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Background: Internet-Based Cognitive Behavioral Therapy (iCBT) holds great potential in addressing mental health issues, yet its real-world implementation poses significant challenges. While prior research has predominantly focused on centralized care models, this study explores the implementation of iCBT in the context of decentralized organizational structures within the Swedish primary care setting, where all interventions traditionally are delivered at local Primary Care Centers (PCCs). Aim: This study aims to enhance our understanding of iCBT implementation in primary care and assess the impact of organizational models on the implementation's outcome using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Method: A mixed-methods research design was employed to identify the factors influencing iCBT implementation across different levels, involving patients, therapists and managers. Data spanning two years was collected and analyzed through thematic analysis and statistical tests. The study encompassed 104 primary care centers, with patient data (n = 1979) sourced from the Swedish National Quality Register for Internet-Based Psychological Treatment (SibeR). Additionally, 53 iCBT therapists and 50 PCC managers completed the Normalization Measure Development Questionnaire, and 15 leaders participated in interviews. Results: Our investigation identified two implementation approaches, one concentrated and one decentralized. Implementation effectiveness was evident through adherence rates suggesting that iCBT is a promising approach for treating mental ill-health in primary care, although challenges were observed concerning patient assessment and therapist drift towards unstructured treatment. Mandatory implementation, along with managerial and organizational support, positively impacted adoption. Results vary in terms of adherence to established protocols, with therapists working in concentrated model showing a significantly higher percentage of registration in the quality register SibeR (X2 (1, N = 2973) = 430.5774, p = 0.001). They also showed significantly higher means in cognitive participation (Z = −2.179, p = 0.029) and in reflective monitoring (Z = −2.548, p = 0.011). Discussion: Overall, the study results demonstrate that iCBT, as a complex and qualitatively different intervention from traditional psychological treatment, can be widely implemented in primary care settings. The study's key finding highlights the substantial advantages of the concentrated organizational model. This model has strengths in sustainability, encourages reflective monitoring among therapists, the use of quality registers, and enforces established protocols. Conclusion: In conclusion, this study significantly contributes to the understanding of the practical aspects associated with the implementation of complex internet interventions, particularly in the context of internet-based cognitive-behavioral therapy (iCBT). The study highlights that effective iCBT integration into primary care requires a multifaceted approach, taking into account organizational models, robust support structures, and a commitment to maintaining quality standards. By emphasizing these factors, our research aims to provide actionable insights that can enhance the practicability and real-world applicability of implementing iCBT in primary care settings.

IntroductionInterest in applying systems thinking (ST) in public health and healthcare improvement has increased in the past decade, but its practical use is still unclear. ST has been found useful in addressing the complexity and dynamics of organizations and welfare systems during periods of change. Exploring how ST is used in practice in national policy programs addressing complex and ill-structured problems can increase the knowledge of the use and eventually the usefulness of ST during complex changes. In ST, a multi-level approach is suggested to coordinate interventions over individual, organizational, and community levels, but most attempts to operationalize ST focus on the individual level. This study aimed to investigate how ST is expressed in policy programs addressing wicked problems and describe the specific action strategies used in practice in a national program in Sweden, using a new conceptual framework comprising ST principles on the organizational level as an analytical tool. The program addresses several challenges and aims to achieve systems change within women's healthcare.MethodsThe case study used a rich set of qualitative, longitudinal data on individual, group, and organizational levels, collected during the implementation of the program. Deductive content analysis provided narrative descriptions of how the ST principles were expressed in actions, based on interviews, observations, and archival data.ResultsThe results showed that the program management team used various strategies and activities corresponding to organizational level ST. The team convened numerous types of actors and used collaborative approaches and many different information sources in striving to create a joint and holistic understanding of the program and its context. Visualization tools and adaptive approaches were used to support regional contact persons and staff in their development work. Efforts were made to identify high-leverage solutions to problems influencing the quality and coordination of care before, during, and after childbirth, solutions adaptable to regional conditions.Discussion/conclusionsThe organizational level ST framework was useful for identifying ST in practice in the policy program, but to increase further understanding of how ST is applied within policy programs, we suggest a multi-dimensional model to identify ST on several levels.

