European survey on national harmonization in clinical research

Background: Clinical trials remain key to the development of evidence-based medical practice. However, they are becoming increasingly complex, mainly in a multinational setting. To address these challenges, the European Union (EU) adopted the Clinical Trial Regulation EU No. 536/2014 (CTR). Once in force, the CTR will lead to more consistent rules and simplification of procedures for conducting clinical trials through-out the EU. Existing harmonization initiatives and “research infrastructures” for clinical trials may facilitate this process. This publication offers a snapshot of the current level of harmonization activities in academic clinical research in Europe. Methods: A survey was performed among the member and observer countries of the European Clinical Research Infrastructure Network (ECRIN), using a standardizedpublishersversionpublishe

Day-to-day variations during clinical drug monitoring of morphine, morphine-3-glucuronide and morphine-6-glucuronide serum concentrations in cancer patients. A prospective observational study

BACKGROUND: The feasibility of drug monitoring of serum concentrations of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) during chronic morphine therapy is not established. One important factor relevant to drug monitoring is to what extent morphine, M6G and M3G serum concentrations fluctuate during stable morphine treatment. METHODS: We included twenty-nine patients admitted to a palliative care unit receiving oral morphine (n = 19) or continuous subcutaneous (sc) morphine infusions (n = 10). Serum concentrations of morphine, M6G and M3G were obtained at the same time on four consecutive days. If readmitted, the patients were followed for another trial period. Day-to-day variations in serum concentrations and ratios were determined by estimating the percent coefficient of variation (CV = (mean/SD) ×100). RESULTS: The patients' median morphine doses were 90 (range; 20–1460) mg/24 h and 135 (range; 30–440) mg/24 h during oral and sc administration, respectively. Intraindividual fluctuations of serum concentrations estimated by median coefficients of day-to-day variation were in the oral group for morphine 46%, for M6G 25% and for M3G 18%. The median coefficients of variation were lower in patients receiving continuous sc morphine infusions (morphine 10%, M6G 13%, M3G 9%). CONCLUSION: These findings indicate that serum concentrations of morphine and morphine metabolites fluctuate. The fluctuations found in our study are not explained by changes in morphine doses, administration of other drugs or by time for collection of blood samples. As expected the day-to-day variation was lower in patients receiving continuous sc morphine infusions compared with patients receiving oral morphine

Periprosthetic Joint Infection After Total Knee Arthroplasty With or Without Antibiotic Bone Cement.

IMPORTANCE Despite increased use of antibiotic-loaded bone cement (ALBC) in joint arthroplasty over recent decades, current evidence for prophylactic use of ALBC to reduce risk of periprosthetic joint infection (PJI) is insufficient. OBJECTIVE To compare the rate of revision attributed to PJI following primary total knee arthroplasty (TKA) using ALBC vs plain bone cement. DESIGN, SETTING, AND PARTICIPANTS This international cohort study used data from 14 national or regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, New Zealand, Norway, Romania, Sweden, Switzerland, the Netherlands, the UK, and the US. The study included primary TKAs for osteoarthritis registered from January 1, 2010, to December 31, 2020, and followed-up until December 31, 2021. Data analysis was performed from April to September 2023. EXPOSURE Primary TKA with ALBC vs plain bone cement. MAIN OUTCOMES AND MEASURES The primary outcome was risk of 1-year revision for PJI. Using a distributed data network analysis method, data were harmonized, and a cumulative revision rate was calculated (1 - Kaplan-Meier), and Cox regression analyses were performed within the 10 registries using both cement types. A meta-analysis was then performed to combine all aggregated data and evaluate the risk of 1-year revision for PJI and all causes. RESULTS Among 2 168 924 TKAs included, 93% were performed with ALBC. Most TKAs were performed in female patients (59.5%) and patients aged 65 to 74 years (39.9%), fully cemented (92.2%), and in the 2015 to 2020 period (62.5%). All participating registries reported a cumulative 1-year revision rate for PJI of less than 1% following primary TKA with ALBC (range, 0.21%-0.80%) and with plain bone cement (range, 0.23%-0.70%). The meta-analyses based on adjusted Cox regression for 1 917 190 TKAs showed no statistically significant difference at 1 year in risk of revision for PJI (hazard rate ratio, 1.16; 95% CI, 0.89-1.52) or for all causes (hazard rate ratio, 1.12; 95% CI, 0.89-1.40) among TKAs performed with ALBC vs plain bone cement. CONCLUSIONS AND RELEVANCE In this study, the risk of revision for PJI was similar between ALBC and plain bone cement following primary TKA. Any additional costs of ALBC and its relative value in reducing revision risk should be considered in the context of the overall health care delivery system

The use of antibiotic-loaded bone cement and systemic antibiotic prophylactic use in 2,971,357 primary total knee arthroplasties from 2010 to 2020: an international register-based observational study among countries in Africa, Europe, North America, and Oceania.

BACKGROUND AND PURPOSE Antibiotic-loaded bone cement (ALBC) and systemic antibiotic prophylaxis (SAP) have been used to reduce periprosthetic joint infection (PJI) rates. We investigated the use of ALBC and SAP in primary total knee arthroplasty (TKA). PATIENTS AND METHODS This observational study is based on 2,971,357 primary TKAs reported in 2010-2020 to national/regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, the Netherlands, New Zealand, Norway, Romania, South Africa, Sweden, Switzerland, the UK, and the USA. Aggregate-level data on trends and types of bone cement, antibiotic agents, and doses and duration of SAP used was extracted from participating registries. RESULTS ALBC was used in 77% of the TKAs with variation ranging from 100% in Norway to 31% in the USA. Palacos R+G was the most common (62%) ALBC type used. The primary antibiotic used in ALBC was gentamicin (94%). Use of ALBC in combination with SAP was common practice (77%). Cefazolin was the most common (32%) SAP agent. The doses and duration of SAP used varied from one single preoperative dosage as standard practice in Bolzano, Italy (98%) to 1-day 4 doses in Norway (83% of the 40,709 TKAs reported to the Norwegian arthroplasty register). CONCLUSION The proportion of ALBC usage in primary TKA varies internationally, with gentamicin being the most common antibiotic. ALBC in combination with SAP was common practice, with cefazolin the most common SAP agent. The type of ALBC and type, dose, and duration of SAP varied among participating countries

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.publishedVersio