A sequence symmetry analysis of the interrelationships between statins, diabetes and skin infections.

AIMS: To determine statins' impact on skin infection risk in view of conflicting literature: that statins may reduce infection risk, but are also associated with diabetes mellitus, a risk factor for skin and soft tissue infections (SSTIs). METHODS: Sequence symmetry analysis was performed on prescription claims (2001-2011) from the Australian Department of Veterans' Affairs to determine the interrelationships between: (i) statins and SSTIs; (ii) statins and diabetes; and (iii) diabetes and SSTIs; as well as whether statins increased the risk of SSTIs, independent of diabetes status. Chi-square tests were performed to detect differences in Index of Relative Socio-economic Advantage and Disadvantage scores of patients within each interrelationship. Prescriptions for statins, antidiabetic medication, and antistaphylococcal antibiotics were evaluated using nonidentifiable client numbers, prescription dates filled, residential electorates, and pharmaceutical codes. Adjusted sequence ratio and confidence interval were calculated at intervals of 91, 182 and 365 days for sequence symmetry analysis studies. RESULTS: Statins were associated with: (i) significant SSTI risk (adjusted sequence ratio > 1; confidence interval >1), (ii) significant diabetes risk, and (iii) diabetic patients had increased risk of SSTIs. Diabetic and nondiabetic statin users had significantly increased risks of SSTIs, while the influence from socioeconomic status was not significant for each of the 3 relationships. CONCLUSIONS: Statins are associated with increased risk of SSTIs via direct and indirect mechanisms, probably independent of diabetes or socioeconomic statuses. We believe that clinicians should be aware of the association between statins and SSTIs, and, where appropriate, monitor blood glucose levels of statin users.

In vitro antibacterial effects of statins against bacterial pathogens causing skin infections.

With financial considerations impeding research and development of new antibiotics, drug repurposing (finding new indications for old drugs) emerges as a feasible alternative. Statins are extensively prescribed around the world to lower cholesterol, but they also possess inherent antimicrobial properties. This study identifies statins with the greatest potential to be repurposed as topical antibiotics and postulates a mechanism of action for statins' antibacterial activity. Using broth microdilution, the direct antibacterial effects of all seven parent statins currently registered for human use and three selected statin metabolites were tested against bacterial skin pathogens Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Serratia marcescens. Simvastatin and pitavastatin lactone exerted the greatest antibacterial effects (minimum inhibitory concentrations of 64 and 128 µg/mL, respectively) against S. aureus. None of the statins tested were effective against E. coli, P. aeruginosa, or S. marcescens, but simvastatin hydroxy acid acid might be active against S. aureus, E. coli, and S. marcescens at drug concentrations > 256 µg/mL. It was found that S. aureus may exhibit a paradoxical growth effect when exposed to simvastatin; thus, treatment failure at high drug concentrations is theoretically probable. Through structure-activity relationship analysis, we postulate that statins' antibacterial action may involve disrupting the teichoic acid structures or decreasing the number of alanine residues present on Gram-positive bacterial cell surfaces, which could reduce biofilm formation, diminish bacterial adhesion to environmental surfaces, or impede S. aureus cell division.

Psychometric Evaluation of the Electronic Pain Assessment Tool: An Innovative Instrument for Individuals with Moderate-to-Severe Dementia.

BACKGROUND/AIMS: Pain is common in aged care residents with dementia; yet it often goes undetected. A novel tool, the electronic Pain Assessment Tool (ePAT), was developed to address this challenging problem. We investigated the psychometric properties of the ePAT. METHODS: In a 10-week prospective observational study, the ePAT was evaluated by comparison against the Abbey Pain Scale (APS). Pain assessments were blindly co-performed by the ePAT rater against the nursing staff of two residential aged care facilities. The residents were assessed twice by each rater: at rest and following movement. RESULTS: The study involved 34 residents aged 85.5 ± 6.3 years, predominantly with severe dementia (Psychogeriatric Assessment Scale - Cognitive Impairment score = 19.7 ± 2.5). Four hundred paired assessments (n = 204 during rest; n = 196 following movement) were performed. Concurrent validity (r = 0.911) and all reliability measures (κw = 0.857; intraclass correlation coefficient = 0.904; α = 0.950) were excellent, while discriminant validity and predictive validity were good. CONCLUSION: The ePAT is a suitable tool for the assessment of pain in this vulnerable population.

