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Procedural sedation and analgesia (PSA) is a core competency for emergency physicians (EP) that is commonly practiced.1–4 PSA entails suppressing a patient’s level of consciousness with sedative or dissociative agents to alleviate pain, anxiety, and suffering to enhance medical procedure performance and patient experience (Table 22.1).1,5
The history of economics, properly read, is very much a history of economics in the public sphere. Sir William Petty developed his most important insights in the process of providing advice on taxation to the monarch. Adam Smith wrote with a view to influencing the habits of thought of both the educated layman and policy makers. Jane Marcet and Harriet Martineau brought early classical political economy to the masses. David Ricardo formulated foundational elements of the nineteenth-century classical system writing policy pamphlets and then entered Parliament with a view to putting policy making on a solid economic footing. Karl Marx’s intended audience was anything but the practitioners of the emerging science of political economy. Alfred Marshall buried his technical analysis in appendices to maximize the exposure of his work. John Maynard Keynes’s influence can be ascribed, without too much injustice, as much to his effectiveness outside the walls of Cambridge as within them and to the use by others of his ideas in that same public realm. Yet, despite this lengthy history of economists’ engagements with various publics, including those pulling the levers of policy, those writing on the history of economics have focused far more intently on the history of theory and the implications for the construction of a body of thought known as “economic analysis” than on the interplay among economists, economic ideas, and the public realm. It is as if the economic conversation went on solely within the space of academic departments of economics, even though those spaces are very recent creations.
We propose a cluster-based control strategy for feedback control of post-stall separated flows over an airfoil. The present approach partitions the flow trajectories (force measurements) into clusters, which correspond to characteristic coarse-grained phases in a low-dimensional feature space. A feedback control law (using blowing/suction actuation) is then sought for each cluster state through iterative evaluation and downhill simplex search to minimize power consumption in aerodynamic flight. The optimized control laws re-route the flow trajectories to the aerodynamically favourable regions in the feature space in a model-free manner. Utilizing a limited number of sensor measurements for both clustering and optimization, these feedback laws were determined in only
iterations. The objective of the present work is not necessarily to suppress flow separation but to minimize the desired cost function to achieve enhanced aerodynamic performance. The present approach is applied to the control of two- and three-dimensional separated flows over a NACA 0012 airfoil in large-eddy simulations at an angle of attack of
, Reynolds number
and free-stream Mach number
. The optimized control laws avoid the intermittent occurrence of long-period shedding associated with high-drag clusters, thus lowering the mean drag. The present work aims to address some of the challenges associated with feedback control design for turbulent separated flows at moderate Reynolds number.
Schizophrenia is associated with robust hippocampal volume deficits but subregion volume deficits, their associations with cognition, and contributing genes remain to be determined.
Hippocampal formation (HF) subregion volumes were obtained using FreeSurfer 6.0 from individuals with schizophrenia (n = 176, mean age ± s.d. = 39.0 ± 11.5, 132 males) and healthy volunteers (n = 173, mean age ± s.d. = 37.6 ± 11.3, 123 males) with similar mean age, gender, handedness, and race distributions. Relationships between the HF subregion volume with the largest between group difference, neuropsychological performance, and single-nucleotide polymorphisms were assessed.
This study found a significant group by region interaction on hippocampal subregion volumes. Compared to healthy volunteers, individuals with schizophrenia had significantly smaller dentate gyrus (DG) (Cohen's d = −0.57), Cornu Ammonis (CA) 4, molecular layer of the hippocampus, hippocampal tail, and CA 1 volumes, when statistically controlling for intracranial volume; DG (d = −0.43) and CA 4 volumes remained significantly smaller when statistically controlling for mean hippocampal volume. DG volume showed the largest between group difference and significant positive associations with visual memory and speed of processing in the overall sample. Genome-wide association analysis with DG volume as the quantitative phenotype identified rs56055643 (β = 10.8, p < 5 × 10−8, 95% CI 7.0–14.5) on chromosome 3 in high linkage disequilibrium with MOBP. Gene-based analyses identified associations between SLC25A38 and RPSA and DG volume.
This study suggests that DG dysfunction is fundamentally involved in schizophrenia pathophysiology, that it may contribute to cognitive abnormalities in schizophrenia, and that underlying biological mechanisms may involve contributions from MOBP, SLC25A38, and RPSA.
We evaluated the impact of an electronic health record based 72-hour antimicrobial time-out (ATO) on antimicrobial utilization. We observed that 6 hours after the ATO, 21% of empiric antimicrobials were discontinued or de-escalated. There was a significant reduction in the duration of antimicrobial therapy but no impact on overall antimicrobial usage metrics.
