‘Mapping’ health state utility values from non-preference-based measures : a systematic literature review in rare diseases

Background: In rare disease (RD) studies, generic preference-based patient-reported outcome measures (PROMs) that yield health state utility values (HSUVs) are seldom collected, as they are considered not sensitive enough for these small and heterogeneous patient populations. In such cases, a HSUV can also be obtained by ‘mapping’ a more sensitive ‘source’ (e.g., disease-specific PROM) to a ‘target' preference-based measure (e.g., EuroQol-5 Dimension (EQ-5D)) through a statistical relationship. Objective: This study aimed to systematically review all published studies using ‘mapping’ to derive HSUVs from non-preference-based measures in RDs (i.e. affecting fewer than 1 in 2,000 people), and identify any critical issue related to the main features of RDs. Methods: The following databases were searched during the first half of 2019 without time, study design or language restrictions: MEDLINE (via PubMed), the School of Health and Related Research Health Utility Database (ScHARRHUD) and the Health Economics Research Centre (HERC) database of mapping studies (version 7.0). The keywords combined terms related to ‘mapping’ with ORPHANET’s list of RD indications (e.g., ‘acromegaly’), in additional to ‘rare’ and ‘orphan’. ‘Very rare’ diseases (i.e. with less than 1000 cases or families documented in the medical literature) were excluded from the searches. A predefined, pilot-tested extraction template (in Excel®) was used to collect structured information from the studies. Results: Two groups of studies were identified in the review. The first group (n=19) developed novel mapping algorithms in thirteen different RDs. As a target measure, the majority used EQ-5D, and the others the Short-Form Six-Dimension (SF-6D) and 15D; most studies adopted Ordinary Least Squares (OLS) regression. The second group of studies (n=9) applied previously existing algorithms in non-RDs to comparable RDs, mainly in the field of cancer. The critical issues relating to ‘mapping’ in RDs included the availability of very few studies, the relatively high number of cancer studies, and the absence of research in paediatric RDs. Moreover, the reviewed studies recruited small samples, hindering the cross-validation of algorithms and application of more complex regression models, showed a limited overlap between RD-specific and generic PROMs, and highlighted the presence of cultural and linguistic factors influencing results in multi-country studies. Additionally, few studies explicitly referred to published recommendations for mapping. Lastly, the application of existing algorithms in non-RDs was likely to produce inaccuracies at the bottom of the EQ-5D scale, due to the greater severity of RDs. Conclusions: More research is encouraged to develop algorithms for a broader spectrum of RDs (including those affecting young children), improve mapping study quality, test the generalizability of algorithms developed in non-RDs (e.g., HIV) to rare variants or evolutions of the same condition (e.g., AIDS wasting syndrome), and verify the robustness of results when mapped HSUVs are used in cost-utility models

Cognitive therapy for compulsive checking in obsessive-compulsive disorder: A pilot trial

We evaluated a novel, empirically-based cognitive therapy for compulsive checking – a common form of obsessive-compulsive disorder. Twelve adults completed 12 sessions of the therapy. Significant reductions in checking-related symptoms were found pre- to post-treatment, and pre-treatment to 6-month follow-up (moderate to large effect sizes). Participants reported high treatment acceptability after the third session, which was maintained at post-treatment. This pilot trial provides preliminary support for treating compulsive checking using this novel cognitive approach

Electrospray mass spectrometry of NeuAc oligomers associated with the C fragment of the tetanus toxin

The Clostridial neurotoxins, botulinum and tetanus, gain entry into neuronal cells by protein recognition involving cell specific binding sites. The sialic or N-acetylneuraminic acid (NeuAc) residues of gangliosides attached to the surface of motor neurons are the suspected recognition and interaction points with Clostridial neurotoxins, although not necessarily the only ones. We have used electrospray ionization mass spectrometry (ESIMS) to examine formation of complexes between the tetanus toxin C fragment, or targeting domain, and carbohydrates containing NeuAc groups to determine how NeuAc residues contribute to ganglioside binding. ESI-MS was used to rapidly and efficiently measure dissociation constants for a number of related NeuAc-containing carbohydrates and NeuAc oligomers, information that has helped identify the structural features of gangliosides that determine their binding to tetanus toxin. The strength of the interactions between the C fragment and (NeuAc){sub n}, are consistent with the topography of the targeting domain of tetanus toxin and the nature of its carbohydrate binding sites. The results suggest that the targeting domain of tetanus toxin contains two binding sites that can accommodate NeuAc (or a dimer). This study also shows that NeuAc must play an important role in ganglioside binding and molecular recognition, a process critical for normal cell function and one frequently exploited by toxins, bacteria and viruses to facilitate their entrance into cells

Spallation Neutron Production by 0.8, 1.2 and 1.6 GeV Protons on various Targets

Spallation neutron production in proton induced reactions on Al, Fe, Zr, W, Pb and Th targets at 1.2 GeV and on Fe and Pb at 0.8, and 1.6 GeV measured at the SATURNE accelerator in Saclay is reported. The experimental double-differential cross-sections are compared with calculations performed with different intra-nuclear cascade models implemented in high energy transport codes. The broad angular coverage also allowed the determination of average neutron multiplicities above 2 MeV. Deficiencies in some of the models commonly used for applications are pointed out.Comment: 20 pages, 32 figures, revised version, accepted fpr publication in Phys. Rev.

