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Abstract Background Hearing loss is highly prevalent and the third largest cause of years lived with disability. The most frequent cause of adult-onset hearing loss is older age. As the retirement age increases in many countries, a growing number of workers will experience hearing loss, which may affect work participation. Limited research has been done on the consequences of hearing loss in workers in communicative professions. The present study examines the associations of hearing loss with work ability and sick leave among teachers. Methods Dutch teachers were recruited via schools, educational sector organizations, and trade unions. Teachers completed a survey questionnaire and performed a valid and reliable online speech-in-noise screening test for hearing loss. The survey measured work ability with the single-item Work Ability Score (range 0–10); scores were dichotomised into poor-moderate (score 0–7) and good-excellent (score 8–10) work ability. Teachers were asked if they had been on sick leave in the past three months (no / yes; if yes: how many days). Robust Poisson regression analyses were performed to examine the cross-sectional associations of hearing loss with both work ability (poor to moderate versus good to excellent) and sick leave (yes versus no), adjusted for age, sex, level of education, type of work tasks (only teaching versus a mixture with other (e.g. management) tasks, current work hours per week, and working as a physical education teacher. Results A total of 737 teachers participated in the study, of whom 86 (12%) had poor and 146 (20%) insufficient hearing. Teachers with poor and insufficient hearing had a higher prevalence of poor-moderate work ability than good hearing teachers (Prevalence Ratio (PR) = 1.67, 95% CI: 1.36–2.06 and PR = 1.40, 95% CI: 1.16–1.70, respectively). Teachers with poor hearing had a higher prevalence of sick leave than good hearing teachers (PR = 1.60, 95% CI: 1.21–2.01). Conclusions Among teachers, hearing loss was associated with poorer work ability and more sick leave. The results highlight the need for periodic hearing screening as recommended by the WHO. Earlier detection of hearing loss could enable timely work accommodations to prevent work disability of teachers.

Abstract Background The Belgian government has taken several measures to increase the uptake of biosimilars in past years. However, no formal evaluation of the impact of these measures has been made yet. This study aimed to investigate the impact of the implemented measures on biosimilar uptake. Methods An interrupted time series analysis was performed using an autoregressive integrated moving average (ARIMA) model with the Box-Jenkins method. All data were expressed as defined daily doses (DDD) per month/quarter and obtained from the Belgian National Institute for Health and Disability Insurance (NIHDI). Three molecules were included in the analysis: etanercept (ambulatory), filgrastim (hospital), and epoetin (hospital). A significance level of 5% was used for all analyses. Results In the ambulatory care, the effect of a financial prescriber incentive of 2019 was investigated. After this intervention, 44.504 (95% CI −61.61 to −14.812; P

Abstract The development of algorithms for remote sensing of water quality (RSWQ) requires a large amount of in situ data to account for the bio-geo-optical diversity of inland and coastal waters. The GLObal Reflectance community dataset for Imaging and optical sensing of Aquatic environments (GLORIA) includes 7,572 curated hyperspectral remote sensing reflectance measurements at 1 nm intervals within the 350 to 900 nm wavelength range. In addition, at least one co-located water quality measurement of chlorophyll a, total suspended solids, absorption by dissolved substances, and Secchi depth, is provided. The data were contributed by researchers affiliated with 59 institutions worldwide and come from 450 different water bodies, making GLORIA the de-facto state of knowledge of in situ coastal and inland aquatic optical diversity. Each measurement is documented with comprehensive methodological details, allowing users to evaluate fitness-for-purpose, and providing a reference for practitioners planning similar measurements. We provide open and free access to this dataset with the goal of enabling scientific and technological advancement towards operational regional and global RSWQ monitoring.

Pompe disease is caused by deficiency of acid α-glucosidase (GAA), resulting in glycogen accumulation in various tissues, including cardiac and skeletal muscles and the central nervous system (CNS). Enzyme replacement therapy (ERT) improves cardiac, motor, and respiratory functions but is limited by poor cellular uptake and its inability to cross the blood-brain barrier. Previously, we showed that hematopoietic stem cell (HSPC)-mediated lentiviral gene therapy (LVGT) with codon-optimized GAA (LV-GAAco) caused glycogen reduction in heart, skeletal muscles, and partially in the brain at high vector copy number (VCN). Here, we fused insulin-like growth factor 2 (IGF2) to a codon-optimized version of GAA (LV-IGF2.GAAco) to improve cellular uptake by the cation-independent mannose 6-phosphate/IGF2 (CI-M6P/IGF2) receptor. In contrast to LV-GAAco, LV-IGF2.GAAco was able to completely normalize glycogen levels, pathology, and impaired autophagy at a clinically relevant VCN of 3 in heart and skeletal muscles. LV-IGF2.GAAco was particularly effective in treating the CNS, as normalization of glycogen levels and neuroinflammation was achieved at a VCN between 0.5 and 3, doses at which LV-GAAco was largely ineffective. These results identify IGF2.GAA as a candidate transgene for future clinical development of HSPC-LVGT for Pompe disease.

Abstract Background A competitive market for off-patent biologicals leads to more affordable and high-quality healthcare. In recent years, Belgium has been characterized by its low use of biosimilars and by its shifts from off-patent biologicals toward new alternative therapies. Yet, the prescribing decisions involved in these observations are poorly understood. This study aims to better understand prescribing choices among Belgian physicians in the ambulatory care setting. Methods This study consisted of two phases. First, a scoping literature review to identify determinants of prescribing choices was conducted. Scientific databases (Embase and PubMed) were searched until 4 November 2021. Second, the nominal group technique (NGT) was employed during focus group discussions with Belgian physicians to consider and validate these determinants for off-patent biologicals in the Belgian context. The qualitative data resulting from the literature review and focus group discussions were analyzed using the thematic framework method. Results Fifty-three scientific articles that discussed elements that determine prescribing choices were identified. Out of these, 17 determinants of prescribing choices were found. These were divided into five categories: (1) product-related, (2) physicians’ personal, (3) healthcare system-related, (4) patient-related, and (5) determinants related to the pharmaceutical company or brand. Nineteen Belgian physicians from different therapeutic areas that regularly prescribe biologicals then participated in focus group discussions. Using the NGT, the group discussions revealed that prescribing choices for off-patent biologicals are determined by a complex set of elements. Clinical data, geographical region, working environment, pharmaceutical marketing, patient profile, clinical guidelines, and preference of key opinion leaders (KOL) were considered most influential. Physicians indicated that the importance of these determinants differs depending on product classes or therapeutic domain. Conclusions Multiple elements determine the choice of an off-patent biological or biosimilar product. The importance of each of these determinants varies depending on the context in which the prescribing choice is made. To increase the prescription of best-value biologicals in the Belgian ambulatory care, a set of synergistic measures is required including information for healthcare providers (HCP) and patients, prescribing feedback, prescribing targets, tangible incentives, KOL involvement, guidelines regarding pharmaceutical promotion, and regular revision of reimbursement modalities.

Remote sensing of inland waters can provide timely and global water quality information to a wide variety of stakeholders. One of the parameters that determines the feasibility of using optical space-based instruments for monitoring inland waters is the ground sampling distance (GSD), defined as the width of a pixel projected on the Earth’s surface. We assume that to analyze a body of water with optical imagery, its characteristic width must be larger than 3 times the GSD to obtain an ‘unmixed’ pixel that doesn’t contain signal from the adjacent land. Here we obtain the size distribution of river lengths, river areas, and lake areas—as a function of width—for rivers and lakes in the Western United States (US) and in Australia. We base this analysis on the Surface Water and Ocean Topography River Database (SWORD) and HydroLAKES databases, extrapolated to 5 m-wide features. We show that the fraction of river length and river area larger than a certain width increases sharply as the width decreases, indicating that even small decreases in the GSD result in significant increases in the number of bodies that can be surveyed. On the other hand, the distribution of lake areas shows a ‘knee’ at around 400 m, indicating that gains from GSDs smaller than 130 m will be modest. We found that a satellite instrument with a GSD capability of 18 m can provide coverage of 4.4% of total river lengths, 38% of total river area, and 94% of total lake area within the study areas. We argue that decreasing the GSD incurs penalties associated with loss of signal-to-noise, larger instrument, smaller swath, and longer revisit times.

