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Executive SummaryThe EC Directive 2013/59/Euratom states in article 56 that exposures of target volumes in nuclear medicine treatments shall be individually planned and their delivery appropriately verified. The Directive also mentions that medical physics experts should always be appropriately involved in those treatments. Although it is obvious that, in nuclear medicine practice, every nuclear medicine physician and physicist should follow national rules and legislation, the EANM considered it necessary to provide guidance on how to interpret the Directive statements for nuclear medicine treatments.For this purpose, the EANM proposes to distinguish three levels in compliance to the optimization principle in the directive, inspired by the indication of levels in prescribing, recording and reporting of absorbed doses after radiotherapy defined by the International Commission on Radiation Units and Measurements (ICRU): Most nuclear medicine treatments currently applied in Europe are standardized. The minimum requirement for those treatments is ICRU level 1 (“activity-based prescription and patient-averaged dosimetry”), which is defined by administering the activity within 10% of the intended activity, typically according to the package insert or to the respective EANM guidelines, followed by verification of the therapy delivery, if applicable. Non-standardized treatments are essentially those in developmental phase or approved radiopharmaceuticals being used off-label with significantly (> 25% more than in the label) higher activities. These treatments should comply with ICRU level 2 (“activity-based prescription and patient-specific dosimetry”), which implies recording and reporting of the absorbed dose to organs at risk and optionally the absorbed dose to treatment regions. The EANM strongly encourages to foster research that eventually leads to treatment planning according to ICRU level 3 (“dosimetry-guided patient-specific prescription and verification”), whenever possible and relevant. Evidence for superiority of therapy prescription on basis of patient-specific dosimetry has not been obtained. However, the authors believe that a better understanding of therapy dosimetry, i.e. how much and where the energy is delivered, and radiobiology, i.e. radiation-related processes in tissues, are keys to the long-term improvement of our treatments.

As part of an International Agency for Research on Cancer (IARC) international epidemiological study of workers in the pulp and paper industry, previously unpublished exposure measurements were assembled in a database. This article summarizes the results of 3,873 measurements carried out in the production departments of paper and paperboard mills and recycling plants in 12 countries. In the paper and paperboard mills, most of the agents were measured in the pulping and refining departments and in on-machine coating and winding of paper/paperboard. Exposures to asbestos, carbon monoxide, formaldehyde, fungal spores, bacteria, nitrogen dioxide, minerals dusts, paper dust, sulphuric acid and different solvents sometimes exceeded exposure limit values. In the re-pulping and de-inking departments of recycling plants high exposures to formaldehyde, fungal spores, bacteria and paper dust were observed. High exposures to asbestos, bioaerosols, carbon monoxide and paper dust were found in many departments; ammonia, formaldehyde, mineral and paper dust and solvents were found in coating machines; and diphenyl and polychlorobiphenyls (PCBs) were found in some special circumstances. Measurements in the newsprint and uncoated paper machine departments revealed only a few elevated exposures. In nearly all departments, measurements of epichlorohydrin, PCBs, sulphur dioxide, hydrogen sulphide and mercaptans tended to be low, often even below their detection limits. In spite of some uncertainties in the measurement data, the study provides new insights into the level and variation of occupational exposures of production workers in the paper and paperboard industry. © Springer-Verlag 2004.

The Papers Presented at the Annual Meetings of the Knee Society Symposium includes selected papers read at the 2007 Annual Interim Meeting of the Knee Society held in Sienna, Italy in September 2007, and the 2008 Open Scientific Meeting of the Knee Society, held in San Francisco in March 2008. The wide range and high quality of the scientific material presented here is a credit to the excellent work of the Knee Society education committee and particularly to its Program Chair, Gil Scuderi, MD. Each of these papers is focused, concise and highly readable, which is a credit to the outstanding work of the staff at CORR in providing clear and consistent guidelines for each of the authors whose work was accepted for publication. The 2008 Ranawat Award was authored by Dr. Patricia Franklin and colleagues for their work on patient-specific attributes that affect the functional outcome after total knee replacement. While considerable interest in patient outcomes research has been present for some time now, we are still uncovering the hidden power, and the hidden pitfalls, of such evaluation tools in orthopaedics. Dr. Franklin and colleagues effectively demonstrate the substantial influence of specific patient characteristics in determining the ultimate functional outcome after knee replacement. These data are useful for surgeons and patients alike as part of the preoperative discussion so that expectations can be managed more appropriately. Further, this paper provides some insight into additional strategies that might be employed prior to knee replacement to affect some patient attributes that adversely impact outcome. The 2008 Coventry Award paper was authored by D’Lima, Colwell, and colleagues from the Scripps Clinic for their innovative report that directly measured the in vivo forces that the knee experiences after total knee arthroplasty. In an outstanding collaboration between basic science researchers, engineers, and clinicians, Dr. Colwell’s group designed and implanted in three patients an instrumented tibial component that allowed the direct measurement of both knee forces and moments in vivo. These results begin to give us a true glimpse of the forces that are seen by total knee bearing surfaces and fixation interfaces thus providing us with a more scientific approach to what have otherwise been empiric recommendations regarding physical activities after total knee arthroplasty. The 2008 John Insall Award paper was authored by Dr. Steven MacDonald and colleagues from London, Ontario and addressed the specific impact of gender on the clinical outcome after total knee arthroplasty. The introduction into the marketplace of so-called gender-specific total knee components has been met with a competing mix of interest and skepticism among surgeons, while among patients curiosity might be the most appropriate descriptor. This scientific work again highlights the powerful relationship between preoperative variables and postoperative outcomes. These authors rightly highlight the importance of focusing on the change or improvement in preoperative to postoperative outcomes measures and balance that against the absolute scores. Female gender was associated with lower preoperative scores with these outcomes tools so perhaps it is not surprising some of the postoperative scores remain lower than those observed in males. The change or improvement from preoperative to postoperative, however, appears to be similar between males and females after total knee arthroplasty. The remaining papers in this symposium are grouped to include new information regarding total knee surgical technique, gender-related issues in technique and outcome, computer navigation, patellar resurfacing, total knee materials and design issues and revision total knee concerns. As surgeons we have specific interest in improving our intraoperative skills. In this symposium there is information on a method to determine rotational position of total knee components, data on the impact of a ligament balancing technique on the rate of lateral retinacular release, and the introduction of an extramedullary femoral referencing system to facilitate less invasive surgery. Gender-related issues are addressed in a series of papers that look at both documenting physical measurement differences in knee anatomy and then measuring outcomes differences. While little doubt exists that gender-associated differences can be measured, what remains to be determined is the clinical importance of such findings, and in that area we collectively still have work to do. While it appears that the initial wave of enthusiasm for computer navigation in total knee arthroplasty has crested, we are now at a point where more definitive scientific data are emerging regarding the benefits and drawbacks to this particular technology. Two of the implicit promises of computer navigation have been that it may make the occasional knee surgeon more like the expert surgeon, and that a navigation system can be the eye that facilitates accurate minimally invasive surgery. In this symposium there are scientific data that cast some doubt on promise number two, and all of us in the scientific community continue to look for evidence that navigation is reproducibly accurate when used by the occasional knee surgeon. The added costs of this technology is an issue yet to be addressed. Revision TKA is an area of ascending importance as the demographics of our population point to a growing need in this area. In this Symposium there are useful data on the outcomes differences between primary and revision TKA, comparative data on in-hospital complications between primary and revision TKA, isolated patellar revision, patellar bone loss problems and the use of stems in conjunction with constrained condylar knee designs. The Knee Society remains committed to advancing scientific knowledge and educating clinicians worldwide regarding surgery of the knee. We hope that our readers find this Symposium to be intellectually rigorous and clinically useful.

The purpose and focus of the Musculoskeletal Tumor Society is stated on the organization’s website. “The mission of the Musculoskeletal Tumor Society is to advance the science of orthopaedic oncology and to promote high standards of patient care. It does this through excellence in education and research” [1]. The 2008 MSTS meeting in Phoenix, AZ, November 6–8, 2008, and hence this symposium, follows part of the prescription, providing an excellent forum for education. The second portion of the mission statement encourages advancing orthopaedic oncology through research. The organization has enjoyed limited success in conducting or promoting research despite valiant efforts by the leaders of the Research Committee. Why? Answers come from the membership, the discipline, and the organization. The membership of the MSTS has changed dramatically over the years. The original “Piranha Club” had 18 domestic orthopaedic surgeons, of whom only one remains actively practicing surgical oncology. The roster has ballooned to over 220 members, including Candidate, Affiliate, and Emeritus Members. While this reflects successful maturation of orthopaedic oncology, it has a dilutive effect on research and possibly even clinical progress. Case volume is correlated with outcome in all other cancer systems studied to date, for disease of organs ranging from prostate to pancreas. Why shouldn’t it also be true for bone and soft tissue sarcomas? As knowledge and training disseminate, experience per surgeon inevitably declines. Smaller case loads prevent concentrated expertise. Paradoxically, the numerical expansion of our membership may have improved our ability to deliver more convenient, good quality care to more people, but it may prevent us from making substantive advances in the field. Single centers usually lack the volume to ask or answer important questions. Collaboration is essential to maintain patient numbers required to study rare diseases. Standardization of treatment protocols is essential if the cases from different centers may be combined. This requires strong-willed commitment on the part of musculoskeletal oncologists to suppress some of their individuality and cooperate. This is necessary to advance the discipline and improve patient care. Large cooperative groups (eg, Children’s Oncology Group or COG, the Southwest Oncology Group or SWOG) have failed due to their cumbersome structure and an inability to channel resources to orthopaedic problems. The greatest success has been in ad hoc collaborations such as that coordinated by the MSTS to review the outcome of patients treated by limb salvage or amputation for distal femoral osteosarcoma [2], or the Toronto Group’s prospective evaluation of prognostic genetic markers (p53 and RB) in osteosarcoma patients from six centers [3]. This symposium includes a variety of novel and informative clinical papers dealing with resection and reconstruction techniques. However, most are single center studies that should be viewed as hypothesis generating ideas. They require confirmation in larger trials involving other centers to show the results can be generalized. The levels of evidence are typically IV. There is also a deficiency in basic and translational research needed to advance the field. Clearly, more effort needs to be expended to improve the quality and generalizability of our research. Investigators and reviewers need to support cluster- and association-based comparative research efforts, clinical trials, and basic investigations. There are national initiatives in this direction. Responding to the challenge proposed by the American Academy of Orthopaedic Surgeons, the Musculoskeletal Tumor Society is trying to develop evidence-based assessments of practice. This symposium includes the Society’s first effort along those lines, summarizing the best available opinion regarding the biopsy of musculoskeletal tumors. More recently, the AAOS/ORS/NIH sponsored a workshop in Albuquerque to define the research agenda for prospective outcome studies in each orthopaedic subspecialty. Two tumor projects made the final cut of recommendations. The first was a prospective study of proximal femoral metastases, comparing internal fixation (rodding) with joint arthroplasty. The second was a long-term followup of reconstructions performed for patients randomized to receive, or not receive, muramyl tripeptide phosphoethanolamine (MTP-PE) in the national Intergroup-133 study. These projects should receive the support of the oncology community, and would be good topics on which the MSTS could focus and include in future CORR Symposia.

AAPS-FDA workshop white paper : Microdialysis principles, application, and regulatory perspectives report from the joint AAPS-FDA workshop, November 4-5, 2005, Nashville, TN

Five years ago our department migrated from a film-based imaging environment to a PACS-based environment. We discovered that our reliance on paper tracking forms for clinical history and dictation information was hindering our practice. Integrating dictation with PACS was one of three key components we needed to free ourselves from the tyranny of paper, the other two being an online worklist and an online patient history. We discuss our evolution to a (mostly) paperless reading room environment, our implementation, general performance, and future development plans, focusing on integrated dictation.

The First Society for Computer Applications in Radiology (SCAR) Transforming the Radiological Interpretation Process (TRIP™) Conference and Workshop, “Transforming Medical Imaging” was held on January 31–February 1, 2005 in Bethesda, MD. Representatives from all areas of medical and scientific imaging—academia, research, industry, and government agencies—joined together to discuss the future of medical imaging and potential new ways to manage the explosion in numbers, size, and complexity of images generated by today's continually advancing imaging technologies. The two-day conference included plenary, scientific poster, and breakout sessions covering six major research areas related to TRIP™. These topic areas included human perception, image processing and computer-aided detection, data visualization, image set navigation and usability, databases and systems integration, and methodology evaluation and performance validation. The plenary presentations provided a general status review of each broad research field to use as a starting point for discussion in the breakout sessions, with emphasis on specific topics requiring further study. The goals for the breakout sessions were to define specific research questions in each topic area, to list the impediments to carrying out research in these fields, to suggest possible solutions and near- and distant-future directions for each general topic, and to report back to the general session. The scientific poster session provided another mechanism for presenting and discussing TRIP™-related research. This report summarizes each plenary and breakout session, and describes the group recommendations as to the issues facing the field, major impediments to progress, and the outlook for radiology in the short and long term. The conference helped refine the definition of the SCAR TRIP™ Initiative and the problems facing radiology with respect to the dramatic growth in medical imaging data, and it underscored a present and future need for the support of interdisciplinary translational research in radiology bridging bench-to-bedside. SCAR will continue to fund research grants exploring TRIP™ solutions. In addition, the organization proposes providing an infrastructure to foster collaborative research partnerships between SCAR corporate and academic members in the form of a TRIP™ Imaging Informatics Network (TRIPI2N).

I have recently returned from the Society for Imaging Informatics in Medicine (SIIM) 2012 Annual Meeting and was reading Dr. Bruce Reiner and Matthew McKinley’s (“Reiner and McKinley’s”) excellent paper on the plane ride home, entitled “Application of Innovation Economics to Medical Imaging and Information System Technologies”, JDI, June 2012. The paper is courageous and shines the light on an incredibly important topic for SIIM, our industry and the healthcare system that we all collectively serve. I was struck by many statements in the paper, and would like to share my thoughts. First, these are the extracted areas that most resonated

The authors present a case of a spondylolisthesis with obvious foraminal stenosis on both sides as shown on the preoperative MRI. A proper operative technique in this case would include a restoration of disc height and the (partial) reduction of the slip. This technique would widen both foramina and no complication like opposite nerve root compression would occur. If reduction or disc height restoration cannot be achieved, decompression of both foramina should be performed. In mild cases a simple posterior distraction may be enough. In their paper the authors agree to this point as they write “decompression of the opposite side has not been judged necessary in the past as it has been commonly assumed that the TLIF spacer increases the disc space height and the foraminal height in the opposite foramen of the TLIF approach.” However, it seems that in the current case the authors failed to achieve restoration of disc height. Figure 7 shows differences between the preoperative and the postoperative CT scan of 1 mm (4 vs. 5 mm) and 1.5 mm (6.5 vs. 8 mm), respectively. The same is true for the “decrease” of foraminal height of 2 mm. I think that these measurements are not reliable since there is no calibration and no matching between the slices. Hence no obvious increase in disc height or decrease in foraminal height can be measured accurately. Anyway, the clinical significance of 1 or 2 mm of reduced foraminal height, if really present, seems to be questionable.

The work, "Ricardo M. The effect of ultrasound on the healing of muscle-pediculated bone graft in scaphoid non-union. Int Orthop. 2006 Apr;30(2):123–127", published by the prestigious journal International Orthopaedics, contains some misprints. In the paper it is reported that the ultrasound intensity emitted by the equipment employed in the study, a Theramed 101B, was 30 mW/cm2. Actually, the reported intensity should have been 50mW/cm2. The error could have come about since initially in the Department of Orthopedics and Traumatology of the Manuel Fajardo Teaching Hospital, a preliminary study was conducted for the stimulation of bone repair that indeed used 30mW/cm2. The first results of this preliminary study were published in the following reference, "O. Rodriguez, R. Monreal. Acceleration of Osseous Fracture Repair by Low-intensity Pulsed Ultrasound Therapy: A Preliminary Study", Proceedings of the II Latin-American Congress on Biomedical Engineering (ISBN 959-7132-57-5), Havana, Cuba, Cod. 265, (2001). Nevertheless after that preliminary study and since the beginning of 2000, the Theramed 101B equipment was modified for an emmision of 50 mW/cm2. Therefore, the year for the beginning of the study described by author should be 2000 and not 1999, and the reported intensity must be 50 mW/cm2, and not 30 mW/cm2. Sincerely yours, Orlando R. Rodriguez Rua (MD), Researcher of the “Instituto de Cibernetica, Matematica y Fisica”, La Habana Cuba. Chief of the project PRI/1/1 of the “Agencia Cubana de Energia Nuclear y Tecnologias de Avanzadas” under which the Theramed 101B was Developer with the collaboration of the “Departamento de Ingenieria Electrica y Electronica, Instituto Tecnologico y de Estudios Superiores de Monterrey, Campus Estado de Mexico, Mexico” and the “Seccion de Bioelectronica, Departamento de Ingenieria Electrica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional, Mexico DF, Mexico”.

OUR RESEARCH APPROACH to the development of a picture archiving and communication system (PACS) has been at the system level. While component technology was developed by various investigators, we felt that our unique role was to look at the PACS from the perspective of network and clinical operations as well as the management of insertion of technology into a complex environment. One of the first questions we tried to address was, “How should one describe PACS?” The paper reprinted here was an early attempt to describe PACS at an operational level without being limited to specific component technology, as we knew the technology would eventually change. This approach as laid the foundation for the performance specifications of the Medical Diagnostic Imaging System that the Department of Defense adopted in the 1990s. During that decade many new efforts were directed toward developing quantitative requirements for the PACS performance, especially to meet the needs of radiologists. Whereas workstation performance and network topologies were topics of intense discussion and development in various quarters, our focus remained on the system level performance and technology deployment. Today PACS is a mature technology. It is difficult to know if any aspects of PACS development influenced the advances in generic computer and information technology. It is reasonable to assume, however, that the PACS initiative has a significant impact on advancing imaging, image processing and image processing technologies. Certainly the PACS efforts in the radiology community have laid the foundation for filmless electronic hospitals and telemedicine. Many major technical issues have been resolved, but as applications expand and the landscape of usage changes, new issues arise. The questions of network topology, workstation performance, image quality on the electronic displays, digital radiography, and clinical acceptance are no longer challenges for PACS today. But the integration of PACS with the radiology information system and other enterprise-wide information and imaging systems continues to pose implementation difficulties. Network security, patient privacy, and health information assurance are a few of the new requirements that the PACS community must address. Through participation in the evolution of PACS, we have experienced firsthand the old lessons associated with the adoption of new technology. This process must begin with proof of the merit of the technology; in addition it requires overcoming entrenched habits and self-interest associated with preserving old technology and old work rules. For PACS, the process of maturation has taken more than 10 years. It was successful because the technology solved difficult problems of managing large amount of complex data for many different stakeholders. The next challenges may be the development of new research programs and patient care capabilities by accessing the vast image databases that are accumulating at PACS hospitals.

IT IS ILLUMINATING and perhaps a little humbling to review a paper written over 15 years ago and compare it to the state-of-the-art in PACS today. Clearly, there have been astounding improvements in the core technology: increased processing power, higher communications bandwidth, cost-effective storage capacity, and superb display technologies. However, the authors’ view (in 1987) that the industry (vendors and customers) needs to focus more on software and systems issues still rings true. Standardization of hardware and software components has come a long way with the digital imaging and communications in medicine (DICOM) and Integrating the Healthcare Enterprise (IHE) standards; without these yeoman efforts, PACS would still be in the dark ages. Also, PACS appears to have “graduated” from being a departmental solution to becoming more and more integrated into the mainstream clinical information systems from information technology providers. Despite these great achievements, I think the industry needs to invest more thought and effort into unleashing the power of PACS with revolutionary workflow and process-change around the technology that will help users realize greater benefits. Interestingly, Louis Gerstner Jr., in an interview about his new book, Who Says Elephants Can’t Dance? says (about the computer industry) “. . . the process of integrating this technology and achieving the benefit is unbelievably painful for companies. The industry has been all about faster, faster, more function, more function. . . .” It appears, at least in this regard, that PACS shares the challenges of the rest of the computer industry!

IT HAS BEEN ASTOUNDING to witness the two-decade computing evolution, which increased processing power, communications bandwidth, and storage capacity while reducing costs. Most of the technology limitations that challenged our early development of picture archiving and communications system (PACS) development have been dissolved. Our quest for modular components has been partially facilitated by the developments of DICOM v3 and more recently by the Radiological Society of North America (RSNA) and the Healthcare Information and Management Systems Society (HIMSS) initiative to address the integration of the healthcare environment (IHE). While many of the commercial systems are still limited in their ability to be tailored to support the radiologist’s need for specialized workflow, adoption of the IHE technical framework holds promise. As in the PACS Workbench experiments, we still find it is essential to have tools to measure image flow, queue arrival times, and queue departure times in order to understand the bounds and performance of our installed commercial systems. The dynamic display of performance metrics, missing in many systems today, continues to be required to enable the “measured, scientific approach” that we sought in our original implementations.

This is a case report of a child with double neural tube defect (NTD) comprising a parietal encephalocoele and an open thoracic myelomeningocoele. The authors use this case to endorse the multi-site neural tube closure theory as aetiology for all multiple NTDs. Proponents of this theory claim that neural tube defects occur at “collision sites” of neural tube closure with opposing closure directions, and because up to five or six of these waves are thought to be operational, there are, accordingly, multiple collision sites. The multi-site closure theory was used originally to explain the different favoured locations of encephalcoeles, and as such, the theory is seductive. At collision sites, the overlying myocutaneous tissues may be potentially weaker and, therefore, susceptible to being stretched but not disrupted by a focal herniation of the alar plates of the already closed cranial neural tube and surrounding meninges. The disorganised gyral development and cortical dysplasia of the herniated brain may be secondary to early tissue distortion. The overlying skin and meninges are intact. Spinal open neural tube defects (ONTD) are due to focal absence of neural plate closure, as shown in numerous, very credible animal experiments. The skin, muscles, neural arches and dura are wide open, and the exposed neural material is an unfused neural plate. This true “closure lesion” is thus fundamentally different from a “collision lesion” exemplified by the encephalocoele. Most spinal ONTDs are terminal lesions involving the end of the primary neural tube, but there are rare examples of segmental lesions in which the “suspended” open neural placode is flanked by normal spinal cord both rostrally and caudally. The incomplete neural plate closure occurs in a square-pulse fashion followed by resumption of normal closure. Three percent of ONTDs in our unit are segmental placodes. Most hemi-myelomeningocoeles associated with split cord malformation (SCM) are segmental lesions. Limited dorsal myeloschisis (LDM), though not technically “open”, is a segmental neural tube closure abnormality, as is dorsal lipoma, a lesion of segmental premature disjunction. If there can be one segmental closure failure, why not two or even three square pulse insults, separated in time, causing in tandem closure lesions resulting in either two segmental ONTDs or one segmental and one terminal ONTD? Other multiple neural tube closure abnormalities, though rare, have been reported, such as double LDMs, double dorsal lipomas and double dermal sinus tracts. Even double SCMs caused by multi-focal gastrulation defects with multiple endomeschymal tracts are well known in the literature. Thus, multiple spinal ONTDs can conceivably occur without invoking the multiple closure-wave theory, which, in the spinal cord will produce a very different lesion. It is not known why there should be abrupt recovery of normal neural tube closure after the square pulse insult. There could conceivably be transient presence of a teratogenic impulse that disturbs certain downstream transcription factors, without a fixed genomic mutation that would perpetuate the developmental error. It is thus the timing of the next transient insult that determines the location of the second neural tube defect, rather than the activities of the colliding zippers.

Background Multiparametric MRI (mpMRI) became recognised in investigating those with suspected prostate cancer between 2010 and 2012; in the USA, the preventative task force moratorium on PSA screening was a strong catalyst. In a few short years, it has been adopted into daily urological and oncological practice. The pace of clinical uptake, born along by countless papers proclaiming high accuracy in detecting clinically significant prostate cancer, has sparked much debate about the timing of mpMRI within the traditional biopsy-driven clinical pathways. There are strongly held opposing views on using mpMRI as a triage test regarding the need for biopsy and/or guiding the biopsy pattern. Objective To review the evidence base and present a position paper on the role of mpMRI in the diagnosis and management of prostate cancer. Methods A subgroup of experts from the ESUR Prostate MRI Working Group conducted literature review and face to face and electronic exchanges to draw up a position statement. Results This paper considers diagnostic strategies for clinically significant prostate cancer; current national and international guidance; the impact of pre-biopsy mpMRI in detection of clinically significant and clinically insignificant neoplasms; the impact of pre-biopsy mpMRI on biopsy strategies and targeting; the notion of mpMRI within a wider risk evaluation on a patient by patient basis; the problems that beset mpMRI including inter-observer variability. Conclusions The paper concludes with a set of suggestions for using mpMRI to influence who to biopsy and who not to biopsy at diagnosis. Key Points • Adopt mpMRI as the first, and primary, investigation in the workup of men with suspected prostate cancer. • PI-RADS assessment categories 1 and 2 have a high negative predictive value in excluding significant disease, and systematic biopsy may be postponed, especially in men with low-risk of disease following additional risk stratification. • PI-RADS assessment category lesions 4 and 5 should be targeted; PI-RADS assessment category lesion 3 may be biopsied as a target, as part of systematic biopsies or may be observed depending on risk stratification. Electronic supplementary material The online version of this article (10.1007/s00330-019-06166-z) contains supplementary material, which is available to authorized users.

