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PURPOSE: Chemotherapy preparation units face peaks in activity leading to high workloads and increased stress. The present study evaluated the impact of work overloads on the safety and accuracy of manual preparations. METHOD: Simulating overwork, operators were asked to produce increasing numbers of syringes (8, 16, and 24), with markers (phenylephrine or lidocaine), within 1 h, in an isolator, under aseptic conditions. Results were analyzed using qualitative and quantitative criteria. Concentration deviations of < 5%, 5%-10%, 10%-30%, and >30% from the expected concentration were considered as accurate, weakly accurate, inaccurate, and wrong concentrations, respectively. RESULTS: Twenty-one pharmacy technicians and pharmacists carried out 63 preparation sessions (n = 1007 syringes). A statistically significant decrease in the manufacturing time for one syringe was observed when workload increased (p < 0.0001). Thirty-nine preparation errors were recorded: 30 wrong concentrations (deviation > 30%), 6 mislabeling, 2 wrong diluents, and 1 wrong drug. There was no statistically significant difference in the mean concentration accuracy of final preparations across the three workloads. The overall error rate increased with the number of preparations made in 1 h: 1.8% for 8 preparations, 2.7% for 16 preparations, and 5.4% for 24 preparations (p < 0.05). CONCLUSION: Although pharmacy technicians and pharmacists were able to increase production speeds with no effect on mean concentration accuracy under stressful conditions, there were greater probability errors being made. These results should encourage actions to spread workloads out over the day to avoid peaks in activity.
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Antineoplásicos/síntese química , Composição de Medicamentos/tendências , Erros de Medicação/tendências , Farmacêuticos/tendências , Técnicos em Farmácia/tendências , Carga de Trabalho , Composição de Medicamentos/métodos , Humanos , Lidocaína/síntese química , Erros de Medicação/prevenção & controle , Erros de Medicação/psicologia , Estresse Ocupacional/psicologia , Farmacêuticos/psicologia , Técnicos em Farmácia/psicologia , Fenilefrina/síntese química , Fatores de Risco , Seringas , Carga de Trabalho/psicologiaRESUMO
BACKGROUND AIMS: Non-revascularizable critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease, with no therapeutic option. Extensive preclinical studies have demonstrated that adipose-derived stroma cell (ASC) transplantation strongly improves revascularization and tissue perfusion in ischemic limbs. This study, named ACellDREAM, is the first phase I trial to evaluate the feasibility and safety of intramuscular injections of autologous ASC in non-revascularizable CLI patients. METHODS: Seven patients were consecutively enrolled, on the basis of the following criteria: (i) lower-limb rest pain or ulcer; (ii) ankle systolic oxygen pressure <50 or 70 mm Hg for non-diabetic and diabetic patients, respectively, or first-toe systolic oxygen pressure <30 mm Hg or 50 mm Hg for non-diabetic and diabetic patients, respectively; (iii) not suitable for revascularization. ASCs from abdominal fat were grown for 2 weeks and were then characterized. RESULTS: More than 200 million cells were obtained, with almost total homogeneity and no karyotype abnormality. The expressions of stemness markers Oct4 and Nanog were very low, whereas expression of telomerase was undetectable in human ASCs compared with human embryonic stem cells. ASCs (10(8)) were then intramuscularly injected into the ischemic leg of patients, with no complication, as judged by an independent committee. Trans-cutaneous oxygen pressure tended to increase in most patients. Ulcer evolution and wound healing showed improvement. CONCLUSIONS: These data demonstrate the feasibility and safety of autologous ASC transplantation in patients with objectively proven CLI not suitable for revascularization. The improved wound healing also supports a putative functional efficiency.
