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Despite the advantages of surgical handrub in terms of the ease of application and effectiveness, chlorhexidine (CHG)-based hand scrubbing remains the preferred method for surgical hand preparation. However, it does not systematically meet the non-inferiority requirement of the European norm (EN) 12791 with respect to n-propanol (the reference product) and does not provide the sustained efficacy expected for these long-lasting agents. Commercially available alcohol-based products have also failed to demonstrate sustained efficacy according to EN 12791. Multi-step protocols enhance the efficacy of hand scrubbing, yet their extended disinfection duration might diminish their allure for healthcare professionals. In this study, we show that hand scrubbing with CHG 4% followed by a 1 min rubbing with the novel formulation of ethanol (Et) 70%/CHG 3% plus 0.3% potassium sorbate food additive (PS) meets the non-inferiority requirement and demonstrates sustained efficacy when tested according to EN 12791. The immediate and 3 h effect of this protocol was significantly higher than that of n-propanol and the homologous disinfection protocol without PS (CHG 4% hand scrub plus Et 70%/CHG 3% rub), demonstrating that the inclusion of PS confers a notable residual effect. We speculate that this non-volatile ingredient acts synergistically with CHG. This promising combination represents an alternative method for the development of new disinfection strategies.
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The surface adhesion of bacterial cells and the in vivo biocompatibility of a new ceramic-metal composite made of zirconium dioxide and tantalum were evaluated. Within the framework of an in vitro study using the crystal violet staining and colony counting methods, a relatively similar adhesion of Streptococcus oralis to the 3Y-TZP/Ta biocermet (roughness Ra = 0.12 ± 0.04 µm) and Ti-Al6-V4 titanium alloy (Ra = 0.04 ± 0.01 µm) was found. In addition, in an in vivo preliminary study focused on the histological analysis of a series of rods implanted in the jaws of beagle dogs for a six-month period, the absence of any fibrous tissue or inflammatory reaction at the interface between the implanted 3Y-TZP/Ta biocermets and the new bone was found. Thus, it can be concluded that the developed ceramic-metal biocomposite may be a promising new material for use in dentistry.
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The aim of the study was to determine the presence of human papillomavirus (HPV) in patients with intractable plantar keratosis (IPK) by comparing the histopathological findings of biopsies. A prospective, observational, and concordance study was carried out. Three different specimens were taken from each IPK. A first punch was sent for histopathological examination, and a second punch and a superficial skin scraping were both sent for HPV polymerase chain reaction (PCR) and type determination. A total of 51 patients were included. From the histopathological examination, it was determined that 35 (68.6%) samples were diagnosed as warts and 16 (31.3%) as keratosis. However, the presence of HPV was confirmed by PCR in 49 (96.1%) and in 42 (82.4%) samples obtained by punch and superficial scraping, respectively. In the 49 PCR-positive samples, the most common HPV types were HPV1, HPV2, HPV27, HPV57, and HPV65, accounting for 81.6% of the samples. In conclusion, this study demonstrates that HPV infection and IPK lesions are very closely related. Although we cannot confirm that HPV is the cause of the development of IPK, the high prevalence of HPV observed in these lesions calls for a change to the procedures for managing IPK.
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Ceratose , Infecções por Papillomavirus , Verrugas , Humanos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Papillomavirus Humano , Estudos Prospectivos , Verrugas/epidemiologia , Papillomaviridae/genética , DNA Viral/genética , DNA Viral/análiseRESUMO
BACKGROUND/AIM: The optimal imaging test for delineation of the gross tumor volume (GTV) in hepatocellular carcinoma has not been defined. The hypothesis is that magnetic resonance imaging (MRI) allows for better visualization of the extent of tumor and will optimize the accuracy of tumor delineation for liver stereotactic radiotherapy compared with computed tomography (CT) only. We evaluated the interobserver agreement in GTV of hepatocellular carcinoma in a multicenter panel and compared MRI and CT in GTV delineation. MATERIALS AND METHODS: After the institutional review boards approved the study, we analyzed anonymous CT and MRI obtained from five patients with hepatocellular carcinoma. Eight radiation oncologists at our center used CT and MRI to delineate five GTVs of liver tumors. In both CT and MRI, the GTV volumes were compared. RESULTS: The median GTV volume on MRI was 2.4 cm3 (range=0.59-15.6 cm3) compared to 3.5 cm3 (range=0.52-24.9 cm3) on CT (p=0.36). The GTV volume as defined on MRI was larger or at least as large as the GTV volume on CT in two cases. Variance and standard deviation between observers in CT and MRI were minor (6 vs. 7.87 cm3, and 2.5 vs. 2.8 cm3 respectively). CONCLUSION: In cases with well-defined tumors, CT is easier and reproducible. In cases with no defined tumor in CT, other tools are needed and MRI can be complementary. The interobserver variability in target delineation of hepatocellular carcinoma in this study is noteworthy.
