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OBJECTIVES: Managed entry agreements and especially financial-based agreements are commonly used in European countries for innovative cancer pharmaceuticals. These agreements facilitate access to innovative treatments while mitigating financial risks for payers. This study focuses on the confidential price agreement made by the Dutch government for the reimbursement of pembrolizumab, the implications of broadening indications on cost-effectiveness, and the viability or desirability of said agreement. METHODS: We selected 5 indications in which pembrolizumab was deemed effective and developed portioned survival models for each indication. Survival and progression-free survival data from the published trials were utilized to recreate individual patient data, and we extrapolated-using parametric models-to a time horizon of 30 years. Inputs for both quality of life and costs were derived from the available literature and were indexed. RESULTS: The incremental cost-effectiveness ratios ranged between 35 313 and 322 349 per quality-adjusted life-year, depending on the indication. Only 1 indication fell under the 80 000 (or 100 000) cost-effectiveness threshold. When applying the average reported discount on intramural pharmaceuticals in The Netherlands, incremental cost-effectiveness ratios ranged between 20 881 and 252 934 per quality-adjusted life-year gained, and the 80 000 (or 100 000) threshold was met in 3 indications out of 5. CONCLUSIONS: Our results show that pembrolizumab could be cost-effective in some indications, depending on the confidential price agreement established. However, the possibility of reimbursing not cost-effective care when the price is anchored in 1 indication remains possible. Indication-based pricing could help align value and price for innovative pharmaceuticals that are subject to indication broadening.
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Aflatoxin B1 (AFB1) is one of the most potent carcinogens and a widespread food and feed contaminant. As for other toxins, many efforts are devoted to find efficient and environmentally-friendly methods to degrade AFB1, such as enzymatic treatments, thus improving the safety of food and feed products. In this regard, the dye decolorizing peroxidase of type B (DypB) can efficiently degrade AFB1. The molecular mechanism, which is required to drive protein optimization in view of the usage of DypB as a mycotoxin reduction agent in large scale application, is unknown. Here, we focused on the role of four DypB residues in the degradation of AFB1 by alanine-scanning (residues 156, 215, 239 and 246), which were identified from biochemical assays to be kinetically relevant for the degradation. As a result of DypB degradation, AFB1 is converted into four products. Interestingly, the relative abundancy of these products depends on the replaced residues. Molecular dynamics simulations were used to investigate the role of these residues in the binding step between protein and manganese, a metal ion which is expected to be involved in the degradation process. We found that the size of the haem pocket as well as conformational changes in the protein structure could play a role in determining the kinetics of AFB1 removal and, consequently, guide the process towards specific degradation products.
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Aflatoxinas , Peroxidasa , Peroxidasas/metabolismo , Aflatoxina B1/metabolismo , Colorantes/químicaRESUMEN
The ratio of n-6 to n-3 fatty acid (FA) is between 2 and 10 times higher in milk replacer (MR) than in whole milk, which may promote inflammation and compromise the integrity of the intestinal epithelium. To evaluate how decreasing the n-6:n-3 FA ratio of MR affects gastrointestinal (GIT) permeability and inflammatory status, 30 dairy calves (2.8 ± 1.06 d of age; mean ± standard deviation) were randomly assigned to be fed an MR with an n-6:n-3 FA ratio of 40:1 (CON; 29.3% crude fat of DM; n = 15) or 6.5:1 (n-3; 29.1% crude fat of DM; n = 15). Calves were fed 7.0 L/d in 2 meals. Calves were weighed and fecal consistency was analyzed weekly. On d 22, calves were administered Cr-EDTA, lactulose, and d-mannitol to assess GIT permeability. Blood and total urine were sequentially collected for 6 and 24 h, respectively, and analyzed for marker content. Whole