A highly conserved tRNA modification contributes to C. albicans filamentation and virulence.

tRNA modifications play important roles in maintaining translation accuracy in all domains of life. Disruptions in the tRNA modification machinery, especially of the anticodon stem loop, can be lethal for many bacteria and lead to a broad range of phenotypes in baker's yeast. Very little is known about the function of tRNA modifications in host-pathogen interactions, where rapidly changing environments and stresses require fast adaptations. We found that two closely related fungal pathogens of humans, the highly pathogenic Candida albicans and its much less pathogenic sister species, Candida dubliniensis, differ in the function of a tRNA-modifying enzyme. This enzyme, Hma1, exhibits species-specific effects on the ability of the two fungi to grow in the hypha morphology, which is central to their virulence potential. We show that Hma1 has tRNA-threonylcarbamoyladenosine dehydratase activity, and its deletion alters ribosome occupancy, especially at 37°C-the body temperature of the human host. A C. albicans HMA1 deletion mutant also shows defects in adhesion to and invasion into human epithelial cells and shows reduced virulence in a fungal infection model. This links tRNA modifications to host-induced filamentation and virulence of one of the most important fungal pathogens of humans.IMPORTANCEFungal infections are on the rise worldwide, and their global burden on human life and health is frequently underestimated. Among them, the human commensal and opportunistic pathogen, Candida albicans, is one of the major causative agents of severe infections. Its virulence is closely linked to its ability to change morphologies from yeasts to hyphae. Here, this ability is linked-to our knowledge for the first time-to modifications of tRNA and translational efficiency. One tRNA-modifying enzyme, Hma1, plays a specific role in C. albicans and its ability to invade the host. This adds a so-far unknown layer of regulation to the fungal virulence program and offers new potential therapeutic targets to fight fungal infections.

Subcellular localization of PD-L1 and cell-cycle-dependent expression of nuclear PD-L1 variants: implications for head and neck cancer cell functions and therapeutic efficacy.

The programmed cell death 1 ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) axis is primarily associated with immunosuppression in cytotoxic T lymphocytes (CTLs). However, mounting evidence is supporting the thesis that PD-L1 not only functions as a ligand but mediates additional cellular functions in tumor cells. Moreover, it has been demonstrated that PD-L1 is not exclusively localized at the cellular membrane. Subcellular fractionation revealed the presence of PD-L1 in various cellular compartments of six well-characterized head and neck cancer (HNC) cell lines, including the nucleus. Via Western blotting, we detected PD-L1 in its well-known glycosylated/deglycosylated state at 40-55 kDa. In addition, we detected previously unknown PD-L1 variants with a molecular weight at approximately 70 and > 150 kDa exclusively in nuclear protein fractions. These in vitro findings were confirmed with primary tumor samples from head and neck squamous cell carcinoma (HNSCC) patients. Furthermore, we demonstrated that nuclear PD-L1 variant expression is cell-cycle-dependent. Immunofluorescence staining of PD-L1 in different cell cycle phases of synchronized HNC cells supported these observations. Mechanisms of nuclear PD-L1 trafficking remain less understood; however, proximity ligation assays showed a cell-cycle-dependent interaction of the cytoskeletal protein vimentin with PD-L1, whereas vimentin could serve as a potential shuttle for nuclear PD-L1 transportation. Mass spectrometry after PD-L1 co-immunoprecipitation, followed by gene ontology analysis, indicated interaction of nuclear PD-L1 with proteins involved in DNA remodeling and messenger RNA (mRNA) splicing. Our results in HNC cells suggest a highly complex regulation of PD-L1 and multiple tumor cell-intrinsic functions, independent of immune regulation. These observations bear significant implications for the therapeutic efficacy of immune checkpoint inhibition.

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.

Direct admission versus interhospital transfer for revascularisation in non-ST-segment elevation myocardial infarction.

BACKGROUND: The differences in outcomes and process parameters for NSTEMI patients who are directly admitted to an intervention centre and patients who are first admitted to a general centre are largely unknown. HYPOTHESIS: There are differences in process indicators, but not for clinical outcomes, for NSTEMI who are directly admitted to an intervention centre and patients who are first admitted to a general centre. METHODS: We aim to compare process indicators, costs and clinical outcomes of non-ST-segment elevation myocardial infarction (NSTEMI) patients stratified by center of first presentation and revascularisation strategy. Hospital claim data from patients admitted with a NSTEMI between 2017 and 2019 were used for this study. Included patients were stratified by center of admission (intervention vs. general center) and subdivided by revascularisation strategy (PCI, CABG, or no revascularisation [noRevasc]). The primary outcome was length of hospital stay. Secondary outcomes included: duration between admission and diagnostic angiography and revascularisation, number of intracoronary procedures, clinical outcomes at 30 days (MACE: all-cause mortality, recurrent myocardial infarction and cardiac readmission) and total costs (accumulation of costs for hospital claims and interhospital ambulance rides). RESULTS: A total of 9641 NSTEMI events (9167 unique patients) were analyzed of which 5399 patients (56%) were admitted at an intervention center and 4242 patients to a general center. Duration of hospitalization was significantly shorter at direct presentation at an intervention centre for all study groups (5 days [2-11] vs. 7 days [4-12], p < 0.001). For PCI, direct presentation at an intervention center yielded shorter time to diagnostic angiography (1 day [0-2] vs. 1 day [1-2], p < 0.01) and revascularisation (1 day [0-3] vs. 4 days [1-7], p < 0.001) and less intracoronary procedures per patient (2 [1-2] vs. 2 [2-2], p < 0.001). For CABG, time to revascularisation was shorter (8 days [5-12] vs. 10 days [7-14], p < 0.001). Total costs were significantly lower in case of direct presentation in an intervention center for all treatment groups €10.211 (8750-18.192) versus €13.741 (11.588-19.381), p < 0.001) while MACE was similar 11.8% versus 12.4%, p = 0.344). CONCLUSION: NSTEMI patients who were directly presented to an intervention center account for shorter duration of hospitalization, less time to revascularisation, less interhospital transfers, less intracoronary procedures and lower costs compared to patients who present at a general center.

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.

TGFß+ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype.

Transforming growth factor ß (TGFß) is a major component of tumor-derived small extracellular vesicles (TEX) in cancer patients. Mechanisms utilized by TGFß+ TEX to promote tumor growth and pro-tumor activities in the tumor microenvironment (TME) are largely unknown. TEX produced by head and neck squamous cell carcinoma (HNSCC) cell lines carried TGFß and angiogenesis-promoting proteins. TGFß+ TEX stimulated macrophage chemotaxis without a notable M1/M2 phenotype shift and reprogrammed primary human macrophages to a pro-angiogenic phenotype characterized by the upregulation of pro-angiogenic factors and functions. In a murine basement membrane extract plug model, TGFß+ TEX promoted macrophage infiltration and vascularization (p < 0.001), which was blocked by using the TGFß ligand trap mRER (p < 0.001). TGFß+ TEX injected into mice undergoing the 4-nitroquinoline-1-oxide (4-NQO)-driven oral carcinogenesis promoted tumor angiogenesis (p < 0.05), infiltration of M2-like macrophages in the TME (p < 0.05) and ultimately tumor progression (p < 0.05). Inhibition of TGFß signaling in TEX with mRER ameliorated these pro-tumor activities. Silencing of TGFß emerges as a critical step in suppressing pro-angiogenic functions of TEX in HNSCC.

Checkpoint Inhibitors in Cancer Therapy: Clinical Benefits for Head and Neck Cancers.

Recently, considerable progress has been achieved in cancer immunotherapy. Targeted immune checkpoint therapies have been established for several forms of cancers, which resulted in a tremendous positive impact on patient survival, even in more advanced tumor stages. With a better understanding of cellular responses to immune checkpoint therapies, it will soon be feasible to find targeted compounds which will make personalized medicine practicable. This is a great opportunity, but it also sets tremendous challenges on both the scientific and clinical aspects. Head and neck tumors evade immune surveillance through various mechanisms. They contain fewer lymphocytes (natural killer cells) than normal tissue with an accumulation of immunosuppressive regulatory T cells. Standard therapies for HNSCC, such as surgery, radiation, and chemotherapy, are becoming more advantageous by targeting immune checkpoints and employing combination therapies. The purpose of this review is to provide an overview of the expanded therapeutic options, particularly the combination of immune checkpoint inhibition with various conventional and novel therapeutics for head and neck tumor patients.

Loss of MMP-27 Predicts Mandibular Bone Invasion in Oral Squamous Cell Carcinoma.

Invasion of the mandibular bone is frequent in oral squamous cell carcinoma (OSCC), which often results in extensive ablative and reconstructive procedures for the patient. The purpose of this single-center, retrospective study was to identify and evaluate potential biomarkers and risk factors for bone invasion in OSCC. Initially, in silico gene expression analysis was performed for different HNSCC tumor T-stages to find factors associated with invasive (T4a) tumor growth. Afterwards, the protein expression of bone-metabolizing MMP-27, TNFRSF11B (Osteoprotegerin, OPG), and TNFSF11 (RANKL) was investigated via Tissue Microarrays (TMAs) for their impact on mandibular bone invasion. TMAs were assembled from the bone-tumor interface of primary OSCCs of the floor of the mouth and gingiva from 119 patients. Sixty-four carcinomas with patho-histological jaw invasion (pT4a) were compared to 55 carcinomas growing along the mandible without invasion (pT2, pT3). Tissue samples were additionally evaluated for patterns of invasion using the WPOI grading system. Statistical analysis of in silico data revealed decreased MMP-27 mRNA expression to be strongly associated with the pT4a-stage in OSCC, indicating invasive tumor growth with infiltration of adjacent anatomical structures. Our own clinico-pathological data on OSCCs presented a significant decrease of MMP-27 in tumors invading the nearby mandible (pT4a), compared to pT2 and pT3 tumors without bone invasion. Loss of MMP27 evolved as the strongest predictor of mandibular bone invasion in binary logistic regression analysis. To our knowledge, this is the first study investigating the role of MMP-27 expression in OSCC and demonstrating the importance of the loss of MMP-27 in mandibular bone invasion.

