Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia.

Results from a pilot, 6-week, randomized, open-label, rater-blinded study, with 46-week extension, indicate very good tolerability with exceptional, clinically important, increasing efficacy of evenamide (7.5, 15, and 30 mg bid), a glutamate modulator, as add-on treatment to antipsychotics in 161 treatment-resistant, schizophrenia patients. Ninety-five percent of patients completed 6 weeks (1 discontinued for adverse event), and 89% continued in the extension. Results from the first 100 patients enrolled showed very low attrition over 1 year (77 completers); data pooled from all dose groups showed the Positive and Negative Syndrome Scale total score improved significantly (P < .001; paired t test; last observation carried forward [LOCF]) from baseline at 6 weeks (-9.4), 6 months (-12.7), and 1 year (-14.7); similarly, the proportion of responders (≥20% improvement) increased over time from 6 weeks (16.5%) to 6 months (39%) to 1 year (47.4%). Noteworthy improvement was also observed at each timepoint on the Clinical Global Impression - Severity scale and Clinical Global Impression of Change, indicating progressively increasing efficacy of evenamide up to 1 year.

Comparison of percutaneous tracheostomy methods in ICU patients: Conventional anatomical landmark method versus ultrasonography method - A randomised controlled trial.

Background and Aims: Percutaneous dilational tracheostomy (PDT) is a common procedure in intensive care unit (ICU) patients requiring long-term mechanical ventilation. PDT has gradually replaced surgical tracheostomy because it is associated with minimal invasiveness, reduced bleeding and simplicity in technique.This study was conducted to compare ultrasound-guided PDT versus conventional tracheostomy in terms of duration of the procedure, number of passes and immediate peri-procedural complications. Methods: A total of 72 patients with clinical indications of tracheostomy were recruited. A total of 12 patients met the exclusion criteria. The remaining were randomly assigned into two groups of 30 each: Group A (Landmark) with traditional anatomical landmark and Group B (USG) with real-time ultrasound guidance. Puncture positions were recorded with bronchoscopy. Midline deviation was captured on a bronchoscopy image using a protractor. Data on procedural safety and efficacy were also collected. Results: Group B had significantly fewer cases of midline deviation (11.33 ± 9.51) in comparison to Group A (16.60 ± 12.31). Trials > 2 were equal to 11 in Group A and 2 in Group B. However, the duration of the procedure was higher in Group B (20.07 ± 3.25 min) as compared to Group A (15.20 ± 3.71 min). Peri-procedural and post-procedural complications were also higher in the Landmark group. Conclusion: Ultrasound-guided PDT showed superiority over landmark PDT in terms of less number of trials, midline puncture and fewer complications. However, it took a little longer to perform USG-guided PDT.

Hyperglycemia Risk Evaluation of Hydrocortisone Intermittent Boluses versus Continuous Infusion in Septic Shock: A Prospective Randomized Trial.

Background: Hydrocortisone showed an important role in reversal of shock when added to standard therapy in managing septic shock. Hyperglycemia is one of the most common side effects associated with corticosteroid treatment. Aims: This study aimed to evaluate the risk of hyperglycemia of intermittent hydrocortisone boluses versus continuous infusion in septic shock patients. Settings and Design: This was a prospective randomized controlled study conducted in a tertiary care teaching hospital. Materials and Methods: One hundred and forty patients with septic shock and who received noradrenaline were enrolled in this randomized study. Group 1 was intermittent bolus hydrocortisone group (n = 70) and Group 2 was continuous infusion group (n = 70). All patients who were admitted with septic shock and who received noradrenaline and hydrocortisone were included in the study. Those patients who had exceeded 200 mg per day of hydrocortisone were excluded from the study. The primary outcome of the study was mean blood glucose. Statistical Analysis Used: Qualitative variables were compared between the two groups with the Chi-square of the Fisher's exact test and continuous variables were compared using the Student's t-test or the Wilcoxon rank-sum test. Results: Out of 112 patients, 54 patients received hydrocortisone as intermittent boluses (48.2%), and 58 patients (51.8%) received continuous infusion. For the primary outcome, no statistically or clinically significant difference was found in the blood glucose estimated marginal mean: 154.44 mg.dL-1 (95% confidence interval [CI]: 144.18-166.88) in the bolus group and 160.2 mg.dL-1 (95% CI: 143.82-176.76) in the infusion group with a mean difference of 05.76 mg.dL-1 (95% CI: -13.86-25.38). For the secondary outcomes of the study, no difference was found between the two groups in hyperglycemic or hypoglycemic events, mortality, length of stay in intensive care unit, and reversal of shock. Conclusions: The risk of hyperglycemia is almost equal in both intermittent and continuous infusions of hydrocortisone in septic shock patients.