blood collected 4 h after the meal was subjected to an ex vivo lipopolysaccharide (LPS) challenge to evaluate cytokine secretion from blood cells. Calves were euthanized on d 25 for collection of intestinal tissue samples. Tissue samples were processed to assess FA composition by gas chromatography, histomorphology by bright-field microscopy, and gene expression of tight junction proteins, lipid metabolism enzymes, and immune molecules by real-time quantitative PCR. Data were analyzed using PROC GLIMMIX in SAS (version 9.4, SAS Institute Inc.). Growth performance and fecal consistency were unaffected. Calves fed MR with a lower ratio of n-6 to n-3 FA had 2-fold higher n-3 FA contents and 2-fold lower ratios of n-6 to n-3 FA in proximal jejunum and ileum tissues. Total urinary recovery (0-24 h relative to marker administration) and plasma concentrations of the markers were unaffected. Expression of TJP1 tended to be higher in proximal jejunum tissue and lower in ileum tissue of n-3 calves. The expression of TLR4 and TNFA tended to be higher and CD14 was higher in ileum tissue of n-3 calves. Plasma concentrations of interleukin-4 were decreased in response to the ex vivo LPS challenge in n-3 calves. Histomorphology and GIT permeability were largely unaffected by treatment. Furthermore, the inclusion of linseed and algae oil may promote inflammation, as suggested by greater concentrations of the acute-phase proteins haptoglobin and serum amyloid A postprandially, demonstrating that fat sources should be evaluated for their suitability for MR formulations. Understanding how MR composition affects dairy calf health may improve nutritional strategies on farm.
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Ácidos Grasos Omega-3 , Sustitutos de la Leche , Animales , Bovinos , Leche , Dieta/veterinaria , Lipopolisacáridos , Permeabilidad , Alimentación Animal/análisis , Destete , Peso CorporalRESUMEN
BACKGROUND AIMS: Drug prices are regarded as one of the most influential factors in determining accessibility and affordability to novel therapies. Cell and gene therapies such as OTL-200 (brand name: Libmeldy) and AVXS-101 (brand name: Zolgensma) with (expected) list prices of 3.0 million EUR and 1.9 million EUR per treatment, respectively, spark a global debate on the affordability of such therapies. The aim of this study was to use a recently published cost-based pricing model to calculate prices for cell and gene therapies, with OTL-200 and AVXS-101 as case study examples. METHODS: Using the pricing model proposed by Uyl-de Groot and Löwenberg, we estimated a price for both therapies. We searched the literature and online public sources to estimate (i) research and development (R&D) expenses adjusted for risk of failure and cost of capital, (ii) the eligible patient population and (iii) costs of drug manufacturing to calculate a base-case price for OTL-200 and AVXS-101. All model input parameters were varied in a stepwise, deterministic sensitivity analysis and scenario analyses to assess their impact on the calculated prices. RESULTS: Prices for OTL-200 and AVXS-101 were estimated at 1 048 138 EUR and 380 444 EUR per treatment, respectively. In deterministic sensitivity analyses, varying R&D estimates had the greatest impact on the price for OTL-200, whereas for AVXS-101, changes in the profit margin changed the calculated price substantially. Highest prices in scenario analyses were achieved when assuming the lowest number of patients for OTL-200 and highest R&D expenses for AVXS-101. The lowest R&D expenses scenario resulted in lowest prices for either therapy. CONCLUSIONS: Our results show that, using the proposed model, prices for both OTL-200 and AVXS-101 lie substantially below the currently (proposed) list prices for both therapies. Nevertheless, the uncertainty of the used model input parameters is considerable, which translates in a wide range of estimated prices. This is mainly because of a lack of transparency from pharmaceutical companies regarding R&D expenses and the costs of drug manufacturing. Simultaneously, the disease indications for both therapies remain heavily understudied in terms of their epidemiological profile. Despite the considerable variation in the estimated prices, our results may support the public debate on value-based and cost-based pricing models, and on "fair" drug prices in general.
