Monolacunary Wells-Dawson Polyoxometalate as a Novel Contrast Agent for Computed Tomography: A Comprehensive Study on In Vivo Toxicity and Biodistribution.

Polyoxotungstate nanoclusters have recently emerged as promising contrast agents for computed tomography (CT). In order to evaluate their clinical potential, in this study, we evaluated the in vitro CT imaging properties, potential toxic effects in vivo, and tissue distribution of monolacunary Wells-Dawson polyoxometalate, α2-K10P2W17O61.20H2O (mono-WD POM). Mono-WD POM showed superior X-ray attenuation compared to other tungsten-containing nanoclusters (its parent WD-POM and Keggin POM) and the standard iodine-based contrast agent (iohexol). The calculated X-ray attenuation linear slope for mono-WD POM was significantly higher compared to parent WD-POM, Keggin POM, and iohexol (5.97 ± 0.14 vs. 4.84 ± 0.05, 4.55 ± 0.16, and 4.30 ± 0.09, respectively). Acute oral (maximum-administered dose (MAD) = 960 mg/kg) and intravenous administration (1/10, 1/5, and 1/3 MAD) of mono-WD POM did not induce unexpected changes in rats' general habits or mortality. Results of blood gas analysis, CO-oximetry status, and the levels of electrolytes, glucose, lactate, creatinine, and BUN demonstrated a dose-dependent tendency 14 days after intravenous administration of mono-WD POM. The most significant differences compared to the control were observed for 1/3 MAD, being approximately seventy times higher than the typically used dose (0.015 mmol W/kg) of tungsten-based contrast agents. The highest tungsten deposition was found in the kidney (1/3 MAD-0.67 ± 0.12; 1/5 MAD-0.59 ± 0.07; 1/10 MAD-0.54 ± 0.05), which corresponded to detected morphological irregularities, electrolyte imbalance, and increased BUN levels.

In vivo toxicity evaluation of a polyoxotungstate nanocluster as a promising contrast agent for computed tomography.

In this study, we demonstrate for the first time, that a discrete metal-oxo cluster α-/ß-K6P2W18O62 (WD-POM) exhibits superior performance as a computed tomography (CT) contrast agent, in comparison to the standard contrast agent iohexol. A toxicity evaluation of WD-POM was performed according to standard toxicological protocols using Wistar albino rats. The maximum tolerable dose (MTD) of 2000 mg/kg was initially determined after oral WD-POM application. The acute intravenous toxicity of single WD-POM doses (1/3, 1/5, and 1/10 MTD), which are at least fifty times higher than the typically used dose (0.015 mmol W kg-1) of tungsten-based contrast agents, was evaluated for 14 days. The results of arterial blood gas analysis, CO-oximetry status, electrolyte and lactate levels for 1/10 MTD group (80% survival rate) indicated the mixed respiratory and metabolic acidosis. The highest deposition of WD-POM (0.6 ppm tungsten) was found in the kidney, followed by liver (0.15 ppm tungsten), for which the histological analysis revealed morphological irregularities, although the renal function parameters (creatinine and BUN levels) were within the physiological range. This study is the first and important step in evaluating side effects of polyoxometalate nanoclusters, which in recent years have shown a large potential as therapeutics and contrast agents.

Attitude towards deprescribing and its association with frailty and complexity of medication regimen: A survey of older inpatients in a district health board in New Zealand.