Faces of Pain in Dementia: Learnings From a Real-World Study Using a Technology-Enabled Pain Assessment Tool.

Pain is common in people living with dementia (PLWD), including those with limited verbal skills. Facial expressions are key behavioral indicators of the pain experience in this group. However, there is a lack of real-world studies to report the prevalence and associations of pain-relevant facial micro-expressions in PLWD. In this observational retrospective study, pain-related facial features were studied in a sample of 3,144 PLWD [mean age 83.3 years (SD = 9.0); 59.0% female] using the Face domain of PainChek®, a point-of-care medical device application. Pain assessments were completed by 389 users from two national dementia-specific care programs and 34 Australian aged care homes. Our analysis focused on the frequency, distribution, and associations of facial action units [AU(s)] with respect to various pain intensity groups. A total of 22,194 pain assessments were completed. Of the AUs present, AU7 (eyelid tightening) was the most frequent facial expression (48.6%) detected, followed by AU43 (closing eyes; 42.9%) and AU6 (cheek raising; 42.1%) during severe pain. AU20 (horizontal mouth stretch) was the most predictive facial action of higher pain scores. Eye-related AUs (AU6, AU7, AU43) and brow-related AUs (AU4) were more common than mouth-related AUs (e.g., AU20, AU25) during higher pain intensities. No significant effect was found for age or gender. These findings offer further understanding of facial expressions during clinical pain in PLWD and confirm the usefulness of artificial intelligence (AI)-enabled real-time analysis of the face as part of the assessment of pain in aged care clinical practice.

Calcium channel blocker associated lower urinary tract symptoms in males: an Australian retrospective observational study.

BACKGROUND: Lower urinary tract symptoms (LUTS) are common and prevalence increases with age. In men, voiding symptoms are more commonly encountered than storage symptoms. LUTS are often associated with chronic diseases but their pathophysiology requires further study. We aimed to determine whether calcium channel blockers (CCBs) worsened, improved or did not alter symptoms of urinary obstruction in males aged 45 years and above with medical conditions associated with urinary obstruction. METHODS: A cohort retrospective observational study was undertaken to identify the effect of the use of CCBs on LUTS in males over 45 years of age. Participants were recruited from four community pharmacies and a general practitioner surgery. Eligible participants provided informed consent and were administered a standardised questionnaire (IPSS) to obtain information on LUTS and quality of life (QOL) prior to and after commencement of CCB therapy. RESULTS: Thirty-eight males were enrolled in the study, and their ages of ranged from 46.2 to 88.7 years, with the mean age being 66.9 years (95% CI: 63.9-69.9). The mean IPPS score prior to commencing a CCB was 3.13 (95% CI: 2.09-4.17) compared to 9.82 (95% CI: 7.83-11.80) whilst on the drug (P<0.001). After adjusting for other medications and conditions which may contribute to LUTS, and for the natural progression of LUTS with ageing, the change remained significant. The increase in IPPS score was associated with a significant decline in the respondents' QOL. CONCLUSION: The results of this study suggest that in middle-aged males the introduction of a CCB may be associated with worsening of LUTS, and an associated decline in QOL, although this will need to be confirmed in large prospective studies. However, given the common use of these agents in males to treat a range of cardiovascular conditions, we would suggest that men prescribed a CCB should be questioned about urinary symptoms before and after commencing treatment.

Pharmacists' and pharmacy technicians' scopes of practice in the management of minor ailments at community pharmacies in Indonesia: a cross-sectional study.

