Angular asymptotics for multi-dimensional non-homogeneous random walks with asymptotically zero drift

We study the first exit time $\tau$ from an arbitrary cone with apex at the origin by a non-homogeneous random walk (Markov chain) on $\Z^d$ ($d \geq 2$) with mean drift that is asymptotically zero. Specifically, if the mean drift at \bx \in \Z^d is of magnitude O(\| \bx\|^{-1}), we show that $\tau<\infty$ a.s. for any cone. On the other hand, for an appropriate drift field with mean drifts of magnitude \| \bx\|^{-\beta}, $\beta \in (0,1)$, we prove that our random walk has a limiting (random) direction and so eventually remains in an arbitrarily narrow cone. The conditions imposed on the random walk are minimal: we assume only a uniform bound on $2$nd moments for the increments and a form of weak isotropy. We give several illustrative examples, including a random walk in random environment model

Non-homogeneous random walks with non-integrable increments and heavy-tailed random walks on strips

We study asymptotic properties of spatially non-homogeneous random walks with non-integrable increments, including transience, almost-sure bounds, and existence and non existence of moments for first-passage and last-exit times. In our proofs we also make use of estimates for hitting probabilities and large deviations bounds. Our results are more general than existing results in the literature, which consider only the case of sums of independent (typically, identically distributed) random variables. We do not assume the Markov property. Existing results that we generalize include a circle of ideas related to the Marcinkiewicz-Zygmund strong law of large numbers, as well as more recent work of Kesten and Maller. Our proofs are robust and use martingale methods. We demonstrate the benefit of the generality of our results by applications to some non-classical models, including random walks with heavy-tailed increments on two-dimensional strips, which include, for instance, certain generalized risk processes

Design of FLAIR:a Phase 2b Study of the 5-Lipoxygenase Activating Protein Inhibitor AZD5718 in Patients With Proteinuric CKD

Introduction: Patients with chronic kidney disease (CKD) remain at risk for kidney and cardiovascular events resulting from residual albuminuria, despite available treatments. Leukotrienes are proinflammatory and vasoconstrictive lipid mediators implicated in the etiology of chronic inflammatory diseases. AZD5718 is a potent, selective, and reversible 5-lipoxygenase activating protein (FLAP) inhibitor that suppresses leukotriene production. Methods: FLAIR (FLAP Inhibition in Renal disease) is an ongoing phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of AZD5718 in patients with proteinuric CKD with or without type 2 diabetes. Participants receive AZD5718 at 3 different doses or placebo once daily for 12 weeks, followed by an 8-week extension in which they also receive dapagliflozin (10 mg/d) as anticipated future standard of care. The planned sample size is 632 participants, providing 91% power to detect 30% reduction in urinary albumin-to-creatinine ratio (UACR) between the maximum dose of AZD5718 and placebo. The dose–response effect of AZD5718 on UACR after the dapagliflozin extension is the primary efficacy objective. Key secondary objectives are the dose–response effect of AZD5718 plus current standard of care on UACR and acute effects of treatment on the estimated glomerular filtration rate. Safety, tolerability, AZD5718 pharmacokinetics, and analyses of biomarkers that may predict or reflect response to AZD5718 are additional objectives. Conclusion: FLAIR will provide data on the effects of 5-lipoxygenase pathway inhibition in patients with proteinuric CKD with or without type 2 diabetes, and will form the basis for future clinical trials (ClinicalTrials.gov: NCT04492722)

Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism.

Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application

Burkholderia pseudomallei infection, or melioidosis, and nephrotic syndrome.

In summary, we present a case of melioidosis that amply demonstrates its ability to cause severe illness, often in patients with pre-existing renal problems, and its propensity to cause further severe derangement in renal function. Usually this is in the form of oliguric acute renal failure presumably caused, in the main, by acute tubular necrosis. However, the case we present indicates that, in common with certain other specific infectious diseases, nephrotic syndrome may be a significant (albeit rare) complication of infection with B. pseudomallei. We postulate that immune-complex mediated renal injury may occur in melioidosis

A Markov chain model of a polling system with parameter regeneration

We study a model of a polling system i.e. a collection of d queues with a single server that switches from queue to queue. The service time distribution and arrival rates change randomly every time a queue is emptied. This model is mapped to a mathematically equivalent model of a random walk with random choice of transition probabilities, a model which is of independent interest. All our results are obtained using methods from the constructive theory of Markov chains. We determine conditions for the existence of polynomial moments of hitting times for the random walk. An unusual phenomenon of thickness of the region of null recurrence for both the random walk and the queueing model is also proved