| 1. |
- Hubert, D., et al.
(author)
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Ground-based assessment of the bias and long-term stability of 14 limb and occultation ozone profile data records
- 2016
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In: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 9:6, s. 2497-2534
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Journal article (peer-reviewed)abstract
- The ozone profile records of a large number of limb and occultation satellite instruments are widely used to address several key questions in ozone research. Further progress in some domains depends on a more detailed understanding of these data sets, especially of their long-term stability and their mutual consistency. To this end, we made a systematic assessment of 14 limb and occultation sounders that, together, provide more than three decades of global ozone profile measurements. In particular, we considered the latest operational Level-2 records by SAGE II, SAGE III, HALOE, UARS MLS, Aura MLS, POAM II, POAM III, OSIRIS, SMR, GOMOS, MIPAS, SCIAMACHY, ACE-FTS and MAESTRO. Central to our work is a consistent and robust analysis of the comparisons against the ground-based ozonesonde and stratospheric ozone lidar networks. It allowed us to investigate, from the troposphere up to the stratopause, the following main aspects of satellite data quality: long-term stability, overall bias and short-term variability, together with their dependence on geophysical parameters and profile representation. In addition, it permitted us to quantify the overall consistency between the ozone profilers. Generally, we found that between 20 and 40km the satellite ozone measurement biases are smaller than ±5%, the short-term variabilities are less than 5-12% and the drifts are at most ±5%decade-1 (or even ±3%decade-1 for a few records). The agreement with ground-based data degrades somewhat towards the stratopause and especially towards the tropopause where natural variability and low ozone abundances impede a more precise analysis. In part of the stratosphere a few records deviate from the preceding general conclusions; we identified biases of 10% and more (POAM II and SCIAMACHY), markedly higher single-profile variability (SMR and SCIAMACHY) and significant long-term drifts (SCIAMACHY, OSIRIS, HALOE and possibly GOMOS and SMR as well). Furthermore, we reflected on the repercussions of our findings for the construction, analysis and interpretation of merged data records. Most notably, the discrepancies between several recent ozone profile trend assessments can be mostly explained by instrumental drift. This clearly demonstrates the need for systematic comprehensive multi-instrument comparison analyses.
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| 2. |
- Auerswald, Guenter, et al.
(author)
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Beyond patient benefit: clinical development in hemophilia
- 2012
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In: Hematology. - 1607-8454. ; 17:1, s. 1-8
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Research review (peer-reviewed)abstract
- Historically in hemophilia, outcome measures have not been collected systematically. Hence, there are insufficient clearly defined, evidence-based measures that can be applied consistently across hemophilia trials. This review focuses on some key challenges to evaluating patient outcomes and performing trials identified by experts at the Fourth and Fifth Zurich Haemophilia Forums. As procedures appear inconsistent across Europe, guidelines require modification to be more appropriate and/or realistically achievable. The outcome measures utilized, and the timing of their collection, should also be standardized, and more objective measures used where feasible. Implementation of outcome measures could be refined through greater understanding of patient heterogeneity, and tailored to differentiate between hemophilia- and aging-related disease effects. Furthermore, robust outcome measures that can also inform health-economic decisions are increasingly needed. Lastly, as patient recruitment poses a challenge, the panel proposed a call for action to motivate physicians and patients to participate in clinical trials.
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| 3. |
- Auerswald, Günter, et al.
(author)
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Pain and pain management in haemophilia
- 2016
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In: Blood Coagulation and Fibrinolysis. - 0957-5235. ; 27:8, s. 845-854
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Research review (peer-reviewed)abstract
- Joint pain is common in haemophilia and may be acute or chronic. Effective pain management in haemophilia is essential to reduce the burden that pain imposes on patients. However, the choice of appropriate pain-relieving measures is challenging, as there is a complex interplay of factors affecting pain perception. This can manifest as differences in patients’ experiences and response to pain, which require an individualized approach to pain management. Prophylaxis with factor replacement reduces the likelihood of bleeds and bleed-related pain, whereas on-demand therapy ensures rapid bleed resolution and pain relief. Although use of replacement or bypassing therapy is often the first intervention for pain, additional pain relief strategies may be required. There is an array of analgesic options, but consideration should be paid to the adverse effects of each class. Nevertheless, a combination of medications that act at different points in the pain pathway may be beneficial. Nonpharmacological measures may also help patients and include active coping strategies; rest, ice, compression, and elevation; complementary therapies; and physiotherapy. Joint aspiration may also reduce acute joint pain, and joint steroid injections may alleviate chronic pain. In the longer term, increasing use of prophylaxis or performing surgery may be necessary to reduce the burden of pain caused by the degenerative effects of repeated bleeds. Whichever treatment option is chosen, it is important to monitor pain and adjust patient management accordingly. Beyond specific pain management approaches, ongoing collaboration between multidisciplinary teams, which should include physiotherapists and pain specialists, may improve outcomes for patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0
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| 4. |
- Benson, Gary, et al.
