Access to episodic primary care: a cross-sectional comparison of walk-in clinics and urgent primary care centers in British Columbia.

AIM: This study aimed to identify publicly reported access characteristics for episodic primary care in BC and provided a clinic-level comparison between walk-in clinics and UPCCs. BACKGROUND: Walk-in clinics are non-hospital-based primary care facilities that are designed to operate without appointments and provide increased healthcare access with extended hours. Urgent and Primary Care Centres (UPCCs) were introduced to British Columbia (BC) in 2018 as an additional primary care resource that provided urgent, but not emergent care during extended hours. METHODS: This cross-sectional study used publicly available data from all walk-in clinics and UPCCs in BC. A structured data collection form was used to record access characteristics from clinic websites, including business hours, weekend availability, attachment to a longitudinal family practice, and provision of virtual services. FINDINGS: In total, 268 clinics were included in the analysis (243 walk-in clinics, 25 UPCCs). Of those, 225 walk-in clinics (92.6%) and two UPCCs (8.0%) were attached to a longitudinal family practice. Only 153 (63%) walk-in clinics offered weekend services, compared to 24 (96%) of UPCCs. Walk-in clinics offered the majority (8,968.6/ 78.4%) of their service hours between 08:00 and 17:00, Monday to Friday. UPCCs offered the majority (889.3/ 53.7%) of their service hours after 17:00. CONCLUSION: Most walk-in clinics were associated with a longitudinal family practice and provided the majority of clinic services during typical business hours. More research that includes patient characteristics and care outcomes, analyzed at the clinic level, may be useful to support the optimization of episodic primary healthcare delivery.

Estimating the cost consequence of the early use of botulinum toxin in post-stroke spasticity: Secondary analysis of a randomised controlled trial.

OBJECTIVE: To estimate the cost-consequence of treating spasticity early with botulinum toxin in the acute stroke unit. DESIGN: Secondary cost-consequence analysis, using data from a double-blind randomised-controlled trial. SETTING: Single-centre specialised stroke unit. SUBJECTS AND INTERVENTIONS: Patients with Action Research Arm Test grasp-score of <2 and who developed spasticity within six weeks of a first stroke were randomised to receive injections of: 0.9% sodium-chloride solution (placebo) or onabotulinumtoxin-A (treatment). MAIN MEASURES: Resource use costs were calculated for the study. Mean contracture costs for each group were calculated. The Barthel Index and Action Research Arm Test were used to generate a cost per unit of improvement. RESULTS: There were no significant differences associated with early treatment use. The mean contracture cost for the treatment group was £817 and for the control group was £2298 (mean difference = -£1481.1(95% CI -£2893.5, -£68.7) (p = 0.04). The cost per unit of improvement for the Barthel Index was -£1240 indicating that the intervention costs less and is more effective. The cost per unit of improvement for the Action Research Arm Test was -£450 indicating that the intervention costs less and is more effective. CONCLUSIONS: Treating spasticity early in stroke patients at risk of contractures with botulinum toxin leads to a significant reduction in contracture costs. The cost per improvement of Barthel and Action Research Arm Test indicates that the intervention costs less and is more effective. TRIAL REGISTRATION DATA: EudraCT(2010-021257-39) and ClinicalTrials.gov-Identifier:NCT01882556.

Finding Primary Care-Repurposing Physician Registration Data to Generate a Regionally Accurate List of Primary Care Clinics: Development and Validation of an Open-Source Algorithm.

BACKGROUND: Some Canadians have limited access to longitudinal primary care, despite its known advantages for population health. Current initiatives to transform primary care aim to increase access to team-based primary care clinics. However, many regions lack a reliable method to enumerate clinics, limiting estimates of clinical capacity and ongoing access gaps. A region-based complete clinic list is needed to effectively describe clinic characteristics and to compare primary care outcomes at the clinic level. OBJECTIVE: The objective of this study is to show how publicly available data sources, including the provincial physician license registry, can be used to generate a verifiable, region-wide list of primary care clinics in British Columbia, Canada, using a process named the Clinic List Algorithm (CLA). METHODS: The CLA has 10 steps: (1) collect data sets, (2) develop clinic inclusion and exclusion criteria, (3) process data sets, (4) consolidate data sets, (5) transform from list of physicians to initial list of clinics, (6) add additional metadata, (7) create working lists, (8) verify working lists, (9) consolidate working lists, and (10) adjust processing steps based on learnings. RESULTS: The College of Physicians and Surgeons of British Columbia Registry contained 13,726 physicians, at 2915 unique addresses, 6942 (50.58%) of whom were family physicians (FPs) licensed to practice in British Columbia. The CLA identified 1239 addresses where primary care was delivered by 4262 (61.39%) FPs. Of the included addresses, 84.50% (n=1047) were in urban locations, and there was a median of 2 (IQR 2-4, range 1-23) FPs at each unique address. CONCLUSIONS: The CLA provides a region-wide description of primary care clinics that improves on simple counts of primary care providers or self-report lists. It identifies the number and location of primary care clinics and excludes primary care providers who are likely not providing community-based primary care. Such information may be useful for estimates of capacity of primary care, as well as for policy planning and research in regions engaged in primary care evaluation or transformation.

