Examining the interplay between internet use disorder tendencies and well-being in relation to sofalizing during the COVID-19 pandemic.

AIMS: The present study investigated the potential links between Internet Use Disorder tendencies, well-being and the impact of COVID-19 on Internet usage patterns. METHOD: A sample of 2498 participants filled out the Compulsive Internet Use Scale (CIUS), the Satisfaction with Life Scale (SWLS; the cognitive facet of well-being) and the Sofalizing Scale which comprises the Online Displacement and Social Compensation dimensions. Participants were also asked to report the extent to which changes in Internet use occurred due to COVID-19 pandemic (i.e., reductions, no changes, increases). The present study comprised a survey study with cross-sectional character. RESULTS: The statistical analyses demonstrated that the aforementioned variables were robustly associated with each other. In a first mediation model, the association between higher levels of Internet Use Disorder and reduced well-being was partially mediated by the two dimensions of the Sofalizing scale called Online Displacement and Social Compensation. The results of the second mediation model showed that the relationship between changes in Internet use due to COVID-19 pandemic and well-being was fully mediated by CIUS scores, suggesting that increased Internet use due to the COVID-19 pandemic increased levels of Internet Use Disorder tendencies, which in turn decreased levels of well-being. DISCUSSION: The findings are discussed in the context of human social needs in a time of crisis, where meeting people in-person was restricted.

Internet Use Disorders: Subjective Importance of Online Friends in the Context of Real-Life Social Support and Comorbid Mental Disorders.

INTRODUCTION: Previous studies analyzing friendships with people only known through the Internet mainly focused on quantitative aspects (e.g., the number of online friends or the time spent with them). Little is known about the perceived quality of online compared to real-life friends in individuals with an Internet use disorder (IUD). This study aimed to analyze associations of the increased subjective importance of online friends and IUD by controlling for the perceived real-life social support and comorbid mental disorders. METHODS: Based on a general population sample, 192 participants who were screened positive for risky Internet use took part in face-to-face clinical diagnostic interviews. IUD was assessed using the structure of the Munich-Composite International Diagnostic Interview (M-CIDI) and the adapted criteria of Internet gaming disorder in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The number and the increased subjective importance of online compared to real-life friends were assessed with the Online and Real-Life Friends scale (ORLF), real-life social support was assessed with the Berlin Social Support Scales (BSSS), and comorbidity was assessed with the M-CIDI. Data were analyzed with binary regression models. RESULTS: Of 192 participants with risky Internet use, 39 participants (19 men; age M = 29.9, SD = 12.2) fulfilled the criteria of IUD in the last 12 months. IUD was not associated with the number or perceived social support of online friends per se. In multivariate analyses, IUD was associated with increased subjective importance of online friends, independently from comorbid anxiety or mood disorders. However, when controlling for real-life social support, associations of IUD and increased subjective importance of online friends were no longer present. CONCLUSION: These findings highlight the necessity of therapeutic interventions aimed at strengthening social skills and engaging in real-life relationships in the prevention and therapy of IUD. Due to the small sample size and the cross-sectional analysis, however, further research is needed.

Psychometric Properties of Screening Instruments for Social Network Use Disorder in Children and Adolescents: A Systematic Review.

Importance: Children and adolescents spend considerable time on the internet, which makes them a highly vulnerable group for the development of problematic usage patterns. A variety of screening methods have already been developed and validated for social network use disorder (SNUD); however, a systematic review of SNUD in younger age groups has not been performed. Objective: To review published reports on screening tools assessing SNUD in children and adolescents with a maximum mean age of 18.9 years. Evidence Review: To identify instruments for the assessment of SNUD, a systematic literature search was conducted in the databases PsycINFO, PubMed, Web of Science, PsycArticles, and Scopus. The final search took place on May 2, 2022. Psychometric properties of available tools were examined and evaluated to derive recommendations for suitable instruments for individuals up to 18 years of age. Findings: A total of 5746 publications were identified, of which 2155 were excluded as duplicates. Of the remaining 3591 nonredundant publications, 3411 studies were assessed as not relevant after title and abstract screening. A full-text analysis of 180 remaining studies classified as potentially eligible resulted in a final inclusion of 29 studies revealing validation evidence for a total of 19 tools. The study quality was mostly moderate. With regard to validation frequency, 3 tools exhibited the largest evidence base: Social Media Disorder Scale (SMDS), the short version of the Bergen Facebook Addiction Scale, and Bergen Social Media Addiction Scale-Short Form (BSMAS-SF). Among these, 1 study tested a parental version (SMDS-P) for its psychometric properties. Taking all criteria into account, the strongest recommendation was made for the SMDS and BSMAS-SF. Conclusions and Relevance: Results suggest that the SMDS-SF and BSMAS-SF were appropriate screening measures for SNUD. Advantages of the SMDS are the availability of a short version and the possibility of an external parental rating.

