Effectiveness and Tolerability of Tapentadol Prolonged Release Compared With Prior Opioid Therapy for the Management of Severe, Chronic Osteoarthritis Pain

BACKGROUND: Tapentadol prolonged release (PR; 100–250 mg twice daily) has been efficacious and well tolerated for managing moderate-to-severe, chronic osteoarthritis hip or knee pain in phase 3 studies with washout of previous analgesic treatment. OBJECTIVE: The objective of this study was to evaluate the effectiveness and tolerability of tapentadol PR (50–250 mg twice daily) after direct rotation from World Health Organization (WHO) step III opioids in patients with severe osteoarthritis knee pain who previously responded to WHO step III therapy but showed poor tolerability. METHODS: This open-label, phase 3b study (NCT00982280) was conducted from October 2009 through June 2010 (prematurely terminated due to slow recruitment and study drug shortages) in clinical care settings in Europe and Australia. The study population included patients with severe, chronic osteoarthritis knee pain who had taken WHO step III opioids daily for ≥2 weeks before screening, responded to therapy (average pain intensity [11-point numerical rating scale-3 (NRS-3)] ≤5 at screening), and reported opioid-related adverse effects as their reason for changing analgesics. Patients switched directly from WHO step III therapy to tapentadol. Patients received oral tapentadol PR (50–250 mg twice daily) during 5-week titration and 7-week maintenance periods. Oral tapentadol immediate release (IR) was permitted (≤twice/day, ≥4 h apart) for acute pain episodes due to index pain or withdrawal symptoms following discontinuation of previous opioids (combined dose of tapentadol [PR and IR] ≤500 mg/day). This study was planned to evaluate conversion to tapentadol PR, based on responder rate 1 (percentage of patients with same/less pain [NRS-3] versus Week −1) at Week 6 (primary endpoint), adverse events (AEs), and discontinuation rates. Equianalgesic ratios were calculated for tapentadol prior to WHO step III opioids (PR and PR plus IR formulations). RESULTS: Of 82 patients enrolled, 63 received study medication. In the per-protocol population, responder rate 1 at Week 6 (last observation carried forward) was 94.3 % (50/53; P < 0.0001 vs. the null hypothesis rate [<60 %]). Mean (standard deviation) pain intensity scores were 4.7 (0.66) at baseline, 2.5 (1.46) at Week 6, and 1.8 (1.41) at Week 12 in the main analysis population (change from baseline at Weeks 6 and 12, P < 0.0001). Tapentadol to transdermal buprenorphine equianalgesic ratios (PR [n = 48], 262.9:1; PR plus IR [n = 48], 281.1:1) and tapentadol to oral oxycodone equianalgesic ratios (PR [n = 4], 4.3:1; PR plus IR [n = 6], 4.6:1) were calculated for the main analysis population. In the safety population, prevalence of AEs reported as associated with prior opioids at Week −1 (reasons for rotation) and related to tapentadol treatment at Week 12 decreased over time; the most common were nausea (46.0 vs. 24.1 %) and constipation (31.7 vs. 7.4 %). Overall, 14.3 % of patients discontinued the study early; reasons included AEs (9.5 %), lack of efficacy (3.2 %), and withdrawal of consent (1.6 %). CONCLUSIONS: Significant improvements in effectiveness were observed for tapentadol PR (50–250 mg twice daily) versus WHO step III opioids in patients with severe, chronic osteoarthritis knee pain who previously responded to WHO step III therapy. Equianalgesic ratios were calculated for tapentadol to transdermal buprenorphine and oral oxycodone and were in line with observations from previous phase 3 studies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-013-0102-0) contains supplementary material, which is available to authorized users

Laboratory-Developed Tests: Design of a Regulatory Strategy in Compliance with the International State-of-the-Art and the Regulation (EU) 2017/746 (EU IVDR [In Vitro Diagnostic Medical Device Regulation])

Purpose: This study aimed at the development of a regulatory strategy for compliance of laboratory-developed tests (LDTs) with requirements of the Regulation (EU) 2017/746 (“EU-IVDR”) under consideration of international requirements for LDTs as established in major regulatory regions. Furthermore, it was analysed in how far elements of current LDT regulation could qualify for an internationally harmonised concept ensuring quality, safety and performance of LDTs. Methods: A review of regulatory literature including legislation as well as guidance documents was performed. The regulatory strategy was adapted from international guidance concepts used for commercially marketed IVD. It was then applied to the example of a large medical laboratory in the EU. A high-level comparison was conducted to identify gaps and matches between the different international regulatory requirements for LDTs. Results: A four-step strategy for compliance of LDTs with the EU IVDR was implemented in an exemplary medical laboratory. On the basis of an internationally used LDT definition, LDTs constitute nearly 50% of the total IVD devices used in the laboratory. While an ISO 15189-compliant QMS is a major component, it should be accompanied by the application of appropriate processes for risk management, performance evaluation and continuous monitoring of LDTs. At least six criteria represent common characteristics of a potential, internationally convergent concept for the regulation/standardization of LDTs. Conclusions: This study confirms the impact of LDTs for individualized and innovative medical laboratory testing. Prerequisites for LDT use as especially given by the IVDR and missing interpretation in the EU with regard to the scope of LDT definition, the application of standards and the extent of documentation for LDTs currently lead to uncertainties for both laboratories and regulatory bodies responsible for LDT oversight. The characteristics identified as common criteria for ensuring quality, safety and performance of LDTs may be considered as central elements of future international consensus guidance. © 2021, The Author(s)

Identification, characterization, and localization to Chromosome 17q21-22 of the human TBX2 homolog, member of a conserved developmental gene family