The Strengths and Difficulties Questionnaire (SDQ) has been used in many epidemiological studies to assess adolescent mental health problems, but cross-country comparisons of the self-report SDQ are scarce and so far failed to find a good-fitting, common, invariant measurement model across countries. The present study aims to evaluate and establish a version of the self-report SDQ that allows for a valid cross-country comparison of adolescent self-reported mental health problems.
Using the Health Behaviour in School-aged Children study, the measurement model and measurement invariance of the 20 items of the self-report SDQ measuring adolescent mental health problems were evaluated. Nationally representative samples of 11-, 13- and 15-year old adolescents (n = 33 233) from seven countries of different regions in Europe (Bulgaria, Germany, Greece, the Netherlands, Poland, Romania, Slovenia) were used.
In order to establish a good-fitting and common measurement model, the five reverse worded items of the self-report SDQ had to be removed. Using this revised version of the self-report SDQ, the SDQ-R, partial measurement invariance was established, indicating that latent factor means assessing conduct problems, emotional symptoms, peer relationships problems and hyperactivity-inattention problems could be validly compared across the countries in this study. Results showed that adolescents in Greece scored relatively low on almost all problem subscales, whereas adolescents in Poland scored relatively high on almost all problem subscales. Adolescents in the Netherlands reported the most divergent profile of mental health problems with the lowest levels of conduct problems, low levels of emotional symptoms and peer relationship problems, but the highest levels of hyperactivity-inattention problems.
With six factor loadings being non-invariant, partial measurement invariance was established, indicating that the 15-item SDQ-R could be used in our cross-country comparison of adolescent mental health problems. To move the field of internationally comparative research on adolescent mental health forward, studies should test the applicability of the SDQ-R in other countries in- and outside Europe, continue to develop the SDQ-R as a cross-country invariant measure of adolescent mental health, and examine explanations for the found country differences in adolescent mental health problems.
Introduction: Abdominal pain is one of the most frequent reasons for an emergency department (ED) visit. Most cases are functional and no therapy has proven effective. Our objective was to determine if hyoscine butylbromide (HBB) (BuscopanTM) is effective for children who present to the ED with functional abdominal pain. Methods: We conducted a randomized, blinded, superiority trial comparing HBB 10 mg plus acetaminophen placebo to oral acetaminophen 15 mg/kg (max 975 mg) plus HBB placebo using a double-dummy approach. We included children 8-17 years presenting to the ED at London Health Sciences Centre with colicky abdominal pain rated >40 mm on a 100 mm visual analog scale (VAS). The primary outcome was VAS pain score at 80 minutes post-administration. Secondary outcomes included adverse effects; caregiver satisfaction with pain management using a five-item Likert scale; recidivism and missed surgical diagnoses within 24-hours of discharge. Analysis was based on intention to treat. Results: We analyzed 225 participants (112 acetaminophen; 113 HBB). The mean (SD) age was 12.4 (3.0) years and 148/225 (65.8%) were females. Prior to enrollment, the median (IQR) duration of pain prior was 2 (4.5) hours and analgesia was provided to 101/225 (44.9%) of participants. The mean (SD) pre-intervention pain scores in the acetaminophen and HBB groups were 62.7 (15.9) mm and 60.3 (17.3) mm, respectively. At 80 minutes, the mean (SD) pain scores in the acetaminophen and HBB groups were 30.1 (28.8) mm and 29.4 (26.4) mm, respectively and there were no significant differences adjusting for pre-intervention scores (p = 0.96). The median (IQR) caregiver satisfaction was high in the acetaminophen [5 (2)] and HBB [5 (1)] groups (p = 0.79). The median (IQR) length of stay between acetaminophen [235 (101)] and HBB [234 (103)] was not significantly different (p = 0.53). The proportion of participants with a return visit for abdominal pain was 4/112 (3.5%) in the acetaminophen group and 6/113 (5.3%) in the HBB group. The most common adverse effect was nausea (9% in each group) and there were no significant differences in adverse effects between acetaminophen (26/112, 23.2%) and HBB (31/113, 27.4%) (p = 0.52). There were no missed surgical diagnoses. Conclusion: For children with presumed functional abdominal pain who present to the ED, both acetaminophen and HBB produce a clinically important (VAS < 30 mm) reduction in pain and should be routinely considered in this clinical setting.
The kidnapping by the local chief, O'Connor Faly, of Henry VIII's governor, Lord Delvin, in 1528 plunged the Dublin administration into crisis. Delvin was the most obvious – but not entirely surprising – casualty of an ingenious but flawed experiment by the king, aimed at bolstering as governor a reliable border baron by harnessing to his governorship the manraed of the traditional ruling magnate, so saving the cost to the king of a border garrison. Delvin's weak administration underlined the low priority accorded to Irish affairs at Henry VIII's court; but even after its predictable collapse, the king disclaimed responsibility. Against advice at court and in Ireland, the king then insisted on reappointing a previously unsuccessful governor, thus simply compounding the difficulties faced by the Dublin administration.