BACKGROUND: Older inpatients, particularly those with frailty, have increased exposure to complex medication regimens. It is not known whether frailty and complexity of medication regimens influence attitudes toward deprescribing. This study aimed to investigate (1) older inpatients' attitudes toward deprescribing; (2) if frailty and complexity of medication regimen influence attitudes and willingness to deprescribe - a relationship that has not been investigated in previous studies. METHODS: In this cross-sectional study, older adults (≥ 65 years) recruited from general medicine and geriatric services in a New Zealand hospital completed the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire. Hospital frailty risk score (HFRS) was calculated using diagnostic codes and other relevant information present at the time of index hospital admission; higher scores indicate higher frailty risk. Medication regimen complexity was quantified using the medication regimen complexity index (MRCI); higher scores indicate greater complexity. Logistic regression analysis was used to identify predictors of attitudes and willingness to deprescribe. RESULTS: A total of 222 patients were included in the study, the median age was 83 years and 63% were female. One in two patients reported feeling they were taking too many medications, and 1 in 5 considered their medications burdensome. Almost 3 in 4 (73%) wanted to be involved in decision-making about their medications, and 4 in 5 (84%) were willing to stop one or more of their medications if their prescriber said it was possible. Patients with higher MRCI had increased self-reported medication burden (adjusted odds ratio (AOR) 2.6, 95% CI 1.29, 5.29) and were more interested in being involved in decision-making about their medications (AOR 1.8, CI 0.99, 3.42) than those with lower MRCI. Patients with moderate HFRS had lower odds of willingness to deprescribe (AOR 0.45, CI 0.22,0.92) compared to the low-risk group. Female patients had a lower desire to be involved in decision-making. The oldest old age group( > 80 years) had lower self-reported medication burden and were less likely to want to try stopping their medications. CONCLUSION: Most older inpatients wanted to be involved in decision-making about their medications and were willing to stop one or more medications if proposed by their prescriber. Medication complexity and frailty status influence patients' attitudes toward deprescribing and thus should be taken into consideration when making deprescribing decisions. Further research is needed to investigate the relationship between frailty and the complexity of medication regimens.

Melatonin Mitigates iNOS-Related Effects of HEMA and Camphorquinone in Human Dental Pulp Cells: Relevance for Postoperative Sensitivity Mechanism in Type 2 Diabetes.

High elution and diffusion of 2-hydroxylethyl methacrylate (HEMA) and camphorquinone (CQ) through dentinal tubules may induce pulp injury and postoperative sensitivity. We aimed to investigate the melatonin protective effect in HEMA- and CQ-treated human dental pulp cells (hDPCs) as well as its relevance in a mechanism for postoperative sensitivity in diabetic patients. hDPCs were exposed to HEMA (5 mM) and/or CQ (1 mM) in the absence and presence of melatonin (MEL) (0.1 mM and 1 mM). Heme oxygenase-1 (HMOX1), NADPH oxidase-4 (NOX4), BCL-2-associated X-protein (BAX), B-cell lymphoma-2 (BCL-2) and caspase-3 (CASP3) gene expression levels, and superoxide dismutase (SOD) activity were measured in hDPCs while inducible nitric oxide synthase (iNOS) and melatonin protein expression were measured in human dental pulp as well, by RT-PCR, by ELISA, and spectrophotometrically. Bioinformatic analyses were performed by using the ShinyGO (v.0.75) application. Type 2 diabetic patients showed a higher incidence of postoperative sensitivity and lower melatonin and higher iNOS content in dental pulp tissue compared with non-diabetic patients. Melatonin, when co-added in hDPC culture, reverses HEMA and CQ cytotoxic effects via anti-apoptotic and anti-inflammatory/antioxidant iNOS-related effects. Enrichment analyses showed that genes/proteins, altered by HEMA and CQ and normalized by melatonin, are the most prominently overrepresented in type 2 diabetes mellitus pathways and that they share subcellular localization in different oligomeric protein complexes consisting of anti- and pro-apoptotic regulators. This is the first evidence of the ability of melatonin to counteract iNOS-mediated inflammatory and stress effects in HEMA- and CQ-treated hDPCs, which could be of significance for the modulation of presently observed immediate postoperative sensitivity after composite restoration in type 2 diabetic patients.

The impact of a community pharmacy service on patients' medication adherence and ambulatory sensitive hospitalizations.

