Crystal structure resolution of two different chlorhexidine salts

This work was partly funded by the British Heart Foundation (NH/11/8/29253) and the EPSRC (EP/K005499/1). CCDC 1416048 and 1416049 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cifTwo salts of the chlorhexidine di-cation (H2CHx2+) – (H2CHx)(SO4)·3H2O and (H2CHx)(CO3)·4H2O – have been synthesised and characterised crystallographically.Publisher PDFPeer reviewe

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Novel nitric oxide delivery systems for biomedical applications

The aim of the research presented in this thesis is to investigate and develop novel nitric oxide (NO) delivery systems, specifically designed for application in medical areas. The initial work has focused on utilising metal organic frameworks (MOFs) as a delivery system for this radical gas, NO. Due to their high porosity, high thermal stability and the presence of coordinated unsaturated metal sites (CUSs) when fully activated, the CPO-27 (Coordination Polymer of Oslo) family of MOFs has been selected as a suitable host framework. CPO-27 (Ni), CPO-27 (Mg) and CPO-27 (Zn) have been prepared using reflux and room temperature processes without recourse to the use of any toxic or harmful solvents. The resulting products are characterised by powder XRD (X-ray diffraction) and SEM (Scanning electron microscopy), and their NO adsorption, storage and release properties are reported. The results indicate that the crystallinity, particle size and NO adsorption, storage and release performance are comparable to those of equivalent samples synthesised via traditional solvothermal methods, paving the way for a more easily scalable and environmentally friendly synthetic procedure for these types of MOF. Depending on which metal is employed; the NO uptake, storage and release varies, the more toxic nickel based framework shows enhanced performance in terms of concentration and duration of NO released against either the magnesium or zinc counterparts. In order therefore to reduce the risk of toxicity whilst retaining good performance, Ni (II) ions were doped into the 3D framework of CPO-27 (Mg) and CPO-27 (Zn) using novel water-based reflux and room temperature crystallization methods. Several characterization techniques strongly support the effective incorporation of Ni (II) ions into the 3D framework. Nitric oxide (NO) adsorption/release data, as well as in vitro tests demonstrate that NO dosage and biological response can be tuned via the Ni doping process allowing enhanced performance without the high toxicity of pure Ni MOFs. Such materials would be extremely advantageous and more applicable for use in medical fields. NONOates and other NO-complexes have also been investigated as alternative NO delivery systems. This study has focused on developing NO-drug complexes using a variety of different compounds commonly used by clinicians, namely the antiseptic (chlorhexidine, CHx), the antibiotic (ciprofloxacin) and diuretic (furosemide). A unique high pressure NO loading methodology has been developed to coordinate nitric oxide to these drug molecules and their NO release performance has been evaluated. The resulting NO-drug complexes are characterised using a series of spectroscopic techniques and the collected data highlights that the radical gas coordinates with the secondary amine groups present in the drug molecules. The interaction between the amine group and the gas is reversible; in fact the release of NO from these complexes can be triggered using water (11% RH) and/or UV-light. In addition, chlorhexidine has been incorporated into the pores of the CPO-27 framework. The amount of antiseptic incorporated was determined using a variety of characterisation techniques. The controlled release of significant concentrations of CHx from the CPO-27 materials are achieved by exposing each CHx loaded sample to a water solution, in doing so topical conditions are simulated. The CHx loaded samples have also been activated and NO loaded following the novel high pressure procedure specifically developed during this research. The resulting NO loaded material released the radical gas in the presence of water and/or UV-light. By incorporating the CHx into the MOF and NO loading this complex the duration and release of NO was greatly enhanced over that of either of the components alone. On formulating the CHx loaded 3D frameworks into pellets, or even into a polyurethane polymer film, their ability to release the antiseptic under simulated topical conditions was maintained. The NO-CHx-CPO-27 composite film that has been prepared has proven to be able to simultaneously store and release both NO and CHx. Each component of the complex has more than one function and the quantity and duration of release of NO is again higher and longer than either of the two moieties alone. The release of these two antibacterial agents from a MOF is novel and is very exciting as it opens up the possibility of engineering products with multiple actions to fight infection. Owing to their high stability and shape persistence properties, the CC3 cage series (CC3, RCC3, FT-RCC3 and AT-RCC3) was chosen as the basis of an investigation into the potential use of porous organic cages as delivery systems for nitric oxide gas. NO has been stored in these porous materials through coordination to amine groups forming Nnitrosamine groups. Release of NO from these types of compounds can be triggered by various mechanisms including water and UV-light, the amine group being regenerated after the release of NO. The release performance significantly increased when the materials were exposed to UV-light and/or suspended in water. As a result of this investigation, these covalent organic molecular cages can now be added to the existing list of NO-based therapies available to medical professionals

