Varying Willingness to Pay Based on Severity of Illness: Impact on Health Technology Assessment Outcomes of Inpatient and Outpatient Drug Therapies in The Netherlands.

OBJECTIVES: Since 2015, Zorginstituut Nederland (ZIN) has linked disease severity ranges of 0.10 to 0.40, 0.41 to 0.70, and 0.71 to 1.00 with willingness-to-pay (WTP) reference values of €20 000, €50 000, and €80 000 per quality-adjusted life year gained, respectively. We sought to review whether these changes have affected ZIN health technology assessment (HTA) outcomes for specialist and outpatient drugs. METHODS: ZIN recommendations for specialist and outpatient drugs published between January 1, 2012, and December 31, 2020, that included a pharmacoeconomic report were reviewed. Data were extracted on disease severity, proportional shortfall calculation, reported WTP reference value, outcomes related to the cost-effectiveness of the product, budget impact, and ZIN's recommendation including rationale for their advice. RESULTS: A total of 51 HTAs were included. Of the 20 HTAs published before June 2015, a total of 9 received positive recommendations, 7 were conditionally reimbursed, and 4 received negative recommendations. None reported WTP reference values. Of the 31 evaluations published after June 2015, a total of 4 products received positive recommendations, 1 was conditionally approved, and 26 received negative recommendations initially. Most products (65%) reported disease severity to be >0.70. CONCLUSIONS: Since 2015, most products have fallen within the highest category of disease severity. Although pre-2015 outcomes were varied, post-2015 products overwhelmingly received negative recommendations, and the proportion of products for which price negotiations were recommended has increased. These differences in outcomes may result from the introduction of an explicit WTP reference value, whether or not in combination with the severity-adjusted ranges, but may also reflect other national policy changes in 2015.

Improving the understanding of how patients with non-dystrophic myotonia are selected for myotonia treatment with mexiletine (NaMuscla): outcomes of treatment impact using a European Delphi panel.

BACKGROUND: Non-dystrophic myotonias (NDMs) comprise muscle chloride and sodium channelopathies due to genetic defects of the CLCN1- and SCN4A-channels. No licensed antimyotonic treatment has been available until approval of mexiletine (NaMuscla®) for adult patients by the EMA in December 2018. This Delphi panel aimed to understand how outcomes of the pivotal phase III Mexiletine study (MYOMEX) translate to real world practice and investigate health resource use, quality of life and the natural history of NDM to support economic modelling and facilitate patient access. METHODS: Nine clinical experts in treating NDM took part in a two-round Delphi panel. Their knowledge of NDM and previous use of mexiletine as an off-label treatment prior to NaMuscla's approval ensured they could provide both qualitative context and quantitative estimates to support economic modelling comparing mexiletine (NaMuscla) to best supportive care. Consensus in four key areas was sought: healthcare resource utilization (HRU), treatment with mexiletine (NaMuscla), patient quality of life (QoL), and the natural history of disease. Concept questions were also asked, considering perceptions on the feasibility of mapping the validated Individualized Neuromuscular Quality of Life (INQoL) instrument to the generic EQ-5D™, and the potential impact on caregiver QoL. RESULTS: Consensus was achieved for key questions including the average long-term dosage of mexiletine (NaMuscla) in practice, the criteria for eligibility of myotonia treatment, the clinical importance of QoL outcomes in MYOMEX, the higher proportion of patients with increased QoL, and the reduction in the need for mental health resources for patients receiving mexiletine (NaMuscla). While consensus was not achieved for other questions, the results demonstrated that most experts felt mexiletine (NaMuscla) reduced the need for HRU and was expected to improve QoL. The QoL mapping exercise suggested that it is feasible to map domains of INQoL to EQ-5D. Points of interest for future research were identified, including that mexiletine (NaMuscla) may slow the annual decrease in QoL of patients over their lifetime, and a significant negative impact on QoL for some caregivers. CONCLUSIONS: This project successfully provided data from an informed group of clinical experts, complementing the currently available clinical trial data for mexiletine (NaMuscla) to support patient access decisions.

Outpatient parenteral antimicrobial therapy: updated recommendations from the UK.

Outpatient parenteral antimicrobial therapy (OPAT) offers safe, effective and patient-centred care for adults and children. The OPAT UK good practice recommendations for adults and children have recently been updated through a process of literature review, expert consensus and extensive stakeholder consultation. Here we discuss the key changes in the updated recommendations in the context of recent developments, including novel antimicrobial agents and delivery devices, the place of oral antimicrobials as an alternative to intravenous therapy, new OPAT service models and the broader antimicrobial stewardship agenda.