Can the early use of botulinum toxin in post stroke spasticity reduce contracture development? A randomised controlled trial.

OBJECTIVE: Does early treatment of spasticity with botulinum-toxin (BoNTA), in (hyper)acute stroke patients without arm-function, reduce contractures and improve function. DESIGN: Randomised placebo-controlled-trial. SETTING: Specialised stroke-unit. PARTICIPANTS & INTERVENTION: Patients with an Action Research Arm Test (ARAT) grasp-score⩽2 who developed spasticity within six-weeks of a first stroke were randomised to receive injections of: 0.9%sodium-chloride solution (placebo) or onabotulinumtoxin-A (treatment). OUTCOME-MEASURES: Spasticity, contractures, splint use and arm function (ARAT) were taken at baseline, 12-weeks post-injection and six-months after stroke. Additionally, spasticity and contractures were measured at weeks-two, four and six post-injection. RESULTS: Ninety three patients were randomised. Mean time to intervention was 18-days (standard deviation = 9.3). Spasticity was lower in the treatment group with difference being significant between week-2 to 12 (elbow) and week-2 to 6 (wrist). Mean-difference (MD) varied between -8.5(95% CI -17 to 0) to -9.4(95% CI -14 to -5) µV.Contracture formation was slower in the treatment group. Passive range of motion was higher in the treatment group and was significant at week-12 (elbow MD6.6 (95% CI -0.7 to -12.6)) and week-6 (wrist MD11.8 (95% CI 3.8 to 19.8)). The use of splints was lower in the treatment group odds ratio was 7.2 (95% CI 1.5 to 34.1) and 4.2 (95% CI 1.3 to 14.0) at week-12 and month-6 respectively.Arm-function was not significantly different between the groups MD2.4 (95% CI -5.3 to 10.1) and 2.9 (95% CI -5.8 to 11.6) at week-12 and month-6 respectively. CONCLUSION: BoNTA reduced spasticity and contractures after stroke and effects lasted for approximately 12-weeks. BoNTA reduced the need for concomitant contracture treatment and did not interfere with recovery of arm function. TRIAL REGISTRATION: EudraCT (2010-021257-39) and ClinicalTrials.gov-Identifier: NCT01882556.

Antitumour effects of metformin and curcumin in human papillomavirus positive and negative head and neck cancer cells.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has significantly increased in recent decades due to human papillomavirus (HPV)-mediated oncogenesis. Unfortunately, a growing number of HPV-positive (+) OPSCC survivors are living with the irreversible side effects of treatment. The novel, well-tolerated chemotherapeutics with improved side effect profiles are, therefore, in high demand. Metformin is one such drug, widely used as a first-line oral agent in the treatment of type 2 diabetes mellitus. Curcumin is another well-tolerated agent quickly gaining attention for its medicinal properties. Both metformin and curcumin have been shown to display anticancer properties. This study aimed to determine the antitumor effects of these agents, individually and combined, in HPV+​​​​ ​​​and HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) cell lines. This was achieved by assessing the efficacy of varying drug concentrations on the overall cell viability, proliferation, and expression of common HNSCC biomarkers. The results from protein and RNA expression data are highly variable, as expected, with multiple pathways being affected in cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and immunofluorescence microscopy suggest that both agents are capable of slowing proliferation and inducing apoptosis. We conclude that curcumin and metformin display effective antitumor effects in both HPV+ and HPV- HNSCC cell lines. The curcumin effects appear more pronounced in the HPV- cell lines. Metformin appears to be more effective at reducing the overall cell numbers in HPV+ cell lines. Metformin and curcumin combined did not appear to have synergistic effects on the proliferation or apoptosis of the treated cell lines.

EGFR as a biomarker of smoking status and survival in oropharyngeal squamous cell carcinoma.

BACKGROUND: This study aims to investigate EGFR as a prognostic biomarker in oropharyngeal squamous cell carcinoma (OPSCC). METHODS: OPSCC patients from retrospective (1998-2009) and prospective cohorts (2014-2017) were included. Retrospectively collected tumors were used to construct tissue microarrays (TMAs), which were stained with EGFR, p16, DAPI and Pan-cytokeratin, and digitally quantified. EGFR, CDKN2A and HPV E6/7 levels from prospectively collected OPSCC was measured by droplet digital PCR (ddPCR). Biomarkers were compared to patient covariates, factors and survival outcomes. RESULTS: A total of 249 patients were included retrospectively and 64 patients were enrolled prospectively. p16 status (p < 0.001), smoking above 10 pack years (p = 0.04), smoking above 20 pack years (p < 0.001), total EGFR tumor levels (p = 0.016), and high EGFR within high or low Ki67 tumor nuclear staining (p = 0.03) were found to be significant predictors of 5-year disease specific survival (DSS). A Cox proportional hazard model of DSS showed smoking status and eGFR expression to be dependent of each other on predicting 5-year DSS. ddPCR analysis showed a significant association between smoking status and EGFR levels. CONCLUSIONS: Total EGFR tumor levels are predictive of 5-year DSS. EGFR levels correlate with. smoking and could be an objective marker for this disease etiology.

Efficacy of EZH2 inhibitory drugs in human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide with rates of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) dramatically increasing. The overexpression of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for the trimethylation at lysine 27 of histone 3 (H3K27me3), is associated with a poor clinical prognosis and aggressive HPV-positive phenotypes. METHODS: We utilized three EZH2 pathway inhibitors, GSK-343, DZNeP, and EPZ-5687, and tested their efficacy in two HPV-positive and two HPV-negative OPSCC cell lines. RESULTS: Treatment with GSK-343 decreased H3K27me3 in all cell lines and treatment with DZNeP decreased H3K27me3 in only HPV-negative cell lines as determined by Western blot. Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3. Epigenetic effect on gene expression was measured via ddPCR utilizing 11 target probes. Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines. GSK-343-treated cells displayed moderate expressional changes, with CCND1 increased in HPV-positive cell lines and decreased TP53 in HPV-negative SCC-1. EPZ-5687-treated cell lines displayed few expressional changes overall. Only DZNeP-treated cells displayed anti-proliferative characteristics shown in wound-healing assays. CONCLUSIONS: Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation.

Epigenetics of oropharyngeal squamous cell carcinoma: opportunities for novel chemotherapeutic targets.

Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Ultrasensitive detection of oncogenic human papillomavirus in oropharyngeal tissue swabs.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by oncogenic human papillomavirus (HPV) is rising worldwide. HPV-OPSCC is commonly diagnosed by RT-qPCR of HPV E6 and E7 oncoproteins or by p16 immunohistochemistry (IHC). Droplet digital PCR (ddPCR) has been recently reported as an ultra-sensitive and highly precise method of nucleic acid quantification for biomarker analysis. To validate the use of a minimally invasive assay for detection of oncogenic HPV based on oropharyngeal swabs using ddPCR. Secondary objectives were to compare the accuracy of ddPCR swabs to fresh tissue p16 IHC and RT-qPCR, and to compare the cost of ddPCR with p16 IHC. METHODS: We prospectively included patients with p16+ oral cavity/oropharyngeal cancer (OC/OPSCC), and two control groups: p16- OC/OPSCC patients, and healthy controls undergoing tonsillectomy. All underwent an oropharyngeal swab with ddPCR for quantitative detection of E6 and E7 mRNA. Surgical specimens had p16 IHC performed. Agreement between ddPCR and p16 IHC was determined for patients with p16 positive and negative OC/OPSCC as well as for healthy control patients. The sensitivity and specificity of ddPCR of oropharyngeal swabs were calculated against p16 IHC for OPSCC. RESULTS: 122 patients were included: 36 patients with p16+OPSCC, 16 patients with p16-OPSCC, 4 patients with p16+OCSCC, 41 patients with p16-OCSCC, and 25 healthy controls. The sensitivity and specificity of ddPCR of oropharyngeal swabs against p16 IHC were 92 and 98% respectively, using 20-50 times less RNA than that required for conventional RT-qPCR. Overall agreement between ddPCR of tissue swabs and p16 of tumor tissue was high at ĸ = 0.826 [0.662-0.989]. CONCLUSION: Oropharyngeal swabs analyzed by ddPCR is a quantitative, rapid, and effective method for minimally invasive oncogenic HPV detection. This assay represents the most sensitive and accurate mode of HPV detection in OPSCC without a tissue biopsy in the available literature.

Pharmacological interventions other than botulinum toxin for spasticity after stroke.

