Peptoids with Antibiofilm Activity against the Gram Negative Obligate Anaerobe, Fusobacterium nucleatum.

Peptoids (oligo N-substituted glycines) are peptide analogues, which can be designed to mimic host antimicrobial peptides, with the advantage that they are resistant to proteolytic degradation. Few studies on the antimicrobial efficacy of peptoids have focused on Gram negative anaerobic microbes associated with clinical infections, which are commonly recalcitrant to antibiotic treatment. We therefore studied the cytotoxicity and antibiofilm activity of a family of peptoids against the Gram negative obligate anaerobe Fusobacterium nucleatum, which is associated with infections in the oral cavity. Two peptoids, peptoid 4 (NaeNpheNphe)4 and peptoid 9 (NahNspeNspe)3 were shown to be efficacious against F. nucleatum biofilms at a concentration of 1 µM. At this concentration, peptoids 4 and 9 were not cytotoxic to human erythrocytes or primary human gingival fibroblast cells. Peptoids 4 and 9 therefore have merit as future therapeutics for the treatment of oral infections.

An evaluation of the additional benefit of population screening for dementia beyond a passive case-finding approach.

OBJECTIVE: General practitioners (GPs) fail to identify more than 50% of dementia cases using the existing passive case-finding approach. Using data from the "Ageing in General Practice" study, we sought to establish the additional benefit of screening all patients over the age of 75 for dementia beyond those patients already identified by passive case-finding. METHOD: Patients were classified as "case-finding" (n = 425) or "screening" (n = 1006) based on their answers to four subjective memory related questions or their GP's clinical judgement of their dementia status. Cognitive status of each patient was formally assessed by a research nurse using the Cambridge Cognition Examination (CAMCOG-R). Patients then attended their usual GP for administration of the GP assessment of Cognition (GPCOG) dementia screening instrument, and follow-up care and/or referral as necessary in light of the outcome. RESULTS: The prevalence of dementia was significantly higher in the case-finding group (13.6%) compared to the screening group (4.6%; p < 0.01). The GPCOG had a positive predictive value (PPV) of 61% in the case-finding group and 39% in the screening group; negative predictive value was >95% in both groups. GPs and their patients both found the GPCOG to be an acceptable cognitive assessment tool. The dementia cases missed via case-finding were younger (p = 0.024) and less cognitively impaired (p = 0.020) than those detected. CONCLUSION: There is a very limited benefit of screening for dementia, as most people with dementia could be detected using a case-finding approach, and considerable potential for social and economic harm because of the low PPV associated with screening.

A comparison of implant-retained mandibular overdentures and conventional dentures on quality of life in edentulous patients: a randomized, prospective, within-subject controlled clinical trial.

OBJECTIVES: To determine any difference in patient response to implant overdentures compared with conventional complete dentures alone. MATERIALS AND METHODS: In a randomized, prospective, controlled study, 122 edentulous patients (Mean age 64; 39 men, 83 women) underwent baseline assessment of denture satisfaction and quality of life using the Oral Health Impact Profile-49 (OHIP-49) and a Denture Satisfaction Questionnaire. All patients were provided with new conventional complete dentures (CCDs) that they wore for 3 months, at which point they were reassessed using the same measures. Patients were randomly assigned either to continue with CCDs (CC group) or to have implant-retained overdentures (IODs) made (CI group). The CC group was assessed after a further 3 months (6 months after receiving CCDs). The CI group was assessed 3 months after receiving IODs. RESULTS: Significant improvements in satisfaction and quality of life were found in the patients 3 months after receiving CCDs (P < 0.05). No further improvements were found in the CC group at 6 months on any of the measures. The CI group showed significant additional improvements at 3 months following IODs on the functional limitation, physical pain, psychological discomfort, physical disability, social disability, psychological disability and handicap scales of the OHIP and on 10 of the 11 scales of the Denture Satisfaction Questionnaire (P < 0.05, ANOVA). CONCLUSIONS: The findings show that, controlling for expectancy bias and variability in baseline levels, IODs significantly increase patient satisfaction, dental function and quality of life over and above those achieved with good quality CCDs.