BACKGROUND: Managing minor ailments in community pharmacy is an evolving pharmacy service in developing countries. Defined scopes of practice for pharmacy staff are essential for the safe management of minor ailments. Limited research exists regarding the perceptions of Indonesian pharmacists' and pharmacy technicians' scopes of practice in providing minor ailments management services. OBJECTIVE: To evaluate pharmacists' and pharmacy technicians' understanding of their scopes of practice, perceived competency and factors influencing the delivery of minor ailments services in Indonesian community pharmacies. METHODS: Cross-sectional surveys were conducted during January-February 2020 of pharmacists and pharmacy technicians attending seminars conducted by relevant Indonesian Associations in Central Java, Indonesia. Percentage of common responses (PCR) described similarity of perceived scopes of practice for pharmacists and pharmacy technicians. Univariate and multivariate analyses identified associations of scopes of practice with pharmacy characteristics. RESULTS: A total of 185 pharmacists and 142 pharmacy technicians participated. Pharmacy technicians performed minor ailment consultations, however, if considered beyond their scope of practice, they referred the patient to the pharmacist (T=120/142, 84.5%). Vaginal thrush, bacterial conjunctivitis, gastro-oesophageal reflux disease, and acute pain were minor ailments perceived only within a pharmacist's scope (PCR above 60%). Of 34 minor ailments, 11 showed PCR values between 40-60% overlapping pharmacists and pharmacy technicians perceived scopes of practice (allergy/rash, back pain, cold sores, dermatitis, diarrhoea, eczema, hayfever, haemorrhoids, rheumatism, sore throat, and superficial wounds). Back pain, cold sores, dermatitis, and sore throat associated pharmacists' scope of practice with years of practice experience (p-value<0.05). Pharmacy technicians perceived their scopes of practice to be wider than perceived by pharmacists. CONCLUSIONS: Discordance between pharmacists' and pharmacy technicians' perceived scopes of minor ailments management highlights the need for clearly defined scopes of practice for each professional group. Each professional group must practise within their competence to ensure safe pharmacy practices.

Evaluation of a community pharmacy-based intervention for improving patient adherence to antihypertensives: a randomised controlled trial.

BACKGROUND: The majority of patients using antihypertensive medications fail to achieve their recommended target blood pressure. Poor daily adherence with medication regimens and a lack of persistence with medication use are two of the major reasons for failure to reach target blood pressure. There is no single intervention to improve adherence with antihypertensives that is consistently effective. Community pharmacists are in an ideal position to promote adherence to chronic medications. This study aims to test a specific intervention package that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications--Hypertension Adherence Program in Pharmacy (HAPPY). METHODS/DESIGN: The HAPPY trial is a multi-centre prospective randomised controlled trial. Fifty-six pharmacies have been recruited from three Australian states. To identify potential patients, a software application (MedeMine CVD) extracted data from a community pharmacy dispensing software system (FRED Dispense). The pharmacies have been randomised to either 'Pharmacist Care Group' (PCG) or 'Usual Care Group' (UCG). To check for 'Hawthorne effect' in the UCG, a third group of patients 'Hidden Control Group' (HCG) will be identified in the UCG pharmacies, which will be made known to the pharmacists at the end of six months. Each study group requires 182 patients. Data will be collected at baseline, three and six months in the PCG and at baseline and six months in the UCG. Changes in patient adherence and persistence at the end of six months will be measured using the self-reported Morisky score, the Tool for Adherence Behaviour Screening and medication refill data. DISCUSSION: To our knowledge, this is the first research testing a comprehensive package of evidence-based interventions that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications. The unique features of the HAPPY trial include the use of MedeMine CVD to identify patients who could potentially benefit from the service, control for the 'Hawthorne effect' in the UCG and the offer of the intervention package at the end of six months to patients in the UCG, a strategy that is expected to improve retention. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12609000705280.

Reducing the cost of proton pump inhibitors by adopting best practice.

OBJECTIVES: To evaluate the appropriateness of proton pump inhibitor (PPI) use by assessing the level of compliance of PPI prescribing practices with published guidelines and to assess the potential cost avoidance through inappropriate prescribing. METHOD: A six-week observational study of PPI prescriptions was undertaken between April and June 2005, involving hospital inpatients who were taking a PPI prior to admission. The patients were evaluated using a standardised questionnaire to obtain information regarding their PPI use and efficacy. RESULTS: Among the 679 patients admitted during the study period, 133 were receiving a PPI, and of these 97 (50 men and 47 women) were enrolled into the study. The commonest indication for PPI use was gastro-oesophageal reflux disease (GORD, n = 71; 73.2%). In this cohort, more than one-quarter of patients (26.6%) were using greater than the standard PPI dose. Over half of the patients had at least one risk factor known to exacerbate GORD (51.5% were overweight, 46.4% alcohol consumers and 14% current smokers), and 71.1% were receiving medications known to cause or worsen reflux symptoms. Of those patients who reported alarm symptoms, 84% had undergone endoscopy. The overall compliance with the Pharmaceutical Benefits Scheme (PBS) prescribing guidelines was 78.4%, with the major reason for non-compliance being use for non-PBS indications. Estimated cost savings through adoption of recommended prescribing practices and the implementation of step-down therapy for GORD patients were up to AUD 90,866 and AUD 118,456 per 100 patient-treatment-years, respectively. CONCLUSION: PPIs continue to be prescribed outside the treatment guidelines. As a result, opportunities exist to reduce the cost of PPI use through management of contributing factors, adherence to recommended dosage schedules and use of step-down therapy in asymptomatic patients where appropriate.