Objectives To compare the cost-effectiveness of first-line gefitinib, erlotinib, afatinib, and osimertinib in patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. Methods A systematic review and network meta-analysis (NMA) were conducted to compare the relative efficacy of gefitinib, erlotinib, afatinib, and osimertinib in EGFR-mutated NSCLC. To assess the cost-effectiveness of these treatments, a Markov model was developed from Dutch societal perspective. The model was based on the clinical studies included in the NMA. Incremental costs per life-year (LY) and per quality-adjusted life-year (QALY) gained were estimated. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Results Total discounted per patient costs for gefitinib, erlotinib, afatinib, and osimertinib were €65,889, €64,035, €69,418, and €131,997, and mean QALYs were 1.36, 1.39, 1.52, and 2.01 per patient, respectively. Erlotinib dominated gefitinib. Afatinib versus erlotinib yielded incremental costs of €27,058/LY and €41,504/QALY gained. Osimertinib resulted in €91,726/LY and €128,343/QALY gained compared to afatinib. PSA showed that gefitinib, erlotinib, afatinib, and osimertinib had 13%, 19%, 43%, and 26% probability to be cost-effective at a threshold of €80,000/QALY. A price reduction of osimertinib of 30% is required for osimertinib to be cost-effective at a threshold of €80,000/QALY. Conclusions Osimertinib has a better effectiveness compared to all other TKIs. However, at a Dutch threshold of €80,000/QALY, osimertinib appears not to be cost-effective.

Objectives Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions. Methods Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact. Results Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (− 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2–€12.8 million (TAVI) for TEHV substitution rates of 25–100%. Conclusions Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.

Background We aimed to investigate the burden of informal care in Hungary (HU), Poland (PL) and Slovenia (SI). Methods A cross-sectional online survey was performed involving representative samples of 1000 respondents per country. Caregiving situations were explored; health status of informal caregivers/care recipients and care-related quality of life were assessed using the EQ-5D-5L and CarerQol-7D. Results The proportion of caregivers was (HU/PL/SI) 14.9, 15.0 and 9.6%, respectively. Their mean age was 56.1, 45.6 and 48.0, and the average time spent on informal care was 27.6, 35.5 and 28.8 h/week. Chronic care was dominant (> 1 year: 78.5%, 72.0%, 74.0%) and care recipients were mainly (own/in-law) parents. Average EQ-5D-5L scores of care recipients were 0.53, 0.49 and 0.52. For Poland and Slovenia, EQ-5D-5L scores of informal care providers were signifcantly lower than of other respondents. Average CarerQol-7D scores were (HU/PL/SI) 76.0, 69.6 and 70.9, and CarerQol-VAS was 6.8, 6.4 and 6.6, respectively. Overall, 89, 87, and 84% of caregivers felt some or a lot fulflment related to caring. Problems with combining tasks with daily activities were most important in Hungary and Slovenia. Women had a higher probability of being a caregiver in Hungary. CarerQol-7D scores were signifcantly associated with caregivers’ EQ-5D-5L scores. In Hungary and Poland, living in a larger household was positively, while caring for patients with mental health problems was negatively associated with CarerQol-7D scores. Conclusions These frst results from the Central and Eastern European region using preference-based measures for the evaluation of informal care can serve as a valuable input for health economic analyses.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swiss National Science Foundation OnBehalf Swiss-AF Investigators Background Atrial fibrillation (AF) is associated with loss of cognition and dementia. Cardiac autonomic dysfunction has been linked to cognitive decline. We aimed to investigate if reduced cardiac autonomic function (CAF) is associated with cognitive impairment in AF patients. Methods Patients with paroxysmal, persistent and permanent AF were enrolled from a multicenter cohort study if they presented in AF ("AF group") or in sinus rhythm ("SR group") on a baseline 5-minute ECG recording. Parameters quantifying CAF (heart rate variability triangular index (HRVI), mean heart rate (MHR), the root mean square of successive differences (RMSSD) and the standard deviation of the normal-to-normal intervals (SDNN)) were calculated. We used the Montreal Cognitive Assessment (MoCA) to assess global cognitive function. Results 1,685 AF patients with a mean age of 73 ± 8 years, 29% females, were included. The MoCA score was 24.5 ± 3.2 in the AF group (n = 710 patients) and 25.4 ± 3.2 in the SR group (n = 975 patients). After adjusting for multiple confounders, lower HRVI was associated with lower MoCA scores, both in the SR group (β=0.049; 95% confidence interval (CI): 0.016 to 0.081; p = 0.003) and in the AF group (β=0.068; 95% CI: 0.020 to 0.116; p = 0.006). In the AF group, higher MHR was associated with a poorer performance in the MoCA (β=-0.008; 95% CI: -0.014 to -0.002; p = 0.014 ). Other parameters of CAF were not associated with cognition. Conclusion Our data suggest that impaired CAF is associated with worse cognitive performance in patients with AF. Elderly AF patients with impaired HRVI might undergo cognitive testing in order to screen for cognitive impairment.

We study the extremely high and low residual spenders in individual health insurance markets in three countries. A high (low) residual spender is someone for whom the residual—spending less payment (from premiums and risk adjustment)—is high (low), indicating that the person is highly underpaid (overpaid). We begin with descriptive analysis of the top and bottom 1% and 0.1% of residuals building to address the question of the degree of persistence in membership at the extremes. Common findings emerge among the countries. First, the diseases found among those with the highest residual spending are also disproportionately found among those with the lowest residual spending. Second, those at the top of the residual spending distribution (where spending exceeds payments the most) account for a massively high share of the unexplained variance in the predictions from the risk adjustment model. Third, in terms of persistence, we find that membership in the extremes of the residual spending distribution is highly persistent, raising concerns about selection-related incentives targeting these individuals. As our results show, the one-in-a-thousand people (on both sides of the residual distribution) play an outsized role in creating adverse incentives associated with health plan payment systems. In response to the observed importance of the extremes of the residual spending distribution, we propose an innovative combination of risk-pooling and reinsurance targeting the predictively undercompensated group. In all three countries, this form of risk sharing substantially improves the overall fit of payments to spending. Perhaps surprisingly, by reducing the burden on diagnostic indicators to predict high payments, our proposed risk sharing policy reduces the gap between payments and spending not only for the most undercompensated individuals but also for the most overcompensated people.

The limited efficacy of glucocorticoids (GCs) during therapy of acute relapses in multiple sclerosis (MS) leads to long-term disability. We investigated the potential of vitamin D (VD) to enhance GC efficacy and the mechanisms underlying this VD/GC interaction. In vitro, GC receptor (GR) expression levels were quantified by ELISA and induction of T cell apoptosis served as a functional readout to assess synergistic 1,25(OH)2D3 (1,25D)/GC effects. Experimental autoimmune encephalomyelitis (MOG35–55 EAE) was induced in mice with T cell-specific GR or mTORc1 deficiency. 25(OH)D (25D) levels were determined in two independent cohorts of MS patients with stable disease or relapses either responsive or resistant to GC treatment (initial cohort: n = 110; validation cohort: n = 85). Gene expression of human CD8+ T cells was analyzed by microarray (n = 112) and correlated with 25D serum levels. In vitro, 1,25D upregulated GR protein levels, leading to increased GC-induced T cell apoptosis. 1,25D/GC combination therapy ameliorated clinical EAE course more efficiently than respective monotherapies, which was dependent on GR expression in T cells. In MS patients from two independent cohorts, 25D deficiency was associated with GC-resistant relapses. Mechanistic studies revealed that synergistic 1,25D/GC effects on apoptosis induction were mediated by the mTOR but not JNK pathway. In line, 1,25D inhibited mTORc1 activity in murine T cells, and low 25D levels in humans were associated with a reduced expression of mTORc1 inhibiting tuberous sclerosis complex 1 in CD8+ T cells. GR upregulation by 1,25D and 1,25D/GC synergism in vitro and therapeutic efficacy in vivo were abolished in animals with a T cell-specific mTORc1 deficiency. Specific inhibition of mTORc1 by everolimus increased the efficacy of GC in EAE. 1,25D augments GC-mediated effects in vitro and in vivo in a T cell-specific, GR-dependent manner via mTORc1 inhibition. These data may have implications for improvement of anti-inflammatory GC therapy. Electronic supplementary material The online version of this article (10.1007/s00401-019-02018-8) contains supplementary material, which is available to authorized users.