Calorimetric Investigation of Copper Binding in the N-Terminal Region of the Prion Protein at Low Copper Loading: Evidence for an Entropically Favorable First Binding Event

Although the Cu²⁺-binding sites of the prion protein have been well studied when the protein is fully saturated by Cu²⁺, the Cu²⁺-loading mechanism is just beginning to come into view. Because the Cu²⁺-binding modes at low and intermediate Cu²⁺ occupancy necessarily represent the highest-affinity binding modes, these are very likely populated under physiological conditions, and it is thus essential to characterize them in order to understand better the biological function of copper–prion interactions. Besides binding-affinity data, almost no other thermodynamic parameters (e.g., Δ<i>H</i> and Δ<i>S</i>) have been measured, thus leaving undetermined the enthalpic and entropic factors that govern the free energy of Cu²⁺ binding to the prion protein. In this study, isothermal titration calorimetry (ITC) was used to quantify the thermodynamic parameters (<i>K</i>, Δ<i>G</i>, Δ<i>H</i>, and <i>T</i>Δ<i>S</i>) of Cu²⁺ binding to a peptide, PrP­(23–28, 57–98), that encompasses the majority of the residues implicated in Cu²⁺ binding by full-length PrP. Use of the buffer <i>N</i>-(2-acetomido)-aminoethanesulfonic acid (ACES), which is also a well-characterized Cu²⁺ chelator, allowed for the isolation of the two highest affinity binding events. Circular dichroism spectroscopy was used to characterize the different binding modes as a function of added Cu²⁺. The <i>K</i>_d values determined by ITC, 7 and 380 nM, are well in line with those reported by others. The first binding event benefits significantly from a positive entropy, whereas the second binding event is enthalpically driven. The thermodynamic values associated with Cu²⁺ binding by the Aβ peptide, which is implicated in Alzheimer’s disease, bear striking parallels to those found here for the prion protein

When it's at: An examination of when cognitive change occurs during cognitive therapy for compulsive checking in obsessive-compulsive disorder

Abstract Background and objectives The cognitive theory of compulsive checking in OCD proposes that checking behaviour is maintained by maladaptive beliefs, including those related to inflated responsibility and those related to reduced memory confidence. This study examined whether and when specific interventions (as part of a new cognitive therapy for compulsive checking) addressing these cognitive targets changed feelings of responsibility and memory confidence. Methods Participants were nine adults with a primary or secondary diagnosis of OCD who reported significant checking symptoms (at least one hour per day) on the Yale-Brown Obsessive-Compulsive Scale. A single-case multiple baseline design was used, after which participants received 12 sessions of cognitive therapy. From the start of the baseline period through to the 1 month post-treatment follow-up assessment session, participants completed daily monitoring of feelings of responsibility, memory confidence, and their time spent engaging in compulsive checking. Results Results revealed that feelings of responsibility significantly reduced and memory confidence significantly increased from baseline to immediately post-treatment, with very high effect sizes. Multilevel modelling revealed significant linear changes in feelings of responsibility (i.e., reductions over time) and memory confidence (i.e., increases over time) occurred following the sessions when these were addressed. Finally, we found that improvements in these over the course of the treatment significantly predicted reduced time spent checking. Limitations The small sample size limits our ability to generalize our results. Conclusions Results are discussed in terms of a focus on the timing of change in cognitive therapy

Knowledge and competency standards for specialized cognitive behavior therapy for adult obsessive-compulsive disorder

Obsessive-Compulsive Disorder (OCD) is a leading cause of disability world-wide (World Health Organization, 2008). Treatment of OCD is a specialized field whose aim is recovery from illness for as many patients as possible. The evidence-based psychotherapeutic treatment for OCD is specialized cognitive behavior therapy (CBT, NICE, 2005, Koran and Simpson, 2013). However, these treatments are not accessible to many sufferers around the world. Currently available guidelines for care are deemed to be essential but insufficient because of highly variable clinician knowledge and competencies specific to OCD. The phase two mandate of the 14 nation International OCD Accreditation Task Force (ATF) created by the Canadian Institute for Obsessive Compulsive Disorders is development of knowledge and competency standards for specialized treatments for OCD through the lifespan deemed by experts to be foundational to transformative change in this field. This paper presents knowledge and competency standards for specialized CBT for adult OCD developed to inform, advance, and offer a model for clinical practice and training for OCD. During upcoming ATF phases three and four criteria and processes for training in specialized treatments for OCD through the lifespan for certification (individuals) and accreditation (sites) will be developed based on the ATF standards