BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

• Klíčová slova
• Clinical outcomes, Clinical trial, Delphi consensus, Fabry disease, Inherited metabolic disorders, Lysosomal storage disorders,
• MeSH
• alfa-galaktosidasa genetika   MeSH
• delfská metoda MeSH
• dospělí MeSH
• enzymová substituční terapie * MeSH
• Fabryho nemoc farmakoterapie   genetika   metabolismus   patologie   MeSH
• globosidy terapeutické užití   MeSH
• glykolipidy terapeutické užití   MeSH
• izoenzymy genetika   MeSH
• klinické zkoušky jako téma * MeSH
• konsensus MeSH
• kvalita života MeSH
• ledviny účinky léků   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• sfingolipidy terapeutické užití   MeSH
• trihexosylceramidy terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• agalsidase beta MeSH Prohlížeč
• alfa-galaktosidasa MeSH
• globosidy MeSH
• globotriaosyl lysosphingolipid MeSH Prohlížeč
• globotrihexosylceramide MeSH Prohlížeč
• glykolipidy MeSH
• izoenzymy MeSH
• sfingolipidy MeSH
• trihexosylceramidy MeSH

Idiopathic inflammatory myopathies (IIM), or myositis, are a heterogeneous group of systemic autoimmune disorders that are associated with significant morbidity and mortality. Conducting high-quality clinical trials in IIM is challenging due to the rare and variable presentations of disease. To address this challenge, the Myositis Clinical Trials Consortium (MCTC) was formed. MCTC is a collaborative international alliance dedicated to facilitating, promoting, coordinating and conducting clinical trials and related research in IIM. This partnership works to advance the discovery of effective evidence-based treatments for IIM by integrating a diverse group of clinical investigators, research professionals, medical centres, patient groups, and industry partners. The Steering Committee, Core Group, and Paediatric Subcommittee of MCTC are comprised of myositis experts and junior investigators from around the world, representing a diversity of genders, geographies, and subspecialties. MCTC works alongside other current myositis organisations to complement existing work by concentrating on the operationalisation of clinical trials. Our pilot Myositis Investigators' Information Survey gathered responses from 173 myositis investigators globally and found considerable variability in proficiency with outcome measures, geographic disparities in patient recruitment, and a significant disconnect between investigators' routine myositis patient load and clinical trial enrolment. MCTC will meet the need to support and diversify myositis clinical trials by facilitating trial planning, feasibility assessments, site selection, and the training and mentoring of junior investigators/centres to establish their readiness for clinical trial participation. Through experienced leadership, strategic collaborations, and interdisciplinary discussions, MCTC will establish standards for IIM clinical trial design, protocols, and outcome measures in myositis.

• MeSH
• dítě MeSH
• dospělí MeSH
• klinické zkoušky jako téma * MeSH
• kooperační chování MeSH
• lidé MeSH
• mezinárodní spolupráce * MeSH
• mladiství MeSH
• myozitida * terapie   diagnóza   MeSH
• výzkumný projekt MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVE: Secukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end-of-study 3-year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study. METHODS: A total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re-randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score-C-reactive protein inactive disease. RESULTS: The retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS-PR) were higher with the 300-mg dose, particularly in tumor necrosis factor (TNF)-inadequate responder (IR) patients. No new safety findings were observed. CONCLUSION: Secukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle end points and in TNF-IR patients. The safety profile of secukinumab was consistent with previous reports.

• Publikační typ
• časopisecké články MeSH

OBJECTIVE: Achieving targeted disease activity (DA) is the primary therapeutic strategy in RA. Point measurements of DA are done at out-patient visits, however true DA between visits remains unobserved. This study sought to describe and validate a new outcome measure, i.e. time in remission (TIR). METHODS: Patients were enrolled in the Czech ATTRA-RA registry. TIR was calculated using linear interpolation of the DAS28-ESR determined at outpatient visits. Correlation coefficients were computed between TIR and DAS28-CRP, HAQ, Simple Disease Activity Index (SDAI), patient global assessment (PGA) and physician global assessment (PhGA). Using logistic regression, TIR was used as a predictor of remission (SDAI ≤3.3) and non-disability (HAQ <0.5). The predictive value of TIR was compared with point and sustained remission using the cross-validated area under receiver-operating curves. RESULTS: Since 2010, 2618 RA patients started anti-TNF therapy and were followed until 2020 or until treatment discontinuation. During the first 6 months of therapy, 56% of patients had no remission (TIR = 0), and 22% of patients reached sustained remission (TIR = 1), while 22% of patients had point remissions with 0 < TIR < 1. EULAR good responders and moderate/non-responders spent 64 ± 42% and 6 ± 18% of time in remission, respectively. The mean TIR grew during the follow-up and was correlated with DAS28-CRP, SDAI, HAQ, PGA, and PhGA (P < 0.0001). TIR at 3 and 6 months predicted remission (SDAI ≤3.3) and non-disability (HAQ <0.5) at 13 and 19 months better than point or sustained remission. CONCLUSIONS: TIR is an intuitive way of estimating unobserved DA between scheduled visits; its calculation only requires two consecutive DA values (https://www.medevio.cz/tir-calculator/). TIR is a valid predictor of RA outcomes.