A case-mix project started in the Netherlands with the primary goal to define a complete set of health care products for hospitals. The definition of the product structure was completed 4 years later. The results are currently being used for billing purposes. This paper focuses on the methodology and techniques that were developed and applied in order to define the casemix product structure. The central research question was how to develop a manageable product structure, i.e., a limited set of hospital products, with acceptable cost homogeneity. For this purpose, a data warehouse with approximately 1.5 million patient records from 27 hospitals was build up over a period of 3 years. The data associated with each patient consist of a large number of a priori independent parameters describing the resource utilization in different stages of the treatment process, e.g., activities in the operating theatre, the lab and the radiology department. Because of the complexity of the database, it was necessary to apply advanced data analysis techniques. The full analyses process that starts from the database and ends up with a product definition consists of four basic analyses steps. Each of these steps has revealed interesting insights. This paper describes each step in some detail and presents the major results of each step. The result consists of 687 product groups for 24 medical specialties used for billing purposes.

Background Hypermobility of the first carpometacarpal joint is mostly surgically treated with a volar approached stabilization by Eaton, but recent studies indicate the importance of the dorsoradial and intermetacarpal ligaments (DRL and IML) for carpometacarpal joint stability. The aim of this study was to compare a dorsal and volar technique for primary carpometacarpal hypermobility regarding pain and functional outcome. Methods Patients with non-degenerative, painful carpometacarpal hypermobility were included and were randomly assigned to either the volar technique using the FCR, or a dorsal technique using the ECRL. After premature termination of the trial, we followed all patients treated with the volar approach. Pain, strength, and ADL function using DASH and Michigan Hand Questionnaires (MHQ) were measured at baseline and 3 and 12 months after surgery. Results After including 16 patients, the randomized trial comparing the volar and dorsal technique was terminated because of significant increased pain in the dorsal group. Although none of the other outcome measures were significant in the underpowered comparison, in line with the pain scores, all variables showed a trend towards a worse outcome in the dorsal group. Between 2009 and 2012, 57 thumbs were surgically stabilized. We found significant better pain and MHQ scores, and after 1 year improved grip and key pinch strength. Patients returned to work within 8 (±7) weeks, of which 85 % in their original job. Conclusions Surgical stabilization of the thumb is an effective method for patients suffering from hypermobility regarding pain, daily function, and strength. We recommend a volar approach. Level of Evidence: Level I, therapeutic study

The authenticity of food is of increasing importance for producers, retailers and consumers. All groups benefit from the correct labelling of the contents of food products. Producers and retailers want to guarantee the origin of their products and check for adulteration with cheaper or inferior ingredients. Consumers are also more demanding about the origin of their food for various socioeconomic reasons. In contrast to this increasing demand, correct labelling has become much more complex because of global transportation networks of raw materials and processed food products. Within the European integrated research project ‘Tracing the origin of food’ (TRACE), a DNA-based multiplex detection tool was developed—the padlock probe ligation and microarray detection (PPLMD) tool. In this paper, this method is extended to a 15-plex traceability tool with a focus on products of commercial importance such as the emmer wheat Farro della Garfagnana (FdG) and Basmati rice. The specificity of 14 plant-related padlock probes was determined and initially validated in mixtures comprising seven or nine plant species/varieties. One nucleotide difference in target sequence was sufficient for the distinction between the presence or absence of a specific target. At least 5% FdG or Basmati rice was detected in mixtures with cheaper bread wheat or non-fragrant rice, respectively. The results suggested that even lower levels of (un-)intentional adulteration could be detected. PPLMD has been shown to be a useful tool for the detection of fraudulent/intentional admixtures in premium foods and is ready for the monitoring of correct labelling of premium foods worldwide.

Network immunization strategies have emerged as possible solutions to the challenges of virus propagation. In this paper, an existing interactive model is introduced and then improved in order to better characterize the way a virus spreads in email networks with different topologies. The model is used to demonstrate the effects of a number of key factors, notably nodes’ degree and betweenness. Experiments are then performed to examine how the structure of a network and human dynamics affects virus propagation. The experimental results have revealed that a virus spreads in two distinct phases and shown that the most efficient immunization strategy is the node-betweenness strategy. Moreover, those results have also explained why old virus can survive in networks nowadays from the aspects of human dynamics.

Objects Deliberate termination of life of newborns (involuntary euthanasia) with meningomyelocele (MMC) is practiced openly only in the Netherlands. ‘Unbearable and hopeless suffering’ is the single most cited criterion for this termination, together with the notion that ‘there are no other proper medical means to alleviate this suffering’. In this paper, both (and other) statements are questioned, also by putting them in a broader perspective. Methods First, a historical overview of the treatment of newborns with MMC is presented, concentrating on the question of selection for treatment. Second, a thorough analysis is made of the criteria used for life termination. Third, a case of a newborn with a very severe MMC is presented as a ‘reference case’. Conclusion ‘Unbearable and hopeless suffering’ cannot be applied to newborns with MMC. They are not ‘terminally ill’ and do have ‘prospects of a future’. In these end-of-life decisions, ‘quality of life judgments’ should not be applied. When such a newborn is not treated, modern palliative care always will suffice in eliminating possible discomfort. There is no reason whatsoever for active life-termination of these newborns.

Purpose To compare the efficacy and safety of TDR to that of the fusion for the treatment of lumbar degenerative disc disease (LDDD). Methods Randomized controlled trials comparing TDR with any other intervention for LDDD were acquired by a comprehensive search in PubMedCentral, MEDLINE, EMBASE, BIOSIS, ClinicalTrials.gov, and the FDA trials register. Methodologic quality was assessed and relevant data were retrieved, and appropriate meta-analysis was performed. Two review authors independently selected studies, extracted data, and assessed risk of bias. Results and upper bounds of confidence intervals were compared with predefined clinically relevant differences. Results Six relevant randomized controlled trials (RCTs) involving 1,603 patients were identified and reported two year follow-up results. Patients in TDR group compared with lumbar fusion group demonstrated significant improvements in ODI, VAS scores and complication rates at the two year follow-up. Meanwhile, except for operating time in anterior group, intra-operative blood loss, operating time in posterior group, and reoperation rate were without clinical significance between the two groups. In addition, the range of motion (ROM) was maintained within normal ranges after TDR. Conclusions The results showed the TDR has significant safety and efficacy comparable to lumbar fusion at two year follow-up. Although superiority compared to fusion could not be proved, by comparing clinical symptoms relieved, motion preserved, and the low reoperation rate during long-term follow-up on TDR, TDR was considered safe and effective. Therefore, the authors suggest adopting TDR on a large scale; with failure of TDR, interbody fusion would be performed.

Purpose The purpose of this study was to evaluate clinical and radiological outcomes of autologous osteochondral transfer (OATS) for femoral head osteonecrosis. Methods Twenty-one hips in 20 patients (one woman and 19 men), average patients' age at the time of surgery of 35.4 (range 20–56) years, were treated with OATS for osteonecrosis of the femoral head (ONFH). Seven patients at pre-collapse ARCO stages IIA and IIB were treated with OATS alone. Thirteen patients with large pre-collapse ARCO IIC and post-collapse ARCO III and IV were treated with OATS and morselised bone allografts (OATS/allograft). Harris hip score (HHS) was used for clinical evaluation of outcomes; X-rays were performed to examine the evolution of the disease. Kaplan-Meier survival curves were used to determine the failure of the procedures with conversion to THR defined as endpoint. Results Follow-up of patients treated with OATS alone was 46.14 (range 18–75) months with HHS improvement from a preoperative mean of 42 to 87.85 points at the latest follow-up examination. Only one patient in this group needed a revision operation with THR. The survival for this group of patients was 85.71 % at four years. Follow-up of patients treated with AOTS/allograft was 32.7 (range 7–84) months with HHS improvement from a preoperative mean of 35.2 to 65.7 points at the latest follow-up examination. One patient died six months after the surgery. There were five conversions to THR because of femoral head collapse in this group of patients with survival of 61.54 % at three years. Conclusion The use of osteochondral grafts offers the possibility of successful treatment for ONFH at small and medium pre-collapse stages. The outcomes of large pre-collapse and post-collapse stages were below our expectations. OATS is a time buying procedure for young patients as it may defer total hip replacement.

