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An author of the paper was omitted in the original version (Ted Conroy, University of Waikato, New Zealand). This has been corrected in the pdf and HTML versions of the paper, and the associated metadata.

BACKGROUND: Decentralisation of healthcare budgets and issuance of local guidelines means that the use of biosimilars can vary by region within a particular country, for example between the 21 counties of Sweden. OBJECTIVES: This study aimed to analyse the county-level market dynamics of biosimilar and originator infliximab, which are hospital products, and to examine how local policy measures and practices, in addition to national policy, influenced market dynamics. METHODS: We first conducted a literature review on (biosimilar) policies in Sweden, then analysed market data provided by IQVIA™ on uptake of originator and biosimilar infliximab within the different counties (Q2 2012 to Q4 2017), including discounts from (tender) contracts. Biosimilar market shares were calculated with volume data (measured as defined daily doses [DDDs]). We then discussed our findings in semi-structured interviews with the national pricing and reimbursement agency, key experts within the county councils of Skåne, Västra Götaland, and Stockholm, and an industry representative. RESULTS: Market shares of biosimilar infliximab vary widely between counties (range 18-96% in 2017). The initial uptake of biosimilar infliximab was slow and variable, with abrupt increments in biosimilar market shares coinciding with expiration of contracts for the originator product. Different approaches taken by counties to achieve a low cost per DDD of infliximab were identified, i.e., a rapid switch to the biosimilar (Skåne), a delayed switch to the biosimilar (Stockholm), or no switch to the biosimilar when a favourable price on the originator product could be obtained (Västra Götaland). Quantitative analysis showed that 59% of the variability in biosimilar market shares could be explained by the relative difference in discounted price between the biosimilar and the originator product. In addition, qualitative analysis indicated the presence of key opinion leaders, local guidelines and initiatives, and whose budget it affects as drivers in the decision-making process. CONCLUSIONS: Variations in the market share of biosimilar infliximab between the Swedish counties is largely explained by the discounted price difference between biosimilar and originator product, and counties used different strategies to leverage such biosimilar competition. Additionally, the presence of key opinion leaders, local guidelines and gainsharing arrangements appeared to play a role in infliximab market dynamics in counties. ispartof: BIODRUGS vol:33 issue:3 pages:285-297 ispartof: location:New Zealand status: published

Exposure to ionizing radiation results in cytotoxic and genotoxic effects caused mainly by the oxidative damage. In the present study, we investigated the radioprotective effect of novel antioxidant cocktail on germ cell apoptosis and spermatogenesis in rats subjected to whole body radiation (WBIR). Adult male rats weighing 250–270 g were divided into four groups, eight rats each. Group 1 served as untreated control, group 2 received an IP single dose of antioxidant cocktail (1 ml). Group 3 was exposed to a WBIR (6 Gy). Group 4 received antioxidant cocktail before WBIR. Rats from each group were killed after 48 h. MDA levels were measured in serum (TBARS assay). Johnsen’s criteria and the number of germinal cell layers were used to categorize spermatogenesis. TUNEL assay was used to determine germ cell apoptosis. Statistical analysis was performed using one-way ANOVA test. WBIR resulted in histological testicular damage (decrease in Johnsen’s criteria, p

One of the major regulators of gastrointestinal tract development is the hedgehog signaling pathway. The purpose of this study was to evaluate the role of sonic hedgehog (SHh) signaling 24 and 48 h following intestinal ischemia–reperfusion (IR) in a rat. Male rats were divided into four experimental groups: (1) Sham-24 h rats underwent laparotomy and were sacrificed after 24 h, (2) Sham-48h rats underwent laparotomy and were sacrificed after 48 h, (3) IR-24h rats underwent occlusion of both superior mesenteric artery and portal vein for 20 min followed by 24 h of reperfusion, and (4) IR-48 h rats underwent ischemia for 20 min followed by 48 h of reperfusion. Intestinal structural changes, enterocyte proliferation and enterocyte apoptosis were determined by immunohistochemistry 24 and 48 h following IR. SHh-related genes and protein expression were determined using real-time PCR, Western blot and immunohistochemistry. IR-24 rats demonstrated a significant decrease in Shh, Ihh, GIL and Ptch2 mRNA in jejunum and ileum compared to Sham-24 animals that was accompanied by a significant decrease in the number of SHH-positive cells (Immunohistochemistry) in jejunum (2.5-fold decrease) and ileum (37%). After 48 h, IR rats demonstrated a significant increase in Dhh, Ihh, Gil and PTCH2 mRNA in jejunum as well as in Dhh, Ihh, SMO, GIL, PTCH2 mRNA in ileum compared to IR-24 animals that was coincided with increased number of SHH-positive cells in jejunum (2.6-fold increase) and ileum (1.4-fold increase). 24 h following intestinal IR, inhibited cell turnover was associated with inhibited SHh signaling pathway. Signs of intestinal recovery appeared 48 h after IR and were correlated with increase in SHh signaling pathway activity.

