Predicting longitudinal changes in patterns of tobacco and nicotine product use among adolescents: A Latent Transition Analysis based on the X:IT study.

INTRODUCTION: Understanding factors influencing the transition from non-use to tobacco and nicotine product initiation among adolescents is crucial for designing and implementing effective preventive strategies. This study explores transition patterns among 13-15-year-old adolescents in lower secondary school, focusing on the transition from non-use to tobacco and nicotine product initiation and the influence of individual, social, risk behavioral, and mental health factors on this transition. METHODS: Based on data from a Danish smoking prevention trial between 2017 and 2019, this study employed questionnaire surveys at three time points: baseline (start of seventh grade, n = 1,990, response rate = 86.3%), eight-month follow-up (end of seventh grade, n = 1,666, response rate = 74,8%), and 20-month follow-up (end of eighth grade, n = 1,149, response rate = 70,6%). Tobacco and nicotine use indicators included current and lifetime use of cigarettes and lifetime use of e-cigarettes, smokeless tobacco, and hookah. A latent transition analysis was applied to identify longitudinal transition patterns across waves and to explore predictors of these patterns. RESULTS: Three user classes emerged across all waves: none-use, lifetime e-cigarette and cigarette use, and poly-tobacco use. While the most prevalent class was the non-user class (71%-86%), the proportion of the lifetime e-cigarette and cigarette class increased over time (from 12% to 17%). Similarly, the poly-tobacco user class increased from 2% to 12%. The probability of transitioning from non-use to lifetime e-cigarette and cigarette use increased from 0.5% at baseline to 12% by the second follow-up, while the probability of transitioning from lifetime e-cigarette and cigarette use remained stable over time (12%-15%). Across all waves, elevated risk behavior predicted this transition. For instance, binge-drinking (OR = 3.76, 95% CI: 1.51-9.34), susceptibility to smoking (OR = 7.63, 95% CI: 3.68-16.83), and truancy (OR = 7.00, 95% CI: 1.98-24.59) influenced the transition from non-use at baseline to lifetime e-cigarette and cigarette use at first follow-up. Additionally, boys, adolescents with low socioeconomic status, low life satisfaction, and those with smoking friends or parents were more likely to transition from non-use to lifetime e-cigarette and cigarette use. CONCLUSION: This study demonstrates that sociodemographic, social risk, behavioral, and mental health factors impact the transition from non-use to lifetime e-cigarette and cigarette use. The findings provide valuable insights for developing targeted preventive strategies focusing on these influencing factors.

Effectiveness of the multi-component intervention 'Focus' on reducing smoking among students in the vocational education setting: a cluster randomized controlled trial.

BACKGROUND: Social inequality in smoking remains an important public health issue. Upper secondary schools offering vocational education and training (VET) comprise more students from lower socioeconomic backgrounds and have higher smoking prevalence than general high schools. This study examined the effects of a school-based multi-component intervention on students' smoking. METHODS: A cluster randomized controlled trial. Eligible participants were schools offering VET basic courses or preparatory basic education in Denmark, and their students. Schools were stratified by subject area and eight schools were randomly allocated to intervention (1,160 invited students; 844 analyzed) and six schools to control (1,093 invited students; 815 analyzed). The intervention program comprised smoke-free school hours, class-based activities, and access to smoking cessation support. The control group was encouraged to continue with normal practice. Primary outcomes were daily cigarette consumption and daily smoking status at student level. Secondary outcomes were determinants expected to impact smoking behavior. Outcomes were assessed in students at five-month follow-up. Analyses were by intention-to-treat and per protocol (i.e., whether the intervention was delivered as intended), adjusted for covariates measured at baseline. Moreover, subgroup analyses defined by school type, gender, age, and smoking status at baseline were performed. Multilevel regression models were used to account for the cluster design. Missing data were imputed using multiple imputations. Participants and the research team were not blinded to allocation. RESULTS: Intention-to-treat analyses showed no intervention effect on daily cigarette consumption and daily smoking. Pre-planned subgroup analyses showed statistically significant reduction in daily smoking among girls compared with their counterparts in the control group (OR = 0.39, 95% CI: 0.16, 0.98). Per-protocol analysis suggested that schools with full intervention had higher benefits compared with the control group (daily smoking: OR = 0.44, 95% CI: 0.19, 1.02), while no marked differences were seen among schools with partial intervention. CONCLUSION: This study was among the first to test whether a complex, multicomponent intervention could reduce smoking in schools with high smoking risk. Results showed no overall effects. There is a great need to develop programs for this target group and it is important that they are fully implemented if an effect is to be achieved. TRIAL REGISTRATION: https://www.isrctn.com/ISRCTN16455577 , date of registration 14/06/2018.

Digital media use and sleep in late adolescence and young adulthood: A systematic review.

Despite much attention on digital media use and young peoples' sleep, the literature on digital media and its impact on sleep in older adolescents and young adults remains to be synthesized. We conducted a systematic review of studies including young people aged 16-25 years. We searched Medline, Web of Science, and CINAHL for observational studies, identifying 60 studies. These studies were assessed for methodological quality. Only studies rated as moderate or high-quality studies were included (n = 42). A narrative synthesis summarized the impact of digital media use on eight sleep outcomes: Bedtime; Sleep onset latency or problems falling asleep; Sleep duration; Early awakening; Sleep disturbance; Daytime tiredness and function; Sleep deficits; Sleep quality. In summary, digital media use was associated to shorter sleep duration and poorer sleep quality. These associations were found for general screen use and use of mobile phone, computer, internet, and social media, but not for television, game console, and tablet use. Most studies investigating bedtime or nighttime use found associations to poor sleep outcomes. Later bedtime and daytime tiredness were associated with mobile phone use at night. Additional research is warranted to draw solid conclusions about the causal direction and to understand the underlying mechanisms.

Evaluating the Effects of Denmark's New Tobacco Control Act on Young People's Use of Nicotine Products: A Study Protocol of the §SMOKE Study.

(1) Background: In December 2020, a broad majority of political parties in Denmark agreed on a new tobacco control act. In addition, price increases on tobacco in 2020 and 2022 became part of the Danish Finance Act. This study protocol describes the study "§SMOKE-A Study of Tobacco, Behavior, and Regulations" designed to monitor and evaluate the implementation and effect of the new strengthened tobacco control acts. The overall aim is to monitor tobacco use among young people before, during, and after implementation of the new tobacco control legislation, including an increased price on tobacco, a ban on point-of-sale tobacco displays, and plain packaging. Subgoals are to monitor overall use of nicotine products, attitudes, and norms. (2) Methods: This study is designed as a five-year impact evaluation with repeated cross-sectional survey data collections. The baseline survey was conducted before implementing an increased price on tobacco, the first step in the new legislation, initiated 1 April 2020. Study participants (n = 37,500) were a random sample of individuals living in Denmark aged 15 to 29 years. (3) Conclusions: This study examines the impact of the new strengthened tobacco control legislation in Denmark from 2020 to 2025. The findings of this study are relevant to other countries facing implementation of similar measures to explore intended and unintended consequences of the legislation and help to identify how the legislation could be further improved.

Exploring factors associated with smokeless tobacco use among young people: A systematic scoping review.

PURPOSE: While smoking is declining among young people, smokeless tobacco use is increasing. Identifying who is using smokeless tobacco and why is essential in preventing smokeless tobacco use. This study aimed to comprehensively explore the factors of young people's use of smokeless tobacco in western countries and identify research gaps. METHODS: We conducted a systematic scoping review of studies that examined factors associated with smokeless tobacco use among young people (ages 13-29) from western countries published between January 2011 and September 2021. Searches were conducted in CINAHL, Medline, and Scopus. Studies on adults, total tobacco use (i.e., did not differentiate between tobacco product types), dual and multiple uses of tobacco, and studies on smokeless tobacco cessation programs were excluded. RESULTS: A total of 160 studies were included in this scoping review. The studies were primarily undertaken in the US and the Scandinavian countries, and the majority explored smokeless tobacco use without distinguishing between the specific types. Smokeless tobacco users were more likely to be male, non-Hispanic white, engaging in physical activity, and using other substances, including cigarettes and alcohol. The role of friends and family were identified as critical factors that were related to the use of smokeless tobacco. CONCLUSIONS: This scoping review suggests that preventative measures against smokeless tobacco use should focus on peer and family members' roles and that these measures may benefit from targeting males. Additional research, including systematic reviews on this area to validate the identified associated factors, would improve the understanding of smokeless tobacco use.

Trends in Use of Alcohol and Cigarettes among Danish Adolescents, 2002-2018: Exclusive and Dual Use.

Many young adolescents experiment with substance use which can have substantial health implications later in life. This study examined trends in substance use among Danish adolescents from 2002 to 2018, including exclusive and dual current use of alcohol and cigarettes. Data on 13- and 15-year-olds (N = 15,295) from five comparable cross-sectional Health Behavior in School-aged Children (HBSC) surveys were used. Cochran-Armitage test for trend assessed the development in substance use patterns over time. Overall, a decreasing trend in current use of alcohol and cigarettes was found among Danish adolescents during the 16-year study period: from 71.7% in 2002 to 51.6% in 2018. In 2018, most adolescents (41.8%) currently used alcohol exclusively, 8.6% had a dual current use of cigarettes and alcohol, and 1.3% smoked cigarettes exclusively. Trends in alcohol use differed according to age groups, while no gender-specific trends in substance use were found. Findings suggest that a significant prevention potential in adolescent substance use remains, and future initiatives may focus on dual use of substances as well as tailored efforts to specific subgroups in high risk of using substances.

Socioeconomic Differences in Cigarette Smoking and Alternative Tobacco Product Use Among Adolescents in a School-Based Smoking Preventive Intervention: Findings From the Second Year of the X:IT II Study.

Background: Health interventions may differently impact adolescents from diverse backgrounds. This study examined whether a smoking preventive intervention was equally effective in preventing cigarette smoking and use of alternative tobacco products (ATPs, i.e., snus, e-cigarettes, and waterpipe) among students from different socioeconomic backgrounds, i.e., occupational social classes (OSC). Methods: Data was from the school-based intervention X:IT II targeting 13- to 15-year-olds Danes. The intervention focused on three main components: smoke-free school time, smoke-free curriculum, and parental involvement. In total, 46 schools were included at baseline (N = 2,307, response rate = 86.3%). Using a difference-in-differences approach, changes in current smoking and ever use of ATPs were estimated among students in high versus low OSC at second follow-up. Analyses were based on available cases (N = 826) and multiple imputations of missing data at the second follow-up (N = 1,965). Results: At baseline (age 13), 1.0% of students from high OSC and 4.8% from low OSC currently smoked cigarettes, while this was the case among 24.5 and 25.6%, respectively, at the second follow-up (age 15). Estimates indicated that social inequalities in current smoking diminished over time (p < 0.001). Regarding ATPs, 10.0% of high OSC students and 13.9% of low OSC students had ever used ATPs at baseline, while at second follow-up, 46.8 and 60.8%, respectively, had ever used ATPs. Estimates indicated that social inequalities in ever use of ATPs widened over time (p < 0.001). Conclusions: The X:IT II intervention seemed to diminish socioeconomic disparities in smoking over the study period. Meanwhile, social inequalities in ever use of ATPs increased. Therefore, besides focusing on narrowing the social disparities in cigarette smoking, future efforts may, to a larger extent, focus on adolescents' use of ATPs.

Electronic media use and sleep in children and adolescents in western countries: a systematic review.

BACKGROUND: Sleep is essential for child and adolescent health and well-being. There is an increasing interest in whether electronic media use affects children and young adolescents' sleep. Prior reviews have focused on a school-aged population. Moreover, it is crucial that research continuously addresses the processes of technology and media use and the implication on sleep. This systematic review examines the evidence of electronic media use related to sleep among 0-15-year-olds. METHODS: Searches were carried out in four databases (CINAHL, Web of Science, EMBASE, and Medline). Inclusion criteria included age ≤ 15 years, and intervention, cohort, or cross-sectional studies from western countries. Methodological quality was rated using the Quality Assessment Tool for Quantitative Studies by two independent reviewers. Data was extracted using a standardized data extraction form. Synthesis was done by summarizing results across studies by age groups of 0-5, 6-12, and 13-15 years within four sleep domains: Bedtime and sleep onset; Sleep quality; Sleep duration; Daytime tiredness. RESULTS: The search identified 10,719 unique studies, of which 109 fulfilled inclusion and exclusion criteria and were assessed for methodological quality. In total, 49 studies were included in the review. The study designs were randomized controlled trials (n = 3), quasi-experimental studies (n = 2), prospective cohort studies (n = 15), and cross-sectional studies (n = 29). Evidence for an association between electronic media use and sleep duration was identified, with stronger evidence for 6-15-years-olds than 0-5-year-olds. The evidence for a relationship between electronic media use and other sleep outcomes was more inconclusive. However, for 6-12-year-old children, there was evidence for associations of electronic media use with delayed bedtime and poor sleep quality. For 13-15-year-olds, there was evidence for associations between screen time and problems falling asleep, and between social media use and poor sleep quality. CONCLUSIONS: Overall, electronic media use was generally associated with shorter sleep duration in children and adolescents. Studies with stronger research design and of higher quality are needed to draw solid conclusions about electronic media's impact on other sleep outcomes. Public awareness and interventions could be promoted about the potential negative impact on children's sleep of electronic media devices that are used excessively and close to bedtime.

Socio-economic differences in smoking among adolescents in a school-based smoking intervention: The X:IT II study.

Aims: Socio-economic inequalities in health behaviour may be influenced by health interventions. We examined whether the X:IT II intervention, aiming at preventing smoking in adolescence, was equally effective among students from different occupational social classes (OSC). Methods: We used data from the multi-component school-based smoking preventive intervention X:IT II, targeting 13- to 15-year-olds in Denmark. The intervention was tested in 46 schools with 2307 eligible students at baseline (response rate=86.6%) and had three main intervention components: smoke-free school time, smoke-free curriculum and parental involvement. We used a difference-in-difference design and estimated the change in current smoking after the first year of implementation in high versus low OSC. Analyses were based on available cases (N=1190) and imputation of missing data at follow-up (N=1967). Results: We found that 1% of the students from high OSC and 4.9% from low OSC were smokers at baseline (imputed data), and 8.2% of the students from high OSC and 12.2% from low OSC were smokers at follow-up. Difference-in-difference estimates were close to zero, indicating no differential trajectory. Conclusions: As intended, the X:IT II intervention, designed to apply equally to students from all socio-economic groups, did not seem to create different trajectories in current smoking among adolescents in high and low socio-economic groups. To diminish social inequality in health, future studies should carefully consider the ability to affect all socio-economic groups equally, or even to appeal mainly to participants from lower socio-economic groups, as they are often the ones most in need of intervention.

Gender differences in attitudes towards a school-based smoking prevention intervention.

AIMS: There are well-known gender differences in smoking, including the pattern of use and the effectiveness of smoking prevention programs. However, little is known about the differences between boys and girls in their attitudes towards smoking prevention interventions. This study explores gender differences in attitudes towards a school-based intervention to prevent smoking. METHODS: We used data from the X:IT II intervention study conducted in 46 Danish elementary schools. RESULTS: Compared to boys, girls were more positive towards smoke-free school time, both concerning rules for teachers smoking (odds ratio (OR) = 1.69, 95% confidence interval (CI): 1.35-2.12) and for students smoking (OR = 1.41, 95% CI: 1.13-1.76). No difference was observed in students signing the smoke-free agreement. However, a larger proportion of girls reported that the agreement was a good occasion to talk about smoking with their parents (OR = 1.36, 95% CI: 1.13-1.76). Girls were also more positive towards the smoke-free curriculum (OR = 1.52, 95% CI: 1.19-1.94). CONCLUSIONS: This study showed that girls were, overall, more positive towards the components of the smoking preventive intervention. Our findings highlight the importance of considering differences in intervention preferences for boys and girls in future health prevention initiatives.

Who are the young users of tobacco products? Prevalence and characteristics of Danish adolescents who have either smoked cigarettes, used alternative tobacco products, or used both.

Aims: We examined characteristics (smoking in social relations, binge drinking, and well-being measures) of Danish 13-year-olds in relation to their tobacco use patterns. Ever use of cigarettes exclusively, ever use of alternative tobacco products (ATPs; e-cigarettes, snus, or waterpipe) exclusively, and use of both cigarettes and ATPs were studied. Methods: We used self-reported data from students at 46 Danish schools in 2017 comprising 2,307 students (response rate = 86%). Multi-level logistic regression analyses were used to examine the associations between student characteristics and the odds for having ever used any tobacco products, smoked cigarettes exclusively, used ATPs exclusively, or used both cigarettes and ATPs compared with never use of any tobacco products. Unadjusted estimates and estimates adjusted for gender were reported. Results: A significant minority of youth (13.2%) had used one or more tobacco products. Of these, 2.0% had exclusively smoked cigarettes, 7.2% had exclusively used ATPs, and 4.0% had used both. Findings showed that all included characteristics (families' and friends' smoking, binge drinking, and well-being characteristics) were associated with using any tobacco product; however, students with friends who smoked, had been binge drinking, and had low well-being at home had notably higher odds for having both smoked cigarettes and used ATPs compared to the other tobacco use patterns. Conclusion: ATPs were popular among Danish adolescents compared with conventional cigarettes. Thus, prevention efforts among adolescents should not merely focus on the health risks of conventional cigarette smoking but also on ATPs. Students with diverse tobacco use patterns were similar on various characteristics. However, findings indicate that adolescents who had used both conventional cigarettes and ATPs constitute a more risk-averse group in special need of prevention efforts. Gender did not markedly influence the results. These findings may help future strategies aiming at the youngest adolescents at risk of using tobacco products.

[Vascular endothelial growth factor therapy in ischaemic heart disease].

Atherosclerosis of coronary arteries can result in a hypoxic state where myocardial cells may become dysfunctional or die. The oxygen sensing transcription factor hypoxia inducible factor 1 responds to low oxygen levels by elevating the production of angiogenic growth factors, such as vascular endothelial growth factor (VEGF). Despite this, endogenous processes and conventional therapies are inefficient in some patients. To stimulate angiogenesis, VEGF has been injected into the myocardium. As stated in this review, this therapy has so far been proven safe and studies are conducted in several countries, including Denmark.

Mannan Enhances IL-12 Production by Increasing Bacterial Uptake and Endosomal Degradation in L. acidophilus and S. aureus Stimulated Dendritic Cells.

The mannose receptor (MR) is a C-type lectin involved in endocytosis and with a poorly defined ability to modulate cellular activation. We investigated the effect of mannan treatment prior to stimulation of murine bone marrow-derived dendritic cells with the Gram-positive bacteria Lactobacillus acidophilus NCFM (L. acidophilus) on the induction of Interleukin (IL)-12. Mannan enhanced the IL-12 production induced by L. acidophilus in a dose dependent manner (up to 230% enhancement). Additionally, mannan-enhanced IL-12 induction was also demonstrated with another Gram-positive bacteria, Staphylococcus aureus (S. aureus), while an IL-12 reducing effect was seen on Escherichia coli stimulated cells. Furthermore, the expression of Interferon ß (Ifnb) was increased in cells treated with mannan prior to stimulation with L. acidophilus. The addition of mannan but not of bacteria led to endocytosis of MR, while addition of mannan prior to L. acidophilus or S. aureus resulted in increased endocytosis of bacteria, a faster killing of endocytosed bacteria, and increased reactive oxygen species production. Expression of signaling lymphocytic activation molecule (SLAMF)1 shown previously to be involved in the facilitation of endosomal degradation was upregulated by mannan but not by L. acidophilus and S. aureus. The IL-12 enhancement by mannan but not the IL-12 induced by the bacteria was abrogated by addition of inhibitors of clathrin coated pits (chlorpromazine and monodansylcadaverine). Furthermore, the addition of acid sphingomyelinase, a facilitator of ceramide raft formation, prior to addition of L. acidophilus enhanced the IL-12 production and the endocytosis of bacteria. In summary, our results show that mannan increases the IL-12 production induced by some Gram-positive bacteria through MR-endocytosis, which increases bacterial endocytosis and endosomal killing. The differential effect of MR activation on the IL-12 production induced by Gram-positive and Gram-negative bacteria may influence the immune response toward allergens and other glycoproteins.

The Nature of Antibacterial Adaptive Immune Responses against Staphylococcus aureus Is Dependent on the Growth Phase and Extracellular Peptidoglycan.

Staphylococcus aureus has evolved different strategies to evade the immune response, which play an important role in its pathogenesis. The bacteria express and shed various cell wall components and toxins during different stages of growth that may affect the protective T cell responses to extracellular and intracellular S. aureus However, if and how the dendritic cell (DC)-mediated T cell response against S. aureus changes during growth of the bacterium remain elusive. In this study, we show that exponential-phase (EP) S. aureus bacteria were endocytosed very efficiently by human DCs, and these DCs strongly promoted production of the T cell polarizing factor interleukin-12 (IL-12). In contrast, stationary-phase (SP) S. aureus bacteria were endocytosed less efficiently by DCs, and these DCs produced small amounts of IL-12. The high level of IL-12 production induced by EP S. aureus led to the development of a T helper 1 (Th1) cell response, which was inhibited after neutralization of IL-12. Furthermore, preincubation with the staphylococcal cell wall component peptidoglycan (PGN), characteristically shed during the exponential growth phase, modulated the DC response to EP S. aureus PGN preincubation appeared to inhibit IL-12p35 expression, leading to downregulation of IL-12 and an increase of IL-23 production by DCs, enhancing Th17 cell development. Taken together, our data indicate that exponential-phase S. aureus bacteria induce a stronger IL-12-dependent Th1 cell response than stationary-phase S. aureus and that this Th1 cell response shifted toward a Th17 cell response in the presence of PGN.

Mental health interventions among older adults: A systematic review.

BACKGROUND: The aim of the present study was to conduct a systematic review to identify documented mental health promotion interventions developed and tested among population-based older adults. METHODS: A systematic review based on PRISMA guidelines. The literature was searched in PsycINFO and PubMed between June and September 2016. The Effective Public Health Practice Project tool was used to assess the quality of the included study. RESULTS: In total 53 randomized controlled trial studies qualified for the systematic review. Across studies, three types of common conceptual themes emerged for interventions, including: 1) individual characteristics; 2) content and structure of the interventions; and 3) implementation of the interventions. CONCLUSIONS: No specific interventions could be recommended on the aforementioned basis. We conclude that a number of factors are of central importance for an intervention to have the desired effect. If these factors are considered, mental health can be successfully promoted among older adults.

Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction.

BACKGROUND: Cell therapy for heart disease has been proven safe and efficacious, despite poor cell retention in the injected area. Improving cell retention is hypothesized to increase the treatment effect. In the present study, human adipose-derived stromal cells (ASCs) were delivered in an in situ forming alginate hydrogel following acute myocardial infarction (AMI) in rats. METHODS: ASCs were transduced with luciferase and tested for ASC phenotype. AMI was inducted in nude rats, with subsequent injection of saline (controls), 1 × 106 ASCs in saline or 1 × 106 ASCs in 1% (w/v) alginate hydrogel. ASCs were tracked by bioluminescence and functional measurements were assessed by magnetic resonance imaging (MRI) and 82rubidium positron emission tomography (PET). RESULTS: ASCs in both saline and alginate hydrogel significantly increased the ejection fraction (7.2% and 7.8% at 14 days and 7.2% and 8.0% at 28 days, resp.). After 28 days, there was a tendency for decreased infarct area and increased perfusion, compared to controls. No significant differences were observed between ASCs in saline or alginate hydrogel, in terms of retention and functional salvage. CONCLUSION: ASCs improved the myocardial function after AMI, but administration in the alginate hydrogel did not further improve retention of the cells or myocardial function.

Rationale and Design of the First Double-Blind, Placebo-Controlled Trial with Allogeneic Adipose Tissue-Derived Stromal Cell Therapy in Patients with Ischemic Heart Failure: A Phase II Danish Multicentre Study.

BACKGROUND: Ischemic heart failure (IHF) has a poor prognosis in spite of optimal therapy. We have established a new allogeneic Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors. It is produced without animal products, in closed bioreactor systems and cryopreserved as an off-the-shelf product ready to use. STUDY DESIGN: A multicentre, double-blind, placebo-controlled phase II study with direct intramyocardial injections of allogeneic CSCC_ASC in patients with chronic IHF. A total of 81 patients will be randomised at 2 : 1 to CSCC_ASC or placebo. There is no HLA tissue type matching needed between the patients and the donors. METHODS: The treatment will be delivered by direct injections into the myocardium. The primary endpoint is change in the left ventricle endsystolic volume at 6-month follow-up. Secondary endpoints are safety and changes in left ventricle ejection fraction, myocardial mass, stroke volume, and cardiac output. Other secondary endpoints are change in clinical symptoms, 6-minute walking test, and the quality of life after 6 and 12 months. CONCLUSION: The aim of the present study is to demonstrate safety and the regenerative efficacy of the allogeneic CSCC_ASC product from healthy donors in a double-blind, placebo-controlled, multicentre study in patients with IHF.

Cryopreserved Off-the-Shelf Allogeneic Adipose-Derived Stromal Cells for Therapy in Patients with Ischemic Heart Disease and Heart Failure-A Safety Study.

The present first-in-human clinical trial evaluated the safety and feasibility of a newly developed and cryopreserved Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors for intramyocardial injection in ten patients with ischemic heart disease and ischemic heart failure (IHF). Batches of CSCC_ASC were isolated from three healthy donors by liposuction from abdominal adipose tissue. Adipose mesenchymal stromal cells were culture expanded in bioreactors without the use of animal constituents, cryopreserved, and stored in vials in nitrogen dry-storage containers until use. Direct injection of CSCC_ASC into the myocardium did not cause any complications or serious adverse events related to either treatment or cell administration in a 6-month follow-up period. Four out of ten heart failure patients developed donor-specific de novo human leukocyte antigen (HLA) class I antibodies, and two out of ten patients had donor-specific HLA antibodies already at baseline. There were no clinical symptoms or changes in inflammatory parameters in the follow-up period that indicated an ongoing immune response. There was a tendency toward improvement in cardiac function after CSCC_ASC treatment at 6-month follow-up: left ventricular end systolic volume decreased and left ventricular ejection fraction increased. In addition, exercise capacity increased. These changes were independent of the presence or absence of HLA antibodies. It is concluded that the newly developed cryopreserved product CSCC_ASC from healthy donors was a safe and feasible treatment. We observed a tendency toward efficacy in patients with IHF. These findings have to be confirmed in larger placebo controlled clinical trials. Stem Cells Translational Medicine 2017;6:1963-1971.

Nutrition support in hospitalised adults at nutritional risk.

BACKGROUND: The prevalence of disease-related malnutrition in Western European hospitals is estimated to be about 30%. There is no consensus whether poor nutritional status causes poorer clinical outcome or if it is merely associated with it. The intention with all forms of nutrition support is to increase uptake of essential nutrients and improve clinical outcome. Previous reviews have shown conflicting results with regard to the effects of nutrition support. OBJECTIVES: To assess the benefits and harms of nutrition support versus no intervention, treatment as usual, or placebo in hospitalised adults at nutritional risk. SEARCH METHODS: We searched Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE (Ovid SP), Embase (Ovid SP), LILACS (BIREME), and Science Citation Index Expanded (Web of Science). We also searched the World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp); ClinicalTrials.gov; Turning Research Into Practice (TRIP); Google Scholar; and BIOSIS, as well as relevant bibliographies of review articles and personal files. All searches are current to February 2016. SELECTION CRITERIA: We include randomised clinical trials, irrespective of publication type, publication date, and language, comparing nutrition support versus control in hospitalised adults at nutritional risk. We exclude trials assessing non-standard nutrition support. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane and the Cochrane Hepato-Biliary Group. We used trial domains to assess the risks of systematic error (bias). We conducted Trial Sequential Analyses to control for the risks of random errors. We considered a P value of 0.025 or less as statistically significant. We used GRADE methodology. Our primary outcomes were all-cause mortality, serious adverse events, and health-related quality of life. MAIN RESULTS: We included 244 randomised clinical trials with 28,619 participants that met our inclusion criteria. We considered all trials to be at high risk of bias. Two trials accounted for one-third of all included participants. The included participants were heterogenous with regard to disease (20 different medical specialties). The experimental interventions were parenteral nutrition (86 trials); enteral nutrition (tube-feeding) (80 trials); oral nutrition support (55 trials); mixed experimental intervention (12 trials); general nutrition support (9 trials); and fortified food (2 trials). The control interventions were treatment as usual (122 trials); no intervention (107 trials); and placebo (15 trials). In 204/244 trials, the intervention lasted three days or more.We found no evidence of a difference between nutrition support and control for short-term mortality (end of intervention). The absolute risk was 8.3% across the control groups compared with 7.8% (7.1% to 8.5%) in the intervention groups, based on the risk ratio (RR) of 0.94 (95% confidence interval (CI) 0.86 to 1.03, P = 0.16, 21,758 participants, 114 trials, low quality of evidence). We found no evidence of a difference between nutrition support and control for long-term mortality (maximum follow-up). The absolute risk was 13.2% in the control group compared with 12.2% (11.6% to 13%) following nutritional interventions based on a RR of 0.93 (95% CI 0.88 to 0.99, P = 0.03, 23,170 participants, 127 trials, low quality of evidence). Trial Sequential Analysis showed we only had enough information to assess a risk ratio reduction of approximately 10% or more. A risk ratio reduction of 10% or more could be rejected.We found no evidence of a difference between nutrition support and control for short-term serious adverse events. The absolute risk was 9.9% in the control groups versus 9.2% (8.5% to 10%), with nutrition based on the RR of 0.93 (95% CI 0.86 to 1.01, P = 0.07, 22,087 participants, 123 trials, low quality of evidence). At long-term follow-up, the reduction in the risk of serious adverse events was 1.5%, from 15.2% in control groups to 13.8% (12.9% to 14.7%) following nutritional support (RR 0.91, 95% CI 0.85 to 0.97, P = 0.004, 23,413 participants, 137 trials, low quality of evidence). However, the Trial Sequential Analysis showed we only had enough information to assess a risk ratio reduction of approximately 10% or more. A risk ratio reduction of 10% or more could be rejected.Trial Sequential Analysis of enteral nutrition alone showed that enteral nutrition might reduce serious adverse events at maximum follow-up in people with different diseases. We could find no beneficial effect of oral nutrition support or parenteral nutrition support on all-cause mortality and serious adverse events in any subgroup.Only 16 trials assessed health-related quality of life. We performed a meta-analysis of two trials reporting EuroQoL utility score at long-term follow-up and found very low quality of evidence for effects of nutritional support on quality of life (mean difference (MD) -0.01, 95% CI -0.03 to 0.01; 3961 participants, two trials). Trial Sequential Analyses showed that we did not have enough information to confirm or reject clinically relevant intervention effects on quality of life.Nutrition support may increase weight at short-term follow-up (MD 1.32 kg, 95% CI 0.65 to 2.00, 5445 participants, 68 trials, very low quality of evidence). AUTHORS' CONCLUSIONS: There is low-quality evidence for the effects of nutrition support on mortality and serious adverse events. Based on the results of our review, it does not appear to lead to a risk ratio reduction of approximately 10% or more in either all-cause mortality or serious adverse events at short-term and long-term follow-up.There is very low-quality evidence for an increase in weight with nutrition support at the end of treatment in hospitalised adults determined to be at nutritional risk. The effects of nutrition support on all remaining outcomes are unclear.Despite the clinically heterogenous population and the high risk of bias of all included trials, our analyses showed limited signs of statistical heterogeneity. Further trials may be warranted, assessing enteral nutrition (tube-feeding) for different patient groups. Future trials ought to be conducted with low risks of systematic errors and low risks of random errors, and they also ought to assess health-related quality of life.

Senescence and quiescence in adipose-derived stromal cells: Effects of human platelet lysate, fetal bovine serum and hypoxia.

BACKGROUND AIMS: Adipose-derived stromal cells (ASCs) are attractive sources for cell-based therapies. The hypoxic niche of ASCs in vivo implies that cells will benefit from hypoxia during in vitro expansion. Human platelet lysate (hPL) enhances ASC proliferation rates, compared with fetal bovine serum (FBS) at normoxia. However, the low proliferation rates of FBS-expanded ASCs could be signs of senescence or quiescence. We aimed to determine the effects of hypoxia and hPL on the expansion of ASCs and whether FBS-expanded ASCs are senescent or quiescent. METHODS: ASCs expanded in FBS or hPL at normoxia or hypoxia until passage 7 (P7), or in FBS until P5 followed by culture in hPL until P7, were evaluated by proliferation rates, cell cycle analyses, gene expression and ß-galactosidase activity. RESULTS: hPL at normoxia and hypoxia enhanced proliferation rates and expression of cyclins, and decreased G0/G1 fractions and expression of p21 and p27, compared with FBS. The shift from FBS to hPL enhanced cyclin levels, decreased p21 and p27 levels and tended to decrease G0/G1 fractions. CONCLUSION: Hypoxia does not add to the effect of hPL during ASC expansion with regard to proliferation, cell cycle regulation and expression of cyclins, p21 and p27. hPL rejuvenates FBS-expanded ASCs with regard to cell cycle regulation and expression of cyclins, p21 and p27. This indicates a reversible arrest. Therefore, we conclude that ASCs expanded until P7 are not senescent regardless of culture conditions.