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Comercio , Humanos , Costos y Análisis de CostoRESUMEN
This study was designed to develop a protocol for repeated intramuscular indomethacin injections to replicate leaky-gut-like symptoms in male Holstein calves to model and study the detrimental effects of leaky gut on gut tissue function and inflammatory response. A generalized randomized block design was used to evaluate how repeated indomethacin intramuscular injections affected the development of leaky gut in 18 male Holstein calves. Animals were enrolled at 3 ± 1 d of life, and after 21 d of adaptation, they were randomly assigned to 1 of 3 treatments consisting of intramuscular saline or indomethacin injections every 12 h for 48 h: (1) control (CTL), saline injection, (2) low intramuscular indomethacin (INDO-L) dosed at 1.2 mg/kg of body weight (BW), and (3) high intramuscular indomethacin (INDO-H) dosed at 2.4 mg/kg of BW. During the challenge, milk intake, starter intake, fecal scores, and rectal temperature were measured daily, and BW was measured at the beginning and at the end of the challenge. Plasma samples were used to measure the recovery of markers of intestinal permeability before and after the challenge by dosing lactulose, d-mannitol, and chromium-EDTA. In addition, several cytokines were measured in plasma during the challenge. Calves were dissected at the end of the challenge to obtain tissue and digesta samples from the gastrointestinal tract and liver. No treatment differences were observed for starter and milk intakes, fecal scores, BW, and rectal temperature. The difference in marker concentrations between pre and post challenges was higher for INDO calves compared with CTL calves in the case of lactulose and chromium-EDTA. In addition, chemokine ligand 2 and 4 and IL-6 were higher for INDO-H calves compared with CTL. Both doses of indomethacin resulted in reductions in villus length and surface area in the distal jejunum and ileum and reductions in crypt depth and width in the colon. We showed that repeated indomethacin injections over a 48-h period induced leaky-gut-like symptoms in a region-specific manner, affecting mainly the distal section of the intestine. This outcome was characterized by histomorphological changes in the distal jejunum, ileum, and colon and by increased gut permeability. Interestingly, changes in liver morphology and immune function also occurred, possibly due to the increased translocation of foreign antigens breaching the epithelial cell wall. The leaky gut challenge model described here could be used to improve understanding of the pathogenesis of intestinal disorders in cattle and provide a reliable alternative for testing feed additives with intestinal health benefits.
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Dieta , Lactulosa , Alimentación Animal/análisis , Animales , Peso Corporal , Bovinos , Cromo , Dieta/veterinaria , Ácido Edético , Indometacina , Inyecciones Intramusculares/veterinaria , Masculino , Leche , DesteteRESUMEN
The patient-provider relationship is a key driver of patient satisfaction as it relates to overall healthcare experience. We surveyed patients undergoing radiation therapy to determine what they consider to be the most valued qualities in their interactions with the healthcare team. An ethics-approved 35-item patient satisfaction survey was developed in-house to gain insights on patients' perception of their relationship with the healthcare team throughout their cancer journey. There were 199 completed survey, median age 68 years, 54% women and 45% men. Almost all (95%) "agreed" or "strongly agreed" that their physicians had been sensitive and compassionate. Over 90% felt that they received adequate explanations about their treatment, and had their questions answered. The vast majority (93%) felt included in the decision-making process. Patients reported the 5 most highly rated qualities among their healthcare providers (HCPs) as knowledge, kindness, honesty, good communication, and a cheerful attitude. Overall satisfaction was high but areas for improvement were identified including being offered future appointments for further discussion, more information about clinical trials, other treatments, and community resources. Patients noted their HCPs tended to focus on the physical and emotional needs of patients, but spiritual and cultural needs were rarely addressed. Patients receiving radiotherapy reported high rates of satisfaction across many aspects of their care. These findings also reinforce the different aspects of holistic care that can be improved, and serve as a reminder to clinicians that patients perceive their role as more than just that of a medical expert.
