Market entry agreements for innovative pharmaceuticals subject to indication broadening: a case study for pembrolizumab in the Netherlands.

OBJECTIVES: Managed entry agreements (MEAs) 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 five indications where 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 available literature and were indexed. RESULTS: The incremental cost-effectiveness ratios (ICERs) ranged between €35,313 and €322, 349 per quality-adjusted life-year (QALY) depending on the indication. Only one indication fell under the €80,000 (or €100,000) cost-effectiveness threshold. When applying the average reported discount on intramural pharmaceuticals in the Netherlands, ICERs ranged between €20,881 and €252,934 per QALY gained, and the €80,000 (or €100,000) threshold was met in three indications out of five. 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 one indication remains possible. Indication-based pricing (IBP) could help align value and price for innovative pharmaceuticals that are subject to indication broadening.

Gastrointestinal permeability and inflammatory status of preweaning dairy calves in response to decreasing the ratio of n-6 to n-3 fatty acid in milk replacer.

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.

Towards sustainability and affordability of expensive cell and gene therapies? Applying a cost-based pricing model to estimate prices for Libmeldy and Zolgensma.

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.

Induction of leaky gut by repeated intramuscular injections of indomethacin to preweaning Holstein calves.

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.

Assessment of Patient Satisfaction Among Cancer Patients Undergoing Radiotherapy.

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.

Intestinal adaptations to energy source of milk replacer in neonatal dairy calves.

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.

Plant growth regulator-mediated anti-herbivore responses of cabbage (Brassica oleracea) against cabbage looper Trichoplusia ni Hübner (Lepidoptera: Noctuidae).

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.

Influence of tree shape and evolutionary time-scale on phylogenetic diversity metrics.

During the last decades, describing, analysing and understanding the phylogenetic structure of species assemblages has been a central theme in both community ecology and macro-ecology. Among the wide variety of phylogenetic structure metrics, three have been predominant in the literature: Faith's phylogenetic diversity (PDFaith), which represents the sum of the branch lengths of the phylogenetic tree linking all species of a particular assemblage, the mean pairwise distance between all species in an assemblage (MPD) and the pairwise distance between the closest relatives in an assemblage (MNTD). Comparisons between studies using one or several of these metrics are difficult because there has been no comprehensive evaluation of the phylogenetic properties each metric captures. In particular it is unknown how PDFaith relates to MDP and MNTD. Consequently, it is possible that apparently opposing patterns in different studies might simply reflect differences in metric properties. Here, we aim to fill this gap by comparing these metrics using simulations and empirical data. We first used simulation experiments to test the influence of community structure and size on the mismatch between metrics whilst varying the shape and size of the phylogenetic tree of the species pool. Second we investigated the mismatch between metrics for two empirical datasets (gut microbes and global carnivoran assemblages). We show that MNTD and PDFaith provide similar information on phylogenetic structure, and respond similarly to variation in species richness and assemblage structure. However, MPD demonstrate a very different behaviour, and is highly sensitive to deep branching structure. We suggest that by combining complementary metrics that are sensitive to processes operating at different phylogenetic depths (i.e. MPD and MNTD or PDFaith) we can obtain a better understanding of assemblage structure.

Tobacco-specific N-nitrosamines NNN and NNK levels in cigarette brands between 2000 and 2014.

The evolution of the levels of tobacco-specific N-nitrosamines (TSNA), N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mainstream (MS) cigarette smoke is investigated based on smoke and tobacco chemistry data of cigarette brands sold by Philip Morris International (PMI) between 2000 and 2014. A total of 315 cigarette samples representing a wide range of product and design characteristics manufactured by PMI between 2008 and 2014 were analyzed and compared to a previously published dataset of PMI brands manufactured in 2000. The data indicate that there is a substantial reduction of NNN and NNK levels in tobacco fillers and MS cigarette smoke per mg of tar and per mg of nicotine using Health Canada Intense (HCI) machine-smoking regime. This observed reduction in NNN and NNK levels in MS cigarette smoke is also supported by the downward trend observed on NNN and NNK levels in USA flue-cured Virginia and Burley tobacco lots from 2000 to 2014 crops, reflecting effectiveness of measures taken on curing and agricultural practices designed to minimize TSNA formation in tobacco.

Fifteen new species of Penicillium.

We introduce 15 new species of Penicillium isolated from a diverse range of locations, including Canada, Costa Rica, Germany, Italy, New Zealand, Tanzania, USA and the Dry Valleys of Antarctica, from a variety of habitats, including leaf surfaces in tropical rain forests, soil eaten by chimpanzees, infrabuccal pockets of carpenter ants, intestinal contents of caterpillars and soil. The new species are classified in sections Aspergilloides (1), Canescentia (2), Charlesia (1), Exilicaulis (3), Lanata-Divaricata (7) and Stolkia (1). Each is characterised and described using classical morphology, LC-MS based extrolite analyses and multigene phylogenies based on ITS, BenA and CaM. Significant extrolites detected include andrastin, pulvilloric acid, penitrem A and citrinin amongst many others.

DypB peroxidase for aflatoxin removal: New insights into the toxin degradation process.

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.

Is D-methionine bioavailable to the dairy cow?