Assessment and management of active and latent TB.

More than 25% of the world population has been infected with tuberculosis (TB), however only 10% of those infected will ever develop active disease. Clinically significant disease occurs through progression of primary infection or through later reactivation of latent TB infection (LTBI); this is most likely to occur in the first few years following infection, although late reactivation can occur several decades later, particularly in individuals who become immunosuppressed. Risk of TB acquisition is increased in people who have come to the UK from high incidence countries or who are born in the UK but come from high-risk ethnic minority groups. In 2015, 73% of those diagnosed with active TB were born outside the UK. Other risk groups include those who are homeless, in prison or who misuse drugs or alcohol. Once infected people who are immunosuppressed are at greater risk of progression to active disease. Infants below the age of 12 months can develop rapidly progressive and potentially fatal infection. Initial clinical assessment with chest radiography and the collection of three deep respiratory samples for smear microscopy and culture remain the standard of care. The management of active TB has not changed significantly over many years. The most significant changes in the 2016 NICE guidance relate to screening for LTBI in individuals who are contacts of a patient with active TB, or who are recent entrants to the UK from a high incidence country. NICE recommends that only contacts of patients with active pulmonary or laryngeal TB be screened.

Patient retention of training in self-administration of intravenous antibiotic therapy in an outpatient parenteral antibiotic therapy service.

AIMS AND OBJECTIVES: To assess patient retention of initial training on completion of self-administration of a prolonged course of intravenous therapy. BACKGROUND: Outpatient parenteral antibiotic therapy is being used increasingly in the UK, and patients requiring prolonged antibiotic courses may be trained to self-administer therapy. DESIGN: Prospective clinical evaluation. METHODS: Patients self-administering parenteral antibiotic therapy through the Sheffield outpatient parenteral antibiotic therapy service were assessed when nearing completion of therapy for correct technique in five key areas of proficiency using a scoring system. RESULTS: Twenty-nine patients and nine carers were reassessed, at a median interval of 35 days after completion of the initial training package. Of these, 35 of 38 were fully competent in all areas. Three patients showed incomplete retention of their initial training. All made errors relating to use of sterile technique. CONCLUSIONS: Overall retention of training was excellent, and this supports earlier reports that patient-administered outpatient parenteral antibiotic therapy is as safe as nurse-administered therapy. However, this study highlighted a small number of patients or carers who were not fully competent at maintaining sterile technique, and as a result, the protocol for training patients has been altered. RELEVANCE TO CLINICAL PRACTICE: In this study, we assess patients' ability to maintain safe self-administration of therapy over a period of time. Patients are increasingly involved and engaged in their own health care, and this study provides a novel approach to assessing their competence in practical procedures.

Enabling Connected Care with a Person-Centred Data Foundation.

Having the right information at the right time and at the fingertips of the right individuals is not just a necessity for a well-functioning healthcare system but it is also the difference between life and death for Canadians. It is particularly critical to enable improved access to and quality of care for equity-deserving individuals because these data eliminate blind spots for clinicians, policy makers and system planners. The COVID-19 pandemic put a spotlight on the health data challenges that exist across Canada and the tangible impact those have on the healthcare system's ability to meet the needs of underserved populations. It sparked unified urgency at the federal and provincial/territorial levels to build a learning health system powered by connected health data for clinical care, patient access, care organization operations, health system use and population/public health. Person-centric data content standards will lie at the foundation of Canada's learning health system, enabling the creation and exchange of data.

Human Factor Health Data Interoperability.

Comprehensive health data interoperability is recognized as an essential element of high-functioning and accountable health service. Canada is lagging in health data interoperability compared to international comparators, and lacks a comprehensive approach to human factor interoperability, defined as system-level relationships that impact the capacity of health sector stakeholders to adopt harmonized health data standards and technology. Without addressing these system-level relationships, the adoption of harmonized health data standards and technology will be obstructed and Canadians will be underserved. The proposed health data interoperability framework articulates the factors that Canada needs to address to optimize health data design to support quality health programs and services.

Outpatient parenteral antimicrobial therapy in a changing NHS: challenges and opportunities.

Up to 4% of inpatients are in hospital solely to receive intravenous antimicrobial therapy. Outpatient parenteral antimicrobial therapy (OPAT) offers the opportunity for improved efficiency and patient choice through early discharge from hospital or admission avoidance, while maintaining quality of care. OPAT aligns well with key priorities in the new NHS and in this article I explore how new developments in the national healthcare context might be exploited to promote the ongoing evolution of OPAT in the UK.

Good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) in adults in the UK: a consensus statement.