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Neoplasias , Satisfacción del Paciente , Anciano , Comunicación , Femenino , Personal de Salud/educación , Humanos , Masculino , Neoplasias/terapia , Relaciones Profesional-PacienteRESUMEN
Most milk replacers (MR) contain more lactose compared with whole milk, which, when fed at a large meal size, could influence gut barrier function in calves. This study evaluated how replacing lactose in MR with fat (on a wt/wt basis) affects intestinal histomorphology and permeability in neonatal dairy calves. Thirty-four Holstein-Friesian bull calves were blocked by dam parity and randomly assigned to 1 of 2 treatments (n = 17): a high-lactose (46.1% lactose, 18.0% crude fat, and 23.9% crude protein of dry matter) or a high-fat MR (HF; 39.9% lactose, 24.6% crude fat, and 24.0% crude protein of dry matter). Calves were individually housed and fed pooled colostrum at 1.5 h and 12 h postnatally, at 18 and 9% of metabolic body weight (BW0.75), respectively. From 24 h postnatally until the end of the study (d 7), calves were transitioned to be fed MR (prepared at 15% solids) at 18% of BW0.75 twice daily at 0700 and 1900 h. During postprandial sampling on d 6, intestinal permeability was assessed by mixing lactulose (1.03 g/kg of BW0.75) and d-mannitol (0.31 g/kg of BW0.75) into the morning meal without altering total meal volume. Sequential blood samples were collected via jugular catheter, and total urine was collected for 12 h to measure the marker content. Calves were euthanized 3 h after the morning meal on d 7, and gastrointestinal tract tissues and digesta were collected for analysis of histomorphology, digesta osmolality, and gene expression. The empty gastrointestinal tracts of HF calves were heavier, although length did not differ and differences in histomorphology were minor. Digesta osmolality changed along the tract without differences between treatments. Plasma lactulose was greater in HF, although plasma d-mannitol and the recovery of both markers in urine were unaffected. No significant differences were detected in gene expression, although HF calves tended to have lower expression of TJP1 and CLDN2 and higher expression of proinflammatory cytokine IL1B in ileum tissue. In conclusion, partially replacing lactose in MR with fat resulted in a heavier and more permeable gut, with minor histomorphological differences.
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Sustitutos de la Leche , Leche , Alimentación Animal/análisis , Animales , Peso Corporal , Bovinos , Dieta/veterinaria , Femenino , Masculino , Embarazo , DesteteRESUMEN
AIMS: We aimed to develop a process for same-day contouring, planning, quality assurance and delivery of volumetric modulated arc therapy (VMAT) for vertebral bone metastases within our institution's rapid-access palliative radiotherapy programme. MATERIALS AND METHODS: Two thoracic (T6-7, T3-7) and two lumbar (L2-3, L1-5) targets were contoured on computed tomography images acquired from an anthropomorphic phantom and five patient scans. Inverse planning aimed to provide coverage of a prescribed dose of 8 Gy with a combined lung V2Gy < 25% and a combined kidney mean dose <2 Gy. Serial plans were created to identify an efficient combination of six main planning variables specific to our treatment planning system: (i) voxel size (3 mm versus 5 mm), (ii) Monte Carlo statistical uncertainty (1% per calculation versus 3% per control point), (iii) fluence smoothing (medium versus high), (iv) number of iterations of segment shape changes during optimisation (1 versus 5), (v) dose calculation algorithm (Monte Carlo versus pencil beam) and (vi) number of arcs (single versus multiple). Contouring, planning, quality assurance and treatment delivery were timed. RESULTS: The combination of planning variables deemed efficient and appropriate was: a 3 mm voxel size, statistical uncertainty of 1% per calculation, medium fluence smoothing, five iterations of segment shape changes, Monte Carlo dose calculation and single full arc delivery. Patient scan contouring times ranged from 7 to 9 min (T6-7), 11-13 min (T3-7), 5-7 min (L2-3) and 8-10 min (L1-5) and planning times ranged from 9 to 15 min (T6-7), 13-25 min (T3-7), 18-25 min (L2-3) and 21-31 min (L1-5). Physics quality assurance times ranged from 15 to 21 min and beam-on times ranged from 3 to 6 min. CONCLUSIONS: The combined elements of VMAT for thoracic and lumbar vertebral bone metastases were completed in under 2 h. This new process makes same-day contouring, planning, quality assurance and treatment delivery of VMAT feasible within our rapid-access palliative radiotherapy programme.
