Noradrenergic and dopaminergic therapy in Parkinson's disease:preclinical studies on L-threo-DOPS, decarboxylase inhibitors and transdermal lisuride

Bij de palliatieve behandeling van de ziekte van Parkinson (PD) blijken nog veel symptomen niet op de gebruikelijke therapie met dopamine (DA) suppleterende of dopaminomimetische farmaka te reageren. De studies bijeen gebracht in dit proefschrift beschrijven twee alternatieve benaderingen in de farmacotherapeutische behandeliig van PD: versterking van de noradrenerge neurotransrnissie met behulp van een precursor van noradrenaline (NA), en het ontwikkelen van een eenvoudig transdermaal toedieningssysteem voor de dopamine agonist lisuride. De niet op dopaminerge therapie reagerende motorische en niet-motorische (autonome, cognitieve) symptomen worden meer en meer toegeschreven aan een eveneens minder functionele noradrenerge neurotransmissie in de hersenen van parkinson patiënten. Het proefschrift beschrijft experimenten in proefdieren welke tot doel hadden het intracerebrale werkingsmechanisme van L-threo-DOPS (DOPS), de precursor van noradrenaline (NA) op te helderen. DOPS is succesvol toegepast bij de behandeling van freezing en akinesie bij japanse parkinson patienten. De standaard therapie bij PD met levodopa (DOPA) in een combinatiepreparaat met een perifere decarboxylase remmer (DCI) werd geëvalueerd op eventuele werkzaamheid van de DCI in het centrale zenuwstelsel (CZS). Het grote verschil in plasma halfwaardetijd van DOPA en de DCI kan mogelijk een rol spelen bij de verminderde werkzaamheid van de DOPAIDCI combinatiepreparaten (Sinemet, Madopar) na 4 à 5 jaar continu gebruik. Eventuele activiteit van de DCI in het CZS zou bovendien eveneens de werkzaamheid van DOPS in het CZS nadelig beinvloeden. De studies werden uitgevoerd in de rat, en bij patienten bij wie ondanks hoge doses DOPAIDCI geen bevredigende klinische respons bereikt kon worden. Tenslotte is gepoogd een transdermaal toedieningssysteem te ontwikkelen voor de dopamine agonist lisuride. Door de continue afgifte via de huid kunnen wellicht fluctuaties in de plasmaspiegel van lisuride en de daaraan gerelateerde grillige klinische respons en bijwerkingen voorkomen worden

Serum Anti-Müllerian Hormone Is Significantly Altered by Downregulation With Daily Gonadotropin-Releasing Hormone Agonist: A Prospective Cohort Study

Research Question: What is the effect of gonadotropin-releasing hormone (GnRH)-agonist treatment on serum anti-Müllerian hormone (AMH)?Design: This prospective cohort study conducted in a tertiary university hospital comprised patients (n = 52) who self-administered daily triptorelin (0.1 mg/0.1 mL) subcutaneously for 14 days from menstrual cycle day 21 ± 3, between July 2015 and March 2016. Enrolled women were 18–43 years old, considered normal ovarian responders, with a planned GnRH agonist controlled ovarian stimulation protocol. The primary endpoint was to evaluate the effect of GnRH agonist on serum AMH levels after 7 and 14 days of treatment.Results: Under GnRH agonist treatment, serum AMH was significantly decreased vs. baseline on day 7 (mean change from baseline: −0.265 ng/mL; 95% confidence interval [CI], −0.395 to −0.135 ng/mL; p < 0.001). On day 14, serum AMH was significantly increased (mean change from baseline: 0.289 ng/mL; 95% CI, 0.140–0.439 ng/mL; p < 0.001). Although the median change in AMH from baseline was only −14.9% on day 7 and +17.4% on day 14, from day 7 to 14 AMH significantly increased by 0.55 ng/mL (43.8%; p < 0.001), which is of paramount clinical importance. A linear, mixed-effect model demonstrated that GnRH agonist treatment for 7 and 14 days had a highly significant effect on serum AMH concentration after adjustment for confounding factors (age, body mass index, baseline antral follicle count, and visit). AMH assay precision was excellent (four aliquots/sample); coefficient of variation was 1.2–1.4%.Conclusions: GnRH agonist treatment had a clinically significant effect on serum AMH, dependent on treatment duration. The clear V-shaped response of AMH level to daily GnRH agonist treatment has important clinical implications for assessing ovarian reserve and predicting ovarian response, thus AMH measurements under GnRH agonist downregulation should be interpreted with great caution

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

From biomarkers to medical tests: The changing landscape of test evaluation

Regulators and healthcare payers are increasingly demanding evidence that biomarkers deliver patient benefits to justify their use in clinical practice. Laboratory professionals need to be familiar with these evidence requirements to better engage in biomarker research and decisions about their appropriate use. This paper by a multidisciplinary group of the European Federation of Clinical Chemistry and Laboratory Medicine describes the pathway of a laboratory assay measuring a biomarker to becoming a medically useful test. We define the key terms, principles and components of the test evaluation process. Unlike previously described linearly staged models, we illustrate how the essential components of analytical and clinical performances, clinical and cost-effectiveness and the broader impact of testing assemble in a dynamic cycle. We highlight the importance of defining clinical goals and how the intended application of the biomarker in the clinical pathway should drive each component of test evaluation. This approach emphasizes the interaction of the different components, and that clinical effectiveness data should be fed back to refine analytical and clinical performances to achieve improved outcomes. The framework aims to support the understanding of key stakeholders. The laboratory profession needs to strengthen collaboration with industry and experts in evidence-based medicine, regulatory bodies and policy makers for better decisions about the use of new and existing medical tests

Setting analytical performance specifications based on outcome studies - is it possible?

The 1st Strategic Conference of the European Federation of Clinical Chemistry and Laboratory Medicine proposed a simplified hierarchy for setting analytical performance specifications (APS). The top two levels of the 1999 Stockholm hierarchy, i.e., evaluation of the effect of analytical performance on clinical outcomes and clinical decisions have been proposed to be replaced by one outcome-based model. This model can be supported by: (1a) direct outcome studies; and (1b) indirect outcome studies investigating the impact of analytical performance of the test on clinical classifications or decisions and thereby on the probability of patient relevant clinical outcomes. This paper reviews the need for outcome-based specifications, the most relevant types of outcomes to be considered, and the challenges and limitations faced when setting outcome-based APS. The methods of Model 1a and b are discussed and examples are provided for how outcome data can be translated to APS using the linked evidence and simulation or decision analytic techniques. Outcome-based APS should primarily reflect the clinical needs of patients; should be tailored to the purpose, role and significance of the test in a well defined clinical pathway; and should be defined at a level that achieves net health benefit for patients at reasonable costs. Whilst it is acknowledged that direct evaluations are difficult and may not be possible for all measurands, all other forms of setting APS should be weighed against that standard, and regarded as approximations. Better definition of the relationship between the analytical performance of tests and health outcomes can be used to set analytical performance criteria that aim to improve the clinical and cost-effectiveness of laboratory test