a 12 month period following the implementation of changes. A total of 232 patients were included in the baseline measurements. The results highlighted a deficiency in the recording of capacity and consent to treatment for adult psychiatric inpatients. The results showed that, of the patients audited, 49.8% had their capacity and consent to treatment assessed on admission, 61.9% had a capacity assessment in the previous 7 days and 60.5% had consent recorded in the previous 7 days. These findings were presented at local hospital teaching sessions at each of the audited sites. These sessions also gave teaching on mental capacity. Audit cycle 1 was conducted 6 months later, this included 213 patients and showed a 30% improvement in the frequency of documentation across all measures. The results showed that 77% of patients audited had their capacity and consent assessed on admission to the ward, 87.3% had a capacity assessment in the previous 7 days and 85.5% had consent recorded in the previous 7 days. After feedback from the teaching sessions, a clerking proforma was produced that had a prompt to assess to capacity. Audit cycle 2 was conducted 12 months after the initial baseline measurements, had a sample size of 229 patients and a sustained improvement in documentation of 26% from baseline was demonstrated across all measures.This project demonstrated that capacity and consent to treatment was not routinely recorded but that the frequency of recording improved through the use of teaching sessions on mental capacity and the introduction of admission clerking proformas with capacity prompts.
Using the Safer Clinical Systems approach and Model for Improvement methodology to decrease Venous Thrombo-Embolism in Elective Surgical Patients
Authors: Humphries Angela , Peden Carol , Jordan Lesley , Crowe Josephine , Peden Carol 
Published: December 2016

A significant incidence of post-procedural deep vein thrombosis (DVT) and pulmonary embolus (PE) was identified in patients undergoing surgery at our hospital. Investigation showed an unreliable peri-operative process leading to patients receiving incorrect or missed venous thromboembolism (VTE) prophylaxis. The Trust had previously participated in a project funded by the Health Foundation using the “Safer Clinical Systems” methodology to assess, diagnose, appraise options, and implement interventions to improve a high risk medication pathway. We applied the methodology from that study to this cohort of patients demonstrating that the same approach could be applied in a different context.Interventions were linked to the greatest hazards and risks identified during the diagnostic phase. This showed that many surgical elective patients had no VTE risk assessment completed pre-operatively, leading to missed or delayed doses of VTE prophylaxis post-operatively. Collaborative work with stakeholders led to the development of a new process to ensure completion of the VTE risk assessment prior to surgery, which was implemented using the Model for Improvement methodology. The process was supported by the inclusion of a VTE check in the Sign Out element of the WHO Surgical Safety Checklist at the end of surgery, which also ensured that appropriate prophylaxis was prescribed. A standardised operation note including the post-operative VTE plan will be implemented in the near future. At the end of the project VTE risk assessments were completed for 100% of elective surgical patients on admission, compared with 40% in the baseline data.Baseline data also revealed that processes for chemical and mechanical prophylaxis were not reliable. Hospital wide interventions included standardisation of mechanical prophylaxis devices and anti-thromboembolic stockings (resulting in a cost saving of £52,000), and a Trust wide awareness and education programme. The education included increased emphasis on use of mechanical prophylaxis when chemical prophylaxis was contraindicated. VTE guidelines were also included in the existing junior Doctor guideline App. and a “CLOTS” anticoagulation webpage was developed and published on the hospital intranet.The improvement in VTE processes resulted in an 80% reduction in hospital associated thrombosis following surgery from 0.2% in January 2014 to 0.04% in December 2015 and a reduction in the number of all hospital associated VTE from a baseline median of 9 per month as of January 2014 to a median of 1 per month by December 2015.
Case Studies in Physiology: Maximal oxygen consumption and performance in a centenarian cyclist
Authors: Billat Véronique , Dhonneur Gilles , Mille-Hamard Laurence , Le Moyec Laurence , Momken Iman , Launay Thierry , Koralsztein Jean Pierre , Besse Sophie 
Published: December 2016