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Radiocirugia , Radioterapia de Intensidad Modulada , Humanos , Método de Montecarlo , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por ComputadorRESUMEN
Background: Humour has long been considered an important coping tool for patients with cancer, but published quantitative data about its significance are limited. The purpose of our study was to survey patients with cancer undergoing radiotherapy regarding their opinions about the use of humour in their care. Methods: An anonymous 35-item questionnaire evaluating the patient experience, including the value of humour, was developed by an interdisciplinary team of health care providers (hcps) working within the Radiation Medicine program. This anonymous, voluntary, paper-based survey for self-completion required approximately 10 minutes to finish and was administered during the fall of 2018 and the spring of 2019. Results: For the 199 patients who completed the survey [108 women, 89 men (2 respondents did not specify)], median age was 68 years. That group represents approximately 30%-35% of the patients on treatment during the study period. Almost all respondents (86%) indicated that, during their visits to the cancer centre, it was "somewhat important" or "very important" for health care providers (hcps) to use appropriate humour, and 61% of respondents indicated using humour "frequently" or "always" when dealing with their individual cancers. Most respondents (79%) said that humour decreased anxiety, and 86% indicated that laughing was considered "somewhat important" or "very important." Approximately 4% of respondents even listed "sense of humour" as being the most important quality that they looked for in their interactions with their hcps. Conclusions: Cancer patients undergoing radiotherapy clearly view humour as being important for coping and dealing with their disease, and oncology hcps should routinely consider incorporating the use of appropriate humour into the care that they provide.
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Risoterapia/métodos , Risa/psicología , Neoplasias/psicología , Oncología por Radiación/métodos , Adulto , Anciano , Anciano de 80 o más Años , Comunicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Penicillium species were commonly isolated during a fungal survey of bat hibernacula in New Brunswick and Quebec, Canada. Strains were isolated from arthropods, bats, rodents (i.e. the deer mouse Peromyscus maniculatus), their dung, and cave walls. Hundreds of fungal strains were recovered, of which Penicillium represented a major component of the community. Penicillium strains were grouped by colony characters on Blakeslee's malt extract agar. DNA sequencing of the secondary identification marker, beta-tubulin, was done for representative strains from each group. In some cases, ITS and calmodulin were sequenced to confirm identifications. In total, 13 species were identified, while eight strains consistently resolved into a unique clade with P. discolor, P. echinulatum and P. solitum as its closest relatives. Penicillium speluncae is described using macroand micromorphological characters, multigene phylogenies (including ITS, beta-tubulin, calmodulin and RNA polymerase II second largest subunit) and extrolite profiles. Major extrolites produced by the new species include cyclopenins, viridicatins, chaetoglobosins, and a microheterogenous series of cyclic and linear tetrapeptides.
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AIMS: The cancer burden among Circumpolar Inuit is high. Palliative radiotherapy is a mainstay treatment for controlling symptoms of advanced cancers, but Inuit are required to travel far distances to access this service. Access to palliative radiotherapy and time away from home communities have not been explored among this population. We sought to describe the time intervals from symptom onset to the start of palliative radiotherapy among Canadian Inuit patients treated at The Ottawa Hospital (TOH). MATERIALS AND METHODS: A retrospective review of Inuit patients from Nunavut treated with radiotherapy between 2005 and 2014 at TOH. RESULTS: Of a total of 152 radiotherapy patients, 88 (58%) were treated palliatively. Of these, 61 (70%) had stage IV disease at diagnosis and 63 (72%) had lung cancer. The median time from referral for specialist care to the patient's first flight to Ottawa was 4 days (range 0-97). The median length of treatment was 7 days (range 0-27), but patients spent a median of 64.5 days (range 14-633) in Ottawa. The median survival from the date of pathological diagnosis was 5.2 months. CONCLUSIONS: Most Inuit radiotherapy patients at TOH were treated palliatively. Patients were brought from Nunavut relatively quickly for specialist care, which is encouraging. However, patients spent over 2 months away from home, in the context of a median survival of less than 6 months. Opportunities for improvement include both provider and system-level changes, which may be applicable to other Circumpolar Inuit regions across Europe and North America.
