Aims
Endothelial‐derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that ...was tested in two phase I studies.
Methods
Single escalating doses of GSK2256294 2–20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected.
Results
GSK2256294 was well‐tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half‐life averaging 25–43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose‐dependent, from an average of 41.9% on 2 mg (95% confidence interval CI –51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen.
Conclusions
GSK2256294 was well‐tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.
Thompson Sampling (TS) is one of the oldest heuristics for multiarmed bandit problems. It is a randomized algorithm based on Bayesian ideas and has recently generated significant interest after ...several studies demonstrated that it has favorable empirical performance compared to the state-of-the-art methods. In this article, a novel and almost tight martingale-based regret analysis for Thompson Sampling is presented. Our technique simultaneously yields both problem-dependent and problem-independent bounds: (1) the first near-optimal problem-independent bound of
O
(√
NT
ln
T
) on the expected regret and (2) the optimal problem-dependent bound of (1 + ϵ)Σ
i
ln
T
/
d
(μ
i
,μ
1
) +
O
(
N
/ϵ
2
) on the expected regret (this bound was first proven by Kaufmann et al. (2012b)).
Our technique is conceptually simple and easily extends to distributions other than the Beta distribution used in the original TS algorithm. For the version of TS that uses Gaussian priors, we prove a problem-independent bound of
O
(√
NT
ln
N
) on the expected regret and show the optimality of this bound by providing a matching lower bound. This is the first lower bound on the performance of a natural version of Thompson Sampling that is away from the general lower bound of Ω (√
NT
) for the multiarmed bandit problem.
In their seminal paper Sleator and Tarjan (1985) 15, the authors conjectured that the splay tree is a dynamically optimal binary search tree (BST). In spite of decades of intensive research, the ...problem remains open. Perhaps a more basic question, which has also attracted much attention, is if there exists any dynamically optimal BST algorithm. One such candidate is ▪ which is a simple and intuitive BST algorithm Lucas (1988) 11; Munro (2000) 12; Demaine et al. (2009) 6. Demaine et al. (2009) 6 showed a novel connection between a geometric problem and the binary search tree problem related to the above conjecture. However, there has been little progress in solving this geometric problem too.
Since dynamic optimality conjecture in its most general form remains elusive despite much effort, researchers have studied this problem on special sequences. Recently, Chalermsook et al. (2015) 2 studied a type of sequences known as k-decomposable sequences in this context, where k parametrizes easiness of the sequence. Using tools from forbidden submatrix theory, they showed that ▪ takes n2O(k2) time on this sequence and explicitly raised the question of improving this bound.
In this paper, we show that ▪ takes O(nlogk) time on k-decomposable sequences. In contrast to the previous approach, ours is based on first principles. One of the main ingredients of our result is a new construction of a lower bound certificate on the performance of any algorithm. This certificate is constructed using the execution of ▪, and is more nuanced and possibly more flexible than the previous independent set certificate of Demaine et al. This result, which is applicable to all sequences, may be of independent interest and may lead to further progress in analyzing ▪ on k-decomposable as well as general sequences.
Introduction and Objective
Pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channel plays a critical role in mediating the development of cardiogenic pulmonary edema. ...GSK2798745 is a first-in-class, highly potent, selective, orally active TRPV4 channel blocker being evaluated in a first-time-in-humans study (NCT02119260).
Methods
GSK2798745 was administered in a randomized, placebo-controlled study design to healthy volunteers in three separate cohorts as single escalating doses, with and without food, and as once-daily repeat doses for up to 14 days, respectively. Two cohorts of subjects with mild to moderate heart failure were also administered GSK2798745 once daily for up to 7 days. Safety, tolerability, and systemic exposure data were collected.
Results
No significant safety issues or serious adverse events were observed with GSK2798745 in healthy volunteers and patients with heart failure. GSK2798745 systemic exposure data demonstrated linear pharmacokinetics up to 12.5 mg, less than twofold accumulation with once-daily dosing, and a systemic half-life of ~ 13 h. There was a slight increase in GSK2798745 exposure 14% increase in area under the plasma concentration–time curve (AUC) and 9% increase in maximum observed plasma concentration (
C
max
) after administration with a high-fat meal.
Conclusions
GSK2798745 was well-tolerated in healthy volunteers and patients with stable heart failure. The safety and exposure data obtained in this study allow further evaluation of the drug in long-term clinical studies in heart failure as well as other indications.