Enzyme replacement therapy (ERT) is the current standard treatment for Pompe disease, a lysosomal storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). ERT has shown to be lifesaving in patients with classic infantile Pompe disease. However, a major drawback is the development of neutralizing antibodies against ERT. Hematopoietic stem and progenitor cell-mediated lentiviral gene therapy (HSPC-LVGT) provides a novel, potential lifelong therapy with a single intervention and may induce immune tolerance. Here, we investigated whether ERT can be safely applied as additional or alternative therapy following HSPC-LVGT in a murine model of Pompe disease. We found that lentiviral expression at subtherapeutic dose was sufficient to induce tolerance to the transgene product, as well as to subsequently administered ERT. Immune tolerance was established within 4–6 weeks after gene therapy. The mice tolerated ERT doses up to 100 mg/kg, allowing ERT to eliminate glycogen accumulation in cardiac and skeletal muscle and normalizing locomotor function. The presence of HSPC-derived cells expressing GAA in the thymus suggested the establishment of central immune tolerance. These findings demonstrate that lentiviral gene therapy in murine Pompe disease induced robust and long-term immune tolerance to GAA either expressed by a transgene or supplied as ERT.

Background: Factors like the number of biosimilar competitors and competitive pricing strategies from originator companies may influence price competition and biosimilar uptake.Objective: The aim of this study was to analyze multiple facets of biosimilar competition of TNF-alpha inhibitors in Europe by exploring the existence of a biosimilar first-mover advantage, pricing strategies of originator companies, and the evolution in patient access.Methods: Sales and volume data on biosimilar and originator infliximab, etanercept, and adalimumab between 2008 and 2020 were provided by IQVIA. Countries included 24 European Union Member States, Norway, Switzerland, United Kingdom, Serbia, and Bosnia and Herzegovina. Sales value was expressed as ex-manufacturer price per defined daily dose (DDD), and volume data were transformed into the number of DDDs per 1,000 inhabitants per day. Descriptive analyses were conducted based on the evolution in price per DDD, trends in biosimilar and originator market shares and utilization trends.Results: Market entry of the first biosimilars of infliximab and adalimumab resulted in a decrease of the volume-weighted average price (VWAP) per DDD by 13.6% and 0.9% on average, whilst the second biosimilars resulted in a decrease by 26.4% and 27.3%, respectively. The first and second etanercept biosimilars generated a similar decrease in the VWAP per DDD by 9.3% and 9.1% on average, respectively. Average market share captured by the first biosimilars was at least twice as large as the second biosimilars for all molecules. In addition, sharp reductions in price per DDD of Humira® in most countries indicated a pricing strategy resulting in low uptake of adalimumab biosimilars. Lastly, utilization of infliximab, etanercept, and adalimumab following biosimilar entry increased by an average of 88.9%, 14.6%, and 22.4%, respectively. However, introduction of (multiple) biosimilar competitors did not necessarily translate into increase in treatment access for all three molecules across some European countries indicating a shift in utilization from one molecule towards the other(s).Conclusion: Overall, this study revealed that biosimilar entry results in increased utilization and price reduction, although at a heterogenous rate among TNF-alpha inhibitors. Observed trends in market shares indicate a biosimilar first-mover advantage whereas pricing strategies considered to be anti-competitive can limit market uptake.

Objectives To develop evidence-based points to consider for cost-effective use of biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in the treatment of inflammatory rheumatic diseases, specifically rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis.Methods Following EULAR procedures, an international task force was formed, consisting of 13 experts in rheumatology, epidemiology and pharmacology from seven European countries. Twelve strategies for cost-effective use of b/tsDMARDs were identified through individual and group discussion. For each strategy, PubMed and Embase were systematically searched for relevant English-language systematic reviews and, for six strategies, additionally for randomised controlled trials (RCTs). Thirty systematic reviews and 21 RCTs were included. Based on the evidence, a set of overarching principles and points to consider was formulated by the task force using a Delphi procedure. Level of evidence (1a–5) and grade (A–D) were determined for each point to consider. Individual voting on the level of agreement (LoA; between 0 (completely disagree) and 10 (completely agree)) was performed anonymously.Results The task force agreed on five overarching principles. For 10 of 12 strategies, the evidence was sufficient to formulate one or more points to consider, leading to 20 in total, regarding response prediction, drug formulary use, biosimilars, loading doses, low-dose initial therapy, concomitant conventional synthetic DMARD use, route of administration, medication adherence, disease activity–guided dose optimisation and non-medical drug switching. Ten points to consider (50%) were supported by level 1 or 2 evidence. The mean LoA (SD) varied between 7.9 (1.2) and 9.8 (0.4).Conclusion These points to consider can be used in rheumatology practices and complement inflammatory rheumatic disease treatment guidelines to incorporate cost-effectiveness in b/tsDMARD treatment.

BackgroundThe availability of biosimilar medicines in Southern European markets has allowed purchasing biologics at a lower cost for healthcare systems. However, the capacity to seize this cost-reduction opportunity in the long run depends on fostering a sustainable competitive environment for all the market players involved. Diverse policies and information campaigns have been launched in Italy, Portugal and Spain to support uptake of “best-value” biologics (BVB). Despite these measures, the utilization of lower-cost biologics in certain regions is low, especially when it comes to the treatment of chronic conditions.ObjectiveWe aim to identify biosimilar uptake determinants in hospital environments in Italy, Portugal and Spain, using the class of TNF-alpha inhibitors as an example.MethodsThis is a mixed-methods study based on (1) the quantitative analysis of regional uptake data for TNF-alpha inhibitor biosimilars and (2) the qualitative processing of semi-structured interviews capturing experts’ views on uptake determinants for biosimilars.ResultsThe organization of multi-stakeholder information campaigns supporting TNF-alpha inhibitor biosimilars use in Italy, Portugal and Spain has resulted in an increased familiarity of healthcare professionals and patients with the prescription/use of these products. However, barriers persist that impede high biosimilars uptake, especially in chronic patient populations eligible for a switch. These are: (1) the late publication of position statements on biosimilars interchangeability by regulatory health authorities; (2) the vague positioning of (national/regional) health authorities on best switching practices (including multiple biosimilar-to-biosimilar switches); (3) the existence of policy frameworks that do not necessarily support the initiation of switching protocols; (4) the establishment of sometimes inefficient purchasing procedures that limit biosimilars potential to compete for market shares. Diverse approaches taken regionally to address these barriers have contributed to heterogeneous TNF-alpha inhibitor biosimilars uptake across Southern Europe.ConclusionOur research signaled the limited reach of biosimilar policies implemented locally, if not supported by a national policy framework. This study highlights the need for the coordinated implementation of policy measures fostering biosimilars use at the regional and national level in Italy, Portugal and Spain. These measures should account for the particularities of off-patent biologic and biosimilar markets and should jointly address supply- and demand-side challenges.

Background: The level of competition achieved following biosimilars market availability varies by country, care setting and molecule. Hence, biosimilars contribution to attaining price reductions and extended access to treatments can also vary.Objective: The aim of this study is to capture market dynamics for tumor necrosis factor (TNF)-alpha inhibitors and competing molecules in Southern European markets (2011–2020), and to evaluate the benefits of the competition generated by the availability of biosimilars.Methods: This study is based on a literature review examining market characteristics for TNF-alfa inhibitors and competing immunomodulator molecules, and on the quantitative analysis of market data for these molecules in Italy, Portugal and Spain.Results: Following biosimilars availability in Italian, Portuguese and Spanish markets, there has been an expansion in the overall access to TNF-alfa inhibitor pharmaceuticals. Further, savings have been generated within the TNF-alfa inhibitors class even after the increased use of these molecules. However, the potential of infliximab, etanercept and adalimumab biosimilars to generate price competition outside of their own drug class appeared limited in the studied markets. Considering this limitation and that shifts towards on-patent and higher-cost therapies have occurred after TNF-alfa inhibitor biosimilars availability, the importance of investing in biosimilars development for still on-patent immunology biologics is emphasized.Conclusion: This study highlights the need for policies that do not only seek higher utilization of biosimilars, but that also support a sustainable market for these products. This is expected to foster the future development of biosimilar medicines.

This paper describes the assessment of climate risks, the vulnerability of farmlands, and the adaptive farming practices to climate change with the use of GIS, field observations, stakeholder consultation and interviews and case documentation. GIS-based climate risk vulnerability assessment maps were generated to pinpoint the areas with the major climate hazards in Agusan del Norte. The vulnerability of the farmlands, and the adaptive capacity of the farms were assessed with index scoring. Also, adaptation to climate change based on the most problematic hazard (flooding) was observed on the two groups of farmers (with and without climate resilient agriculture (CRA)/cropping system adjustments) for cost and benefit comparison. The results show flooding and drought as the significant hazards in Agusan del Norte (Caraga Region) and high vulnerability to these hazards due to low coping mechanisms for most farms. Low adaptive capacity was also observed among these farms. Case-based observations on adaptation in Jabonga, Agusan del Norte revealed that well-timed adjustments to the usual cropping system can increase farm income despite of the flood and inundation for 2–3 months. This study recommends for harmonized measures toward advocating strengthened adaptive capacity for agriculture across Agusan del Norte. Further climate R&D and increasing policy support on climate financing and CRA options are highly encouraged for the agricultural stakeholders to take action. For hard-pressed farmers with constrained access to improved varieties and technologies, timing is potentially essential to circumvent damages from climate change to gain economic and psychosocial benefits with well-timed adaptation measures.

Background: By improving the affordability and accessibility of biologicals, biosimilar competition provides important benefits to healthcare systems and patients. In Belgium, biosimilar uptake and competition is limited compared to other European markets. Whereas other countries have initiated structured biosimilar introduction or switching plans, no such framework or guiding principles are yet available in Belgium.Objective: This study aims to develop recommendations that can inform policy action in Belgium on biosimilar use, especially in the context of switch decision-making, and this by drawing from the perspectives of healthcare professionals involved in procuring, prescribing, switching and dispensing biologicals including biosimilars.Methods: This study made use of the consensus-building Nominal Group Technique, consisting of a three-step process 1) individual grading, 2) three structured Focus Group Discussions, 3) final individual grading involving an expert group of Belgian healthcare professionals (physician specialists and hospital pharmacists).Results: Participants (n = 13) voiced challenges with the use of biosimilars and switching in practice, and a lack of incentives to use them. Six concrete areas for policy development to support stakeholders with biosimilar use and switch decision-making were identified: 1) address stakeholder hesitations regarding (multiple) switching, 2) provide meaningful incentives, 3) guide healthcare professionals with product decision-making, 4), align practical product modalities when possible, 5) involve healthcare professionals in policy making, and 6) provide practical switch support and patient information material, particularly in the ambulatory care setting. For each area, specific consensus-based recommendations were developed. Furthermore, a set of switch management and patient communication principles was derived, including amongst others, generating buy-in from involved stakeholders prior to switching and communicating with a one-voice message.Conclusion: Without cohesive actions to reduce hurdles and without tangible benefits or steering mechanisms, changes in biosimilar use are unlikely in Belgium. To overcome this and stimulate market competitiveness, this study advances a set of concrete policy recommendations. At large, policy makers should develop an integrated policy framework, with a pro-active, best-value biological implementation roadmap that provides guidance and compelling measures to incentivize healthcare professionals to use biosimilars. Particular consideration should go to the ambulatory care setting, since drivers for biosimilar use are quasi absent in this context.

BackgroundBeyond evaluation and approval, European and national regulators have a key role in providing reliable information on biosimilars and the science underpinning their development, approval, and use.ObjectivesThis study aims to (i) review biosimilar information and guidance provided by EMA and national medicines agencies and (ii) explore stakeholder perspectives on the role of regulators in enabling acceptance and use of biosimilars.MethodsThis study consists of (i) a comparative review of regulatory information and position statements across medicine agencies (n = 32) and (ii) qualitative interviews with stakeholders in Europe (n = 14).ResultsThe comparative analysis showed that regulatory information and guidance about biosimilars offered by national medicines agencies in Europe varies, and is limited or absent in multiple instances. Approximately 40% (13/31) of the national medicines agencies' websites did not offer any information regarding biosimilars, and for about half (15/31) no educational materials were provided. Only less than half of national medicines agencies provided guidance on biosimilar interchangeability and switching (8/31 and 12/31, respectively). Among the national medicines agencies that did offer guidance, the extent (e.g., elaborate position vs. brief statement) and content (e.g., full endorsement vs. more cautious) of the guidance differed substantially. Countries that have a strong involvement in EU level biosimilar regulatory activities generally had more elaborate information nationally. Interviewees underwrote the need for (national) regulators to intensify biosimilar stakeholder guidance, especially in terms of providing clear positions regarding biosimilar interchangeability and switching, which in turn can be disseminated by the relevant professional societies more locally.ConclusionThis study revealed that, despite strong EU-level regulatory biosimilar guidance, guidance about biosimilars, and their use differs considerably across Member States. This heterogeneity, together with the absence of a clear EU-wide position on interchangeability, may instill uncertainty among stakeholders about the appropriate use of biosimilars in practice. Regulators should strive for a clear and common EU scientific position on biosimilar interchangeability to bridge this gap and unambiguously inform policy makers, healthcare professionals, and patients. Furthermore, there is a clear opportunity to expand information at the national level, and leverage EU-developed information materials more actively in this regard.

Background and objectives: Biosimilar medicines have been on the European market for 15 years. Despite the extensive and positive experience with biosimilars across Europe, their uptake remains limited in Belgium. One of the possible factors limiting uptake in clinical practice is the inadequate understanding and lack of trust in biosimilars among patients. This study aimed to assess the level of knowledge and perceptions about biosimilar medicines among Belgian patients in the ambulatory care.Methods: This study consisted of online questionnaires among Belgian patients in the ambulatory care (i.e., rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, ulcerative colitis, diabetes mellitus type I and II). The results were collected between December 2020 and February 2021. The data were analyzed with descriptive and inferential statistics.Results: In total, 657 patients across all disease areas of interest participated in this study. Only 38% of patients had heard of biosimilars before. Of those patients, most (58%) were aware that biosimilars are as safe and effective as their reference product. The vast majority of respondents (68%) would agree with transitioning to a biosimilar if their physician prescribed it, only 3% would never agree with a transition to a biosimilar. If a physician would propose to change their current originator biological therapy with its biosimilar, nearly all patients (95%) want their physician to explain the decision and inform them. For additional information about biosimilars, Belgian patients prefer brochures or folders (41%), or available resources on the internet (35%). Physicians were indicated as the preferred source of information (95%), followed by pharmacists (51%), academia (39%), and patient associations (35%). Most patients require information regarding the safety and efficacy (78%), price and reimbursement (64%), and the clinical development process (56%) of the biosimilar.Conclusion: Belgian patients require information about biosimilar medicines. However, most patients are open and positive towards transitioning their current biological therapy with its biosimilar if sufficiently supported by their healthcare providers.

Genealogical research usually begins with the discovery of affinity among individual humans. Such kinship is induced by direct observation, as well as by hearsay (indirect observation) that can be independently confirmed. Those who want to continue investigating a case history after the observational mode of fact-finding is no longer sustainable have no other choice than to switch to the discovery of consanguineous relationships. This involves a paradigm shift, where investigation dramatically changes from observation to inference, from inductive to deductive reasoning. Individuation is important in characterizing the personhood of an individual, but those same facts are of little empirical value in establishing the unification of a family. In addition, genealogists rely on marriage as an observable source of evidence for unification. However, this extrapolation is not completely convincing because marriage does not take into account the uncertainty of paternity. Individual parents usually descend from different parts of family history, which suggests genealogists should evaluate cultural factors responsible for non-random mating in attempting to infer consanguinity. For example, there is the incest taboo, a cultural convention which addresses the abnormal genetic consequences of inbreeding. Other non-random mating factors of a more general nature may also be identified in the unification of genetically different individuals. Here, for example, causality is expected in cultural principles that are of a cohesive and integrative nature. Those kinds of evidence may determine an unmarried pair’s earliest engagement and may also be responsible for the origin and maintenance of the marriage relationship, even throughout post-reproductive life. Lastly, current genealogical research is severely infected with confirmation bias, and from which it must be protected if it is to achieve the status of a scientific discipline. Critical rationalism provides a solution to that kind of problem. It is with remediation in mind, as it applies to all of the aforementioned issues, that genealogical systematics is characterized.

Background With the approval of biosimilars for subcutaneously administered products, such as adalimumab, etanercept and insulin, biosimilars become increasingly available in ambulatory care. Little is known about the knowledge and attitudes of healthcare providers who are in charge of dispensing and prescribing biosimilars in this context. This study aims to assess the knowledge and perception about biosimilars among community pharmacists and physicians. Methods Belgian community pharmacists (n = 177) and physicians (n = 30) were surveyed on their knowledge, experience with dispensing/prescribing biologicals including biosimilars, perception regarding interchangeability, switching and substitution and informational and educational needs. Descriptive and statistical analyses were performed. Results Only 32% of community pharmacists and 52% of physicians had yet dispensed/prescribed a biosimilar. Approximately 35% of community pharmacists felt insufficiently trained to counsel patients with biosimilar therapy, which was significantly higher compared to their self-assessed competence to counsel patients with biological therapy in general (p = 0.023). Community pharmacists experienced questions about similarity between reference products and biosimilars (47%) and their interchangeability (42%). Over 40% of physicians found patient uncertainty about efficacy and safety challenging when prescribing biosimilars. A similar proportion of physicians would only prescribe a biosimilar in indications for which the biosimilar has been tested clinically. The majority of pharmacists (58%) was in favor of substitution of biologicals, on the condition that the prescriber would be contacted. Also over 40% of physicians was open to this approach in case of substitution. Educational support, budget for additional staff and transparency about savings were considered suitable stimuli to incentivize biosimilar use. The need for information about biologicals including biosimilars was nearly unanimous among community pharmacists. Also 67% of physicians requested more information. Both community pharmacists and physicians preferred to be informed by their respective professional associations. Conclusions This study showed a substantial need for targeted educational measures to increase the knowledge and confidence about both biological medicines in general and biosimilars in particular among Belgian community pharmacists and physicians. The results may inform educational and policy measures to stimulate biosimilar use in ambulatory care.

Background and objective: Best-value biological medicines may generate competition in the off-patent biologicals market, resulting in having more resources available to provide patients with access to necessary medicines while maintaining high-quality care. Belgium is a country known to have low biosimilar market shares, suggesting a malfunctioning market for off-patent biologicals. This study aims to gain an in-depth understanding of the Belgian off-patent biologicals market, by looking at the evolution in volumes and costs of the relevant products in the market.Methods: This study included a combination of quantitative and qualitative research methods. The quantitative part of this study consisted of the analysis of market data obtained by the National Institute for Health and Disability Insurance (NIHDI) for all relevant products in the Belgian off-patent biologicals market (i.e. TNF-inhibitors, insulins, granulocyte colony-stimulating factors, epoetins, rituximab, trastuzumab). In addition, for the qualitative part of this study, semi-structured interviews with Belgian stakeholders were conducted between December 2019 and March 2020.Results: Belgian market data and stakeholder perceptions suggest a suboptimal market environment for off-patent biological and biosimilar medicines. Shifts are observed after loss of exclusivities of originator biologicals toward second-generation products or new therapeutic class products, at a higher cost and often limited added value. Moreover, cost reductions for off-patent biologicals after biosimilar market entry are mainly determined by mandatory price reductions applicable to both originator and biosimilar products, and not by lower prices induced by competition. For products used in the retail setting, significant mandatory price reductions for both originator and reference products with low biosimilar volumes were pointed out as the main reasons for the lack of price competition. For products dispensed in hospitals, the hospital financing system is important. First, it does not always encourage the use of lower cost alternatives. Second, competition mainly takes place at the level of confidential discounts in tenders. Most interviewees acknowledged the lack of a competitive environment, which is not supportive of a sustainable Belgian off-patent biologicals market.Conclusion: Market data and stakeholder perceptions indicate that the sustainability of the Belgian market for off-patent biologicals is challenged. A sustainable market ensures access to biological therapies now and in the future.

Background: From October 2018, adalimumab biosimilars could enter the European market. However, in some countries, such as Netherlands, high discounts reported for the originator product may have influenced biosimilar entry.Objectives: The aim of this paper is to provide a European overview of (list) prices of originator adalimumab, before and after loss of exclusivity; to report changes in the reimbursement status of adalimumab products; and discuss relevant policy measures.Methods: Experts in European countries received a survey consisting of three parts: 1) general financing/co-payment of medicines, 2) reimbursement status and prices of originator adalimumab, and availability of biosimilars, and 3) policy measures related to the use of adalimumab.Results: In May 2019, adalimumab biosimilars were available in 24 of the 30 countries surveyed. Following introduction of adalimumab biosimilars, a number of countries have made changes in relation to the reimbursement status of adalimumab products. Originator adalimumab list prices varied between countries by a factor of 2.8 before and 4.1 after loss of exclusivity. Overall, list prices of originator adalimumab decreased after loss of exclusivity, although for 13 countries list prices were unchanged. When reported, discounts/rebates on originator adalimumab after loss of exclusivity ranged from 0% to approximately 26% (Romania), 60% (Poland), 80% (Denmark, Italy, Norway), and 80–90% (Netherlands), leading to actual prices per pen or syringe between €412 (Finland) and €50 – €99 (Netherlands). To leverage competition following entry of biosimilar adalimumab, only a few countries adopted measures specifically for adalimumab in addition to general policies regarding biosimilars. In some countries, a strategy was implemented even before loss of exclusivity (Denmark, Scotland), while others did not report specific measures.Conclusion: Even though originator adalimumab is the highest selling product in the world, few countries have implemented specific policies and practices for (biosimilar) adalimumab. Countries with biosimilars on the market seem to have competition lowering list or actual prices. Reported discounts varied widely between countries.