This study evaluated the perception of veterinarians in including the emerging metastrongyloid Angiostrongylus vasorum in the differential diagnosis for dogs referred with appropriate signs. Veterinarians at teaching hospitals, private practices or kennels collected faecal samples from 606 symptomatic dogs in six different areas of Italy. The samples were examined with the Baermann technique. Fourteen dogs scored positive for A. vasorum, all showing different clinical pictures, with the most common reason for inclusion in the study being a combination of respiratory signs along with general signs. The most reported sign was cough, followed by aspecific distresses. Other respiratory signs were dyspnoea, tachypnoea and breathing sounds, while bleeding diathesis occurred in one dog. Gastrointestinal disorders were diarrhoea and vomitus, while no neurological signs were detected. Four key cases are herein described, with a special focus on their clinical description, findings at the collateral diagnostic imaging and therapeutic options with moxidectin. This survey provides new data on distribution of A. vasorum in Europe and on the clinical impact of the disease. The results confirm that clinical angiostrongylosis overlaps a series of other conditions of dogs. Awareness among vet practitioners is discussed along with the importance of including A. vasorum on the list of differential diagnoses in canine clinical practice and of performing appropriate diagnostic methods.

Purpose Trastuzumab and chemotherapy is the current standard of care in HER2+ early or locally advanced breast cancer, but there are scanty literature data of its real world effectiveness. Methods We retrospectively reviewed 205 patients with HER2+ breast cancer diagnosed in 10 Italian Medical Oncology Units between July 2003 and October 2011. All patients received neoadjuvant systemic therapy (NST) with trastuzumab in association with chemotherapy. Many different chemotherapy regimens were used, even if 90 % of patients received schemes including anthracyclines and 99 % received taxanes. NST was administered for more than 21 weeks (median: 24) in 130/205 (63.4 %) patients, while trastuzumab was given for more than 12 weeks (median: 12 weeks) in 101/205 (49.3 %) patients. pCR/0 was defined as ypT0+ypN0, and pCR/is as ypT0/is+ypN0. Results pCR/0 was obtained in 24.8 % and pCR/is in 46.8 % of the patients. At multivariate logistic regression, nonluminal/HER2+ tumors (P

The aim of this health economic analysis was to compare the cost-effectiveness of ticagrelor versus clopidogrel within the German health care system. A two-part decision model was adapted to compare treatment with ticagrelor or clopidogrel in a low-dose acetylsalicylic acid (ASA) cohort (≤150 mg) for all ACS patients and subtypes NSTEMI/IA and STEMI. A decision-tree approach was chosen for the first year after initial hospitalization based on trial observations from a subgroup of the PLATO study. Subsequent years were estimated by a Markov model. Following a macro-costing approach, costs were based on official tariffs and published literature. Extensive sensitivity analyses were performed to test the robustness of the model. One-year treatment with ticagrelor is associated with an estimated 0.1796 life-years gained (LYG) and gained 0.1570 quality-adjusted life-years (QALY), respectively, over the lifetime horizon. Overall average cost with ticagrelor is estimated to be EUR 11,815 vs. EUR 11,387 with generic clopidogrel over a lifetime horizon. The incremental cost-effectiveness ratio (ICER) was EUR 2,385 per LYG (EUR 2,728 per QALY). Comparing ticagrelor with Plavix® or the lowest priced generic clopidogrel, ICER ranges from dominant to EUR 3,118 per LYG (EUR 3,567 per QALY). These findings are robust under various additional sensitivity analyses. Hence, 12 months of ACS treatment using ticagrelor/ASA instead of clopidogrel/ASA may offer a cost-effective therapeutic option, even when the generic price for clopidogrel is employed. Electronic supplementary material The online version of this article (doi:10.1007/s00392-013-0552-7) contains supplementary material, which is available to authorized users.

Purpose The aim of the study was to assess bone graft incorporation after revision hip arthroplasty in patients with rheumatoid arthritis (RA). Methods We report an acetabular reconstruction using impacted, morselized, frozen, radiation sterilized bone allografts in 71 patients suffering from RA. There were sixty-six women and five men at a mean age of 57.5 years. Reconstruction was performed in 78 revision total hip arthroplasties (THAs) for aseptic loosening of acetabular component. The mean follow-up was five years and four months. In 38 cases, a revision was done with use of reinforcement devices. Results In four revised hips (10 %) without reinforcement implants, resorption of the allografts was noticed. All Mueller rings and 50 % of unscrews cages (Link, Howmedica) were revised because of aseptic loosening and bone graft resorption. In all of 17 hips with the Burch-Schneider cage, no measurable migration or bone allografts resorption occurred. There were no major general complications. Conclusions Acetabular reconstruction with use of morselized, frozen, radiation sterilized bone allografts and the Burch-Schneider cage can be highly successful in managing massive deficiency of acetabular bone stock in revision hip arthroplasty in RA patients.

Purpose Recurrences and deaths are known to occur, even if less frequently, in small, node-negative breast cancer patients, and decision on adjuvant treatments remains controversial. In the present analysis, we evaluate recurrence risk in patients with pT1 a, b, c, node-negative, breast cancer, accordingly with some prognostic biological factors. Methods We retrospectively evaluated 900 node-negative patients (pT1a, b, c) surgery treated between 2000 and 2009 in four Italian oncologic centers. We defined 3 different cohorts: ER positive (ER+); Her-2 positive (Her-2+); and triple negative (TN). Results pT1a was seen in 7.6% of patients, 37.7 % pT1b, 54.8 % pT1c. Concerning the 3 different cohorts, 58.2 % were ER+; 10.8 % were Her-2+; 8.2 % were TN. Overall, chemotherapy was given to 3.0 %, 27.2 %, 69.8 % of pT1a, b, c, respectively, and to 22.7 %, 58.8 %, 68.9 % of ER+, Her-2+, TN subgroups. At a median follow-up of 67 months, 5-year DFS was 96.3 %, 89.2 %, 89.4 % in pT1a, b, c, respectively (100 %, 93.6 %, 89.8 % in ER+; 100 %, 78.7 %, 85.0 % in Her-2+; 100 %, 76.8 %, 85.2 % in TN) (p = ns). At multivariate analysis, histologic grade and Ki-67 resulted independent prognostic factors. Overall, 5-year OS was 98 %, without differences among pT1a, b, c, or among the 3 cohorts. Conclusions Overall, 5-year DFS was very favorable in this series of small, node-negative breast cancers, but Her-2+ and TN cohorts have a higher recurrence rate than ER+ cohort (p

The aim of this study was to evaluate the clinical effectiveness of covered Niti-S stent placement under multidetector CT and fluoroscopy guidance for the palliation of dysphagia in patients with cervical esophageal cancer. Under radiological imaging guidance using axial and sagittal CT scans, and fluoroscopy, Niti-S esophageal stents were placed in ten consecutive patients with complete obstruction caused by cervical esophageal cancer (9 men and 1 woman; age range = 54–79 years; mean age = 68.1 years) between February 2010 and December 2011. The procedure time and technical success rate were evaluated. Swallowing improvement was assessed by the following items: ability to eat and/or swallow (graded as follows: 3 = ability to eat normal diet, 2 = ability to eat semisolids, 1 = ability to swallow liquids, 0 = complete obstruction). Procedural and post-procedural complications were also evaluated. Survival (mean ± SD) was examined. The mean (±SD) procedure time was 40 ± 19 min (range = 21–69 min). Stent placement was technically successful in all patients; inadequate stent deployment did not occur in any case. Ability to eat and/or swallow was improved and scored 2.4 (score 3 in 5 cases, score 2 in 4 cases, score 1 in 1 case, and score 0 in no case) after stent placement. No major or post-procedural complications were encountered. The mean survival time was 131 ± 77 days (range = 31–259 days). Niti-S stents appeared to be a safe and effective device for the palliation of dysphagia caused by advanced cervical esophageal cancer. Multidetector CT and fluoroscopy image guidance helped the operators accurately place the stents in the cervical esophagus.