(author)
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Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice.
- 2012
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In: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 88:5, s. 371-379
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Journal article (peer-reviewed)abstract
- For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to Factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda Units, and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For hemophilia B patients, there may be a benefit to genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥5 Bethesda Units) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications. © 2012 John Wiley & Sons A/S.
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| 5. |
- Cayuela, Hugo, et al.
(author)
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Thermal conditions predict intraspecific variation in senescence rate in frogs and toads
- 2024
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:49
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Journal article (peer-reviewed)abstract
- Variation in temperature is known to influence mortality patterns in ectotherms. Even though a few experimental studies on model organisms have reported a positive relationship between temperature and actuarial senescence (i.e., the increase in mortality risk with age), how variation in climate influences the senescence rate across the range of a species is still poorly understood in free-ranging animals. We filled this knowledge gap by investigating the relationships linking senescence rate, adult lifespan, and climatic conditions using long-term capture–recapture data from multiple amphibian populations. We considered two pairs of related anuran species from the Ranidae (Rana luteiventris and Rana temporaria) and Bufonidae (Anaxyrus boreas and Bufo bufo) families, which diverged more than 100 Mya and are broadly distributed in North America and Europe. Senescence rates were positively associated with mean annual temperature in all species. In addition, lifespan was negatively correlated with mean annual temperature in all species except A. boreas. In both R. luteiventris and A. boreas, mean annual precipitation and human environmental footprint both had negligible effects on senescence rates or lifespans. Overall, our findings demonstrate the critical influence of thermal conditions on mortality patterns across anuran species from temperate regions. In the current context of further global temperature increases predicted by Intergovernmental Panel on Climate Change scenarios, a widespread acceleration of aging in amphibians is expected to occur in the decades to come, which might threaten even more seriously the viability of populations and exacerbate global decline.
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| 6. |
- Dolan, Gerry, et al.
(author)
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Haemophilia B : Where are we now and what does the future hold?
- 2018
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In: Blood Reviews. - : Elsevier BV. - 0268-960X. ; 32:1, s. 52-60
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Research review (peer-reviewed)abstract
- Research has been lacking on the natural history, complications, and treatment of haemophilia B, which is less common than haemophilia A and was recognized as a distinct clinical entity in 1947. Although the two diseases share the same clinical manifestations, they differ in causative mutation, risk of inhibitor development, and patient quality of life. Frequently debated is whether haemophilia B is as clinically severe as haemophilia A, with much of the published data on overall and haemophilia-specific health outcomes suggesting that haemophilia B may have a less severe clinical phenotype. However, although fewer haemophilia B than haemophilia A patients appear to experience bleeding, bleeds are just as severe. We review distinguishing characteristics of haemophilia B and its treatment, including management strategies for neonates, therapeutic approaches for patients who develop inhibitors, pharmacokinetics of factor IX concentrates administered as replacement therapy, and potential future treatments.
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| 7. |
- Hermans, Cedric, et al.
(author)
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Outcome measures for adult and pediatric hemophilia patients with inhibitors
- 2017
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In: European Journal of Haematology. - : Wiley. - 0902-4441. ; 99:2, s. 103-111
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Research review (peer-reviewed)abstract
- Recent advancements in almost all aspects of hemophilia treatment have vastly improved patient care and management, and new and emerging treatments hold the promise of further progress. However, there remains a scarcity of data on long-term outcomes in hemophilia, particularly among those patients with inhibitors, for whom no validated outcome assessment tools are currently available. At the 15th Zürich Haemophilia Forum, an expert panel reviewed the most important outcome measures in inhibitor patients and considered the challenges associated with assessing outcomes in this population. A framework for outcome assessment in inhibitor patients incorporates traditional hemophilia outcome measures, such as bleed frequency and mortality, alongside measures of health, functioning, disability, social participation, quality of life, and economic considerations. It is important to remember that inhibitor patients differ in their clinical needs, perspectives, and priorities according to age, inhibitor status, degree of joint disease, and activity levels; as a result, the relative importance of different outcome measures will change throughout an inhibitor patient's life. Challenges inherent in measuring long-term outcomes in inhibitor patients include the small number of known patients, the subjective nature of many outcome assessment tools, and the risk of overburdening patients with repeated requests to complete questionnaires or participate in studies. Therefore, there is an urgent need to reach consensus on the most important and appropriate assessment tools for measuring outcomes in this population. These tools should ideally be standardized, easily applied, and internationally applicable in order to collect and generate quality outcome data.
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| 8. |
- Jiménez-Yuste, Victor, et al.
