Effects of methylphenidate on impulsive choice and delay aversion in Lewis rats.

Attention-deficit/hyperactivity disorder (ADHD), a common behavioral disorder in children and young adults, is characterized by symptoms of impulsivity, inattention, and hyperactivity. The purpose of this study was to evaluate the Lewis rat strain as a model of ADHD by testing their impulsive choices. Lewis rats were compared to their source strain, the Wistar rat, on an impulsive choice task. Rats completed the tasks on and off methylphenidate, a commonly prescribed medication for ADHD. Off methylphenidate, Lewis rats made more impulsive choices than Wistar rats. Analyses of acquisition of choice behavior suggested that both strains were able to discriminate reward sizes, but Lewis rats still chose the smaller-sooner option more than the larger-later (LL) option when the delays to reward were the same. This may be due to an aversion to the LL lever, which was associated with the longest delays to reward. Higher doses of methylphenidate increased LL choices in Lewis rats but decreased LL choices in Wistar rats. Altogether, these results suggest Lewis rats may be a viable model for ADHD in individuals whose symptoms are characterized by impulsive choices.

Comparative analgesic efficacy and safety of intermittent local anaesthetic epidural bolus for labour: a systematic review and meta-analysis.

BACKGROUND: Continuous epidural infusion (CEI) is commonly used for labour analgesia, but concerns over potential motor block, second-stage labour complications, and ineffective analgesia in late labour have prompted examining intermittent epidural bolus (IEB) as an alternative. However, evidence comparing these modalities is conflicting. The meta-analysis evaluates the analgesic efficacy of CEI vs IEB. METHODS: Databases were searched for trials comparing CEI to IEB for labour analgesia. The two co-primary outcomes were risk of breakthrough pain and difference in area under the curve (AUC) for pain scores during the first 4 h post-epidural initiation. Local anaesthetic consumption, maternal outcomes (i.e. delivery mode, labour duration, and maternal satisfaction), and side-effects of epidural analgesia were also evaluated. Results were pooled using random-effects modelling. Trial sequential analysis (TSA) was used to evaluate evidence reliability. RESULTS: Twenty-seven studies (3133 patients) were analysed. Compared with CEI, IEB decreased risk of breakthrough pain by 38% (risk ratio [95% confidence interval {CI}] of 0.62 [0.48, 0.81]; P=0.0004; I2=47%; 1164 patients) and reduced AUC of pain during the 4 h interval by 32.9% (mean difference [95% CI] of -16.7 mm h-1 [-18.9, -14.4]; P<0.0001; 1638 patients). Intermittent epidural bolus enhanced maternal satisfaction, shortened labour duration, decreased motor block, and reduced local anaesthetic consumption. The difference between the two groups was not statistically significant for epidural side-effects or mode of delivery. The TSA indicated adequate power for reliable inferences. CONCLUSIONS: Intermittent epidural bolus provides improved labour pain control during the first 4 h after epidural initiation with less breakthrough pain. Moderate- to high-quality evidence of intermittent epidural bolus superiority support its use as a safe and effective continuous epidural infusion alternative for labour analgesia.

Explaining the Immigrant Paradox: The Influence of Acculturation, Enculturation, and Acculturative Stress on Problematic Alcohol Consumption.

The present study explored the Immigrant Paradox (IP), generational differences in problematic alcohol use (alcohol consumption and alcohol-related consequences), among immigrants and US born groups from a number of ethnic minority backgrounds. Our approach separates group differences in problematic alcohol consumption in a counterfactual manner for immigrants and the US born to answer the following counterfactual question: "What would problematic alcohol use levels be for the US born had they been exposed to the alcohol use generation (or protective) processes of immigrants and vice versa?" Multidimensional measures of enculturation (involvement with heritage culture), acculturation (involvement with US culture), acculturative stress, and demographic covariates were used to statistically explain these differences. The sample consisted of Asian American (n = 1,153), Black American (n = 833), and Latinx (n = 1,376) college students from 30 universities. Results indicated significant generational differences in mean levels of alcohol consumption but not alcohol-related consequences. Differences in measured characteristics (endowments) marginally explained differences between immigrants and the US born. On the other hand, endowments significantly explained generational differences and represented an increase in alcohol consumption among immigrants if they had the endowments of the U.S. born. Results are discussed in light of cultural and social factors that contribute to the IP.