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PURPOSE: The CyberKnife quality assurance (QA) program relies mainly on the use of radiochromic film (RCF). We aimed at evaluating high-resolution arrays of detectors as an alternative to films for CyberKnife machine QA. METHODS: This study will test the SRS Mapcheck (Sun Nuclear, Melbourne, Florida, USA) diode array and its own software, which allows three tests of the CyberKnife QA program to be performed. The first one is a geometrical accuracy test based on the delivery of two orthogonal beams (Automated Quality Assurance, AQA). Besides comparing the constancy and repeatability of both methods, known errors will be introduced to check their sensitivity. The second checks the constancy of the iris collimator field sizes (Iris QA). Changes in the field sizes will be introduced to study the array sensitivity. The last test checks the correct positioning of the multileaf collimator (MLC). It will be tested introducing known systematic displacements to whole banks and to single leaves. RESULTS: The results of the RCF and diode array were equivalent (maximum differences of 0.18 ± 0.14 mm) for the AQA test, showing the array a higher reproducibility. When known errors were introduced, both methods behaved linearly with similar slopes. Regarding Iris QA, the array measurements are highly linear when changes in the field sizes are introduced. Linear regressions show slopes of 0.96-1.17 with r2 above 0.99 in all field sizes. Diode array seems to detect changes of 0.1 mm. In MLC QA, systematic errors of the whole bank of leaves were not detected by the array, while single leaf errors were detected. CONCLUSIONS: The diode array is sensitive and accurate in the AQA and Iris QA tests, which give us the possibility of substituting RCF with a diode array. QA would be performed faster than using the film procedure, obtaining reliable results. Regarding the MLC QA, the inability to detect systematic displacements make it difficult to confidently use the detector.
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Radioterapia de Intensidade Modulada , Software , Humanos , Reprodutibilidade dos Testes , Garantia da Qualidade dos Cuidados de Saúde/métodos , Radioterapia de Intensidade Modulada/métodos , Planejamento da Radioterapia Assistida por Computador , Dosagem RadioterapêuticaRESUMO
Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.
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Doença de Parkinson , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Drosophila melanogaster/metabolismo , Doença de Parkinson/metabolismo , Iridoides/farmacologia , Fenóis , LipídeosRESUMO
PURPOSE: To study and analyze the effect of the use of a thin guide-wire instead of a Foley catheter for urethral definition in prostate stereotactic body radiation therapy (SBRT) treatments and to compare treatment parameters in both situations. MATERIAL AND METHODS: Thirty-seven prostate SBRT patients were employed in this study. A Foley catheter was employed in nine of them, and a guide-wire was employed in the other 28 patients. For each of the 28 patients in which the guide-wire was employed, a comparison between urethral positions in both situations was performed, allowing for a margin definition of the urethra when a Foley catheter was employed. Displacements of the prostate during treatment were obtained, allowing for an analysis of prostate positions in both situations. Also, different treatment parameters such as the number of treatment interruptions, couch movements performed, and x-rays needed were gathered. RESULTS: Large differences between urethral positions can be found in the anterior-posterior (AP) directions compared to those in the lateral (LAT) direction. Differences are also larger in areas closer to the base of the prostate, where margins applied in the case of using a Foley catheter are 16 mm with a mean displacement of 6 mm in the posterior direction. No differences in the treatment parameters were found during treatment in both situations. The difference found in absolute prostate pitch rotations suggests that the Foley catheter provokes a shift of the prostate position, which does not occur when employing the guide-wire. CONCLUSIONS: Foley catheters shift the urethral position, making them a wrong surrogate of the urethra when no catheters are present. The margins needed to assess uncertainties introduced by the use of a Foley catheter are larger than those usually applied. The use of a Foley catheter did not present any additional difficulty during treatment delivery in terms of images employed or interruptions produced.