The bio-optical properties of coral reef waters were examined across coral reef ecosystems not influenced by land-derived run-off, in the Great Barrier Reef lagoon (Heron Island) and the Coral Sea (the Coringa-Herald and Lihou Reefs). The aim was to determine whether the absorption properties, the concentration-specific absorption properties, and the phytoplankton and non-algal pigmented particle (NAP) absorption concentrations varied from the ocean waters flushing onto the reef at high tide to those waters on the reef or flushing off the reef at low tide. The optical and biogeochemical properties of on-reef waters systematically differed from the surrounding ocean waters. The chl a concentration values varied up to 7-fold and the NAP concentrations up to 29-fold; for the reef samples, the chl a values were on average 2 to 3 times lower than for the oceans whilst the NAP values were slightly higher on the reefs. The spectral absorption values of the chl a, NAP, and colored dissolved organic matter (CDOM) varied up to 6-fold for reef waters and up to 15-fold for ocean waters. The spectral absorption for chl a was up to 3-fold lower on the reef waters, the absorption by the CDOM was up to 2-fold higher and the NAP absorption was 1.6-fold higher on the reef waters. The concentration-specific absorption coefficients for chl a and NAP varied up to 9-fold in reef waters and up to 30-fold in ocean waters. In the case of Heron Island and Coringa-Herald cays, this concentration-specific absorption was on average 1.3 to 1.7-fold higher for chl a and up to 2-fold lower for NAP on the reefs. The Lihou Reef measurements were more ambiguous between the reef waters and ocean waters due to the complex nature and size of this reef. Based on our results, the assumption that the optical properties of on-reef waters and the adjacent ocean waters are the same was shown to be invalid. Ocean waters flowing on to the reef are higher in phytoplankton, whilst waters on the reef or flowing off the reefs are higher in CDOM and NAP. We found differences in the pico,- nano-, and microplankton distributions as well as in the ratios of photosynthetic to photoprotective pigments. The variability in the bio-optical properties between the reef waters and adjacent ocean waters has implications for the estimations of sunlight absorption along the water column, the UV penetration depth, the temperature distributions, and the nutrient and carbon fluxes in coral reef ecosystems. As Earth observation algorithms require proper parameterization for the water column effects when estimating benthic cover, the actual optical properties need to be used. These results will improve the use of Earth observation to systematically map the differences in the water quality between reefs and the adjacent ocean.

The main objectives of this symposium were to review the value of biosimilars in sustainable treatment for haematologic malignancies and to recognise the developmental differences between biosimilars and their reference products. The meeting also aimed to evaluate the data on monoclonal antibodies for the treatment of haematologic malignancies and the role of biosimilars to address gaps in healthcare. Dr Cornes highlighted recent innovations in cancer treatment and presented biosimilars as economic tools that can address the financial issues that hamper progress. Prof Vulto discussed the need for healthcare professionals to be well informed about the principles of biosimilarity and aware of current and emerging therapies. Prof Jurczak presented the case for rituximab (and its biosimilars) as the standard of care for first-line B cell non-Hodgkin’s lymphoma (NHL) and its potential as maintenance treatment for indolent NHL (iNHL).

As patents on many high-selling biological medicines are expiring, non-innovator versions, such as biosimilars, may enter this multi-billion dollar market. This study aims to map patents and patent applications for innovator as well as biosimilar monoclonal antibodies in Europe, and investigates legal challenges associated with patenting the innovator product and alleged infringing activities, focusing on consequences for biosimilar developers. Via an exploratory literature review in PubMed and a database analysis in Darts-ip, Derwent Innovation, and Espacenet, an overview of basic patents and exclusivity rights for some of the best-selling biologicals is given, supplemented with a detailed analysis of patents taken during the medicine’s life cycle via three specific case studies (trastuzumab, bevacizumab, cetuximab). Case law was used to determine which patents were viewed by biosimilar developers as blocking market entry. For the selected monoclonal antibodies, the key protection instruments appeared to be the basic patent and the additional protection provided by a supplementary protection certificate. We observed that additional patents filed after the basic patent are hard to obtain and often insufficient in blocking market entry of biosimilars, but can in some cases be a substantial hurdle for biosimilar developers to overcome in patent litigation cases or to invent around, creating uncertainty on the launch date of a biosimilar on the market. These hurdles, however, seem to be surmountable, given that many cases were won by biosimilar developers. Also, biosimilars can be protected by filing new patents and these mainly pertain to new formulations.

Background: Limited previous research and guidelines on the design of economic evaluation for biosimilars have led to unresolved methodological questions on how to assess biosimilars. Objectives: We want to raise awareness of and explore methodological issues for the economic evaluation of biosimilars. Methods: We relied on a literature review, exploratory interviews, and our experiences. Results and Conclusions: In the majority of cases in which reimbursement for a biosimilar is sought, it will not be necessary to conduct an economic evaluation, given that the reference product is already reimbursed and standard of care. If the latter is not the case, a full economic evaluation of the biosimilar versus standard of care is needed. This might also be needed in the case of differences in administration form or adherence (for example, due to a nocebo effect) and to take into account value-added services. The entry of biosimilars and of next-generation biological products should trigger a re-assessment of the entire product class. HTA bodies and reimbursement agencies should provide clear guidance on how to assess the value of a biosimilar in each of these circumstances.

This study aimed to compare drug costs and healthcare costs of a 1 year adjuvant course with intravenous biosimilar trastuzumab vs. subcutaneous reference trastuzumab in HER2-positive breast cancer from the Belgian hospital perspective. Our simulation is based on the methodology used by Tjalma and colleagues, and considered costs of drugs, healthcare professional time and consumables. We calculated intravenous drug costs for different body weights, and computed drug costs and healthcare costs to treat 100 patients with either trastuzumab formulation, assuming a binomial body weight distribution in this sample. Scenarios were run to account for drug discounts and intravenous vial sharing. Drug costs amounted to €1,431,282 with intravenous biosimilar trastuzumab and €1,522,809 with subcutaneous reference trastuzumab for a sample of 100 patients in the base case analysis. When healthcare professional time and consumables were also considered, healthcare costs with intravenous biosimilar trastuzumab were similar to those with subcutaneous reference trastuzumab. Differences in healthcare costs between intravenous biosimilar trastuzumab and subcutaneous reference trastuzumab depended on the level of discounts on these formulations and on intravenous vial sharing. Our case study demonstrates that comparing costs of intravenous vs. subcutaneous formulations is complex and multifactorial, and entails more than a simple cost comparison of products.

Background: In Europe, off-patent biologicals and biosimilars are largely procured by means of tender procedures. The organization and design of tenders may play a key role in the evolving biosimilar market, and currently, it is not fully elucidated how tenders for off-patent biologicals and biosimilars are designed and if approaches are aligned with sustaining market competition and societal savings for healthcare systems over the long term. This study aims to (i) explore the design and implementation of tender procedures for off-patent biologicals and biosimilars in Europe, (ii) identify learnings for sustainable tender approaches from purchasers and suppliers, and (iii) formulate recommendations in support of competitive and sustainable tender practices in the off-patent biologicals market. Methods: A mixed methods design was applied. A quantitative web-survey was conducted with hospital pharmacists and purchasers (N = 60, of which 47 completed the survey in full), and qualitative expert-interviews with purchasers and suppliers (N = 28) were carried out. Results: The web survey results showed that the organization and design of tenders for off-patent biologicals and biosimilars, and the experience of hospital pharmacists and purchasers with this, considerably varies on several elements across European countries. From the qualitative interviews, signals emerged across the board that some of the current tender approaches might negatively affect market dynamics for off-patent biologicals and biosimilars. The focus on generating short-term savings and existence of originator favouring tender practices were identified as elements that may limit timely competition from and market opportunity for biosimilar suppliers. The need to optimize tender processes, considering a more long-term strategic and sustainable view, was expressed. In addition, challenges appear to exist with differentiating between products beyond price, showing the need and opportunity to guide stakeholders with the (appropriate) inclusion of award criteria beyond price. Due to the variety in tender organization in Europe, a ‘one size fits all’ tendering framework is not possible. However, on an overarching level, it was argued that tender procedures must aim to (i) ensure market plurality and (ii) include award criteria beyond price (warranted that criteria are objectively and transparently defined, scored and competitively rewarded). Depending on the market (maturity), additional actions may be needed. Conclusions: Findings suggest the need to adjust tender procedures for off-patent biologicals and biosimilars, considering a more long-term strategic and market sustainable view. Five main avenues for optimization were identified: (i) safeguarding a transparent, equal opportunity setting for all suppliers with an appropriate use of award criteria; (ii) fostering a timely opening of tender procedures, ensuring on-set competition; (iii) ensuring and stimulating adherence to laws on public procurement; (iv) securing an efficient process, improving plannability and ensuring timely product supply and (v) safeguarding long-term sustainable competition by stimulating market plurality.