Evidence for fungi and gold redox interaction under Earth surface conditions.

Microbial contribution to gold biogeochemical cycling has been proposed. However, studies have focused primarily on the influence of prokaryotes on gold reduction and precipitation through a detoxification-oriented mechanism. Here we show, fungi, a major driver of mineral bioweathering, can initiate gold oxidation under Earth surface conditions, which is of significance for dissolved gold species formation and distribution. Presence of the gold-oxidizing fungus TA_pink1, an isolate of Fusarium oxysporum, suggests fungi have the potential to substantially impact gold biogeochemical cycling. Our data further reveal that indigenous fungal diversity positively correlates with in situ gold concentrations. Hypocreales, the order of the gold-oxidizing fungus, show the highest centrality in the fungal microbiome of the auriferous environment. Therefore, we argue that the redox interaction between fungi and gold is critical and should be considered in gold biogeochemical cycling.

Publisher Correction: Natural gold particles in Eucalyptus leaves and their relevance to exploration for buried gold deposits.

This corrects the article DOI: 10.1038/ncomms3614.

A Study of the Pharmacokinetic Properties and the In Vivo Kinetics of Erythrocytes Loaded With Dexamethasone Sodium Phosphate in Healthy Volunteers.

The objectives of this 2-phase study were to elucidate pharmacokinetics (PK), in vivo 24-hour recovery, and red blood cell (RBC) survival properties of RBC-encapsulated dexamethasone sodium phosphate (DSP) prepared using the EryDex System (EDS). The 24-hour RBC recovery and T50 survival phase studied subjects were randomized to receive autologous RBCs loaded with either 15-20 mg DSP (Group 1A) or sham saline (Group 2A). Loaded RBCs were radiolabeled with 51-Cr, and the labeled RBCs were followed over time in vivo. The PK phase evaluated dose levels of 2.5-5 mg (Group 1B) and 15-20 mg (Group 2B) DSP encapsulated in RBCs infused into healthy randomized subjects. The mean ± SD 24-hour RBC recovery was 77.9% ± 3.3% and 72.7% ± 10.5% for Groups 1A and 2A, respectively. The mean ± SD RBC life span was 84.3 ± 8.3 days in Group 1A and 88.9 ± 6.2 days in Group 2A. The PK phase actual DSP loading doses (mean ± SEM) were 4.2 ± 0.27 mg and 16.9 ± 0.90 mg in Groups 1B and 2B, respectively. Release of dexamethasone from RBCs in vivo peaked at 1 hour, and a sustained release of dexamethasone could be detected until 35 days after the single intravenous infusion in Group 2B. The mean RBC in vivo recovery for DSP-loaded processed cells compares similarly to the 24-hour recovery of regulated RBC products intended for transfusion. There was a minimal but acceptable adverse impact on the survival of EDS-processed RBCs. DSP-loaded autologous RBCs, prepared using the EDS, delivered a sustained dose of dexamethasone in vivo.

Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial.

IMPORTANCE: Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge. OBJECTIVE: To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations. DESIGN, SETTING, AND PARTICIPANTS: From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with "off" time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient's regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group. INTERVENTIONS: Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg. MAIN OUTCOMES AND MEASURES: The prespecified primary outcome was each treatment group's mean change from baseline to week 24 (or last "on" treatment value) in daily "on" time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data. RESULTS: At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]). CONCLUSIONS AND RELEVANCE: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00627640.

Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease.

In a 6-month double-blind, placebo-controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON-time without increasing dyskinesia. Further long-term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON-time over 24 months. Other efficacy endpoints included change in ON-time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2-year, controlled study of add-on safinamide in mid-to-late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON-time (without troublesome dyskinesia), OFF-time, activities of daily living, motor symptoms, quality of life, and symptoms of depression.

Natural gold particles in Eucalyptus leaves and their relevance to exploration for buried gold deposits.

Eucalyptus trees may translocate Au from mineral deposits and support the use of vegetation (biogeochemical) sampling in mineral exploration, particularly where thick sediments dominate. However, biogeochemistry has not been routinely adopted partly because biotic mechanisms of Au migration are poorly understood. For example, although Au has been previously measured in plant samples, there has been doubt as to whether it was truly absorbed rather than merely adsorbed on the plant surface as aeolian contamination. Here we show the first evidence of particulate Au within natural specimens of living biological tissue (not from laboratory experimentation). This observation conclusively demonstrates active biogeochemical adsorption of Au and provides insight into its behaviour in natural samples. The confirmation of biogeochemical adsorption of Au, and of a link with abiotic processes, promotes confidence in an emerging technique that may lead to future exploration success and maintain continuity of supply.

Unilateral RS3PE in a Patient of Seronegative Rheumatoid Arthritis.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare but well-reported clinical entity. It is classically described as symmetrical involvement of both upper extremities. Asymmetrical involvement had also been reported, but unilateral presentation is very rare. We hereby report a case of unilateral RS3PE in a patient of seronegative rheumatoid arthritis which was initially misdiagnosed as cellulitis and was given high dose antibiotics without any significant improvement. Later a rheumatologic consultation leads to a prompt diagnosis, and treatment with steroids leads to dramatic reversal of symptoms. This case demonstrates the rare presentation of this rare clinical entity and highlights the necessity of awareness regarding unilateral disease to clinicians.

Bl-1020, a new γ-aminobutyric acid-enhanced antipsychotic: results of 6-week, randomized, double-blind, controlled, efficacy and safety study.

OBJECTIVE: BL-1020 is a γ-aminobutyric acid (GABA)-enhanced antipsychotic that combines dopamine antagonism with GABA agonist activity. On the basis of animal models, we tested the hypotheses that BL-1020 would be effective in ameliorating both psychotic symptoms and cognitive impairments, with a favorable safety profile in acutely ill schizophrenia patients. METHOD: 363 hospital-based psychiatric patients in India, Romania, and United States aged 18 to 65 years and meeting criteria for DSM-IV-TR diagnosis of chronic schizophrenia were randomized double-blind to receive BL-1020 10 mg/d, BL-1020 20-30 mg/d, placebo, or risperidone (2-8 mg/d) for 6 weeks. The main outcome measures were the positive and negative syndrome scale (PANSS), brief assessment of cognition in schizophrenia, readiness for discharge questionnaire, clinical global impressions scale (CGI) , and extrapyramidal symptom rating scale. The study ran from July 2008 to June 2009. RESULTS: BL-1020 20-30 mg was significantly better than placebo on PANSS (P = .02) and CGI (P < .001) measurements, with no significant differences noted between BL-1020 20-30 mg and risperidone. There were no significant differences in the maximum change on extrapyramidal symptom rating scale between risperidone and BL-1020 20-30 mg, and both were significantly worse (P < .001) than placebo. BL-1020 20-30 mg was associated with significantly greater improvements on cognitive functioning as measured by the brief assessment of cognition in schizophrenia composite score when compared to placebo (effect size = 0.50, P = .009), risperidone (effect size = 0.43, P = .019), and BL-1020 10 mg (effect size = 0.42, P = .013) after 6 weeks. CONCLUSIONS: BL-1020 appears to be an effective antipsychotic with possible procognitive effects that will need to be further tested for short- and long-term effects. A further randomized controlled trial using the U.S. Food and Drug Administration-recommended Measurement and Treatment Research to Improve Cognition in Schizophrenia cognitive battery is ongoing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00567710.