Background The usefulness of right heart catherization (RHC) has long been debated, and thus, we aimed to study the real-world impact of the use of RHC in cardiogenic shock. Methods and Results In ...the Nationwide Readmissions Database using
(
), we identified 236 156 patient hospitalizations with cardiogenic shock between 2016 and 2017. We sought to evaluate the impact of RHC during index hospitalization on management strategies, complications, and outcomes as well as on 30-day readmission rate. A total 25 840 patients (9.6%) received RHC on index admission. The RHC group had significantly more comorbidities compared with the non-RHC group. During the index admission, the RHC group had lower death (25.8% versus 39.5%,
<0.001) and stroke rates (3.1% versus 3.4%,
<0.001). Thirty-day readmission rates (18.7% versus 19.7%,
=0.04) and death on readmission (7.9% versus 9.3%,
=0.03) were also lower in the RHC group. After adjustment, RHC was associated with lower index admission mortality (odds ratio, 0.69; 95% CI, 0.66-0.72), lower stroke rate (odds ratio, 0.81; 95% CI, 0.72-0.90), lower 30-day readmission (odds ratio, 0.83; 95% CI, 0.78-0.88), and higher left ventricular assist device implantations/orthotopic heart transplants (odds ratio, 6.05; 95% CI, 4.43-8.28) during rehospitalization. Results were not meaningfully different after excluding patients with cardiac arrest. Conclusions RHC use in cardiogenic shock is associated with improved outcomes and increased use of downstream advanced heart failure therapies. Further blinded randomized studies are required to confirm our findings.
A single 300 mg dose of tafenoquine, in combination with chloroquine, is currently approved in several countries for the radical cure (prevention of relapse) of
malaria in patients aged ≥16 years. ...Recently, however, Watson et al. suggested that the approved dose of tafenoquine is insufficient for radical cure, and that a higher 450 mg dose could reduce P. vivax recurrences substantially (Watson et al., 2022). In this response, we challenge Watson et al.'s assertion based on empirical evidence from dose-ranging and pivotal studies (published) as well as real-world evidence from post-approval studies (ongoing, therefore currently unpublished). We assert that, collectively, these data confirm that the benefit-risk profile of a single 300 mg dose of tafenoquine, co-administered with chloroquine, for the radical cure of
malaria in patients who are not G6PD-deficient, continues to be favourable where chloroquine is indicated for
malaria. If real-world evidence of sub-optimal efficacy in certain regions is observed or dose-optimisation with other blood-stage therapies is required, then well-designed clinical studies assessing safety and efficacy will be required before higher doses are approved for clinical use.
The Lovasz local lemma (LLL) P. Erdos and L. Lovasz, Problems and results on 3-chromatic hypergraphs and some related questions, in Infinite and Finite Sets, Vol. II, A. Hajnal, R. Rado, and V. T. ...Sos, eds., North--Holland, Amsterdam, 1975, pp. 609--627 is a powerful result in probability theory that informally states the following: the probability that none of a set of bad events happens is positive if the probability of each event is small compared to the number of events that depend on it. The LLL is often used for nonconstructive existence proofs of combinatorial structures. A prominent application is to $k$-CNF formulas, where the LLL implies that if every clause in a formula shares variables with at most $d \leq 2^k/e-1$ other clauses, then such a formula has a satisfying assignment. Recently, a randomized algorithm to efficiently construct a satisfying assignment in this setting was given by Moser A constructive proof of the Lovasz local lemma, in STOC '09: Proceedings of the 41st Annual ACM Symposium on Theory of Computing, ACM, New York, 2009, pp. 343--350. Subsequently Moser and Tardos J. ACM, 57 (2010), pp. 11:1--11:15 gave a general algorithmic framework for the LLL and a randomized algorithm within this framework to construct the structures guaranteed by the LLL. The main problem left open by Moser and Tardos was to design an efficient deterministic algorithm for constructing structures guaranteed by the LLL. In this paper we provide such an algorithm. Our algorithm works in the general framework of Moser and Tardos with a minimal loss in parameters. For the special case of constructing satisfying assignments for $k$-CNF formulas with $m$ clauses, where each clause shares variables with at most $d \leq 2^{k/(1+\epsilon)}/e - 1$ other clauses, for any $\epsilon\in (0,1)$, we give a deterministic algorithm that finds a satisfying assignment in time $\tilde{O}(m^{2(1+1/\epsilon)})$. This improves upon the deterministic algorithms of Moser and of Moser and Tardos with running times $m^{\Omega(k^2)}$ and $m^{\Omega(d \log d)}$, respectively, which are superpolynomial for $k=\omega(1)$ and $d=\omega(1)$, and upon the previous best deterministic algorithm of Beck, which runs in polynomial time only for $d\leq 2^{k/16}/4$. Our algorithm is the first deterministic algorithm that works in the general framework of Moser and Tardos. We also give a parallel NC algorithm for the same setting, improving upon an algorithm of Alon Random Structures Algorithms, 2 (1991), pp. 367--378. PUBLICATION ABSTRACT
Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced
in vitro
and
in vivo
characterization can improve our understanding of the injection ...space and aid in describing the long-acting injectable (LAI) drug’s behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on
in vitro
release methods, available biopharmaceutical models and reported
in vitro/in vivo correlations
(IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.
Graphical Abstract
Count in Time So All is Fine Sharma, Ankur; Chandnani, Naina; Vincent, Navin ...
Indian journal of otolaryngology, and head, and neck surgery,
09/2023, Letnik:
75, Številka:
3
Journal Article
Recenzirano
Dislodgement of surgical sponge into airway during the intraoperative period is uncommon as the airway, in most cases secured by an endotracheal tube. We report such an unusual case during micro ...laryngeal surgery and direct laryngoscopy assessment under general anaesthesia. This shows early suspicion and quick action to avoid disaster.
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