The purpose of this study was to examine the physiological characteristics of an elite centenarian cyclist who, at 101 yr old, established the 1-h cycling record for individuals ≥100 yr old (24.25 km) and to determine the physiological factors associated with his performance improvement 2 yr later at 103 yr old (26.92 km; +11%). Before each record, he performed an incremental test on a cycling ergometer. For 2 yr, he trained 5,000 km/yr with a polarized training that involved cycling 80% of mileage at “light” rate of perceived exertion (RPE) ≤12 and 20% at “hard” RPE ≥15 at a cadence between 50 and 70 rpm. His body weight and lean body mass did not change, while his maximal oxygen consumption (V̇o2max) increased (31–35 ml·kg−1·min−1; +13%). Peak power output increased from 90 to 125 W (+39%), mainly because of increasing the maximal pedaling frequency (69–90 rpm; +30%). Maximal heart rate did not change (134–137 beats/min) in contrast to the maximal ventilation (57–70 l/min, +23%), increasing with both the respiratory frequency (38–41 cycles/min; +8%) and the tidal volume (1.5–1.7 liters; +13%). Respiratory exchange ratio increased (1.03–1.14) to the same extent as tolerance to V̇co2. In conclusion, it is possible to increase performance and V̇o2max with polarized training focusing on a high pedaling cadence even after turning 100 yr old. NEW & NOTEWORTHY This study shows, for the first time, that maximal oxygen consumption (+13%) and performance (+11%) can still be increased between 101 and 103 yr old with 2 yr of training and that a centenarian is able, at 103 yr old, to cover 26.9 km/h in 1 h.
Neurons derived from different brain regions are inherently different in vitro: a novel multiregional brain-on-a-chip
Authors: Dauth Stephanie , Maoz Ben M. , Sheehy Sean P. , Hemphill Matthew A. , Murty Tara , Macedonia Mary Kate , Greer Angie M. , Budnik Bogdan , Parker Kevin Kit 
Published: December 2016

Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiology, potential neurotoxic effects of chemicals, and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell composition, protein expression, metabolism, and electrical activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and observed a reduction of overall firing activity, as well as altered amounts of astrocytes and specific neuronal cell types compared with separately cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas separately while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features.NEW & NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections.
Segmental specificity in belly dance mimics primal trunk locomotor patterns
Authors: Nugent Marilee M. , Milner Theodore E. 
Published: December 2016

Belly dance was used to investigate control of rhythmic undulating trunk movements in humans. Activation patterns in lumbar erector spinae muscles were recorded using surface electromyography at four segmental levels spanning T10 to L4. Muscle activation patterns for movement tempos of 2 Hz, 3 Hz, and as fast as possible (up to 6 Hz) were compared to test the hypothesis that frequency modulates muscle timing, causing pattern changes analogous to gait transitions. Groups of trained and untrained female subjects were compared to test the hypothesis that experience modifies muscle coordination patterns and the capacity for selective motion of spinal segments. Three distinct coordination patterns were observed. An ipsilateral simultaneous pattern (S) and a diagonal synergy (D) dominated at lower frequencies. The S pattern was selected most often by novices and resembled the standing wave of activation underlying the alternating lateral trunk bending in salamander trotting. At 2 Hz, most trained subjects selected the D pattern, suggesting a greater capacity for segmental specificity compared with untrained subjects. At 3–4 Hz, there emerged an asynchronous pattern (A) analogous to the rostral-caudal traveling wave in salamander and lamprey swimming. The neural networks and mechanisms identified in primitive vertebrates, such as chains of coupled oscillators and segmental crossed inhibitory connections, could explain the patterns observed in this study in humans. Training allows modification of these patterns, possibly through improved capacity for selectively exciting or inhibiting segmental pattern generators. NEW & NOTEWORTHY Belly dance provides a novel approach for studying spinal cord neural circuits. New evidence suggests that primitive locomotor circuits may be conserved in humans. Erector spinae activation patterns during the hip shimmy at different tempos are similar to those observed in salamander walking and swimming. As movement frequency increases, a sequential pattern similar to lamprey swimming emerges, suggesting that primal involuntary control mechanisms dominate in fast lateral rhythmic spine undulations even in humans.
Presynaptic gain control by endogenous cotransmission of dopamine and GABA in the olfactory bulb
Authors: Vaaga Christopher E. , Yorgason Jordan T. , Williams John T. , Westbrook Gary L. 
Published: December 2016