The Renaissance of Cyclin Dependent Kinase Inhibitors.

Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.

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.

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.

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.

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.

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).

Increased PD-L1 expression in radioresistant HNSCC cell lines after irradiation affects cell proliferation due to inactivation of GSK-3beta.

At present, targeting PD-1/PD-L1 axis for immune checkpoint inhibition has improved treatment of various tumor entities, including head and neck squamous cell carcinoma (HNSCC). However, one part of the patient cohort still shows little improvement or even hyperprogression. We established three radioresistant (RR) and three radiosensitive (RS) HNSCC cell lines. RR cells showed prolonged survival as well as delayed and diminished apoptosis after irradiation with vimentin expression but no E-cadherin expression, whereas RS cell lines died early and exhibited early apoptosis after irradiation and high vimentin expression. Here, we present results demonstrating differential basal PD-L1 gene and protein expression in RR and RS HNSCC cell lines. Moreover, we observed a radiation dose dependent increase of total PD-L1 protein expression in RR cell lines up to 96h after irradiation compared to non-irradiated (non-IRR) cells. We found a significant GSK-3beta phosphorylation, resulting in an inactivation, after irradiation of RR cell lines. Co-immunoprecipitation experiments revealed decreased interaction of GSK-3beta with PD-L1 in non-IRR compared to irradiated (IRR) RR cells leading to PD-L1 stabilization in RR cells. PD-L1 knockdown in RR cells showed a strong decrease in cell survival. In summary, our results suggest an irradiation dependent increase in basal PD-L1 expression in RR HNSCC cell lines via GSK-3beta inactivation.

A novel model to study neonatal Escherichia coli sepsis and the effect of treatment on the human immune system using humanized mice.

PROBLEM: Neonatal sepsis is a serious threat especially for preterm infants. As existing in vitro and in vivo models have limitations, we generated a novel neonatal sepsis model using humanized mice and tested the effect of Betamethasone and Indomethacin which are used in the clinic in case of premature birth. METHOD OF STUDY: Humanized mice were infected with Escherichia coli (E. coli). Subsequently, the effect of the infection itself, and treatment with Betamethasone and Indomethacin on survival, recovery, bacterial burden, leukocyte populations, and cytokine production, was analyzed. RESULTS: The human immune system in the animals responded with leukocyte trafficking to the site of infection and granulopoiesis in the bone marrow. Treatment with Indomethacin had no pronounced effect on the immune system or bacterial burden. Betamethasone induced a decline of splenocytes. CONCLUSION: The human immune system in humanized mice responds to the infection, making them a suitable model to study neonatal E. coli sepsis and the immune response of the neonatal immune system. Treatment with Betamethasone could have potential negative long-term effects for the immune system of the child.

Use of an intraoperative checklist to decrease the incidence of re-exploration for postoperative bleeding after cardiac surgery.

OBJECTIVES: We have implemented an intraoperative checklist aiming to reduce the incidence of re-exploration for bleeding after cardiac surgery. The present report addresses the results of adopting such a checklist regarding the incidence of postoperative bleeding. METHODS: The checklist was implemented by presenting it in several staff meetings of the Catharina Heart Center. Copies of the checklist were presented in every operating room. Data were collected by the Catharina Heart Center, aligned with the 'Meetbaar Beter' data manual and validated by 'Meetbaar Beter' through their data quality system. The incidence of re-exploration for bleeding was analysed in a variable life-adjusted display curve. The patient population operated after the implementation of the checklist was compared with a recent historical population before its implementation. RESULTS: From January 2013 through April 2016, 4817 cardiac surgical procedures were performed in our institution. Before May 2015, 3210 procedures were performed (Group 1), complicated by 112 re-exploration for bleeding (3.5%). The 'reoperation for bleeding checklist' was implemented on 1 May 2015. After this date, the number of re-explorations for bleeding decreased to 29 (1.8%) of the 1607 cardiac surgical procedures (Group 2) (P < 0.05). CONCLUSIONS: An intraoperative checklist is feasible to implement, low cost, quick and simple to measure with a significant reduction in the incidence of re-exploration for bleeding. This report shows an example of the positive effects of transparency in publishing outcomes' data in cardiac surgery.

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.

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.