Devastating Brain Injuries: Assessment and Management Part I: Overview of Brain Death

“To the world you may be one person, but to one person you may be the world.

Using participatory methods to design an mHealth intervention for a low income country, a case study in Chikwawa, Malawi

This research was conducted by the Scotland Chikwawa Health Initiative. We would like to thank Sothin Ziba and Rossanie Daudi for their contribution to the facilitation of the focus group discussions. This study was funded by the Scottish Government grant MW22.Peer reviewedPublisher PD

A new approach to railway track switch actuation:dynamic simulation and control of a self-adjusting switch

The track switch is one of the key assets in any railway network. It is essential to allow trains to change route; however, when it fails significant delays are almost inevitable. A relatively common fault is ‘loss of detection’, which can happen when gradual track movement occurs and the switch machines (actuators) no longer close the gap between the switch rail and stock rail to within safe tolerances. Currently, such misalignment is mitigated by a preventative programme of inspection and manual re-adjustment. In contrast to many other industries, the actuators are exclusively operated in open-loop with sensors (often limit switches) mainly being used for detection. Hence, an opportunity exists to investigate closed-loop control concepts for improving the operation of the switch. This paper proposes two advances; first, a novel approach is taken to modelling the dynamic performance of track switch actuators and the moving permanent-way components of the switch. The model is validated against real data from an operational switch. Secondly, the resulting dynamic model is then used to examine the implementation of closed-loop feedback control as an integral part of track-switch actuation. The proposed controller is found to provide suitable performance and to offer the potential of ‘self-adjustment’ i.e., re-adjust itself to close any gap (within a predefined range) between the stock and switch rails; thereby completing the switching operation

Strategies to Improve Post-procedural Safe Patient Handoffs

STRATEGIES TO IMPROVE SAFE PATIENT HANDOFFS AND POST PROCEDURAL FLOW During patient transfers from one care unit to another, it is imperative for patient safety and satisfaction that timely and complete communication between staff occurs. In an academic tertiary care medical center, a team consisting of representatives from 6 patient care units used improvement methods of operational excellence to improve patient centered movement. The goal of this project was to improve the percentages of two questions related to information sharing on the FY2018 AHRQ Culture of Patient Safety Survey. Using baseline metrics to reflect the current state of patient wait times and performing a detailed root cause analysis, resulted in the establishment of several countermeasures. Through problem statement development, current state mapping, and fishbone diagramming six joint KPIs were developed for post Kaizen implementation and sustainment. Next steps include reviewing results of the 2018 Culture of Safety Survey, using champions of this work to coach other teams on joint KPI development and implementation and hardwiring ideal state map tool utilizing multiple waves of joint KPIs between 2-3 departments

Pyrosequencing Bacillus anthracis

Pyrosequencing technology was used to rapidly and specifically identify Bacillus anthracis

Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1

Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJun–cFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS ≤ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases

Novel suppressors of α-synuclein toxicity identified using yeast

The mechanism by which the Parkinson’s disease-related protein α-synuclein (α-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from α-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing α-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes—ENT3, IDP3, JEM1, ARG2 and HSP82—ranked highest in their ability to block α-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of α-syn as judged by growth defects compared with wild-type cells expressing α-syn, which indicates that these genes protect cells from α-syn. Strikingly, four of the five genes are specific for α-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that α-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes α-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of α-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans

Role of Adjuvant Multimodality Therapy After Curative-Intent Resection of Ampullary Carcinoma

Importance: Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined. Objective: To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype. Design, setting, and participants: This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates. Exposures: Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy. Main outcomes and measures: Overall survival. Results: A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score-matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41). Conclusions and relevance: Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined