A novel in vitro high-content imaging assay for the prediction of drug-induced lung toxicity.

The development of inhaled drugs for respiratory diseases is frequently impacted by lung pathology in non-clinical safety studies. To enable design of novel candidate drugs with the right safety profile, predictive in vitro lung toxicity assays are required that can be applied during drug discovery for early hazard identification and mitigation. Here, we describe a novel high-content imaging-based screening assay that allows for quantification of the tight junction protein occludin in A549 cells, as a model for lung epithelial barrier integrity. We assessed a set of compounds with a known lung safety profile, defined by clinical safety or non-clinical in vivo toxicology data, and were able to correctly identify 9 of 10 compounds with a respiratory safety risk and 9 of 9 compounds without a respiratory safety risk (90% sensitivity, 100% specificity). The assay was sensitive at relevant compound concentrations to influence medicinal chemistry optimization programs and, with an accessible cell model in a 96-well plate format, short protocol and application of automated imaging analysis algorithms, this assay can be readily integrated in routine discovery safety screening to identify and mitigate respiratory toxicity early during drug discovery. Interestingly, when we applied physiologically-based pharmacokinetic (PBPK) modelling to predict epithelial lining fluid exposures of the respiratory tract after inhalation, we found a robust correlation between in vitro occludin assay data and lung pathology in vivo, suggesting the assay can inform translational risk assessment for inhaled small molecules.

Effect of an interactive mobile health support system and daily weight measurements for pediatric obesity treatment, a 1-year pragmatical clinical trial.

BACKGROUND: Pediatric obesity lifestyle treatment is not always successful. Frequent clinical visits are of major importance to certify sufficient effect but are difficult due to the associated costs and the great demands on families. We hypothesized that an interactive digital support may reduce the need for frequent physical visits. The aim of the study was to assess 1-year weight outcome for patients using a digital support system compared with standard care. METHODS: An obesity lifestyle treatment with a digital support system was implemented in one clinic in Stockholm, Sweden. Measurements from a custom-made body scale without digits for daily home measurement of weights were transferred via Bluetooth to a mobile application, where BMI Z-score was calculated and presented graphically with an individualized weight loss target curve. An automatic transfer of data to the web-based clinic interface enables a close monitoring of treatment progress, and frequent written communication between the clinical staff and families via the application. One-year outcome was compared with a randomly retrieved, age and sex matched control group from the Swedish childhood obesity treatment register (BORIS), which received standard treatment at other clinics. Main outcome was change in BMI Z-score and missing data was imputed. RESULTS: 107 children were consecutively included to digi-physical treatment and 321 children to standard care. Age range 4.1-17.4 years (67% males). The attrition rate was 36% and 46% respectively, p = 0.08. After 1 year, the mean ± SD change in BMI Z-score in the treatment group was -0.30 ± 0.39 BMI Z-score units and in the standard care group -0.15 ± 0.28, p = 0.0002. The outcome was better for both sexes and all age groups in the digi-physical treated group. CONCLUSION: A digital support system with a personalized weight-loss target curve and daily weight measurements shared by the family and the clinic is more effective than a standard care childhood obesity treatment. GOV ID: NCT04323215.

Sourdough cultures as reservoirs of maltose-negative yeasts for low-alcohol beer brewing.

De novo sourdough cultures were here assessed for their potential as sources of yeast strains for low-alcohol beer brewing. NGS analysis revealed an abundance of ascomycete yeasts, with some influence of grain type on fungal community composition. Ten different ascomycete yeast species were isolated from different sourdough types (including wheat, rye, and barley) and seven of these were screened for a number of brewing-relevant phenotypes. All seven were maltose-negative and produced less than 1% (v/v) alcohol from a 12 °Plato wort in initial fermentation trials. Strains were further screened for their bioflavouring potential (production of volatile aromas and phenolic notes, reduction of wort aldehydes), stress tolerance (temperature extremes, osmotic stress and ethanol tolerance) and flocculence. Based on these criteria, two species (Kazachstania servazzii and Pichia fermentans) were selected for 10 L-scale fermentation trials and sensory analysis of beers. The latter species was considered particularly suitable for production of low-alcohol wheat beers due to its production of the spice/clove aroma 4-vinylguaiacol, while the former showed potential for lager-style beers due to its clean flavour profile and tolerance to low temperature conditions.

A novel interactive mobile health support system for pediatric obesity treatment: a randomized controlled feasibility trial.

BACKGROUND: In order to achieve improved weight status, behavioral pediatric obesity treatment is resource intensive. Mobile Health (mHealth) is more accessible than standard care but effective approaches are scarce. Therefore, the aim of this feasibility trial was to study trial design, mHealth usage, compliance, and acceptability of a novel mHealth approach in pediatric obesity treatment. METHODS: This six-month parallel two-arm feasibility trial took place at three pediatric outpatient clinics in Stockholm, Sweden. Participants, 5-12 years, starting obesity treatment were randomized to using an mHealth support system as an addition to standard care (intervention) or to standard care alone (control). The intervention included daily self-monitoring of weight transferred to a mobile application (app) used by parents, a website in which clinicians could track treatment progress, prespecified treatment goals for change in degree of obesity shown in the app and on the website, and text message interactions between clinicians and parents. The main outcome was description of feasibility. Height and weight were measured at baseline, three, and 6 months to explore changes in body mass index standard deviation score (BMI SDS). RESULTS: Of 40 children eligible for inclusion, 28 agreed to participate (54% girls) and were randomized to intervention (n = 15) or control (n = 13). Weight was measured at home regularly throughout the entire trial period by 12/15 children in the intervention group. Attendance at appointments were better in the intervention group (p = 0.024). Both parents and clinicians had a positive experience and found the mHealth support system accessible. At 6 months the intervention group had a greater reduction of 0.24 units in BMI SDS than standard care (- 0.23 vs. 0.01, p = 0.002). CONCLUSIONS: The mHealth support system was a feasible and innovative treatment approach which, in addition to standard care, generated better treatment results than standard care alone. Future research should evaluate the treatment effects over a longer follow-up time in a larger study sample. TRIAL REGISTRATION: This trial was retrospectively registered at ClinicalTrials.gov , ID: NCT03380598 , on November 8, 2017.

Reference values and secular trends for cardiorespiratory fitness in children and adolescents with obesity.

AIM: To present specific reference values for cardiorespiratory fitness (CRF) in children with obesity and to analyse secular trends of CRF in the studied population. METHODS: Cardiorespiratory fitness, the maximal oxygen uptake (VO2 max), was estimated with the Åstrand-Rhyming submaximal bicycle test, in 705 Swedish children (356 girls, 8-20 years) with obesity according to the International Obesity Task Force (IOTF). Data were collected from 1999 to 2013. Secular trends, analysed with multiple linear regression, were adjusted for age, height and body mass index standard deviation score (BMI SDS). RESULTS: All children had low CRF compared with normal weight standards but there was a marked variability of CRF in children with obesity, which was possible to quantify with the developed obesity specific CRF reference values. The mean value of absolute VO2 max (L/min) increased with age and relative VO2 max (mL/kg/min) decreased with age in both boys and girls. There was a negative secular trend in both sexes (P < .001). CONCLUSION: These are the first obesity specific reference values of CRF in children enabling clinical evaluation in childhood obesity treatment. Cardiorespiratory fitness in children with obesity has declined the last decades, indicating that also within this vulnerable group physical activity has gone down.

Associations between cardiorespiratory fitness and cardiometabolic risk factors in children and adolescents with obesity.

It is unclear if associations between cardiorespiratory fitness (CRF) and cardiometabolic risk factors are independent of degree of obesity, in children with obesity. The aim of this cross-sectional study on 151 children (36.4% girls), 9-17 years, from a Swedish obesity clinic, was to investigate associations between CRF and cardiometabolic risk factors, adjusted for body mass index standard deviation score (BMI SDS), in children with obesity. CRF was objectively assessed with the Åstrand-Rhyming submaximal cycle ergometer test, and blood samples (n = 96) and blood pressure (BP) (n = 84) according to clinical routine. Obesity specific reference values for CRF were used to create CRF levels. CRF was inversely associated with high-sensitivity C-reactive protein (hs-CRP), independent of BMI SDS, age, sex, and height. The inverse associations between CRF and diastolic BP did not remain significant when adjusted for BMI SDS. CRF and high-density lipoprotein cholesterol became inversely associated when adjusted for BMI SDS. Independent of degree of obesity, lower CRF is associated with higher levels of hs-CRP, as a biomarker of inflammation, in children with obesity and regular assessment of CRF should be encouraged. Future research in children with obesity should investigate if low-grade inflammation decreases when CRF is improved.

User experiences of an app-based mHealth intervention (MINISTOP 2.0) integrated in Swedish primary child healthcare among Swedish-, Somali- and Arabic-speaking parents and child healthcare nurses: A qualitative study.

Background: Preventive and scalable interventions, accessible to all, to counteract childhood obesity are urgently needed. We have recently developed a novel, digital parental intervention (MINISTOP 2.0 app) available in Swedish, Somali, Arabic and English. We have previously reported its positive effects on children's health behaviors and on parental self-efficacy. However, before introducing the app at scale in primary child healthcare, implementation aspects also need to be explored. Aim: This study aims to explore and describe user experiences as well as acceptability and feasibility of the MINISTOP 2.0 app-based intervention in a diverse group of parents (end-users) and Swedish child healthcare nurses (implementers). Methods: Individual interviews were conducted with Swedish- (n = 9), Somali- (n = 9), Arabic- (n = 5) and English-speaking (n = 1) parents as well as Swedish primary child healthcare nurses (n = 15). Data was analyzed using content analysis with an inductive latent approach. Results: Parents described how the app facilitated behavior change through increased awareness regarding current diet and physical activity behaviors. Furthermore, the evidence-based app content further facilitated trust and behavior change. Both parents and nurses acknowledged the app's preventive potential and the potential for reaching parents with diverse backgrounds or in need of extra support. Conclusion: The MINISTOP 2.0 app was perceived as a useful tool for health promotion both by parents and healthcare professionals, especially since it was adapted to several languages. These findings coupled with the previously shown beneficial effects on health behaviors support the large-scale implementation of the app in primary child healthcare.

Nationwide survey of subjectively reported adverse drug reactions in Sweden.

BACKGROUND: Adverse drug reactions (ADRs) and the safety of drugs continue to be widely discussed. However, information on the prevalence of subjectively experienced ADRs (SADRs) and their subsequent burden in the general population is largely lacking. OBJECTIVE: To analyze, from an epidemiologic perspective, SADRs with respect to occurrence and health status. METHODS: A cross-sectional mail survey to a random national sample in Sweden of inhabitants aged 18-84 years was conducted; 61% (N = 4875) of the sample answered the questionnaire. Self-reported SADRs occurring during a 2-week period of using prescription, over-the-counter (OTC), or herbal drugs were classified according to Meyler's classification of ADRs. Self-perceived health status was assessed with a visual analog scale graded from 0 (worst possible health/death) to 1 (perfect health). RESULTS: SADRs were reported by 6.4% of the total study sample, 10.2% of the 2851 users of prescription drugs, 1.0% of the 2862 users of OTC drugs, and 0.1% of the 1352 users of herbal drugs. Of the total sample, 3.3% reported SADRs of the nervous system, 2.6% of the gastrointestinal system, and 0.6% of the cardiovascular system. Users of prescription drugs with SADRs reported a mean health status score of 0.655, while those who did not report SADRs scored 0.744. Among users of OTC and herbal drugs, the corresponding scores were 0.720 and 0.818, respectively. Those in the population who did not use any drugs rated their health status as 0.846. CONCLUSIONS: Both the prevalence of SADRs and the magnitude of the decrease in subjective health status in respondents experiencing them reflect the importance of individual subjective perceptions for public health. However, in a cross-sectional study like this, causal relationships cannot be firmly established. Further, other factors, such as comorbidity or disappointment with treatment outcomes, could be associated with the decrease in health status.