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Neoplasias , Cuidados Paliativos/métodos , Adulto , Anciano , Anciano de 80 o más Años , Canadá/epidemiología , Femenino , Humanos , Inuk , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/patología , Neoplasias/radioterapia , Nunavut/epidemiología , Estudios RetrospectivosRESUMEN
This article reviews the development and summarizes the state-of-the-art in absorbed dose calorimetry for all the common clinical beam modalities covered in reference dosimetry codes of practice, as well as for small and nonstandard fields, and brachytherapy. It focuses primarily on work performed in the last ten years by national laboratories and research institutions and is not restricted to primary standard instruments. The most recent absorbed dose calorimetry review article was published over twenty years ago by Ross and Klassen (1996 Phys. Med. Biol. 41 1-29), and even then, its scope was limited to water calorimeters. Since the application of calorimetry to the measurement of radiation has a long and often overlooked history, a brief introduction into its origins is provided, along with a summary of some of the landmark research that have shaped the current landscape of absorbed dose calorimeters. Technical descriptions of water and graphite calorimetry are kept general, as these have been detailed extensively in relatively recent review articles (e.g. McEwen and DuSautoy (2009 Metrologia 46 S59-79) and Seuntjens and Duane (2009 Metrologia 46 S39-58). The review categorizes calorimeters by the radiation type for which they are applied; from the widely established standards for Co-60 and high-energy x-rays, to the prototype calorimeters used in high-energy electrons and hadron therapy. In each case, focus is placed on the issues and constraints affecting dose measurement in that beam type, and the innovations developed to meet these requirements. For photons, electrons, proton and carbon ion beams, a summary of the ionization chamber beam quality conversion factors (k Q ) determined using said calorimeters is also provided. The article closes with a look forward to some of the most promising new techniques and areas of research and speculates about the future clinical role of absorbed dose calorimetry.
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Calorimetría , Radiometría/métodos , Dosis de Radiación , Radiometría/instrumentaciónRESUMEN
Fusarium head blight (FHB) caused by Fusarium graminearum is a disease that results in yield loss and mycotoxin contamination in wheat globally. This study assessed the effect of a plant biostimulant prepared from a brown macroalga Ascophyllum nodosum (Liquid Seaweed Extract; LSE) alone and in combination with chitosan in controlling Fusarium. Wheat seedlings drenched with LSE and chitosan in combination showed reduced severity of F. graminearum infection on leaves as evidenced by a significant reduction in necrotic area and fewer number of conidia produced in the necrotic area. Gene expression studies showed that the combination of LSE and chitosan amplified the response of pathogenesis-related genes (TaPR1.1, TaPR2, TaPR3, TaGlu2) in wheat seedlings infected with Fusarium spores above that observed for the individual treatments. The combination treatments were more effective in enhancing the activity of various defense related enzymes such as peroxidase and polyphenol oxidase. FHB studies on adult plants showed a reduction of bleached spikes in wheat heads treated with the combination of LSE and chitosan. Mycotoxin content appeared to be correlated with FHB severity. Combination treatments of LSE and chitosan reduced the levels of mycotoxins deoxynivalenol and sambucinol in wheat grains. Systemic disease resistance appears to be induced by LSE and chitosan in response to F. graminearum in wheat by inducing defense genes and enzymes.
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Ascophyllum/química , Quitosano/farmacología , Fusarium/efectos de los fármacos , Fitoquímicos/farmacología , Enfermedades de las Plantas/microbiología , Triticum/microbiología , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Quitosano/química , Quitosano/aislamiento & purificación , Contaminación de Alimentos , Microbiología de Alimentos , Pruebas de Sensibilidad Microbiana , Micotoxinas , Fitoquímicos/química , Fitoquímicos/aislamiento & purificaciónRESUMEN
2,2'-Dipyridylamines (dpa) and related compounds belong to the family of polydentate nitrogen ligands. More than a century has passed since their first report but new complexes and applications have been emerging in recent years owing to the versatility of dpa-based architectures. This review aims to present and highlight the main achievements attained with dpa-containing metal complexes in the domains of homogeneous catalysis and luminescent materials.