Neutralizing Antibody Correlates Analysis of Tetravalent Dengue Vaccine Efficacy Trials in Asia and Latin America.

Background: In the CYD14 and CYD15 Phase 3 trials of the CYD-TDV dengue vaccine, estimated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue (VCD) occurring between months 13 and 25 was 56.5% and 60.8%, respectively. Methods: Neutralizing antibody titers to the 4 dengue serotypes in the CYD-TDV vaccine insert were measured at month 13 in a randomly sampled immunogenicity subcohort and in all VCD cases through month 25 (2848 vaccine, 1574 placebo) and studied for their association with VCD and with the level of VE to prevent VCD. Results: For each trial and serotype, vaccinees with higher month 13 titer to the serotype had significantly lower risk of VCD with that serotype (hazard ratios, 0.19-0.43 per 10-fold increase). Moreover, for each trial, vaccinees with higher month 13 average titer to the 4 serotypes had significantly higher VE against VCD of any serotype (P < .001). Conclusions: Neutralizing antibody titers postdose 3 correlate with CYD-TDV VE to prevent dengue. High titers associate with high VE for all serotypes, baseline serostatus groups, age groups, and both trials. However, lowest titers do not fully correspond to zero VE, indicating that other factors influence VE.

Leveraging constraints and biotelemetry data to pinpoint repetitively used spatial features.

Satellite telemetry devices collect valuable information concerning the sites visited by animals, including the location of central places like dens, nests, rookeries, or haul-outs. Existing methods for estimating the location of central places from telemetry data require user-specified thresholds and ignore common nuances like measurement error. We present a fully model-based approach for locating central places from telemetry data that accounts for multiple sources of uncertainty and uses all of the available locational data. Our general framework consists of an observation model to account for large telemetry measurement error and animal movement, and a highly flexible mixture model specified using a Dirichlet process to identify the location of central places. We also quantify temporal patterns in central place use by incorporating ancillary behavioral data into the model; however, our framework is also suitable when no such behavioral data exist. We apply the model to a simulated data set as proof of concept. We then illustrate our framework by analyzing an Argos satellite telemetry data set on harbor seals (Phoca vitulina) in the Gulf of Alaska, a species that exhibits fidelity to terrestrial haul-out sites.

Dual instrument passive acoustic monitoring of belugas in Cook Inlet, Alaska.

As part of a long-term research program, Cook Inlet beluga (Delphinapterus leucas) presence was acoustically monitored with two types of acoustic sensors utilized in tandem in moorings deployed year-round: an ecological acoustic recorder (EAR) and a cetacean and porpoise detector (C-POD). The EAR was used primarily to record the calls, whistles, and buzzes produced by belugas and killer whales (Orcinus orca). The C-POD was used to log and classify echolocation clicks from belugas, killer whales, and porpoises. This paper describes mooring packages that maximized the chances of successful long-term data collection in the particularly challenging Cook Inlet environment, and presents an analytical comparison of odontocete detections obtained by the collocated EAR and C-POD instruments from two mooring locations in the upper inlet. Results from this study illustrate a significant improvement in detecting beluga and killer whale presence when the different acoustic signals detected by EARs and C-PODs are considered together. Further, results from concurrent porpoise detections indicating prey competition and feeding interference with beluga, and porpoise displacement due to ice formation are described.

Animal movement constraints improve resource selection inference in the presence of telemetry error.