These good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) are an update to a previous consensus statement on OPAT in the UK published in 1998. They are based on previous national and international guidelines, but have been further developed through an extensive consultation process, and are underpinned by evidence from published literature on OPAT. They provide pragmatic guidance on the development and delivery of OPAT services, looking at all aspects of service design, care delivery, outcome monitoring and quality assurance, with the aim of ensuring that OPAT services provide high-quality, low-risk care, whatever the healthcare setting. They will provide a useful resource for teams developing new services, as well as a practical set of quality indicators for existing services.

Outpatient parenteral antibiotic therapy for infective endocarditis: a review of 4 years' experience at a UK centre.

OBJECTIVES: To review the role of outpatient parenteral antibiotic therapy (OPAT) in the management of infective endocarditis (IE) with the aim to guide further development of the service modality both locally and at other centres, in light of the evolving recommendations on patient suitability in international guidelines. METHODS: A retrospective case review of all patients receiving OPAT for IE in Sheffield between January 2006 and October 2010 was conducted. Data were collected on site and microbiology of infection, antibiotic regimens, adverse events during OPAT therapy and outcomes were studied. RESULTS: A total of 36 episodes of IE were treated in 34 patients. All patients received initial treatment as inpatients. Treatment was successful in 34/36 episodes (94.4%) with no evidence of recurrence at a median of 30 months follow-up. One patient had a relapse 2 months after completion of OPAT for enterococcal endocarditis and was found to have concurrent chronic prostatitis. One patient died of a ruptured pulmonary root abscess while receiving OPAT. Adverse events occurred in 12 episodes (33.3%), of which seven were line associated. In four cases adverse events resulted in re-hospitalisation. A successful outcome was achieved in 22/24 episodes (91.7%) deemed to be less suitable for OPAT due to higher risk of complications by Infectious Diseases Society of America guidelines. CONCLUSIONS: OPAT is a safe and effective means of completing therapy for IE, including prosthetic valve endocarditis and other cases at a higher risk of complicated disease. However, the relatively high rate of adverse events highlights the need for well-developed protocols and policies for patient selection and follow-up within the context of a formal OPAT service.

Tuberculosis in UK cities: workload and effectiveness of tuberculosis control programmes.

BACKGROUND: Tuberculosis (TB) has increased within the UK and, in response, targets for TB control have been set and interventions recommended. The question was whether these had been implemented and, if so, had they been effective in reducing TB cases. METHODS: Epidemiological data were obtained from enhanced surveillance and clinics. Primary care trusts or TB clinics with an average of > 100 TB cases per year were identified and provided reflections on the reasons for any change in their local incidence, which was compared to an audit against the national TB plan. RESULTS: Access to data for planning varied (0-22 months). Sputum smear status was usually well recorded within the clinics. All cities had TB networks, a key worker for each case, free treatment and arrangements to treat HIV co-infection. Achievement of targets in the national plan correlated well with change in workload figures for the commissioning organizations (Spearman's rank correlation R = 0.8, P < 0.01) but not with clinic numbers. Four cities had not achieved the target of one nurse per 40 notifications (Birmingham, Bradford, Manchester and Sheffield). Compared to other cities, their loss to follow-up during treatment was usually > 6% (χ2 = 4.2, P < 0.05), there was less TB detected by screening and less outreach. Manchester was most poorly resourced and showed the highest rate of increase of TB. Direct referral from radiology, sputum from primary care and outreach workers were cited as important in TB control. CONCLUSION: TB control programmes depend on adequate numbers of specialist TB nurses for early detection and case-holding.Please see related article: http://www.biomedcentral.com/1741-7015/9/127.

New tests will improve detection of latent TB.

In the UK cases of active TB have risen substantially over the past 20 years. This increase has occurred almost exclusively in individuals born outside the UK, who now constitute more than two-thirds of cases. Only around one in ten people who are infected will develop active disease. The remaining 90% are presumed to have latent TB infection (LTBI) where viable mycobacteria are thought to persist for decades, and may reactivate if the host's immune system is weakened. In a country such as the UK with a low incidence of TB, a high proportion of cases result from reactivation of latent TB, rather than transmission by infectious cases. In the past 10 years a novel type of diagnostic test for LTBI has been developed: the interferon-gamma release assays (IGRA). Their major advantage over the tuberculin skin test is that they are not affected by prior BCG vaccination and they have a specificity of well over 90%. These tests are unable to distinguish between active and latent TB infection: this distinction must be performed purely on clinical grounds. Patients with a positive test should be assessed by a clinician with expertise in TB to ensure an appropriate management plan for each patient. The role of IGRAs in diagnosis of active TB is limited since in a patient with suspected active TB a positive result may indicate LTBI in combination with an alternative diagnosis. At a population level screening and chemoprophylaxis contributes usefully to TB control. However, only those under 35 with LTBI should receive prophylaxis. After this age the increasing risks of hepatotoxicity begin to outweigh the diminishing benefits of prophylaxis. The exceptions are healthcare workers, where the benefits are not just to the individual but also extend to their patients, and immunocompromised patients. The IGRAs represent a major development in the diagnosis of LTBI. While currently most of their use is through established TB screening services, it is likely in future that they will also be used routinely in general practice to screen individuals at high risk of LTBI.

