Supporting prescribing in Irish primary care: protocol for a non-randomised pilot study of a general practice pharmacist (GPP) intervention to optimise prescribing in primary care.

BACKGROUND: Prescribing for patients taking multiple medicines (i.e. polypharmacy) is challenging for general practitioners (GPs). Limited evidence suggests that the integration of pharmacists into the general practice team could improve the management of these patients. The aim of this study is to develop and test an intervention involving pharmacists, working within GP practices, to optimise prescribing in Ireland, which has a mixed public and private primary healthcare system. METHODS: This non-randomised pilot study will use a mixed-methods approach. Four general practices will be purposively sampled and recruited. A pharmacist will join the practice team for 6 months. They will participate in the management of repeat prescribing and undertake medication reviews (which will address high-risk prescribing and potentially inappropriate prescribing, deprescribing and cost-effective and generic prescribing) with adult patients. Pharmacists will also provide prescribing advice regarding the use of preferred drugs, undertake clinical audits, join practice team meetings and facilitate practice-based education. Throughout the 6-month intervention period, anonymised practice-level medication (e.g. medication changes) and cost data will be collected. A nested Patient Reported Outcome Measure (PROM) study will be undertaken during months 4 and 5 of the 6-month intervention period to explore the impact of the intervention in older adults (aged ≥ 65 years). For this, a sub-set of 50 patients aged ≥ 65 years with significant polypharmacy (≥ 10 repeat medicines) will be recruited from each practice and invited to a medication review with the pharmacist. PROMs and healthcare utilisation data will be collected using patient questionnaires, and a 6-week follow-up review conducted. Acceptability of the intervention will be explored using pre- and post-intervention semi-structured interviews with key stakeholders. Quantitative and qualitative data analysis will be undertaken and an economic evaluation conducted. DISCUSSION: This non-randomised pilot study will provide evidence regarding the feasibility and potential effectiveness of general practice-based pharmacists in Ireland and provide data on whether a randomised controlled trial of this intervention is indicated. It will also provide a deeper understanding as to how a pharmacist working as part of the general practice team will affect organisational processes and professional relationships in a mixed public and private primary healthcare system.

Ivacaftor for cystic fibrosis: An evaluation of real world utilisation and expenditure in the Irish Healthcare Setting.

In Ireland, Ivacaftor is reimbursed, on the High-Tech Drug Scheme, for the treatment of cystic fibrosis in patients age 6 years and older who have the G551D mutation. The aim of this study was to analyse the utilisation and expenditure of Ivacaftor on this scheme in the 12 month period post-reimbursement. All patients who had received Ivacaftor (regardless of General Medical Services Scheme eligibility/ineligibility) were included. A total of 140 individuals (male=74; 53%) received Ivacaftor over the defined 12 month study period (from January 2015 to December 2015 inclusive). The cohort ranged in age from 6 years to 61 years. The mean age was 22 years; a positive skew in age distribution indicated that a greater number of the cohort were in the younger age groups. No statistically significant difference was detected in the mean ages of the male and female subgroups. Drug acquisition expenditure by the Health Services Executive on Ivacaftor over the 12 month study period was €29.81 million.

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction.

We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na+] and [Cl-] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.

The cost of inpatient management of heart failure patients: a microcosting study in the Irish healthcare setting.

AIMS: To formally assess the resource use and cost of the inpatient treatment of heart failure (HF) from the health-payer's perspective. In addition, to compare costs in our cohort to (a) locally derived patient-level costs (PLC) and (b) national costs as per disease-related group (DRG). METHODS AND RESULTS: Study population Demographics and resource utilisation data were obtained from a cohort of 30 patients (57% male, mean age 70 years) admitted into a single tertiary centre with heart failure. Patients were identified retrospectively. Costing A microcosting approach was used to examine admission costs that were compared to PLC costs and DRG costs. Main outcome measure The bootstrap estimation was used to determine mean inpatient length of stay (LOS) with standard deviation (±SD) and mean costs ±SD. RESULTS: The bootstrapped mean cost per HF episode was €10,474 ± 2478. The major cost drivers were ward stay (mean cost €6068 ± €1681): laboratory costs (€1373 ± 79) and cath lab costs (€1415 ± 729). HF was more expensive to manage in patients ≤65 years (€18,930 ± 5546) compared to those aged over 65 years (€6209 ± 1732); p = 0.001. No significant difference was found in managing heart failure in males (€11,035 ± 3564) versus females (€9629 ± 3294), p = 0.69. DRG costing frequently over or underestimated the admission cost. PLC costs were similar to microcosting derived costs. The bootstrapped mean LOS per HF episode was 15.7 days ± 3.4. CONCLUSIONS: This study confirms that heart failure is a costly condition and that inpatient stay is the major cost driver. HF was significantly more expensive to manage in patients ≤65 years compared to those aged over 65 years. DRG costing frequently over or underestimated the admission cost. Patient-level costs and microcosting are more accurate methods of costing inpatient HF admissions. To our knowledge, this is the first study of the cost of the inpatient treatment of HF within the context of the Irish healthcare setting.

Immune reactivity after adenoviral-mediated aquaporin-1 cDNA transfer to human parotid glands.

OBJECTIVES: The purpose of this study was to examine the humoral and cellular immune reactivity to adenoviral vector (AdhAQP1) administration in the human parotid gland over the first 42 days of a clinical gene therapy trial. METHODS: Of eleven treated subjects, five were considered as positive responders (Baum et al, 2012). Herein, we measured serum neutralizing antibody titers, circulating cytotoxic lymphocytes, and lymphocyte proliferation in peripheral blood mononuclear cells. Additionally, after adenoviral vector stimulation of lymphocyte proliferation, we quantified secreted cytokine levels. RESULTS: Responders showed little to modest immune reactivity during the first 42 days following gene transfer. Additionally, baseline serum neutralizing antibody titers to serotype 5-adenovirus generally were not predictive of a subject's response to parotid gland administration of AdhAQP1. Cytokine profiling from activated peripheral blood mononuclear cells could not distinguish responders and non-responders. CONCLUSIONS: The data are the first to describe immune responses after adenoviral vector administration in a human parotid gland. Importantly, we found that modest (2-3 fold) changes in systemic cell-mediated immune reactivity did not preclude positive subject responses to gene transfer. However, changes beyond that level likely impeded the efficacy of gene transfer.

Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter.

In 2012, we reported that 5 out of 11 subjects in a clinical trial (NCT00372320) administering AdhAQP1 to radiation-damaged parotid glands showed increased saliva flow rates and decreased symptoms over the initial 42 days. AdhAQP1 is a first-generation, E1-deleted, replication-defective, serotype 5 adenoviral vector encoding human aquaporin-1 (hAQP1). This vector uses the human cytomegalovirus enhancer/promoter (hCMVp). As subject peak responses were at times much longer (7-42 days) than expected, we hypothesized that the hCMVp may not be methylated in human salivary gland cells to the extent previously observed in rodent salivary gland cells. This hypothesis was supported in human salivary gland primary cultures and human salivary gland cell lines after transduction with AdhAQP1. Importantly, hAQP1 maintained its function in those cells. Conversely, when we transduced mouse and rat cell lines in vitro and submandibular glands in vivo with AdhAQP1, the hCMVp was gradually methylated over time and associated with decreased hAQP1 expression and function in vitro and decreased hAQP1 expression in vivo. These data suggest that the hCMVp in AdhAQP1was probably not methylated in transduced human salivary gland cells of responding subjects, resulting in an unexpectedly longer functional expression of hAQP1.

The cost of the inpatient management of febrile neutropenia in cancer patients--a micro-costing study in the Irish healthcare setting.

The objective was to evaluate the resource use and cost of hospitalisation for febrile neutropenia (FN) from the health-payer's perspective. This was a single centre study. Adults undergoing chemotherapy, who were admitted for FN, were identified prospectively. Patient medical records were reviewed retrospectively. Demographics and resource utilisation data were obtained from a cohort of 32 patients (69% female, mean age = 58.8 years). Twenty-five per cent of patients had more than one FN episode. In total, 42 FN episodes were captured; 60% of episodes had occurred within the first two cycles of chemotherapy. The bootstrap estimation was used to determine mean hospital length of stay (LOS) with standard deviation (±SD) and mean costs ± SD. The mean LOS was 7.3 ± 0.5 days. The mean cost per FN episode was €8915 ± 718. The major cost driver was hospital bed-stay (mean cost of €6851 ± 549). Other cost drivers included antibacterial treatment at €760 ± 156, laboratory investigations at €538 ± 47 and the requirement for blood bank products at €525 ± 189. To our knowledge, this is the first investigation of the cost of chemotherapy induced FN within the context of the Irish healthcare setting.

Measures of user experience in a streptococcal pharyngitis and pneumonia clinical decision support tools.

OBJECTIVE: To understand clinician adoption of CDS tools as this may provide important insights for the implementation and dissemination of future CDS tools. MATERIALS AND METHODS: Clinicians (n=168) at a large academic center were randomized into intervention and control arms to assess the impact of strep and pneumonia CDS tools. Intervention arm data were analyzed to examine provider adoption and clinical workflow. Electronic health record data were collected on trigger location, the use of each component and whether an antibiotic, other medication or test was ordered. Frequencies were tabulated and regression analyses were used to determine the association of tool component use and physician orders. RESULTS: The CDS tool was triggered 586 times over the study period. Diagnosis was the most frequent workflow trigger of the CDS tool (57%) as compared to chief complaint (30%) and diagnosis/antibiotic combinations (13%). Conversely, chief complaint was associated with the highest rate (83%) of triggers leading to an initiation of the CDS tool (opening the risk prediction calculator). Similar patterns were noted for initiation of the CDS bundled ordered set and completion of the entire CDS tool pathway. Completion of risk prediction and bundled order set components were associated with lower rates of antibiotic prescribing (OR 0.5; CI 0.2-1.2 and OR 0.5; CI 0.3-0.9, respectively). DISCUSSION: Different CDS trigger points in the clinician user workflow lead to substantial variation in downstream use of the CDS tool components. These variations were important as they were associated with significant differences in antibiotic ordering. CONCLUSIONS: These results highlight the importance of workflow integration and flexibility for CDS success.

User centered clinical decision support tools: adoption across clinician training level.

BACKGROUND: Dissemination and adoption of clinical decision support (CDS) tools is a major initiative of the Affordable Care Act's Meaningful Use program. Adoption of CDS tools is multipronged with personal, organizational, and clinical settings factoring into the successful utilization rates. Specifically, the diffusion of innovation theory implies that 'early adopters' are more inclined to use CDS tools and younger physicians tend to be ranked in this category. OBJECTIVE: This study examined the differences in adoption of CDS tools across providers' training level. PARTICIPANTS: From November 2010 to 2011, 168 residents and attendings from an academic medical institution were enrolled into a randomized controlled trial. INTERVENTION: The intervention arm had access to the CDS tool through the electronic health record (EHR) system during strep and pneumonia patient visits. MAIN MEASURES: The EHR system recorded details on how intervention arm interacted with the CDS tool including acceptance of the initial CDS alert, completion of risk-score calculators and the signing of medication order sets. Using the EHR data, the study performed bivariate tests and general estimating equation (GEE) modeling to examine the differences in adoption of the CDS tool across residents and attendings. KEY RESULTS: The completion rates of the CDS calculator and medication order sets were higher amongst first year residents compared to all other training levels. Attendings were the less likely to accept the initial step of the CDS tool (29.3%) or complete the medication order sets (22.4%) that guided their prescription decisions, resulting in attendings ordering more antibiotics (37.1%) during an CDS encounter compared to residents. CONCLUSION: There is variation in adoption of CDS tools across training levels. Attendings tended to accept the tool less but ordered more medications. CDS tools should be tailored to clinicians' training levels.

Prescribing trends for dabigatran etexilate in primary care.

At the time of the analysis, dabigatran etexilate was licensed, in Ireland, for thromboprophylaxis in adults after elective total hip- and total knee-replacement only. A retrospective review (January 2010 to June 2011) of the National General Medical Services Prescription Database showed that 1929 patients had received prescriptions for dabigatran etexilate. Of these, 42% had received it for longer than the licensed maximum duration (at that time) of 35 days. The Eastern Health board dabigatran etexilate cohort (n = 510) was analysed further. Here 64.5% had received the drug for longer than 35 days. Seventy-six (32.5%) of the 234 patients who had received more than 90 days of dabigatran etexilate had concurrently received rate/rhythm control therapy. Likewise, 47 (31%) of the 152 patients who had received more than 180 days of dabigatran etexilate had been co-prescribed rate/rhythm control therapy. It is possible that dabigatran etexilate had been prescribed for stroke prevention in atrial fibrillation.

Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals.

OBJECTIVE: The aim of this study was to assess the efficacy, safety and tolerability of pegylated interferon and ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients, prescribed for the same duration and at the same dosage as that used in HCV monoinfection studies. DESIGN: It was an open-label, single-centre, prospective study. METHODS: Forty-five patients coinfected with HIV and HCV with CD4 counts >200 cells/microL were treated with pegylated interferon-alpha2b 1.5 microg/kg/week and ribavirin 1000-1200 mg/day for 24-48 weeks depending on HCV genotype. Safety and tolerability were assessed weekly for the first month and monthly thereafter. Virological response was assessed at weeks 4, 12 and 24 and at the end of treatment and 12 and 24 weeks post completion of treatment. The primary endpoint was defined as undetectable HCV RNA at 24 weeks post completion of treatment [sustained virological response (SVR)]. RESULTS: The majority of patients were male and had been injecting drug users. Sixty per cent were on antiretroviral therapy. In an intention-to-treat analysis, 53% had an SVR (genotype 1, 19% and genotype 2/3, 75%). All patients who had undetectable HCV RNA at week 4 of HCV treatment [very early virological response (VEVR)] had a SVR. On multivariate analysis only HCV genotype predicted SVR. Adverse events occurred frequently. CONCLUSIONS: These results indicate that 24 weeks of HCV treatment may be adequate for HIV-infected individuals coinfected with HCV genotype 2 or 3. VEVR can predict SVR in this group and may be used to guide the subgroup of genotype 2/3 individuals who will respond to 24 weeks of treatment.

Auditory dysfunction in Stickler syndrome.

OBJECTIVES: To characterize the natural history and possible mechanisms of hearing loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthro-ophthalmopathy) and to determine if the auditory phenotype is a useful discriminating feature for the differential diagnosis of this group of disorders. DESIGN: Multifamily study. SETTING: Outpatient audiology and otolaryngology clinics at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Rockville, Md. SUBJECTS: Forty-six affected individuals from 29 different families segregating Stickler syndrome. INTERVENTIONS: Clinical audiologic and otolaryngological examinations were performed on all individuals, including pure-tone audiometry, speech audiometry, and middle ear immittance testing. Otoacoustic emissions, auditory brainstem response, infrared video electronystagmography, and temporal bone computed tomography were performed on a subset of participants. RESULTS: The hearing loss was most often sensorineural in adults, and approximately 28 (60%) of the 46 adult patients had 2 or more thresholds greater than the corresponding 95th percentile values for an age-matched, otologically normal population. The hearing loss most often affected high frequencies (4000-8000 Hz) and was generally no more progressive than that due to age-related hearing loss. Type A(D) tympanograms (classification using the Jerger model), indicating hypermobile middle ear systems, were observed in 21 (46%) of the 46 affected individuals. Computed tomography of the temporal bones revealed no inner ear malformations in 19 affected individuals. CONCLUSIONS: The hypermobile middle ear systems observed in ears with normal-appearing tympanic membranes represent a novel finding for Stickler syndrome and are likely to be a useful diagnostic feature for this disorder. The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome. This difference will be a useful discriminatory feature in the differential diagnosis of this group of disorders.

Overcoming the top 10 tracheotomy self-care learning barriers.

Multispecialty inpatient units are the norm in today's acute care settings. Since few units have the luxury of seasoned otorhinolaryngology (ORL) nurses, care of the postoperative patient with a tracheotomy, including discharge teaching and planning are left to the generalists. Generalist nurses and new ORL nurses may find themselves experiencing fear and anxiety along with the tracheotomy patients they care for and teach. Experienced ORL nurses are continually challenged to find ways to share their expertise with patients and less experienced nurses in effective ways. This article presents a unique approach to preparing nurses to teach self-tracheotomy care to their patients. Medical-surgical staff nurses attended a 90-minute inservice program presenting actual clinical scenarios of temporarily learning-impaired patients with tracheotomies, and were asked to role play effective interventions. The program content is designed to address the reluctance of inexperienced, busy nurses to confront learning barriers and motivate patients to accomplish early postoperative involvement in tracheotomy self care. The widespread nature of the challenges faced by nurses and patients regarding tracheotomy care has been confirmed by discussions with colleagues on a national level. It has been confirmed further by the first author's clinical experiences in a wide variety of health care settings. Recommended nursing actions and responses to learning barriers presented here are based on expert opinion and clinical experience.

Use of herbal therapies by adults seen in an ambulatory care research setting: an exploratory survey.