Multiple factors complicate the analysis of animal telemetry location data. Recent advancements address issues such as temporal autocorrelation and telemetry measurement error, but additional challenges remain. Difficulties introduced by complicated error structures or barriers to animal movement can weaken inference. We propose an approach for obtaining resource selection inference from animal location data that accounts for complicated error structures, movement constraints, and temporally autocorrelated observations. We specify a model for telemetry data observed with error conditional on unobserved true locations that reflects prior knowledge about constraints in the animal movement process. The observed telemetry data are modeled using a flexible distribution that accommodates extreme errors and complicated error structures. Although constraints to movement are often viewed as a nuisance, we use constraints to simultaneously estimate and account for telemetry error. We apply the model to simulated data, showing that it outperforms common ad hoc approaches used when confronted with measurement error and movement constraints. We then apply our framework to an Argos satellite telemetry data set on harbor seals (Phoca vitulina) in the Gulf of Alaska, a species that is constrained to move within the marine environment and adjacent coastlines.

A comparison of functional magnetic resonance imaging findings in children with and without a history of early exposure to general anesthesia.

BACKGROUND: Functional magnetic resonance imaging (fMRI) has been used to evaluate the long-term consequences of early exposure to neurotoxic agents. fMRI shows that different patterns of brain activation occur in ethanol-exposed subjects performing a go/no-go response inhibition task. Pharmacologically, ethanol and general anesthetics have similar receptor-level activity in the brain. This study utilizes fMRI to examine brain activation patterns in children exposed to general anesthesia and surgery during early brain development. METHODS: After obtaining Nationwide Children's Hospital IRB approval, a surgical database was utilized to identify children aged 10-17 years with a history of at least 1 h of exposure to general anesthetics and surgery when they were between 0 and 24 months of age. Age- and gender-matched children without anesthesia exposure were recruited as a control group. All subjects were scanned while being presented with a go/no-go response inhibition task. Reaction time and accuracy data were acquired, and the blood-oxygen-level-dependent (BOLD) fMRI signal was measured as a biomarker for regional neuronal activity. RESULTS: There were no differences in terms of performance accuracy and response time. The analysis did not reveal any significant activation differences in the primary region of interest (prefrontal cortex and caudate nucleus); however, activation differences were seen in other structures, including the cerebellum, cingulate gyrus, and paracentral lobule. CONCLUSIONS: Early anesthetic exposure and surgery did not affect accuracy, response time, or activation patterns in the primary region of interest during performance of the task. Intergroup differences in activation patterns in other areas of the brain were observed, and the significance of these findings is unknown. fMRI appears to be a useful tool in evaluating the long-term effects of early exposure to general anesthesia.

Passive acoustic monitoring of Cook Inlet beluga whales (Delphinapterus leucas).

The endangered beluga whale (Delphinapterus leucas) population in Cook Inlet, AK faces threats from a variety of anthropogenic factors, including coastal development, oil and gas exploration, vessel traffic, and military activities. To address existing gaps in understanding about the occurrence of belugas in Cook Inlet, a project was developed to use passive acoustic monitoring to document the year-round distribution of belugas, as well as killer whales (Orcinus orca), which prey on belugas. Beginning in June 2009, ten moorings were deployed throughout the Inlet and refurbished every two to eight months. Despite challenging conditions consisting of strong tidal currents carrying debris and seasonal ice cover, 83% of mooring deployments were successfully recovered. Noise from water flow, vessel traffic, and/or industrial activities was present at several sites, potentially masking some signals. However, belugas were successfully detected at multiple locations. Detections were relatively common in the upper inlet and less common or absent at middle and lower inlet locations. Killer whale signals were also recorded. Some seasonal variability in the occurrence of both belugas and killer whales was evident.

Estimating pulsatile ocular blood volume from intraocular pressure, ocular pulse amplitude, and axial length.