E’ Dio il vero tema. Cesare Cattaneo e il sacro

none2Maria Antonietta Crippa; Damiano CattaneoCrippa, MARIA ANTONIETTA; Damiano, Cattane

Water based scale-up of CPO-27 synthesis for nitric oxide delivery

The authors thank Scottish Enterprise for funding for the scale up work (POC13). We gratefully acknowledge the EPSRC (EP/K025112/1) and the Royal society for the Brian Mercer Award for Innovation (MI120033).The applicability of water-based reflux and room temperature synthesis processes for the production of CPO-27 MOFs, suitable for NO delivery applications, is investigated. NO adsorption, storage and release performance of products obtained under reflux conditions are comparable to those of equivalent samples synthesised from traditional solvothermal methods at small scale. Products obtained from room temperature processes show lower NO release capability, although the quantities that are released are still more than adequate for biomedical applications. Results also reveal differences for the first time in NO uptake, storage and release depending on whether Zn, Ni or Mg is employed. The results indicate that while the crystallinity of CPO-27 (Zn) and CPO-27 (Mg) is not affected by moving to lower temperature methods, the crystallinity of CPO-27 (Ni) is reduced. Particle morphology and size is also affected. The low temperature processes are successfully demonstrated at 20L and 100L scale and the main problems encountered during scale-up are outlined. The 100L scale is in itself an appropriate production scale for some niche biomedical products. Indeed, results indicate that this synthesis approach is suitable for commercial production of MOFs for this application field. We also confirm that BET surface area from nitrogen adsorption at 77 K is not a good indicator for successful adsorption of NO.Publisher PDFPeer reviewe

Occupational exposure to arsenic and cadmium in thin-film solar cell production

Introduction: Workers involved in the production of Cd/As-based photovoltaic modules may be routinely or accidentally exposed to As-or Cd-containing inorganic compounds. Methods: Workers' exposure to As and Cd was investigated by environmental monitoring following a worst-case approach and biological monitoring from the preparation of the working facility to its decommissioning. Workplace surface contamination was also evaluated through wipe-test sampling. Results: The highest mean airborne concentrations were found during maintenance activities (As = 0.0068 g m3; Cd = 7.66 g m3) and laboratory simulations (As = 0.0075 g m3; Cd = 11.2 g m3). These types of operations were conducted for a limited time during a typical work shift and only in specifically suited containment areas, where the highest surface concentrations were also found (laboratory: As = 2.94 g m2, Cd = 167 g m2; powder containment booth: As = 4.35 g m2, Cd = 1500 g m2). The As and Cd urinary levels (Asu; Cdu) were not significantly different for exposed (Asu = 6.11 1.74 g l1; Cdu = 0.24 2.36 g g1 creatinine) and unexposed workers (Asu = 6.11 1.75 g l1; Cdu = 0.22 2.08 g g1 creatinine). Conclusion: Despite airborne arsenic and cadmium exposure well below the threshold limit value (TLV) when the operation is appropriately maintained in line, workers who are involved in various operations (maintenance, laboratory test) could potentially be at risk of significant exposure, well in excess of the TLV. Nevertheless, the biological monitoring data did not show significant occupationally related arsenic and cadmium intake in workers and no significant changes or differences in arsenic and cadmium urinary level among the exposed and unexposed workers were found