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Tecido Adiposo/citologia , Células-Tronco Adultas/metabolismo , Extremidades/patologia , Isquemia/terapia , Doença Arterial Periférica/terapia , Transplante de Células-Tronco , Células Estromais/metabolismo , Adulto , Células-Tronco Adultas/citologia , Células-Tronco Adultas/transplante , Idoso , Idoso de 80 Anos ou mais , Técnicas de Cultura de Células , Células Cultivadas , Extremidades/irrigação sanguínea , Extremidades/transplante , Estudos de Viabilidade , Feminino , Proteínas de Homeodomínio/metabolismo , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Proteína Homeobox Nanog , Neovascularização Fisiológica , Fator 3 de Transcrição de Octâmero/metabolismo , Células Estromais/citologia , Células Estromais/transplante , Resultado do TratamentoRESUMO
BACKGROUND: Dialysis recovery time (DRT) and fatigue are two important patient-reported outcomes that highly affect hemodialysis patients' well-being and survival. This study aimed to identify all modifiable dialysis-related factors, associated with DRT and fatigue, that could be addressed in future clinical trials. METHODS: This multicenter observational study included adult patients, undergoing chronic hemodialysis for > 3 months during December 2023. Patients admitted to hospital, with cognitive problems, or active cancer were excluded. DRT was determined by asking over six sessions: "How long did it take you to recover from your last dialysis session?" Fatigue was assessed using the French-validated SONG-HD fatigue scale. Logistic regression analysis assessed the association between DRT>12 hours and fatigue score ≥4 with all dialysis-related factors. A sub-analysis of DRT-related factors was performed for very elderly ≥ 85 years. RESULTS: A total of 536 patients and 2967 sessions were analyzed. Mean age was 68.1 ±14.3 years, 60.9% were males, 33.2% had diabetes, 63.3% were on hemodiafiltration. Median dialysate sodium was 138 (136, 140). Median DRT was 140 (45, 440) minutes and 14.9% of patients had DRT >12 hours. Fatigue score was 3.1 ±2.3, 18% had no fatigue and 37.7% had a score ≥4. DRT and fatigue score were significantly associated. In multivariable regression analysis, intradialytic reduction in serum sodium and frequency of dialysis were significantly associated with DRT. Factors associated with fatigue included female sex and lower hemoglobin. In patients ≥85 years, hemodiafiltration was associated with prolonged DRT. CONCLUSION: Modifiable factors associated with prolonged DRT are not exactly similar to those associated with fatigue. Intradialytic reduction in serum sodium and low frequency of dialysis are two independent factors associated with longer DRT, with hemodiafiltration associated with longer recovery in very elderly patients. The hemoglobin level is the modifiable independent factor associated with fatigue. These modifiable factors can be addressed in future interventional trials in order to improve patients' outcomes.
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INTRODUCTION: Bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue-derived stem cells share immunosuppressive capacities, suggesting that the latter could be a general property of stromal cells. METHODS: To check this hypothesis, we compared human BM-MSC and fibroblasts for their in vitro multi-potentiality, expandability and their immunomodulatory properties under normalized optimized culture conditions. RESULTS: We report that, unlike BM-MSCs, fibroblasts cannot differentiate in vitro into adipocytes and osteoblasts and differ from BM-MSCs by the expression of membrane CD106, CD10 and CD26 and by the expression of collagen VII mRNA. Like BM-MSCs, fibroblasts are unable to provoke in vitro allogeneic reactions, but strongly suppress lymphocyte proliferation induced by allogeneic mixed lymphocyte culture (MLC) or mitogens. We show that fibroblasts' immunosuppressive capacity is independent from prostaglandin E2, IL-10 and the tryptophan catabolising enzyme indoleamine 2,3-dioxygenase and is not abrogated after the depletion of CD8+ T lymphocytes, NK cells and monocytes. CONCLUSION: Finally, fibroblasts and BM-MSCs act at an early stage through blockage of lymphocyte activation, as demonstrated by down-regulation of GZMB (granzyme B) and IL2RA (CD25) expression.
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Fibroblastos/imunologia , Células-Tronco Mesenquimais/imunologia , Tecido Adiposo/citologia , Células da Medula Óssea , Células Cultivadas , Regulação para Baixo/genética , Fibroblastos/citologia , Granzimas/genética , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Ativação Linfocitária , Células-Tronco Mesenquimais/citologia , Células Estromais/imunologiaRESUMO
The Channel Islands are located in the Normand-Breton Gulf (NBG), in the mid-part of the English Channel (France, Normandy). In the northern part, off Cap La Hague, controlled amounts of radioactive liquid waste are discharged by the ORANO La Hague nuclear fuel reprocessing plant (RP). Radionuclides were monitored in the NBG to assess the dispersion of radioactive discharges from the RP in the marine environment. The temporal and spatial distribution of the data are consistent with the history of the discharges, with most gamma emitter radionuclide environmental levels being close to or below the current limits of detection. A clear fingerprint of H-3, C-14 and I-129 radionuclides discharged from the RP is measured. The hydrodynamics in the NBG do not yield a simple gradient with linear distance from the outfall of the RP. Modelling tools were used to understand how radioactive discharges spread from the source of input. Dispersion patterns clearly illustrate the different behaviours of soluble and non-soluble radionuclides. The study indicated that the footprint of radioactive liquid discharges by French nuclear facilities was still measurable in species collected from the NBG for the mostly dissolved radionuclides. The less conservative ones, with a high affinity for suspended matter, are potentially influenced by old releases. These pathways could be investigated by dedicated hydrodynamic dispersion models. Overall, in the Channel Islands the levels are low and consistent with the general decrease in liquid radionuclide discharges by the RP since the 1990s.
