Digital Smoking Cessation Intervention for Cancer Survivors: Analysis of Predictors and Moderators of Engagement and Outcome Alongside a Randomized Controlled Trial.

BACKGROUND: Recent studies have shown positive, though small, clinical effects of digital smoking cessation (SC) interventions for cancer survivors. However, research on associations among participant characteristics, intervention engagement, and outcomes is limited. OBJECTIVE: This study aimed to explore the predictors and moderators of engagement and outcome of MyCourse-Quit Smoking (in Dutch: "MijnKoers-Stoppen met Roken"), a digital minimally guided intervention for cancer survivors. METHODS: A secondary analysis of data from the randomized controlled trial was performed. The number of cigarettes smoked in the past 7 days at 6-month follow-up was the primary outcome measure. We analyzed interactions among participant characteristics (11 variables), intervention engagement (3 variables), and outcome using robust linear (mixed) modeling. RESULTS: In total, 165 participants were included in this study. Female participants accessed the intervention less often than male participants (B=-11.12; P=.004). A higher Alcohol Use Disorders Identification Test score at baseline was associated with a significantly higher number of logins (B=1.10; P<.001) and diary registrations (B=1.29; P<.001). A higher Fagerström Test for Nicotine Dependence score at baseline in the intervention group was associated with a significantly larger reduction in tobacco use after 6 months (B=-9.86; P=.002). No other associations and no moderating effects were found. CONCLUSIONS: Overall, a limited number of associations was found between participant characteristics, engagement, and outcome, except for gender, problematic alcohol use, and nicotine dependence. Future studies are needed to shed light on how this knowledge can be used to improve the effects of digital SC programs for cancer survivors. TRIAL REGISTRATION: Netherlands Trial register NTR6011/NL5434; https://onderzoekmetmensen.nl/nl/trial/22832.

Secondhand smoke exposure in public outdoor spaces in the Netherlands: The stronger the smell, the more exposure to nicotine.

INTRODUCTION: While secondhand smoke exposure in outdoor spaces has been investigated before, no data on outdoor secondhand smoke exposure have been collected in the Netherlands. Such data could help policymakers gain support for smoke-free outdoor public spaces. METHODS: Between May and November 2021, we visited 25 outdoor locations across the Netherlands. At each location, we conducted four measurements with smokers and one measurement without smokers. During each measurement, we counted the number of smokers present and we rated tobacco smell intensity on a five-point scale. Airborne nicotine and 3-ethenylpyridine (3-EP) data were collected through active sampling on thermal desorption tubes. The contents of these tubes were later analyzed using gas chromatography-mass spectrometry. Using linear mixed models, we investigated the association between levels of nicotine and the presence of smokers, the number of smokers, and the intensity of tobacco smell. We also investigated these association with levels of 3-EP. RESULTS: Nicotine levels were higher when smokers were present (B=1.40; 95% CI: 0.69-2.11, p<0.001). For each additional smoker present, we measured higher levels of nicotine (B=0.23; 95% CI: 0.10-0.37, p=0.001). When the smell of tobacco smoke was noted to be stronger by the researchers, higher levels of nicotine were measured through sampling (B=0.85; 95% CI: 0.44-1.26, p<0.001). We found similar results for 3-EP levels. CONCLUSIONS: This study showed that both nicotine and 3-EP are useful in quantifying levels of secondhand smoke in various outdoor locations. The level of nicotine exposure outdoors was positively associated with the number of smokers nearby. The intensity of the tobacco smell was also related to nicotine exposure: the stronger the smell of tobacco smoke, the more nicotine was measured in the air.

Accuracy of upper endoscopies with random biopsies to identify patients with gastric premalignant lesions who can safely be exempt from surveillance.

INTRODUCTION: Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. METHODS: This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1-6 years. Patients were defined 'low risk' if they fulfilled requirements for discharge, and 'high risk' if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined 'low risk' with progression of disease during follow-up (FU) were considered 'misclassified' as low risk. RESULTS: 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were 'misclassified', showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were 'misclassified'. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were 'misclassified'. Seven patients developed gastric cancer (GC) or dysplasia, four patients were 'misclassified' based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4-83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. CONCLUSION: One-third of patients that would have been discharged from GC surveillance, appeared to be 'misclassified' as low risk. One additional endoscopy will reduce this risk by 70%.

