Safety of direct-acting oral anticoagulant (DOAC) prescribing: OpenSAFELY-TPP analysis of 20.5 million adults' electronic health records.

BACKGROUND: During the COVID-19 pandemic many patients were switched from warfarin to direct-acting oral anticoagulants (DOACs), which require the creatinine clearance (CrCl) calculated to ensure the correct dose is prescribed to avoid bleeding or reduced efficacy. AIM: To identify the study population proportion prescribed a DOAC. Of these, the proportion with recorded: weight, estimated glomerular filtration rate (eGFR), creatinine, CrCl and atrial fibrillation (AF). To analyse the proportion of patients with recorded AF and CrCl prescribed a recommended DOAC dose. DESIGN & SETTING: A retrospective cohort study of 20.5 million adult NHS patients' electronic health records (EHRs) in England in the OpenSAFELY-TPP platform (January 2018-February 2023). METHOD: Patients on DOACs were analysed for age, sex, recorded weight, eGFR, creatinine, CrCl and AF. Prescribed DOAC doses in patients with recorded AF were compared with recommended doses for recorded CrCl and determined as either recommended, higher than recommended (overdose), or lower than recommended (underdose). RESULTS: In February 2023, weight, eGFR, creatinine, CrCl, and AF were recorded in 72.8%, 92.4%, 94.3%, 73.5%, and 73.9% of study population, respectively. Both AF and CrCl were recorded for 56.7% of patients. Of these, 86.2% received the recommended, and 13.8% non-recommended, DOAC doses. CONCLUSION: CrCl is not recorded for a substantial number of patients on DOACs. We recommend that national organisations tasked with safety, collectively update guidance on the appropriate weight to use in the Cockcroft-Gault equation, clarify that CrCl is not equivalent to eGFR, and work with GP clinical system suppliers to standardise the calculation of CrCl in the EHR.

In Vivo Assessment of Bone Regeneration in Alginate/Bone ECM Hydrogels with Incorporated Skeletal Stem Cells and Single Growth Factors.

The current study has investigated the use of decellularised, demineralised bone extracellular matrix (ECM) hydrogel constructs for in vivo tissue mineralisation and bone formation. Stro-1-enriched human bone marrow stromal cells were incorporated together with select growth factors including VEGF, TGF-ß3, BMP-2, PTHrP and VitD3, to augment bone formation, and mixed with alginate for structural support. Growth factors were delivered through fast (non-osteogenic factors) and slow (osteogenic factors) release PLGA microparticles. Constructs of 5 mm length were implanted in vivo for 28 days within mice. Dense tissue assessed by micro-CT correlated with histologically assessed mineralised bone formation in all constructs. Exogenous growth factor addition did not enhance bone formation further compared to alginate/bone ECM (ALG/ECM) hydrogels alone. UV irradiation reduced bone formation through degradation of intrinsic growth factors within the bone ECM component and possibly also ECM cross-linking. BMP-2 and VitD3 rescued osteogenic induction. ALG/ECM hydrogels appeared highly osteoinductive and delivery of angiogenic or chondrogenic growth factors led to altered bone formation. All constructs demonstrated extensive host tissue invasion and vascularisation aiding integration and implant longevity. The proposed hydrogel system functioned without the need for growth factor incorporation or an exogenous inducible cell source. Optimal growth factor concentrations and spatiotemporal release profiles require further assessment, as the bone ECM component may suffer batch variability between donor materials. In summary, ALG/ECM hydrogels provide a versatile biomaterial scaffold for utilisation within regenerative medicine which may be tailored, ultimately, to form the tissue of choice through incorporation of select growth factors.

Developmental cues for bone formation from parathyroid hormone and parathyroid hormone-related protein in an ex vivo organotypic culture system of embryonic chick femora.

Enhancement and application of our understanding of skeletal developmental biology is critical to developing tissue engineering approaches to bone repair. We propose that use of the developing embryonic femur as a model to further understand skeletogenesis, and the effects of key differentiation agents, will aid our understanding of the developing bone niche and inform bone reparation. We have used a three-dimensional organotypic culture system of embryonic chick femora to investigate the effects of two key skeletal differentiation agents, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), on bone and cartilage development, using a combination of microcomputed tomography and histological analysis to assess tissue formation and structure, and cellular behavior. Stimulation of embryonic day 11 (E11) organotypic femur cultures with PTH and PTHrP initiated osteogenesis. Bone formation was enhanced, with increased collagen I and STRO-1 expression, and cartilage was reduced, with decreased chondrocyte proliferation, collagen II expression, and glycosaminoglycan levels. This study demonstrates the successful use of organotypic chick femur cultures as a model for bone development, evidenced by the ability of exogenous bioactive molecules to differentially modulate bone and cartilage formation. The organotypic model outlined provides a tool for analyzing key temporal stages of bone and cartilage development, providing a paradigm for translation of bone development to improve scaffolds and skeletal stem cell treatments for skeletal regenerative medicine.

