Lung adenocarcinoma (LUAD), largely remains a primary cause of cancer-related death worldwide. The molecular mechanisms in LUAD metastasis have not been completely uncovered.In this study, we identified differentially expressed genes (DEGs), miRNAs (DEMs) and lncRNAs (DELs) underlying metastasis of LUAD from The Cancer Genome Atlas database. Intersection mRNAs were used to perform gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and co-expression network analysis. In addition, survival analyses of intersection mRNAs were conducted. Finally, intersection mRNAs, miRNAs and lncRNAs were subjected to construct miRNA-mRNA-lncRNA network.A total of 1015 DEGs, 54 DEMs and 22 DELs were identified in LUAD metastasis and non-metastasis samples. GO and KEGG pathway analysis had proven that the functions of intersection mRNAs were closely related with many important processes in cancer pathogenesis. Among the co-expression interactions network, 22 genes in the co-expression network were over the degree 20. These genes imply that they have connections with many other gene nodes. In addition, 14 target genes  were found to be associated with survival in patients with LUAD significantly (log-rank P < 0.05). Two lncRNAs (LOC96610 and ADAM6) acting as ceRNAs were identified based on the miRNA-mRNA-lncRNA network.Taken together, the results may provide a novel perspective to develop a multiple gene diagnostic tool for LUAD prognosis, which might also provide potential biomarkers or therapeutic targets for LUAD.The online version of this article (10.1186/s12967-018-1732-z) contains supplementary material, which is available to authorized users. Lung cancer is the leading cause of cancer-related deaths worldwide, despite advances in lung cancer therapy, the average 5-year survival rate is only 18% . A majorNumerous published articles demonstrate that dysregulated genes are essential for initiation and progression of lung cancer. In recent years, the development of microarray technology has served as an effective measure to identify differentially expressed genes , and proThe Cancer Genome Atlas (TCGA) is one prominent example of the renowned public databases which provides a platform of RNA sequencing with mRNA, miRNA and lncRNA data of various cancers. By integratively analysis RNA-Seq and miRNA-Seq data of LUAD samples from TCGA database, we successfully corhorted a set of differentially expression genes (DEGs), miRNAs (DEMs) and lncRNAs (DELs) underlying LUAD metastasis and non-metastasis samples. Based on intersection mRNAs, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and co-expression analysis were conducted. Furthermore, we performed a receiver operating characteristic (ROC) analysis to investigate the diagnostic value of intersection mRNAs. Finally, miRNA-mRNA-lncRNA network were constructed. Our study might provide a meaningful contribution to exploring the mechanisms of LUAD metastasis and candidate diagnostic biomarkers and therapeutic targets.https://gdc-portal.nci.nih.gov/). The mRNA and lncRNA expression data included a total of 372 samples consisting of 25 LUAD metastasis and 347 non-metastasis samples. The miRNA expression data included a total of 305 samples consisting of 19 LUAD metastasis and 286 non-metastasis samples. The clinical characteristics of the 384 TCGA patients are shown in Table The LUAD metastasis and non-metastasis RNA-Seq and miRNA-Seq data were downloaded from the TCGA database using The GDC Data Portal (http://mirdb.org/miRDB/) to predict target genes, and using miRanda (http://www.microrna.org/microrna/home.do) to find the lncRNA-miRNA interactions. Then we combined the information of miRNAs predicted and differentially expressed data of TCGA by using Excel to obtain the repeating part to choose the intersection lncRNAs and mRNAs.Predicted DEMs targets in this study were determined using miRBase targets (http://david.abcc.ncifcrf.gov/). Up and down-regulated genes were analyzed, respectively. Two-side Fisher’s exact test and χ2 test were used to classify the GO category, and the false discovery rate (FDR) was calculated to correct the P-value,the smaller the FDR, the smaller the error in judging the p-value [Nk refers to the number of Fisher’s test P-values less than χ2 test P-values. We computed P-values for the GOs of all the differential genes. Enrichment provides a measure of the significance of the function: as the enrichment increases, the corresponding function can be more specific, which helps us to find those GOs with more concrete function description in the experiment. Within the significant category, the enrichment Re was given by: Re = (nf/n)/(Nf/N) where “nf” is the number of flagged genes within the particular category, “n” is the total number of genes within the same category, “Nf” is the number of flagged genes in the entire microarray, and “N” is the total number of genes in the microarray [Differentially expressed intersection mRNAs were obtained from the Database for Annotation, Visualization and Integrated Discovery (DAVID), which provided a comprehensive set of functional annotation tools for investigators to understand the biological meaning behind large lists of genes  was used to analyze the potential functions of these genes participated in the pathways [χ2 test to select the significant pathway, and the threshold of significance was defined by P-value and FDR. The enrichment Re was calculated like the equation above [KEGG  and recurrence free survival (RFS) time and identify survival-associated genes. The survival curves were plotted and tested using the Kaplan–Meier method and log-rank test. According to the median risk score, LUAD patients were divided into high- and low-risk groups. The mRNAs with log-rank P < 0.05 between high-risk and low-risk groups were considered statistically significant. R software and Bio-conductor were used for all these analyses. Next, we get target genes by combining significant survival-associated genes and genes incorporated into the gene co-expression network.In order to assess the diagnostic value of target genes in LUAD, receiver operating characteristic (ROC) analysis were performed using pROC package in R language . DiagnosAccording to the relationship among mRNA, miRNA and lncRNA, the posttranscriptional regulation of mRNA transcripts bound by single-stranded miRNAs is basically established. We have established a theory based on lncRNA regulating miRNA abundance by isolating and binding them, acting as a so-called miRNA sponge . Then, aAll data in the present study were analyzed using GraphPad Prism 6.0 software. Mean ± standard deviation and independent-samples t-test was used in the statistical analysis. A P-value less than 0.05 was considered statistically significant.The present study consists of several processes sequentially Fig. , that isA total of 1019 genes were considered as DEGs in LUAD metastasis samples compared to non-metastasis samples, including 581 (57.0%) up-regulated and 438 (43.0%) down-regulated genes. And the top 20 DEGs in LUAD metastasis samples compared with non-metastasis samples were shown in Table The mRBase targets method was used to analyse the target mRNAs of DEMs and obtained the 915 miRNA targeted mRNAs. The miRanda method was used to analyse the target lncRNAs of DEM and obtained the 22 miRNA-targeted lncRNAs. Then the study combined the information of miRNAs predicted and differentially expressed data of TCGA, and obtain 915 intersection mRNAs and 20 intersection lncRNAs.Predicted functions of DEGs in this study were determined by intersection mRNAs. The 915 intersection mRNAs were further analyzed by GO analysis. We analyzed the enrichment of these genes. Enrichment provides a measure of the significance of the function, and as the enrichment increases, the corresponding function is more specific, which helped us to identify GO with a more definitive functional description . The resPathway analysis indicated that 87 pathways corresponded to up-regulated transcripts and up-regulated genes were mainly related to cytokine–cytokine receptor interaction, osteoclast differentiation, cell adhesion molecules (CAMs), PI3K-Akt signaling pathway and focal adhesion, while down-regulated DEGs were associated with Fanconi anemia pathway, mismatch repair, spliceosome, DNA replication and cell cycle . While we choose 14 target genes which were obtained by combining significant survival associated genes and genes incorporated into the gene co-expression network. In order to reveal association between the 14 target genes expression levels and LUAD prognosis, we performed Kaplan–Meier survival curves. The results show that patients with lower expression levels of five genes including ARHGAP11A, ASPM, HELLS, PRC1 and TMPO have better survival prognoses than those with higher expression levels of these five genes in LUAD. Patients with higher expression levels of the rest nine genes  were associated with poor survival in patients with LUAD  . In our study, the results identified that 2 lncRNAs (LOC96610 and ADAM6), 22 miRNAs and 4 mRNAs  were involved in