Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome.

A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFß modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining the Cre-LoxP recombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGFß signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGFß-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grown in vitro were longer and released less TGFß than the wild-type counterparts. Moreover, addition of recombinant TGFß1 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGFß signaling locally and improper GP differentiation distally.

FN (Fibronectin)-Integrin α5 Signaling Promotes Thoracic Aortic Aneurysm in a Mouse Model of Marfan Syndrome.

BACKGROUND: Marfan syndrome, caused by mutations in the gene for fibrillin-1, leads to thoracic aortic aneurysms (TAAs). Phenotypic modulation of vascular smooth muscle cells (SMCs) and ECM (extracellular matrix) remodeling are characteristic of both nonsyndromic and Marfan aneurysms. The ECM protein FN (fibronectin) is elevated in the tunica media of TAAs and amplifies inflammatory signaling in endothelial and SMCs through its main receptor, integrin α5ß1. We investigated the role of integrin α5-specific signals in Marfan mice in which the cytoplasmic domain of integrin α5 was replaced with that of integrin α2 (denoted α5/2 chimera). METHODS: We crossed α5/2 chimeric mice with Fbn1mgR/mgR mice (mgR model of Marfan syndrome) to evaluate the survival rate and pathogenesis of TAAs among wild-type, α5/2, mgR, and α5/2 mgR mice. Further biochemical and microscopic analysis of porcine and mouse aortic SMCs investigated molecular mechanisms by which FN affects SMCs and subsequent development of TAAs. RESULTS: FN was elevated in the thoracic aortas from Marfan patients, in nonsyndromic aneurysms, and in mgR mice. The α5/2 mutation greatly prolonged survival of Marfan mice, with improved elastic fiber integrity, mechanical properties, SMC density, and SMC contractile gene expression. Furthermore, plating of wild-type SMCs on FN decreased contractile gene expression and activated inflammatory pathways whereas α5/2 SMCs were resistant. These effects correlated with increased NF-kB activation in cultured SMCs and mgR aortas, which was alleviated by the α5/2 mutation or NF-kB inhibition. CONCLUSIONS: FN-integrin α5 signaling is a significant driver of TAA in the mgR mouse model. This pathway thus warrants further investigation as a therapeutic target.

Protein structure-based gene expression signatures.

Gene expression signatures (GES) connect phenotypes to differential messenger RNA (mRNA) expression of genes, providing a powerful approach to define cellular identity, function, and the effects of perturbations. The use of GES has suffered from vague assessment criteria and limited reproducibility. Because the structure of proteins defines the functional capability of genes, we hypothesized that enrichment of structural features could be a generalizable representation of gene sets. We derive structural gene expression signatures (sGES) using features from multiple levels of protein structure (e.g., domain and fold) encoded by the mRNAs in GES. Comprehensive analyses of data from the Genotype-Tissue Expression Project (GTEx), the all RNA-seq and ChIP-seq sample and signature search (ARCHS4) database, and mRNA expression of drug effects on cardiomyocytes show that sGES are useful for characterizing biological phenomena. sGES enable phenotypic characterization across experimental platforms, facilitates interoperability of expression datasets, and describe drug action on cells.

Whole cell response to receptor stimulation involves many deep and distributed subcellular biochemical processes.

Neurite outgrowth is an integrated whole cell response triggered by the cannabinoid-1 receptor. We sought to identify the many different biochemical pathways that contribute to this whole cell response. To understand underlying mechanisms, we identified subcellular processes (SCPs) composed of one or more biochemical pathways and their interactions required for this response. Differentially expressed genes and proteins were obtained from bulk transcriptomics and proteomic analysis of extracts from cells stimulated with a cannabinoid-1 receptor agonist. We used these differentially expressed genes and proteins to build networks of interacting SCPs by combining the expression data with prior pathway knowledge. From these SCP networks, we identified additional genes that when ablated, experimentally validated the SCP involvement in neurite outgrowth. Our experiments and informatics modeling allowed us to identify diverse SCPs such as those involved in pyrimidine metabolism, lipid biosynthesis, and mRNA splicing and stability, along with more predictable SCPs such as membrane vesicle transport and microtubule dynamics. We find that SCPs required for neurite outgrowth are widely distributed among many biochemical pathways required for constitutive cellular functions, several of which are termed 'deep', since they are distal to signaling pathways and the key SCPs directly involved in extension of the neurite. In contrast, 'proximal' SCPs are involved in microtubule growth and membrane vesicle transport dynamics required for neurite outgrowth. From these bioinformatics and dynamical models based on experimental data, we conclude that receptor-mediated regulation of subcellular functions for neurite outgrowth is both distributed, that is, involves many different biochemical pathways, and deep.

Functional Effects of Cardiomyocyte Injury in COVID-19.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1ß. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19.

Barriers and facilitators for sustainable weight loss in the pre-conception period among Danish women with overweight or obesity - a qualitative study.

BACKGROUND: The prevalence of overweight or obesity in women of reproductive age continues to increase. A high pre-pregnancy body mass index (BMI) has been shown to increase the risk of pregnancy complications and predispose offspring to childhood obesity. However, little is known about factors affecting women's ability to achieve sustainable weight management and very few studies have applied behavior change theory to qualitative data. AIM: This study aimed to explore barriers and facilitators for weight management among women with overweight or obesity, who wanted to lose weight before pregnancy. METHODS: We conducted semi-structured interviews with 17 women with a BMI ≥ 27 kg/m2, who planned to become pregnant in the near future. Data were analyzed using an abductive approach and the Capability, Opportunity, Motivation, and Behavior model was applied as a conceptual framework. RESULTS: The women's strongest motivator for pre-conception weight loss was their ability to become pregnant. Barriers to successful weight management included their partners' unhealthy behaviors, mental health challenges, competing priorities, and internalized weight stigmatization. The women described careful planning, partners' health behaviors, social support, and good mental health as facilitators for sustainable weight management. CONCLUSION: Our study provides insights into factors affecting weight management among women with overweight or obesity in the pre-conception period. Future interventions on weight management require a holistic approach, including a focus on social support, especially from the partner, and mental health, as well as an effort to limit internalized weight stigma.

Childhood social capital and drug use disorder in adulthood: A retrospective study on antecedent determinants of the type of drug use.

Based on a sample of Danish adults who were enroled in treatment for drug use disorders as a prerequisite for qualifying for receiving unemployment benefits, we analyse the relationship between low social capital in childhood (LSCC) and the type of drug use in adulthood. The type of drug use is measured by distinguishing between those who were treated for using hard drugs (e.g., heroin and cocaine) and those who were treated for using soft drugs (cannabis). Extracting data from the initial treatment registration report, social capital is operationalised into seven different LSCC categories, and the total number of LSCC (the LSCC score) is recorded. Based on logistic regressions, the LSCC score shows a strong graded dose-response relationship with hard drug use. With each additional LSCC, the probability of being treated for hard drug use increases with 9%. Parental child abuse is the most important single predictor of being treated for hard drug use. Having been parentally abused as a child raises the probability by 32%. The results hold after controlling for age, initiation age, and number of years of drug use, all of which show a significant reversed U-shaped relationship with hard drug use.

Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS). Approach and Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-ß/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness. Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.

Efficacy and safety of a novel mucoadhesive clobetasol patch for treatment of erosive oral lichen planus: A phase 2 randomized clinical trial.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disorder of the oral mucosa. Currently there is no approved treatment for OLP. We report on the efficacy and safety of a novel mucoadhesive clobetasol patch (Rivelin® -CLO) for the treatment of OLP. METHODS: Patients with confirmed OLP and measurable symptomatic ulcer(s) participated in a randomized, double-blind, placebo-controlled, multicenter clinical trial testing a novel mucoadhesive clobetasol patch (Rivelin® -CLO) in OLP across Europe, Canada, and the United States. Patients were randomized to placebo (nonmedicated), 1, 5, 20 µg Clobetasol/patch, twice daily, for 4 weeks. The primary endpoint was change in total ulcer area compared to baseline. Secondary endpoints included improvement from baseline in pain, disease activity, and quality of life. RESULTS: Data were analyzed and expressed as mean [SD]. One hundred thirty-eight patients were included in the study; 99 females and 39 males, mean age was 61.1 [11.6] years. Statistical analyses revealed that treatment with 20-µg Rivelin® -CLO patches demonstrated significant improvement with ulcer area (p = 0.047), symptom severity (p = 0.001), disease activity (p = 0.022), pain (p = 0.012), and quality of life (p = 0.003) as compared with placebo. Improvement in OLP symptoms from beginning to the end of the study was reported as very much better (best rating) in the 20-µg group (25/32) patients compared to the placebo group (11/30), (p = 0.012). Adverse events were mild/moderate. Candidiasis incidence was low (2%). CONCLUSIONS: Rivelin® -CLO patches were superior to placebo demonstrating statistically significant, clinically relevant efficacy in objective and subjective improvement and, with a favorable safety profile.

Examining Phenotypic Traits Contributing to the Spread in Northern European Potato Crops of EU_41_A2, a New Clonal Lineage of Phytophthora infestans.

Until recently, genotypes of Phytophthora infestans were regionally distributed in Europe, with populations in western Europe being dominated by clonal lineages and those in northern Europe being genetically diverse because of frequent sexual reproduction. However, since 2013 a new clonal lineage (EU_41_A2) has successfully established itself and expanded in the sexually recombining P. infestans populations of northern Europe. The objective of this study was to study phenotypic traits of the new clonal lineage of P. infestans, which may explain its successful establishment and expansion within sexually recombining populations. Fungicide sensitivity, aggressiveness, and virulence profiles of isolates of EU_41_A2 were analyzed and compared with those of the local sexual populations from Denmark, Norway, and Estonia. None of the phenotypic data obtained from the isolates collected from Denmark, Estonia, and Norway independently explained the invasive success of EU_41_A2 within sexual Nordic populations. Therefore, we hypothesize that the expansion of this new genotype could result from a combination of fitness traits and more favorable environmental conditions that have emerged in response to climate change.

Early recognition method for patients with schizophrenia or bipolar disorder in community mental health care: Illness insight, self-management and control.

AIMS AND OBJECTIVE: To investigate how participating in the early recognition method treatment strategy affect illness insight and management, in patients with schizophrenia or bipolar disorder in community mental healthcare. BACKGROUND: The current practice in mental healthcare focus on shared decision-making and self-managing capacity, but poor insight is a predictor of poor adherence and dropout. Engagement in illness management and recovery predict the treatment response. DESIGN: Semi-structured interviews with a phenomenological-hermeneutic approach. METHODS: We conducted 36 semi-structured interviews with 26 patients. The interviews were conducted before and after participating in the intervention using the early recognition method strategy. The analysis was based on Ricoeur's theory of interpretation: Naive reading, structural analysis, interpretation and discussion. The COREQ checklist was used as reporting guideline. RESULTS: The experience of participating in treatment as usual and early recognition method revealed two main themes. The first theme 'patient care' describes how dialogue and collaboration increase awareness of the illness and how to gain control. The second theme 'insight and experience' describes how illness affects personality and self-image, and how insight entails control and self-confidence. CONCLUSION: Managing life with severe mental illness is complex and challenging. However, the experience of guidance, support and collaboration between patient and nurse are essential to improve these circumstances. RELEVANCE TO CLINICAL PRACTICE: A systematic approach to the patient' symptoms, as in the early recognition method strategy, enhances knowledge of the individual patient' symptoms, both for nurse and patient. A knowledge that is significant for meeting individual treatment needs. Therefore, applying this strategy is likely to enhance collaboration and improve treatment outcome.

Patients' experiences of home-based psychotherapy via videoconference: A qualitative study.

The aim of this study is to explore adult outpatients' experiences with home-based psychotherapy via videoconferencing in a Danish mental health service. Participants found videoconferencing-based psychotherapy for preventive relapse sessions very useful, and they believed that it was possible to maintain a good therapeutic relationship via videoconferencing when they knew their therapist in advance. However, experiences with more in-depth psychotherapy are more unclear as some felt alienated and preferred other ways to communicate. In general, participants found videoconferencing-based psychotherapy to be less personal but worth considering when travel hassles outweigh the need for meeting in person.

Reducing patient-staff contact in fast-track total hip arthroplasty has no effect on patient-reported outcomes, but decreases satisfaction amongst patients with self-perceived complications: analysis of 211 patients.

BACKGROUND AND PURPOSE: Several studies have compared fast-track with conventional pathways for total hip arthroplasty (THA) patients, but none have compared different fast-track pathways. Due to COVID-19 restrictions, our department had to minimize patient-staff contact in the THA pathway. First, telephone consultations were implemented instead of an outpatient clinic visit and subsequently preoperative patient education was discontinued. This enabled us to compare patient-reported outcomes and satisfaction among 3 fast-track pathways. PATIENTS AND METHODS: We collected data from patients treated for hip osteoarthritis with THA at Gødstrup Hospital between 2018 and 2021. The patients had experienced 1 of 3 pathways and were interviewed via telephone between 2 and 6 months after discharge. We analyzed the influence of patient pathway on patient-reported pain and mobility level, self-perceived complications, and compliance using logistic regression. We then compared the pathway's effect on patient satisfaction both for the total sample and for the patients who experienced complications. RESULTS: The amount of patient-staff contact in the patient pathway did not have any influence on patientreported outcomes or the probability of self-perceived complications. For the full sample, patient-staff contact had no statistically significant influence on patient satisfaction either, but for the subgroup of patients experiencing complications, the pathways with less patient-staff contact reduced satisfaction. Patient satisfaction was primarily related to pain and mobility outcomes. INTERPRETATION: Our results indicate that reducing patient-staff contact in fast-track THA can be done without influencing mobility and pain outcomes, but the overall satisfaction among patients with self-perceived complications will be negatively affected.

A call for HoLEP: en-bloc vs. two-lobe vs. three-lobe.

PURPOSE: Holmium Laser Enucleation of the Prostate (HoLEP) is widely accepted as standard laser enucleation technique for patients with benign prostate obstruction (BPO). Initially developed as a three-lobe enucleation technique, several modifications have been published. Comparison of the enucleation techniques is lacking. Therefor we aimed to compare outcomes of three enucleation techniques (en-bloc vs. two-lobe vs. three-lobe). MATERIAL AND METHODS: We prospectively collected data of 600 patients treated between 01/2017 and 12/2017 with HoLEP for BPO. Patients were randomised to either enbloc, two-lobe, or three-lobe enucleation, respectively. Data collection consisted of parameters on operation time, perioperative parameters, and functional outcomes. Univariate and multivariate analyses (ANOVA-test for continuous variables; Chi2-test for categorical variables) were performed regarding differences between the three enucleation techniques. RESULTS: Patient characteristics were not significantly different (all p > 0.05). Significant differences were observed with respect to overall operation time (en-bloc vs. two-lobe vs. three-lobe: 40.5 vs. 40.7 vs. 47.9, respectively; p < 0.001), speed (g/min.) (en-bloc vs. two-lobe vs. three-lobe, 1.82 vs. 1.76 vs. 1.67, respectively; p 0.006), and enucleation time (en-bloc vs. two-lobe vs. three-lobe: 31.7 vs. 32 vs. 37.7, respectively; p < 0.001). When solely comparing en-bloc vs. two-lobe enucleation, differences in terms of enucleation time, operation time, and speed were not significantly different (p 0.8, 0.9, and 0.2, respectively). Postoperative outcomes were not significantly different. CONCLUSION: All three HoLEP enucleation techniques show similar postoperative outcomes. However, enbloc and two-lobe enucleation are significantly faster with respect to enucleation, overall operation time, and speed compared to the three-lobe technique.

Corticosteroid delivery using oral mucosa equivalents for the treatment of inflammatory mucosal diseases.

Oral lichen planus (OLP) is an immune-mediated disease of the oral mucosa with idiopathic aetiology. It is frequently treated with topical corticosteroids (applied as gels, mouthwashes, or sprays); however, the mucosal exposure times of topical corticosteroids are short because of removal by the constant flow of saliva and mechanical forces. In this study we used cell monolayers, as well as oral mucosal equivalents (OMEs) containing activated T-cells, to examine corticosteroid potency and delivery of clobetasol-17-propionate from a novel electrospun mucoadhesive patch. The OMEs displayed tight junctions, desmosomes, hemidesmosomes, and an efficient permeability barrier. Following application of corticosteroids to cells cultured as monolayers, the degree of cytotoxicity measured correlated to the level of potency recognized for each corticosteroid; by contrast, OMEs were largely unaffected by corticosteroid treatment. Permeation of clobetasol-17-propionate into and through the OMEs was time- and dose-dependent, regardless of whether this corticosteroid was delivered in liquid form or from a mucoadhesive patch, and both liquid- and patch-delivered clobetasol-17-propionate significantly reduced the secretion of interleukin-2 by activated T-cells. This study confirms that OMEs are more suitable models than cell monolayers for evaluating toxicity and drug delivery. After topical exposure, clobetasol-17-propionate accumulated in OMEs at a higher level than betamethasone-17-valerate and hydrocortisone-17-valerate, and exerted its immunosuppressive actions following application via the patch delivery system, highlighting the efficacy of this mode of drug delivery to treat OLP.

Single-use device endoscopy for the diagnosis of acute bacterial rhinosinusitis in primary care: A pilot and feasibility study.

OBJECTIVE: Antibiotics are largely overprescribed for acute rhinosinusitis in primary care, mainly due to the lack of diagnostic tests to confirm or rule out bacterial infection. The study objective was to assess the on-site applicability and safety of the newly developed JGG endoscope® for the diagnosis of acute bacterial rhinosinusitis in primary care. DESIGN: Five Swiss primary care centres and one university-affiliated ENT unit participated in this single-arm pilot study. PARTICIPANTS: Adults with acute suspected bacterial rhinosinusitis. The newly developed JGG endoscope® , which is attached to a pocket otoscope, was used to inspect after local anaesthesia the nasal cavity and middle meatus and to gain material for bacterial culture from paranasal sinuses draining ostium. MAIN OUTCOME MEASURES: Applicability and safety. RESULTS: The visualisation of the middle meatus was successful in 16 of 21 patients (13 in both sides and three in one side), and unclear or unsuccessful in five patients. Sample collection from the middle meatus was successful in 10 patients (six on both and four on one side) and unclear or unsuccessful in the remaining patients. Only one culture-confirmed bacterial rhinosinusitis and 11 PCR-confirmed viral infections were identified from collected samples. After a 2-week follow-up, no serious adverse events were observed. CONCLUSIONS: The on-site use of the JGG endoscope® in daily primary care routine is feasible and safe and was well accepted by the trial physicians and patients (assessed with structured questionnaires). The JGG endoscope® may support general practitioners to differentiate between bacterial and viral rhinosinusitis.

Early Recognition Method - Amplifying relapse management in community mental health care; a comprehensive study of the effects on relapse and readmission.

This naturalistic multicenter study explored the relationship between participating in the Early Recognition Method (ERM) intervention and relapse, defined as spending at least one night at a psychiatric ward. The intervention was tailored to adult patients with schizophrenia or bipolar disorder in an outpatient mental health care setting. Before the intervention, the staff received training in application of the strategy. The ERM strategy is protocolized and includes identification and monitoring of individual early warning signs and development of a personal plan of action. The study showed a reduction in mean number and duration of readmissions during the period the patients participated in the intervention, compared to an equal pre-intervention period. For patients with bipolar disorder the reduction was statistical significant. The difference in outcome between the two diagnostic groups suggests that further tailoring of the application of the ERM strategy might improve the relapse prevention outcome.

Transitions between body mass index categories, South Africa.

OBJECTIVE: To profile the prevalence of the three body mass index (BMI) categories by sociodemographic characteristics, and to calculate the percentage transitioning (or not) from one BMI category to another, to inform South African health policy for the control of obesity and noncommunicable diseases. METHODS: We used data from the National Income Dynamics Study, including sociodemographic characteristics and BMI measurements collected in 2008, 2010, 2012, 2014 and 2017. For each data collection wave and each population group, we calculated mean BMI and prevalence by category. We also calculated the percentage making an upwards transition (e.g. from overweight to obese), a downwards transition or remaining within a particular category. We used a multinomial logistic regression model to estimate transition likelihood. FINDINGS: Between 2008 and 2017, mean BMI increased by 2.3 kg/m2. We calculated an increased prevalence of obesity from 19.7% (3686/18 679) to 23.6% (3412/14 463), with the largest increases in prevalence for those aged 19-24 years and those with at least high school education. The percentages of upwards transitions to overweight or obese categories increased sharply between the ages of 19 and 50 years. Once overweight or obese, the likelihood of transitioning to a normal BMI is low, particularly for women, those of higher age groups, and those with a higher income and a higher level of education. CONCLUSION: In the development of national strategies to control obesity and noncommunicable diseases, our results will allow limited public health resources to be focused on the relevant population groups.

Dynamic balance between vesicle transport and microtubule growth enables neurite outgrowth.

Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. Simulations predict redundancies between lower level sibling SCPs within each type of high level SCP. In contrast, higher level SCPs, such as vesicle transport and exocytosis or microtubule growth characteristic of each type need to be strictly coordinated with each other and imbalances result in stalling of neurite outgrowth. From these simulations, we predicted the effect of changing the activities of SCPs involved in vesicle exocytosis or microtubule growth could lead to formation of dystrophic bulbs. siRNA ablation experiments verified these predictions. We conclude that whole cell dynamics requires balance between the higher-level SCPs involved and imbalances can terminate whole cell responses such as neurite outgrowth.

Danish 'add-in' school-based health promotion: integrating health in curriculum time.

Schools provide an important setting for health promotion and health education. In countries where health education is not a specific subject, it is typically undertaken by teachers in health-integrating subjects such as biology, home economics or physical education. More ambitious and holistic frameworks and whole school approaches such as health promoting schools have been considered best practice for the past three decades. Recently, more attention has been given to policy initiatives integrating health activities into school curriculum time. This paper discusses potentials and challenges of school-based health promotion applying an 'add-in' approach, that integrates health activities into teachers' curricular obligations without taking time away from them, based on a presentation of three Danish cases. This may serve as a supplement to health promotion activities that have been initiated over and above the day-to-day teaching (add-on). We contend that an 'add-in' approach to school health promotion provides a potential win-win situation where both health and core education stand to gain; makes it possible to reach a wider range of schools; mobilizes additional resources for health promotion; and leads to more sustainable activities. However, potential limitations including not addressing structural aspects of health promotion and reliance on a relatively limited evidence base should also be considered.