Study protocol for a randomised controlled trial of an e-health stepped care approach for the treatment of internet use disorders versus a placebo condition: the SCAPIT study.

INTRODUCTION: Excessive internet use can lead to problems for some individuals. The WHO has introduced Gaming Disorder in the International Classification of Diseases-11 (ICD-11). Previous research has shown that other internet applications can cause serious mental health problems as well. It is important to provide measures of prevention, early intervention and therapy for internet use disorders (IUDs). METHODS AND ANALYSIS: The study 'Stepped Care Approach for Problematic Internet use Treatment' is a randomised, two-arm, parallel-group, observer-blind trial. The aim of the study is to investigate if a stepped care approach is effective to reduce symptom severity for IUD. The sample is primarily recruited online with a focus on employees in companies with support of health insurances. After screening, the stepped care approach depends on the success of the previous step-that is, the successful reduction of criteria-and comprise: (1) app-intervention with questionnaires and feedback, (2) two telephone counsellings (duration: 50 min) based on motivational interviewing, (3) online therapy over 17 weeks (15 weekly group sessions, eight individual sessions) based on cognitive-behavioural therapy. A follow-up is conducted after 6 months. A total of 860 participants will be randomised. Hierarchical testing procedure is used to test the coprimary endpoints number of Diagnostic and Statistical Manual of Mental Disorders, fifth edition and ICD-11 criteria. Primary analysis will be performed with a sequential logit model. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committees of the Universities of Lübeck (file number: 21-068), Mainz (file number: 2021-15907) and Berlin (file number: 015.2021). Results will be reported in accordance to the CONSORT statement. If the approach is superior to the control condition, it may serve as part of treatment for IUD. TRIAL REGISTRATION NUMBER: DRKS00025994.

Motivational brief interventions for adolescents and young adults with Internet use disorders: A randomized-controlled trial.

Background: Adolescents and young adults (AYA) have an increased risk for Internet use disorders (IUD) compared to older individuals that may lead to functional impairments in daily life. To date, evidence-based brief interventions are lacking. This study aimed to test the efficacy of a low-threshold counseling approach based on Motivational Interviewing (MI) in a vocational school setting. Methods: Of 8.230 vocational students (age M=20.56, SD=4.68; 51.85% female) being proactively screened for IUD, 937 with positive screenings took part in telephone-based diagnostic interviews. IUD were assessed in line with the criteria of the Internet Gaming Disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). Readiness to change, self-efficacy, and impairments in daily life were additionally assessed with standardized screening instruments. Participants fulfilling at least two IUD criteria were randomized to the intervention group (n=240, up to three MI-based counseling sessions via telephone) or the control group (n=257, information brochure on responsible Internet use). Follow-up interviews were conducted after five and ten months. The primary outcome was the reduction of IUD criteria. Secondary outcomes were improvements of readiness/ self-efficacy to change and the reduction of daily impairments. Data were analyzed with Intention-to-Treat (ITT) and complier average causal effect (CACE) analyses. Results: Overall, 153 (63.75%) individuals assigned to the intervention group participated at least in one counseling session (=compliers). Both groups reduced the number of IUD criteria over time. In ITT analyses, however, we did not find intervention effects for primary and secondary outcomes. Bayes statistics were inconclusive. Based on low participation rates in the intervention group, explorative CACE analyses were conducted to compare compliers in the intervention group to potential compliers in the control group. Again, we did not find intervention effects apart from improvements in self-efficacy after five months. Discussion: Telephone-based counseling seems not appropriate to address AYA at risk for IUD. Low participation rates in the intervention group caused underpowered analyses. Besides, dealing with the own Internet use during intensive assessments and receiving an information brochure led to behavioral changes also in the control group. Since the efficacy of brief interventions under the condition of higher participation rates cannot be fully ruled out, further research is required by taking the implications of this study into account.