A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson's disease patients.

Safinamide is an α-aminoamide with both dopaminergic and nondopaminergic mechanisms of action evaluated as an add-on to dopamine agonist (DA) therapy in early-stage PD. In this 24-week, double-blind study, patients with early PD receiving a stable dose of a single DA were randomized to once-daily safinamide 100 mg, safinamide 200 mg, or placebo. The primary efficacy variable was UPDRS part III (motor examination) total score. Analysis was hierarchical: 200 mg of safinamide versus placebo was tested first; the success of safinamide 100 mg versus placebo was contingent on this. Two hundred sixty-nine patients received safinamide 100 mg (n = 90), safinamide 200 mg (n = 89), or placebo (n = 90); 70, 81, and 81 patients, respectively, completed the study. Mean improvements from baseline to week 24 in UPDRS III total scores were -3.90 for safinamide 200 mg, -6.0 for safinamide 100 mg and -3.60 for placebo. The difference between safinamide 200 mg and placebo was not significant [point estimate: -0.4; 95% confidence interval (CI): -2.3-1.4; P = 0.6504]. Although the difference between 100 mg/day and placebo was significant (point estimate: -1.9; 95% CI: -3.7 to -0.1; P = 0.0419), these results are considered exploratory. No clinically meaningful differences from placebo were observed for any safety variables. This study did not demonstrate a significant improvement of the primary endpoint for safinamide 200 mg/day. Exploratory analysis of the primary endpoint for 100 mg/day demonstrated that the addition of safinamide to a stable dose of DA improves motor symptoms in early PD and warrants further investigation.

Bacterial communities associated with a mineral weathering profile at a sulphidic mine tailings dump in arid Western Australia.

We investigated bacterial community assemblages and functions down a hill slope contaminated by tailings from a volcanogenic massive sulphide mine in arid Western Australia. Weathering of waste rock, high in S and Fe, had resulted in a varying elemental dispersal down a face of the tailings hill. Bacterial community assemblage, characterised by PCR-DGGE fingerprinting, was significantly associated with electrical conductivity (E.C.) (ρ = 0.664; P < 0.01). Analysis of mobile salts showed that E.C. values were driven by ionic S, Zn, Cl and Al. The bacterial community assemblage was directly characterised across an E.C. gradient using an oligonucleotide microarray (PhyloChip). The dominant taxa at the site were Proteobacteria, Actinobacteria and Firmicutes; however, 37 phyla were detected. The most responsive taxa to variation in E.C. was Acidobacteria (negative correlation). Patterns of heterotrophic processes (BioLog analysis) were also best explained by variation in E.C. (ρ = 0.53; P < 0.01), showing a link between primary mineral weathering by lithotrophic bacteria and abiotic processes, and secondary biogeochemical processes by heterotrophic taxa. These data significantly broaden our knowledge of the bacteria present in metallomorphic ecosystems, establish that mobile phase elements are key drivers of community structure, and that primary biogeochemical cycling is directly influencing other geochemical interactions in the samples.

Use of a relapse monitoring board: an independent assessment for determining relapse in clinical trials for bipolar disorder.

OBJECTIVE: Independent review boards can provide an objective appraisal of investigators' decisions and may be useful for determining complex primary outcomes, such as bipolar disorder relapse, in crossnational studies. This article describes the use of an independent, blinded relapse monitoring board to assess the primary outcome (relapse) in an international clinical trial of risperidone long-acting therapy adjunctive to standard-care pharmacotherapy for patients with bipolar disorder. DESIGN: The fully autonomous relapse monitoring board was composed of a chair and two additional members-all psychiatrists and experts in the diagnostic, clinical, and therapeutic management of bipolar disorder. The relapse monitoring board met six times during the study to review patient relapse data and was charged with the responsibility of determining if the events described by investigators qualified as relapses. Additionally, the relapse monitoring board reviewed data for all randomized patients to identify any relapse events not recognized by investigators. RESULTS: Primary efficacy results were similar and significant for investigator- and relapse monitoring board-determined relapses. Ten discrepancies were noted: two of the 42 investigator-determined relapses did not meet the intended clinical relapse threshold as determined by the relapse monitoring board; conversely, the relapse monitoring board confirmed eight relapse events not identified by investigators. The relapse monitoring board had no direct interactions with patients and had to rely on the accuracy of investigator assessments. Also, once an investigator determined a relapse and the patients discontinued the study, less information was available to the relapse monitoring board for relapse assessment. CONCLUSIONS: Use of the relapse monitoring board supported the validity of the study by incorporating a level of standardization to mitigate the risk that local practice in different cultures and medical systems at the sites would confound study results.