Launched onboard the BepiColombo Mercury Planetary Orbiter (MPO) in October 2018, the Mercury Radiometer and Thermal Infrared Spectrometer (MERTIS) is on its way to planet Mercury. MERTIS consists of a push-broom IR-spectrometer (TIS) and a radiometer (TIR), which operate in the wavelength regions of 7-14 μm and 7-40 μm, respectively. This wavelength region is characterized by several diagnostic spectral signatures: the Christiansen feature (CF), Reststrahlen bands (RB), and the Transparency feature (TF), which will allow us to identify and map rock-forming silicates, sulfides as well as other minerals. Thus, the instrument is particularly well-suited to study the mineralogy and composition of the hermean surface at a spatial resolution of about 500 m globally and better than 500 m for approximately 5-10% of the surface. The instrument is fully functional onboard the BepiColombo spacecraft and exceeds all requirements (e.g., mass, power, performance). To prepare for the science phase at Mercury, the team developed an innovative operations plan to maximize the scientific output while at the same time saving spacecraft resources (e.g., data downlink). The upcoming fly-bys will be excellent opportunities to further test and adapt our software and operational procedures. In summary, the team is undertaking action at multiple levels, including performing a comprehensive suite of spectroscopic measurements in our laboratories on relevant analog materials, performing extensive spectral modeling, examining space weathering effects, and modeling the thermal behavior of the hermean surface.

Muscular fatigue, which reduces force output and position sense, often leads to increased sway and potential balance impairments. In contrast, visually-guided saccadic eye movements (saccades) can attenuate sway more than fixating gaze on an external target. The goals of this study were to determine whether the use of saccades could reduce the increased postural sway in a fatigued state and to better understand the contributions to fatigue-induced increased sway. We compared the effects of gazing at a fixation point (FP) and performing saccades (SAC) on various spatial and temporal measures of the center of pressure (CoP) while participants stood as still as possible on a force plate. Participants used either a narrow or wide base of support and performed three trials for each eye movement condition (SAC, FP) in three states (non-fatigued-NF, stretched-S, and fatigued-F). Calf raises to exhaustion induced ankle fatigue. Extreme plantar- and dorsi-flexion induced stretch. SAC significantly decreased sway and increased time-series complexity (sample entropy) compared to FP. F increased sway and decreased time-series complexity compared to NF and S states, which were similar. Reduced force production, which accompanies muscle fatigue and stretching, did not account for increased sway associated with acute bouts of ankle muscle fatigue. Increased position sense often associated with muscle stretching likely compensated for any reduced force output for S, while the decreased position sense associated with F probably explained the increased sway in this state. Performing saccadic eye movements during quiet stance can help reduce sway under various states.

Using a complete factorial, randomized block design, the effects of seed density (430 or 860 seeds/m2), seed stratification (stratified, non-stratified), split planting (complete seed mix planted in spring vs. non-aggressive species in spring and aggressive species in fall), and distance to groundwater (−5 or − 30 cm) were studied in a mesocosm complex in central Iowa. All 16 treatment combinations were replicated 5 times for a total of 80 mesocosms. The seed mix sown contained 25 species. At the end of the study, groundwater levels had the greatest effect on species richness, total shoot density, and total biomass. Seed stratification, seed density and delayed planting all had a significant impact on species richness and total shoot density. Delaying the planting of aggressive species significantly increased total shoot densities and biomass of non-aggressive species. Of the 20 species actually found in the mesocosms, 12 had higher shoot densities in the delayed planting, 11 in the high groundwater, 7 in the stratified seed, and 3 in the high seed density treatment. Overall, groundwater level and delayed planting of aggressive species had the largest impact on species diversity and shoot density.