Impact of concurrent treatment with omeprazole on phenylbutazone-induced equine gastric ulcer syndrome (EGUS).

BACKGROUND: Phenylbutazone is commonly prescribed for treatment of various painful or inflammatory disorders in horses, but is associated with gastrointestinal (GI) adverse effects. Anecdotally, many practitioners prescribe omeprazole concurrently with phenylbutazone to reduce development of equine gastric ulcer syndrome (EGUS), but the efficacy and safety of this practice remains unknown. OBJECTIVES: To evaluate the effect of omeprazole on phenylbutazone-induced equine glandular gastric disease (EGGD) and equine squamous gastric disease (ESGD). STUDY DESIGN: Randomised block experimental design. METHODS: Twenty-two horses with EGGD and ESGD scores ≤2 were included. Horses were assigned to treatment groups: phenylbutazone (4.4 mg/kg PO q 12 h; PBZ), phenylbutazone plus omeprazole (4 mg/kg PO q. 24 h; PBZ/OME) or placebo (CON) in a randomised block design based upon initial EGGD score. Horses were treated for up to 14 days. Gastroscopy was performed weekly; CBC and biochemistry were performed at Day 0 and study end. Horses were monitored for signs of colic and/or diarrhoea. RESULTS: EGGD score increased in PBZ (median change 1, inter-quartile range, [IQR], 0-2) compared to PBZ/OME (median change 0, IQR -1 to 0; P = .05). PBZ/OME (6/8) had more intestinal complications than CON (0/6; difference between proportions = 75%; 95% CI, 23%-93%; P = .03). Plasma protein concentrations decreased in PBZ, compared to CON (mean difference between groups, 14 g/L; 95% CI, 1.04-27; P = .03). Five horses were withdrawn from the study due to intestinal complications (n = 3 PBZ/OME and n = 2 PBZ); one horse (PBZ) was withdrawn due to severe grade 4 EGGD. MAIN LIMITATIONS: Small sample size and changes in management for the 2-3 days prior to study initiation; variable treatment duration among groups due to development of complications. CONCLUSIONS: Administration of omeprazole ameliorated PBZ-induced EGGD, but was associated with an increase in intestinal complications. Caution should be exercised when co-prescribing NSAIDs and omeprazole in horses, particularly in association with change in management.

Ertapenem administered as outpatient parenteral antibiotic therapy for urinary tract infections caused by extended-spectrum-beta-lactamase-producing Gram-negative organisms.

OBJECTIVES: Infections with extended-spectrum-beta-lactamase-producing organisms are an increasing public health concern. We reviewed the use of an outpatient parenteral antibiotic therapy (OPAT) programme to facilitate the early discharge from hospital of patients with ESBL-associated urinary tract infections. METHODS: A retrospective review of patients treated for urinary tract infections caused by ESBL-producing organisms through the OPAT programme at the Royal Hallamshire Hospital, Sheffield, UK over a 4 year period to January 2010 was conducted. Data on patient demographics, clinical presentation and laboratory results were collected. RESULTS: Twenty-four OPAT episodes involving 11 patients were identified. Six patients (54.5%) had an underlying urological abnormality on presentation to OPAT. All patients were treated with parenteral ertapenem. Two patients had multiple infections treated by OPAT. The mean duration of the OPAT episodes was 9.9 days (range 3-42). A total of 238 inpatient bed days were avoided, with resultant cost savings. CONCLUSIONS: Ertapenem administration through OPAT may help to decrease the costs associated with ESBL infections by reducing the number of inpatient bed days required for their successful treatment.

Effects of Epinephrine, Detomidine, and Butorphanol on Assessments of Insulin Sensitivity in Mares.