Understanding ‘responsibility’ in its normal sense of freely fulfilling a role in a collaborative scheme, rather than as a basic agent integrity or prosocial disposition, I argue that the desirability of responsibility is one of the main supporting and constraining factors in the formation of religious thought and practice, with diversely typical manifestations. For those who are disposed to assume responsibility and to be religious, religious beliefs and practices offer a way of maximally enlarging one's responsibility, an intrinsically appealing prospect. The global relevance of religious responsibility is shown by comparing exemplars in a wide range of cultures. Aeneas, Kongzi, Dharmakara, and Miaoshan each embody maximal responsibility in a distinct way that motivates and sets standards for a religiosity.
This pilot randomised controlled study evaluated the effects of a nutrient-supported intermittent energy restriction nutrition programme to prevent weight gain in healthy overweight adults during the 6-week winter holiday period between Thanksgiving and New Year. For 52 d, twenty-two overweight adults (mean age 41·0 years, BMI 27·3 kg/m2) were assigned to either the nutrition programme (n 10; two fasting days of 730 kcal/d (3050 kJ/d) of balanced shake and dietary supplements to support weight management efforts, followed by 5 d of habitual diet) or a control group (n 12; habitual diet). A significant weight loss from baseline (pre-holiday 10 d before Thanksgiving) to day 52 (post-holiday 3 January) was observed in the nutrition programme (75·0 (sd 9·8) v. 76·3 (sd 9·8) kg; P < 0·05). Body weight did not significantly change in the control group and there was no between-group difference. Increases from baseline in fasting insulin (42·9 %; P = 0·0256), updated homoeostasis model assessment (HOMA2) (43 %; P = 0·025), LDL-cholesterol (8·4 %; P = 0·0426) and total cholesterol (7·1 %; P = 0·0154) levels were also reported in the control group. In the nutrition programme group, baseline HDL-cholesterol and TAG levels measured after two fasting days increased (13 %; P = 0·0245) and decreased (22·8 %; P = 0·0416), respectively. There was no significant change in HOMA2. Between-group differences in changes in insulin levels (P = 0·0227), total cholesterol:HDL-cholesterol ratio (P = 0·0419) and HOMA2 (P = 0·0210) were significant. Overall compliance rate was 98 % and no severe adverse events were reported. These preliminary findings suggest that this intermittent energy restriction intervention might support weight management efforts and help promote metabolic health during the winter holiday season.
As bottom water warms, destabilisation of gas hydrates may increase the extent of methane-rich sediments. The authors present an assessment of organic carbon processing by the benthic community in methane-rich sediments, including one of the first investigations of inorganic C fixation in a non-hydrothermal vent setting. This topic was previously poorly studied, and there is much need to fill the gaps in knowledge of such ecosystems. The authors hypothesized that benthic C fixation would occur, and that a high biomass macrofaunal community would play a substantial role in organic C cycling. Experiments were conducted at a 257 m deep site off South Georgia. Sediment cores were amended with 13C and 15N labelled algal detritus, or 13C labelled bicarbonate solution. In the bicarbonate experiment, labelling of bacteria-specific phospholipid fatty acids provided direct evidence of benthic C fixation, with transfer of fixed C to macrofauna and dissolved organic carbon (DOC). In the algae experiment, macrofauna played an active role in organic carbon cycling. Compared to similar experiments, low temperature supressed the rates of community respiration and macrofaunal C uptake. While benthic C fixation occurred, the biological processing of organic carbon was dominantly controlled by low temperature and high photic zone productivity.
Increasing the number of quantum bits while preserving precise control of their quantum electronic properties is a significant challenge in materials design for the development of semiconductor quantum computing devices. Semiconductor heterostructures can host multiple quantum dots that are electrostatically defined by voltages applied to an array of metallic nanoelectrodes. The structural distortion of multiple-quantum-dot devices due to elastic stress associated with the electrodes has been difficult to predict because of the large micrometer-scale overall sizes of the devices, the complex spatial arrangement of the electrodes, and the sensitive dependence of the magnitude and spatial variation of the stress on processing conditions. Synchrotron X-ray nanobeam Bragg diffraction studies of a GaAs/AlGaAs heterostructure reveal the magnitude and nanoscale variation of these distortions. Investigations of individual linear electrodes reveal lattice tilts consistent with a 28-MPa compressive residual stress in the electrodes. The angular magnitude of the tilts varies by up to 20% over distances of less than 200 nm along the length of the electrodes, consistent with heterogeneity in the metal residual stress. A similar variation of the crystal tilt is observed in multiple-quantum-dot devices, due to a combination of the variation of the stress and the complex electrode arrangement. The heterogeneity in particular can lead to significant challenges in the scaling of multiple-quantum-dot devices due to differences between the charging energies of dots and uncertainty in the potential energy landscape. Alternatively, if incorporated in design, stress presents a new degree of freedom in device fabrication.