The purpose of this study was to develop a method of estimating pulsatile ocular blood volume (POBV) from measurements taken during an ophthalmic exam, including axial length and using a tonometer capable of measuring intraocular pressure (IOP) and ocular pulse amplitude (OPA). Unpublished OPA data from a previous invasive study was used in the derivation, along with central corneal thickness (CCT) and axial length (AL), as well as IOP from the PASCAL dynamic contour tonometer (DCT) and intracameral (ICM) measurements of IOP for 60 cataract patients. Intracameral mean pressure was set to 15, 20, and 35 mmHg (randomized sequence) in the supine position, using a fluid-filled manometer. IOP and OPA measurements were acquired at each manometric setpoint (DCT and ICM simultaneously). In the current study, ocular rigidity (OR) was estimated using a published significant relationship of OR to the natural log of AL in which OR was invasively measured through fluid injection. Friedenwald's original pressure volume relationship was then used to derive the estimated POBV, delivered to the choroid with each heartbeat as a function of OR, systolic IOP (IOPsys), diastolic IOP (IOPdia), and OPA, according to the derived equation POBV = log (IOPsys/IOPdia) / OR. Linear regression analyses were performed comparing OPA to OR and calculated POBV at each of the three manometric setpoints. POBV was also compared to OPA/IOPdia with all data points combined. Significance threshold was p < 0.05. OR estimated from AL showed a significant positive relationship to OPA for both DCT (p < 0.011) and ICM (p < 0.006) at all three manometric pressure setpoints, with a greater slope for lower IOP. Calculated POBV also showed a significant positive relationship to OPA (p < 0.001) at all three setpoints with greater slope at lower IOP, and a significant negative relationship with IOPdia. In the combined analysis, POBV showed a significant positive relationship to OPA/ IOPdia (p < 0.001) in both ICM and DCT measurements with R2 = 0.9685, and R2 = 0.9589, respectively. POBV provides a straight-forward, clinically applicable method to estimate ocular blood supply noninvasively. Higher IOP in combination with lower OPA results in the lowest values of POBV. The simplified ratio, OPA/ IOPdia, may also provide a useful clinical tool for evaluating changes in ocular blood supply in diseases with a vascular component, such as diabetic retinopathy and normal tension glaucoma. Future studies are warranted.

The comparative effects of lipid, epinephrine, and their combination in the reversal of bupivacaine-induced asystole in the isolated rat heart.

BACKGROUND: It remains unclear whether lipid combined with epinephrine is superior or inferior to either drug alone in treating bupivacaine cardiotoxicity. We compared the effects of lipid, epinephrine, and the combination of the two in reversing bupivacaine-induced asystole in the isolated rat heart model. We also measured the effects of lipid, epinephrine, and the combination of the two on bupivacaine content in cardiac tissue. METHODS: Hearts from male Sprague-Dawley rats were excised and retrograde-perfused in a nonrecirculating Langendorff preparation. Bupivacaine 100 µmol/L was perfused until 3 minutes after asystole. Two percent lipid and 30 µmol/L bupivacaine mixture was then perfused in the lipid group; 0.15 µg/mL epinephrine and 30 µmol/L bupivacaine mixture in the epinephrine group; 2% lipid combined with 0.15 µg/mL epinephrine and 30 µmol/L bupivacaine in the combination group; and 30 µmol/L bupivacaine alone in the control group. Recovery of heartbeat was defined as unassisted regular rhythm with a rate-pressure product (RPP) >10% of baseline for >1 minute. We compared the time from the end of 100 µmol/L bupivacaine infusion to recovery of heartbeat (T(recovery)) for each group. The variables of cardiac function were recorded for 40 minutes after recovery of heartbeat. The cardiac apex of each heart was taken for measurement of the bupivacaine content by liquid chromatography-tandem mass spectrometry at the end of the experiment. RESULTS: Time to recovery (T(recovery)) in the lipid and combination groups was significantly shorter than that in the epinephrine and control groups (P < 0.001), and T(recovery) in the epinephrine group was shorter than that in the control group (P < 0.05). The rank order of the mean RPP during the 40 minutes after recovery of heartbeat from highest to lowest was the combination group > the lipid and epinephrine groups > the control group (P < 0.01). The rank order of the highest RPP value during recovery (RPP(maximum)) and the ratio of RPP(maximum) to baseline value (RPP(maximum)/RPP(baseline)) from highest to lowest was the combination group > the lipid and epinephrine groups > the control group (P < 0.01). There was no significant difference between the lipid and epinephrine groups for RPP, RPP(maximum), and RPP(maximum)/RPP(baseline). Cardiac tissue bupivacaine content in the epinephrine and control groups was higher than that in the lipid and combination groups (P < 0.001). CONCLUSIONS: Lipid combined with epinephrine resulted in better recovery of cardiac function than either drug alone in reversal of bupivacaine-induced asystole in the isolated rat heart model.