Biosimilar medicines support the sustainability of national healthcare systems, by reducing costs of biological therapies through increased competition. However, their adoption into clinical practice largely depends on the acceptance of healthcare providers and patients. Patients are different from health care professionals (HCPs), who are informing themselves professionally. For patients, the biosimilar debate only becomes actual when they are confronted with disease and drug choices. This paper provides a literature review on how patients are and should be informed about biosimilars, searching in scientific databases (i.e., Medline, Embase). Several large surveys have shown a lack of knowledge and trust in biosimilars among European patients in recent years. This review identified five main strategies to inform patients about biosimilars: (1) provide understandable information, (2) in a positive and transparent way, (3) tailored to the individual’s needs, (4) with one voice, and (5) supported by audiovisual material. Moreover, the importance of a multistakeholder approach was underlined by describing the role of each stakeholder. Patients are a large and diffuse target group to be reached by educational programs. Therefore, patient associations have become increasingly important in correctly informing patients about biosimilar medicines. This has led to widespread biosimilar information for patients among European patient associations. Therefore, a web-based screening of European Patients’ Forum (EPF) and International Alliance of Patients’ Organizations (IAPO) member organizations on publicly available information about biosimilars was performed. We found that the level of detail, correctness, and the tone of the provided information varied. In conclusion, it is paramount to set up a close collaboration between all stakeholders to communicate, develop, and disseminate factual information about biosimilars for patients.

Introduction: Biosimilars have the potential to enhance the sustainability of evolving health care systems. A sustainable biosimilars market requires all stakeholders to balance competition and supply chain security. However, there is significant variation in the policies for pricing, procurement, and use of biosimilars in the European Union. A modified Delphi process was conducted to achieve expert consensus on biosimilar market sustainability in Europe. Methods: The priorities of 11 stakeholders were explored in three stages: a brainstorming stage supported by a systematic literature review (SLR) and key materials identified by the participants; development and review of statements derived during brainstorming; and a facilitated roundtable discussion. Results: Participants argued that a sustainable biosimilar market must deliver tangible and transparent benefits to the health care system, while meeting the needs of all stakeholders. Key drivers of biosimilar market sustainability included: (i) competition is more effective than regulation; (ii) there should be incentives to ensure industry investment in biosimilar development and innovation; (iii) procurement processes must avoid monopolies and minimize market disruption; and (iv) principles for procurement should be defined by all stakeholders. However, findings from the SLR were limited, with significant gaps on the impact of different tender models on supply risks, savings, and sustainability. Conclusions: A sustainable biosimilar market means that all stakeholders benefit from appropriate and reliable access to biological therapies. Failure to care for biosimilar market sustainability may impoverish biosimilar development and offerings, eventually leading to increased cost for health care systems and patients, with fewer resources for innovation.

Drug budget and prescription control measures are implemented regionally in Germany, meaning that the uptake of pharmaceuticals, including biosimilars, can vary by region. We examine regional market dynamics of tumor necrosis factor alpha (TNFα) inhibitor originators and biosimilars in Germany and studied the influence of biosimilar policies on these dynamics. This study is based on: (1) a literature review in which German biosimilar policies are identified, (2) the analysis of dispensing data (2010–2018) for the class of TNFα inhibitors, and (3) ten semi-structured interviews investigating prescribers’ and insurers’ views on factors potentially influencing biosimilar uptake. The analysis of biosimilar market shares of infliximab and etanercept revealed wide variations across the 17 German Regional Associations of Statutory Health Insurance Accredited Physicians (PA regions). Quantitative analyses indicated that biosimilar market shares for infliximab and etanercept were significantly lower in former East Germany when compared to former West Germany regions. Through qualitative interview analyses, this study showed that the use of infliximab and etanercept biosimilars across Germany is primarily influenced by (1) the regional-level implementation of biosimilar quotas and the presence of monitoring/sanctioning mechanisms to ensure adherence to these quotas, (2) the different insurer-manufacturer discount contracts, and (3) gainsharing arrangements established at the insurer-prescriber level.

Background and objectives: To investigate the effects of vinegar ingestion upon high-intensity cycle performance in recreationally trained individuals. Materials and methods: Twenty-two participants consumed one of the following in a randomized order on four separate visits: (1) 29 mL of vinegar along with 451 mL of water, (2) 39 g of sucrose along with 441 mL of water, (3) 29 mL of vinegar and 39 g of sucrose along with 412 mL of water, or (4) 480 mL of water alone. For each of the experimental testing sessions, all participants completed in order: (1) high-intensity cycle test 1, (2) fatiguing cycle test, (3) high-intensity cycle test 2, (4) supplement consumption, (5) 90 min rest period, and (6) high-intensity cycle test 3. Total time to exhaustion (TTE) and average heart rate (HR) for each set of sprints was used in analysis. Results: There was no supplement by time interaction or significant main treatment effect observed (p > 0.05) for either TTE or HR. However, there was a main time effect observed, with TTE (p = 0.0001) being lower for cycle test 2 than both cycle test 1 and cycle test 3, and cycle test 3 being lower than cycle test 1. HR (p = 0.0001) was lower for cycle test 3 than both cycle test 1 and cycle test 2, but HR for cycle test 1 did not differ significantly from HR for cycle test 2. Conclusions: The addition of vinegar or sucrose alone, or in combination, was ineffective in improving cycle sprinting TTE when performing three cycle tests.

This paper studies the measurement requirements of spectral resolution and radiometric sensitivity to enable the quantitative determination of water constituents and benthic parameters for the majority of optically deep and optically shallow waters on Earth. The spectral and radiometric variability is investigated by simulating remote sensing reflectance (Rrs) spectra of optically deep water for twelve inland water scenarios representing typical and extreme concentration ranges of phytoplankton, colored dissolved organic matter and non-algal particles. For optically shallow waters, Rrs changes induced by variable water depth are simulated for fourteen bottom substrate types, from lakes to coastal waters and coral reefs. The required radiometric sensitivity is derived for the conditions that the spectral shape of Rrs should be resolvable with a quantization of 100 levels and that measurable reflection differences at at least one wavelength must occur at concentration changes in water constituents of 10% and depth differences of 20 cm. These simulations are also used to derive the optimal spectral resolution and the most sensitive wavelengths. Finally, the Rrs spectra and their changes are converted to radiances and radiance differences in order to derive sensor (noise-equivalent radiance) and measurement requirements (signal-to-noise ratio) at the water surface and at the top of the atmosphere for a range of solar zenith angles.