ALKS 3831, currently under development for the treatment of schizophrenia, is composed of olanzapine (OLZ) and a fixed dose of 10mg of samidorphan. In a Phase 2 study in stable patients with schizophrenia, ALKS 3831mitigated OLZ-associated weight gain while maintaining an antipsychotic efficacy profile similar to OLZ.
To assess the efficacy and safety of ALKS 3831 in patients with acute exacerbation of schizophrenia.
This was a Phase 3, 4-week, randomized, double-blind, active and placebo (PBO)-controlled study of ALKS 3831 in patients with acute exacerbation of schizophrenia (ClinicalTrials.gov: NCT02634346). Eligible patients (N=403) were randomized 1:1:1 to receive ALKS 3831, OLZ, or PBO. Patients were treated in an inpatient setting for the first 2weeks of the study and could be treated as inpatients or outpatients for the remaining 2weeks. Patients were excluded if they received OLZ within 6months prior to screening. Antipsychotic efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression–Severity (CGI-S) and CGI–Improvement (CGI-I) scales. Safety and tolerability were assessed as adverse events (AEs).
Of 401 randomized patients who received ALKS 3831, OLZ, or PBO, 91%, 89%, and 83% of patients, respectively, completed treatment. The most common reason for discontinuation was withdrawal by patient (6% in both the ALKS 3831and PBO groups, and 7% in the OLZ group). Baseline characteristics were generally similar between groups; however, baseline mean body mass index was higher in the OLZ group than in the ALKS 3831 group. Baseline mean±standard deviation scores were 101.7±11.9 for PANSS total score and 5.1±0.7 for CGI-S scale score. The mean OLZ dose was 18.4mg/day in both active treatment arms. Least squares (LS) mean difference±standard error (SE) vs PBO from baseline to Week 4 in PANSS total score was –6.4±1.8 (P<.001) for the ALKS 3831 group and –5.3±1.8 (P=.004) for the OLZ group. LS mean difference±SE vs PBO from baseline to Week 4 in CGI-S scale score was −0.4±0.1 (P=.002) for the ALKS3831 group and −0.4±0.1 (P<.001) for the OLZ group. The percentage of patients with improvement in PANSS response (≥30% from baseline) at Week 4 was 60%, 54%, and 38% in the ALKS 3831, OLZ, and PBO groups, respectively. The percentage of patients with an improvement in CGI-I scale response (score of ≤2) at Week 4 was 58%, 51%, and 33% in the ALKS 3831, OLZ, and PBO groups, respectively. Discontinuation due to AEs was low in all groups. Common AEs (≥5% in any group) included weight gain, somnolence, dry mouth, anxiety, headache, and schizophrenia.
Treatment with ALKS 3831 was more effective than PBO, as measured by the PANSS and CGI-S scale, and its antipsychotic efficacy was similar to the active control OLZ. The safety profile of ALKS 3831 was similar toOLZ.
Funding Acknowledgements: This study was funded by Alkermes, Inc.
The current study explored the temporal pathways of change within two treatments, the Healthy Activity Program (HAP) for depression and the Counselling for Alcohol Problems (CAP) Program for harmful drinking.
The study took place in the context of two parallel randomized controlled trials in Goa, India. N = 50 random participants who met a priori criteria were selected from each treatment trial and examined for potential direct and mediational pathways. In HAP, we examined the predictive roles of therapy quality and patient-reported activation, assessing whether activation mediated the effects of therapy quality on depression (Patient Health Questionnaire-9) outcomes. In CAP, we examined the predictive roles of therapy quality and patient change- and counter-change-talk, assessing whether change- or counter-change-talk mediated the effects of therapy quality on daily alcohol consumption.
In HAP, therapy quality (both general and treatment-specific skills) was associated with patient activation; patient activation but not therapy quality significantly predicted depression outcomes, and patient activation mediated the effects of higher general skills on subsequent clinical outcomes [a × b = −2.555, 95% confidence interval (CI) −5.811 to −0.142]. In CAP, higher treatment-specific skills, but not general skills, were directly associated with drinking outcomes, and reduced levels of counter-change talk both independently predicted, and mediated the effects of higher general skills on, reduced alcohol consumption (a × b = −24.515, 95% CI −41.190 to −11.060). Change talk did not predict alcohol consumption and was not correlated with counter-change talk.
These findings suggest that therapy quality in early sessions operated through increased patient activation and reduced counter-change talk to reduce depression and harmful drinking respectively.