Inger Natvig Norderhaug

The B-cell system of human mucosae and exocrine glands.

Summary: The mucosae and exocrine glands harbour the largest activated B‐cell system of the body, amounting to some 80–90% of all immunoglobulins (Ig)‐producing cells. The major product of these immunocytes is polymeric (p)IgA (mainly dimers) with associated J chain. Both pIgA and pentameric IgM contain a binding site for the polymeric Ig receptor (pIgR), or secretory component (SC), which is a requirement for their active external transport through secretory epithelia. The pIgR/SC binding site depends on covalent incorporation of the J chain into the quaternary structure of the polymers when they are produced by the local immunocytes. This important differentiation characteristic appears to be sufficient functional justification for the J chain to be expressed also by most B cells terminating at secretory effector sites with IgD or IgG production; they probably represent a ‘spin‐off’ from sequential downstream CH switching on its way to pIgA expression, thus apparently reflecting a maturational stage of effector B‐cell clones compatible with homing to these sites. Observations in IgA‐deficient individuals suggest that the magnitude of this homing is fairly well maintained even when the differentiation pathway to IgA is blocked. Certain microenvironmental elements such as specific cytokines and dendritic cells appear to be required for induction of IgA synthesis, but it remains virtually unknown why this isotype normally is such a dominating product of local immunocytes and why they have such a high level of J chain expression. Also, despite the recent identification of some important requirements in terms of adhesion molecules (e.g. integrin α4β7 and MAdCAM‐1) that explain the “gut‐seeking” properties of enterically induced B cells, the origin of regionalized homing of B cells to secretory effector sites outside the gut remains elusive. Moreover, little is known about immune regulation underlying the striking disparity of both the class (IgD, IgM) and subclass (IgA1, IgA2, IgGI, IgG2) production patterns shown by local iinmttnocytes in various regions of the body, although the topical microbiota and other environmental stimuli might be important. Rational design of local vaccines will depend on better knowledge of both inductive and migratory properties of human mucosal B cells.

Rapid reviews versus full systematic reviews: An inventory of current methods and practice in health technology assessment

OBJECTIVES This review assessed current practice in the preparation of rapid reviews by health technology assessment (HTA) organizations, both internationally and in the Australian context, and evaluated the available peer-reviewed literature pertaining to the methodology used in the preparation of these reviews. METHODS A survey tool was developed and distributed to a total of fifty International Network of Agencies for Health Technology Assessment (INAHTA) members and other selected HTA organizations. Data on a broad range of themes related to the conduct of rapid reviews were collated, discussed narratively, and subjected to simple statistical analysis where appropriate. Systematic searches of the Cochrane Library, EMBASE, MEDLINE, and the Australian Medical Index were undertaken in March 2007 to identify literature pertaining to rapid review methodology. Comparative studies, guidelines, program evaluations, methods studies, commentaries, and surveys were considered for inclusion. RESULTS Twenty-three surveys were returned (46 percent), with eighteen agencies reporting on thirty-six rapid review products. Axiomatic trends were identified, but there was little cohesion between organizations regarding the contents, methods, and definition of a rapid review. The twelve studies identified by the systematic literature search did not specifically address the methodology underpinning rapid review; rather, many highlighted the complexity of the area. Authors suggested restricted research questions and truncated search strategies as methods to limit the time taken to complete a review. CONCLUSIONS Rather than developing a formalized methodology by which to conduct rapid reviews, agencies should work toward increasing the transparency of the methods used for each review. It is perhaps the appropriate use, not the appropriate methodology, of a rapid review that requires future consideration.

The HTA Core Model: A novel method for producing and reporting health technology assessments

OBJECTIVES The aim of this study was to develop and test a generic framework to enable international collaboration for producing and sharing results of health technology assessments (HTAs). METHODS Ten international teams constructed the HTA Core Model, dividing information contained in a comprehensive HTA into standardized pieces, the assessment elements. Each element contains a generic issue that is translated into practical research questions while performing an assessment. Elements were described in detail in element cards. Two pilot assessments, designated as Core HTAs were also produced. The Model and Core HTAs were both validated. Guidance on the use of the HTA Core Model was compiled into a Handbook. RESULTS The HTA Core Model considers health technologies through nine domains. Two applications of the Model were developed, one for medical and surgical interventions and another for diagnostic technologies. Two Core HTAs were produced in parallel with developing the model, providing the first real-life testing of the Model and input for further development. The results of formal validation and public feedback were primarily positive. Development needs were also identified and considered. An online Handbook is available. CONCLUSIONS The HTA Core Model is a novel approach to HTA. It enables effective international production and sharing of HTA results in a structured format. The face validity of the Model was confirmed during the project, but further testing and refining are needed to ensure optimal usefulness and user-friendliness. Core HTAs are intended to serve as a basis for local HTA reports. Core HTAs do not contain recommendations on technology use.

Rapid versus full systematic reviews: Validity in clinical practice?

Introduction:  Rapid reviews are being produced with greater frequency by health technology assessment (HTA) agencies in response to increased pressure from end‐user clinicians and policy‐makers for rapid, evidence‐based advice on health‐care technologies. This comparative study examines the differences in methodologies and essential conclusions between rapid and full reviews on the same topic, with the aim of determining the validity of rapid reviews in the clinical context and making recommendations for their future application.

Brachytherapy for prostate cancer: a systematic review of clinical and cost effectiveness.

OBJECTIVES Brachytherapy is emerging as a new treatment option for prostate cancer, and is increasingly being used in Europe and North America. METHODS A systematic review of studies that compared clinical or cost effectiveness of prostate brachytherapy with radical prostatectomy or external beam radiation for patients with localised prostate cancer. RESULTS No randomised controlled trials were identified, but five observational studies with comparable patient groups were included in the review. There were no valid data on overall or disease-free survival. There was no difference in disease-free survival based on PSA as a surrogate measure, or in rates of complications. No cost effectiveness studies were found. Based on Norwegian data, the one-year cost of the three treatment options seem fairly similar, while long term cost data are lacking due to lack of data on long term clinical outcome. CONCLUSION The evidence on the clinical effectiveness of therapies for localised prostate cancer is scarce, but the outcome appears to be comparable for radical prostatectomy, external beam radiotherapy and brachytherapy.

Recombinant expression of polymeric IgA: incorporation of J chain and secretory component of human origin

Mucosal J (joining) chain‐expressing IgA immunocytes produce dimeric IgA that is actively transported by the epithelial polymeric Ig receptor (pIgR) to exocrine secretions. Release of secretory IgA (SIgA) occurs by cleavage of the covalently linked pIgR ectodomain, also known as bound secretory component. We have identified the human J‐chain cDNA sequence through database screening, and isolated it from B cells for recombinant expression. Co‐expression of this cDNA with an α heavy chain and a λ light chain in Chinese hamster ovary (CHO) cells resulted in a mixture of recombinant monomeric and dimeric IgA in culture supernatants. This dimeric IgA was transported by the pIgR‐mediated mechanism in vitro. Furthermore, expression of the human pIgR ectodomain together with the dimeric IgA, resulted in production of complete SlgA by the CHO cells. These results demonstrated that co‐expression of the necessary polypeptide components allows a single mammalian cell to produce SlgA. Development of production systems for human antigen‐specific recombinant SIgA may be important for applications in passive mucosal vaccination.

Domain deletions in the human polymeric Ig receptor disclose differences between its dimeric IgA and pentameric IgM interaction.

The human polymeric Ig receptor (pIgR), or transmembrane secretory component, is basolaterally expressed on secretory epithelial cells; its function is to transport externally J chain‐containing dimeric IgA and pentameric IgM. The ligand‐binding extracellular part of this receptor contains five disulfide‐stabilized domains which show considerable homology with the variable domains of Ig chains. The N‐terminal domain 1 (D1) mediates the initial noncovalent ligand interaction. In this study we made deletions of the human pIgR D2 and D3 (pIgRΔ2,3), or D4 and D5 (pIgRΔ4,5), to investigate the influence of these domains in receptor binding and transport of dimeric IgA and pentameric IgM across MDCK cells transfected with the truncated receptors. Both mutants were found to bind pentameric IgM, but only pIgRΔ4,5 bound dimeric IgA. These results showed that the two ligands interact differently with human pIgR; binding of pentameric IgM apparently depends fully on strong interactions with D1, while binding of dimeric IgA in addition depends on elements within D2 and / or D3 to support the initial noncovalent binding to D1. Moreover, our studies imply that dimeric human IgA binds differently to pIgR from various species. This observation cautions against interpretation of functional studies performed with non‐homologous receptor‐ligand pairs.