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Background: Radiation therapists play an important role in helping patients to safely manage and triage potentially life-threatening symptoms. The purpose of the present study was to assess factors influencing the use by radiation therapists of evidence-informed symptom practice guides for patients experiencing cancer treatment-related symptoms. Methods: In a mixed-methods descriptive study guided by the Knowledge-to-Action framework, interviews and a barriers survey were conducted. Two independent reviewers conducted a content analysis of interview transcripts. Barriers survey data were analyzed using frequency distributions and univariate descriptive statistics. Open-ended data from the surveys underwent content analysis and were triangulated with interview findings. Results: Of 90 radiation therapists approached, 58 completed the survey (64%), and 14 were interviewed. Of the 98% who reported providing symptom management to patients undergoing radiation treatment, 53% used evidence-informed practice guidelines. Radiation therapists had moderate moral norms (4.6 of 7) and beliefs about the consequences of using costars (pan-Canadian Oncology Symptom Triage and Remote Support) practice guides (4.8), but neutral intention (3.4) and beliefs about their own capabilities (3.9). Environmental barriers included lack of time (2.0), lack of access (2.5), and neutral organizational support (3.0). Radiation therapists identified a need for training (5.5). Common unique barriers to practice guide use were lack of time during radiation treatments, unclear fit with scope of practice, disparate focus on site-specific symptoms, and lack of medication knowledge. Conclusions: The symptom practice guides were perceived by the radiation therapists to benefit patients, enhance their own knowledge of symptom management, and promote consistent practice. Additional work is required to identify the scope of practice of radiation therapists within the interprofessional team.
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Técnicos Medios en Salud , Adhesión a Directriz , Neoplasias/radioterapia , Guías de Práctica Clínica como Asunto , Radioterapia/efectos adversos , Adulto , Medicina Basada en la Evidencia , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The two SIBLING (Small Integrin Binding Ligand N-linked Glycoproteins), bone sialoprotein (BSP) and osteopontin (OPN) are expressed in osteoblasts and osteoclasts. In mature BSP knockout (KO, -/-) mice, both bone formation and resorption as well as mineralization are impaired. OPN-/- mice display impaired resorption, and OPN is described as an inhibitor of mineralization. However, OPN is overexpressed in BSP-/- mice, complicating the understanding of their phenotype. We have generated and characterized mice with a double KO (DKO) of OPN and BSP, to try and unravel their respective contributions. Despite the absence of OPN, DKO bones are still hypomineralized. The SIBLING, matrix extracellular phosphoglycoprotein with ASARM motif (MEPE) is highly overexpressed in both BSP-/- and DKO and may impair mineralization through liberation of its ASARM (Acidic Serine-Aspartate Rich MEPE associated) peptides. DKO mice also display evidence of active formation of trabecular, secondary bone as well as primary bone in the marrow-ablation repair model. A higher number of osteoclasts form in DKO marrow cultures, with higher resorption activity, and DKO long bones display a localized and conspicuous cortical macroporosity. High bone formation and resorption parameters, and high cortical porosity in DKO mice suggest an active bone modeling/remodeling, in the absence of two key regulators of bone cell performance. This first double KO of SIBLING proteins thus results in a singular, non-trivial phenotype leading to reconsider the interpretation of each single KO, concerning in particular matrix mineralization and the regulation of bone cell activity.
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Remodelación Ósea/fisiología , Huesos/fisiopatología , Calcificación Fisiológica/fisiología , Eliminación de Gen , Sialoproteína de Unión a Integrina/deficiencia , Osteopontina/deficiencia , Animales , Biomarcadores/metabolismo , Médula Ósea/patología , Matriz Ósea/fisiopatología , Hueso Esponjoso/fisiopatología , Diferenciación Celular , Proteínas de la Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Sialoproteína de Unión a Integrina/metabolismo , Ratones Noqueados , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Osteopontina/metabolismo , Reproducibilidad de los ResultadosRESUMEN
Cyclometallated iridium(iii) dipyridylamine complexes present antibacterial activity against P. aeruginosa, a highly resistant pathogenic bacterium. This activity is increased when the complex is conjugated to biotin, a bacterial nutrient, and a MIC of 4 µM (4 µg mL-1) has been observed. The irradiation of P. aeruginosa cultures with blue LED light potentiates the anti-bacterial activities of these iridium(iii) complexes when they are conjugated to a glycoside.