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Neoplasias da Próstata , Radiocirurgia , Masculino , Humanos , Uretra , Próstata , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Cateterismo UrinárioRESUMO
Triclosan 0.5% by scrubbing does not meet the UNE-EN12791 criteria to be used in the surgical hand preparation (SHP). Triclosan 0.5% by scrubbing followed by ethanol 70% hand rubbing is suitable without the additional characteristic of sustained effect. This limited effectiveness implies that triclosan should be avoided in SHP given the restrictions on its use in consumer antiseptic products. The trial was registered at ClinicalTrials.gov (ID: NCT04538365).
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Anti-Infecciosos Locais , Triclosan , Humanos , Triclosan/farmacologia , Carga Bacteriana , Desinfecção das Mãos , Anti-Infecciosos Locais/farmacologia , AntissepsiaRESUMO
Few studies have checked the impact of the hormonal/immunological dimorphism of patients on the cellular composition of platelet-rich plasma products (PRP). Whole blood (WB) from 26 volunteers was concentrated using a device previously characterized. Platelet and white blood cell (WBC) counts in WB and PRP were compared between genders, and after the population was split into pre (≤50 years)- and post (>50 years)-menopausal ages. In WB, platelet−total WBC densities were comparable in men and women. The phagocytic cell composition differed (p ≤ 0.04). After dividing by ages, phagocytic cell discrepancies were linked to women > 50 years (p ≤ 0.05), and differences emerged in lymphocyte counts (lower in >50 years groups, within and between genders, p ≤ 0.05). In PRP, densities were significantly higher, but the PRP/WB ratios varied according to blood cell (lower for phagocytic cells) and between subjects (more favorable at a lower density of a particular blood cell in WB). This "system compensatory efficiency" reduced/reverted PRP differences in the leukocyte composition between genders/age−sex groups in WB. In PRP, neutrophils were higher in younger men than older women (p < 0.05). WB lymphocyte differences between age−sex groups persisted. Age is a more determining factor than sex in the preparation of PRP. Post-menopause, sexual dimorphism strongly influences the composition of leukocytes, also conditioned by the capture efficiency of the system.
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Background: Over-supination processes of the foot and ankle involving peroneus longus (PL) damage during running sports have been treated conservatively with passive control tools, such as tapes, braces, or external ankle supports, but the effect of orthoses with typical lateral wedging orthoses (TLWO) on the muscular activity of PL during running remains unclear. Here we investigate the effects of innovative medial cushioning orthoses (IMCO) on PL activity during the full running gait cycle. In addition, we wished to ascertain the effects of innovative medial cushioning orthoses (IMCO) on PL activity during running. Methods: Thirty-one healthy recreational runners (mean age 34.5 ± 3.33) with neutral foot posture index scores, were selected to participate in the present study. They ran on a treadmill at 9 km/h wearing seven different orthoses (NRS, IMCO 3 mm, IMCO 6 mm, IMCO 9 mm, TLWO 3 mm, TLWO 6 mm and TLWO 9 mm), randomly performed on the same day while electromyographic activity of the PL muscle was recorded. Statistical intraclass correlation coefficient (ICC) to test reliability was carried out and the Wilcoxon test with Bonferroni's correction was developed to analyze the differences between the conditions. Results: the reliability of all assessments showed data higher than 0.81, that is, "almost perfect reliability"; all EMG PL values wearing either TLWO or IMCO showed a statistically significant reduction versus NRS during the fully analyzed running gait cycle; the highest difference was set on NRS 23.08 ± 6.67 to TLWO 9 mm 17.77 ± 4.794 (p < 0.001). Conclusions: Muscular EMG activity of the PL during the full running gait cycle decreases when wearing either TLWO or IMCO relative to NRS; therefore, these orthoses could be prescribed to treat the strain and overload pathologies of PL. In addition, IMCOas it less thick, compared with TLWOcan be used when aiming to achieve better running economy.