OBJECTIVE: To identify and characterize patterns of use of herbal products among patients participating in selected research clinics. DESIGN: Survey of three National Institutes of Health (NIH) ambulatory care research clinics. SUBJECTS: Convenience sample of 490 adult patients (168 male, 322 female) attending rheumatology, liver, and endocrinology/metabolic research clinics. RESULTS: Of the patients surveyed, 16.7%: (n = 82) reported using herbs. There were no significant sociodemographic differences between herb and nonherb users. Indications for herb use differed among the disease groups; patients in the endocrine and rheumatology clinics were taking herbs predominantly for "energy" or "wellness"; those attending the liver clinic tended to use herbal therapies as treatment for their disease. Mean and median monthly expenditure for herbal products was $30 and $10, respectively. There was a significant positive correlation between number of herbs used and use of other dietary supplements (p < 0.0001). CONCLUSIONS: One in six patients in ambulatory clinical research settings may be taking herbal products in addition to prescribed treatment. This figure is lower than in the general population, possibly because the patients may stop using herbs when participating in a research project. Although empirical evidence on the beneficial or adverse effects of herb therapy alone or in combination with drug therapies is limited, clinical researchers should be aware of the potential for confounding clinical trial results.

Asymptomatic laryngeal malformations are common in patients with Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) comprises hypothalamic hamartoma, polydactyly, pituitary dysfunction, laryngotracheal cleft, imperforate anus, and other anomalies. Some patients with PHS have a bifid epiglottis, a rare malformation. Greig cephalopolysyndactyly syndrome (GCPS) comprises polydactyly with craniofacial malformations without the PHS malformations. Both disorders are caused by mutations in the GLI3 gene. Laryngoscopy on 26 subjects with PHS showed that 15 had a bifid or cleft epiglottis (58%) and none of 14 subjects with GCPS had a cleft epiglottis. The malformed epiglottis was asymptomatic in all of the prospectively evaluated subjects. One additional PHS subject was found to have bifid epiglottis and a posterior laryngeal cleft on autopsy. We conclude that bifid epiglottis is common in PHS but not GCPS. Posterior laryngeal clefts are an uncommon manifestation of PHS and are identified only in severely affected patients. The diagnosis of a bifid epiglottis should prompt a thorough search for other sometimes asymptomatic anomalies of PHS to provide better medical care and recurrence risk assessment for affected individuals and families.

Endoscope reprocessing: taking the mystery out of high-level disinfection.

Flexible endoscopes used in otolaryngology are often unable to withstand heat sterilization. An acceptable alternative to heat sterilization for these devices used to examine the aerodigestive tract is high-level disinfection. A review of otolaryngology (ORL) nursing clinical practice indicates that there is confusion regarding the recommended disinfectant solutions to use and the proper manner in which to use them. This article describes a method that is useful in determining the level of risk of infection posed by ORL endoscopy, a description of appropriate levels of disinfection, points to consider for achieving high-level disinfection, and appropriate personal protective measures.

Expression of proinflammatory and proangiogenic cytokines in patients with head and neck cancer.

Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma (HNSCC), and many of these responses have been linked with aggressive malignant behavior and a decrease in prognosis. In this study, we examined the hypothesis that HNSCC cells produce cytokines that regulate immune, inflammatory, and angiogenesis responses. We identified important regulatory cytokines in supernatants of well-defined and freshly cultured HNSCC cell lines by ELISA and determined whether these cytokines are detected in tumor cell lines and tissue specimens by immunohistochemistry. The serum concentration of the cytokines and cytokine-dependent acute phase inflammatory responses (i.e., fibrinogen, C-reactive protein, and erythrocyte sedimentation rate) from patients with HNSCC was determined, and the potential relationship of serum cytokine levels to tumor volume was analyzed. Cytokines interleukin (IL)-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor were detected in similar concentration ranges in the supernatants of a panel of established University of Michigan squamous cell carcinoma (UM-SCC) cell lines and supernatants of freshly isolated primary HNSCC cultures. Evidence for the expression of IL-1alpha, IL-6, IL-8, granulocyte-macrophage colony-stimulating factor, and VEGF in HNSCC cells within tumor specimens in situ was obtained by immunohistochemistry. In a prospective comparison of the cytokine level and cytokine-inducible acute-phase proteins in serum, we report that cytokines IL-6, IL-8, and VEGF were detected at higher concentrations in the serum of patients with HNSCC compared with patients with laryngeal papilloma or age-matched control subjects (at P < 0.05). The serum concentrations of IL-8 and VEGF were found to be weakly correlated with large primary tumor volume (R2 = 0.2 and 0.4, respectively). Elevated IL-1- and IL-6-inducible acute-phase responses were also detected in cancer patients but not in patients with papilloma or control subjects (at P < 0.05). We therefore conclude that cytokines important in proinflammatory and proangiogenic responses are detectable in cell lines, tissue specimens, and serum from patients with HNSCC. These cytokines may increase the pathogenicity of HNSCC and prove useful as biomarkers or targets for therapy.