Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials.

RATIONALE & OBJECTIVE: Tolvaptan is associated with risk of drug-induced liver injury when used to treat autosomal dominant polycystic kidney disease (ADPKD). After this risk was described based on the clinical trials TEMPO 3:4 and TEMPO 4:4, additional data from the REPRISE trial and a long-term extension of TEMPO 4:4, REPRISE, and other tolvaptan trials in ADPKD have become available. To further characterize the hepatic safety profile of tolvaptan, an analysis of the expanded dataset was conducted. STUDY DESIGN: Analysis of safety data from prospective clinical trials of tolvaptan. SETTING & PARTICIPANTS: Multicenter clinical trials including more than 2,900 tolvaptan-treated participants, more than 2,300 with at least 18 months of drug exposure. INTERVENTION: Tolvaptan administered twice daily in split-dose regimens. OUTCOMES: Frequency of liver enzyme level increases detected by regular laboratory monitoring. RESULTS: In the placebo-controlled REPRISE trial, more tolvaptan- than placebo-treated participants (38 of 681 [5.6%] vs 8 of 685 [1.2%]) experienced alanine aminotransferase level increases to >3× the upper limit of normal (ULN), similar to TEMPO 3:4 (40 of 957 [4.4%] vs 5 of 484 [1.0%]). No participant in REPRISE or the long-term extension experienced concurrent alanine aminotransferase level increases to >3× ULN and total bilirubin increases to >2× ULN ("Hy's Law" laboratory criteria). Based on the expanded dataset, liver enzyme increases most often occurred within 18 months after tolvaptan initiation and were less frequent thereafter. Increased levels returned to normal or near normal after treatment interruption or discontinuation. Thirty-eight patients were rechallenged with tolvaptan after the initial drug-induced liver injury episode, with return of liver enzyme level increases in 30; 1 additional participant showed a clinical "adaptation" after the initial episode, with resolution of the enzyme level increases despite continuation of tolvaptan. LIMITATIONS: Retrospective analysis. CONCLUSIONS: The absence of Hy's Law cases in REPRISE and the long-term extension trial support monthly liver enzyme monitoring during the first 18 months of tolvaptan exposure and every 3 months thereafter to detect and manage enzyme level increases, as is recommended on the drug label. FUNDING: Otsuka Pharmaceutical Development & Commercialization, Inc. TRIAL REGISTRATION: Trials included in the dataset were registered at ClinicalTrials.gov with study numbers NCT00428948 (TEMPO 3:4), NCT01214421 (TEMPO 4:4), NCT02160145 (REPRISE), and NCT02251275 (long-term extension).

Mastering the game of Go without human knowledge.

A long-standing goal of artificial intelligence is an algorithm that learns, tabula rasa, superhuman proficiency in challenging domains. Recently, AlphaGo became the first program to defeat a world champion in the game of Go. The tree search in AlphaGo evaluated positions and selected moves using deep neural networks. These neural networks were trained by supervised learning from human expert moves, and by reinforcement learning from self-play. Here we introduce an algorithm based solely on reinforcement learning, without human data, guidance or domain knowledge beyond game rules. AlphaGo becomes its own teacher: a neural network is trained to predict AlphaGo's own move selections and also the winner of AlphaGo's games. This neural network improves the strength of the tree search, resulting in higher quality move selection and stronger self-play in the next iteration. Starting tabula rasa, our new program AlphaGo Zero achieved superhuman performance, winning 100-0 against the previously published, champion-defeating AlphaGo.

Indirect Associations Between Posttraumatic Stress Symptoms and Other Psychiatric Symptoms, Alcohol Use, and Well-being via Psychological Flexibility Among Police Officers.

