Tacrolimus overexposure in kidney transplant recipients during the first post‐operative week: caution is required in older patients

In liver transplantation, tacrolimus trough concentrations (Cmin) above 20 ng/mL during the first days led to worse outcome at 1 year but data in the kidney transplant (KT) era are scarce. The aim of this study was to evaluate the impact of tacrolimus overexposure during the first week post‐transplantation on the kidney function (KF) of KT recipients. In this retrospective study, 105 KT recipients were attributed to overexposure group (OG) or normal group according to their Cmin during the first week of treatment. KF was evaluated by comparing the rate of delayed graft function (DGF) and by collecting plasma creatinine from day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 and at 1 year. Risk factors for developing DGF were also investigated using a multivariate model. DGF was more frequent in OG (43% of patients; P = 0.027) which has higher plasma creatinine on day 7, 14, and 21. OG patients were older with more extended criteria donor's grafts. In the multivariate analysis, only cold ischemia time (CIT) remained associated with DGF (OR = 1.003), while TAC overexposure did not reach significance (P = 0.06; OR = 3.9). In this study, we confirmed the predominant role of CIT as a risk factor for the onset of DGF in kidney transplantation. 43% of KT recipients were overexposed with more DGF, especially older patients.     

Stabilization and formulation of a recombinant Human Cytomegalovirus vector for use as a candidate HIV-1 vaccine

Live attenuated viral vaccine/vector candidates are inherently unstable and infectivity titer losses can readily occur without defining appropriate formulations, storage conditions and clinical handling practices. During initial process development of a candidate vaccine against HIV-1 using a recombinant Human Cytomegalovirus vector (rHCMV-1), large vector titer losses were observed after storage at 4 °C and after undergoing freeze-thaw. Thus, the goal of this work was to develop candidate frozen liquid formulations of rHCMV-1 with improved freeze-thaw and short-term liquid stability for potential use in early clinical trials. To this end, a virus stability screening protocol was developed including use of a rapid, in vitro cell-based immunofluorescence focus assay to quantitate viral titers. A library of ∼50 pharmaceutical excipients (from various known classes of additives) were evaluated for their effect on vector stability after freeze-thaw cycling or incubation at 4 °C for several days. Certain additives including sugars and polymers (e.g., trehalose, sucrose, sorbitol, hydrolyzed gelatin, dextran 40) as well as removal of NaCl (lower ionic strength) protected rHCMV-1 against freeze-thaw mediated losses in viral titers. Optimized solution conditions (e.g., solution pH, buffers and sugar type) slowed the rate of rHCMV-1 titer losses in the liquid state at 4 °C. After evaluating various excipient combinations, three new candidate formulations were designed and rHCMV-1 stability was benchmarked against both the currently-used and a previously reported formulation. The new candidate formulations were significantly more stable in terms of reducing rHCMV-1 titer losses after 5 freeze-thaw cycles or incubation at 4 °C for 30 days. This case study highlights the utility of semi-empirical design of frozen liquid formulations of a live viral vaccine candidate, where protection against infectivity titer losses due to freeze-thaw and short-term liquid storage are sufficient to enable more rapid initiation of early clinical trials.     

Phage therapy: What factors shape phage pharmacokinetics and bioavailability? Systematic and critical review

Bacteriophages are not forgotten viruses anymore: scientists and practitioners seek to understand phage pharmacokinetics in animals and humans, investigating bacteriophages as therapeutics, nanocarriers or microbiome components. This review provides a comprehensive overview of factors that determine phage circulation, penetration, and clearance, and that in consequence determine phage applicability for medicine. It makes use of experimental data collected by the phage community so far (PubMed 1924-2016, including non-English reports), combining elements of critical and systematic review. This study covers phage ability to enter a system by various routes of administration, how (and if) the phage may access various tissues and organs, and finally what mechanisms determine the courses of phage clearance. The systematic review method was applied to analyze (i) phage survival in the gut (gut transit) and (ii) phage ability to enter the mammalian system by many administration routes. Aspects that have not yet been covered by a sufficient number of reports for mathematical analysis, as well as mechanisms underlying trends, are discussed in the form of a critical review. In spite of the extraordinary diversity of bacteriophages and possible phage applications, the analysis revealed that phage morphology, phage specificity, phage dose, presence of sensitive bacteria or the characteristics of treated individuals (age, taxonomy) may affect phage bioavailability in animals and humans. However, once phages successfully enter the body, they reach most organs, including the central nervous system. Bacteriophages are cleared mainly by the immune system: innate immunity removes phages even when no specific response to bacteriophages has yet developed.     