Background Drug-coated balloons (DCBs) have been developed for the percutaneous treatment of coronary artery disease. An initial focus has been the management of in-stent restenosis (ISR) but randomised controlled trials (RCTs) have been small and powered only for angiographic endpoints. Objective The aim of the work was to assess the clinical and angiographic outcomes of patients treated for ISR with DCB versus control (balloon angioplasty or drug-eluting stents) by a meta-analysis of RCTs. Methods A comprehensive search was performed of RCTs where patients with ISR were randomly assigned to either DCB or alternative coronary intervention. Outcome measurements were death, myocardial infarction (MI), target lesion revascularisation (TLR), binary definition of restenosis and in-lesion late luminal loss (LLL). Results Four studies were identified that fulfilled the inclusion criteria. Pooled odds ratios (ORs) were calculated for patients treated for ISR (n = 399). Mean follow-up duration was 14.5 months. DCBs were associated with lower rates of TLR [8.8 vs. 29.7 % OR (95 % confidence interval, CI) 0.20 (0.11–0.36), p

Purpose Surgical treatment of an acute Achilles tendon rupture can effectively reduce the risk of re-rupture, but it increases the probability of surgical complications. We postulated that a minimally invasive surgical treatment might reduce the number of complications related to open surgery and improve the functional results. Method We enrolled 47 patients with acute Achilles tendon ruptures in a prospective, randomised trial to compare clinical results and complications between a minimally invasive procedure with the Achillon® device and traditional open surgery with Krackow-type sutures. The average patient age was 46 years. The follow up time was 24 months. Results No Achilles tendon re-rupture or nerve injury occurred in treated patients. There were two cases of wound infections in the open surgery group, and one superficial wound infection occurred in the minimally invasive group. The groups were not significantly different in the amount of pain, range of ankle movements, the single heel-rise test, calf circumference, or time to return to work and sports. Conclusion After a two year follow-up period, we found no significant differences in clinical outcomes between groups treated with traditional open surgery or minimally invasive surgery.

Objective We tested whether bedside testing for H-FABP is, alone or integrated in combination models, useful for rapid risk stratification of non-high-risk PE. Methods We prospectively studied 136 normotensive patients with confirmed PE. H-FABP was determined using a qualitative bedside-test showing a positive result for plasma concentration >7 ng/ml. Results Overall, 11 patients (8.1 %) had an adverse 30-day outcome. Of 58 patients (42.6 %) with a positive H-FABP bedside-test, 9 (15.5 %) had an unfavourable course compared to 2 of 78 patients (2.6 %) with a negative test result (p = 0.009). Logistic regression analysis indicated a sevenfold increased risk for an adverse outcome (95 % CI, 1.45–33.67; p = 0.016) for patients with a positive H-FABP bedside-test. Additive prognostic information were obtained by a novel score including the H-FABP bedside-test (1.5 points), tachycardia (2 points), and syncope (1.5 points) (OR 11.57 [2.38–56.24]; p = 0.002 for ≥3 points). Increasing points were associated with a continuous exponential increase in the rate of an adverse 30-day outcome (0 % for patients with 0 points and 44.4 % for ≥5 points). Notably, this simple score provided similar prognostic value as the combination of the H-FABP bedside-test with echocardiographic signs of right ventricular dysfunction (OR 12.73 [2.51–64.43]; p = 0.002). Conclusions Bedside testing for H-FABP appears a useful tool for immediate risk stratification of non-high-risk patients with acute PE, who may be at increased risk of an adverse outcome, in particular if integrated in a novel score without the need of echocardiographic examination.

Globalization has led to new health challenges for the twenty-first century. These new health challenges have transnational implications and involve a large range of actors and stakeholders. National governments no longer hold the sole responsibility for the health of their people. These changes in health trends have led to the rise of global health governance as a theoretical notion for health policy making. The Southeast Asian region is particularly prone to public health threats such as emerging infectious diseases and faces future health challenges including those of noncommunicable diseases. This study looks at the potential of the Association of Southeast Asian Nations (ASEAN) as a regional organization to lead a regional dynamic for health cooperation in order to overcome these challenges. Through a comparative study with the regional mechanisms of the European Union (EU) for health cooperation, we look at how ASEAN could maximize its potential as a global health actor. Our study is based on primary research and semistructured field interviews. To illustrate our arguments, we refer to the extent of regional cooperation for health in ASEAN and the EU for (re)emerging infectious disease control and for tobacco control. We argue that regional institutions and a network of civil society organizations are crucial in relaying global initiatives, and ensuring the effective implementation of global guidelines at the national level. ASEAN's role as a regional body for health governance will depend both on greater horizontal and vertical integration through enhanced regional mechanisms and a wider matrix of cooperation.

There is a broad literature on the consequences of applying different welfare standards in merger control. Total welfare is usually defined as the sum of consumer and provider surplus, i.e., potential external effects are not considered. The general result is then that consumer welfare is a more restrictive standard than total welfare, which is advantageous in certain situations. This relationship between the two standards is not necessarily true when the merger has significant external effects. We model mergers on hospital markets and allow for not-profit-maximizing behavior of providers and mandatory health insurance. Mandatory health insurance detaches the financial and consumption side of health care markets, and the concept consumer in merger control becomes non-evident. Patients not visiting the merging hospitals still are affected by price changes through their insurance premiums. External financial effects emerge on not directly affected consumers. We show that applying a restricted interpretation of consumer (neglecting externality) in health care merger control can reverse the relation between the two standards; consumer welfare standard can be weaker than total welfare. Consequently, applying the wrong standard can lead to both clearing socially undesirable and to blocking socially desirable mergers. The possible negative consequences of applying a simple consumer welfare standard in merger control can be even stronger when hospitals maximize quality and put less weight on financial considerations. We also investigate the implications of these results for the practice of merger control.

Immune-mediated rejection of human cancer is a relatively rare but well-documented phenomenon. Its rate of occurrence progressively increases from the occasional observation of spontaneous regressions to the high rate of complete remissions observed in response to effective treatments. For two decades, our group has focused its interest in understanding this phenomenon by studying humans following an inductive approach. Sticking to a sequential logic, we dissected the phenomenon by studying to the best of our capability both peripheral and tumor samples and reached the conclusion that immune-mediated cancer rejection is a facet of autoimmunity where the target tissue is the cancer itself. As we are currently defining the strategy to effectively identify the mechanisms leading in individual patients to rejection of their own tumors, we considered useful to summarize the thought process that guided us to our own interpretation of the mechanisms of immune responsiveness.

The availability of high density panels of molecular markers has prompted the adoption of genomic selection (GS) methods in animal and plant breeding. In GS, parametric, semi-parametric and non-parametric regressions models are used for predicting quantitative traits. This article shows how to use neural networks with radial basis functions (RBFs) for prediction with dense molecular markers. We illustrate the use of the linear Bayesian LASSO regression model and of two non-linear regression models, reproducing kernel Hilbert spaces (RKHS) regression and radial basis function neural networks (RBFNN) on simulated data and real maize lines genotyped with 55,000 markers and evaluated for several trait–environment combinations. The empirical results of this study indicated that the three models showed similar overall prediction accuracy, with a slight and consistent superiority of RKHS and RBFNN over the additive Bayesian LASSO model. Results from the simulated data indicate that RKHS and RBFNN models captured epistatic effects; however, adding non-signal (redundant) predictors (interaction between markers) can adversely affect the predictive accuracy of the non-linear regression models.

We assessed the safety and efficacy of sorafenib with cryotherapy (cryoRx) in advanced hepatocellular carcinoma (HCC). One hundred four HCC patients were enrolled, who met the following criteria: (i) Barcelona Clinic Liver Cancer stage C; (ii) HCC without distant metastasis; (iii) the presence of portal vein thrombosis (PVT); (iv) Child-Pugh class A or B; and (v) life expectancy of at least 12 weeks. The patients were randomly divided into sorafenib-cryoRx and sorafenib (control) groups. Primary endpoint was time to progression (TTP); secondary endpoints included overall survival (OS) and tolerability. Microvessel density (MVD) was assessed by CD34-immunostaining. After a median 10.5 (4–26) months follow-up, the data showed that median TTP was 9.5 (8.4–13.5) months in combinatorial therapy group vs. 5.3 (3.8–6.9) months in sorafenib group (P = 0.02). The median OS was 12.5 (95 % CI 10.6–16.4) months in combination therapy group vs. 8.6 (7.3–10.4) months in sorafenib group (P = 0.01). Low MVD patients in combination therapy exhibited significantly longer median TTP and OS than controls. High MVD was predictive of poor responses to sorafenib. CryoRx did not increase frequency/degree of sorafenib-related adverse events. Therefore, it was concluded that the addition of cryoRx significantly improved clinical outcomes of Sorafenib therapy in advanced HCC with acceptable tolerance and similar safety profiles as previously reported.