Think-aloud analysis of commonly used screening instruments for Internet use disorders: The CIUS, the IGDT-10, and the BSMAS.

Background: Despite the constant publication of new screening instruments for Internet use disorders (IUD), little is known about their content validity. This study aimed to identify potential mismatches between the items' intention and young adults' interpretation of these items when answering three screening instruments that are commonly used in research and clinical settings: The Compulsive Internet Use Scale (CIUS), the 10 Item-Internet Gaming Disorder Test (IGDT-10), and the Bergen Social Media Addiction Scale (BSMAS). Methods: In total, 30 vocational students (50% female, age = 21.3; SD = 2.1) took part in individual think-aloud interviews. All participants were asked to report their thoughts while completing the CIUS. In addition, participants who reported online games (OG) as their main Internet activity (n = 11) answered the IGDT-10. Participants who reported social networks (SN) as their main Internet activity (n = 18) answered the BSMAS. One participant used OG and SN equally and completed both screening instruments. All interviews were audio-recorded, transcribed, and content-analysed. Results: Overall, four potential sources for errors were identified: (1) High scorings were often not congruent with the underlying diagnostic criteria. In particular, such discrepancies were found in items aimed to assess dysfunctional emotional regulation strategies and cognitive involvement. (2) Some participants were uncertain which time frame or Internet activity should be considered in their answers. (3) Long and complex items led to the building of mean values or the choice of the middle answer category. (4) Some wordings were perceived to be outdated and difficult to understand. Discussion: These findings might help to provide recommendations on how to improve screening instruments for IUD. Most important, items should more clearly distinguish between Internet use as a "normal" leisure activity and Internet use that leads to functional impairments in daily life.

A semaphorin-plexin-Rasal1 signaling pathway inhibits gastrin expression and protects against peptic ulcers.

Peptic ulcer disease is a frequent clinical problem with potentially serious complications such as bleeding or perforation. A decisive factor in the pathogenesis of peptic ulcers is gastric acid, the secretion of which is controlled by the hormone gastrin released from gastric G cells. However, the molecular mechanisms regulating gastrin plasma concentrations are poorly understood. Here, we identified a semaphorin-plexin signaling pathway that operates in gastric G cells to inhibit gastrin expression on a transcriptional level, thereby limiting food-stimulated gastrin release and gastric acid secretion. Using a systematic siRNA screening approach combined with biochemical, cell biology, and in vivo mouse experiments, we found that the RasGAP protein Rasal1 is a central mediator of plexin signal transduction, which suppresses gastrin expression through inactivation of the small GTPase R-Ras. Moreover, we show that Rasal1 is pathophysiologically relevant for the pathogenesis of peptic ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs), a main risk factor of peptic ulcers in humans. Last, we show that application of recombinant semaphorin 4D alleviates peptic ulcer disease in mice in vivo, demonstrating that this signaling pathway can be harnessed pharmacologically. This study unravels a mode of G cell regulation that is functionally important in gastric homeostasis and disease.

Intravenous Drug Use: a Significant Risk Factor for Serratia Bacteremia.