Consumption of whole grain food and its determinants in a general Italian population: Results from the INHES study

Background and aimsWhole grain (WG) food consumption is associated with lower risk of cardiovascular disease, cancer and neurological diseases. The aim of this study was to assess the consumption of WG food and its major demographic, socioeconomic, psychosocial and behavioral determinants in a general Italian population.Methods and resultsData were from the Italian Nutrition & Health Survey (INHES), a telephone-based survey established in 2010–2013 including 9422 participants aged ≥5 years from all over Italy. WG food intake was assessed by the European Food Propensity Questionnaire and included bread, pasta, breakfast cereals, biscuits and WG soups. WG consumption was categorized as none, occasional (<1 time/week) and regular (≥1 time/week). Overall, 26.9% of the sample reported a regular consumption of WG food (27.2% of adults aged 20–97 y, and 21.9% of children/adolescents aged 5–19 y). In both age-groups, the major food source contributing to total WG intake was WG bread followed by WG pasta. Among adults, greater consumption of WG was associated with healthier lifestyle (e.g. sport activity), and higher educational level. Eating meals outside of the house in adults, and spending >2 h/day watching TV in children/adolescents were inversely associated with WG intake.ConclusionsThe percentage of WG consumers in Italy in 2010–2013 appears to be quite low and still below that recorded in other countries of Europe where consumption is frequently over 50 percent. WG consumption is likely to be influenced by socioeconomic status and is associated with a number of psychosocial factors, meal patterns and eating-related behaviors.     

Complications in patients of acetabular fractures and the factors affecting the quality of reduction in surgically treated cases

IntroductionAcetabulum fractures, though relatively uncommon, are associated with significant morbidity and mortality. These involve high energy trauma and due to their complex nature, the management requires understanding the relevant surgical anatomy, defining the injury via appropriate radiographic assessment and determining a suitable treatment plan. Literature is scarce for the demographic data, fracture patterns, associated injuries, management and early complications in the Indian scenario. These factors play a pivotal role in the ultimate recovery of the patients. Therefore this study was conceptualised to assess the epidemiology and evaluate the complications of these fractures. Furthermore the effects of various factors determining the quality of reduction in surgically treated patients were also assessed.MethodologyThis was a prospective observational study in which patients presenting to the advance trauma centre of our institute with acetabulum fractures were included. Demographical data of the patients, mechanisms of injuries, fractures morphologies, complications and radiological outcomes were recorded prospectively.Results116 patients with acetabular fractures were included in the study. 81% of these were males, with average age of 39.95 ± 15.87 years; with road traffic accidents being the predominant mode of injuries. Mortality was reported in 5 patients; 4 patients had deep venous thrombosis and sciatic nerve injuries were seen in 12 patients of which 4 were iatrogenic. 8 patients had some form of infection, out of which 4 required multiple debridements. 4 cases developed heterotrophic ossification while 2 cases had loss of reduction. The timing of surgery and other associated fractures had significant effect on the quality of reduction (p < 0.05); while age, gender, mode of injury or individual fracture patterns had no such effect.ConclusionsProper radiological assessment and evaluation of fracture configuration is important for management of acetabulum fractures. When indicated, this should be followed by early open reduction and internal fixation to achieve anatomical reduction, with management of associated injuries for better outcomes.     

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations

Posaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty‐seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1‐7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8‐2.7) for prophylaxis and 1.76 mg/L (IQR 1.3‐2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.     

The Relationship Between Air Pollution and Lung Cancer in Nonsmokers in Taiwan

Introduction

For never-smokers (smoked <100 lifetime cigarettes), lung cancer (LC) has emerged as an important issue. We aimed to investigate the effects of prevalence changes in tobacco smoking and particulate matter (PM) 2.5 (PM_2.5) levels on LC in Taiwan, in relation to contrasting PM_2.5 levels, between Northern Taiwan (NT) and Southern Taiwan (ST).