BACKGROUND: The long-term risk of stroke increases with age, and stroke is a common cause of disability in the community. Spasticity is considered a significantly disabling impairment that develops in people who have had a stroke. The burden of care is higher in stroke survivors who have spasticity when compared with stroke survivors without spasticity with regard to treatment costs, quality of life, and caregiver burden. OBJECTIVES: To assess if pharmacological interventions for spasticity are more effective than no intervention, normal practice, or control at improving function following stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 5), MEDLINE (1946 to May 2016), Embase (2008 to May 2016), CINAHL (1982 to May 2016), AMED (1985 to May 2016), and eight further databases and trial registers. In an effort to identify further studies, we undertook handsearches of reference lists and contacted study authors and commercial companies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any systemically acting or locally acting drug versus placebo, control, or comparative drug with the aim of treating spasticity. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the studies for inclusion and extracted the data. We assessed the included studies for both quality and risk of bias. We contacted study authors to request further information when necessary. MAIN RESULTS: We included seven RCTs with a total 403 participants. We found a high risk of bias in all but one RCT. Two of the seven RCTs assessed a systemic drug versus placebo. We pooled data on an indirect measure of spasticity (160 participants) from these two studies but found no significant effect (odds ratio (OR) 1.66, 95% confidence interval (CI) 0.21 to 13.07; I2 = 85%). We identified a significant risk of adverse events per participant occurring in the treatment group versus placebo group (risk ratio (RR) 1.65, 95% CI 1.12 to 2.42; 160 participants; I2 = 0%). Only one of these studies used a functional outcome measure, and we found no significant difference between groups.Of the other five studies, two assessed a systemic drug versus another systemic drug, one assessed a systemic drug versus local drug, and the final two assessed a local drug versus another local drug. AUTHORS' CONCLUSIONS: The lack of high-quality RCTs limited our ability to make specific conclusions. Evidence is insufficient to determine if systemic antispasmodics are effective at improving function following stroke.

Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer.

BACKGROUND: In recent decades, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising worldwide as a result of increasing oncogenic human papillomavirus (HPV) infections in the oropharynx. EZH2 is an epigenetic regulatory protein associated with tumor aggressiveness and negative survival outcomes in several human cancers. We aimed to determine the role of EZH2 as a potential therapeutic epigenetic target in HPV-positive and negative OPSCC. METHODS: The expression of EZH2 was measured by immunohistochemistry (IHC) and droplet digital PCR (ddPCR) in 2 HPV-positive and 2 HPV-negative cell lines. The cell lines were then cultured and treated with one of 3 EZH2 epigenetic inhibitors (3-deazaneplanocin A, GSK-343 and EPZ005687) or DMSO (control). Following 2, 4 and 7 days of treatment, cells were analyzed and compared by gene expression, cell survival and proliferation assays. RESULTS: EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines. The expression profile of genes important in OPSCC also differed according to HPV-positivity for Ki67, CCND1, MET and PTEN/PIK3CA, but remained unchanged for EGFR, CDKN2A and p53. CONCLUSION: Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines. EZH2 is a promising epigenetic target for the treatment of OPSCC.

The early use of botulinum toxin in post-stroke spasticity: study protocol for a randomised controlled trial.

BACKGROUND: Patients surviving stroke but who have significant impairment of function in the affected arm are at more risk of developing pain, stiffness and contractures. The abnormal muscle activity, associated with post-stroke spasticity, is thought to be causally associated with the development of these complications. Treatment of spasticity is currently delayed until a patient develops signs of these complications. METHODS/DESIGN: This protocol is for a phase II study that aims to identify whether using OnabotulinumtoxinA (BoNT-A) in combination with physiotherapy early post stroke when initial abnormal muscle activity is neurophysiologically identified can prevent loss of range at joints and improve functional outcomes.The trial uses a screening phase to identify which people are appropriate to be included in a double blind randomised placebo-controlled trial. All patients admitted to Sandwell and West Birmingham NHS Trust Hospitals with a diagnosis of stroke will be screened to identify functional activity in the arm. Those who have no function will be appropriate for further screening. Patients who are screened and have abnormal muscle activity identified on EMG will be given electrical stimulation to forearm extensors for 3 months and randomised to have either injections of BoNT-A or normal saline. The primary outcome measure is the action research arm test - a measure of arm function. Further measures include spasticity, stiffness, muscle strength and fatigue as well as measures of quality of life, participation and caregiver strain. TRIAL REGISTRATIONS: ISRCTN57435427, EudraCT2010-021257-39, NCT01882556.