Interventions to Expand Community Pharmacists' Scope of Practice.

BACKGROUND: The role of community pharmacists has evolved beyond the dispensing of medicines. The aim of this scoping review was to describe the interventions that expand the pharmacist's scope of practice within a community pharmacy setting and assess their effectiveness. METHODS: We performed a scoping review to identify randomised controlled trials (RCTs), published worldwide from 2013 to 2024, which focused on interventions designed to expand pharmacists' scope of practice in the community. The review was undertaken in accordance with the Joanna Briggs Institute methodology for scoping reviews. To address the aim of this scoping review, the included RCTs were mapped to themes influenced by the Professional Practice Standards 2023 as developed by the Pharmaceutical Society of Australia: medication management, collaborative care and medication adherence. RESULTS: Twelve studies demonstrated the potential to expand community pharmacists' scope of practice. Two RCTs resulted in no effect of the intervention. One RCT (conducted in Italy) led to an actual change to community pharmacists' scope of practice, with a statistically significant improvement in the proportion of patients with controlled asthma. CONCLUSIONS: On the whole, this scoping review synthesised the findings of peer-reviewed RCT studies that revealed expanding community pharmacists' scope of practice may result in improved patient outcomes, a reduced burden for the healthcare system, and greater productivity.

Exploring the link between comorbidities and Alzheimer's dementia in the Australian Imaging, Biomarker & Lifestyle (AIBL) study.

INTRODUCTION: Mounting evidence suggests that certain comorbidities may influence the clinical evolution of Alzheimer's dementia (AD). METHODS: We conducted logistic regression analyses on the medical history and cognitive health diagnoses of participants in the Australian Imaging, Biomarker & Lifestyle study (n = 2443) to investigate cross-sectional associations between various comorbidities and mild cognitive impairment (MCI)/AD. RESULTS: A mixture of associations were observed. Higher comorbidity of anxiety and other neurological disorders was associated with higher odds of AD, while arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD. DISCUSSION: This study underscores the links between specific comorbidities and MCI/AD. Further research is needed to elucidate the longitudinal comorbidity-MCI/AD associations and underlying mechanisms of these associations. Highlights: Comorbidities that significantly increased AD odds included anxiety and other neurological disorders.Arthritis, cancer, gastric complaints, high cholesterol, joint replacement, visual defect, kidney and liver disease were associated with lower odds of AD.Alcohol consumption had the most significant confounding effect in the study.Visual-AD association was modified by age, sex, and APOE ε4 allele status.Anxiety-AD and depression-AD associations were modified by sex.

Polyunsaturated fatty acids-induced ferroptosis suppresses pancreatic cancer growth.

Despite recent advances in science and medical technology, pancreatic cancer remains associated with high mortality rates due to aggressive growth and no early clinical sign as well as the unique resistance to anti-cancer chemotherapy. Current numerous investigations have suggested that ferroptosis, which is a programed cell death driven by lipid oxidation, is an attractive therapeutic in different tumor types including pancreatic cancer. Here, we first demonstrated that linoleic acid (LA) and α-linolenic acid (αLA) induced cell death with necroptotic morphological change in MIA-Paca2 and Suit 2 cell lines. LA and αLA increased lipid peroxidation and phosphorylation of RIP3 and MLKL in pancreatic cancers, which were negated by ferroptosis inhibitor, ferrostatin-1, restoring back to BSA control levels. Similarly, intraperitoneal administration of LA and αLA suppresses the growth of subcutaneously transplanted Suit-2 cells and ameliorated the decreased survival rate of tumor bearing mice, while co-administration of ferrostatin-1 with LA and αLA negated the anti-cancer effect. We also demonstrated that LA and αLA partially showed ferroptotic effects on the gemcitabine-resistant-PK cells, although its effect was exerted late compared to treatment on normal-PK cells. In addition, the trial to validate the importance of double bonds in PUFAs in ferroptosis revealed that AA and EPA had a marked effect of ferroptosis on pancreatic cancer cells, but DHA showed mild suppression of cancer proliferation. Furthermore, treatment in other tumor cell lines revealed different sensitivity of PUFA-induced ferroptosis; e.g., EPA induced a ferroptotic effect on colorectal adenocarcinoma, but LA or αLA did not. Collectively, these data suggest that PUFAs can have a potential to exert an anti-cancer effect via ferroptosis in both normal and gemcitabine-resistant pancreatic cancer.

Exploring the association between cancer and cognitive impairment in the Australian Imaging Biomarkers and Lifestyle (AIBL) study.