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Monitoramento de Radiação , Radioatividade , Ilhas Anglo-Normandas , Radioisótopos do Iodo , Poluentes Radioativos da Água/análiseRESUMO
BACKGROUND AND STUDY AIM: Advanced therapy medicinal products (ATMP) frequently lack of clinical data on efficacy to substantiate a future clinical use. This study aims to evaluate the efficacy to heal long bone delayed unions and non-unions, as secondary objective of the EudraCT 2011-005441-13 clinical trial, through clinical and radiological bone consolidation at 3, 6 and 12 months of follow-up, with subgroup analysis of affected bone, gender, tobacco use, and time since the original fracture. PATIENTS AND METHODS: Twenty-eight patients were recruited and surgically treated with autologous bone marrow derived mesenchymal stromal cells expanded under Good Manufacturing Practices, combined to bioceramics in the surgical room before implantation. Mean age was 39 ± 13 years, 57% were males, and mean Body Mass Index 27 ± 7. Thirteen (46%) were active smokers. There were 11 femoral, 4 humeral, and 13 tibial non-unions. Initial fracture occurred at a mean ± SD of 27.9 ± 31.2 months before recruitment. Efficacy results were expressed by clinical consolidation (no or mild pain if values under 30 in VAS scale), and by radiological consolidation with a REBORNE score over 11/16 points (value of or above 0.6875). Means were statistically compared and mixed models for repeated measurements estimated the mean and confidence intervals (95%) of the REBORNE Bone Healing scale. Clinical and radiological consolidation were analyzed in the subgroups with Spearman correlation tests (adjusted by Bonferroni). RESULTS: Clinical consolidation was earlier confirmed, while radiological consolidation at 3 months was 25.0% (7/28 cases), at 6 months 67.8% (19/28 cases), and at 12 months, 92.8% (26/28 cases including the drop-out extrapolation of two failures). Bone biopsies confirmed bone formation surrounding the bioceramic granules. All locations showed similar consolidation, although this was delayed in tibial non-unions. No significant gender difference was found in 12-month consolidation (95% confidence). Higher consolidation scale values were seen in non-smoking patients at 6 (p = 0.012, t-test) and 12 months (p = 0.011, t-test). Longer time elapsed after the initial fracture did not preclude the occurrence of consolidation. CONCLUSION: Bone consolidation was efficaciously obtained with the studied expanded hBM-MSCs combined to biomaterials, by clinical and radiological evaluation, and confirmed by bone biopsies, with lower consolidation scores in smokers.
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Materiais Biocompatíveis/farmacologia , Consolidação da Fratura/fisiologia , Fraturas Ósseas/terapia , Fraturas não Consolidadas/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Adulto , Europa (Continente) , Feminino , Fêmur/patologia , Humanos , Úmero/patologia , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Pessoa de Meia-Idade , Osteogênese , Radiografia , Tíbia/patologia , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS: Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10â¯cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS: With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION: Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING: EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).
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Materiais Biocompatíveis/farmacologia , Fosfatos de Cálcio/farmacologia , Fêmur/patologia , Fraturas Ósseas/terapia , Fraturas não Consolidadas/terapia , Úmero/patologia , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Tíbia/patologia , Proliferação de Células/efeitos dos fármacos , Estudos de Viabilidade , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Transplante AutólogoRESUMO
Adipose tissue represents an abundant source of stem cells. Along with anti-inflammatory effects, ASC secrete various factors that may modulate metabolism of extracellular matrix in osteoarthritic (OA) cartilage, suggesting that the presence of ASC could be advantageous for OA cartilage due to the recovery of homeostasis between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs). To evaluate these effects, cartilage explants (CE) were cocultured with ASC for 3 and 7 days under stimulation with or without IL-1ß. The pattern of gene expression in CE was modified by ASC, including the upregulation of COL1A1 and COL3A1 and the downregulation of MMP13 and COL10A1. The production of MMP-1, MMP-3, and MMP-13 by ASC was not significant; moreover, cocultures with ASC reduced MMP-13 production in CE. In conclusion, active production of TIMP-1, TIMP-2, TIMP-3, IL-6, IL-8, and gelatinases MMP-2 and MMP-9 by ASC may be involved in the extracellular matrix remodelling, as indicated by the altered expression of collagens, the downregulated production of MMP-13, and the reduced chondrocyte apoptosis in the cocultured CE. These data suggest that ASC modulated homeostasis of MMPs/TIMPs in degenerated OA cartilage in vitro and might be favourable in case of the intra-articular application of ASC therapy for the treatment of OA.
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UNLABELLED: : Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 10(6) cells), medium dose (10 × 10(6)), and high dose (50 × 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy. SIGNIFICANCE: Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose-derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long-term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.