A governance model for integrated primary/secondary care for the health-reforming first world - results of a systematic review.

BACKGROUND: Internationally, key health care reform elements rely on improved integration of care between the primary and secondary sectors. The objective of this systematic review is to synthesise the existing published literature on elements of current integrated primary/secondary health care. These elements and how they have supported integrated healthcare governance are presented. METHODS: A systematic review of peer-reviewed literature from PubMed, MEDLINE, CINAHL, the Cochrane Library, Informit Health Collection, the Primary Health Care Research and Information Service, the Canadian Health Services Research Foundation, European Foundation for Primary Care, European Forum for Primary Care, and Europa Sinapse was undertaken for the years 2006-2012. Relevant websites were also searched for grey literature. Papers were assessed by two assessors according to agreed inclusion criteria which were published in English, between 2006-2012, studies describing an integrated primary/secondary care model, and had reported outcomes in care quality, efficiency and/or satisfaction. RESULTS: Twenty-one studies met the inclusion criteria. All studies evaluated the process of integrated governance and service delivery structures, rather than the effectiveness of services. They included case reports and qualitative data analyses addressing policy change, business issues and issues of clinical integration. A thematic synthesis approach organising data according to themes identified ten elements needed for integrated primary/secondary health care governance across a regional setting including: joint planning; integrated information communication technology; change management; shared clinical priorities; incentives; population focus; measurement - using data as a quality improvement tool; continuing professional development supporting joint working; patient/community engagement; and, innovation. CONCLUSIONS: All examples of successful primary/secondary care integration reported in the literature have focused on a combination of some, if not all, of the ten elements described in this paper, and there appears to be agreement that multiple elements are required to ensure successful and sustained integration efforts. Whilst no one model fits all systems these elements provide a focus for setting up integration initiatives which need to be flexible for adapting to local conditions and settings.

Infective endocarditis and oral surgery input before cardiac surgery: time to prick the paradigm of pre-cardiac surgery assessments?

Purpose To review current practice regarding oral surgery input for patients awaiting cardiac valvular surgery and who are at risk of infective endocarditis (IE) in the context of the COVID-19 pandemic, and to stimulate debate around the indications for pre-operative oral surgery assessment. It also opens the way to developing a new research-based approach which is patient-centred, safe, effective and efficient.Methods A desk-top based patient review was undertaken between 27 March 2020 and 1 July 2022 to record the outcome of patients undergoing cardiac valvular surgery in Northern Ireland, following the revision of the referral guidelines for oral surgery intervention. Data were collected for all cardiac referrals to the oral surgery on-call service in the Royal Victoria Hospital, Belfast. Complications were recorded at two weeks, two months, and six months post-surgery, using Northern Ireland Electronic Care Records.Results In total, 67 cardiac patients were identified between 27 March 2020 and 1 July 2022: 65.7% of patients were male and had an average age of 68, while the female patients had an average age of 61. The mean interval of date of cardiology referral to surgery date was 9.7 working days, with 36% of patients referred within five days of the planned surgery date. Moreover, 39% had valvular surgery in combination with another type of cardiac surgery. No complications linked to dental aetiology were noted.Conclusions This paper raises questions about the advisability of oral surgery input before cardiac surgery for anything other than pain relief, management of acute dental sepsis, or IE whose source has been identified as an oral commensal. The COVID-19 pandemic has presented an opportunity to review current practice and open the way to developing a new approach which is patient-centred, safe, effective and efficient.

Ageing in general practice (AGP) trial: a cluster randomised trial to examine the effectiveness of peer education on GP diagnostic assessment and management of dementia.