In the olfactory bulb, lateral inhibition mediated by local juxtaglomerular interneurons has been proposed as a gain control mechanism, important for decorrelating odorant responses. Among juxtaglomerular interneurons, short axon cells are unique as dual-transmitter neurons that release dopamine and GABA. To examine their intraglomerular function, we expressed channelrhodopsin under control of the DAT-cre promoter and activated olfactory afferents within individual glomeruli. Optical stimulation of labeled cells triggered endogenous dopamine release as measured by cyclic voltammetry and GABA release as measured by whole cell GABAAreceptor currents. Activation of short axon cells reduced the afferent presynaptic release probability via D2and GABABreceptor activation, resulting in reduced spiking in both mitral and external tufted cells. Our results suggest that short axon cells influence glomerular activity not only by direct inhibition of external tufted cells but also by inhibition of afferent inputs to external tufted and mitral cells.NEW & NOTEWORTHY Sensory systems, including the olfactory system, encode information across a large dynamic range, making synaptic mechanisms of gain control critical to proper function. Here we demonstrate that a dual-transmitter interneuron in the olfactory bulb controls the gain of intraglomerular afferent input via two distinct mechanisms, presynaptic inhibition as well as inhibition of a principal neuron subtype, and thereby potently controls the synaptic gain of afferent inputs.
Cutaneous neurturin overexpression alters mechanical, thermal, and cold responsiveness in physiologically identified primary afferents
Authors: Jankowski Michael P. , Baumbauer Kyle M. , Wang Ting , Albers Kathryn M. , Davis Brian M. , Koerber H. Richard 
Published: December 2016

Neurotrophic factors play an important role in the regulation of functional properties of sensory neurons under normal and pathological conditions. The GDNF family member neurturin is one such factor that has been linked to modulating responsiveness to peripheral stimuli. Neurturin binds to the GFRα2 receptor, a receptor found primarily in isolectin B4-expressing polymodal cutaneous nociceptors. Previous work has shown that knockout of GFRα2 alters heat, but not mechanical, responses in dissociated sensory neurons and reduces pain-related behaviors during the second phase of the formalin test. Research has also shown that overexpression of neurturin in basal keratinocytes increases behavioral responsiveness to mechanical stimulation and innocuous cooling of the skin without affecting noxious heat responses. Here we directly examined the impact of neurturin overexpression on cutaneous afferent function. We compared physiological responses of individual sensory neurons to mechanical and thermal stimulation of the skin, using an ex vivo skin-nerve-dorsal root ganglion-spinal cord preparation produced from neurturin-overexpressing (NRTN/OE) mice and wild-type littermate controls. We found that neurturin overexpression increases responsiveness to innocuous mechanical stimuli in A-fiber nociceptors, alters thermal responses in the polymodal subpopulation of C-fiber sensory neurons, and changes the relative numbers of mechanically sensitive but thermally insensitive C-fiber afferents. These results demonstrate the potential roles of different functional groups of sensory neurons in the behavioral changes observed in mice overexpressing cutaneous neurturin and highlight the importance of neurturin in regulating cutaneous afferent response properties.NEW & NOTEWORTHY GDNF family neurotrophic factors regulate the development and function of primary sensory neurons. Of these, neurturin has been shown to modulate mechanical and cooling sensitivity behaviorally. Here we show that overexpression of neurturin in basal keratinocytes regulates mechanical responsiveness in A-fiber primary sensory neurons while increasing the overall numbers of cold-sensing units. Results demonstrate a crucial role for cutaneous neurturin in modulating responsiveness to peripheral stimuli at the level of the primary afferent.
Reprogramming Medulloblastoma-Propagating Cells by a Combined Antagonism of Sonic Hedgehog and CXCR4
Authors: Ward Stacey A. , Warrington Nicole M. , Taylor Sara , Kfoury Najla , Luo Jingqin , Rubin Joshua B. 
Published: December 2016

Abstract
The CXCR4 chemokine and Sonic Hedgehog (SHH) morphogen pathways are well-validated therapeutic targets in cancer, including medulloblastoma. However, single-agent treatments with SHH or CXCR4 antagonists have not proven efficacious in clinical trials to date. Here, we discovered that dual inhibition of the SHH and CXCR4 pathways in a murine model of SHH-subtype medulloblastoma exerts potent antitumor effects. This therapeutic synergy resulted in the suppression of tumor-propagating cell function and correlated with increased histone H3 lysine 27 trimethylation within the promoters of stem cell genes, resulting in their decreased expression. These results demonstrate that CXCR4 contributes to the epigenetic regulation of a tumor-propagating cell phenotype. Moreover, they provide a mechanistic rationale to evaluate the combination of SHH and CXCR4 inhibitors in clinical trials for the treatment of medulloblastoma, as well as other cancers driven by SHH that coexpress high levels of CXCR4. Cancer Res; 77(6); 1416–26. ©2016 AACR.
Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire
Authors: Oh David Y. , Cham Jason , Zhang Li , Fong Grant , Kwek Serena S. , Klinger Mark , Faham Malek , Fong Lawrence 
Published: December 2016