Triple-threat activity of PEDF in bone tumors: Tumor inhibition, tissue preservation and cardioprotection against doxorubicin.

Pigment epithelium-derived factor (PEDF) is known for its osteogenic properties, but its effects against primary and secondary bone tumors have not comprehensively been demonstrated. We show the ubiquitous expression of PEDF in murine embryonic tissue. Continuous administration of PEDF in pregnant mice for five days did not adversely affect foetal health, despite PEDF's known potent antiangiogenic properties. In the case of the devastating childhood bone cancer osteosarcoma, PEDF has direct anticancer activity per se, and protects against the toxicity of doxorubicin in the heart, small intestine and testes. PEDF demonstrated anti-proliferative and pro-apoptotic effects against human prostate and breast cancer cells, tumors which are known to metastasize to bone as the preferred secondary site. Caspase-2 was activated in both tumor cell types by PEDF. In models of prostate and breast cancer in bone, PEDF significantly reduced tumor volumes. When combined with zoledronic acid, continuously-administered PEDF significantly reduced breast tumor volume at the bone, and was able to preserve the quality of bone better than the combination therapy. These multiple positive findings make PEDF an ideal endogenous and safe biological for possible future clinical testing.

Clinimetric properties of the electronic Pain Assessment Tool (ePAT) for aged-care residents with moderate to severe dementia.

PURPOSE: Accurate pain assessment is critical to detect pain and facilitate effective pain management in dementia patients. The electronic Pain Assessment Tool (ePAT) is a point-of-care solution that uses automated facial analysis in conjunction with other clinical indicators to evaluate the presence and intensity of pain in patients with dementia. This study aimed to examine clini-metric properties (clinical utility and predictive validity) of the ePAT in this population group. METHODS: Data were extracted from a prospective validation (observational) study of the ePAT in dementia patients who were ≥65 years of age, living in a facility for ≥3 months, and had Psychogeriatric Assessment Scales - cognitive scores ≥10. The study was conducted in two residential aged-care facilities in Perth, Western Australia, where residents were sampled using purposive convenience strategy. Predictive validity was measured using accuracy statistics (sensitivity, specificity, positive predictive value, and negative predictive value). Positive and negative clinical utility index (CUI) scores were calculated using Mitchell's formula. Calculations were based on comparison with the Abbey Pain Scale, which was used as a criterion reference. RESULTS: A total of 400 paired pain assessments for 34 residents (mean age 85.5±6.3 years, range 68.0-93.2 years) with moderate-severe dementia (Psychogeriatric Assessment Scales - cognitive score 11-21) were included in the analysis. Of those, 303 episodes were classified as pain by the ePAT based on a cutoff score of 7. Unadjusted prevalence findings were sensitivity 96.1% (95% CI 93.9%-98.3%), specificity 91.4% (95% CI 85.7%-97.1%), accuracy 95.0% (95% CI 92.9%-97.1%), positive predictive value 97.4% (95% CI 95.6%-99.2%), negative predictive value 87.6% (95% CI 81.1%-94.2%), CUI+ 0.936 (95% CI 0.911-0.960), CUI- 0.801 (95% CI 0.748-0.854). CONCLUSION: The clinimetric properties demonstrated were excellent, thus supporting the clinical usefulness of the ePAT when identifying pain in patients with moderate-severe dementia.

A Technical Note on the PainChek™ System: A Web Portal and Mobile Medical Device for Assessing Pain in People With Dementia.

Background: Pain in dementia is predominant particularly in the advanced stages or in those who are unable to verbalize. Uncontrolled pain alters the course of behaviors in patients with dementia making them perturbed, unsettled, and devitalized. Current measures of assessing pain in this population group are inadequate and underutilized in clinical practice because they lack systematic evaluation and innovative design. Objective: To describe a novel method and system of pain assessment using a combination of technologies: automated facial recognition and analysis (AFRA), smart computing, affective computing, and cloud computing (Internet of Things) for people with advanced dementia. Methods and Results: Cognification and affective computing were used to conceptualize the system. A computerized clinical system was developed to address the challenging problem of identifying pain in non-verbal patients with dementia. The system is composed of a smart device enabled app (App) linked to a web admin portal (WAP). The App "PainChek™" uses AFRA to identify facial action units indicative of pain presence, and user-fed clinical information to calculate a pain intensity score. The App has various functionalities including: pain assessment, pain monitoring, patient profiling, and data synchronization (into the WAP). The WAP serves as a database that collects the data obtained through the App in the clinical setting. These technologies can assist in addressing the various characteristics of pain (e.g., subjectivity, multidimensionality, and dynamicity). With over 750 paired assessments conducted, the App has been validated in two clinical studies (n = 74, age: 60-98 y), which showed sound psychometric properties: excellent concurrent validity (r = 0.882-0.911), interrater reliability (Kw = 0.74-0.86), internal consistency (α = 0.925-0.950), and excellent test-retest reliability (ICC = 0.904), while it possesses good predictive validity and discriminant validity. Clinimetric data revealed high accuracy (95.0%), sensitivity (96.1%), and specificity (91.4%) as well as excellent clinical utility (0.95). Conclusions: PainChek™ is a comprehensive and evidence-based pain management system. This novel approach has the potential to transform pain assessment in people who are unable to verbalize because it can be used by clinicians and carers in everyday clinical practice.

A novel pain assessment tool incorporating automated facial analysis: interrater reliability in advanced dementia.

OBJECTIVES: Regardless of its severity, dementia does not negate the experience of pain. Rather, dementia hinders self-reporting mechanisms in affected individuals because they lose the ability to do so. The primary aim of this study was to examine the interrater reliability of the electronic Pain Assessment Tool (ePAT) among raters when assessing pain in residents with moderate-to-severe dementia. Secondly, it sought to examine the relationship between total instrument scores and facial scores, as determined by automated facial expression analysis. STUDY DESIGN: A 2-week observational study. SETTING: An accredited, high-care, and dementia-specific residential aged care facility in Perth, Western Australia. PARTICIPANTS: Subjects were 10 residents (age range: 63.1-84.4 years old) predominantly with severe dementia (Dementia Severity Rating Scale score: 46.3±8.4) rated for pain by 11 aged care staff. Raters (female: 82%; mean age: 44.1±12.6 years) consisted of one clinical nurse, four registered nurses, five enrolled nurses, and one care worker. MEASUREMENTS: ePAT measured pain using automated detection of facial action codes and recordings of pain behaviors. RESULTS: A total of 76 assessments (rest =38 [n=19 pairs], movement =38 [n=19 pairs]) were conducted. At rest, raters' agreement was excellent on overall total scores (coefficient of concordance =0.92 [95% CI: 0.85-0.96]) and broad category scores (κ=1.0). Agreement was moderate (κ=0.59) on categorical scores upon movement, while it was exact in 68.4% of the cases. Agreement in actual pain category scores gave κw=0.72 (95% CI: 0.58-0.86) at rest and κw=0.69 (95% CI: 0.50-0.87) with movement. All raters scored residents with higher total scores post-mobilization compared to rest. More facial action unit codes were also detected during pain (mean: 2.5 vs 1.9; p<0.0012) and following mobilization (mean: 2.5 vs 1.7; p<0.0001) compared to no pain and rest, respectively. CONCLUSIONS: ePAT, which combines automated facial expression analysis and clinical behavioral indicators in a single observational pain assessment tool, demonstrates good reliability properties, which supports its appropriateness for use in residents with advanced dementia.

Alginate Bead-Encapsulated PEDF Induces Ectopic Bone Formation In Vivo in the Absence of Co-Administered Mesenchymal Stem Cells.

BACKGROUND: Bone defects can be severely debilitating and reduce quality of life. Osteoregeneration can alleviate some of the complications in bony defects. For therapeutic use in future, a single factor that can cause potent bone regeneration is highly preferred as it will be more costeffective, any off-target effects will be more easily monitored and potentially managed, and for ease of administration which would lead to better patient compliance and satisfaction. OBJECTIVE: We demonstrate that pigment epithelium-derived factor (PEDF), one such factor that is known to be potent against angiogenesis, promotes osteoblastogenesis in mesenchymal stem cells in vitro, but does not need co-encapsulation of cells in alginate bead scaffolds for osteogeneration in vivo. RESULTS: Osteogenic differentiation by PEDF in vitro was confirmed with immunoblotting and immunocytochemical staining for bone markers (alkaline phosphatase, osteocalcin, osteopontin, collagen I), calcified mineral deposition, and assay for alkaline phosphatase activity. PEDF-mediated bone formation in a muscle pocket in vivo model was confirmed by microcomputed tomography (microCT), histology (haematoxylin and eosin, Alcian blue staining), immunostaining for bone markers and for collagen I-processing proteins (heat shock protein 47 and membrane type I matrix metalloproteinase). CONCLUSION: PEDF therefore presents itself as a promising biological for osteogeneration.