Long chain fatty acids (LCFAs) appear to be powerful stimulants for small bowel adaptation in patients with short bowel syndrome (SBS). However, the dietary lipid content may alter intestinal lipid transport. The aim of this study was to investigate the effects of a high fat diet (HFD) on in vivo lipid absorption and molecular and cellular mechanisms of LCFAs uptake by the remaining bowel. Male Sprague-Dawley rats (240–280) were randomly assigned to one of three groups: sham rats fed normal chow (sham-NC), SBS rats fed NC (SBS-NC) and SBS rats fed HFD (SBS-HFD). SBS rats underwent a 75% small bowel resection. Rats were sacrificed on day 3 or 14. Body weight, fat intake and fat clearance (total fecal fat) were measured twice a week. Fat absorbability was calculated as intake minus clearance and was expressed as percent of intake. Total RNA from the mucosa of duodenum, jejunum and ileum was extracted using TRIZOL Reagent. Northern blot analysis was performed to determine FAT/CD36 mRNA levels. Enterocyte LCFA transport was measured on day 14. LCFA uptake was determined by measuring cellular [3H]-oleate uptake over time (4–120 s). Mean (±SE) FAT/CD36 mRNA levels and oleate uptake kinetic parameters were analyzed using ANOVA. Fat absorbability diminished after bowel resection, suggesting fat malabsorption. Remaining bowel in SBS-NC rats responded by an increase in FAT/CD36 mRNA levels in the duodenum and ileum on day 3, and the duodenum and jejunum on day 14 compared to sham-NC animals, and was accompanied by an increase in enterocyte LCFA transport in all segments. Exposure to a HFD for 14 days resulted in significantly increased fat absorbability after 3 days compared to SBS-NC rats. However, FAT/CD36 mRNA levels (vs. SBS-NC) decreased in all segments on day 3. On day 14, FAT/CD36 mRNA levels were decreased in the duodenum and ileum and were accompanied by reduced oleate uptake by isolated enterocytes in the ileum (vs. SBS-NC). In a rat model of SBS, early high fat diet increased lipid absorptive capacity of the intestinal remnant as seen by increased fat absorbability. The main mechanisms of this effect may be an acceleration of structural intestinal adaptation resulting in an increased number of enterocytes. However, at molecular and cellular levels HFD decreased mucosal FAT/CD36 mRNA levels and oleic acid uptake by isolated enterocytes.

Pullthrough procedures for Hirschsprung diseases typically have favorable results. However, some children experience long-term postoperative complications comprising stooling disorders, such as intermittent enterocolitis, severe stool retention, intestinal obstruction, as well as incontinence. Reoperative Hirschsprung Disease surgery is complex. This begins with the workup after the initial presentation following primary pullthrough, continues with the definitive surgical correction with redo pullthrough, and ends with long-term follow-up of individuals. The decision tree can be varied with each patient. The operating pediatric surgeon must be able to utilize different operations and treatment options available. While lesser procedures may provide relief in a select population, those with residual aganglionosis or transition zone pathology or mechanical problems will likely require a redo pullthrough. Thus, the diagnostic workup, treatment plan, and definitive surgical care should be coordinated, and executed by an experienced, specialized team at a pediatric referral center.

Biosimilars zijn kopieen van biologische geneesmiddelen en worden al meer dan tien jaar door specialisten in ziekenhuizen voorgeschreven. De laatste tijd krijgen ook huisartsen de beschikking over biosimilars. Hoe verloopt de ontwikkeling van deze nieuwe categorie geneesmiddelen en hoe gebruikt u ze in de praktijk?

The hedgehog (Hh) signaling pathway is one of the key regulators of gastrointestinal tract development. Recent studies point to the role of hedgehog signaling in regulating adult stem cells involved in maintenance and regeneration of intestinal stem cells. The purpose of this study was to evaluate the role of Hh signaling during intestinal adaptation in a rat model of short bowel syndrome (SBS). Male rats were divided into two groups: Sham rats underwent bowel transection and SBS rats underwent a 75 % bowel resection. Parameters of intestinal adaptation, enterocyte proliferation, and apoptosis were determined 2 weeks after operation. Illumina’s Digital Gene Expression analysis was used to determine the Hh signaling gene expression profiling. Hh-related genes and protein expression were determined using Real-Time PCR, Western blotting, and immunohistochemistry. Massive small bowel resection resulted in a significant increase in enterocyte proliferation and concomitant increase in cell apoptosis. From the total number of 20,000 probes, 13 genes related to Hh signaling were investigated. In jejunum, eight genes were down-regulated, three genes up-regulated, and two genes remained unchanged. In ileum, five genes were down-regulated and six genes were unchanged in SBS vs sham animals. SBS rats also demonstrated a significant three- to fourfold decrease in SMO, GIL, and PTCH mRNA, and protein levels (determined by Real-Time PCR and Western blot) compared to control animals. Two weeks following massive bowel resection in rats, the accelerated cell turnover was accompanied by an inhibited Hh signaling pathway. Hh signaling may serve as an important mediator of reciprocal interactions between the epithelium and the underlying mesenchymal stroma during intestinal adaptation following massive bowel resection in a rat.