Curative ablation for atrial fibrillation: a systematic review.

Objective. To perform a systematic review of randomized controlled trials (RCTs) on catheter ablation for atrial fibrillation (AF). Background. Radiofrequency catheter (RF)-ablation around pulmonary vein ostia and in left atrium may reduce or prevent recurrence of AF, as documented in observational studies and registry reports; however, few RCTs are available. Methods. Using relevant search phrases, Cochrane Library, MEDLINE and EMBASE were searched for RCTs, last time in May 2007. Titles and abstracts were screened. When entry criteria were fulfilled, full-text papers were read and graded according to quality and relevance. Results. One thousand and ninety four abstracts were evaluated, and five RCTs included (578 randomized patients). The studies had moderate quality and relevance, but the results were consistent: ablation is better than drug treatment in preventing AF recurrence; the relative risk (95% CI)) one year after ablation ranged from 0.20 (0.08–0.51) to 0.62 (0.39–0.99). Conclusions. Results from observational and registry studies are confirmed: RF-ablation reduces recurrence rate of AF, and can be done with few serious complications. Limitations are few patients >70 years, and only one year follow-up.

Early identification and assessment of new and emerging health technologies : Actions, progress, and the future direction of an international collaboration-EuroScan

OBJECTIVES To report on a workshop, and subsequent discussions, that reviewed the achievements and progress of the EuroScan collaboration since its establishment in 1999 to share information on the methods and results of early identification and assessment of new and emerging health technologies; considered challenges to the collaboration; and discussed its possible future direction. METHODS A workshop was held in Stockholm in September 2006, with thirty-two participants from ten countries and representatives from EuroScan member agencies, policy makers involved in policy or decision making relating to new technologies, and invited external commentators from international HTA networks. The workshop used a mix of presentations, panel and audience discussions, and small group work to consider the achievements and challenges put forward. RESULTS EuroScan has developed as a sustainable network, and has made progress on all tasks in its initial action plan, with the EuroScan information sharing database on new and emerging technologies being one of the collaborations key achievements. Identified immediate concerns for the network included consideration of the impact of its current name and membership model; acknowledgement and publication of the full range of benefits of membership; contribution to and development of the database to encourage increased information sharing; and EuroScans ongoing interaction with the wider HTA world. CONCLUSIONS The workshop was a useful mechanism for reviewing the work of EuroScan and for creating a platform to take the collaboration forward. The workshop affirmed the benefits of the network to individual members; posed some significant challenges to the network to consider; and acted as a stimulus for an interim name change to better represent the global membership, and a major review of the EuroScan database of identified and assessed emerging health technologies.

Health technology assessment and implications for clinical practice: the case of prostate cancer screening

We describe an initiative to disseminate evidence from systematic reviews about the clinical effectiveness of prostate cancer screening to general practitioners and urologists in Norway. The Norwegian Centre for Health Technology Assessment invited The Norwegian Medical Association, The Norwegian Cancer Society, The Norwegian Board of Health, The Norwegian Urological Cancer Group and The Norwegian Patient Association to develop and disseminate clinical practice recommendations. The clinical effectiveness of prostate cancer screening has been assessed in nine independent systematic reviews, which are summarized in a joint INAHTA report. The conclusion was that there is no evidence from appropriately designed trials that early detection and treatment of prostate cancer can reduce mortality, morbidity or improve quality of life. The number of prostate‐specific antigen (PSA) tests analysed in Norway increased by 30% from 1996 to 1999; at the county level the increase ranged from 12 to 48%. On this background we disseminated leaflets with information about PSA and prostate cancer to 4100 general practitioners and specialists in urology. The main message was, i) PSA should not be taken in healthy men, ii) if the test is wanted, the physician is obliged to give information about the possible consequences. Despite efforts to anchor the information campaign within the mentioned organizations, this met with notable opposition from The Norwegian Urological Society. A survey among agencies within the INAHTA network showed that more than half of the countries within this collaboration have implemented guidelines or recommendations on prostate cancer screening. In conclusion, evidence obtained through an international collaboration such as the INAHTA collaboration may be used to develop and implement national guidelines or recommendations.