An inverse association between cancer and Alzheimer's disease (AD) has been demonstrated; however, the association between cancer and mild cognitive impairment (MCI), and the association between cancer and cognitive decline are yet to be clarified. The AIBL dataset was used to address these knowledge gaps. The crude and adjusted odds ratios for MCI/AD and cognitive decline were compared between participants with/without cancer (referred to as C+ and C- participants). A 37% reduction in odds for AD was observed in C+ participants compared to C- participants after adjusting for all confounders. The overall risk for MCI and AD in C+ participants was reduced by 27% and 31%, respectively. The odds of cognitive decline from MCI to AD was reduced by 59% in C+ participants after adjusting for all confounders. The risk of cognitive decline from MCI to AD was halved in C+ participants. The estimated mean change in Clinical Dementia Rating-Sum of boxes (CDR-SOB) score per year was 0.23 units/year higher in C- participants than in C+ participants. Overall, an inverse association between cancer and MCI/AD was observed in AIBL, which is in line with previous reports. Importantly, an inverse association between cancer and cognitive decline has also been identified.

How Can We Use Mathematical Modeling of Amyloid-ß in Alzheimer's Disease Research and Clinical Practices?

The accumulation of amyloid-ß (Aß) plaques in the brain is considered a hallmark of Alzheimer's disease (AD). Mathematical modeling, capable of predicting the motion and accumulation of Aß, has obtained increasing interest as a potential alternative to aid the diagnosis of AD and predict disease prognosis. These mathematical models have provided insights into the pathogenesis and progression of AD that are difficult to obtain through experimental studies alone. Mathematical modeling can also simulate the effects of therapeutics on brain Aß levels, thereby holding potential for drug efficacy simulation and the optimization of personalized treatment approaches. In this review, we provide an overview of the mathematical models that have been used to simulate brain levels of Aß (oligomers, protofibrils, and/or plaques). We classify the models into five categories: the general ordinary differential equation models, the general partial differential equation models, the network models, the linear optimal ordinary differential equation models, and the modified partial differential equation models (i.e., Smoluchowski equation models). The assumptions, advantages and limitations of these models are discussed. Given the popularity of using the Smoluchowski equation models to simulate brain levels of Aß, our review summarizes the history and major advancements in these models (e.g., their application to predict the onset of AD and their combined use with network models). This review is intended to bring mathematical modeling to the attention of more scientists and clinical researchers working on AD to promote cross-disciplinary research.

Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide.

Prolonged activation of microglia leads to excessive release of proinflammatory mediators, which are detrimental to brain health. Therefore, there are significant efforts to identify pathways mediating microglial activation. Recent studies have demonstrated that fatty acid-binding protein 4 (FABP4), a lipid binding protein, is a critical player in macrophage-mediated inflammation. Given that we have previously identified FABP4 in microglia, the aim of this study was to assess whether FABP4 activity contributed to inflammation, metabolism and immune function (i.e. immunometabolism) in immortalised mouse microglia (BV-2 cells) using the proinflammatory stimulus lipopolysaccharide (LPS) to induce general microglial activation. Microglial FABP4 expression was significantly increased following exposure to LPS, an outcome associated with a significant increase in microglial proliferation rate. LPS-stimulated BV-2 microglia demonstrated a significant increase in the production of reactive oxygen species (ROS) and tumour necrosis factor-alpha (TNF-α), phosphorylation of c-Jun N-terminal kinase (JNK), increased expression of Toll-like receptor 4 (TLR4), and reduced expression of uncoupling protein 2 (UCP2), all of which were reversed following FABP4 genetic silencing and chemical inhibition with BMS309403. The oxidation rate of 3H-oleic acid and microglial uptake of 3H-2-deoxy-D-glucose were modulated with LPS activation, processes which were restored with genetic and chemical inhibition of FABP4. This is the first study to report on the critical role of FABP4 in mediating the deleterious effects of LPS on microglial immunometabolism, suggesting that FABP4 may present as a novel therapeutic target to alleviate microglia-mediated neuroinflammation, a commonly reported factor in multiple neurodegenerative diseases.

Blockade of Microglial Kv1.3 Potassium Channels by the Peptide HsTX1[R14A] Attenuates Lipopolysaccharide-mediated Neuroinflammation.