Background: Since it has been shown that spending 18 h under dim light conditions can result in reduced handgrip endurance, it was questioned whether or not a shorter exposure to dim light (i.e., 1 h) would have similar influence upon muscular endurance. Therefore this study compared the number of weighted knee extension lifts that could be done after spending 1 h in either dim or bright light. Methods: Participants (5 women, 11 men, college students 19–26 years) performed knee extension lifts to exhaustion with a load approximating 40% of their body weight. The lifts to exhaustion were measured immediately following 1 h of exposure to each of the following three conditions: dark (DL), room light (RL), and room light plus 5 mg melatonin (RLM). A minimum of 48 h separated each condition, and all participants started the exposures in a rested fed condition. Results: Average (±SD) number of knee extension lifts for RL (62.0 ± 22.0) was significantly (p

Trichodesmium, a filamentous bloom-forming marine cyanobacterium, plays a key role in the biogeochemistry of oligotrophic ocean regions because of the ability to fix nitrogen. Naturally occurring in the Great Barrier Reef (GBR), the contribution of Trichodesmium to the nutrient budget may be of the same order as that entering the system via catchment runoff. However, the cyclicity of Trichodesmium in the GBR is poorly understood and sparsely documented because of the lack of sufficient observations. This study provides the first systematic analysis of Trichodesmium spatial and temporal occurrences in the GBR over the decade-long MERIS ocean color mission (2002-2012). Trichodesmium surface expressions were detected using the Maximum Chlorophyll Index (MCI) applied to MERIS satellite imagery of the GBR lagoonal waters. The MCI performed well (76%), albeit tested on a limited set of images (N = 25) coincident with field measurements. A north (Cape York) to south (Fitzroy) increase in the extent, frequency and timing of the surface expressions characterized the GBR, with surface expressions extending over several hundreds of kilometers. The two southernmost subregions Mackay and Fitzroy accounted for the most (70%) bloom events. The bloom timing of Trichodesmium varied from May in the north to November in the south, with wet season conditions less favorable to Trichodesmium aggregations. MODIS-Aqua Sea Surface Temperature (SST) datasets, wind speed and field measurements of nutrient concentrations were used in combination with MCI positive instances to assess the blooms' driving factors. Low wind speed ( 24°C were associated with the largest surface aggregations. Generalized additive models (GAM) indicated an increase in bloom occurrences over the 10-year period with seasonal bloom patterns regionally distinct. Interannual variability in SST partially (14%) explained bloom occurrences, and other drivers, such as the subregion and the nutrient budget, likely regulate Trichodesmium surface aggregations in the GBR.

Background: Biopharmaceutical medicines represent a growing share of the global pharmaceutical market, and with many of these biopharmaceutical products facing loss of exclusivity rights, also biosimilars may now enter the biopharmaceutical market.Objectives: This study aims to identify and document which investment and development strategies are adopted by industrial players in the global biopharmaceutical market.Methods: A descriptive analysis was undertaken of the investment and development strategies of the top 25 pharmaceutical companies according to 2015 worldwide prescription drug sales. Strategies were documented by collecting data on manufacturing plans, development programs, acquisition and collaboration agreements, the portfolio and pipeline of biosimilar, originator and next-generation biopharmaceutical products. Data were extracted from publicly available sources.Results: Various investment and development strategies can be identified in the global biopharmaceutical market: (a) development of originator biopharmaceuticals, (b) investment in biotechnology, (c) development of next-generation biopharmaceuticals, (d) development of biosimilars, (e) investment in emerging countries, and (f) collaboration between companies. In the top 25 pharmaceutical companies almost every company invests in originator biopharmaceuticals and in biotechnology in general, but only half of them develops next-generation biopharmaceuticals. Furthermore, only half of them invest in development of biosimilars. The companies' biosimilar pipeline is mainly focused on development of biosimilar monoclonal antibodies and to some extent on biosimilar insulins. A common strategy is collaboration between companies and investment in emerging countries.Conclusions: A snapshot of investment and development strategies used by industrial players in the global biopharmaceutical market shows that all top 25 pharmaceutical companies are engaged in the biopharmaceutical market and that this industrial landscape is diverse. Companies do not focus on a single strategy, but are involved in multiple investment and development strategies. A common strategy to market biopharmaceuticals is collaboration between companies. These collaborations can as well be used to gain access in regions the company has less experience with. With patents expiring for some of the highest selling monoclonal antibodies, this snapshot highlights the interest of companies to invest in the development of these molecules and/or enter into collaborations to create access to these molecules.

Introduction: Introducing biosimilar infliximab for the treatment in rheumatology (rheumatoid arthritis and ankylosing spondylitis) and inflammatory bowel disease (Crohn's disease and ulcerative colitis) may reduce treatment costs associated with biologics. This study aimed to investigate the budget impact of adopting biosimilar infliximab in five European countries, considering that the budget impact includes the adoption of biosimilar infliximab and the availability of biologic alternatives such as vedolizumab, biosimilar etanercept, biosimilar rituximab, and other relevant factors.Methods: An existing budget impact model was adapted to forecast the budget impact in the UK, Germany, France, Spain, and Italy. Epidemiological parameters were derived from published literature reviewed in July 2015. Current market shares of biologics were derived from Therapy Watch (2012/2013 data). Respondents in a Delphi panel, conducted in 2015 and consisting of several leading rheumatologists and gastroenterologists from different nationalities, were asked to forecast uptake of biosimilar infliximab and estimate the proportion of patients eligible for a particular type of biological treatment, including biosimilar infliximab. Scenario analyses assessed the influence of various factors, including price reductions, on the budget.Results: Uptake of biosimilar infliximab was particularly expected for naïve patients; switching patients that already received other biologics was not expected much. Market shares after 5 years of biosimilar infliximab were ~2% in rheumatology in all five countries and in gastroenterology ranged from 4% in France to over 30% in Italy. Except for France, budgets were expected to decrease for rheumatologic diseases. For gastroenterology, budgets were expected to decrease in Spain and Italy. Budgets were expected to increase substantially in the UK and Germany, due to the introduction of vedolizumab in the studied period. In France, budget was expected to slightly increase for ankylosing spondylitis, Crohn's Disease, and ulcerative collitis. Savings in budget were expected in all countries, for all diseases, when larger price discounts on biosimilar infliximab were used.Discussion and Conclusion: This study has shown that only when price reductions are large enough (i.e., 50% or more), physicians indicated that they will prescribe biosimilars. Policy makers should ensure substantial price reductions and stimulate physicians to use biosimilar products, to obtain savings in healthcare budgets.

This study used a reef-up approach to map coral reef benthos, substrates and bathymetry, with high spatial resolution hyperspectral image data. It investigated a physics-based inversion method for mapping coral reef benthos and substrates using readily available software: Hydrolight and ENVI. Compact Airborne Spectrographic Imager (CASI) data were acquired over Heron Reef in July 2002. The spectral reflectance of coral reef benthos and substrate types were measured in-situ, and using the HydroLight 4.2 radiative transfer model a spectral reflectance library of subsurface reflectance was simulated using water column depths from 0.5–10.0 m at 0.5 m intervals. Using the Spectral Angle Mapper algorithm, sediment, benthic micro-algae, algal turf, crustose coralline algae, macro-algae, and live coral were mapped with an overall accuracy of 65% to a depth of around 8.0 m; in waters deeper than 8.0 m the match between the classified image and field validation data was poor. Qualitative validation of the maps showed accurate mapping of areas dominated by sediment, benthic micro-algae, algal turf, live coral, and macro-algae. A bathymetric map was produced for water column depths 0.5–10.0 m, at 0.5 m intervals, and showed high correspondence with in-situ sonar data (R2 value of 0.93).

The spatial and temporal variability of phytoplankton blooms was investigated in two tropical coastal regions of northern Australia using the MEdium Resolution Imaging Spectrometer (MERIS) full mission (2002–2012) reduced resolution dataset. Satellite-derived proxies for phytoplankton (Chlorophyll-a (Chl), Fluorescence Line Height (FLH), Maximum Chlorophyll Index (MCI)) and suspended sediment (Total Suspended Matter (TSM)) were jointly analyzed for two clusters of the Great Barrier Reef Wet tropics (GBRW; 15°–19.5°S; Queensland) and the Van Diemen Gulf (VDG; 9°–13°S; Northern Territory). The analysis of time-series and Hovmöller diagrams of the four MERIS products provided a unique perspective on the processes linking phytoplankton blooms and river runoff, or resuspension, across spatio-temporal scales. Both regions are characterized by a complex oceanography and seasonal inflows of sediment, freshwater and nutrients during the tropical wet season months (November to April). The GBRW is characterized by a great variability in water clarity (Secchi depth 0–25 m). A long history of agricultural land use has led to a large increase in the seasonal discharge of sediments and nutrients, triggering seasonal phytoplankton blooms (>0.4 mg∙m−3) between January and April. In contrast, the VDG is a poorly flushed, turbid (Secchi depth 1.0 mg∙m−3) than in the GBRW, occurring up to twice a year between January and April. Over the 10-year MERIS mission, a weak decline in Chl and TSM was observed for the VDG (Sen slope: −2.85%/decade, τ = −0.32 and −3.57%/decade, τ = −0.24; p 0.05), while no significant trend in those two satellite products was observed in the GBRW. Cyanobacteria surface algal blooms occur in both regions between August and October. The MCI and FLH products were found to adequately complement Chl, while TSM provided relevant insight for the assessment of sediment resuspension and river runoff.

Deprescribing is the general practice fashion accessory that no prescriber can be seen without. However, it is in danger of becoming a “fig leaf” substitute for the entire medication review suite.

Background: It has been shown that a bout of jumping exercise with weighted vests increases the subsequent countermovement jump height. However, it is not clear whether the improvement in jump height is due to the enhancement of joint power or due to other mechanisms such as neural adaptations. Methods: To investigate this dichotomy, we tested the acute neuromechanical changes following a preloaded exercise protocol (3 sets of 5 consecutive CMJs with a weighed vest equal to 15% of the body mass of the participant) that successfully increased the subsequent jump height. On average, jump height increased 1.52 cm (5.40%) after this exercise as compared to CMJs prior to the exercise protocol. Results: A significant decrease in the time from the start of the movement to take off (pre-take off duration) was observed. This decrease was exclusively caused by exercising with a weighted vest, since such a change was not observed in the control sessions in which participants exercised without the weighted vest. Our data showed that jumpers leave the ground with some degrees of knee flexion and upon exercising with weighted vest this amount of flexion increased and hence an increase in the jump height. However, no significant changes in peak values of lower limb joint angle, velocity, moment and power were observed. Conclusion: It is suggested that for designing weighted vest exercise protocols with the aim of increasing jump height, the idea of modifying the timing of the movement should be considered as a cause of the enhancement. This novel idea adds another mechanism for increasing the jump height following weighted vest exercise, along with the general belief of muscle potentiation.

Across European countries, differences exist in biosimilar policies, leading to variations in uptake of biosimilars and divergences in savings all over Europe.The aim of this article is to provide an overview of different initiatives and policies that may influence the uptake of biosimilars in different European countries. Recommendations will be formulated on how to create sustainable uptake.An overview of policies on biosimilars was obtained via a questionnaire, supplemented with relevant articles. Topics were organized in five themes: availability, pricing, reimbursement, demand-side policies, and recommendations to enhance uptake.In all countries studied, biological medicines are available. Restrictions are mainly dependent on local organization of the healthcare system. Countries are willing to include biosimilars for reimbursement, but for commercial reasons they are not always marketed. In two thirds of countries, originator and biosimilar products may be subjected to internal reference pricing systems. Few countries have implemented specific incentives targeting physicians. Several countries are implementing pharmacist substitution; however, the scope and rules governing such substitution tend to vary between these countries. Reported educational policies tend to target primarily physicians, whereas fewer initiatives were reported for patients. Recommendations as proposed by the different country experts ranged from the need for information and communication on biosimilars to competitive pricing, more support for switching and guidance on substitution.Most countries have put in place specific supply-side policies for promoting access to biosimilars. To supplement these measures, we propose that investments should be made to clearly communicate on biosimilars and educate stakeholders. Especially physicians need to be informed on the entry and use of biosimilars in order to create trust. When physicians are well-informed on the treatment options, further incentives should be offered to prescribe biosimilars. Gainsharing can be used as an incentive to prescribe, dispense or use biosimilars. This approach, in combination with binding quota, may support a sustainable biosimilar market.

Members of the Mycobacterium chelonae-abscessus complex represent Mycobacterium species that cause invasive infections in immunocompetent and immunocompromised hosts. We report the detection of a new pathogen that had been misidentified as M. chelonae with an atypical antimicrobial drug susceptibility profile. The discovery prompted a multicenter investigation of 26 patients. Almost all patients were from the northeastern United States, and most had underlying sinus or pulmonary disease. Infected patients had clinical features similar to those with M. abscessus infections. Taxonomically, the new pathogen shared molecular identity with members of the M. chelonae-abscessus complex. Multilocus DNA target sequencing, DNA-DNA hybridization, and deep multilocus sequencing (43 full-length genes) support a new taxon for these microorganisms. Because most isolates originated in Pennsylvania, we propose the name M. franklinii sp. nov. This investigation underscores the need for accurate identification of Mycobacterium spp. to detect new pathogens implicated in human disease.

Novel nontoxigenic Corynebacterium diphtheriae was isolated from a domestic cat with severe otitis. Contact investigation and carrier study of human and animal contacts yielded 3 additional, identical isolates from cats, although no evidence of zoonotic transmission was identified. Molecular methods distinguished the feline isolates from known C. diphtheriae.

Efficient phagocytosis of cells undergoing apoptosis by macrophages is important to prevent immunological responses and development of chronic inflammatory disorders such as systemic lupus erythematosus, cystic fibrosis and atherosclerosis. To study phagocytosis of apoptotic cells (AC) by macrophages in tissue, we validated different apoptosis markers (DNA fragmentation, caspase-3 activation and cleavage of its substrate poly(ADP-ribose)polymerase-1) in combination with macrophage immunostaining. Human tonsils were used as a model because they show a high apoptosis frequency under physiological conditions as well as efficient phagocytosis of AC by macrophages. On the other hand, advanced human atherosclerotic plaques were examined since plaques show severely impaired phagocytosis of AC. Our results demonstrate that the presence of non-phagocytized terminal deoxynucleotidyl transferase end labelling (TUNEL)-positive AC represents a suitable marker of poor phagocytosis by macrophages in situ. Other markers for apoptosis, such as cleavage of caspase-3 or PARP-1, should not be used to assess phagocytosis effi ciency, because activation of the caspase cascade and cleavage of their substrates can occur in AC when they have not yet been phagocytized by macrophages.

Background: The positive effects of ozone therapy have been described in many gastrointestinal disorders. The mechanisms of this positive effect of ozone therapy are poorly understood. The purpose of the present study was to investigate whether the use of ozone may potentiate the gut intestinal mucosal homeostasis in a rat model. Methods: Adult rats weighing 250–280 g were randomly assigned to one of three experimental groups of 8 rats each: 1) Control rats were given 2 mL of water by gavage and intraperitoneally (IP) for 5 days; 2) O3-PO rats were treated with 2 mL of ozone/oxygen mixture by gavage and 2 mL of water IP for 5 days; 3) O3-IP rats were treated with 2 mL of water by gavage and 2 mL of ozone/oxygen mixture IP for 5 days. Rats were sacrificed on day 6. Bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depth, and cell proliferation and apoptosis were evaluated following sacrifice. Results: The group of O3-IP rats demonstrated a greater jejunal and ileal villus height and crypt depth, a greater enterocyte proliferation index in jejunum, and lower enterocyte apoptosis in ileum compared to control animals. Oral administration of the ozone/oxygen mixture resulted in a less significant effect on cell turnover. Conclusions: Treatment with an ozone/oxygen mixture stimulates intestinal cell turnover in a rat model. Intraperitoneal administration of ozone resulted in a more significant intestinal trophic effect than oral administration.