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Antibacterianos/farmacología , Biotina/química , Glicósidos/química , Iridio/farmacología , Compuestos Organometálicos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Antibacterianos/química , Iridio/química , Luz , Luminiscencia , Compuestos Organometálicos/química , Pseudomonas aeruginosa/crecimiento & desarrollo , Pseudomonas aeruginosa/efectos de la radiaciónRESUMEN
Plant elicitors can be biological or chemical-derived stimulators of jasmonic acid (JA) or salicylic acid (SA) pathways shown to prime the defenses in many crops. Examples of chemical elicitors of the JA and SA pathways include methyl-jasmonate and 1,2,3-benzothiadiazole-7-carbothioate (BTH or the commercial plant activator Actigard 50WG, respectively). The use of specific elicitors has been observed to affect the normal interaction between JA and SA pathways causing one to be upregulated and the other to be suppressed, often, but not always, at the expense of the plant's herbivore or pathogen defenses. The objective of this study was to determine whether insects feeding on Brassica crops might be negatively affected by SA inducible defenses combined with an inhibitor of detoxification and anti-oxidant enzymes that regulate the insect response to the plant's defenses. The relative growth rate of cabbage looper Trichoplusia ni Hübner (Lepidoptera: Noctuidae) fed induced cabbage Brassica oleraceae leaves with the inhibitor, quercetin, was significantly less than those fed control cabbage with and without the inhibitor. The reduced growth was related to the reduction of glutathione S-transferases (GSTs) by the combination of quercetin and increased levels of indole glucosinolates in the cabbage treated with BTH at 2.6× the recommended application rate. These findings may offer a novel combination of elicitor and synergist that can provide protection from plant disease and herbivores in cabbage and other Brassica crops.
Asunto(s)
Brassica/metabolismo , Brassica/parasitología , Lepidópteros/efectos de los fármacos , Reguladores del Crecimiento de las Plantas/farmacología , Animales , Glucosinolatos/metabolismo , Glutatión Transferasa/metabolismo , Herbivoria/efectos de los fármacos , Indoles/metabolismo , Lepidópteros/patogenicidad , Hojas de la Planta/metabolismo , Hojas de la Planta/parasitología , Quercetina/farmacología , Ácido Salicílico/farmacologíaRESUMEN
The aim of this work is to develop and adapt a formalism to determine absorbed dose to water from graphite calorimetry measurements in carbon-ion beams. Fluence correction factors, [Formula: see text], needed when using a graphite calorimeter to derive dose to water, were determined in a clinical high-energy carbon-ion beam. Measurements were performed in a 290 MeV/n carbon-ion beam with a field size of 11 × 11 cm2, without modulation. In order to sample the beam, a plane-parallel Roos ionization chamber was chosen for its small collecting volume in comparison with the field size. Experimental information on fluence corrections was obtained from depth-dose measurements in water. This procedure was repeated with graphite plates in front of the water phantom. Fluence corrections were also obtained with Monte Carlo simulations through the implementation of three methods based on (i) the fluence distributions differential in energy, (ii) a ratio of calculated doses in water and graphite at equivalent depths and (iii) simulations of the experimental setup. The [Formula: see text] term increased in depth from 1.00 at the entrance toward 1.02 at a depth near the Bragg peak, and the average difference between experimental and numerical simulations was about 0.13%. Compared to proton beams, there was no reduction of the [Formula: see text] due to alpha particles because the secondary particle spectrum is dominated by projectile fragmentation. By developing a practical dose conversion technique, this work contributes to improving the determination of absolute dose to water from graphite calorimetry in carbon-ion beams.