BACKGROUND: In July 2012 a nationwide community pharmacy-based service was launched in New Zealand. The Long Term Conditions (LTC) service was introduced to help patients with chronic medical conditions, who have difficulties adhering to their medication regimens, improve their adherence. As part of the service pharmacists provide a variety of interventions including: patient education, medication reconciliation, medication synchronization, as well as preparing adherence support aids such as blister packs, sending reminders, and providing tailored dispensing frequencies. Seven years after its introduction scant data are available measuring the impact of the service on patients' health outcomes. OBJECTIVE: To examine the impact of LTC on patients' medication adherence and ambulatory sensitive hospitalizations. METHODS: This was a retrospective matched-cohort study using routinely collected health data. The population studied were individuals enrolled in LTC between July 2013 and December 2014 and a control group of propensity score matched individuals who never received the service. Outcomes were assessed during and after completion of the intervention. Sensitivity analysis was also undertaken whereby only those who completed the intervention and their controls were used in the analysis. RESULTS: The matched cohort consisted of 51,138 individuals in the intervention and 51,138 in the control. Enrolment in LTC was associated with greater medication adherence, with individuals in the intervention group having 2.99 (95% CI: 2.79-3.20) greater odds of being adherent 12 months after the start of the study period, compared to the control group. These patients also had 1.86 (95% CI: 1.78-1.96) greater odds of having an ambulatory sensitive hospitalization 12 months after the start of the study period, compared to the control group. CONCLUSION: This study found that enrolment in LTC achieved one of the service's primary aims of improved medication adherence. However, enrolment in the service also appears to be associated with greater ambulatory sensitive hospitalizations, which is an unexpected finding. Further research is needed to better understand this.

Community pharmacist-led interventions and their impact on patients' medication adherence and other health outcomes: a systematic review.

INTRODUCTION: Medication adherence can be defined as the extent to which one's medication-taking behaviour follows that mutually agreed upon by the prescribing physician. Optimal medication adherence is often deemed crucial for the success of a patient's treatment, as suboptimal adherence may lead to treatment failure and unnecessary medical expenditure. Increasing evidence has highlighted the positive contribution community pharmacist-led interventions can have on improving patients' adherence and health outcomes. OBJECTIVES: To provide an overview of the published literature on community pharmacist-led interventions and their effectiveness in improving patients' adherence and health outcomes. METHODS: A search strategy was developed, aiming to retrieve published reports of community pharmacy interventions worldwide. Medline, EMBASE, International Pharmaceutical Abstracts, Google Scholar and ProQuest Dissertations and Theses databases were searched. Articles meeting the inclusion criteria were collated, relevant data extracted, and a risk of bias assessment undertaken. KEY FINDINGS: Twenty-two studies were included in the analysis, and their outcomes were reported in 26 peer-reviewed journal articles. Community pharmacist-led interventions have been shown to improve patients' adherence and contribute to better blood pressure control, cholesterol management, chronic obstructive pulmonary disease and asthma control. Studies in this review, however, did not report statistically significant effects of interventions on diabetes or depression control. CONCLUSION: Community pharmacist-led interventions have been shown to contribute to improved adherence and better disease control. Future research should attempt to better understand which particular intervention components make the greatest contribution towards improving adherence and health outcomes, for patients with different medical conditions.

MicroRNA-146a and microRNA-155 as novel crevicular fluid biomarkers for periodontitis in non-diabetic and type 2 diabetic patients.

AIM: Recent studies point at the crucial role of epigenetic mechanisms in the development of multifactorial diseases such as periodontitis and diabetes mellitus (DM) type 2. In addition, circulatory microRNAs (miRs) have emerged as novel biomarkers for various diseases. Aim of this study was to investigate the levels of miR-146a and miR-155 and superoxide dismutase (SOD) activity in gingival crevicular fluid (GCF) of periodontitis patients with (CPDM) and without (CP) DM type 2 as well as in periodontally healthy, control groups (PHDM and PH, respectively). MATERIAL AND METHODS: miR modulation was analysed using quantitative real-time PCR while SOD activity was measured spectrophotometrically. RESULTS: The upregulation of miR-146a and miR-155 was observed in CP and CPDM patients' baseline, while the levels decreased after 6 weeks of the non-surgical therapy to the levels comparable to PH and PHDM, respectively. Expression levels of miRs positively correlated with SOD activity. Levels of miR-146a were higher in PHDM compared to PH patients. Multivariate analysis revealed that levels of miR-146a and miR-155 were significantly associated with periodontitis when adjusting for age and gender. CONCLUSIONS: miR-146a and miR-155 may be considered as possible novel biomarkers for periodontitis in non-diabetic and type 2 diabetic patients.