BACKGROUND: Dementia is increasing in prevalence as the population ages. An earlier rather than later diagnosis allows persons with dementia and their families to plan ahead and access appropriate management. However, most diagnoses are made by general practitioners (GPs) later in the course of the disease and are associated with management that is poorly adherent to recommended guidelines. This trial examines the effectiveness of a peer led dementia educational intervention for GPs. METHODS: The study is a cluster randomised trial, conducted across three states and five sites. All GPs will complete an audit of their consenting patients aged 75 years or more at three time points - baseline, 12 and 24 months. GPs allocated to the intervention group will receive two educational sessions from a peer GP or nurse, and will administer the GPCOG to consenting patients at baseline and 12 months. The first education session will provide information about dementia and the second will provide individualised feedback on audit results. GPs in the waitlist group will receive the RACGP Guidelines by post following the 12 month audit OUTCOMES: Primary outcomes are carer and consumer quality of life and depression. Secondary outcomes include: rates of GP identification of dementia compared to a more detailed gold standard assessment conducted in the patient's home; GP identification of differential diagnoses including reversible causes of cognitive impairment; and GP referral to specialists, Alzheimers' Australia and support services. A "case finding" and a "screening" group will be compared and the psychometrics of the GPCOG will be examined. SAMPLE SIZE: Approximately 2,000 subjects aged 75 years and over will be recruited through approximately 160 GPs, to yield approximately 200 subjects with dementia (reducing to 168 by 24 months). DISCUSSION: The trial outlined in this paper has been peer reviewed and supported by the Australian National Health and Medical Research Council. At the time of submission of this paper 2,034 subjects have been recruited and the intervention delivered to 114 GPs. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000117415.

Point of care troponin decreases time in the emergency department for patients with possible acute coronary syndrome: a randomised controlled trial.

OBJECTIVE: To determine the effect of cardiac troponin I testing with a point-of-care (POC) device versus central laboratory on length of stay (LOS) in emergency department (ED) patients presenting with possible acute coronary syndromes (ACS). METHODS: A 12-week randomised controlled trial at two metropolitan ED in eastern Australia with a combined annual census of 80,000. Participants were all patients presenting with possible ACS. Exclusions were a diagnosis of ACS before arrival, ST elevation and failure to wait for complete assessment. Randomisation was by week when POC was made available. Primary outcome was LOS from patient arrival to physical departure from the ED. The proportion of patients meeting a government target of less than 8 h stay was compared. Analysis was by intention to treat. RESULTS: Despite underutilisation of POC, LOS was shorter during weeks when it was available. The time savings translates into approximately 48 minutes (95% CI 12 to 84) per average LOS of almost 7 h, which did not reach statistical significance (p=0.063), or an absolute increase of 10% (95% CI 4.3 to 16.6) in the number of people discharged from the ED within the target LOS of less than 8 h, which did reach significance (p=0.007). These savings were more pronounced in the setting without 24 h central laboratory availability. CONCLUSIONS: POC testing for troponin in the ED tended to reduce the LOS for possible ACS patients. The degree of this benefit is likely to be markedly dependent on its acceptance and uptake by attending personnel, and on the ED setting in which it is used.

Healthcare teams - a practical framework for integration.

BACKGROUND: Delivering integrated team care is a major priority for many countries. In Australia this is a component of the GP Super Clinic Program but it is also a focus of the broader primary care sector. Explicit consideration of human dynamics and team process is often absent from the move to integrated team care. OBJECTIVE: To provide a practical framework that will inform the development and evaluation of integrated healthcare teams. DISCUSSION: The Team Focused and Clinical Content Framework is an approach to building integrated teams. This has the potential to be used to monitor and evaluate team development and functioning. Both the framework and clinical pathways provide practical tools for clinics to address the need to build integration into teams.

Antimicrobial activity of truncated alpha-defensin (human neutrophil peptide (HNP)-1) analogues without disulphide bridges.