Improving safety by developing trust with a just culture.

This article presents a simple conceptual road map for implementing a just culture in healthcare settings. The concept of just culture was developed as one of five fundamental elements of a safety culture by psychology professor James Reason in 1997. A just culture requires an unbiased method of judging human error and is designed to develop organisational trust so that adverse medical events (errors) are reported and corrected before they combine with other errors to cause injury or death. To implement a just culture properly so as to increase organisational safety, practitioners must understand its role in enabling the error reporting needed to develop a safety culture. This article reviews these foundational concepts and explores the human causes of errors that a just culture addresses, the psychological importance of a just culture in enabling error reporting and how to implement a just culture in organisations.

The influence of sea ice on the detection of bowhead whale calls.

Bowhead whales (Balaena mysticetus) face threats from diminishing sea ice and increasing anthropogenic activities in the Arctic. Passive acoustic monitoring is the most effective means for monitoring their distribution and population trends, based on the detection of their calls. Passive acoustic monitoring, however, is influenced by the sound propagation environment and ambient noise levels, which impact call detection probability. Modeling and simulations were used to estimate detection probability for bowhead whale frequency-modulated calls in the 80-180 Hz frequency band with and without sea ice cover and under various noise conditions. Sound transmission loss for bowhead calls is substantially greater during ice-covered conditions than during open-water conditions, making call detection ~ 3 times more likely in open-water. Estimates of daily acoustic detection probability were used to compensate acoustic detections for sound propagation and noise effects in two recording datasets in the northeast Chukchi Sea, on the outer shelf and continental slope, collected between 2012 and 2013. The compensated acoustic density suggests a decrease in whale presence with the retreat of sea ice at these recording sites. These results highlight the importance of accounting for effects of the environment on ambient noise and acoustic propagation when interpreting results of passive acoustic monitoring.

Patients first! Engaging the hearts and minds of nurses with a patient-centered practice model.

Like every healthcare system today, the Cleveland Clinic health system is a combination of medical hospitals, institutes, and services in which the implementation of uniform care methodologies faces significant barriers. The guiding principle of the Cleveland Clinic, 'Patients First,' focuses on the principle of patient- and family-centered care (PFCC) but deliberately lacks details due to the wide scope of care delivered by the organization. The Stanley Shalom Zielony Institute of Nursing Excellence (the Nursing Institute) at the Cleveland Clinic was charged with standardizing nursing practice across a system with 11,000 registered nurses and 800 advanced practice nurses. The challenge involved providing firm direction on delivering PFCC that was appropriate for all clinical disciplines and could be implemented quickly across existing practices and technologies. Successful implementation required full engagement in the concept of PFCC by what the Institute for Healthcare Improvement has termed the 'hearts and minds' of nurses. To achieve these ends, development of a systemwide nursing practice model was initiated. In this article the authors identify the essence of PFCC, consider barriers to PFCC, review their process of developing PFCC, and describe how the Cleveland Clinic health system has implemented a PFCC nursing practice model. In doing so the authors explore how the concept of 'Passion for Nursing' was used to stimulate nurse engagement in PFCC.

Insight into the behavior of engineered aerosolized nanoparticles: a method for understanding their fate from an aerosol release in the workplace environment.

We present a method to assess the behavior of aerosol nanoparticles as a function of time and of selected aerosol chamber and environmental conditions upon exposure to polydisperse silicon dioxide (SiO2) aerosol nanoparticles (NPs). Through synthesis of SiO2 aerosol NPs, a well-controlled, stable source of aerosol NPs was used to probe aerosol behavior in an enclosed aerosol chamber. This paper describes a procedure to interface an aerosol chamber downstream of a SiO2 aerosol NP reactor that is capable of synthesizing SiO2 NPs with particle diameters from 10 to 100 nm at particle concentrations of approximately 10(4) to 10(7) particles/cm3. This paper also describes the relative impact on aerosol and aerosol chamber variables, such as chamber volume, the entering aerosol NP size distribution, and environmental parameters, such as relative humidity and ambient particle concentrations, on the observed changes in aerosol NPs over time under unmixed conditions. These findings provide insights into aerosol NP behavior under ideal, well-controlled conditions which can be further refined to include more occupationally relevant conditions that would be important for establishing guidance on suitable workplace containment and controls.

