Probing the Basis of α-Synuclein Aggregation by Comparing Simulations to Single-Molecule Experiments.

Intrinsically disordered proteins often play an important role in protein aggregation. However, it is challenging to determine the structures and interactions that drive the early stages of aggregation because they are transient and obscured in a heterogeneous mixture of disordered states. Even computational methods are limited because the lack of ordered structure makes it difficult to ensure that the relevant conformations are sampled. We address these challenges by integrating atomistic simulations with high-resolution single-molecule measurements reported previously, using the measurements to help discern which parts of the disordered ensemble of structures in the simulations are most probable while using the simulations to identify residues and interactions that are important for oligomer stability. This approach was applied to α-synuclein, an intrinsically disordered protein that aggregates in the context of Parkinson's disease. We simulated single-molecule pulling experiments on dimers, the minimal oligomer, and compared them to force spectroscopy measurements. Force-extension curves were simulated starting from a set of 66 structures with substantial structured content selected from the ensemble of dimer structures generated at zero force via Monte Carlo simulations. The pattern of contour length changes as the structures unfolded through intermediate states was compared to the results from optical trapping measurements on the same dimer to discern likely structures occurring in the measurements. Simulated pulling curves were generally consistent with experimental data but with a larger number of transient intermediates. We identified an ensemble of ß-rich dimer structures consistent with the experimental data from which dimer interfaces could be deduced. These results suggest specific druggable targets in the structural motifs of α-synuclein that may help prevent the earliest steps of oligomerization.

Pharmacists' perceptions of their emerging general practice roles in UK primary care: a qualitative interview study.

BACKGROUND: UK general practice is experiencing a workload crisis. Pharmacists are the third largest healthcare profession in the UK; however, their skills are a currently underutilised and potentially highly valuable resource for primary health care. This study forms part of the evaluation of an innovative training programme for pharmacists who are interested in extended roles in primary care, advocated by a UK collaborative '10-point GP workforce action plan'. AIM: To explore pharmacists' perceptions of primary care roles including the potential for greater integration of their profession into general practice. DESIGN AND SETTING: A qualitative interview study in UK primary care carried out between October 2015 and July 2016. METHOD: Pharmacists were purposively sampled by level of experience, geographical location, and type of workplace. Two confidential semi-structured telephone interviews were conducted - one before and one after the training programme. A constant comparative, inductive approach to thematic analysis was used. RESULTS: Sixteen participants were interviewed. The themes related to: initial expectations of the general practice role, varying by participants' experience of primary care; the influence of the training course with respect to managing uncertainty, critical appraisal skills, and confidence for the role; and predictions for the future of this role. CONCLUSION: There is enthusiasm and willingness among pharmacists for new, extended roles in primary care, which could effectively relieve GP workload pressures. A definition of the role, with examples of the knowledge, skills, and attributes required, should be made available to pharmacists, primary care teams, and the public. Training should include clinical skills teaching, set in context through exposure to general practice, and delivered motivationally by primary care practitioners.

Phase transitions and structure analysis in wild-type, A30P, E46K, and A53T mutants of α-synuclein.

α-Synuclein has been implicated in the development of neural plaques in Parkinson's Disease and Lewy-Body Dementia. This paper reports on the structural phase change behavior exhibited over a relevant range of temperatures in canonical protein Monte Carlo simulations for wild-type α-synuclein and three of its familial variants. We performed and analyzed these simulations to determine residue occupancy variations above and below this phase transition. From this analysis, we found regions above the phase transition temperature that consistently exhibited increased propensity for formation of long-chain beta-sheets, suggesting a possible role in α-synuclein aggregation.

Groups need selves, but which selves? Dual selves in groups and the downsides of individuation.

It may be true that "groups need selves," as Baumeister et al. contend. However, certain types of selfhood and too much selfhood can both be detrimental to group functioning. I draw on theory and research on dual selves in work groups and teams to outline boundary conditions to the hypothesis that emphasizing individual selves yields positive effects for groups.

Cognition in organizations.

