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All the factors potentially influencing tacrolimus dose requirement and combinations thereof have never been thoroughly investigated, precluding accurate prediction of tacrolimus starting dose. This prospective, non-interventional, multicenter study in de novo adult kidney transplant recipients over the first year after transplantation aimed to investigate the factors influencing tacrolimus dose-standardized trough blood concentration (C 0 /D) over the first week post-transplant (D4-D7, primary objective), D8-M3 and M3-M12 (secondary objectives). Statistical analysis employed mixed linear models with repeated measures. Eighteen sites enrolled 440 patients and followed them up for 9.5 ± 4.1 months. Age at baseline ( p = 0.0144), end-stage renal disease ( p = 0.0092), CYP3A phenotype ( p < 0.0001), dyslipidemia at baseline ( p = 0.0031), hematocrit ( p = 0.0026), total bilirubin ( p = 0.0261) and plasma creatinine ( p = 0.0484) independently increased with log(C 0 /D) over D4-D7, explaining together 72.3% of the interindividual variability, and representing a robust model to estimate tacrolimus initial dose. Donor age and CYP3A phenotype were also influential over D8-M3 and M3-12, in addition to recipient age. Corticosteroids, diabetes at baseline, and ASAT yielded inconstant results between D8-M3 and M3-M12. We found no ethnicity effect when CYP3A phenotype was accounted for, and no food effect. Intra-individual variability over M3-M12 was moderate, and significantly lower in patients with chronic hepatic disorder ( p = 0.0196) or cancer ( p = 0.0132)., Competing Interests: SA and LS are employees of SANDOZ S.A.S, Levallois-Perret, France, which funded the study. JB, SG, and AL-C are employees of RCTs, the contract research organization that conducted the study on behalf of SANDOZ S.A.S. AH is a biostatistician at University Hospital of Limoges, France. PM, DA, and LR received honoraria from SANDOZ S.A.S as members of the study’s independent Scientific Committee. PM is a consultant/medical expert for Astellas, BMS, Chiesi, Exeltis, MedIncell, Pfizer, Siemens and Womed. DA is a consultant/medical expert for Astellas, Astra Zeneca, BMS and Chiesi. LR is a consultant/medical expert for BMS and Sanofi., (Copyright © 2024 Marquet, Anglicheau, Humeau, Adrouche, Saada, Bisiaux, Guillemin, Lardy-Cléaud and Rostaing.)

Recurrent urinary tract infections are a common problem faced by clinicians across many specialities. For the patient, recurrent urinary tract infections can be burdensome and detrimental to their quality of life. For the clinician, they can be challenging to manage, and the socioeconomic burden on healthcare systems can also be substantial. Investigations serve to rule out any underlying structural or pathological abnormalities. In conjunction with behavioural prevention methods, treatment strategies include antibiotic and non-antibiotic approaches and holistic management approaches. This article provides an overview of the investigation and treatment of urinary tract infections and includes algorithms which can be used in daily clinical practice.

Nitric Oxide, synthesized from L-arginine by the nitric oxide synthases, has a complex role within the human body. It contributes to almost every physiological system and has been found to be both protective and toxic in disease states. An aging population faces an increasing incidence of neurodegenerative disease and the pathological action of nitric oxide in Alzheimer's and Parkinson's diseases may be important therapeutic targets for the future. Nitric oxide's protective effects are also important to consider, through inhibition of caspase-3, nitrosylation of NMDA and increased activation of protein kinase B and CREB transcription factor. Nitric oxide has been shown to play a part in long term potentiation, revealing its importance in synaptic plasticity. Due to nitric oxide's mixed effects it is an exciting and varied therapeutic target. Currently, the impact of these therapies has been explored and developed in animal studies, but is yet to be fully realized in human trials. This paper outlines both the pathological and protective roles of nitric oxide in the central nervous system and the potential pharmacological therapies and targets these indicate.