Antimicrobial peptides play an important role in host defence, particularly in the oral cavity where there is constant challenge by microorganisms. The alpha-defensin antimicrobial peptides comprise 30-50% of the total protein in the azurophilic granules of human neutrophils, the most abundant of which is human neutrophil peptide 1 (HNP-1). Despite its antimicrobial activity, a limiting factor in the potential therapeutic use of HNP-1 is its chemical synthesis with the correct disulphide topology. In the present study, we synthesised a range of truncated defensin analogues lacking disulphide bridges. All the analogues were modelled on the C-terminal region of HNP-1 and their antimicrobial activity was tested against a range of microorganisms, including oral pathogens. Although there was variability in the antimicrobial activity of the truncated analogues synthesised, a truncated peptide named 2Abz(23)S(29) displayed a broad spectrum of antibacterial activity, effectively killing all the bacterial strains tested. The finding that truncated peptides, modelled on the C-terminal beta-hairpin region of HNP-1 but lacking disulphide bridges, display antimicrobial activity could aid their potential use in therapeutic interventions.

Translating the Elements of Health Governance for Integrated Care from Theory to Practice: A Case Study Approach.

INTRODUCTION: Against a paucity of evidence, a model describing elements of health governance best suited to achieving integrated care internationally was developed. The aim of this study was to explore how health meso-level organisations used, or planned to use, the governance elements. METHODS: A case study design was used to offer two contrasting contexts of health governance. Semi-structured interviews were conducted with participants who held senior governance roles. Data were thematically analysed to identify if the elements of health governance were being used, or intended to be in the future. RESULTS: While all participants agreed that the ten elements were essential to developing future integrated care, most were not used. Three major themes were identified: (1) organisational versus system focus, (2) leadership and culture, and, (3) community (dis)engagement. DISCUSSION: Several barriers and enablers to the use of the elements were identified and would require addressing in order to make evidence-based changes. CONCLUSION: Despite a clear international policy direction in support of integrated care this study identified a number of significant barriers to its implementation. The study reconfirmed that a focus on all ten elements of health governance is essential to achieve integrated care.

Effectiveness of a peer-mediated educational intervention in improving general practitioner diagnostic assessment and management of dementia: a cluster randomised controlled trial.

OBJECTIVE: Test effectiveness of an educational intervention for general practitioners (GPs) on quality of life and depression outcomes for patients. DESIGN: Double-blind, cluster randomised controlled trial. SETTING: General practices in Australia between 2007 and 2010. PARTICIPANTS: General practices were randomly allocated to the waitlist (n=37) or intervention (n=66) group, in a ratio of 1:2. A total of 2030 (1478 intervention; 552 waitlist) community-dwelling participants aged 75 years or older were recruited via 168 GPs (113 intervention; 55 waitlist). INTERVENTIONS: A practice-based academic detailing intervention led by a peer educator that included: (1) training in use of the GP assessment of cognition dementia screening instrument; (2) training in diagnosis and management based on Royal Australian College of General Practitioners Dementia Guidelines; (3) addressing GPs' barriers to dementia diagnosis; and (4) a business case outlining a cost-effective dementia assessment approach. OUTCOME MEASURES: Primary outcome measures were patient quality of life and depression; secondary outcome measures were: (1) sensitivity and specificity of GP identification of dementia; (2) referral to medical specialists and/or support services; (3) patient satisfaction with care; and (4) carer quality of life, depression and satisfaction with care. RESULTS: The educational intervention had no significant effect on patient quality of life or depression scores after 12 months. There were however improvements in secondary outcome measures including sensitivity of GP judgement of dementia (p=0.002; OR 6.0, 95% CI 1.92 to 18.73), satisfaction with GP communication for all patients (p=0.024; mean difference 2.1, 95% CI 0.27 to 3.93) and for patients with dementia (p=0.007; mean difference 7.44, 95% CI 2.02 to 12.86) and enablement of carers (p=0.0185; mean difference 24.77, 95% CI 4.15 to 45.40). CONCLUSION: Practice-based academic detailing did not improve patient quality of life or depression scores but did improve detection of dementia in primary care and patient satisfaction with GP communication. TRIAL REGISTRATION NUMBER: ACTRN12607000117415; Pre-results.

A comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly.

BACKGROUND: Treatment of hypertension with diuretics, beta-blockers, or both leads to improved outcomes. It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone. We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme (ACE) inhibitors with the outcomes in those treated with diuretic agents. METHODS: We conducted a prospective, randomized, open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practices. Subjects were followed for a median of 4.1 years, and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models. RESULTS: At base line, the treatment groups were well matched in terms of age, sex, and blood pressure. By the end of the study, blood pressure had decreased to a similar extent in both groups (a decrease of 26/12 mm Hg). There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group (56.1 per 1000 patient-years) and 736 cardiovascular events or deaths from any cause in the diuretic group (59.8 per 1000 patient-years; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [95 percent confidence interval, 0.79 to 1.00]; P=0.05). Among male subjects, the hazard ratio was 0.83 (95 percent confidence interval, 0.71 to 0.97; P=0.02); among female subjects, the hazard ratio was 1.00 (95 percent confidence interval, 0.83 to 1.21; P=0.98); the P value for the interaction between sex and treatment-group assignment was 0.15. The rates of nonfatal cardiovascular events and myocardial infarctions decreased with ACE-inhibitor treatment, whereas a similar number of strokes occurred in each group (although there were more fatal strokes in the ACE-inhibitor group). CONCLUSIONS: Initiation of antihypertensive treatment involving ACE inhibitors in older subjects, particularly men, appears to lead to better outcomes than treatment with diuretic agents, despite similar reductions of blood pressure.

The cytotoxic effects of human neutrophil peptide-1 (HNP1) and lactoferrin on oral squamous cell carcinoma (OSCC) in vitro.

Alpha-defensin or human neutrophil peptide-1 (HNP1) is a neutrophil-derived antimicrobial peptide with cytotoxic effects towards cancer cells. Lactoferrin is also stored in human neutrophils and is a glycoprotein involved in mediating cytotoxicity towards tumour cells. This study investigated the sensitivity of normal oral keratinocyte and oral squamous cell carcinoma (OSCC) cells to HNP1 and lactoferrin in various combinations. A concentration of 100 microg/ml HNP1 induced the most significant cytotoxic effect on both normal and OSCC cells. Lactoferrin (12.5, 25 and 250 microg/ml) also significantly induced cell death in OSCC cells after 72 h. Of note, a combination of 10 microg/ml HNP1 and 50 microg/ml lactoferrin induced a differential effect, not observed with either concentration alone, which stimulated proliferation in normal cells, but induced cell death in OSCC cells throughout the study. These results indicate a potentially important co-operative role for HNP1 and lactoferrin in facilitating a selective cytotoxic effect on tumour cells.

Predictors of failure to initiate randomized treatment in a large trial of antihypertensive drug therapy in the aged.

BACKGROUND: The identification of factors that contribute to noncompliance with trial drug initiation where virtually complete compliance might be expected, may help identify patients whose management is least likely to comply with clinical guidelines and study protocols. METHODS: Examination of cross-sectional and longitudinal data arising from the Second Australian National Blood Pressure Study. Prevalence rate ratios (RR) and 95% confidence intervals (CI) estimated from log-binomial models were used to assess associations between subject characteristics and whether the randomized drug was prescribed at trial randomization. The study population consisted of 6083 hypertensive Australians aged 65 to 84 years. RESULTS: After adjusting for each variable in a multivariate model the following were significant predictors of failure to prescribe RR (95% CI): not previously prescribed antihypertensive drugs 2.89 (2.52-3.32); lower systolic blood pressure (BP) 1.51 (1.59-1.43) or diastolic BP 1.18 (1.22-1.13); younger age 80 to 84 v 65 to 79 years 0.75 (0.59-0.95); total cholesterol >or=6.6 v

Impact of multiple low-level anticholinergic medications on anticholinergic load of community-dwelling elderly with and without dementia.