This article reviews major developments from 2000 to early 2007 in the psychological analysis of cognition in organizations. Our review, the first in this series to survey cognitive theory and research spanning the entire field of industrial and organizational psychology, considers theoretical, empirical, and methodological advances across 10 substantive domains of application. Two major traditions, the human factors and organizational traditions, have dominated cognitively oriented research in this field. Our central message is that the technological and human systems underpinning contemporary organizational forms are evolving in ways that demand greater cooperation among researchers across both traditions. Such cooperation is necessary in order to gain theoretical insights of sufficient depth and complexity to refine the explanation and prediction of behavior in organizations and derive psychologically sound solutions to the unprecedented information-processing burdens confronting the twenty-first century workforce.

Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation.

OBJECTIVE: Dexmedetomidine (DEX) may provide a sedation level that enables sleep and communication, with less amnesia and pain medication requirements, during mechanical ventilation. Our study directly assessed patient-perceived satisfaction with coronary artery bypass graft surgery after administration of DEX or propofol for intensive care unit (ICU) sedation. DESIGN: Prospective, randomized clinical study with subsequent questionnaire administration. SETTING: Tertiary care surgical ICU. PATIENTS: A total of 89 adult, nonemergent, coronary artery bypass graft patients with an expected length of intubation of <24 hrs. INTERVENTIONS: Patients were randomized to either DEX or propofol; drug administration was performed via standardized anesthesia and nursing protocols. MEASUREMENTS: Patients reported perceptions of their ICU experience after mechanical ventilation with a modified numerical-scale Hewitt questionnaire, validated specifically for ICU patients. Patients were questioned regarding awareness, recall, generalized comfort, level of pain, ability to interact with healthcare providers and family, feelings of agitation and anxiety, perceived ease of extubation, ability to sleep or rest, and satisfaction with ICU experience. MAIN RESULTS: Groups were well matched at baseline, with a mean +/- sd age of 63.0 +/- 10.4 yrs and weight of 88.7 +/- 16.7 kg. No difference was observed for length of surgery, length of intubation, or ICU stay (p > .05). DEX patients perceived a shorter length of intubation (p = .044). A deeper sedation level was found in the propofol group (p = .021), with similar morphine and midazolam requirements (p = .317). Patient-rated level of overall awareness as a marker of amnesia did not differ between groups (p = .653). The ability to rest or sleep trended toward significance favoring propofol (p = .051). On evaluation of questionnaire ratings, DEX patients expressed more discomfort (p = .046), pain (p = .096), and sleeping difficulty (p = .036). Similar comfort levels were reported during extubation (p = .179). CONCLUSIONS: Despite theoretical advantages of DEX to improve overall patient satisfaction, the two agents provide similar responses to amnesia and pain control. According to our findings, DEX does not seem to have any advantage compared with propofol for short-term sedation after coronary artery bypass graft surgery.

Do proton pump inhibitors increase the incidence of nosocomial pneumonia and related infectious complications when compared with histamine-2 receptor antagonists in critically ill trauma patients?

BACKGROUND: Proton pump inhibitors (PPI) may increase the risk of nosocomial pneumonia caused by profound irreversible gastric acid suppression. The study purpose was to characterize differences in nosocomial pneumonia and related infections in trauma patients administered either histamine2-receptor antagonists (H2RA) or PPI. METHODS: Observational evaluation of consecutive critically ill adult trauma patients administered either omeprazole or famotidine during a 22-month period. Nosocomial infection was evaluated daily based on published CDC definitions. RESULTS: Eighty of 269 patients fulfilled study criteria. The PPI group (n = 40) exhibited increased baseline risk for infection, demonstrated by higher ISS (p = 0.020), more chest tube placements (p = 0.031), and increased chest trauma (p = 0.025). Overall number of patients infected per group included 33% and 40% of patients administered PPI and H2RA, respectively (p = 0.64). Despite baseline differences, the incidence of nosocomial infection was similar (p = 0.87), and extrapolation of pneumonia based on 1000 patient days revealed a ratio 51.7 vs 52.2 in the PPI vs H2RA groups, respectively, which was not significant (p = 0.99). CONCLUSIONS: Proton pump inhibitor administration does not increase risk of nosocomial pneumonia or other nosocomial infections compared with H2RA therapy in the critically ill trauma patient.

Improving the Glasgow Coma Scale score: motor score alone is a better predictor.