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The benefit of autologous platelet-rich plasma (PRP) treatment is still under discussion. Variations in PRP products, consequence of the lack of a standardised protocol for the multitude of commercially available blood separation systems and the lack of knowledge of the optimal composition of PRP or its suitability for the proposed indication are some of the reasons behind clinical inconsistencies. The impact of inter-subject variability in PRP has received less attention in comparison. The purpose of this study was to determine the inter-subject variability, based on age, in the concentrates prepared by a new blood concentration system. Twenty-six healthy volunteers of both genders (29-93 years) were enrolled. Whole blood (WB) was collected from each participant to prepare PRP using the Easy PRP kit. Platelets and white blood cells (WBC) from WB and PRP were analysed after split population by age; patients younger than 65 years (n = 13) and patients ≥65 years old (n = 13). Among the demographic characteristics tested, only age was significantly different between the groups. Cell capture efficiency of the system was specific for each type of blood cell and identical for both age groups. Platelets and WBC in PRP were higher than in WB (P < .001). In WB, platelets and WBC concentrations were significantly lower in older group (P ≤ .035). These differences persisted in the prepared PRP (P ≤ .004). The ageing of population has a strong influence on the haematocrit and therefore on the composition of PRP. Because the efficiency of blood separator system seems to be constant across individuals, the inter-subject haematocrit variability based on age could be used as a predictor of resulting PRP. The clinical application of PRP should be restricted to the specific cell capture capacity of the different commercial devices.
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Plaquetas , Plasma Rico em Plaquetas , Idoso , Feminino , Voluntários Saudáveis , Humanos , Contagem de Leucócitos , Leucócitos , MasculinoRESUMO
OBJECTIVE: Clinical studies claim that platelet-rich plasma (PRP) accelerates tissue healing due to its high concentration of growth factors and that the combination with leukocytes improves the antimicrobial effect of the concentrate. Most of these studies obtained PRP using different separation systems, and few analyzed the content of the PRP used for treatment. This study characterized the composition of PRP and white blood cells (WBC) from a single donor produced by three commercially available PRP separation systems and two anticoagulated general analytical tubes. METHODS: Five patients donated 50 mL of blood, which was processed to produce PRP and WBC using three PRP concentration systems (i.e., Easy PRP Kit, GloPRP, and Wego) and two tubes for general analysis anticoagulated with ethylenediaminetetraacetic acid (EDTA) and citrate. Platelets and WBC in combination with their concentrates were analyzed by automated systems in a clinical laboratory. RESULTS: There were no significant differences in the average concentrations of PRP platelets and WBC between GloPRP and the tubes for general analysis with EDTA and citrate; however, the Easy PRP Kit gave results much superior to the rest of the methods, especially comparing it with the Wego Kit, whose concentrates were especially low, even nonexistent for WBC. CONCLUSIONS: The Easy PRP Kit concentrates WBC-rich PRP, resulting in increased WBC concentrations, compared with low WBC-low PRP of GloPRP and general tube methods for EDTA and citrate analysis and the even lower concentration of PRP from the Wego Kit, with the absence of leukocytes.