(author)
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Practical considerations for nonfactor-replacement therapies in the treatment of haemophilia with inhibitors
- 2021
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In: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 27:3, s. 340-350
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Research review (peer-reviewed)abstract
- New therapeutic agents for haemophilia with inhibitors that are in development or already licensed are expected to provide transformative treatment options. Many of these new therapies are not based on simply replacing the missing factor; new strategies include bispecific antibody technology that mimics factor VIII coagulation function (emicizumab), and inhibition of anticoagulant proteins such as tissue factor pathway inhibitor (eg PF-06741086) and antithrombin (eg fitusiran). These agents are administered subcutaneously and should significantly reduce treatment burden and increase the ability to deliver prophylaxis for patients. Limited real-world data and validated practical guidance on these recently licensed/upcoming treatments resulted in the authors convening to discuss recommendations on their use. Emicizumab is currently the only licenced nonfactor therapy; thus, our recommendations focus on this product. Target candidates for emicizumab prophylaxis are difficult-to-treat patients with haemophilia A and inhibitors and/or venous access issues, frequent bleeds and target joints. In case of breakthrough bleeding while receiving emicizumab, patients still require treatment with bypassing agents; the adjunct treatment of choice is recombinant activated factor VII. This treatment is also recommended to prevent bleeds in patients with inhibitors undergoing surgery. Our recommendations on suitable laboratory assays and monitoring new products, as well as the benefit of patient-reported outcomes (such as pain and physical activity levels), are included. We also briefly discuss future treatment options for patients with haemophilia B and inhibitors. Although these nonfactor treatments offer great promise, further data and real-world evidence are needed.
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| 9. |
- Lambert, Thierry, et al.
(author)
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Joint disease, the hallmark of haemophilia: What issues and challenges remain despite the development of effective therapies?
- 2014
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In: Thrombosis Research. - : Elsevier BV. - 1879-2472 .- 0049-3848. ; 133:6, s. 967-971
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Research review (peer-reviewed)abstract
- Although effective therapies for haemophilia have been available for decades, the prevention and treatment of joint disease remain major clinical concerns for all haemophilia patients. Early identification of joint disease is vital to initiate or modify treatment, and prevent arthropathy. However, there remains a need for more sensitive and accurate methods, which may also detect improvement in patient outcome with new therapies or different prophylaxis regimens. These topics were explored at the Ninth Zürich Haemophilia Forum. A summary of our shared views on the limitations of current assessment methods, and the potential advantages of more recently developed tools, is provided. Ultrasonography enables more frequent routine monitoring and the early detection of joint disease. In addition, serological markers may provide suitable biomarkers of early arthropathy. To prevent arthropathy, in our opinion, prophylaxis is key to prevent joint bleeds and subsequent initiation of the 'vicious circle of joint disease'. However, issues remain, including when prophylaxis should be started, stopped, and if it is efficacious for inhibitor patients. Once joint bleeding has occurred, enhanced on-demand treatment should be considered. For more advanced stages of joint disease, the issues regarding the treatment options available are explored. Radiosynovectomy should be performed to treat chronic synovitis, and may prevent the need for elective orthopaedic surgery (EOS). Ultimately, however, EOS can be considered once all other treatment options have been explored. While, bypassing agents have facilitated the use of EOS in inhibitor patients, a multidisciplinary approach and careful surveillance is required for good patient outcome.
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| 10. |
- Lambert, Thierry, et al.
(author)
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Practical aspects of extended half-life products for the treatment of haemophilia
- 2018
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In: Therapeutic advances in hematology. - : SAGE Publications. - 2040-6207 .- 2040-6215. ; 9:9, s. 295-308
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Research review (peer-reviewed)abstract
- Haemophilia A and haemophilia B are congenital X-linked bleeding disorders caused by deficiency of coagulation factor VIII (FVIII) and IX (FIX), respectively. The preferred treatment option for patients with haemophilia is replacement therapy. For patients with severe disease, prophylactic replacement of coagulation factor is the treatment of choice; this has been shown to reduce arthropathy significantly, reduce the frequency of bleeds and improve patients' quality of life. Prophylaxis with standard recombinant factor requires regular intravenous infusion at least two (FIX) to three (FVIII) times a week. Recombinant FVIII and FIX products with an extended half-life are in development, or have been recently licensed. With reported mean half-life extensions of 1.5-1.8 times that of standard products for FVIII and 3-5 times that of standard products for FIX, these products have the potential to address many of the unmet needs of patients currently treated with standard factor concentrates. For example, they may encourage patients to switch from on-demand treatment to prophylaxis and improve the quality of life of patients receiving prophylaxis. Indeed, extended half-life products have the potential to reduce the burden of frequent intravenous injections, reducing the need for central venous lines in children, promote adherence, improve outcomes, potentially allow for more active lifestyles and, depending on the dosing regimen, increase factor trough levels. Members of the Zürich Haemophilia Forum convened for their 19th meeting to discuss the practicalities of incorporating new treatments into the management of people with haemophilia. This review of extended half-life products considers their introduction in haemophilia treatment, including the appropriate dose and schedule of infusions, laboratory monitoring, patient selection, safety considerations, and the economic aspects of care.
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