BACKGROUND: The Glasgow Coma Scale (GCS) has served as an assessment tool in head trauma and as a measure of physiologic derangement in outcome models (e.g., TRISS and Acute Physiology and Chronic Health Evaluation), but it has not been rigorously examined as a predictor of outcome. METHODS: Using a large trauma data set (National Trauma Data Bank, N = 204,181), we compared the predictive power (pseudo R2, receiver operating characteristic [ROC]) and calibration of the GCS to its components. RESULTS: The GCS is actually a collection of 120 different combinations of its 3 predictors grouped into 12 different scores by simple addition (motor [m] + verbal [v] + eye [e] = GCS score). Problematically, different combinations summing to a single GCS score may actually have very different mortalities. For example, the GCS score of 4 can represent any of three mve combinations: 2/1/1 (survival = 0.52), 1/2/1 (survival = 0.73), or 1/1/2 (survival = 0.81). In addition, the relationship between GCS score and survival is not linear, and furthermore, a logistic model based on GCS score is poorly calibrated even after fractional polynomial transformation. The m component of the GCS, by contrast, is not only linearly related to survival, but preserves almost all the predictive power of the GCS (ROC(GCS) = 0.89, ROC(m) = 0.87; pseudo R2(GCS) = 0.42, pseudo R2(m) = 0.40) and has a better calibrated logistic model. CONCLUSION: Because the motor component of the GCS contains virtually all the information of the GCS itself, can be measured in intubated patients, and is much better behaved statistically than the GCS, we believe that the motor component of the GCS should replace the GCS in outcome prediction models. Because the m component is nonlinear in the log odds of survival, however, it should be mathematically transformed before its inclusion in broader outcome prediction models.

Charges and reimbursement at a rural level I trauma center: a disparity between effort and reward among professionals.

BACKGROUND: A Level I trauma center must provide immediate availability general (trauma) surgical expertise. In the current practice few patients require a general surgical procedure. The expertise of subspecialists may also be required and frequently these patients will require subspecialty operative care. We hypothesized that trauma surgeons would receive less reimbursement than their subspecialty colleagues despite a greater commitment of time and effort in taking care of the multiply-injured patient. METHODS: Three fellowship trained trauma surgeons were specifically hired to cover the trauma service for the year 2000. Professional billings, contribution to margin (reimbursement minus direct costs) of the trauma surgeons and subspecialists were obtained from the hospital financial information system. A surrogate for effort was assessed by the number of attending notes in the chart. A surrogate for complexity of care was assessed by the length of notes in the chart. Weekly time sheets assessed the percentage of time involved in the care of trauma patients. RESULTS: There were 344 patients cared for exclusively on the trauma service for the year 2000. The billing generated per patient was $1005 for the trauma surgeon, $5904 for the subspecialists, and $27,554 for the hospital. Orthopedics and radiology generated more professional billing on the trauma patients than the trauma surgeons. The trauma surgeons spent 52% of their weekly clinical activity in the care of trauma patients, yet this activity accounted for only 16% of their billings (the rest came from general surgery and ICU care). The effort and complexity of care provided by the trauma surgeons was significantly greater than the subspecialists. CONCLUSION: The Level I trauma service is a conduit for patients coming into the hospital that provides a significant remuneration to the subspecialty services. Trauma surgeons are able to bill much less than many of their subspecialty colleagues despite expending significantly greater amounts of time and effort in the care of these patients. Strategies for improved reimbursement for trauma surgeons must be devised or trauma surgery will suffer the same fate as other areas of surgery, losing our brightest and best to more financially sound subspecialty services such as radiology and orthopedics.

A simple mathematical modification of TRISS markedly improves calibration.