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Plasma Rico em Plaquetas , Separação Celular , Centrifugação , Estudos Transversais , Humanos , Contagem de LeucócitosRESUMO
Antibiotic resistance in Streptococcus pneumoniae has increased worldwide, making fluoroquinolones an alternative therapeutic option. Fluoroquinolones inhibit the type II DNA topoisomerases (topoisomerase IV and gyrase). In this study we have evaluated the in vivo activity of seconeolitsine, an inhibitor of topoisomerase I. Levofloxacin (12.5 to 50 mg/kg) or seconeolitsine (5 to 40 mg/kg) were administered every 12 h during two days in mice infected with a serotype 8-resistant strain. At 48 h, a 70% protection was obtained with seconeolitsine (40 mg/kg; p < 0.001). However, survival with levofloxacin was 20%, regardless of the dose. In addition, seconeolitsine decreased bacteremia efficiently. Levofloxacin had higher levels in serum than seconeolitsine (Cmax of 14.7 vs. 1.6; p < 0.01) and higher values of area under the serum concentration-time curve (AUC0-12h of 17.3 vs. 5; p < 0.01). However, seconeolitsine showed higher levels of time to peak concentration and elimination half-life. This is consistent with the higher binding of seconeolitsine to plasma proteins (40% and 80% when used at 1 µg/mL and 50 µg/mL, respectively) in comparison to levofloxacin (12% at 5 µg/mL and 33% at 50 µg/mL). Our results suggest that seconeolitsine would be a promising therapeutic alternative against pneumococcal isolates with high fluoroquinolone resistance levels.
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A crossover trial was conducted to compare hand rub and hand scrub-brush methods for reducing bacterial loads when using propan-1-ol-60% according to European regulations. Both methods significantly reduced the bacterial load immediately after antisepsis, but only the hand rub method achieved significant bacterial load reduction 3 hours after the procedure.
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Anti-Infecciosos Locais , Antissepsia , Carga Bacteriana , Estudos Cross-Over , Mãos , Desinfecção das Mãos , HumanosRESUMO
PURPOSE: To compare tumor motion amplitudes measured with 2D fluoroscopic images (FI) and with an inhale/exhale CT (IECT) technique MATERIALS AND METHODS: Tumor motion of 52 patients (39 lung patients and 13 liver patients) was obtained with both FI and IECT. For FI, tumor detection and tracking was performed by means of a software developed by the authors. Motion amplitude and, thus, internal target volume (ITV), were defined to cover the positions where the tumor spends 95% of the time. The algorithm was validated against two different respiratory motion phantoms. Motion amplitude in IECT was defined as the difference in the position of the centroid of the gross tumor volume in the image sets of both treatments. RESULTS: Important differences exist when defining ITVs with FI and IECT. Overall, differences larger than 5 mm were obtained for 49%, 31%, and 9.6% of the patients in Superior-Inferior (SI), Anterior-Posterior (AP), and Lateral (LAT) directions, respectively. For tumor location, larger differences were found for tumors in the liver (73.6% SI, 27.3% AP, and 6.7% in LAT had differences larger than 5 mm), while tumors in the upper lobe benefitted less using FI (differences larger than 5 mm were only present in 27.6% (SI), 36.7% (AP), and 0% (LAT) of the patients). CONCLUSIONS: Use of FI with the linac built-in CBCT system is feasible for ITV definition. Large differences between motion amplitudes detected with FI and IECT methods were found. The method presented in this work based on FI could represent an improvement in ITV definition compared to the method based on IECT due to FI permits tumor motion acquisition in a more realistic situation than IECT.
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Neoplasias Pulmonares , Radiocirurgia , Tomografia Computadorizada Quadridimensional , Humanos , Fígado/diagnóstico por imagem , Pulmão , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Planejamento da Radioterapia Assistida por Computador , Respiração , Tomografia Computadorizada por Raios X , Raios XRESUMO
PURPOSE: The purpose of the study was to compare the three most common technologies available in digital mammography based in the evaluation of average glandular dose and contrast noise ratio (CNR). METHOD: The average glandular dose was estimated with a direct digital detector (aSe) with a pixel size of 0.85 µm, a photon counter with a pixel size of 50 µm and a computerized radiography (CR) system. A semiconductor detector was used to measure the input kerma to the detector, and the average glandular dose was calculated from the conversion factors dependent on the anode filter combination, half value layer and breast glandularity. RESULTS: The average glandular dose obtained with polymethyl methacrylate and CNR of mean thickness 4.5 cm using direct digital equipment was 1.02 mGy and CNR = 7.4; using the photon counter it was 0.43 mGy and CNR = 4.7 in C100 mode, and 0.64 mGy and CNR = 5.7 in C120 mode; and using the photostimulable CR, the estimated value was 1.65 mGy and CNR = 5.1. CONCLUSIONS: The photon counter offers a lower average glandular dose than the other two devices with adequate image quality (CNR). The CR equipment offers a similar CNR value but delivers a higher dose than the new generations of available mammograms.