Abstract
While immune checkpoint blockade elicits efficacious responses in many patients with cancer, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAEs are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T-cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T-cell repertoire in IRAE patients compared with patients without IRAEs. Specifically, ipilimumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T-cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T-cell numbers relative to patients without IRAEs. Prostate-specific antigen responses to ipilimumab were also associated with increased T-cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for patients with cancer. Cancer Res; 77(6); 1322–30. ©2016 AACR.
Functional Activation of Mutant p53 by Platinum Analogues in Cisplatin-Resistant Cells Is Dependent on Phosphorylation
Authors: Xie Xiaolei , He Guangan , Siddik Zahid H. 
Published: December 2016

Abstract
Dysfunctionality of the p53 tumor suppressor is a major cause of therapeutic drug resistance in cancer. Recently, we reported that mutant, but otherwise functional, p53v172F was inactivated in cisplatin-resistant 2780CP/Cl-16 and 2780CP/Cl-24 human ovarian tumor cells by increased recruitment of the inhibitor MDM4. The current study demonstrates that, unlike cisplatin, platinum analogues oxaliplatin and DACH-diacetato-dichloro-Pt(IV) (DAP) strongly stabilize and activate p53v172F in resistant cells, as indicated by prolonged p53 half-life and transactivation of targets p21 (CDKN1A) and MDM2. This increase in MDM2 reduced MDM4 levels in cell lysates as well as the p53 immunocomplex and prevented reversion of p53 to the inactive p53-MDM2-MDM4–bound state. Phosphorylation of p53 at Ser15 was demonstrated by all three drugs in sensitive A2780 and corresponding resistant 2780CP/Cl-16 and 2780CP/Cl-24 cell lines. However, cisplatin induced Ser20 phosphorylation in A2780 cells only, but not in resistant cells; in contrast, both DAP and oxaliplatin induced this phosphorylation in all three cell lines. The inference that Ser20 phosphorylation is more important for p53 activation was confirmed by ectopic expression of a phosphomimetic (S20D) mutant p53 that displayed reduced binding, relative to wild-type p53, to both MDM2 and MDM4 in p53-knockout A2780 cells. In consonance, temporal studies demonstrated drug-induced Ser15 phosphorylation coincided with p53 stabilization, whereas Ser20 phosphorylation coincided with p53 transactivation.
Implications: Cisplatin fails to activate the pathway involved in phosphorylating mutant p53v172F at Ser20 in resistant cells, but this phosphorylation is restored by oxaliplatin and DAP that reactivates p53 function and circumvents cisplatin resistance. Mol Cancer Res; 15(3); 328–39. ©2016 AACR.
A Systematic Analysis of Negative Growth Control Implicates the DREAM Complex in Cancer Cell Dormancy
Authors: MacDonald James , Ramos-Valdes Yudith , Perampalam Pirunthan , Litovchick Larissa , DiMattia Gabriel E. , Dick Frederick A. 
Published: December 2016

Abstract
Epithelial ovarian cancer (EOC) generates multicellular aggregates called spheroids that detach from the primary tumor and disseminate through ascites. Spheroids possess a number of characteristics of tumor dormancy including withdrawal from the cell cycle and resistance to chemotherapeutics. This report systematically analyzes the effects of RNAi depletion of 21 genes that are known to contribute to negative regulation of the cell cycle in 10 ovarian cancer cell lines. Interestingly, spheroid cell viability was compromised by loss of some cyclin-dependent kinase inhibitors such as p57Kip2, as well as Dyrk1A, Lin52, and E2F5 in most cell lines tested. Many genes essential for EOC spheroid viability are pertinent to the mammalian DREAM repressor complex. Mechanistically, the data demonstrate that DREAM is assembled upon the induction of spheroid formation, which is dependent upon Dyrk1A. Loss of Dyrk1A results in retention of the b-Myb–MuvB complex, elevated expression of DREAM target genes, and increased DNA synthesis that is coincident with cell death. Inhibition of Dyrk1A activity using pharmacologic agents Harmine and INDY compromises viability of spheroids and blocks DREAM assembly. In addition, INDY treatment improves the response to carboplatin, suggesting this is a therapeutic target for EOC treatment.
Implications: Loss of negative growth control mechanisms in cancer dormancy lead to cell death and not proliferation, suggesting they are an attractive therapeutic approach. Mol Cancer Res; 15(4); 371–81. ©2016 AACR.