BACKGROUND: Elderly people, particularly those with dementia, are sensitive to adverse anticholinergic drug effects. This study examines the prevalence of anticholinergic medication, and anticholinergic load and its predictors, in community-dwelling elderly patients (aged 75 years and older) in Australia. METHODS: A research nurse visited the home of each participant (n = 1,044), compiled a list of current medications, and assessed participants' cognitive status using a subsection of the revised Cambridge Examination for Mental Disorders of the Elderly (CAMCOG-R). Anticholinergic load was determined for each patient using the Anticholinergic Drug Scale (ADS). RESULTS: Multivariate analysis identified several patient factors that were associated with higher anticholinergic burden, including polypharmacy (i.e. taking five or more medications) (p < 0.001), increasing age (p = 0.018), CAMCOG-R dementia (p = 0.003), depression (p = 0.003), and lower physical quality of life (p < 0.001). The dementia group (n = 86) took a significantly higher number of medications (4.6 vs. 3.9; p = 0.04), and had a significantly higher anticholinergic load (1.5 vs. 0.8; p = 0.002) than those without dementia (n = 958). Approximately 60% of the dementia group and 40% of the non-dementia group were receiving at least one anticholinergic drug. This difference was due to the higher proportion of dementia patients taking level 1 (potentially anticholinergic) (p = 0.002) and level 3 (markedly anticholinergic) (p = 0.005) drugs. CONCLUSIONS: There is considerable scope for the improvement of prescribing practices in the elderly, and particularly those with dementia. Importantly, level 1 anticholinergics have been identified as major contributors to the anticholinergic load in people with dementia. Longitudinal studies are required to determine the effects of increased and decreased anticholinergic load on cognitive function and other clinical outcomes for people with dementia.

Effect of changes in antibiotic prescribing on patient outcomes in a community setting: a natural experiment in Australia.

This study examined whether a significant change in antibiotic use caused by an Australian government directive targeted at amoxicillin with clavulanic acid (AC) was associated with changes in prescription share, health care costs, and patient outcomes. We used an integrated database of computerized general practice medical records, which included data regarding 34,242 patients and 318,234 recorded patient visits. There were 15,303 antibiotic prescriptions provided to 9921 patients during a 4-year period, with AC prescribed for 1453 (14.6%) of these patients. A total of 5125 patient outcomes were identified. There was a shift away from best-practice antibiotic prescribing, and a significant association was identified between the rate and cost of process-of-care and patient outcomes and the decrease in AC-prescription share. This policy initiative created unintended changes in prescribing behavior, increased costs to the government, and a trend toward poorer patient outcomes. Detailed analyses are required before instigating initiatives aimed at changing clinicians' prescribing behavior.

Identification and overexpression of human neutrophil alpha-defensins (human neutrophil peptides 1, 2 and 3) in squamous cell carcinomas of the human tongue.

To date, little attention has been paid to the possible role of alpha-defensins (human neutrophil peptides 1-3), HNP-1, HNP-2 and HNP-3 in innate host defence against tumour invasion. In the current study, using a single-dimensional high pressure liquid chromatography (HPLC) method for peptide separation, followed by mass spectrometry and amino acid sequencing for identification and quantitation, we report the overexpression of HNP-1, HNP-2 and HNP-3 in squamous cell carcinomas of the human tongue compared with autogenous non-tumour tissue. Using a specific antibody we show that the defensins are abundant in neutrophils infiltrating human oral squamous cell carcinoma tissue. In the context of their previously reported oncolytic activity, our results may imply a role for alpha-defensins in host defence against oral squamous cell carcinoma.