Pain Assessment in Dementia: Evaluation of a Point-of-Care Technological Solution.

Pain is common among people with moderate to severe dementia, but inability of patients to self-report means it often goes undetected and untreated. We developed the electronic Pain Assessment Tool (ePAT) to address this issue. A point-of-care App, it utilizes facial recognition technology to detect facial micro-expressions indicative of pain. ePAT also records the presence of pain-related behaviors under five additional domains (Voice, Movement, Behavior, Activity, and Body). In this observational study, we assessed the psychometric properties of ePAT compared to the Abbey Pain Scale (APS). Forty aged care residents (70% females) over the age of 60 years, with moderate to severe dementia and a history of pain-related condition(s) were recruited into the study. Three hundred and fifty-three paired pain assessments (either at rest or post-movement) were recorded and analyzed. The ePAT demonstrated excellent concurrent validity (r = 0.882, 95% CI: 0.857-0.903) and good discriminant validity. Inter-rater reliability score was good overall (weighted κ= 0.74, 95% CI: 0.68-0.80) while internal consistency was excellent. ePAT has psychometric properties which make it suitable for use in non-communicative patients with dementia. ePAT also has the advantage of automated facial expression assessment which provides objective and reproducible evidence of the presence of pain.

Statins: antimicrobial resistance breakers or makers?

INTRODUCTION: The repurposing of non-antibiotic drugs as adjuvant antibiotics may help break antimicrobial resistance (AMR). Statins are commonly prescribed worldwide to lower cholesterol. They also possess qualities of AMR "breakers", namely direct antibacterial activity, synergism with antibiotics, and ability to stimulate the host immune system. However, statins' role as AMR breakers may be limited. Their current extensive use for cardiovascular protection might result in selective pressures for resistance, ironically causing statins to be AMR "makers" instead. This review examines statins' potential as AMR breakers, probable AMR makers, and identifies knowledge gaps in a statin-bacteria-human-environment continuum. The most suitable statin for repurposing is identified, and a mechanism of antibacterial action is postulated based on structure-activity relationship analysis. METHODS: A literature search using keywords "statin" or "statins" combined with "minimum inhibitory concentration" (MIC) was performed in six databases on 7th April 2017. After screening 793 abstracts, 16 relevant studies were identified. Unrelated studies on drug interactions; antifungal or antiviral properties of statins; and antibacterial properties of mevastatin, cerivastatin, antibiotics, or natural products were excluded. Studies involving only statins currently registered for human use were included. RESULTS: Against Gram-positive bacteria, simvastatin generally exerted the greatest antibacterial activity (lowest MIC) compared to atorvastatin, rosuvastatin, and fluvastatin. Against Gram-negative bacteria, atorvastatin generally exhibited similar or slightly better activity compared to simvastatin, but both were more potent than rosuvastatin and fluvastatin. DISCUSSION: Statins may serve as AMR breakers by working synergistically with existing topical antibiotics, attenuating virulence factors, boosting human immunity, or aiding in wound healing. It is probable that statins' mechanism of antibacterial activity involves interference of bacterial cell regulatory functions via binding and disrupting cell surface structures such as wall teichoic acids, lipoteichoic acids, lipopolysaccharides, and/or surface proteins. The widespread use of statins for cardiovascular protection may favor selective pressures or co-selection for resistance, including dysbiosis of the human gut microbiota, sublethal plasma concentrations in bacteremic patients, and statin persistence in the environment, all possibly culminating in AMR. CONCLUSION: Simvastatin appears to be the most suitable statin for repurposing as a novel adjuvant antibiotic. Current evidence better supports statins as potential AMR breakers, but their role as plausible AMR makers cannot be excluded. Elucidating the mechanism of statins' antibacterial activity is perhaps the most important knowledge gap to address as this will likely clarify statins' role as AMR breakers or makers.

Calcium channel blockers and breast cancer incidence: An updated systematic review and meta-analysis of the evidence.