Cocaine self-administration differentially activates microglia in the mouse brain.

The evidence showing the involvement of microglial activation in the development of drug addiction remain scarce as microglia have not been systematically investigated in self-administered mice, a gold standard rodent model for drug addiction. Here we established the stable cocaine self-administration mice to examine microglial activation levels in various brain regions related to reward circuitry. Immunostaining for Iba1 showed a significant upregulation of intensity in the striatum but not in the medial prefrontal cortex (mPFc), hippocampus or thalamus. Further validation experiments showed that cocaine self-administered mice had significantly increased mRNA expression of ccl2 and IL1ß in the striatum but not the mPFc compared to saline controls. Consistently, we found elevated protein levels of Iba1, CCL2, TLR4 and mature IL1ß in the striatum, not in the mPFc of cocaine-receiving mice. In addition, cocaine-stimulated microglia had modified morphology including a reduced number of intersections, a shortened length and number of processes in the NAc. In summary, our results demonstrated that cocaine mediated microglial activation in a region-specific manner in vivo. These findings indicate that microglia could be activated in the early stage of cocaine addiction directly supporting the rationale that dysregulation on neuroimmune signaling is inherently involved in the development of drug addiction.

Continuous Epidural Hydromorphone Infusion for Post-Cesarean Delivery Analgesia in a Patient on Methadone Maintenance Therapy: A Case Report.

The prevalence of opioid use disorder (OUD) in the United States has more than quadrupled over the past two decades. This patient population presents a number of challenges to clinicians, including difficult pain management after surgical procedures due to the development of opioid tolerance. Significantly greater opioid consumption and pain scores after cesarean delivery have been reported in patients with OUD compared to other obstetric patients. A multi-modal analgesic regimen is generally recommended, but there are few well-established pain management strategies after cesarean delivery specific to patients with OUD. We present the case of a patient with OUD maintained on daily methadone that received a continuous epidural hydromorphone infusion for post-cesarean analgesia, a technique not previously reported in obstetric patients and only rarely described for patients undergoing other surgical procedures. The patient received epidural anesthesia for cesarean delivery, and after surgery, the epidural catheter was left in place for the epidural hydromorphone infusion, initiated at 140 mcg/hr and continued for approximately 40 hrs. This strategy reduced her average daily oral opioid consumption by 97%, reduced self-reported pain scores, shortened the length of hospitalization and improved ability to ambulate compared to her previous cesarean delivery. The use of continuous epidural hydromorphone infusion was effective in this case, and this analgesic technique may also be applicable to other types of surgical procedures with the potential for significant post-operative pain, particularly in patients with OUD.

Microneutralization assay titer correlates analysis in two phase 3 trials of the CYD-TDV tetravalent dengue vaccine in Asia and Latin America.

We previously showed that Month 13 50% plaque reduction neutralization test (PRNT50) neutralizing antibody (nAb) titers against dengue virus (DENV) correlated with vaccine efficacy (VE) of CYD-TDV against symptomatic, virologically-confirmed dengue (VCD) in the CYD14 and CYD15 Phase 3 trials. While PRNT is the gold standard nAb assay, it is time-consuming and costly. We developed a next-generation high-throughput microneutralization (MN) assay and assessed its suitability for immune-correlates analyses and immuno-bridging applications. We analyzed MN and PRNT50 titers measured at baseline and Month 13 in a randomly sampled immunogenicity subset, and at Month 13 in nearly all VCD cases through Month 25. For each serotype, MN and PRNT50 titers showed high correlations, at both baseline and Month 13, with MN yielding a higher frequency of baseline-seronegatives. For both assays, Month 13 titer correlated inversely with VCD risk. Like PRNT50, high Month 13 MN titers were associated with high VE, and estimated VE increased with average Month 13 MN titer. We also studied each assay as a valid surrogate endpoint based on the Prentice criteria, which supported each assay as a valid surrogate for DENV-1 but only partially valid for DENV-2, -3, and -4. In addition, we applied Super-Learner to assess how well demographic, Month 13 MN, and/or Month 13 PRNT50 titers could predict Month 13-25 VCD outcome status; prediction was best when using demographic, MN, and PRNT50 information. We conclude that Month 13 MN titer performs comparably to Month 13 PRNT50 titer as a correlate of risk, correlate of vaccine efficacy, and surrogate endpoint. The MN assay could potentially be used to assess nAb titers in immunogenicity studies, immune-correlates studies, and immuno-bridging applications. Additional research would be needed for assessing the utility of MN titer in correlates analyses of other DENV endpoints and over longer follow-up periods.