• Klíčová slova
• Czech Republic, RA, anti-TNF, biological therapy, disease activity, interpolation, outcome measure, prediction, registry, remission,
• MeSH
• antirevmatika * terapeutické užití   MeSH
• hodnocení výsledků zdravotní péče MeSH
• indukce remise MeSH
• inhibitory TNF MeSH
• lidé MeSH
• prospektivní studie MeSH
• revmatoidní artritida * farmakoterapie   MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antirevmatika * MeSH
• inhibitory TNF MeSH

Vitamin D, either in its D2 or D3 form, is essential for normal human development during intrauterine life, kidney function and bone health. Vitamin D deficiency has also been linked to cancer development and some autoimmune diseases. Given this huge impact of vitamin D on human health, it is important for daily clinical practice and clinical research to have reliable tools to judge on the vitamin D status. The major circulating form of vitamin D is 25-hydroxyvitamin D (25(OH)D), although it is not the most active metabolite, the concentrations of total 25-hydroxyvitamin D in the serum are currently routinely used in clinical practice to assess vitamin D status. In the circulation, vitamin D - like other steroid hormones - is bound tightly to a special carrier - vitamin D-binding protein (DBP). Smaller amounts are bound to blood proteins - albumin and lipoproteins. Only very tiny amounts of the total vitamin D are free and potentially biologically active. Currently used vitamin D assays do not distinguish between the three forms of vitamin D - DBP-bound vitamin D, albumin-bound vitamin D and free, biologically active vitamin D. Diseases or conditions that affect the synthesis of DBP or albumin thus have a huge impact on the amount of circulating total vitamin D. DBP and albumin are synthesized in the liver, hence all patients with an impairment of liver function have alterations in their total vitamin D blood concentrations, while free vitamin D levels remain mostly constant. Sex steroids, in particular estrogens, stimulate the synthesis of DBP. This explains why total vitamin D concentrations are higher during pregnancy as compared to non-pregnant women, while the concentrations of free vitamin D remain similar in both groups of women. The vitamin D-DBP as well as vitamin D-albumin complexes are filtered through the glomeruli and re-uptaken by megalin in the proximal tubule. Therefore, all acute and chronic kidney diseases that are characterized by a tubular damage, are associated with a loss of vitamin D-DBP complexes in the urine. Finally, the gene encoding DBP protein is highly polymorphic in different human racial groups. In the current review, we will discuss how liver function, estrogens, kidney function and the genetic background might influence total circulating vitamin D levels and will discuss what vitamin D metabolite is more appropriate to measure under these conditions: free vitamin D or total vitamin D.

• Klíčová slova
• 1,25(OH)(2) vitamin D, Bioavailable vitamin D, Calculated free 25(OH) vitamin D, Directly measured free vitamin D, Free 25(OH) vitamin D, Free vitamin D, Genetic polymorphism, Total 25(OH) vitamin D, Vitamin D-binding protein,
• MeSH
• biologické markery krev   MeSH
• lidé MeSH
• nedostatek vitaminu D krev   diagnóza   MeSH
• protein vázající vitamin D metabolismus   MeSH
• vitamin D analogy a deriváty   krev   MeSH
• vitaminy krev   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• 25-hydroxyvitamin D MeSH Prohlížeč
• biologické markery MeSH
• protein vázající vitamin D MeSH
• vitamin D MeSH
• vitaminy MeSH

OBJECTIVE: To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). METHODS: Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. RESULTS: Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001). CONCLUSION: The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

• MeSH
• alanintransaminasa metabolismus   MeSH
• aldolasa metabolismus   MeSH
• antirevmatika terapeutické užití   MeSH
• aspartátaminotransferasy metabolismus   MeSH
• dermatomyozitida farmakoterapie   metabolismus   patofyziologie   MeSH
• hodnocení výsledků péče pacientem MeSH
• hodnocení výsledků zdravotní péče MeSH
• kreatinkinasa metabolismus   MeSH
• L-laktátdehydrogenasa metabolismus   MeSH
• lidé MeSH
• logistické modely MeSH
• polymyozitida farmakoterapie   metabolismus   patofyziologie   MeSH
• průzkumy a dotazníky MeSH
• revmatologie MeSH
• společnosti lékařské MeSH
• svalová síla MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• Geografické názvy
• Evropa MeSH
• Spojené státy americké MeSH
• Názvy látek
• alanintransaminasa MeSH
• aldolasa MeSH
• antirevmatika MeSH
• aspartátaminotransferasy MeSH
• kreatinkinasa MeSH
• L-laktátdehydrogenasa MeSH