The number of dominant vegetation types (wet prairies, sawgrass flats, ridges and sloughs, sloughs, and tree islands) historically and currently found in the Everglades, FL, USA, as with other wetlands with standing water, appears to be primarily a function of the magnitude of interannual water-level fluctuations. Analyses of 40 years of water-depth data were used to estimate the magnitude of contemporary (baseline) water-level fluctuations in undisturbed ridge and slough landscapes. Baseline interannual water-level fluctuations above the soil surface were at least 1.5 m. Predicted changes in interannual water-level fluctuations in 2060 were examined for seven climate change scenarios. When rainfall is predicted to increase by 10 %, the wettest scenario, the interannual range of water-level fluctuation increases to 1.8 m above the soil surface in sloughs. When rainfall is predicted to decrease by 10 % and temperatures to increase by 1.5 °C, the driest scenario, the range of interannual range of water-level fluctuations is predicted to decrease to 1.2 m above the soil surface in sloughs. A change of 25-30 cm in interannual water-level fluctuations is needed to change the number of vegetation types in a wetland. This suggests that the two most extreme climate change scenarios could have a significant impact on the overall structure of wetland vegetation, i.e., the number of vegetation types or zones, found in the Everglades.

Rates of community-associated Staphylococcus aureus, and particularly of methicillin-resistant Staphylococcus aureus (MRSA) in children, have increased in recent years. We investigated rates of nasal colonization of S. aureus, and a possible correlation between nasal carriage and wound infection.A prospective study of children scheduled for elective day-care surgical procedures between January 2008 and December 2012 at one medical center. Nasal swabs were taken before surgery, and follow-up was performed 1-2 weeks following surgery.Of 1,127 children (median age 2 years, 70.6% males), positive nasal swabs were detected in 228 (20.2%). Rates of S. aureus nasal carriage were lowest for ages 6 months to 2 years and highest for ages 4-11 years. Child's sex did not associate with the risk for positive nasal swabs. Positive nasal swabs for MRSA were detected in five boys (0.62% of the population). Five children (0.44%) had wound infection. None of them was a nasal carrier.No correlation was observed between positive nasal swabs and wound infection in children who were candidates for elective ambulatory operations. This suggests that evaluation of S. aureus nasal carriage and eradication may not be necessary in this population.

Growing evidence suggests that ozone (O3) protects the host against pathological conditions mediated by reactive oxygen species by increasing the activity of antioxidant enzymes. The purpose of the present study was to examine the effect of O3 on intestinal recovery and enterocyte turnover after intestinal ischemia-reperfusion (IR) injury in rats.Male Sprague-Dawley rats were divided into four experimental groups: (1) sham rats underwent laparotomy; (2) sham-O3 rats underwent laparotomy and were treated with an ozone/oxygen mixture intraperitoneally and intraluminally (50 %/50 %); (3) IR rats underwent occlusion of both superior mesenteric artery and portal vein for 20 min followed by 48 h of reperfusion, and (4) IR-O3 rats underwent IR and were treated with an ozone/oxygen mixture similar to group 2. Intestinal structural changes, Park's injury score, enterocyte proliferation and enterocyte apoptosis were determined 48 h following IR. Western blot was used to determine ERK and Bax protein levels. A non-parametric Kruskal-Wallis ANOVA test was used for statistical analysis with p0.05 considered statistically significant.Treatment of IR rats with O3 resulted in a significant increase in mucosal weight in jejunum (70 %) and ileum (32 %), mucosal DNA (twofold increase) and protein (35 %) in ileum, villus height and crypt depth in jejunum (61 and 16 %, correspondingly) and ileum (31 and 43 %, correspondingly) compared to IR animals. IR-O3 rats also had a significantly lower intestinal injury score as well as a lower apoptotic index in jejunum and ileum compared and IR animals. A significant increase in cell proliferation rates in IR-O3 animals was accompanied by increased levels of p-ERK protein.Treatment with ozone prevents intestinal mucosal damage, stimulates cell proliferation and inhibits programmed cell death following intestinal IR in a rat.