Objective The purpose of this study was to review the epidemiology and the clinical, radiological, pathological, and follow-up data of all surgically treated pediatric meningiomas during the last 35 years in The Netherlands. Methods Patients were identified in the Pathological and Anatomical Nationwide Computerized Archive database, the nationwide network and registry of histopathology and cytopathology in The Netherlands. Pediatric patients of 18 years or younger at first operation in 1974–2009 with the diagnosis meningioma were included. Clinical records, follow-up data, radiological findings, operative reports, and pathological examinations were reviewed. Results In total, 72 patients (39 boys) were identified. The incidence of operated meningiomas in the Dutch pediatric population is 1:1,767,715 children per year. Median age at diagnosis was 13 years (range 0–18 years). Raised intracranial pressure and seizures were the most frequent signs at presentation. Thirteen (18 %) patients had neurofibromatosis type 2 (NF2). Fifty-three (74 %) patients had a meningioma World Health Organization grade I. Total resection was achieved in 35 of 64 patients. Fifteen patients received radiotherapy postoperatively. Mean follow-up was 4.8 years (range 0–27.8 years). Three patients died as a direct result of their meningioma within 3 years. Four patients with NF2 died as a result of multiple tumors. Nineteen patients had disease progression, requiring additional treatment. Conclusion Meningiomas are extremely rare in the pediatric population; 25 % of all described meningiomas show biological aggressive behavior in terms of disease progression, requiring additional treatment. The 5-year survival is 83.9 %, suggesting that the biological behavior of pediatric menigiomas is more aggressive than that of its adult counterparts.

Personal genetic information has become increasingly accessible to the public as a result of direct-to-consumer (DTC) genetic tests; however, concerns have been raised over their value and potential risks. We compared the effects of providing genotype-based dietary advice with general recommendations on behavioral outcomes using a randomized controlled study. Participants were men and women from the Toronto Nutrigenomics and Health Study between the ages of 20–35 years (n = 149) who completed a survey to assess their awareness of DTC genetic tests and nutrigenomics, as well as potential motivations for undergoing genetic testing. Participants were then randomized into an intervention (I) or control (C) group and were given either genotype-based personalized dietary advice or general dietary advice, respectively. A second survey was administered to assess the participants’ opinions of the dietary reports they received. A greater proportion of participants in the intervention group agreed that they understood the dietary advice they were given (93% (I) vs. 78% (C); p = 0.009). Participants in the intervention group were more likely to agree that the dietary recommendations they received would be useful when considering their diet (88% (I) vs. 72% (C); p = 0.02) and wanted to know more about the recommendations (95% (I) vs. 76% (C); p

Neonatal fungal infections are associated with substantial mortality and morbidity. Although prophylactic use of several antifungals has been proposed, this practice remains controversial. In order to evaluate the use of fluconazole prophylaxis in European NICUs, we conducted a cross-sectional survey by means of a structured questionnaire that was sent to European level II and III neonatal intensive care units, over a 9-month period, as part of a neonatal research FP7 European project. A total of 193 questionnaires from 28 countries were analysed. Use of antifungal prophylaxis was reported by 55% of the responders, and the most frequently used antifungal agent was fluconazole (92%). Main indications for prophylaxis were low gestational age (

Background Cost-effectiveness analyses of behavioral interventions typically use a dichotomous outcome criterion. However, achieving behavioral change is a complex process involving several steps towards a change in behavior. Delayed effects may occur after an intervention period ends, which can lead to underestimation of these interventions. To account for such delayed effects, intermediate outcomes of behavioral change may be used in cost-effectiveness analyses. The aim of this study is to model cognitive parameters of behavioral change into a cost-effectiveness model of a behavioral intervention. Methods The cost-effectiveness analysis (CEA) of an existing dataset from an RCT in which an high-intensity smoking cessation intervention was compared with a medium-intensity intervention, was re-analyzed by modeling the stages of change of the Transtheoretical Model of behavioral change. Probabilities were obtained from the dataset and literature and a sensitivity analysis was performed. Results In the original CEA over the first 12 months, the high-intensity intervention dominated in approximately 58% of the cases. After modeling the cognitive parameters to a future 2nd year of follow-up, this was the case in approximately 79%. Conclusion This study showed that modeling of future behavioral change in CEA of a behavioral intervention further strengthened the results of the standard CEA. Ultimately, modeling future behavioral change could have important consequences for health policy development in general and the adoption of behavioral interventions in particular.

Purpose We conducted this study to gauge the health-related problems, quality of life and the performance of the Health Utility Index Mark 3 (HUI-3) in patients with syndromic and complex craniosynostosis. Patients with syndromic and complex craniosynostosis have various physical and mental problems. More insight on these problems, per syndrome, could provide guidance to improve patient treatment and follow-up. Methods A cross-sectional, comparative study on 131 patients and their parents was performed. Health-related quality of life was measured with the HUI-3 and the Visual Analogue Scale (VAS). All data were compared to a normative Dutch population. Vision, hearing and intelligence were objectively measured. Results The HUI-3 and the VAS were significant lower compared to the normative Dutch population. All syndromes have a high prevalence of vision and speech problems. Cognitive problems were mainly reported in patients with Apert, Crouzon and Muenke syndrome. Ambulation and dexterity problems were seen in Apert, Crouzon, Saethre–Chotzen and complex craniosynostosis. Only patients with Apert syndrome scored significantly worse on pain. The HUI-3 had a medium to strong correlation with the objectively measured outcomes. Conclusions The overall quality of life is lower in patients with syndromic and complex craniosynostosis. To improve quality of life, more attention is needed for problems with vision and speech.

The principle of stretching wound margins for primary wound closure is commonly practiced and used for various skin defects, leading at times to excessive tension and complications during wound closure. Different surgical techniques, skin stretching devices and tissue expanders have been utilized to address this issue. Previously designed skin stretching devices resulted in considerable morbidity. They were invasive by nature and associated with relatively high localized tissue pressure, frequently leading to necrosis, damage and tearing of skin at the wound margins. To assess the clinical effectiveness and performance and, to determine the safety of TopClosure® for gradual, controlled, temporary, noninvasive and invasive applications for skin stretching and secure wound closing, the TopClosure® device was applied to 20 patients for preoperative skin lesion removal and to secure closure of a variety of wound sizes. TopClosure® was reinforced with adhesives, staples and/or surgical sutures, depending on the circumstances of the wound and the surgeon’s judgment. TopClosure® was used prior to, during and/or after surgery to reduce tension across wound edges. No significant complications or adverse events were associated with its use. TopClosure® was effectively used for preoperative skin expansion in preparation for dermal resection (e.g., congenital nevi). It aided closure of large wounds involving significant loss of skin and soft tissue by mobilizing skin and subcutaneous tissue, thus avoiding the need for skin grafts or flaps. Following surgery, it was used to secure closure of wounds under tension, thus improving wound aesthetics. A sample case study will be presented. We designed TopClosure®, an innovative device, to modify the currently practiced concept of wound closure by applying minimal stress to the skin, away from damaged wound edges, with flexible force vectors and versatile methods of attachment to the skin, in a noninvasive or invasive manner.

Background/aims Chronic hepatitis B (CHB) infection is a serious public health problem due to its potential liver disease sequelae and highly expensive medical costs such as the need for liver transplantation. The aim of this study was to quantify the burden of active CHB in terms of mortality and morbidity, the eligibility of antiviral treatment and to assess various treatment scenarios and possible salvage combinations for cost-effectiveness. Methods A population cohort from a large data base of chronic hepatitis B patients was constructed and stratified according to 10-year age groups, the prevalence of HBsAg, HBV DNA level, ALT level, HBeAg status and the presence of cirrhosis. An age-specific Markov model for disease progression and cost-effectiveness analysis was constructed and calibrated for the specific population setting. Results Of about 3.2 million estimated HBsAg carriers, 25 % are eligible for treatment. If the active cohort remains untreated, 31 % will die due to liver related complications. Within a 20-year period, 11 % will have developed decompensated cirrhosis, 12 % liver cancer and 6 % will need liver transplantation. Quality adjusted life years (QALYs) for the no treatment scenario ranged from 9.3 to 14.0. For scenarios with antiviral treatment, QALYs ranged from 9.9 to 14.5 for lamivudine, 13.0–17.5 for salvage therapy, and 16.6–19.0 for the third generation drugs entecavir and tenofovir. Conclusion In a country with considerable amount of active CHB patients, monotherapy with a highly potent third generation drug has the most health-gain, and is cost-effective in both HBeAg-positive and negative in all stages of liver disease. Electronic supplementary material The online version of this article (doi:10.1007/s10198-012-0413-8) contains supplementary material, which is available to authorized users.