BACKGROUND: Serratia is an opportunistic pathogen known to cause an array of infectious presentations. Aside from case reports, intravenous (IV) drug use has not been adequately quantified as a major risk factor for Serratia infection. METHODS: A retrospective cohort study of 103 adult patients admitted to four community hospitals in Ohio from January 2014 to December 2018 with a positive blood culture for Serratia species. A complete data set of 103 patients was analyzed for demographics, comorbidities, initial diagnosis, treatment, and outcomes. Outcomes were recurrence of infection, in hospital mortality, 90-day mortality, length of hospital stay (LOS), complications (endocarditis, osteomyelitis, abscess), and evaluation for resistance to third-generation cephalosporins and extended-spectrum beta-lactamase (ESBL) activity. Descriptive statistics were performed using frequencies for discrete variables and median [interquartile range (IQR)] for continuous variables. RESULTS: Serratia marcescens was the predominate species 94 (91%). Demographics were White 88 (85%) and male 63 (62%); 42 (42%) were IV drug users. IV drug users were younger than non-IV drug users with a median (IQR) age of 40 [33-50] versus 71 years [41-72] and likely to have hepatitis C virus (HCV) infection 37 (88%) versus 3 (5%), p < 0.0001. Culture and susceptibility analysis revealed 36% of isolates with possible or confirmed ESBL production. The most common complications were endocarditis (12%) and osteomyelitis (10%). In-hospital mortality was 2%, 90-day mortality (2%), with 90-day readmission (21%). The median (IQR) LOS is 7 [3.25-14.75]. CONCLUSION: This is the largest study to our knowledge evaluating non-nosocomial Serratia bacteremia. Our study shows that a high proportion of patients hospitalized with a positive Serratia culture are IV drug users and have HCV co-infection. There is significant ceftriaxone resistance and ESBL activity noted in our population. Based on this, we suggest empiric treatment with cefepime or consider carbapenem therapy for Serratia bloodstream isolates pending full susceptibility data. Focus should be on proper antibiotic treatment as the readmission rate and LOS are high.

Dispositional and online-specific Fear of Missing Out are associated with the development of IUD symptoms in different internet applications.

BACKGROUND AND AIMS: An increasing number of people experience negative consequences from the excessive use of different Internet applications or sites (e.g., Instagram, League of Legends, YouTube). These consequences have been referred to as specific Internet Use Disorders (IUDs). The present study aims to examine the Fear of Missing Out (FoMO) on rewarding experiences with respect to specific Internet activities. FoMO has been found to mediate the link between psychopathology and symptoms of Internet Communication Disorder (ICD). However, the role of FoMO in other IUDs is controversial. METHODS: The current study (N = 7,990) consecutively screened in vocational schools) analyzed the associations between online-specific state-FoMO, general trait-FoMO, mental health, and IUD symptoms in a structural equation model. After testing the model for the entire sample of Internet users, it was analyzed separately for the two main user groups: Social Networking Site (SNS) users and gamers. RESULTS: The proposed model explained 42.0% of the variance in IUD symptoms in the total sample, 46.8% for SNS users, and 32.8% for gamers. Results suggest that impaired mental health and high trait-FoMO predict IUD symptoms. For both SNS users and gamers, trait-FoMO mediated the link between low mental health and IUD, whereas state-FoMO mediated the link between trait-FoMO and IUD in both user groups. DISCUSSION: Our results partly support the theoretical model of specific IUDs, highlighting trait-FoMO as a predisposing fear of disconnection related to general mental health. Online-specific FoMO appears to contribute to problematic Internet use mainly because of its link to the general fear of disconnection. Moreover, the described mechanism seems to be comparable for both females and males. CONCLUSIONS: FoMO is a multidimensional construct underlying IUD symptoms related to the use of socially gratifying, but distinct Internet applications. FoMO and psychopathology should be targeted together in prevention and treatment plans of IUDs.

Association of Increased Impulsiveness and Internet Use Disorder in Adolescents and Young Adults with Different Main Activities on the Internet.

Objective: Increased impulsiveness is a risk factor for health-endangering behavior patterns. Little is known about whether increased impulsiveness is associated with Internet Use Disorder (IUD) and whether individuals with various main activities on the internet differ in their levels of impulsiveness. Methods: In total, we screened 8,230 vocational students for problematic internet use with the Compulsive Internet Use Scale (CIUS). Participants scoring at least 21 points in the CIUS took part in an in-depth diagnostic interview. IUD was assessed according to the criteria of Internet Gaming Disorder (IGD) as suggested in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Impulsiveness was assessed with the Barratt Impulsiveness Scale (BIS-15). We analyzed the data using binary logistic regression models and nonparametric tests. Results: Participants with IUD (n = 144) showed increased impulsiveness (p = .005) compared to those without IUD (n = 774). Participants with different main activities on the internet did not differ in their levels of impulsiveness. Conclusions: Results indicate that impulsiveness is associated with IUD, independent of the main internet activity. This highlights the necessity to consider patients' impulsiveness in prevention and therapeutic approaches. Because of the cross-sectional study design, further research with longitudinal study designs is needed.