Identification and characterization of two consistent osteoarthritis subtypes by transcriptome and clinical data integration.

OBJECTIVE: To identify OA subtypes based on cartilage transcriptomic data in cartilage tissue and characterize their underlying pathophysiological processes and/or clinically relevant characteristics. METHODS: This study includes n = 66 primary OA patients (41 knees and 25 hips), who underwent a joint replacement surgery, from which macroscopically unaffected (preserved, n = 56) and lesioned (n = 45) OA articular cartilage were collected [Research Arthritis and Articular Cartilage (RAAK) study]. Unsupervised hierarchical clustering analysis on preserved cartilage transcriptome followed by clinical data integration was performed. Protein-protein interaction (PPI) followed by pathway enrichment analysis were done for genes significant differentially expressed between subgroups with interactions in the PPI network. RESULTS: Analysis of preserved samples (n = 56) resulted in two OA subtypes with n = 41 (cluster A) and n = 15 (cluster B) patients. The transcriptomic profile of cluster B cartilage, relative to cluster A (DE-AB genes) showed among others a pronounced upregulation of multiple genes involved in chemokine pathways. Nevertheless, upon investigating the OA pathophysiology in cluster B patients as reflected by differentially expressed genes between preserved and lesioned OA cartilage (DE-OA-B genes), the chemokine genes were significantly downregulated with OA pathophysiology. Upon integrating radiographic OA data, we showed that the OA phenotype among cluster B patients, relative to cluster A, may be characterized by higher joint space narrowing (JSN) scores and low osteophyte (OP) scores. CONCLUSION: Based on whole-transcriptome profiling, we identified two robust OA subtypes characterized by unique OA, pathophysiological processes in cartilage as well as a clinical phenotype. We advocate that further characterization, confirmation and clinical data integration is a prerequisite to allow for development of treatments towards personalized care with concurrently more effective treatment response.

Helicobacter pylori seroprevalence in six different ethnic groups living in Amsterdam: The HELIUS study.

BACKGROUND: Helicobacter pylori prevalence varies greatly worldwide. We explored the prevalence of H. pylori and CagA seropositivity among adults aged 18-44 years living in the Netherlands by ethnicity and migration status (first vs second generation). MATERIALS AND METHODS: Participants from six different ethnic groups were selected from the population-based multi-ethnic HELIUS study in Amsterdam, the Netherlands. Serum samples were tested for H. pylori antigens using a validated Luminex-based multiplex serology assay. Prevalence ratios were estimated using Poisson regression analysis. RESULTS: A total of 4683 participants aged 18-44 years were randomly selected based on sex, ethnicity, and age. H. pylori seroprevalence was highest in the Ghanaian group (84%), followed by Moroccan (81%), Turkish (66%), African Surinamese (51%), South-Asian Surinamese (48%), and Dutch (17%) participants. All ethnic minority groups had a significantly higher risk of being H. pylori seropositive compared to the Dutch group. This association was strongest among participants born outside the Netherlands (first generation), but was still significant and apparent among second-generation participants. Among first-generation participants, all groups, except the Moroccans, had a significantly higher proportion of individuals with a cagA + H. pylori strain compared to the Dutch participants. CONCLUSION: Helicobacter pylori seroprevalence among first-generation migrants is high in the Netherlands and remains elevated among second-generation migrants (ie, those born in the Netherlands). High exposure to H. pylori, and especially to the more virulent cagA+ strain, highlights the need for tailored prevention of gastric diseases (notably peptic ulcers and cancers) among migrants.

Increased WISP1 expression in human osteoarthritic articular cartilage is epigenetically regulated and decreases cartilage matrix production.

OBJECTIVES: Previously, we have shown the involvement of Wnt-activated protein Wnt-1-induced signaling protein 1 (WISP1) in the development of OA in mice. Here, we aimed to characterize the relation between WISP1 expression and human OA and its regulatory epigenetic determinants. METHODS: Preserved and lesioned articular cartilage from end-stage OA patients and non-OA-diagnosed individuals was collected. WISP1 expression was determined using immunohistochemistry and damage was classified using Mankin scoring. RNA expression and DNA methylation were assessed in silico from genome-wide datasets (microarray analysis and RNA sequencing, and 450 k-methylationarrays, respectively). Effects of WISP1 were tested in pellet cultures of primary human chondrocytes. RESULTS: WISP1 expression in cartilage of OA patients was increased compared with non-OA-diagnosed controls and, within OA patients, WISP1 was even higher in lesioned compared with preserved regions, with expression strongly correlating with Mankin score. In early symptomatic OA patients with disease progression, higher synovial WISP1 expression was observed as compared with non-progressors. Notably, increased WISP1 expression was inversely correlated with methylation levels of a positional CpG-dinucleotide (cg10191240), with lesioned areas showing strong hypomethylation for this CpG as compared with preserved cartilage. Additionally, we observed that methylation levels were allele-dependent for an intronic single-nucleotide polymorphism nearby cg10191240. Finally, addition of recombinant WISP1 to pellets of primary chondrocytes strongly inhibited deposition of extracellular matrix as reflected by decreased pellet circumference, proteoglycan content and decreased expression of matrix components. CONCLUSION: Increased WISP1 expression is found in lesioned human articular cartilage, and appears epigenetically regulated via DNA methylation. In vitro assays suggest that increased WISP1 is detrimental for cartilage integrity.

Surveillance of premalignant gastric lesions: a multicentre prospective cohort study from low incidence regions.

OBJECTIVE: International guidelines recommend endoscopic surveillance of premalignant gastric lesions. However, the diagnostic yield and preventive effect require further study. We therefore aimed to assess the incidence of neoplastic progression and to assess the ability of various tests to identify patients most at risk for progression. DESIGN: Patients from the Netherlands and Norway with a previous diagnosis of atrophic gastritis (AG), intestinal metaplasia (IM) or dysplasia were offered endoscopic surveillance. All histological specimens were assessed according to the updated Sydney classification and the operative link on gastric intestinal metaplasia (OLGIM) system. In addition, we measured serum pepsinogens (PG) and gastrin-17. RESULTS: 279 (mean age 57.9 years, SD 11.4, male/female 137/142) patients were included and underwent at least one surveillance endoscopy during follow-up. The mean follow-up time was 57 months (SD 36). Four subjects (1.4%) were diagnosed with high-grade adenoma/dysplasia or invasive neoplasia (ie, gastric cancer) during follow-up. Two of these patients were successfully treated with endoscopic submucosal dissection, while the other two underwent a total gastrectomy. Compared with patients with extended AG/IM (PGI/II≤3 and/or OGLIM stage III-IV), patients with limited AG/IM (PG I/II>3 and OLGIM stage 0-II) did not develop high-grade adenoma/dysplasia or invasive neoplasia during follow-up (p=0.02). CONCLUSION: In a low gastric cancer incidence area, a surveillance programme can detect gastric cancer at an early curable stage with an overall risk of neoplastic progression of 0.3% per year. Use of serological markers in endoscopic surveillance programmes may improve risk stratification.

Genome-wide association and functional studies identify a role for matrix Gla protein in osteoarthritis of the hand.

OBJECTIVE: Osteoarthritis (OA) is the most common form of arthritis and the leading cause of disability in the elderly. Of all the joints, genetic predisposition is strongest for OA of the hand; however, only few genetic risk loci for hand OA have been identified. Our aim was to identify novel genes associated with hand OA and examine the underlying mechanism. METHODS: We performed a genome-wide association study of a quantitative measure of hand OA in 12 784 individuals (discovery: 8743, replication: 4011). Genome-wide significant signals were followed up by analysing gene and allele-specific expression in a RNA sequencing dataset (n=96) of human articular cartilage. RESULTS: We found two significantly associated loci in the discovery set: at chr12 (p=3.5 × 10-10) near the matrix Gla protein (MGP) gene and at chr12 (p=6.1×10-9) near the CCDC91 gene. The DNA variant near the MGP gene was validated in three additional studies, which resulted in a highly significant association between the MGP variant and hand OA (rs4764133, Betameta=0.83, Pmeta=1.8*10-15). This variant is high linkage disequilibrium with a coding variant in MGP, a vitamin K-dependent inhibitor of cartilage calcification. Using RNA sequencing data from human primary cartilage tissue (n=96), we observed that the MGP RNA expression of the hand OA risk allele was significantly lowercompared with the MGP RNA expression of the reference allele (40.7%, p<5*10-16). CONCLUSIONS: Our results indicate that the association between the MGP variant and increased risk for hand OA is caused by a lower expression of MGP, which may increase the burden of hand OA by decreased inhibition of cartilage calcification.