Police officers experience a high number of potentially traumatic events (PTEs) often associated with elevated posttraumatic stress symptoms (PTSS). In addition, PTSS are related to co-occurring psychiatric symptoms (e.g., anxiety, depression), alcohol misuse, and low perceived well-being. Yet, behavioral processes that may account for the associations between PTSS and unfavorable outcomes remain unspecified. Psychological flexibility, or one's response to private experiences (e.g., PTE-related memories) with an open, aware, and active approach, may be one such process. The present study aimed to evaluate psychological flexibility as both a mediator and moderator of PTSS and commonly co-occurring psychiatric symptoms, alcohol use, and general well-being, using cross-sectional data provided by a sample of police officers (N = 459) recruited from three regionally distributed U.S. police agencies. Structural equation modeling indicated a well-fitting model wherein psychological flexibility indirectly accounted for associations among PTSS and endogenous outcomes, χ2 (107, N = 457) = 225.33, p < .001, CFI = .99, TLI = .98, RMSEA = .05, 90% CI [.04, .06], SRMR = .03. Psychological flexibility also moderated associations between PTSS and psychiatric symptoms, B = 1.58 (SE = 0.22), p < .001; and well-being, B = -3.84 (SE = 0.46), p < .001. Although additional research is needed, these preliminary results suggest psychological flexibility may be a behavioral process that accounts for negative outcomes associated with PTSS and a productive intervention target in the context of PTSS and generalized distress. Further research regarding the role of psychological flexibility in PTSS-related outcomes for police officers appears warranted.

Micro-x-ray fluorescence, micro-x-ray absorption spectroscopy, and micro-x-ray diffraction investigation of lead speciation after the addition of different phosphorus amendments to a smelter-contaminated soil.

The stabilization of Pb on additions of P to contaminated soils and mine spoil materials has been well documented. It is clear from the literature that different P sources result in different efficacies of Pb stabilization in the same contaminated material. We hypothesized that the differences in the efficacy of Pb stabilization in contaminated soils on fluid or granular P amendment addition is due to different P reaction processes in and around fertilizer granules and fluid droplets. We used a combination of several synchrotron-based techniques (i.e., spatially resolved micro-X-ray fluorescence, micro-X-ray absorption near-edge structure spectroscopy, and micro-X-ray diffraction) to speciate Pb at two incubation times in a smelter-contaminated soil on addition of several fluid and granular P amendments. The results indicated that the Pb phosphate mineral plumbogummite was an intermediate phase of pyromorphite formation. Additionally, all fluid and granular P sources were able to induce Pb phosphate formation, but fluid phosphoric acid (PA) was the most effective with time and distance from the treatment. Granular phosphate rock and triple super phosphate (TSP) amendments reacted to generate Pb phosphate minerals, with TSP being more effective at greater distances from the point of application. As a result, PA and TSP were the most effective P amendments at inducing Pb phosphate formation, but caution needs to be exercised when adding large amounts of soluble P to the environment.

Clarifying relations of emotion regulation, emotional avoidance and anxiety symptoms in a community-based treatment-seeking sample.

OBJECTIVES: Anxiety is a global problem that is readily treatable with psychosocial interventions, though many individuals do not benefit following participation in extant treatment protocols. Accordingly, clarification of process-related variables that may be leveraged to enhance outcomes appears warranted. Emotion regulation (ER) is a robust correlate of anxiety symptoms and is often targeted in behavioural treatments applied to anxiety-related problems. Yet, some evidence suggests ER difficulties may be a proxy variable for emotional avoidance (EA). Clarifying the relative influence of ER and EA on anxiety symptom severity may improve specificity in targeting behavioural processes within psychosocial treatments designed to alleviate anxiety-related suffering. Accordingly, we examined relations of ER and EA to anxiety symptom severity after accounting for anxiety sensitivity and anxiolytic medication use in a community-based treatment-seeking sample. DESIGN: A four-step hierarchical linear regression analysis of cross-sectional data provided by a community-based treatment-seeking sample. METHODS: Totally, 120 participants (Mage = 39.18; Female = 58.3%) completed a questionnaire packet upon intake to an anxiety disorders clinic. RESULTS: EA and ER were strongly correlated, and each accounted for significant variance over and above model covariates. EA was a dominant risk factor for anxiety symptom severity, as ER was not a significant predictor (p = .073) following the inclusion of EA in the model (p = .006). CONCLUSIONS: EA appears to be a dominant risk factor, and ER a proxy risk factor, for anxiety symptom severity. EA may be an avenue for greater treatment specificity for those with anxiety symptoms.

