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BackgroundeHealth technology can help patients with cardiovascular disease adopt and maintain a healthy lifestyle by supporting self-management and offering guidance, coaching, and tailored information. However, to support patients over time, eHealth needs to blend in with their needs, treatment, and daily lives. Just as needs can differ between patients, needs can change within patients over time. To better adapt technology features to patients’ needs, it is necessary to account for these changes in needs and contexts of use. ObjectiveThis study aimed to identify and monitor patients’ needs for support from a web-based health management platform and how these needs change over time. It aimed to answer the following research questions: “How do novice and more advanced users experience an online health management platform?” “What user expectations support or hinder the adoption of an online health management platform, from a user perspective?” and “How does actual usage relate to user experiences and adoption?” MethodsA mixed methods design was adopted. The first method involved 2 rounds of usability testing, followed by interviews, with 10 patients at 0 months (round 1) and 12 patients at 6 months (round 2). In the second method, log data were collected to describe the actual platform use. ResultsAfter starting cardiac rehabilitation, the platform was used frequently. The patients mentioned that they need to have an incentive, set goals, self-monitor their health data, and feel empowered by the platform. However, soon after the rehabilitation program stopped, use of the platform declined or patients even quit because of the lack of continued tailored or personalized advice. The reward system motivated them to log data, but most participants indicated that being healthy should be the main focus, not receiving gifts. A web-based platform is flexible, accessible, and does not have any obligations; however, it should be implemented as an addition to regular care. ConclusionsAlthough use of the platform declined in the longer term, patients quitting the technology did not directly indicate that the technology was not functioning well or that patients no longer focused on achieving their values. The key to success should not be user adherence to a platform but adherence to healthy lifestyle habits. Therefore, the implementation of eHealth should include the transition to a stage where patients might no longer need support from a technology platform to be independently and sustainably adherent to their healthy lifestyle habits. This emphasizes the importance of conducting multi-iterative evaluations to continuously monitor whether and how patients’ needs and contexts of use change over time. Future research should focus on how this transition can be identified and monitored and how these insights can inform the design and implementation of the technology.

BackgroundLong-term weight maintenance after weight loss is challenging, and innovative solutions are required. Digital technologies can support behavior change and, therefore, have the potential to be an effective tool for weight loss maintenance. However, to create meaningful and effective digital behavior change interventions that support end user values and needs, a combination of persuasive system design (PSD) principles and behavior change techniques (BCTs) might be needed. ObjectiveThis study aimed to investigate how an evidence-informed digital behavior change intervention can be designed and developed by combining PSD principles and BCTs into design features to support end user values and needs for long-term weight loss maintenance. MethodsThis study presents a concept for how PSD principles and BCTs can be translated into design features by combining design thinking and Agile methods to develop and deliver an evidence-informed digital behavior change intervention aimed at supporting weight maintenance. Overall, 45 stakeholders participated in the systematic and iterative development process comprising co-design workshops, prototyping, Agile development, and usability testing. This included prospective end users (n=17, 38%; ie, people with obesity who had lost ≥8% of their weight), health care providers (n=9, 20%), healthy volunteers (n=4, 9%), a service designer (n=1, 2%), and stakeholders from the multidisciplinary research and development team (n=14, 31%; ie, software developers; digital designers; and eHealth, behavior change, and obesity experts). Stakeholder input on how to operationalize the design features and optimize the technology was examined through formative evaluation and qualitative analyses using rapid and in-depth analysis approaches. ResultsA total of 17 design features combining PSD principles and BCTs were identified as important to support end user values and needs based on stakeholder input during the design and development of eCHANGE, a digital intervention to support long-term weight loss maintenance. The design features were combined into 4 main intervention components: Week Plan, My Overview, Knowledge and Skills, and Virtual Coach and Smart Feedback System. To support a healthy lifestyle and continued behavior change to maintain weight, PSD principles such as tailoring, personalization, self-monitoring, reminders, rewards, rehearsal, praise, and suggestions were combined and implemented into the design features together with BCTs from the clusters of goals and planning, feedback and monitoring, social support, repetition and substitution, shaping knowledge, natural consequences, associations, antecedents, identity, and self-belief. ConclusionsCombining and implementing PSD principles and BCTs in digital interventions aimed at supporting sustainable behavior change may contribute to the design of engaging and motivating interventions in line with end user values and needs. As such, the design and development of the eCHANGE intervention can provide valuable input for future design and tailoring of evidence-informed digital interventions, even beyond digital interventions in support of health behavior change and long-term weight loss maintenance. Trial RegistrationClinicalTrials.gov NCT04537988; https://clinicaltrials.gov/ct2/show/NCT04537988

The monitoring of antimicrobial resistance (AMR) in bacterial pathogens of animals is not currently coordinated at European level. To fill this gap, experts of the European Union Joint Action on Antimicrobial Resistance and Healthcare Associated Infections (EU-JAMRAI) recommended building the European Antimicrobial Resistance Surveillance network in Veterinary medicine (EARS-Vet). In this study, we (i) identified national monitoring systems for AMR in bacterial pathogens of animals (both companion and food-producing) among 27 countries affiliated to EU-JAMRAI, (ii) described their structures and operations, and (iii) analyzed their respective strengths, weaknesses, opportunities and threats (SWOT). Twelve countries reported having at least one national monitoring system in place, representing an opportunity to launch EARS-Vet, but highlighting important gaps in AMR data generation in Europe. In total, 15 national monitoring systems from 11 countries were described and analyzed. They displayed diverse structures and operations, but most of them shared common weaknesses (e.g., data management and representativeness) and common threats (e.g., economic vulnerability and data access), which could be addressed collectively under EARS-Vet. This work generated useful information to countries planning to build or improve their system, by learning from others’ experience. It also enabled to advance on a pragmatic harmonization strategy: EARS-Vet shall follow the European Committee on Antimicrobial Susceptibility Testing (EUCAST) standards, collect quantitative data and interpret AMR data using epidemiological cut-off values.

BackgroundThe full potential of eHealth technologies to support self-management and disease management for patients with chronic diseases is not being reached. A possible explanation for these lacking results is that during the development process, insufficient attention is paid to the needs, wishes, and context of the prospective end users. To overcome such issues, the user-centered design practice of creating personas is widely accepted to ensure the fit between a technology and the target group or end users throughout all phases of development. ObjectiveIn this study, we integrate several approaches to persona development into the Persona Approach Twente to attain a more holistic and structured approach that aligns with the iterative process of eHealth development. MethodsIn 3 steps, a secondary analysis was carried out on different parts of the data set using the Partitioning Around Medoids clustering method. First, we used health-related electronic patient record data only. Second, we added person-related data that were gathered through interviews and questionnaires. Third, we added log data. ResultsIn the first step, 2 clusters were found, with average silhouette widths of 0.12 and 0.27. In the second step, again 2 clusters were found, with average silhouette widths of 0.08 and 0.12. In the third step, 3 clusters were identified, with average silhouette widths of 0.09, 0.12, and 0.04. ConclusionsThe Persona Approach Twente is applicable for mixed types of data and allows alignment of this user-centered design method to the iterative approach of eHealth development. A variety of characteristics can be used that stretches beyond (standardized) medical and demographic measurements. Challenges lie in data quality and fitness for (quantitative) clustering.

BackgroundeHealth can revolutionize the way self-management support is offered to chronically ill individuals such as those with a cardiovascular disease (CVD). However, patients’ fluctuating motivation to actually perform self-management is an important factor for which to account. Tailoring and personalizing eHealth to fit with the values of individuals promises to be an effective motivational strategy. Nevertheless, how specific eHealth technologies and design features could potentially contribute to values of individuals with a CVD has not been explicitly studied before. ObjectiveThis study sought to connect a set of empirically validated, health-related values of individuals with a CVD with existing eHealth technologies and their design features. The study searched for potential connections between design features and values with the goal to advance knowledge about how eHealth technologies can actually be more meaningful and motivating for end users. MethodsUndertaking a technical investigation that fits with the value sensitive design framework, a content analysis of existing eHealth technologies was conducted. We matched 11 empirically validated values of CVD patients with 70 design features from 10 eHealth technologies that were previously identified in a systematic review. The analysis consisted mainly of a deductive coding stage performed independently by 3 members of the study team. In addition, researchers and developers of 6 of the 10 reviewed technologies provided input about potential feature-value connections. ResultsIn total, 98 connections were made between eHealth design features and patient values. This meant that some design features could contribute to multiple values. Importantly, some values were more often addressed than others. CVD patients’ values most often addressed were related to (1) having or maintaining a healthy lifestyle, (2) having an overview of personal health data, (3) having reliable information and advice, (4) having extrinsic motivators to accomplish goals or health-related activities, and (5) receiving personalized care. In contrast, values less often addressed concerned (6) perceiving low thresholds to access health care, (7) receiving social support, (8) preserving a sense of autonomy over life, and (9) not feeling fear, anxiety, or insecurity about health. Last, 2 largely unaddressed values were related to (10) having confidence and self-efficacy in the treatment or ability to achieve goals and (11) desiring to be seen as a person rather than a patient. ConclusionsPositively, existing eHealth technologies could be connected with CVD patients’ values, largely through design features that relate to educational support, self-monitoring support, behavior change support, feedback, and motivational incentives. Other design features such as reminders, prompts or cues, peer-based or expert-based human support, and general system personalization were also connected with values but in narrower ways. In future studies, the inferred feature-value connections must be validated with empirical data from individuals with a CVD or similar chronic conditions.

BackgroundeHealth interventions are developed to support and facilitate patients with lifestyle changes and self-care tasks after being diagnosed with a cardiovascular disease (CVD). Creating long-lasting effects on lifestyle change and health outcomes with eHealth interventions is challenging and requires good understanding of patient values. ObjectiveThe aim of the study was to identify values of importance to patients with CVD to aid in designing a technological lifestyle platform. MethodsA mixed method design was applied, combining data from usability testing with an additional online survey study, to validate the outcomes of the usability tests. ResultsA total of 11 relevant patient values were identified, including the need for security, support, not wanting to feel anxious, tailoring of treatment, and personalized, accessible care. The validation survey shows that all values but one (value 9: To have extrinsic motivation to accomplish goals or activities [related to health/lifestyle]) were regarded as important/very important. A rating of very unimportant or unimportant was given by less than 2% of the respondents (value 1: 4/641, 0.6%; value 2: 10/641, 1.6%; value 3: 9/641, 1.4%; value 4: 5/641, 0.8%; value 5: 10/641, 1.6%; value 6: 4/641, 0.6%; value 7: 10/639, 1.6%; value 8: 4/639, 0.6%; value 10: 3/636, 0.5%; value 11: 4/636, 0.6%) to all values except but one (value 9: 56/636, 8.8%). ConclusionsThere is a high consensus among patients regarding the identified values reflecting goals and themes central to their lives, while living with or managing their CVD. The identified values can serve as a foundation for future research to translate and integrate these values into the design of the eHealth technology. This may call for prioritization of values, as not all values can be met equally.

Polymyxin E (colistin) is a medically important active substance both in human and veterinary medicine. Colistin has been used in veterinary medicine since the 1950s. Due to the discovery of the plasmid-borne mcr gene in 2015 and the simultaneously increased importance in human medicine as a last-resort antibiotic, the use of colistin for animals was scrutinised. Though veterinary colistin sales dropped by 76.5% between 2011 to 2020, few studies evaluated real-world data on the use patterns of colistin in different European countries and sectors. A survey among veterinarians revealed that 51.9% did not use or ceased colistin, 33.4% decreased their use, 10.4% stabilised their use, and 2.7% increased use. The most important indications for colistin use were gastrointestinal diseases in pigs followed by septicaemia in poultry. A total of 106 (16.0%) responding veterinarians reported governmental/industry restrictions regarding colistin use, most commonly mentioning “use only after susceptibility testing” (57%). In brief, colistin was perceived as an essential last-resort antibiotic in veterinary medicine for E. coli infections in pigs and poultry, where there is no alternative legal, safe, and efficacious antimicrobial available. To further reduce the need for colistin, synergistic preventive measures, including improved biosecurity, husbandry, and vaccinations, must be employed.

BackgroundA promising new approach to support lifestyle changes in patients with cardiovascular disease (CVD) is the use of financial incentives. Although financial incentives have proven to be effective, their implementation remains controversial, and ethical objections have been raised. It is unknown whether health care professionals (HCPs) involved in CVD care find it acceptable to provide financial incentives to patients with CVD as support for lifestyle change. ObjectiveThis study aims to investigate HCPs’ perspectives on using financial incentives to support healthy living for patients with CVD. More specifically, we aim to provide insight into attitudes toward using financial incentives as well as obstacles and facilitators of implementing financial incentives in current CVD care. MethodsA total of 16 semistructured, in-depth, face-to-face interviews were conducted with Dutch HCPs involved in supporting patients with CVD with lifestyle changes. The topics discussed were attitudes toward an incentive system, obstacles to using an incentive system, and possible solutions to facilitate the use of an incentive system. ResultsHCPs perceived an incentive system for healthy living for patients with CVD as possibly effective and showed generally high acceptance. However, there were concerns related to focusing too much on the extrinsic aspects of lifestyle change, disengagement when rewards are insignificant, paternalization and threatening autonomy, and low digital literacy in the target group. According to HCPs, solutions to mitigate these concerns included emphasizing intrinsic aspects of healthy living while giving extrinsic rewards, integrating social aspects to increase engagement, supporting autonomy by allowing freedom of choice in rewards, and aiming for a target group that can work with the necessary technology. ConclusionsThis study mapped perspectives of Dutch HCPs and showed that attitudes are predominantly positive, provided that contextual factors, design, and target groups are accurately considered. Concerns about digital literacy in the target group are novel findings that warrant further investigation. Follow-up research is needed to validate these insights among patients with CVD.

Major efforts have been made by veterinary professionals to reduce the need for antibiotic use in animals. An online survey launched by the Federation of Veterinarians of Europe (FVE) aimed to gather responses from practicing veterinarians with field experience in metaphylactic livestock group treatment. Only 17% of all veterinarians (n = 183/1087, all species-specific responses merged) applied metaphylactic group treatments to 75% or more of all their treatments. Significantly less metaphylactic group treatments were reported in mixed practices (p = 0.002) and practices specialized in cattle (p < 0.001) as well as small (p = 0.007) and very small practices (p = 0.009). Gram-negative bacteria, mostly composed of Enterobacteriaceae and Pasteurellaceae, were considered by 75.3% (n = 967/1385) as the most devastating bacterial pathogens. Respondents alleged morbidity (20.1%, n = 201/998) and mortality (42.2%, n = 421/998) as major consequences for animal health and welfare if metaphylaxis would be banned. Responding veterinarians pointed towards vaccinations; improved biosecurity, including hygiene measures; and improved herd health management as the three most effective alternative measures to prevent metaphylactic treatment. However, more research is needed on how to implement appropriate alternatives in a holistic hurdle approach. Active support on a national level will be necessary for the development and application of targeted veterinary treatment guidelines for practitioners, which promote the understanding of drivers and include initiation criteria for metaphylactic group treatments in livestock.

The application of biomolecular magnetic resonance imaging becomes increasingly important in the context of early cartilage changes in degenerative and inflammatory joint disease before gross morphological changes become apparent. In this limited technical report, we investigate the correlation of MRI T1, T2 and T1ρ relaxation times with quantitative biochemical measurements of proteoglycan and collagen contents of cartilage in close synopsis with histologic morphology. A recently developed MRI sequence, T1ρ, was able to detect early intracartilaginous degeneration quantitatively and also qualitatively by color mapping demonstrating a higher sensitivity than standard T2-weighted sequences. The results correlated highly with reduced proteoglycan content and disrupted collagen architecture as measured by biochemistry and histology. The findings lend support to a clinical implementation that allows rapid visual capturing of pathology on a local, millimeter level. Further information about articular cartilage quality otherwise not detectable in vivo, via normal inspection, is needed for orthopedic treatment decisions in the present and future.

BackgroundAn increasing number of eHealth interventions aim to support healthy behaviors that facilitate weight loss. However, there is limited evidence of the effectiveness of the interventions and little focus on weight loss maintenance. Knowledge about end user values and needs is essential to create meaningful and effective eHealth interventions, and to identify persuasive system design (PSD) principles and behavior change techniques (BCTs) that may contribute to the behavior change required for successful long-term weight loss maintenance. ObjectiveThis study aimed to provide insight into the design of eHealth interventions supporting behavior change for long-term weight maintenance. The study sought to identify the values and needs of people with obesity aiming to maintain weight after weight loss, and to identify PSD principles, BCTs, and design requirements that potentially enable an eHealth intervention to meet end user values and needs. MethodsThis study presents the concept of integrating PSD principles and BCTs into the design process of eHealth interventions to meet user values and needs. In this study, individual interviews and focus groups were conducted with people with obesity (n=23) and other key stakeholders (n=27) to explore end user values and needs related to weight loss maintenance. Design thinking methods were applied during the focus group sessions to identify design elements and to explore how eHealth solutions can support the needs to achieve sustainable weight loss maintenance. The PSD model and behavior change taxonomy by Michie were used to identify PSD principles and BCT clusters to meet end user values and needs. ResultsA total of 8 key end user values were identified, reflecting user needs for weight loss maintenance support: self-management, personalized care, autonomy, feel supported, positive self-image, motivation, happiness, and health. Goals and planning, feedback and monitoring, repetition and substitution, shaping knowledge, social support, identity, and self-belief were some of the BCT clusters identified to address these concepts, together with PSD principles such as personalization, tailoring, self-monitoring, praise, and suggestions. ConclusionsThe process of translating end user values and needs into design elements or features of eHealth technologies is an important part of the design process. To our knowledge, this is the first study to explore how PSD principles and BCTs can be integrated when designing eHealth self-management interventions for long-term weight loss maintenance. End users and other key stakeholders highlighted important factors to be considered in the design of eHealth interventions supporting sustained behavior change. The PSD principles and BCTs identified provide insights and suggestions about design elements and features to include for supporting weight loss maintenance. The findings indicate that a combination of BCTs and PSD principles may be needed in evidence-based eHealth interventions to stimulate motivation and adherence to support healthy behaviors and sustained weight loss maintenance. Trial RegistrationClinicalTrials.gov NCT04537988; https://clinicaltrials.gov/ct2/show/NCT04537988

BackgroundAlthough eMental health interventions, especially when delivered in a blended way, have great potential to improve the quality and efficiency of mental health care, their use in practice lags behind expectations. The Fit for Blended Care (FfBC) instrument was developed to support therapists and clients in shaping blended care in a way that optimally fits their needs. However, this existing version cannot be directly applied to specific branches of mental health care as it is too broad and generic. ObjectiveThe goal of this study is to adapt the existing FfBC instrument to fit a specific, complex setting—forensic mental health care—by means of participatory development with therapists. MethodsThe participatory process was divided into 4 phases and was executed by a project team consisting of 1 manager, 3-5 therapists, and 1 researcher. In phase 1, general requirements for the adaptation of the existing instrument were discussed in 2 focus groups with the project team. In phase 2, patient-related factors that influence the use of an existing web-based intervention were elicited through semistructured interviews with all 18 therapists working at an outpatient clinic. In phase 3, multiple focus groups with the project teams were held to create the first version of the adapted FfBC instrument. In phase 4, a digital prototype of the instrument was used with 8 patients, and the experiences of the 4 therapists were discussed in a focus group. ResultsIn phase 1, it became clear that the therapists’ main requirement was to develop a much shorter instrument with a few items, in which the content was specifically tailored to the characteristics of forensic psychiatric outpatients. The interviews showed a broad range of patient-related factors, of which 5 were used in the instrument: motivation for blended treatment; writing about thoughts, feelings, and behavior; conscientiousness; psychosocial problems; and social support. In addition, a part of the instrument was focused on the practical necessary preconditions that patients should fill by themselves before the treatment was developed. The use of the web-based prototype of the instrument in treatment resulted in overall positive experiences with the content; however, therapists indicated that the items should be formulated in a more patient-centered way to encourage their involvement in discussing the factors. ConclusionsThe participatory, iterative process of this study resulted in an adapted version of the FfBC instrument that fits the specific forensic context and supports shared decision making. In general, the adaptiveness of the instrument is important: its content and implementation should fit the type of care, the organization, and eHealth intervention. To adapt the instrument to other contexts, the guidelines described in this paper can be followed.

BackgroundElectronic health (eHealth) is a rapidly evolving field informed by multiple scientific disciplines. Because of this, the use of different terms and concepts to explain the same phenomena and lack of standardization in reporting interventions often leaves a gap that hinders knowledge accumulation. Interventions focused on self-management support of cardiovascular diseases through the use of remote monitoring technologies are a cross-disciplinary area potentially affected by this gap. A review of the underlying frameworks, models, and theories that have informed projects at this crossroad could advance future research and development efforts. ObjectiveThis research aimed to identify and compare underlying approaches that have informed interventions focused on self-management support of cardiovascular diseases through the use of remote monitoring technologies. The objective was to achieve an understanding of the distinct approaches by highlighting common or conflicting principles, guidelines, and methods. MethodsThe metaethnography approach was used to review and synthesize researchers’ reports on how they applied frameworks, models, and theories in their projects. Literature was systematically searched in 7 databases: Scopus, Web of Science, EMBASE, CINAHL, PsycINFO, Association for Computing Machinery Digital Library, and Cochrane Library. Included studies were thoroughly read and coded to extract data for the synthesis. Studies were mainly related by the key ingredients of the underlying approaches they applied. The key ingredients were finally translated across studies and synthesized into thematic clusters. ResultsOf 1224 initial results, 17 articles were included. The articles described research and development of 10 different projects. Frameworks, models, and theories (n=43) applied by the projects were identified. Key ingredients (n=293) of the included articles were mapped to the following themes of eHealth development: (1) it is a participatory process; (2) it creates new infrastructures for improving health care, health, and well-being; (3) it is intertwined with implementation; (4) it integrates theory, evidence, and participatory approaches for persuasive design; (5) it requires continuous evaluation cycles; (6) it targets behavior change; (7) it targets technology adoption; and (8) it targets health-related outcomes. ConclusionsThe findings of this review support and exemplify the numerous possibilities in the use of frameworks, models, and theories to guide research and development of eHealth. Participatory, user-centered design, and integration with empirical evidence and theoretical modeling were widely identified principles in the literature. On the contrary, less attention has been given to the integration of implementation in the development process and supporting novel eHealth-based health care infrastructures. To better integrate theory and evidence, holistic approaches can combine patient-centered studies with consolidated knowledge from expert-based approaches. Trial RegistrationPROSPERO CRD42018104397; https://tinyurl.com/y8ajyajt International Registered Report Identifier (IRRID)RR2-10.2196/13334

Denosumab is a potent osteoclast inhibitor targeted to prevent osteoporotic bone loss and thereby reduce fractures in the aging population. Recently, an elevated risk of rebound fractures following denosumab discontinuation was identified, unless patients were transitioned to an alternative antiresorptive medication. How denosumab affects the interaction of mechanosensitive osteocytes and bone quality remains unknown. We hypothesized that denosumab influences osteocyte function contributing to bone reorganization and increased fractures during discontinuation. Bone quality and osteocytes were assessed in archived iliac crest bone biopsies obtained from patients with high fracture occurrence from 2011 to 2016. Biopsies were obtained due to high fracture occurrence prior and during osteoporosis therapy from (i) patients with at least two semiannual subcutaneous injections of 60 mg denosumab, (ii) patients with rebound fractures during discontinuation, and (iii) patients of a treatment-naive group. In total, biopsies from 43 individuals were analyzed (mean age, 65.5 ± 12.1 years). Our results showed that during denosumab treatment, iliac cortical bone had a higher bone tissue hardness compared to treatment-naive bone (p = 0.0077) and a higher percentage of mineralized osteocyte lacunae (p = 0.0095). The density of empty osteocyte lacunae was higher with denosumab compared to treatment-naive (p = 0.014) and remained high in trabecular bone during discontinuation (p = 0.0071). We conclude that during denosumab treatment, increased bone hardness may contribute to improved fracture resistance. In biopsies from patients with high fracture occurrence, denosumab treatment reduced osteocyte viability, an effect that persisted during treatment discontinuation. High-resolution imaging of osteocyte viability indicates a role for osteocytes as a potential future mechanistic target to understand rebound bone loss and increased fractures with denosumab discontinuation.

BackgroundSeveral agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate).Methodology/principal findingsBiopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis.Conclusions/significanceMicrostructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch.

INTRODUCTION:Liver metastases from neuroendocrine tumors in multiple endocrine neoplasia syndrome are common (75%) and significantly impairs the prognosis. Characterisation of liver lesions in these patients is challenging, as liver metastases are difficult to differentiate from benign liver lesions such as haemangioma. METHODS:In this study we aimed to characterize the radiological findings of hepatic metastases in MEN patients. The findings of contrast-enhanced CT were considered for the main diagnosis. We retrospectively evaluated 25 patients with MEN-syndrome (10 MEN1/ 15 MEN2) including 11 men and 14 women between 28-62 years of age. RESULTS:Liver metastases (48%, 12/25) and hemangioma (40%, 10/25) were the most common liver lesions among our patients. The most common primary tumors in our MEN1 and MEN2 patients with liver metastases were of pancreatic neuroendocrine tumor (70%, 7/10) und medullary thyroid carcinoma (100%, 15/15) origin, respectively. CT-characteristics were grouped into three main categories, depending on contrast dynamics. The majority of hepatic metastases (75%, 14/25) are presented as multiple lesions with a slow growth in an average 5 years of follow-up-period. We were able to find a common CT pattern and categorise these for each MEN-syndrome. Hepatic metastases in MEN1 presented commonly a blurred arterial enhancement with a low portal venous enhancement and less frequently a prominent enhancement in the arterial phase, which mimics the classical haemangioma. In MEN2 the liver metastases exhibited disseminated mixed hyper- and hypo-enhanced lesions in CT-scans. Moreover, lesion calcifications are pathognomonic in MEN2. The main limitation of this study is the missing histopathological confirmation in the majority of cases. CONCLUSIONS:In this retrospective imaging study, we were able to categorise and find a common CT pattern for hepatic lesions in patients with MEN-syndrome. In order to differentiate these lesions sufficiently, a combination of a 3-phasic CT-scan with US is required. Other liver specific imaging modalities (MRI, CEUS, SMS-PET/CT) should complement the diagnosis in individual cases.

In this month's editorial, the PLOS Medicine Editors discuss the challenges of addressing a growing population with Alzheimer disease and dementia amidst disappointing news from the pharmaceutical industry.