Rumen-protected forms of Met contain an equimolar mixture of the D- and L-isomers. Only L-Met can be directly used for protein synthesis, but it is unclear how much of the D-isomer can be transformed into L-Met in ruminants. Four lactating dairy cows, with an average milk yield of 32.4 kg/d, received a basal diet (12.5% crude protein, supplying 1,718 g/d of metabolizable protein) in 12 equal meals per day plus an abomasal infusion of amino acids (590 g/d, casein profile without Met). They were used in 3 consecutive studies to determine utilization of D-Met. First, the cows each received portal vein infusions for d of 5, 10, or 15 g/d of DL-Met in a Youden square. On the last day of each period, 6 arterial samples were collected at 45-min intervals. Concentrations of L- and D-Met were determined on a chiral column by gas chromatography-mass spectrometry. Portal infusion of 5, 10, and 15 g/d of DL-Met increased plasma total Met concentrations (19.7, 25.0, and 34.4±0.6 µM) and the proportion of Met as D (19.4, 30.5, and 37.3±0.7%). The fractional removal of D-Met was 6 to 7 times lower than the fractional removal of L-Met, with mean half-lives of 52 versus 8 min, respectively. Second, the same cows were infused for 8 h with L[methyl-(2)H(3)]Met at 1.3 mmol/h; at 2 h, cows received a bolus injection i.v. of D-[1-(13)C]Met (6.8 mmol), and arterial samples were collected after 10, 20, 30, 40, 60, 90, 120, 150, 180, 240, 300, 360, 420, and 480 min. Expressed relative to L-[(12)C]Met; that is, as tracer:tracee ratios, enrichments of plasma D-[1-(13)C]Met and L-[1-(13)C]Met averaged 1.77±0.14 and 0.144±0.026, respectively, 10 min after the bolus injection and declined exponentially thereafter. A minimum of 75±3% of the D-[1-(13)C]Met was transformed into L-[1-(13)C]Met. Third, the cows received, in a crossover design, an abomasal infusion for D of either DL-Met or L-Met (1g/d) and, on the last day of each experimental period, blood samples were collected simultaneously from arterial, portal, hepatic, and mammary vessels. Arterial total Met concentrations were higher with DL- versus L-Met infusions (37.4 vs. 25.4±0.5 µM), with 37.1±5.0% as D-Met. The mammary gland did not extract any D-Met. Hepatic removal of D-Met was observed, but was numerically lower than the fractional extraction of L-Met. In conclusion, much of the D-Met is transformed into L-Met by the dairy cow but at a slow rate. No uptake of D-Met occurs across the mammary gland but L-Met synthesized from the D-isomer elsewhere in the body can be utilized for milk protein synthesis.

Targeting of c-kit+ haematopoietic progenitor cells prevents hypoxic pulmonary hypertension.

Haematopoietic c-kit+ progenitor cells may contribute to pulmonary vascular remodelling and pulmonary hypertension (PH). Stromal derived factor-1 (SDF-1/CXCL12) and its receptors CXCR4 and CXCR7 have been shown to be critical for homing and mobilisation of haematopoietic c-kit+ progenitor cells in the perivascular niche. We administered AMD3100, a CXCR4 antagonist, and CCX771, a CXCR7 antagonist, to chronic hypoxia exposed mice in order to study the role of c-kit+ progenitor cells in PH. CXCL12, CXCR4 and CXCR7 protein expression, haemodynamic parameters, right ventricular mass, extent of vascular remodelling and perivascular progenitor cell accumulation were studied. Chronic hypoxia-exposed mice showed increased total lung tissue expression of CXCR4, CXCR7 and CXCL12 after development of PH. This was associated with significantly increased right ventricular systolic pressure and evidence of right ventricular hypertrophy, vascular remodelling and perivascular c-kit+/sca-1+ progenitor cell accumulation. CCX771 administration did not abrogate these effects. In contrast, administration of AMD3100, whether alone or combined with CCX771, prevented vascular remodelling, PH and perivascular accumulation of c-kit+/sca-1+ progenitor cells, with a synergistic effect of these agents. This study offers important pathophysiological insights into the role of haematopoietic c-kit+ progenitors in hypoxia-induced vascular remodelling and may have therapeutic implications for PH.

A Pre-implementation Study of Volumetric Modulated Arc Therapy for Same-day Planning and Treatment of Vertebral Bone Metastases Within a Rapid-access Palliative Radiotherapy Programme.

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.

Absorbed dose calorimetry.

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.

The importance of humour in oncology: a survey of patients undergoing radiotherapy.

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.

Penicillium diversity in Canadian bat caves, including a new species, P. speluncae.

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.

Time to Diagnosis and Treatment with Palliative Radiotherapy among Inuit Patients with Cancer from the Arctic Territory of Nunavut, Canada.

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.

Messenger RNA induction of fast sodium ion channels in cultured cardiac myoblasts.

Incubation with adult heart messenger RNA caused the appearance of fast sodium ion channels in young myocardial cells whose development has been arrested in vitro. The induction was blocked by cycloheximide, indicating dependence on protein synthesis. Thus, cardiac myoblasts can be made to differentiate in vitro, and membrane properties can be altered by exogenous RNA.