Characterization of a L136P mutation in Formin-like 2 (FMNL2) from a patient with chronic inflammatory bowel disease.

Diaphanous related formins are highly conserved proteins regulated by Rho-GTPases that act as actin nucleation and assembly factors. Here we report the functional characterization of a non-inherited heterozygous FMNL2 p.L136P mutation carried by a patient who presented with severe very early onset inflammatory bowel disease (IBD). We found that the FMNL2 L136P protein displayed subcellular mislocalization and deregulated protein autoinhibition indicating gain-of-function mechanism. Expression of FMNL2 L136P impaired cell spreading as well as filopodia formation. THP-1 macrophages expressing FMNL2 L136P revealed dysregulated podosome formation and a defect in matrix degradation. Our data indicate that the L136P mutation affects cellular actin dynamics in fibroblasts and immune cells such as macrophages.

Mechanochemical control of epidermal stem cell divisions by B-plexins.

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data define a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.

Honeybee colonies compensate for pesticide-induced effects on royal jelly composition and brood survival with increased brood production.

Sublethal doses of pesticides affect individual honeybees, but colony-level effects are less well understood and it is unclear how the two levels integrate. We studied the effect of the neonicotinoid pesticide clothianidin at field realistic concentrations on small colonies. We found that exposure to clothianidin affected worker jelly production of individual workers and created a strong dose-dependent increase in mortality of individual larvae, but strikingly the population size of capped brood remained stable. Thus, hives exhibited short-term resilience. Using a demographic matrix model, we found that the basis of resilience in dosed colonies was a substantive increase in brood initiation rate to compensate for increased brood mortality. However, computer simulation of full size colonies revealed that the increase in brood initiation led to severe reductions in colony reproduction (swarming) and long-term survival. This experiment reveals social regulatory mechanisms on colony-level that enable honeybees to partly compensate for effects on individual level.

Addressing taxonomic challenges for Internet Use Disorders in light of changing technologies and diagnostic classifications. •.

Drawing a distinction between mobile and non-mobile Internet Use Disorders is an important step to clarify blurred current concepts in the field of behavioral addictions. Similarly, future technological advances related to virtual or augmented reality, artificial intelligence or the Internet of things might lead to further modifications or new taxonomies. Moreover, diagnostic specifiers like offline/online might change with technological advances and trends of use. An important taxonomical approach might be to look for common structural characteristics of games and applications that will be amenable to new technical developments. Diagnostic and taxonomical approaches based on empirical evidence are important goals in the study of behavioral addictions.

Economic Analysis of the European Healthcare Burden of Sternal-Wound Infections Following Coronary Artery Bypass Graft.

Background: Sternal wound infections (SWIs) can be some of the most complex surgical-site infections (SSIs) and pose a considerable risk following coronary artery bypass graft surgery (CABG). Objective: To capture the cost burden of SWIs following CABG across European countries. Methods: We modeled a standardized care pathway for CABG, starting at the point of surgery and extending to 1-year post surgery. The Markov model captures the incidence and cost of an SWI (deep or superficial SWIs). The cost burden is calculated from a hospital perspective such that the main inputs relating to costs were intensive-care-unit (ICU) and general-ward (GW) days. Outpatient care, not in the hospital setting, has no cost in this analysis. Model input parameters were taken from Eurostat and a review of published, peer-reviewed literature. European countries were included in this analysis when values for 50% of the required input parameters per country were identified. Missing data points were interpolated from available data. The robustness of results was assessed via probabilistic sensitivity analysis. Results: Full required input data were available for 8 European countries; a further 18 countries had sufficient data for analysis. The median (interquartile range) for SWI incidence across the 26 countries was 3.9% (2.9-5.6%). The total burden for all 26 countries of SWIs after CABG was €170.8 million. These costs were made up of 25,751 additional ICU days, 137,588 additional GW days, and 7,704 readmissions. The mean cost of an SWI ranged from €8,924 in Poland to €21,321 in Denmark. Relative to the costs of post-CABG care without an SWI complication, the incremental cost of an SWI was highest in Greece (24.9% increase) and lowest in the UK (3.8% increase) with a median (interquartile range) of 12% (10-16%) across all 26 countries. Conclusions: SWIs following CABG present a considerable burden to healthcare budgets.