Controversy exists regarding the potential association between taking calcium channel blockers (CCBs) and the development of breast cancer. As a positive association would have important public health implications due to the widespread use of CCBs, this study aimed to incorporate new evidence to determine whether an association is likely to exist. We searched MEDLINE, EMBASE and the Cochrane Library to 28 June 2016 for relevant literature. References and citing articles were checked and authors contacted as necessary. Two authors independently selected articles and extracted data. Twenty-nine studies were reviewed; 26 were non-randomised studies (NRS). Meta-analysis of study data where adjustment for 'confounding by indication' was judged to be present suggests that an association, if any, is likely to be modest in magnitude (pooled odds/risk ratio 1.09 (95% confidence interval (CI) 1.03-1.15, I2=0%, 8 sub-studies; pooled hazard ratio 0.99 (95% CI 0.94-1.03, I2=35%, 9 sub-studies)). There are credible study data showing an increased relative risk with long-term use of CCBs, but the results of our meta-analysis and of meta-regression of log relative risk against minimum follow-up time are mixed. The current summative evidence does not support a clear association between taking CCBs and developing breast cancer. However, uncertainty remains, especially for long-term use and any association might not be uniform between different populations and/or breast cancer sub-types. We thus recommend further NRS in settings where CCB use is highly prevalent and population-based cancer, prescription and health-registries exist, to resolve this continuing uncertainty. PROSPERO, CRD42015026712.

Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism.

BACKGROUND: Statins are a class of therapeutics used to regulate serum cholesterol and reduce the risk of heart disease. Although statins are highly effective in removing cholesterol from the blood, their consumption has been linked to potential adverse effects in some individuals. The most common events associated with statin intolerance are myopathy and increased risk of developing type 2 diabetes mellitus. However, the pathological mechanism through which statins cause these adverse effects is not well understood. RESULTS: Using a murine model, we describe for the first time profound changes in the microbial composition of the gut following statin treatment. This remodelling affected the diversity and metabolic profile of the gut microbiota and was associated with reduced production of butyrate. Statins altered both the size and composition of the bile acid pool in the intestine, tentatively explaining the observed gut dysbiosis. As also observed in patients, statin-treated mice trended towards increased fasting blood glucose levels and weight gain compared to controls. Statin treatment affected the hepatic expression of genes involved in lipid and glucose metabolism. Using gene knockout mice, we demonstrated that the observed effects were mediated through pregnane X receptor (PXR). CONCLUSION: This study demonstrates that statin therapy drives a profound remodelling of the gut microbiota, hepatic gene deregulation and metabolic alterations in mice through a PXR-dependent mechanism. Since the demonstrated importance of the intestinal microbial community in host health, this work provides new perspectives to help prevent the statin-associated unintended metabolic effects.

The Pharmacists’ and pharmacy technicians’ scopes of practice in the management of minor ailments at community pharmacies in Indonesia: a cross-sectional study

Background: Managing minor ailments in community pharmacy is an evolving pharmacy service in developing countries. Defined scopes of practice for pharmacy staff are essential for the safe management of minor ailments. Limited research exists regarding the perceptions of Indonesian pharmacists’ and pharmacy technicians’ scopes of practice in providing minor ailments management services. Objective: To evaluate pharmacists’ and pharmacy technicians’ understanding of their scopes of practice, perceived competency and factors influencing the delivery of minor ailments services in Indonesian community pharmacies. Methods: Cross-sectional surveys were conducted during January-February 2020 of pharmacists and pharmacy technicians attending seminars conducted by relevant Indonesian Associations in Central Java, Indonesia. Percentage of common responses (PCR) described similarity of perceived scopes of practice for pharmacists and pharmacy technicians. Univariate and multivariate analyses identified associations of scopes of practice with pharmacy characteristics. Results: A total of 185 pharmacists and 142 pharmacy technicians participated. Pharmacy technicians performed minor ailment consultations, however, if considered beyond their scope of practice, they referred the patient to the pharmacist (T=120/142, 84.5%). Vaginal thrush, bacterial conjunctivitis, gastro-oesophageal reflux disease, and acute pain were minor ailments perceived only within a pharmacist’s scope (PCR above 60%). Of 34 minor ailments, 11 showed PCR values between 40-60% overlapping pharmacists and pharmacy technicians perceived scopes of practice (allergy/rash, back pain, cold sores, dermatitis, diarrhoea, eczema, hayfever, haemorrhoids, rheumatism, sore throat, and superficial wounds). Back pain (AU)