A novel approach for studying the temporal modulation of embryonic skeletal development using organotypic bone cultures and microcomputed tomography.

Understanding the structural development of embryonic bone in a three dimensional framework is fundamental to developing new strategies for the recapitulation of bone tissue in latter life. We present an innovative combined approach of an organotypic embryonic femur culture model, microcomputed tomography (µCT) and immunohistochemistry to examine the development and modulation of the three dimensional structures of the developing embryonic femur. Isolated embryonic chick femurs were organotypic (air/liquid interface) cultured for 10 days in either basal, chondrogenic, or osteogenic supplemented culture conditions. The growth development and modulating effects of basal, chondrogenic, or osteogenic culture media of the embryonic chick femurs was investigated using µCT, immunohistochemistry, and histology. The growth and development of noncultured embryonic chick femur stages E10, E11, E12, E13, E15, and E17 were very closely correlated with increased morphometric indices of bone formation as determined by µCT. After 10 days in the organotpyic culture set up, the early aged femurs (E10 and E11) demonstrated a dramatic response to the chondrogenic or osteogenic culture conditions compared to the basal cultured femurs as determined by a change in µCT morphometric indices and modified expression of chondrogenic and osteogenic markers. Although the later aged femurs (E12 and E13) increased in size and structure after 10 days organotpypic culture, the effects of the osteogenic and chondrogenic organotypic cultures on these femurs were not significantly altered compared to basal conditions. We have demonstrated that the embryonic chick femur organotpyic culture model combined with the µCT and immunohistochemical analysis can provide an integral methodology for investigating the modulation of bone development in an ex vivo culture setting. Hence, these interdisciplinary techniques of µCT and whole organ bone cultures will enable us to delineate some of the temporal, structural developmental paradigms and modulation of bone tissue formation to underpin innovative skeletal regenerative technology for clinical therapeutic strategies in musculoskeletal trauma and diseases.

A transitional care service for elderly chronic disease patients at risk of readmission.

BACKGROUND: Multiple hospital admissions, especially those related to chronic disease, represent a particular challenge to the acute health care sector in Australia. OBJECTIVE: To determine whether a nurse-led chronic disease management model of transitional care reduced readmissions to acute care. DESIGN: A quasi-experimental controlled trial. SETTING: A large tertiary metropolitan teaching hospital. PARTICIPANTS: 166 general medical patients aged > or = 65 years with either a history of readmissions to acute care or multiple medical comorbidities. INTERVENTION: Implementation of a chronic disease management model of transitional care aimed at improving patient management and reducing readmissions to acute care. MAIN OUTCOME MEASURES: Readmission rates and emergency department presentation rates at 3-and 6-month follow up. Secondary outcome measures include quality of life, discharge destination, and primary health care service utilisation. RESULTS: There was no difference in readmission rates, emergency department presentation rates, quality of life, discharge destination or primary health care service utilisation. The difficulties inherent in evaluating this type of multifactorial intervention are discussed and consideration is given to patient factors, the difficulty of influencing readmission rates, and local system issues. CONCLUSION: The outcomes of this study reflect the tension that exists between implementing multifaceted integrated health service programs and attempting to evaluate them within complex and changing environments using robust research methodologies.

Yttrium-90 microspheres for the treatment of hepatocellular carcinoma.

Unresectable hepatocellular carcinoma is extremely difficult to treat. TheraSphere consists of yttrium-90 (a pure beta emitter) microspheres, which are injected into the hepatic arteries. This article reviews the safety and survival of patients with hepatocellular carcinoma who were treated with yttrium-90 microspheres. Eighty patients were selected from a database of 108 yttrium-90 microsphere-treated patients and were staged by using Child-Pugh, Okuda, and Cancer of the Liver Italian Program scoring systems. Patients were treated with local, regional, and whole-liver approaches. Survival from first treatment was analyzed with Kaplan-Meier and Cox regression methods. Adverse events and complications of treatment were coded by using the Southwest Oncology Group toxicity scoring system. Patients received liver doses ranging from 47 to 270 Gy. Thirty-two patients (40%) received more than 1 treatment. Survival correlated with pretreatment Cancer of the Liver Italian Program scores ( P = .002), as well as with the individual Cancer of the Liver Italian Program components, Child-Pugh class, alpha-fetoprotein levels, and percentage of tumor replacement. Patients classified as Okuda stage I (n = 54) and II (n = 26) had median survival durations and 1-year survival rates of 628 days and 63%, and 384 days and 51%, respectively ( P = .02). One patient died of liver failure judged as possibly related to treatment. Thus, in selected patients with hepatocellular carcinoma, yttrium-90 microsphere treatment is safe and well tolerated. On the basis of these results, a randomized controlled trial is warranted comparing yttrium-90 microsphere treatment with transarterial chemoembolization by using the Cancer of the Liver Italian Program system for prospective stratified randomization.