Sympathoadrenal stimulation may perturb results of endocrine tests performed on fractious horses. Sedation may be beneficial; however, perturbation of results may preclude useful information. Four experiments were designed to 1) determine the effects of epinephrine on insulin response to glucose (IR2G), 2) assess the effects of detomidine (DET), alone or combined with butorphanol (DET/BUT), on IR2G and glucose response to insulin (GR2I), and 3) assess the effects of BUT alone on IR2G. In Experiment 1, mares were administered saline or epinephrine (5 µg/kg BW) immediately before infusion of glucose (100 mg/kg BW). Glucose stimulated (P < .05) insulin release in controls at 5 minutes that persisted through 30 minutes; insulin was suppressed (P < .05) by epinephrine from 5 to 15 minutes, rising gradually through 30 minutes. Experiments 2 (IR2G) and 3 (GR2I) were conducted as triplicated 3 × 3 Latin squares with the following treatments: saline (SAL), DET, and DET/BUT (all administered at .01 mg/kg BW). Glucose stimulated (P < .05) insulin release that persisted through 30 minutes in SAL mares; DET and DET/BUT severely suppressed (P < .0001) the IR2G. Sedation did not affect resting glucose and had inconsistent effects on the GR2I when mares were treated with 50 mIU/kg BW recombinant human insulin. Butorphanol had no effect on IR2G. In conclusion, adrenergic agonists severely suppress the IR2G and cannot be used for sedation for this test. The use of DET did not alter the GR2I, and therefore may be useful for conducting this test in fractious horses.

Expression and function of T cell homing molecules in Hodgkin's lymphoma.

Circulating T lymphocytes enter a tissue if they express appropriate chemokine receptors and adhesion molecules to engage ligands presented at this site. To aid rational development of T cell-based therapies for Hodgkin's lymphoma (HL), we have assessed the expression and function of homing receptors on tumour-infiltrating T cells in HL and compared them with T cells from unaffected lymph nodes and colorectal cancer tissue. Chemokine receptors CXCR3, CXCR4 and CCR7 were expressed on a large proportion of T cells within HL tissue and mediated chemotaxis to purified chemokine. The corresponding ligands (CXCL10, CXCL12, CCL21) were expressed on the malignant cells and/or vascular endothelium. Adhesion molecules including CD62L were widely expressed on HL-derived T cells and their corresponding ligands were detected on vessels within the tumour. This homing phenotype was distinct from T cells isolated from colorectal cancer, but matched closely the phenotype of T cells from unaffected lymph nodes. Thus, T cell recruitment to HL resembles entry of naïve/central memory T cells into normal lymph nodes. This has important implications for current approaches to treat HL using T cells activated and expanded in vitro that lack CCR7 and CD62L expression.

Clinical efficacy and cost-effectiveness of outpatient parenteral antibiotic therapy (OPAT): a UK perspective.

OBJECTIVES: Outpatient parenteral antibiotic therapy (OPAT) is an effective treatment strategy for a wide variety of infections as long as clinical risk is minimized by conforming to practice guidelines. However, its cost-effectiveness has not been established in the setting of the UK National Health Service. We examined the clinical efficacy and cost-effectiveness of an OPAT service based in a large UK teaching hospital, predominantly using the outpatient 'infusion centre' and patient/carer administration models of service delivery. PATIENTS AND METHODS: Data on clinical activity and outcomes were collected prospectively on 334 episodes of treatment administered by the Sheffield OPAT service between January 2006 and January 2008. Cost-effectiveness was calculated by comparing real costs of OPAT with estimated inpatient costs for these patient episodes incorporating two additional sensitivity analyses. RESULTS: Of the OPAT episodes, 87% resulted in cure or improvement on completion of intravenous therapy. The readmission rate was 6.3%, and patient satisfaction was high. OPAT cost 41% of equivalent inpatient costs for an Infectious Diseases Unit, 47% of equivalent inpatient costs using national average costs and 61% of inpatient costs using minimum inpatient costs for each diagnosis. CONCLUSIONS: Using this service model, OPAT is safe and clinically effective, with low rates of complications/readmissions and high levels of patient satisfaction. OPAT is cost-effective when compared with equivalent inpatient care in the UK healthcare setting.

Acute diarrhea in hospitalized horses.

The development of diarrhea among hospitalized horses is a major concern for equine veterinary hospitals and referral centers. It is a potential complication of hospitalization for surgical or medical procedures and can contribute to the morbidity and mortality of horses with gastrointestinal and non-gastrointestinal diseases. Unfortunately, it can be difficult to pinpoint the exact cause of acute diarrhea or colitis, and in most cases, the specific etiologic agent is presumptive or undetermined. This article discusses the major etiologic agents of diarrhea in hospitalized horses, considers factors that place hospitalized horses at special risk for diarrhea, and examines several infectious colitis outbreaks that have occurred at veterinary referral centers.