Effects of succinobucol (AGI-1067) after an acute coronary syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Oxidative stress and inflammation are involved in the pathophysiology of atherosclerosis. Our aim was to assess the effects of the antioxidant succinobucol (AGI-1067) on cardiovascular outcomes in patients with recent acute coronary syndromes already managed with conventional treatments. METHODS: After an acute coronary syndrome occurring 14-365 days before recruitment, 6144 patients were randomly assigned with a computer-generated randomisation list, stratified by study site, to receive succinobucol (n=3078) or placebo (n=3066) in addition to standard of care. Enrolment began in July, 2003; this event-driven trial was stopped in August, 2006, after the prespecified number of primary outcome events had occurred. The composite primary endpoint was time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, unstable angina, or coronary revascularisation. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00066898. FINDINGS: All randomised patients were included in the efficacy analyses. Succinobucol had no effect on the primary endpoint (530 events in succinobucol group vs 529 in placebo group; hazard ratio 1.00, 95% CI 0.89-1.13, p=0.96). The composite secondary endpoint of cardiovascular death, cardiac arrest, myocardial infarction, or stroke occurred in fewer patients in the succinobucol group than in the placebo group (207 vs 252 events; 0.81, 0.68-0.98, p=0.029). The tertiary endpoint of new-onset diabetes developed in fewer patients without diabetes at baseline in the succinobucol group than in such patients in the placebo group (30 of 1923 vs 82 of 1950 patients; 0.37, 0.24-0.56, p<0.0001). New-onset atrial fibrillation occurred more often in the succinobucol group than in the placebo group (107 of 2818 vs 55 of 2787 patients; 1.87, 1.67-2.09, p=0.0002). Although the number of patients who reported any treatment emergent adverse event was much the same in the two groups, more patients in the succinobucol group than in the placebo group reported bleeding episodes or anaemia (32 vs 18 and 37 vs ten, respectively) as serious adverse events. Relative to treatment with placebo, succinobucol increased LDL cholesterol and systolic blood pressure, and decreased HDL cholesterol and glycated haemoglobin (p<0.0001 for all). INTERPRETATION: Although succinobucol had no effect on the primary endpoint, changes in the rates of other clinical outcomes-both beneficial and harmful-will need to be further assessed before succinobucol is used in patients with atherosclerosis or as an antidiabetic agent.

On the use of nonparametric tests for comparing immunological Reverse Cumulative distribution curves (RCDCs).

Reverse Cumulative Distribution Curves (RCDCs) have proven to be a useful tool in summarizing immune response profiles in vaccine studies since their introduction by Reed, Meade, and Steinhoff (RMS) (1995). They are able to display virtually all of the treatment data and characterize summary statistics such as means or even their confidence intervals (CIs) that might be obscure. RMS mentioned their similarity to survival curves often used to summarize time-to-event data which are usually not normally distributed. The RCDCs, while intuitively pleasing and useful, contain important properties which allow for more powerful statistical applications. In this paper, we will suggest several widely used rank-based tests to compare the curves in the context of vaccine studies. These rank-based tests allow for comparisons between treatments, for stratified analyses, weighted analyses, and other modifications that make them the alternative of parametric analyses without the normality assumptions. Clinical trial identification: NCT01712984 and NCT01230957.