Postmitotic expansion of cell nuclei requires nuclear actin filament bundling by α-actinin 4.

The actin cytoskeleton operates in a multitude of cellular processes including cell shape and migration, mechanoregulation, and membrane or organelle dynamics. However, its filamentous properties and functions inside the mammalian cell nucleus are less well explored. We previously described transient actin assembly at mitotic exit that promotes nuclear expansion during chromatin decondensation. Here, we identify non-muscle α-actinin 4 (ACTN4) as a critical regulator to facilitate F-actin reorganization and bundling during postmitotic nuclear expansion. ACTN4 binds to nuclear actin filament structures, and ACTN4 clusters associate with nuclear F-actin in a highly dynamic fashion. ACTN4 but not ACTN1 is required for proper postmitotic nuclear volume expansion, mediated by its actin-binding domain. Using super-resolution imaging to quantify actin filament numbers and widths in individual nuclei, we find that ACTN4 is necessary for postmitotic nuclear actin reorganization and actin filament bundling. Our findings uncover a nuclear cytoskeletal function for ACTN4 to control nuclear size and chromatin organization during mitotic cell division.

Sternal-Wound Infections following Coronary Artery Bypass Graft: Could Implementing Value-Based Purchasing be Beneficial?

BACKGROUND/OBJECTIVES: Sternal-wound infections (SWIs) are rare but consequential healthcare-healthcare-associated infections following coronary artery bypass graft surgery (CABG). The impact of SWIs associated on the cost of health care provision is unknown. The aim of this study was to quantify the burden of CABG-related SWIs across countries with mature health care systems and estimate value-based purchasing (VBP) levels based on the local burden. METHODS: A structured literature review identified relevant data for 14 countries (the Netherlands, France, Germany, Austria, the United Kingdom, Canada, Italy, Japan, Spain, the United States, Brazil, Israel, Taiwan, and Thailand). Data, including SWI rates, CABG volume, and length of stay, were used to populate a previously published Markov model that simulates the patient's CABG-care pathway and estimates the economic (US$) and care burden of SWIs for each country. Based on this burden, scenarios for VBP were explored for each country. A feasible cost of intervention per patient for an intervention providing a 20% reduction in the SWI rate was calculated. RESULTS: The SWI burden varied considerably between settings, with SWIs occurring in 2.8% (the United Kingdom) to 10.4% (the Netherlands) of CABG procedures, while the costs per SWI varied between US$8172 (Brazil) to US$54 180 (Japan). Additional length of stay after SWI was the largest cost driver. The overall highest annual burden was identified in the United States (US$336 million) at a mean cost of US$36 769 per SWI. Given the SWI burden, the median cost of intervention per patient that a hospital could afford ranged from US$20 (US$13 to US$42) in France to US$111 (US$65 to US$183) in Japan. CONCLUSIONS: SWIs represent a large burden with a median cost of US$13 995 per case and US$900 per CABG procedure. By tackling SWIs, there is potential to simultaneously reduce the burden on health care systems and improve outcomes for patients. Mutually beneficial VBP agreements might be one method to promote uptake of novel methods of SWI prevention.

A Systematic Literature Review of Three Stenting Strategies for Bifurcation Lesions in Coronary Artery Disease.