BACKGROUND: TRISS has reigned as the preeminent trauma outcome prediction model for 20 years. Despite this endorsement, the calibration of TRISS has been poor in most data sets where it has been examined. We hypothesized that the lack of calibration of TRISS was because of the inappropriate mathematical specification of the model that TRISS is based on, rather than the predictors in the model. In particular, we hypothesized that the nonlinearity of the Injury Severity Score (ISS) in the log odds of death was responsible for the poor calibration of TRISS, and further, that this nonlinearity could be corrected by the simple addition of an ISS squared term to the TRISS model. METHODS: We examined ISS in the log odds of mortality for linearity in one large trauma data set, the National Pediatric Trauma Registry (NPTR) (n = 53,113 from 1985-1996; mortality, 1.3%); and two small data sets, the University of New Mexico (UNM) (n = 3,142 from 1991-1995; mortality, 8.6%) and Portland, Oregon (PORT) (n = 2,916 from 1990-1994; mortality, 1.75%). In addition, in the NPTR we compared the calibration of TRISS models with and without linearity in the log odds of death. RESULTS: In the NPTR, ISS was profoundly nonlinear in the log odds of death for both blunt and penetrating trauma (p < 0.001). Moreover, the overall calibration of the TRISS model for the NPTR data was significantly improved when the nonlinearity of ISS was corrected by the addition of a quadratic ISS term as demonstrated by a 70% reduction (improvement) in the Hosmer-Lemeshow statistic. Interestingly, the addition of the ISS squared term did not affect the discrimination of the model. The log odds of survival in the UNM and PORT data sets were also better modeled when an ISS squared term was added (UNM, p = 0 0.052; PORT, p = 0.014), but improvements in the Hosmer-Lemeshow statistic were smaller, possibly because of the small size of these data sets. CONCLUSION: The TRISS model for outcome prediction currently uses ISS in a mathematically inappropriate way that impairs the calibration, but not the discrimination, of its predictions. If TRISS is to continue as the prediction standard for trauma, a quadratic ISS term must be added to the model. In the future, outcome prediction models should undergo thorough statistical modeling and evaluation before being released. Injury severity descriptors other than ISS (such as ASCOT, ICISS, or NISS) may require other modeling techniques to optimize the calibration of survival models that use these injury scores.

Complications in surgical patients.

HYPOTHESIS: Complications are common in hospitalized surgical patients. Provider error contributes to a significant proportion of these complications. DESIGN: Surgical patients were concurrently observed for the development of explicit complications. All complications were reviewed by the attending surgeon and other members of the service and evaluated for the severity of sequelae (major or minor) and for whether the complication resulted from medical error (avoidable) or not. SETTING: University teaching hospital with a level I trauma designation. PATIENTS: All inpatients (operative or nonoperative) from 4 different surgical services: general surgery, combined general surgery and trauma, vascular surgery, and cardiothoracic surgery. MAIN OUTCOME MEASURES: Total complication rate (number of complications divided by the number of patients) and the number of patients with complications. Complications were separated into those with major or minor sequelae and the proportion of each type that were due to medical error (avoidable). Rates of complications in a recent Institute of Medicine report were used as a criterion standard. RESULTS: The data for the respective groups (general surgery, vascular surgery, combined general surgery and trauma, and cardiothoracic surgery) are as follows. The number of patients was 1363, 978, 914, and 1403; number of complications, 413, 409, 295, and 378; total complication rate, 30.3%, 42.4%, 32.3%, and 26.9%; minor complication rate, 13.3%, 19.9%, 13.5%, and 13.0% (percentage of minor complications that were avoidable, 37.4%, 59.0%, 51.2%, and 49.5%); major complication rate, 16.2%, 21.1%, 18.1%, and 12.9% (percentage of major complications that were avoidable, 53.4%, 60.7%, 38.8%, and 38.7%); and mortality rate, 1.83%, 3.33%, 2.28%, and 3.34% (percentage of mortality that was avoidable, 28.0%, 44.1%, 19.0%, and 25.0%). CONCLUSIONS: Despite mortality rates that compare favorably with national benchmarks, a prospective examination of surgical patients reveals complication rates that are 2 to 4 times higher than those identified in an Institute of Medicine report. Almost half of these adverse events were judged contemporaneously by peers to be due to provider error (avoidable). Errors in care contributed to 38 (30%) of 128 deaths. Recognition that provider error contributes significantly to adverse events presents significant opportunities for improving patient outcomes.

H(2) antagonist-induced thrombocytopenia: is this a real phenomenon?

Critically ill patients routinely receive H(2) antagonists for stress ulcer prophylaxis while at risk for gastrointestinal bleeding. In these patients it is often difficult to assess accurately the cause of adverse effects such as thrombocytopenia. We evaluate the literature to better define thrombocytopenia related to H(2) antagonist administration and discuss mechanism, potential as a risk factor and case reports describing the severity and duration of thrombocytopenia.