The expression of voltage-gated potassium Kv1.3 channels is increased in activated microglia, with non-selective blockade reported to attenuate microglial-mediated neuroinflammation. In this study, we evaluated the impact of a potent and selective peptidic blocker of Kv1.3 channels, HsTX1[R14A], on microglial-mediated neuroinflammation in vitro and in vivo. Treatment with both 0.1 and 1 µg/mL lipopolysaccharide (LPS) significantly (p < 0.05) increased Kv1.3 abundance on the surface of BV-2 microglia in association with increased levels of mRNA for tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The increased transcription of TNF-α and IL-6 was significantly attenuated (by 24.9 and 20.2%, respectively) by HsTX1[R14A] (100 nM). The concomitant increase in TNF-α and IL-6 release from BV-2 microglia was significantly attenuated by HsTX1[R14A] by 10.7 and 12.6%, respectively. In LPS-treated primary mouse microglia, the levels of TNF-α and nitric oxide were also attenuated by HsTX1[R14A] (26.1 and 20.4%, respectively). In an LPS-induced mouse model of neuroinflammation, both an immediate and delayed subcutaneous dose of HsTX1[R14A] (2 mg/kg) significantly reduced plasma and brain levels of the pro-inflammatory mediators TNF-α, IL-1ß and IL-6, with no impact on the anti-inflammatory IL-10. These results demonstrate that HsTX1[R14A] is a promising therapeutic candidate for the treatment of diseases with a neuroinflammatory component.

Development and validation of a LC-MS/MS assay for quantifying the uptake of docosahexaenoic acid-d5 into mouse microglia.

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid with the capacity to reduce the proinflammatory response of activated microglia that occurs during neuroinflammation. The uptake of DHA into microglia is essential for it to exert its neuroprotective effects. However, quantifying the uptake of DHA into microglia is complicated by the presence of endogenous DHA interfering with any quantification technique. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was therefore developed and validated in order to assess the microglial uptake of docosahexaenoic acid-d5 (DHA-d5) as a surrogate for DHA. Using a mobile phase consisting of 90 % (v/v) acetonitrile and 10 % (v/v) water containing 2 mM ammonium acetate, a flow rate of 0.3 mL/min, and MS/MS detection in the negative ionization mode, DHA-d5 was detected at m/z transitions of 332.1/228.3/234.2, with good linearity between chromatographic area under the curve (AUC) and DHA-d5 mass (R2 = 0.999) over the range of 0.0063-0.1 ng. The precision and accuracy values for the quality control samples (0.0063, 0.025, and 0.1 ng) were less than 9.3 % and 96.6-109.8 %, respectively, and a comparison of DHA-d5 AUC when prepared in PBS or in microglial cell lysate demonstrated no significant difference between quantification of these quality control samples. Utilizing this quantification approach (with preparation of DHA-d5 calibration standards in PBS), the uptake of DHA-d5 into BV-2 microglial cells over a 15 min period was assessed, following the spiking of DHA-d5 at 50 ng/mL. Following protein normalization using a BCA protein assay, a rapid and linear uptake of DHA-d5 into BV-2 cells was observed in the first 2 min, after which a plateau in uptake was observed, in line with that reported for DHA uptake in other cell types. This novel LC-MS/MS technique can now be exploited to unravel the processes involved in microglial uptake of DHA, insights that may be used to maximize the anti-inflammatory effects of DHA in neuroinflammation.

Pioglitazone Increases Blood-Brain Barrier Expression of Fatty Acid-Binding Protein 5 and Docosahexaenoic Acid Trafficking into the Brain.

Brain levels of docosahexaenoic acid (DHA), an essential cognitively beneficial fatty acid, are reduced in Alzheimer's disease (AD). We have demonstrated in an AD mouse model that this is associated with reduced blood-brain barrier (BBB) transport of DHA and lower expression of the key DHA-trafficking protein, fatty acid-binding protein 5 (FABP5). This study focused on assessing the impact of activating peroxisome proliferator-activated receptor (PPAR) isoforms on FABP5 expression and function at the BBB. Using immortalized human brain endothelial (hCMEC/D3) cells, a 72 h treatment with the PPARα agonist clofibrate (100 µM), and PPARß/δ agonists GW0742 (1 µM) and GW501506 (0.5 µM), did not affect FABP5 protein expression. In contrast, the PPARγ agonists rosiglitazone (5 µM), pioglitazone (25 µM), and troglitazone (1 µM) increased FABP5 protein expression by 1.15-, 1.18-, and 1.24-fold in hCMEC/D3 cells, respectively, with rosiglitazone and pioglitazone also increasing mRNA expression of FABP5. In line with an increase in FABP5 expression, pioglitazone increased 14C-DHA uptake into hCMEC/D3 cells 1.20- to 1.33-fold over a 2 min period, and this was not associated with increased expression of membrane transporters involved in DHA uptake. Furthermore, treating male C57BL/6J mice with pioglitazone (40 mg/kg/day for 7 days) led to a 1.79-fold increase in BBB transport of 14C-DHA over 1 min, using an in situ transcardiac perfusion technique, which was associated with a 1.82-fold increase in brain microvascular FABP5 protein expression. Overall, this study demonstrated that PPARγ can regulate FABP5 at the BBB and facilitate DHA transport across the BBB, important in restoring brain levels of DHA in AD.