Distribution of metals in the termite Tumulitermes tumuli (Froggatt): two types of Malpighian tubule concretion host Zn and Ca mutually exclusively.

The aim of this study was to determine specific distribution of metals in the termite Tumulitermes tumuli (Froggatt) and identify specific organs within the termite that host elevated metals and therefore play an important role in the regulation and transfer of these back into the environment. Like other insects, termites bio-accumulate essential metals to reinforce cuticular structures and utilize storage detoxification for other metals including Ca, P, Mg and K. Previously, Mn and Zn have been found concentrated in mandible tips and are associated with increased hardness whereas Ca, P, Mg and K are accumulated in Malpighian tubules. Using high resolution Particle Induced X-Ray Emission (PIXE) mapping of whole termites and Scanning Electron Microscope (SEM) Energy Dispersive X-ray (EDX) spot analysis, localised accumulations of metals in the termite T. tumuli were identified. Tumulitermes tumuli was found to have proportionally high Mn concentrations in mandible tips. Malpighian tubules had significant enrichment of Zn (1.6%), Mg (4.9%), P (6.8%), Ca (2.7%) and K (2.4%). Synchrotron scanning X-ray Fluorescence Microprobe (XFM) mapping demonstrated two different concretion types defined by the mutually exclusive presence of Ca and Zn. In-situ SEM EDX realisation of these concretions is problematic due to the excitation volume caused by operating conditions required to detect minor amounts of Zn in the presence of significant amounts of Na. For this reason, previous researchers have not demonstrated this surprising finding.

An open-label tolerability study of BL-1020 antipsychotic: a novel gamma aminobutyric acid ester of perphenazine.

BACKGROUND: BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A). OBJECTIVE: This is the first study to examine tolerability and safety of BL-1020 in schizophrenia. METHODS: This was a phase-II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted. RESULTS: All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change. CONCLUSIONS: These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials.

What is causing the reduced drug-placebo difference in recent schizophrenia clinical trials and what can be done about it?

On September 18, 2007, a collaborative session between the International Society for CNS Clinical Trials and Methodology and the International Society for CNS Drug Development was held in Brussels, Belgium. Both groups, with membership from industry, academia, and governmental and nongovernmental agencies, have been formed to address scientific, clinical, regulatory, and methodological challenges in the development of central nervous system therapeutic agents. The focus of this joint session was the apparent diminution of drug-placebo differences in recent multicenter trials of antipsychotic medications for schizophrenia. To characterize the nature of the problem, some presenters reported data from several recent trials that indicated higher rates of placebo response and lower rates of drug response (even to previously established, comparator drugs), when compared with earlier trials. As a means to identify the possible causes of the problem, discussions covered a range of methodological factors such as participant characteristics, trial designs, site characteristics, clinical setting (inpatient vs outpatient), inclusion/exclusion criteria, and diagnostic specificity. Finally, possible solutions were discussed, such as improving precision of participant selection criteria, improving assessment instruments and/or assessment methodology to increase reliability of outcome measures, innovative methods to encourage greater subject adherence and investigator involvement, improved rater training and accountability metrics at clinical sites to increase quality assurance, and advanced methods of pharmacokinetic/pharmacodynamic modeling to optimize dosing prior to initiating large phase 3 trials. The session closed with a roundtable discussion and recommendations for data sharing to further explore potential causes and viable solutions to be applied in future trials.