Mapping PTSD, depression, and anxiety: A network analysis of co-occurring symptoms in treatment-seeking first responders.

First responders are at high risk for a range of co-occurring mental health conditions due to their repeated exposure to traumatic events. When first responders present for treatment, their complex presentation of symptoms including posttraumatic stress disorder (PTSD), depression, and generalized anxiety disorder (GAD) can prove challenging to differentiate for clinical purposes. Network analysis provides a means to identify the nuanced associations between the symptoms of these conditions and to identify groups of related symptoms. In this study, a treatment-seeking sample of first responders (N = 432) completed self-report measures of PTSD, depression, and GAD. Network analysis was used to identify symptom clusters within the sample. Our cross-sectional data yielded six empirically distinct communities: depression symptoms, GAD symptoms, and four communities comprising PTSD symptoms - intrusion and avoidance; irritability and aggression; negative affect; and arousal and sleep. Network associations underscore the heterogeneity of PTSD and also highlight overlapping and diverging symptoms of depression and GAD. These findings are discussed within the context of existing research on first responders, and recommendations for further study and treatment interventions are provided.

Zinc speciation in proximity to phosphate application points in a lead/zinc smelter-contaminated soil.

The use of P to immobilize Pb in contaminated soils has been well documented. However, the influence of P on Zn speciation in soils has not been extensively examined, and these two metals often occur as co-contaminants. We hypothesized that additions of P to a Pb/Zn-contaminated soil would induce Zn phosphate mineral formation and fluid P sources would be more effective than granular P amendments. A combination of different synchrotron-based techniques, namely, spatially resolved micro-X-ray fluorescence (µ-XRF), micro-extended X-ray absorption fine structure spectroscopy (µ-EXAFS), and micro-X-ray diffraction (µ-XRD), were used to speciate Zn at two incubation times in the proximity of application points (0 to 4 mm) for fluid and granular P amendments in a Pb/Zn smelter-contaminated soil. Phosphate rock (PR), triple super phosphate (TSP), monoammonium phosphate (MAP), and fluid ammonium polyphosphate induced Zn phosphate formation. Ammonium polyphosphate was more effective at greater distances (up to 3.7 mm) from the point of P application. Phosphoric acid increased the presence of soluble Zn species because of increased acidity. Soluble Zn has implications with respect to Zn bioavailability, which may negatively impact vegetation and other sensitive organisms. Although additions of P immobilize Pb, this practice needs close monitoring due to potential increases in Zn solubility in a Pb/Zn smelter-contaminated soil.

The effectiveness of quality control samples in pharmaceutical bioanalysis.

The use of quality control (QC) samples in bioanalysis is well established and consistent with regulatory guidance. However, a systematic evaluation of whether QC samples serve the intended purpose of improving data quality has not been undertaken. The Translational and ADME Sciences Leadership Group (TALG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) conducted an evaluation to assess whether closer agreement is observed when comparing pharmacokinetic data from two passed runs, than when comparing data from failed and passed (retest) runs. Analysis of data collected across organizations, molecular types and analytical platforms, revealed that bioanalytical methods are very reproducible; and that QC samples improve the overall quality of pharmacokinetic concentration data and justifies their continued use.

Next-Generation DILI Biomarkers: Prioritization of Biomarkers for Qualification and Best Practices for Biospecimen Collection in Drug Development.

The diagnosis and management of drug-induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts.

Efficient palladium-catalyzed nucleophilic addition of triorganoindium reagents to carbocyclic derivatives.

Palladium (0)-catalyzed allylic substitution reactions employing triorganoindium reagents have been investigated. In situ generated vinyl- and arylindiums react with substituted and unsubstituted cyclohex-2-enyl esters in the presence of 1-3 mol % Pd(2)(dba)(3) to produce vinyl- or arylcyclohexenes in moderate to excellent yields. The stereoselectivity of this process was also examined, and evidence is presented that the reaction proceeds with inversion of stereochemical configuration.