The T-box motif is present in a family of gene whose structural features and expression patterns support their involvement in developmental gene regulation. Previously, sequence comparisons among the T-box domains of ten vertebrate and invertebrate T-box ( Tbx ) genes established a phylogenetic tree with three major branches. The Tbx2 -related branch includes mouse Mm-Tbx2 and Mm-Tbx3, Drosophila optomotor-blind ( Dm-Omb ), and Caenorhabditis elegans Ce-Tbx2 and Ce-Tbx7 genes. From the localization of Mm-Tbx2 to Chromosome (Chr) 11, we focused our search for the human homolog, Hs-TBX2, within a region of synteny conservation on Chr 17q. We used Dm-Omb polymerase chain reaction (PCR) primers to amplify a 137-basepair (bp) product from human genomic, Chr 17 monochromosome hybrid, and fetal kidney cDNA templates. The human PCR product showed 89% DNA sequence identity and 100% petide sequence identity to the corresponding T-box segment of Mm-Tbx2 . The putative Hs-TBX2 locus was isolated within a YAC contig that included three anonymous markers, D17S792, D17S794 , and D17S948 , located at Chr 17q21-22. Hybridization-and PCR-based screening of a 15-week fetal kidney cDNA library yielded several TBX2 clones. Sequence analysis of clone λcTBX2-1 confirmed homology to Mm-Tbx2 -90% DNA sequence identity over 283 nt, and 96% peptide sequence identity over 94 amino acids. Similar analysis of Hs-TBX2 cosmid 15F11 confirmed the cDNA coding sequence and also identified a 1.7-kb intron located at the same relative position as in Mm-Tbx2 . Phylogenetic analyses of the T-box domain sequences found in several vertebrate and invertebrate species further suggested that the putative human TBX2 and mouse Tbx2 are true homologs. Northern blot analysis identified two major TBX2 transcripts of 3.5 and 2.8kb, with high levels of TBX2 expression in fetal kidney and lung; and in adult kidney, lung, ovary, prostate, spleen, and testis. Reduced expression levels were seen in heart, white blood cells, small intestine, and thymus. These results suggest that Hs-TBX2 could play important roles in both developmental and postnatal gene regulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47017/1/335_2004_Article_BF00539006.pd

Mid-term outcomes of the R3™ delta ceramic acetabular system in total hip arthroplasty

BackgroundWhilst bony fixation of hip replacement has stable solutions, there remains controversy over which bearing best optimizes longevity and function. Ceramic-on-ceramic (CoC) bearing combinations are associated with lower risk of revision due to aseptic loosening and dislocation. Evidence for long-term functional outcomes of modern, 4th generation CoC bearings is limited. The aim of this study was to analyze outcomes and complications of the R3 (TM) Acetabular System (Smith & Nephew, Inc., Cordova, TN, USA) in combination with BIOLOX (R) Delta ceramic femoral head in patients undergoing primary total hip arthroplasty (THA).MethodsBetween June 2009 and May 2011, 175 patients (178 hips) were enrolled into a prospective, study at 6 sites in Europe and prospectively followed-up at 3 months and 1, 3, 5, and 7 years postoperative.ResultsTotal WOMAC score improved from 63 (range, 22-91) preoperative to 8 (range, 0-8) at 1-year follow-up and remained unchanged at 7-year follow-up. Modified Harris hip score improved from 45 (range, 10-87) preoperative to 83 (range, 25-100) at 3 months, 91 (range, 42-100) at 1 year, and 92 (range, 46, 100) at 7 years. UCLA Activity Rating Scale score improved from 3.3 (range, 1-8) preoperative to 6.2 (range, 2-8) at 1 year; it marginally declined to 5.8 (range, 3-8) at 7-year follow-up. There were 4 trochanteric fractures and 5 patients died of unrelated reasons. Three hips were revised (2 periprosthetic fractures and 1 subluxation). The 7-year cumulative survival rate was 98.3%.ConclusionClinical and functional improvements of THA with CoC bearing are maintained at 7 years postoperative.Trial registrationClinicalTrials.Gov, NCT03566082, Registered 10 January 2018-retrospectively registered

A new measurement for posterior tilt predicts reoperation in undisplaced femoral neck fractures: 113 consecutive patients treated by internal fixation and followed for 1 year

Background and purpose Preoperative posterior tilt in undisplaced (Garden I–II) femoral neck fractures is thought to influence rates of reoperation. However, an exact method for its measurement has not yet been presented. We designed a new measurement for posterior tilt on preoperative lateral radiographs and investigated its association with later reoperation

Treatment of hallux valgus by modified McBride procedure: a 6-year follow-up

PubMed ID: 20505975Background Surgical decision-making was reevaluated by comparison with an algorithm designed to analyze treatment of hallux valgus deformities. Materials and methods A modified McBride procedure was performed on 52 feet of 35 patients with hallux valgusdeformity. From this series, 36 feet of 21 patients were evaluated preoperatively, early postoperatively, and late postoperatively by means of subjective evaluation and clinical and radiological findings. Results The hallux valgus angle preoperatively, early postoperatively, and late postoperatively was 32.7 ± 8.5°, 10.1 ± 6.9°, and 20.6 ± 9.5°, respectively. Hallux valgus recurrence of 72.2% was observed. Subjective results were better and the patients rated their satisfaction with the procedure as excellent or high in 23 cases (63.9%) and moderate, low, or unsatisfactory in 13 cases (36.1%). Conclusions This level of patient satisfaction demonstrates that the McBride procedure is an efficient approach for eliminating pain due to hallux valgus deformity. © The Author(s) 2010