It is widely acknowledged that systems thinking (ST) should be implemented in the area of public health, but how this should be done is less clear. In this commentary we focus on sense-making and double-loop learning processes when using ST and soft systems methodology in research collaborations with policy-makers. In their study of policy-makers’ experiences of ST, Haynes et al emphasize the importance of knowledge processes and mutual learning between researchers and policy-makers, processes which can change how policy-makers think and thus have impact on real-world policy concerns. We provide some additional examples from Sweden on how ST has been applied to create learning and shared mental models among stakeholders and researchers in national and regional healthcare development initiatives. We conclude that investigating and describing such processes on micro-level can aid the knowledge on how to implement ST in public health.

Bowen et al highlight the trend towards partnership research to address the complex challenges currently facing healthcare systems and organizations world-wide. They focus on important strategic actors in partner organizations and their experiences, views and advice for sustainable collaboration, within a Canadian context. The authors call for a multi-system change to provide better conditions for research partnerships. They highlight needs to re-imagine research, to move beyond an ‘acute care’ and clinical focus in research, to re-think research funding, and to improve the academic preparation for research partnerships. In this commentary we provide input to the discussion on practical guidance for those involved in research partnerships based on our partnership experiences from ten research projects conducted within the Swedish healthcare system since 2007. We also highlight areas that need attention in future research in order to learn from approaches used for collaborative and partnership research.

Abstract Aim The aim was to investigate assistant nurses’ perceptions of how working with national quality registries affected their work situation in care of older people. Design Qualitative interview study. Methods Sixteen semi‐structured interviews were conducted at four special housing units in Sweden, and a conventional content analysis, with elements of thematic analysis, was applied. Results The introduction of national quality registries contributed to role clarifications and the development of new formal work procedures in terms of documentation and arenas and routines for communication. The increased systematics and effectiveness gained from these changes had a perceived positive effect on the work situation, workload, work satisfaction, staff interactions and learning and reflection.

Abstract Background Person-centered care (PCC) emphasize the importance of supporting individuals’ involvement in care provided and self-care. PCC has become more important in chronic care as the number of people living with chronic conditions is increasing due to the demographic changes. Digital tools have potential to support interaction between patients and healthcare providers, but empirical examples of how to achieve PCC in chronic care and the role of digital tools in this process is limited. The aim of this study was to investigate strategies to achieve PCC used by the healthcare professionals at an outpatient Rheumatology clinic (RC), the strategies’ relation to digital tools, and the perceived impact of the strategies on healthcare professionals and patients. Methods A single case study design was used. The qualitative data consisted of 14 semi-structured interviews and staff meeting minutes, covering the time period 2017–2019. The data were analyzed using conventional content analysis, complemented with document analyses. Results Ten strategies on two levels to operationalize PCC, and three categories of perceived impact were identified. On the individual patient level strategies involved several digital tools focusing on flexible access to care, mutual information sharing and the distribution of initiatives, tasks, and responsibilities from provider to patients. On the unit level, strategies concerned involving patient representatives and individual patients in development of digital services and work practices. The roles of both professionals and patients were affected and the importance of behavioral and cultural change became clear. Conclusions By providing an empirical example from chronic care the study contributes to the knowledge on strategies for achieving PCC, how digital tools and work practices interact, and how they can affect healthcare staff, patients and the unit. A conclusion is that the use of the digital tools, spanning over different dimensions of engagement, facilitated the healthcare professionals’ interaction with patients and the patients’ involvement in their own care. Digital tools complemented, rather than replaced, care practices.

Abstract Background Swedish National Quality Registries (NQRs) are observational clinical registries that have long been seen as an underused resource for research and quality improvement (QI) in health care. In recent years, NQRs have also been recognised as an area where patients can be involved, contributing with self-reported experiences and estimations of health effects. This study aimed to investigate what the registry management perceived as barriers and facilitators for the use of NQRs in QI, research, and interaction with patients, and main activities undertaken to enhance their use for these purposes. The aim was further to identify potential differences between various types of NQRs for their use in these areas. Methods In this multiple case study, nine NQRs were purposively selected. Interviews (n = 18) were conducted and analysed iteratively using conventional and directed content analysis. Results A recent national investment initiative enabled more intensive work with development areas previously identified by the NQR management teams. The recent focus on value-based health care and other contemporary national healthcare investments aiming at QI and public benchmarking were perceived as facilitating factors. Having to perform double registrations due to shortcomings in digital systems was perceived as a barrier, as was the lack of authority on behalf of the registry management to request participation in NQRs and QI activities based on registry outcomes. The registry management teams used three strategies to enhance the use of NQRs: ensuring registering of correct and complete data, ensuring updated and understandable information available for patients, clinicians, researchers and others stakeholders, and intensifying cooperation with them. Varied characteristics of the NQRs influenced their use, and the possibility to reach various end-users was connected to the focus area and context of the NQRs. Conclusions The recent national investment initiative contributed to already ongoing work to strengthen the use of NQRs. To further increase the use, the demands of stakeholders and end-users must be in focus, but also an understanding of the NQRs’ various characteristics and challenges. The end-users may have in common a need for training in the methodology of registry based research and benchmarking, and how to be more patient-centred.

Abstract Background Eldercare and care of people with functional impairments is organized by the municipalities in Sweden. Improving care in these areas is complex, with multiple stakeholders and organizations. Appropriate strategies to develop capability for continuing organizational improvement and learning (COIL) are needed. The purpose of our study was to develop and pilot-test a flexible, multilevel approach for COIL capability building and to identify what it takes to achieve changes in key actors’ approaches to COIL. The approach, named “Sustainable Improvement and Development through Strategic and Systematic Approaches” (SIDSSA), was applied through an action-research and action-learning intervention. Methods The SIDSSA approach was tested in a regional research and development (R&D) unit, and in two municipalities handling care of the elderly and people with functional impairments. Our approach included a multilevel strategy, development loops of five flexible phases, and an action-learning loop. The approach was designed to support systems understanding, strategic focus, methodological practices, and change process knowledge - all of which required double-loop learning. Multiple qualitative methods, i.e., repeated interviews, process diaries, and documents, provided data for conventional content analyses. Results The new approach was successfully tested on all cases and adopted and sustained by the R&D unit. Participants reported new insights and skills. The development loop facilitated a sense of coherence and control during uncertainty, improved planning and problem analysis, enhanced mapping of context and conditions, and supported problem-solving at both the individual and unit levels. The systems-level view and structured approach helped participants to explain, motivate, and implement change initiatives, especially after working more systematically with mapping, analyses, and goal setting. Conclusions An easily understood and generalizable model internalized by key organizational actors is an important step before more complex development models can be implemented. SIDSSA facilitated individual and group learning through action-learning and supported systems-level views and structured approaches across multiple organizational levels. Active involvement of diverse organizational functions and levels in the learning process was facilitated. However, the time frame was too short to fully test all aspects of the approach, specifically in reaching beyond the involved managers to front-line staff and patients.

Abstract Background Implementation of interventions concerning prevention and health promotion in health care has faced particular challenges resulting in a low frequency and quality of these services. In November 2011, the Swedish National Board of Health and Welfare released national clinical practice guidelines to counteract patients’ unhealthy lifestyle habits. Drawing on the results of a previous study as a point of departure, the aim of this two-year follow up was to assess the progress of work with lifestyle interventions in primary healthcare as well as the uptake and usage of the new guidelines on lifestyle interventions in clinical practice. Methods Longitudinal study among health professionals with survey at baseline and 2 years later. Development over time and differences between professional groups were calculated with Pearson chi-square test. Results Eighteen percent of the physicians reported to use the clinical practice guidelines, compared to 58% of the nurses. Nurses were also more likely to consider them as a support in their work than physicians did. Over time, health professionals usage of methods to change patients’ tobacco habits and hazardous use of alcohol had increased, and the nurses worked to a higher extent than before with all four lifestyles. Knowledge on methods for lifestyle change was generally high; however, there was room for improvement concerning methods on alcohol, unhealthy eating and counselling. Forty-one percent reported to possess thorough knowledge of counselling skills. Conclusions Even if the uptake and usage of the CPGs on lifestyle interventions so far is low, the participants reported more frequent counselling on patients’ lifestyle changes concerning use of tobacco and hazardous use of alcohol. However, these findings should be evaluated acknowledging the possibility of selection bias in favour of health promotion and lifestyle guidance, and the loss of one study site in the follow up. Furthermore, this study indicates important differences in physicians and nurses’ attitudes to and use of the guidelines, where the nurses reported working to a higher extent with all four lifestyles compared to the first study. These findings suggest further investigations on the implementation process in clinical practice, and the physicians’ uptake and use of the CPGs.

Hydrophobic long-chain alkyl ethers of Sephadex have been synthesized and tested for use in liquid chromatography. With columns prepared in such polar solvents as methanol, reversed-phase systems are obtained where compounds separate in order of decreasing polarity. In such nonpolar solvents as heptane, straight-phase systems are formed, and separations occur in order of increasing polarity. The retention volume of a compound is determined mainly by its polarity, the type and degree of substitution of Sephadex, and the nature of the solvent system. Examples are given of straight- and reversed-phase separations of waxes, fatty acids, glycerides, glycerol ethers, sterols, bile acids, and hormonal steroids. The Sephadex derivatives are simple to make, the columns are easy to prepare, and they can be used over long periods of time. Liquid-gel chromatography on alkyl ethers of Sephadex is a mild separation technique and should be a useful complement to other chromatographic methods.

Abstract Background Migration has increased the number of immigrant women in western countries, which has led to a need to adapt sexual and reproductive health (SRH) care to a larger variety of experiences. Examples of problems are poor access/utilization of SRH services among migrants and a comparatively higher rate of mortality and morbidity in relation to pregnancy, especially among those from low- and middle-income settings. Attempts to improve SHR care must consider the complexity of both the problem and the system. A national program to improve women’s health in Sweden provided opportunities to study interventions aimed at immigrant women, using a complexity theory lens. The purpose was to explore the characteristics and complexity of regional interventions aiming to improve care and health of immigrant women before, during and after childbirth, and provide knowledge on how regional healthcare actors perceive and address problems in these areas. Methods This archival research study is based on qualitative data from detailed yearly reports of all regional program interventions (n = 21 regions) performed between January 2017 and January 2019. The archival data consists of the regional actors’ answers to an extensive questionnaire-like template, where the same questions were to be filled in for each reported intervention. Data analyses were performed in several steps, combining classic and directive content analysis. Results Six problem categories were addressed by 54 regional interventions, 26 directed at immigrant women and their families, 11 at healthcare staff, and 17 at the organizational system. The simple level interventions (n = 23) were more unilateral and contained information campaigns, information material and translation, education, mapping e.g., of genital mutilation, and providing staff and/or financial resources. The complicated interventions (n = 10) concerned increasing communication diversity e.g., by adding iPads and out-reach visits. The complex interventions (n = 21), e.g., health schools, integration of care, contained development, adaptions, and flexibility with regards to the immigrant women’s situation, and more interaction among a diversity of actors, also from the wider welfare system. Conclusions It is important that complex problems, such as ensuring equal care and health among a diverse population, are addressed with a mix of simple, complicated, and complex interventions. To enhance intended change, we suggest that pre-requisites e.g., communication channels and knowledge on behalf of immigrant women and staff, are ensured before the launch of complex interventions. Alternatively, that simple level interventions are embedded in complex interventions.

Abstract Background Getting research into policy and practice in healthcare is a recognised, world-wide concern. As an attempt to bridge the gap between research and practice, research funders are requesting more interdisciplinary and collaborative research, while actual experiences of such processes have been less studied. Accordingly, the purpose of this study was to gain more knowledge on the interdisciplinary, collaborative and partnership research process by investigating researchers’ experiences of and approaches to the process, based on their participation in an inventive national research programme. The programme aimed to boost collaborative and partnership research and build learning structures, while improving ways to lead, manage and develop practices in Swedish health and social services. Methods Interviews conducted with project leaders and/or lead researchers and documentation from 20 projects were analysed using directed and conventional content analysis. Results Collaborative approaches were achieved by design, e.g. action research, or by involving practitioners from several levels of the healthcare system in various parts of the research process. The use of dual roles as researcher/clinician or practitioner/PhD student or the use of education designed especially for practitioners or ‘student researchers’ were other approaches. The collaborative process constituted the area for the main lessons learned as well as the main problems. Difficulties concerned handling complexity and conflicts between different expectations and demands in the practitioner’s and researcher’s contexts, and dealing with human resource issues and group interactions when forming collaborative and interdisciplinary research teams. The handling of such challenges required time, resources, knowledge, interactive learning and skilled project management. Conclusions Collaborative approaches are important in the study of complex phenomena. Results from this study show that allocated time, arenas for interactions and skills in project management and communication are needed during research collaboration to ensure support and build trust and understanding with involved practitioners at several levels in the healthcare system. For researchers, dealing with this complexity takes time and energy from the scientific process. For practitioners, this puts demands on understanding a research process and how it fits with on-going organisational agendas and activities and allocating time. Some of the identified factors may be overlooked by funders and involved stakeholders when designing, performing and evaluating interdisciplinary, collaborative and partnership research.

In the distal colon, mucus secreting goblet cells primarily confer protection from luminal microorganisms via generation of a sterile inner mucus layer barrier structure. Bacteria-sensing sentinel goblet cells provide a secondary defensive mechanism that orchestrates mucus secretion in response to microbes that breach the mucus barrier. Previous reports have identified mucus barrier deficiencies in adult germ-free mice, thus implicating a fundamental role for the microbiota in programming mucus barrier generation. In this study, we have investigated the natural neonatal development of the mucus barrier and sentinel goblet cell-dependent secretory responses upon postnatal colonization. Combined in vivo and ex vivo analyses of pre- and post-weaning colonic mucus barrier and sentinel goblet cell maturation demonstrated a sequential microbiota-dependent development of these primary and secondary goblet cell-intrinsic protective functions, with dynamic changes in mucus processing dependent on innate immune signalling via MyD88, and development of functional sentinel goblet cells dependent on the NADPH/Dual oxidase family member Duox2. Our findings therefore identify new mechanisms of microbiota-goblet cell regulatory interaction and highlight the critical importance of the pre-weaning period for the normal development of colonic barrier function.

Background: This study aimed to evaluate clinically relevant improvement after conservative self-management of urinary incontinence via a mobile app. It further aimed to establish Minimum Important Differences (MIDs) based on the severity and type of urinary incontinence., Methods: Data was collected in a prospective cohort study that evaluated the freely available app Tät®. The app provided pelvic floor muscle training (PFMT) and life-style advice. Non-pregnant, non-postpartum women (≥ 18 years) who downloaded the app to treat urinary incontinence were included, if they completed the Patient Global Impression of Improvement (PGI-I) question at the 3-month follow-up (n = 1,733). Participants answered the International Consultation on Incontinence Questionnaire (ICIQ-UI SF) at baseline and after 3 months. The score change was analysed for correlation (Spearman) with the PGI-I. We then analysed one-way ANOVAs to determine whether there were significant differences between the groups based on the answers to the PGI-I. The MID was set to the mean change of the group that selected the answer "a little better" to the PGI-I question., Results: The one-way ANOVA showed significant differences between PGI-I groups (p < 0.001). The MID for the general group was set to 1.46 (95% Confidence Interval [CI] 1.26-1.67). In the sub-group analyses, a MID for the group with slight incontinence could not be determined. For the group with moderate severity the MID was determined to be 1.33 (95% CI 1.10-1.57) and for the severe/very severe group it was 3.58 (95% CI 3.08-4.09). Analysis of different types of incontinence showed no difference in MIDs., Conclusions: The MID for self-management via a mobile app was lower than previously established MIDs, but differed depending on baseline severity. This study shows that MIDs need adjustment for baseline severity and treatment intensity when interpreting clinical trial results. If using MIDs as exact numbers, the study population and the treatment must be comparable., (© 2024. The Author(s).)

Background: Many women experience urgency (UUI) and mixed (MUI) urinary incontinence but commonly hesitate to seek care. Treatment access and self-management for these conditions can be supported through eHealth approaches., Objective: This study aimed to investigate the efficacy of the mobile app Tät II for self-management of UUI and MUI in women., Methods: This randomized controlled trial included women ≥18 years old with UUI or MUI and ≥2 leakages per week. Those with red-flag symptoms were excluded. Participants were recruited via analog and digital advertisements and screened for initial selection through a web-based questionnaire. Data were collected using another questionnaire and a 2-day bladder diary. A telephone interview confirmed the symptom diagnosis. Participants were randomized (1:1) to receive access to a treatment app (including pelvic floor muscle training, bladder training, psychoeducation, lifestyle advice, tailored advice, exercise log, reinforcement messages, and reminders) or an information app (control group), with no external treatment guidance provided. The primary outcome was incontinence symptoms at the 15-week follow-up, measured using the International Consultation on Incontinence Questionnaire (ICIQ)-Urinary Incontinence Short Form (ICIQ-UI SF). Urgency symptoms were assessed using the ICIQ-Overactive Bladder Module (ICIQ-OAB) and quality of life using the ICIQ-Lower Urinary Tract Symptoms Quality of Life Module (ICIQ-LUTSqol). Incontinence episode frequency (IEF) was calculated per bladder diary entries. Improvement was measured using the Patient's Global Impression of Improvement. All outcomes were self-reported. Cure was defined as no leakages per the bladder diary. Intention-to-treat analysis was performed., Results: Between April 2017 and March 2018, 123 women (mean age 58.3, SD 9.6 years) were randomized to the treatment (n=60, 2 lost to follow-up) or information (n=63) group. Of these, 35 (28%) women had UUI, and 88 (72%) had MUI. Mean ICIQ-UI SF score at follow-up was lower in the treatment group than in the information group (estimated difference -3.1, 95% CI -4.8 to -1.3). The estimated between-group difference was -1.8 (95% CI -2.8 to -0.99) for mean ICIQ-OAB score and -6.3 (95% CI -10.5 to -2.1) for the mean ICIQ-LUTSqol score at follow-up. IEF reduction from baseline to follow-up was greater in the treatment group (-10.5, IQR -17.5 to -3.5) than in the information group (P<.001). Improvement was reported by 87% (52/60) of treatment group participants and by 30% (19/63) of information group participants. The cure rate was 32% in the treatment group, and 6% in the information group (odds ratio 5.4, 95% CI 1.9-15.6; P=.002). About 67% (40/60) of the treatment group participants used the app more than thrice a week., Conclusions: The treatment app was effective for improving urgency and mixed incontinence in women. When self-management is appropriate, this app may be a good alternative to pharmacological treatment or other conservative management, thus increasing access to care., Trial Registration: ClinicalTrials.gov NCT03097549; https://clinicaltrials.gov/ct2/show/NCT03097549., (©Towe Wadensten, Emma Nyström, Karin Franzén, Anna Lindam, Elisabet Wasteson, Eva Samuelsson. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 05.04.2021.)

One of the main treatment challenges in alcohol use disorder (AUD) is the high rate of craving in combination with decreased cognitive functioning including impaired decision making and impulse control that often lead to relapse. Recent studies show that guanfacine, an α-2-adrenoceptor agonist and FDA-approved ADHD medication, attenuates stress-induced relapse of several drugs of abuse including alcohol. Here we evaluated guanfacine's effects on voluntary alcohol intake, the alcohol deprivation effect (ADE), alcohol seeking behavior, and cue/priming-induced reinstatement in Wistar rats that had voluntarily consumed alcohol for at least 2 months before treatment. In addition, guanfacine's ability to regulate glutamatergic neurotransmission was evaluated through electrophysiological recordings in medial prefrontal cortex (mPFC) slices prepared from long-term drinking rats (and alcohol-naive controls) that had received three daily guanfacine (0.6 mg/kg/day) or vehicle injections in vivo. Guanfacine decreased alcohol intake in high, but not low, alcohol-consuming rats and the effects were generally more long lasting than that of the AUD medication naltrexone. Repeated guanfacine treatment induced a long-lasting decrease in alcohol intake, persistent up to five drinking sessions after the last injection. In addition, guanfacine attenuated the ADE as well as alcohol seeking and cue/priming-induced reinstatement of alcohol seeking. Finally, subchronic guanfacine treatment normalized an alcohol-induced dysregulated glutamatergic neurotransmission in the mPFC. These results support previous studies showing that guanfacine has the ability to improve prefrontal connectivity through modulation of the glutamatergic system. Together with the fact that guanfacine appears to be clinically safe, these results merit evaluation of guanfacine's clinical efficacy in AUD individuals.

Fundamental open questions in signal transduction remain concerning the sequence and distribution of molecular signaling events among individual cells. In this work, we have characterized the intercellular variability of transforming growth factor β-induced Smad interactions, providing essential information about TGF-β signaling and its dependence on the density of cell populations and the cell cycle phase. By employing the recently developed in situ proximity ligation assay, we investigated the dynamics of interactions and modifications of Smad proteins and their partners under native and physiological conditions. We analyzed the kinetics of assembly of Smad complexes and the influence of cellular environment and relation to mitosis. We report rapid kinetics of formation of Smad complexes, including native Smad2-Smad3-Smad4 trimeric complexes, in a manner influenced by the rate of proteasomal degradation of these proteins, and we found a striking cell to cell variation of signaling complexes. The single-cell analysis of TGF-β signaling in genetically unmodified cells revealed previously unknown aspects of regulation of this pathway, and it provided a basis for analysis of these signaling events to diagnose pathological perturbations in patient samples and to evaluate their susceptibility to drug treatment.

Background/objectives: Sweden has had a salt iodination program since 1936. This first national surveillance study on iodine nutrition infers an adequate level of urinary iodine concentration (UIC 125 μg/l) and the aim is now to evaluate thyroid volume (Tvol) in the same national sample., Subjects/methods: A stratified probability proportionate to size cluster sampling was used to obtain a representative national sample of Swedish children aged 6-12 years. Median Tvol obtained ultrasonographically and the prevalence of enlarged thyroid glands were compared with an international reference standard. Regional differences were evaluated through comparisons of Tvol between coastal and inland areas, urban and rural regions, and former goitre and non-goitre regions., Results: Tvol was correlated with age, body surface area (BSA), weight, height and body mass index for both sexes (P<0.0001) but not with UIC. The most important predictors for Tvol were age (girls: P<0.0001, boys: P=0.001) and BSA (girls: P<0.0001, boys: P<0.01). Median Tvol was higher in Sweden than in the reference study (P<0.0001). The prevalence of goitre was higher in Sweden (correlated to age 22.3%, BSA 15.7%, weight 17.6%, height 12.9%) than in the international reference (correlated to age 2.5%, BSA 2.5%, weight 2.5%, height 2.5%) (P<0.0001). Thyroids were larger in boys from urban and former non-goitre areas., Conclusions: Tvols were higher in Swedish school children than in the international reference study although iodine intake is considered optimal in Sweden. These findings underline the importance of regular monitoring of iodine intake, especially with regard to the decreased intake of table salt that is likely to follow initiation of health campaigns.