BACKGROUND: Bifurcation lesions represent 15-20% of all patients undergoing a percutaneous coronary intervention (PCI) for coronary artery disease. The provisional 1-stent stenting strategy is the preferred strategy to treat bifurcation lesions. Other strategies used to treat bifurcation lesions include 2-stent complex stenting strategies and the Tryton Side Branch Stent® (TSB)-a dedicated side-branch stent for bifurcation lesions, which gained FDA approval in March 2017. OBJECTIVES: To conduct a systematic literature review of the safety and effectiveness of three stenting strategies (provisional, complex, and Tryton Side Branch Stent®) for bifurcation lesions with a side-branch diameter ≥2.25 mm, undergoing PCI. METHODS: Literature searches in Medline, Cochrane Library, Web of Science and Embase were conducted to identify prospective clinical trials from January 2007-July 2017. RESULTS: 602 articles were identified. Nine articles (6275 patients) met all inclusion criteria. Seven studies (5282 patients) compared provisional to complex stenting strategies. Two studies (993 patients) compared provisional to the TSB. Outcomes of interest reported were target vessel failure in 2 studies, major adverse cardiac event (MACE) (cardiac death, all myocardial infarction, ischemic driven target legion revascularization TLR) in 5 studies. For target vessel failure, the provisional strategy ranged from 5.6% to 15.6 %; complex at 7.2% (one study); and TSB from 11.3% to 17.4%. For MACE, provisional strategy ranged from 8%-13.2%; complex from 11.9%-15.2%; and TSB from 8.2%-18.6%. CONCLUSIONS: To our knowledge, this is the first review comparing three bifurcation lesion stenting strategies. Significant heterogeneity in the study design of the nine studies reviewed prevented a meta-analysis. A clinical trial comparing the TSB to both the provisional and complex strategies would provide better inference on the safety and effectiveness when comparing strategies.

Cell type-selective pathways and clinical associations of lysophosphatidic acid biosynthesis and signaling in the ovarian cancer microenvironment.

The peritoneal fluid of ovarian carcinoma patients promotes cancer cell invasion and metastatic spread with lysophosphatidic acid (LPA) as a potentially crucial mediator. However, the origin of LPA in ascites and the clinical relevance of individual LPA species have not been addressed. Here, we show that the levels of multiple acyl-LPA species are strongly elevated in ascites versus plasma and are associated with short relapse-free survival. Data derived from transcriptome and secretome analyses of primary ascite-derived cells indicate that (a) the major route of LPA synthesis is the consecutive action of a secretory phospholipase A2 (PLA2 ) and autotaxin, (b) that the components of this pathway are coordinately upregulated in ascites, and (c) that CD163+CD206+ tumor-associated macrophages play an essential role as main producers of PLA2 G7 and autotaxin. The latter conclusion is consistent with mass spectrometry-based metabolomic analyses of conditioned medium from ascites cells, which showed that tumor-associated macrophages, but not tumor cells, are able to produce 20:4 acyl-LPA in lipid-free medium. Furthermore, our transcriptomic data revealed that LPA receptor (LPAR) genes are expressed in a clearly cell type-selective manner: While tumor cells express predominantly LPAR1-3, macrophages and T cells also express LPAR5 and LPAR6 at high levels, pointing to cell type-selective LPA signaling pathways. RNA profiling identified cytokines linked to cell motility and migration as the most conspicuous class of LPA-induced genes in macrophages, suggesting that LPA exerts protumorigenic properties at least in part via the tumor secretome.

Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5.

Mutations in the p53 tumor suppressor gene are the most frequent genetic alteration in cancer and are often associated with progression from benign to invasive stages with metastatic potential. Mutations inactivate tumor suppression by p53, and some endow the protein with novel gain of function (GOF) properties that actively promote tumor progression and metastasis. By comparative gene expression profiling of p53-mutated and p53-depleted cancer cells, we identified ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) as a mutant p53 target gene, which functions as a uridine 5'-diphosphatase (UDPase) in the endoplasmic reticulum (ER) to promote the folding of N-glycosylated membrane proteins. A comprehensive pan-cancer analysis revealed a highly significant correlation between p53 GOF mutations and ENTPD5 expression. Mechanistically, mutp53 is recruited by Sp1 to the ENTPD5 core promoter to induce its expression. We show ENTPD5 to be a mediator of mutant p53 GOF activity in clonogenic growth, architectural tissue remodeling, migration, invasion, and lung colonization in an experimental metastasis mouse model. Our study reveals folding of N-glycosylated membrane proteins in the ER as a mechanism underlying the metastatic progression of tumors with mutp53 that could provide new possibilities for cancer treatment.