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

DNA Methylation in Osteoarthritis.

Osteoarthritis (OA) is a prevalent disease of articular joints and primarily characterized by degradation and calcification of articular cartilage. Presently, no effective treatment other than pain relief exists and patients ultimately need to undergo replacement surgery of the affected joint. During disease progression articular chondrocytes, the single cell type present in articular cartilage, show altered transcriptional profiles and undergo phenotypic changes that resemble the terminal differentiation route apparent in growth plate chondrocytes. Hence, given its prominent function in both regulating gene expression and maintaining cellular phenotypes, DNA methylation of CpG dinucleotides is intensively studied in the context of OA. An increasing number of studies have been published that employed a targeted approach on genes known to play a role in OA pathophysiology. As of such, it has become clear that OA responsive DNA methylation changes seem to mediate disease associated aberrant gene expression. Furthermore, established OA susceptibility alleles such as GDF5 and DIO2 appear to confer OA risk via DNA methylation and respective pathophysiological expression changes. In more recent years, genome wide profiling of DNA methylation in OA affected articular cartilage has emerged as a powerful tool to address the epigenetic changes in their entirety, which has resulted in the identification of putative patient subgroups as well as generic OA associated pathways.

Translating genomics into mechanisms of disease: Osteoarthritis.

Osteoarthritis (OA) is the most common age-related arthritic disorder and is characterized by aberrant extracellular matrix (ECM) content and surface disruptions that range from fibrillation, clefting and delamination, leading to articular surface erosion. Worldwide, over 20% of the population is affected with OA and 80% of these patients have limitations in movement, whereas 25% experience inhibition in major daily activities of life. OA is the most common disabling arthritic disease; nevertheless, no disease-modifying treatment is available except for the expensive total joint replacement surgery at end-stage disease. Lack of insight into the underlying pathophysiological mechanisms of OA has considerably contributed to the inability of the scientific community to develop disease-modifying drugs. To overcome this critical barrier, focus should be on translation of identified robust gene deviations towards the underlying biological mechanisms.

Current pharmacotherapy options for gastritis.

INTRODUCTION: Gastritis is a broad term, which is used for different conditions by clinicians, endoscopists and pathologists. Classification strategies have led to more congruence between specialists. The histological evaluation of the gastric mucosa is mandatory for diagnosing and classifying gastritis. Main aetiologic factor is infection with Helicobacter pylori. The clinical importance of gastritis lays in the fact that it predisposes to more pronounced damage to the gastric mucosa, in particular peptic ulcer disease, and eventually atrophic gastritis, intestinal metaplasia and gastric malignancy, both adenocarcinoma and MALT lymphoma. AREAS COVERED: This review covers the current pharmacotherapy options for different forms of gastritis. The main focus is on H. pylori-induced gastritis. Thereafter, other forms of gastritis like autoimmune gastritis and non-steroidal anti-inflammatory drug (NSAID)-related gastropathy are covered. EXPERT OPINION: The emerging problem of antibiotic resistance requires an accurate knowledge of local eradication rates. Standard triple therapy should be abandoned in regions with high clarithromycin resistance. In these areas, sequential or quadruple therapy is best initial treatment. Further research should focus on non-invasive and effective techniques of susceptibility testing, making a tailored and cost-effective approach. Primary prevention of NSAID-related gastropathy can be enhanced by better education for clinicians and patients, so that both right prescription of gastroprotective agents as therapy adherence will improve.