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

• Klíčová slova
• Dermatomyositis, Polymyositis, Treatment,
• MeSH
• dermatomyozitida terapie   MeSH
• dítě MeSH
• dospělí MeSH
• hodnocení výsledků zdravotní péče normy   MeSH
• konsensus MeSH
• lidé MeSH
• mladiství MeSH
• polymyozitida terapie   MeSH
• předškolní dítě MeSH
• randomizované kontrolované studie jako téma MeSH
• senzitivita a specificita MeSH
• stupeň závažnosti nemoci * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• směrnice pro lékařskou praxi MeSH
• validační studie MeSH

Cellular repair enzymes remove virtually all DNA damage before it is fixed; repair therefore plays a crucial role in preventing cancer. Repair studied at the level of transcription correlates poorly with enzyme activity, and so assays of phenotype are needed. In a biochemical approach, substrate nucleoids containing specific DNA lesions are incubated with cell extract; repair enzymes in the extract induce breaks at damage sites; and the breaks are measured with the comet assay. The nature of the substrate lesions defines the repair pathway to be studied. This in vitro DNA repair assay has been modified for use in animal tissues, specifically to study the effects of aging and nutritional intervention on repair. Recently, the assay was applied to different strains of Drosophila melanogaster proficient and deficient in DNA repair. Most applications of the repair assay have been in human biomonitoring. Individual DNA repair activity may be a marker of cancer susceptibility; alternatively, high repair activity may result from induction of repair enzymes by exposure to DNA-damaging agents. Studies to date have examined effects of environment, nutrition, lifestyle, and occupation, in addition to clinical investigations.

• Klíčová slova
• DNA repair, animal studies, base excision repair (BER), clinical studies, comet assay, human biomonitoring, nucleotide excision repair (NER), occupational studies,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVES: Olfactory dysfunction (OD) is common and carries significant personal and societal burden. Accurate assessment is necessary for good clinical and research practice but is highly dependent on the assessment technique used. Current practice with regards to UK/international clinical assessment is unknown. We aimed to capture current clinical practice, with reference to contemporaneously available guidelines. We further aimed to compare UK to international practice. DESIGN: Anonymous online questionnaire with cross-sectional non-probability sampling. Subgroup analysis according to subspeciality training in rhinology ('rhinologists' and 'non-rhinologists') was performed, with geographical comparisons only made according to subgroup. PARTICIPANTS: ENT surgeons who assess olfaction. RESULTS: Responses were received from 465 clinicians (217 from UK and 17 countries total). Country-specific response rate varied, with the lowest rate being obtained from Japan (1.4%) and highest from Greece (72.5%). Most UK clinicians do not perform psychophysical smell testing during any of the presented clinical scenarios-though rhinologists did so more often than non-rhinologists. The most frequent barriers to testing related to service provision (e.g., time/funding limitations). Whilst there was variability in practice, in general, international respondents performed psychophysical testing more frequently than those from the UK. Approximately 3/4 of all respondents said they would like to receive training in psychophysical smell testing. Patient reported outcome measures were infrequently used in the UK/internationally. More UK respondents performed diagnostic MRI scanning than international respondents. CONCLUSIONS: To our knowledge, this is the most comprehensive UK-based, and only international survey of clinical practice in the assessment of OD. We present recommendations to improve practice, including increased education and funding for psychophysical smell testing. We hope this will promote accurate and reliable olfactory assessment, as is the accepted standard in other sensory systems.

• Klíčová slova
• UK, assessment, clinical practice, international, olfactory dysfunction,
• MeSH
• čich * fyziologie   MeSH
• hodnocení výsledků péče pacientem MeSH
• lidé MeSH
• poruchy čichu * diagnóza   MeSH
• průřezové studie MeSH
• průzkumy a dotazníky MeSH
• stupeň vzdělání MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Contemporary medicine brings requirement of the best available research evidence for the physician's decision on the diagnosis, therapy, prognosis and prevention. Such evidence is provided by clinical epidemiology, which represents the application of principles of the epidemiological methodology into the problems of clinical medicine. The knowledge of basic principles of clinical epidemiology is essential for the use of information of published results of medical research and for their proper and critical interpretation.

• MeSH
• epidemiologická měření MeSH
• epidemiologie * MeSH
• klinické lékařství MeSH
• lidé MeSH
• medicína založená na důkazech * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH