Pulsed field versus cryoballoon ablation for atrial fibrillation: a real-world observational study on procedural outcomes and efficacy.

INTRODUCTION: Atrial fibrillation often necessitates catheter ablation when antiarrhythmic drug therapy fails. Single-shot technologies using thermal energy, such as cryoballoon ablation, are commonly used, but pulsed field ablation (PFA), an innovative non-thermal ablation technique, is a potential alternative. This retrospective observational study aimed to compare the safety and efficacy of cryoballoon ablation and PFA in patients undergoing their first pulmonary vein isolation (PVI) procedure for atrial fibrillation treatment. METHODS: We utilised real-world data from patients who underwent PVI using cryoballoon ablation or PFA. The primary outcome encompassed procedural complications, including phrenic nerve palsy, cardiac tamponade, thromboembolic complications, bleeding complications and mortality. Secondary outcomes were procedural characteristics including procedure duration, length of hospital admission, and re-do ablation rates within 6 months. RESULTS: A total of 1714 procedures were analysed: 1241 in the cryoballoon group and 473 in the PFA group. Gender distribution (p = 0.03) and estimated glomerular filtration rate (p = 0.01) differed significantly. With regard to the primary outcome, the cryoballoon group demonstrated a higher incidence of phrenic nerve palsy compared with the PFA group (15 vs 0; p = 0.02). The procedure duration was shorter in the PFA group, even after adjusting for baseline characteristics (95.0 vs 74.0 min; p < 0.001). After adjustment for baseline characteristics, admission duration differed between the groups as well (p = 0.04). CONCLUSION: The study results supported the safety and efficacy of PFA over cryoballoon ablation for PVI, highlighting advantages such as shorter procedure duration and absence of phrenic nerve palsy.

Opposing MMP-9 Expression in Mesenchymal Stromal Cells and Head and Neck Tumor Cells after Direct 2D and 3D Co-Culture.

Bone marrow-derived mesenchymal stromal cells (BMSCs) respond to a variety of tumor cell-derived signals, such as inflammatory cytokines and growth factors. As a result, the inflammatory tumor microenvironment may lead to the recruitment of BMSCs. Whether BMSCs in the tumor environment are more likely to promote tumor growth or tumor suppression is still controversial. In our experiments, direct 3D co-culture of BMSCs with tumor cells from the head and neck region (HNSCC) results in strong expression and secretion of MMP-9. The observed MMP-9 secretion mainly originates from BMSCs, leading to increased invasiveness. In addition to our in vitro data, we show in vivo data based on the chorioallantoic membrane (CAM) model. Our results demonstrate that MMP-9 induces hemorrhage and increased perfusion in BMSC/HNSCC co-culture. While we had previously outlined that MMP-9 expression and secretion originate from BMSCs, our data showed a strong downregulation of MMP-9 promoter activity in HNSCC cells upon direct contact with BMSCs using the luciferase activity assay. Interestingly, the 2D and 3D models of direct co-culture suggest different drivers for the downregulation of MMP-9 promoter activity. Whereas the 3D model depicts a BMSC-dependent downregulation, the 2D model shows cell density-dependent downregulation. In summary, our data suggest that the direct interaction of HNSCC cells and BMSCs promotes tumor progression by significantly facilitating angiogenesis via MMP-9 expression. On the other hand, data from 3D and 2D co-culture models indicate opposing regulation of the MMP-9 promoter in tumor cells once stromal cells are involved.

BMSC-HNC Interaction: Exploring Effects on Bone Integrity and Head and Neck Cancer Progression.

In recent research, the tumor microenvironment has been shown to attract mesenchymal stromal cells (MSCs), which is of particular interest due to its implications for cancer progression. The study focused on understanding the interaction between bone marrow-derived MSCs (BMSCs) and head and neck cancer (HNC) cells. This interaction was found to activate specific markers, notably the osteogenic marker alkaline phosphatase and the oncogene Runx2. These activations corresponded with the release of collagenase enzymes, MMP9 and MMP2. To gain insights into bone resorption related to this interaction, bovine bone slices were used, supporting the growth of "heterogeneous spheroids" that contained both BMSCs and HNC cells. Through scanning electron microscopy and energy-dispersive X-ray (EDX) analysis, it was observed that these mixed spheroids were linked to a notable increase in bone degradation and collagen fiber exposure, more so than spheroids of just BMSCs or HNC cells. Furthermore, the EDX results highlighted increased nitrogen content on bone surfaces with these mixed clusters. Overall, the findings underscore the significant role of BMSCs in tumor growth, emphasizing the need for further exploration in potential cancer treatment strategies.

Candidalysin delivery to the invasion pocket is critical for host epithelial damage induced by Candida albicans.

The human pathogenic fungus Candida albicans is a frequent cause of mucosal infections. Although the ability to transition from the yeast to the hypha morphology is essential for virulence, hypha formation and host cell invasion per se are not sufficient for the induction of epithelial damage. Rather, the hypha-associated peptide toxin, candidalysin, a product of the Ece1 polyprotein, is the critical damaging factor. While synthetic, exogenously added candidalysin is sufficient to damage epithelial cells, the level of damage does not reach the same level as invading C. albicans hyphae. Therefore, we hypothesized that a combination of fungal attributes is required to deliver candidalysin to the invasion pocket to enable the full damaging potential of C. albicans during infection. Utilising a panel of C. albicans mutants with known virulence defects, we demonstrate that the full damage potential of C. albicans requires the coordinated delivery of candidalysin to the invasion pocket. This process requires appropriate epithelial adhesion, hyphal extension and invasion, high levels of ECE1 transcription, proper Ece1 processing and secretion of candidalysin. To confirm candidalysin delivery, we generated camelid VH Hs (nanobodies) specific for candidalysin and demonstrate localization and accumulation of the toxin only in C. albicans-induced invasion pockets. In summary, a defined combination of virulence attributes and cellular processes is critical for delivering candidalysin to the invasion pocket to enable the full damage potential of C. albicans during mucosal infection. TAKE AWAYS: Candidalysin is a peptide toxin secreted by C. albicans causing epithelial damage. Candidalysin delivery to host cell membranes requires specific fungal attributes. Candidalysin accumulates in invasion pockets created by invasive hyphae. Camelid nanobodies enabled visualisation of candidalysin in the invasion pocket.

Buparlisib modulates PD-L1 expression in head and neck squamous cell carcinoma cell lines.

High expression of the immune checkpoint receptor PD-L1 is associated with worse patient outcome in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Binding of PD-L1 with its partner PD-1 generates an inhibitory signal that dampens the immune system. Immunotherapy, that is blocking the PD-1/PD-L1 checkpoint, has proven to be an effective tool in cancer therapy. However, not all patients are able to benefit from this immune checkpoint inhibition. Therefore, evidence is growing of intrinsic PD-L1 signaling in cancer cells. For example, intrinsic PD-L1 expression was associated with PI3K/Akt/mTOR signaling, which is part of diverse oncogenic processes including cell proliferation, growth and survival. In this study we demonstrate the effects of PI3K/Akt/mTOR pathway inhibition by buparlisib on PD-L1 expression in HNSCC cell lines. After buparlisib treatment for 72 h, PD-L1 was downregulated in total cell lysates of HNSCC cells. Moreover, flow cytometry revealed a downregulation of PD-L1 membrane expression. Interestingly, the buparlisib mediated effects on PD-L1 expression were reduced by additional irradiation. In PD-L1 overexpressing cells, the buparlisib induced inhibition of proliferation was neutralized. In summary, our findings imply that blocking the PI3K/Akt/mTOR pathway could be a good additional therapy for patients who show poor response to immune checkpoint therapy.

Differential Expression of PD-L1 during Cell Cycle Progression of Head and Neck Squamous Cell Carcinoma.

The expression of PD-L1 by tumor cells is mainly associated with its immunosuppressive effect. In fact, PD-1/PD-L1 immune checkpoint inhibitors demonstrated remarkable effects in advanced cancer patients including HNSCC. In this context, irradiation is currently being investigated as a synergistic treatment modality to immunotherapy. However, the majority of HNSCC patients still show little improvement or even hyperprogression. Interestingly, there is increasing evidence for additional cell-intrinsic functions of PD-L1 in tumor cells. In previous studies, we showed that PD-L1 has a strong influence on proliferation, migration, invasion, and survival after irradiation. We demonstrated that cellular expression and localization of PD-L1 differed depending on sensitivity to irradiation. Here, we show that PD-L1 is also differentially expressed during cell cycle progression of HNSCC. Furthermore, cellular localization of PD-L1 also changes depending on a particular cell cycle phase. Moreover, distinct observations occurred depending on the general differentiation status. Overall, the function of PD-L1 cannot be generalized. Rather, it depends on the differentiation status and microenvironment. PD-L1 expression and localization are variable, depending on different factors. These findings may provide insight into why differential response to PD-1/PD-L1 antibody therapy can occur. Detailed understanding of cell-intrinsic PD-L1 functions will further allow antibody-based immunotherapy to be optimized.

Improving clinical outcomes and patient satisfaction among patients with coronary artery disease: an example of enhancing regional integration between a cardiac centre and a referring hospital.

BACKGROUND: Value-based healthcare (VBHC) is a promising strategy to increase patient value. For a successful implementation of VBHC, intensive collaborations between organizations and integrated care delivery systems are key conditions. Our aim was to evaluate the effects of a pilot study regarding enhancing regional integration between a cardiac centre and a referring hospital on patient-relevant clinical outcomes and patient satisfaction. METHODS: The study population consisted of a sample of patients treated for coronary artery disease by use of a coronary artery bypass graft (CABG) or a percutaneous coronary intervention between 2011 and 2016. Since 2013, the two hospitals have implemented different interventions to improve clinical outcomes and the degree of patient satisfaction, e.g. improvement of communication, increased consultant capacity, introduction of outpatient clinic for complex patients, and improved guideline adherence. To identify intervention effects, logistic regression analyses were conducted. Patients' initial conditions, like demographics and health status, were included in the model as predictors. Clinical data extracted from the electronic health records and the hospitals' cardiac databases as well as survey-based data were used. RESULTS: Our findings indicate a non-significant increase of event-free survival of patients treated for coronary artery disease between 2014 and 2016 compared to patients treated between 2011 and 2013 (97.4% vs. 96.7% respectively). This non-significant improvement over time has led to significant better outcomes for patients referred from the study referring hospital compared to patients referred from other hospitals. The level of patient satisfaction (response rate 32.2%; 216 out of 669) was improved and reached statistically significant higher scores regarding patient information and education (p = .013), quality of care (p = .007), hospital admission and stay (p = .032), personal contact with the physician (p = .024), and total impression (p = .007). CONCLUSIONS: This study shows a promising effect of regional integration. An intensified collaboration in the care chain, organized in a structured manner between a cardiac centre and a referring hospital and aiming at high quality, resulted in successful improvement of clinical outcomes and degree of patient satisfaction. The applied method may be used as a starting point of regional integration with other referring hospitals. We encourage others to organize the whole care chain to continuously improve patient-relevant outcomes and patient satisfaction. TRIAL REGISTRATION: ISRCTN11311830. Registered 01 October 2018 (retrospectively registered).

PD-L1 Influences Cell Spreading, Migration and Invasion in Head and Neck Cancer Cells.

The programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis blockade has been implemented in advanced-stage tumor therapy for various entities, including head and neck squamous cell carcinoma (HNSCC). Despite a promising tumor response in a subgroup of HNSCC patients, the majority suffer from disease progression. PD-L1 is known to influence several intrinsic mechanisms in cancer cells, such as proliferation, apoptosis, migration and invasion. Here, we modulated PD-L1 expression in three HNSCC cell lines with differential intrinsic PD-L1 expression. In addition to an alteration in the epithelial-to-mesenchymal transition (EMT) marker expression, we observed PD-L1-dependent cell spreading, migration and invasion in a spheroid spreading assay on four different coatings (poly-L-lysine, collagen type I, fibronectin and Matrigel®) and a chemotactic transwell migration/invasion assay. Furthermore, the overexpression of PD-L1 led to increased gene expression and small interfering ribonucleic acid (siRNA) knockdown and decreased gene expression of Rho-GTPases and related proteins in a RT2 Profiler™ PCR Array. Rac1 and Rho-GTPase pulldown assays revealed a change in the activation state concordantly with PD-L1 expression. In summary, our results suggest a major role for PD-L1 in favoring cell motility, including cell spreading, migration and invasion. This is presumably caused by altered N-cadherin expression and changes in the activation states of small Rho-GTPases Rho and Rac1.

Effect of betamethasone, indomethacin and fenoterol on neonatal and maternal mononuclear cells stimulated with Escherichia coli.

Despite considerable progress in the field of perinatal care, infectious diseases, especially when caused by gram negative bacteria, remain a major reason for neonatal morbidity and mortality. Notably infants born prematurely and those with very low birth weight are at risk due to their immature and deficient immune system and their prolonged hospitalization which promotes nosocomial infections. In case of impending preterm birth, betamethasone is given to induce lung maturation and tocolytic agents like indomethacin or fenoterol are administered to suppress premature labor. The aim of this study was to analyze the effects of these drugs on the immune system of mothers and neonates. Therefore, mononuclear cells from cord blood and peripheral maternal blood were stimulated with Escherichia coli and incubated with betamethasone, indomethacin and fenoterol. Subsequently the effect of the treatment on cytokine production was determined. Betamethasone alone and in combination with tocolytic agents inhibited the production of pro- and anti-inflammatory cytokines. Not only does betamethasone dampen the immune response by reducing the production of cytokines, it also has a variety of other detrimental short- and long-term effects on the neonate. In conclusion we would recommend using biological markers to determine if premature labor actually leads to preterm birth and subsequently administer betamethasone only to mothers giving birth prematurely.

Effectiveness and treatment moderators of internet interventions for adult problem drinking: An individual patient data meta-analysis of 19 randomised controlled trials.

BACKGROUND: Face-to-face brief interventions for problem drinking are effective, but they have found limited implementation in routine care and the community. Internet-based interventions could overcome this treatment gap. We investigated effectiveness and moderators of treatment outcomes in internet-based interventions for adult problem drinking (iAIs). METHODS AND FINDINGS: Systematic searches were performed in medical and psychological databases to 31 December 2016. A one-stage individual patient data meta-analysis (IPDMA) was conducted with a linear mixed model complete-case approach, using baseline and first follow-up data. The primary outcome measure was mean weekly alcohol consumption in standard units (SUs, 10 grams of ethanol). Secondary outcome was treatment response (TR), defined as less than 14/21 SUs for women/men weekly. Putative participant, intervention, and study moderators were included. Robustness was verified in three sensitivity analyses: a two-stage IPDMA, a one-stage IPDMA using multiple imputation, and a missing-not-at-random (MNAR) analysis. We obtained baseline data for 14,198 adult participants (19 randomised controlled trials [RCTs], mean age 40.7 [SD = 13.2], 47.6% women). Their baseline mean weekly alcohol consumption was 38.1 SUs (SD = 26.9). Most were regular problem drinkers (80.1%, SUs 44.7, SD = 26.4) and 19.9% (SUs 11.9, SD = 4.1) were binge-only drinkers. About one third were heavy drinkers, meaning that women/men consumed, respectively, more than 35/50 SUs of alcohol at baseline (34.2%, SUs 65.9, SD = 27.1). Post-intervention data were available for 8,095 participants. Compared with controls, iAI participants showed a greater mean weekly decrease at follow-up of 5.02 SUs (95% CI -7.57 to -2.48, p < 0.001) and a higher rate of TR (odds ratio [OR] 2.20, 95% CI 1.63-2.95, p < 0.001, number needed to treat [NNT] = 4.15, 95% CI 3.06-6.62). Persons above age 55 showed higher TR than their younger counterparts (OR = 1.66, 95% CI 1.21-2.27, p = 0.002). Drinking profiles were not significantly associated with treatment outcomes. Human-supported interventions were superior to fully automated ones on both outcome measures (comparative reduction: -6.78 SUs, 95% CI -12.11 to -1.45, p = 0.013; TR: OR = 2.23, 95% CI 1.22-4.08, p = 0.009). Participants treated in iAIs based on personalised normative feedback (PNF) alone were significantly less likely to sustain low-risk drinking at follow-up than those in iAIs based on integrated therapeutic principles (OR = 0.52, 95% CI 0.29-0.93, p = 0.029). The use of waitlist control in RCTs was associated with significantly better treatment outcomes than the use of other types of control (comparative reduction: -9.27 SUs, 95% CI -13.97 to -4.57, p < 0.001; TR: OR = 3.74, 95% CI 2.13-6.53, p < 0.001). The overall quality of the RCTs was high; a major limitation included high study dropout (43%). Sensitivity analyses confirmed the robustness of our primary analyses. CONCLUSION: To our knowledge, this is the first IPDMA on internet-based interventions that has shown them to be effective in curbing various patterns of adult problem drinking in both community and healthcare settings. Waitlist control may be conducive to inflation of treatment outcomes.

Acute food deprivation separates motor-activating from anxiolytic effects of caffeine in a rat open field test model.

Similar doses of caffeine have been shown to produce either anxiolytic or anxiogenic effects in rats. The reasons for these conflicting results are not known. We hypothesized that food deprivation stress interacts with the stimulant effects of caffeine to increase anxiety-like behavior. We tested 32 female Sprague Dawley rats in a dim open field for 10 min. Half of the animals were food deprived for 24 h and injected (intraperitoneal) with caffeine (30 mg/kg; n=7) or deionized water (n=8) 20 min before the open field test. The other half was nondeprived and injected with caffeine (30 mg/kg; n=8) or deionized water (n=9). Results showed that nondeprived rats injected with caffeine moved longer distances and at a greater speed in the periphery and moved longer distances and spent more time in the center than rats treated with vehicle, indicative of motor-activating and/or anxiolytic effects of caffeine. Rats that were food deprived and injected with caffeine moved longer distances in the center and tended to spend more time there, indicative of anxiolysis. We conclude that caffeine had two effects on behavior, motor activation and a reduction of anxiety, and that food deprivation separated these effects.

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

mHealth or eHealth? Efficacy, Use, and Appreciation of a Web-Based Computer-Tailored Physical Activity Intervention for Dutch Adults: A Randomized Controlled Trial.

BACKGROUND: Until a few years ago, Web-based computer-tailored interventions were almost exclusively delivered via computer (eHealth). However, nowadays, interventions delivered via mobile phones (mHealth) are an interesting alternative for health promotion, as they may more easily reach people 24/7. OBJECTIVE: The first aim of this study was to compare the efficacy of an mHealth and an eHealth version of a Web-based computer-tailored physical activity intervention with a control group. The second aim was to assess potential differences in use and appreciation between the 2 versions. METHODS: We collected data among 373 Dutch adults at 5 points in time (baseline, after 1 week, after 2 weeks, after 3 weeks, and after 6 months). We recruited participants from a Dutch online research panel and randomly assigned them to 1 of 3 conditions: eHealth (n=138), mHealth (n=108), or control condition (n=127). All participants were asked to complete questionnaires at the 5 points in time. Participants in the eHealth and mHealth group received fully automated tailored feedback messages about their current level of physical activity. Furthermore, they received personal feedback aimed at increasing their amount of physical activity when needed. We used analysis of variance and linear regression analyses to examine differences between the 2 study groups and the control group with regard to efficacy, use, and appreciation. RESULTS: Participants receiving feedback messages (eHealth and mHealth together) were significantly more physically active after 6 months than participants in the control group (B=8.48, df=2, P=.03, Cohen d=0.27). We found a small effect size favoring the eHealth condition over the control group (B=6.13, df=2, P=.09, Cohen d=0.21). The eHealth condition had lower dropout rates (117/138, 84.8%) than the mHealth condition (81/108, 75.0%) and the control group (91/127, 71.7%). Furthermore, in terms of usability and appreciation, the eHealth condition outperformed the mHealth condition with regard to participants receiving (t182=3.07, P=.002) and reading the feedback messages (t181=2.34, P=.02), as well as the clarity of the messages (t181=1.99, P=.049). CONCLUSIONS: We tested 2 Web-based computer-tailored physical activity intervention versions (mHealth and eHealth) against a control condition with regard to efficacy, use, usability, and appreciation. The overall effect was mainly caused by the more effective eHealth intervention. The mHealth app was rated inferior to the eHealth version with regard to usability and appreciation. More research is needed to assess how both methods can complement each other. TRIAL REGISTRATION: Netherlands Trial Register: NTR4503; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4503 (Archived by WebCite at http://www.webcitation.org/6lEi1x40s).

Tailored eHealth Lifestyle Promotion: Which Behavioral Modules Do Users Prefer?

Health risk behaviors are widespread among adults and often co-occur. eHealth computer-tailored technology provides individuals with personalized feedback regarding multiple lifestyle behaviors. First, the authors investigated individuals' preferences for particular lifestyle modules and hypothesised that health preventive behavior modules would be preferred over addictive behavior modules. Second, characteristics associated with these choices were examined. A web-based questionnaire assessed demographics, health status, and five lifestyle behaviors (i.e., physical activity, fruit consumption, vegetable consumption, alcohol intake and tobacco use) among adults (N = 1,828). Responses were translated into a health risk appraisal outlining whether respondents adhered to the national guidelines for these behaviors. Next, respondents could select one of the lifestyle modules providing personalized advice. More than 60% of the participants failed to meet the guidelines for more than one lifestyle behavior. The physical activity module was the most popular, followed by the smoking and fruit modules. Young adults tended to prefer the physical activity and fruit modules, whereas the vegetable module was more popular among older adults. No consistent pattern was identified for the alcohol and smoking modules. The results support the authors' hypothesis that health preventive behaviors-in particular, physical activity-would be preferred. Although this could imply that physical activity could serve as a gateway behavior when aiming at multiple behavior changes, it is also conceivable that other mechanisms, such as the actual success of behavior change, or the fact that people can choose, may increase chances of multiple behavior change. Hence, mechanisms leading to multiple behavior change need to be further explored.

Who Follows eHealth Interventions as Recommended? A Study of Participants' Personal Characteristics From the Experimental Arm of a Randomized Controlled Trial.

BACKGROUND: Computer-tailored eHealth interventions to improve health behavior have been demonstrated to be effective and cost-effective if they are used as recommended. However, different subgroups may use the Internet differently, which might also affect intervention use and effectiveness. To date, there is little research available depicting whether adherence to intervention recommendations differs according to personal characteristics. OBJECTIVE: The aim was to assess which personal characteristics are associated with using an eHealth intervention as recommended. METHODS: A randomized controlled trial was conducted among a sample of the adult Dutch population (N=1638) testing an intervention aimed at improving 5 healthy lifestyle behaviors: increasing fruit and vegetable consumption, increasing physical activity, reducing alcohol intake, and promoting smoking cessation. Participants were asked to participate in those specific online modules for which they did not meet the national guideline(s) for the respective behavior(s). Participants who started with fewer than the recommended number of modules of the intervention were defined as users who did not follow the intervention recommendation. RESULTS: The fewer modules recommended to participants, the better participants adhered to the intervention modules. Following the intervention recommendation increased when participants were older (χ(2)1=39.8, P<.001), female (χ(2)1=15.8, P<.001), unemployed (χ(2)1=7.9, P=.003), ill (χ(2)1=4.5, P=.02), or in a relationship (χ(2)1=7.8, P=.003). No significant relevant differences were found between groups with different levels of education, incomes, or quality of life. CONCLUSION: Our findings indicate that eHealth interventions were used differently by subgroups. The more frequent as-recommended intervention use by unemployed, older, and ill participants may be an indication that these eHealth interventions are attractive to people with a greater need for health care information. Further research is necessary to make intervention use more attractive for people with unhealthy lifestyle patterns.

Impact of Educational Level on Study Attrition and Evaluation of Web-Based Computer-Tailored Interventions: Results From Seven Randomized Controlled Trials.

BACKGROUND: Web-based computer-tailored interventions have shown to be effective in improving health behavior; however, high dropout attrition is a major issue in these interventions. OBJECTIVE: The aim of this study is to assess whether people with a lower educational level drop out from studies more frequently compared to people with a higher educational level and to what extent this depends on evaluation of these interventions. METHODS: Data from 7 randomized controlled trials of Web-based computer-tailored interventions were used to investigate dropout rates among participants with different educational levels. To be able to compare higher and lower educated participants, intervention evaluation was assessed by pooling data from these studies. Logistic regression analysis was used to assess whether intervention evaluation predicted dropout at follow-up measurements. RESULTS: In 3 studies, we found a higher study dropout attrition rate among participants with a lower educational level, whereas in 2 studies we found that middle educated participants had a higher dropout attrition rate compared to highly educated participants. In 4 studies, no such significant difference was found. Three of 7 studies showed that participants with a lower or middle educational level evaluated the interventions significantly better than highly educated participants ("Alcohol-Everything within the Limit": F2,376=5.97, P=.003; "My Healthy Behavior": F2,359=5.52, P=.004; "Master Your Breath": F2,317=3.17, P=.04). One study found lower intervention evaluation by lower educated participants compared to participants with a middle educational level ("Weight in Balance": F2,37=3.17, P=.05). Low evaluation of the interventions was not a significant predictor of dropout at a later follow-up measurement in any of the studies. CONCLUSIONS: Dropout attrition rates were higher among participants with a lower or middle educational level compared with highly educated participants. Although lower educated participants evaluated the interventions better in approximately half of the studies, evaluation did not predict dropout attrition. Further research is needed to find other explanations for high dropout rates among lower educated participants.

Metadata Correction: Impact of Educational Level on Study Attrition and Evaluation of Web-Based Computer-Tailored Interventions: Results From Seven Randomized Controlled Trials.

[This corrects the article DOI: .].

Synaptic abnormalities in the infralimbic cortex of a model of congenital depression.

Multiple lines of evidence suggest that disturbances in excitatory transmission contribute to depression. Whether these defects involve the number, size, or composition of glutamatergic contacts is unclear. This study used recently introduced procedures for fluorescence deconvolution tomography in a well-studied rat model of congenital depression to characterize excitatory synapses in layer I of infralimbic cortex, a region involved in mood disorders, and of primary somatosensory cortex. Three groups were studied: (1) rats bred for learned helplessness (cLH); (2) rats resistant to learned helplessness (cNLH); and (3) control Sprague Dawley rats. In fields within infralimbic cortex, cLH rats had the same numerical density of synapses, immunolabeled for either the postsynaptic density (PSD) marker PSD95 or the presynaptic protein synaptophysin, as controls. However, PSD95 immunolabeling intensities were substantially lower in cLH rats, as were numerical densities of synapse-sized clusters of the AMPA receptor subunit GluA1. Similar but less pronounced differences (comparable numerical densities but reduced immunolabeling intensity for PSD95) were found in the somatosensory cortex. In contrast, non-helpless rats had 25% more PSDs than either cLH or control rats without any increase in synaptophysin-labeled terminal frequency. Compared with controls, both cLH and cNLH rats had fewer GABAergic contacts. These results indicate that congenital tendencies that increase or decrease depression-like behavior differentially affect excitatory synapses.

Current approaches for RNA labeling in vitro and in cells based on click reactions.

Over recent years, click reactions have become recognized as valuable and flexible tools to label biomacromolecules such as proteins, nucleic acids, and glycans. Some of the developed strategies can be performed not only in aqueous solution but also in the presence of cellular components, as well as on (or even in) living cells. These labeling strategies require the initial, specific modification of the target molecule with a small, reactive moiety. In the second step, a click reaction is used to covalently couple a reporter molecule to the biomolecule. Depending on the type of reporter, labeling by the click reaction can be used in many different applications, ranging from isolation to functional studies of biomacromolecules. In this minireview, we focus on labeling strategies for RNA that rely on the click reaction. We first highlight click reactions that have been used successfully to label modified RNA, and then describe different strategies to introduce the required reactive groups into target RNA. The benefits and potential limitations of the strategies are critically discussed with regard to possible future developments.