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Neoplasias da Mama/diagnóstico por imagem , Mamografia/métodos , Radiometria/métodos , Feminino , Humanos , Fótons , Doses de RadiaçãoRESUMO
Radiomics has revolutionized the world of medical imaging. The aim of this review is to guide oncologists in radiomics and its applications in diagnosis, prediction of response and damage, prediction of survival, and prognosis in lung cancer. In this review, we analyzed published literature on PubMed and MEDLINE with papers published in the last 10 years. We included papers in English language with information about radiomics features and diagnostic, predictive, and prognosis of radiomics in lung cancer. All citations were evaluated for relevant content and validation. RELEVANCE FOR PATIENTS: The evolution of technology allows the development of computer algorithms that facilitate the diagnosis and evaluation of response after different oncological treatments and their non-invasive follow-up.
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PURPOSE: To propose adaptive setup protocols using Bayesian statistics that facilitate, based on a prediction of coverage probability, making a decision on which patients should follow daily imaging prior to treatment delivery. MATERIALS AND METHODS: The suitability of the treatment margins was assessed combining interfraction variability measurements of the first days of treatment with previous data gathered from our patient population. From this information, we decided if a patient needs an online imaging protocol to perform daily isocenter correction before each treatment fraction. We applied our method to five different datasets. Protocol parameters were selected from each dataset based on coverage probability, the expected imaging workload of the treatment unit, and the accuracy of patient classification. Time trends were assessed and included in the proposed protocols. To validate the accuracy of the protocols, they were applied to a validation dataset of prostate cancer patients. RESULTS: Adaptive setup protocols lead expected population coverage >97% in all datasets analyzed when time trends were considered. The reduction in imaging workload ranged from 40% in lung treatments to 28.5% in prostate treatments. Results of the protocol on the validation dataset were very similar to those previously predicted. CONCLUSIONS: The adaptive setup protocols based on Bayesian statistics presented in this study enable the optimization of imaging workload in the treatment unit ensuring that appropriate dose coverage remains unchanged.
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Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem , Teorema de Bayes , Fracionamento da Dose de Radiação , Humanos , Masculino , Neoplasias da Próstata/radioterapiaRESUMO
OBJECTIVES: Bacterial viability and enrichment of resistance resulting from three different amikacin administration schedules with respect to haemodialysis (HD) were assessed against three OXA-48-producing Klebsiella pneumoniae isolated during an outbreak in a Spanish hospital. METHODS: A previously described two-compartment dynamic system was used. Three possible amikacin administration schedules were simulated: (i) haemodialysis immediately after amikacin infusion (pre-HD); (ii) infusion immediately after haemodialysis (post-HD); and (iii) infusion at 50% interdialytic period. Amikacin standard dose (SD) and double dose (DD) were simulated for each schedule. Values of Cmax/MIC, Cmax/MPC (mutant prevention concentration), AUC0-48h/MIC, AUC0-48h/MPC and %TMSW (percentage of time that the concentration was inside the mutant selection window) were determined with experimental data and were correlated with the area under the bacterial killing curve of the total population and the resistant subpopulation. RESULTS: Both with SD and DD, the pre-HD schedule resulted in increases at 48h in bacterial counts of the total population at the expense of enrichment of pre-existing resistant subpopulations from 12h onwards for all strains. The estimated %TMSW that prevented enrichment of resistant mutants was <61.5%. The AUC0-48h/MPC (with values of ≈40 being associated with countering of increases in resistant subpopulations) was better than the %TMSW as a predictive parameter. CONCLUSION: This study showed that the longest times concentrations were above the MPC (i.e. highest AUC0-48h/MPC, lowest %TMSW), the lowest enrichment of resistant subpopulations. This implies use of the highest possible amikacin dose (limited by toxicity) and post-HD as the best administration schedule.