the ceRNA network. The functions of LOC96610 and ADAM6 acting as ceRNAs were predicted through pathway analysis of 4 mRNAs  in the miRNA-lncRNA-mRNA interaction network. The results indicated that four mRNAs participated in three upregulated pathways which involved in immune response, endoplasmic reticulum unfolded protein response and male meiosis I. As a consequence, it was believed that compared with the other lncRNAs, these two lncRNAs (LOC96610 and ADAM6) might played more significant functions in the whole ceRNA network  were with the degree over 20, which implied the five genes not only had better important regulatory value for the network, but also had diagnostic value of LUAD metastasis. ARHGAP30, a previously uncharacterized RhoGAP domain-containing protein, as a candidate Wrch-1-binding protein. ARHGAP30 is closely related to the Cdc42-specific RhoGAP CdGAP , and togMoreover, our study identified that 2 lncRNAs (LOC96610 and ADAM6), 22 miRNAs and 4 mRNAs  were involved in the miRNA-lncRNA-mRNA interaction network. LOC96610, located at 22q11.22, the official symbol is BMS1P20 . As a survival-related lncRNA, BMS1P20 was found significantly correlated with the pathogenesis, development and metastasis of liver hepatocellular carcinoma . FurtherIn summary, our findings documented that 1019 DEGs, 54 DEMs and 21 DELs were differently expressed in LUAD metastatic samples compared with non-metastatic samples. Among these altered mRNAs, many are significantly associated with LUAD patient’s survival time, and might play critical roles in LUAD metastasis. Our study highlights the important roles of mRNAs, miRNAs and lncRNAs in LUAD metastasis and may provide useful candidates as diagnostic markers and potential targets for LUAD therapy. The present study also has a few limitations, for example, the data used were obtained from TCGA, rather than directly from LUAD patients, thus a series of verification experiments must be performed to confirm our results. Overall, our findings will improve our understanding of the molecular mechanisms of LUAD and aid in finding potential targets for diagnostic and therapeutic usage.Additional file 1. Clinical data of LUAD from TCGA cohort.Additional file 2. DEGs in LUAD metastasis samples compared with non-metastasis samples.


There is an association between osteoarthritis-related pain severity and function, yet clear evidence about the sole influence of neuropathic-like symptoms on joint function and health-related quality of life (HRQoL) is lacking. Previous studies among knee OA patients show an association between neuropathic-like symptoms, lower functional status and lower quality of life, however analyses were unadjusted or had limited adjustment for influential covariates like pain intensity. The aim of this study was therefore to determine the influence of neuropathic-like symptoms—adjusted for multiple influential covariates—on joint-specific function and HRQoL in hip and knee OA patients.In this observational study 255 patients (117 with hip OA and 138 with knee OA) completed the modified painDETECT questionnaire (mPDQ) to identify subjects with neuropathic-like symptoms . The WOMAC and the RAND-36 were used to asses respectively function and HRQoL. Results were adjusted stepwise for age, sex and BMI (Model 1); back disorder, painful body regions, comorbidities and previous surgery (Model 2); and pain intensity and analgesic usage (Model 3).A possible NP phenotype was experienced by 37% of hip and 46% of knee OA patients. Final model 3 analysis revealed that hip OA patients with neuropathic-like symptoms scored significantly lower on pain-related aspects of HRQoL  compared to patients with the unlikely NP phenotype. In knee OA patients, a possible NP phenotype was associated with diminished joint function  and more deficits on the physical functional aspect of HRQoL .Neuropathic-like symptoms deteriorate the subjective rating of pain-related quality of life in hip OA patients and significantly influence function in knee OA patients. Hip and knee osteoarthritis (OA) is among the leading causes of disability around the world. This degenerative joint disease has a major impact on quality of life, especially in terms of pain and functional disability . Around As indicated, a common and invalidating key symptom of OA is pain . MultiplDespite the clear association between OA-related pain severity and functional limitations ,18, unamAlthough in the available literature more neuropathic-like symptoms are associated with a lower functional status ,12,19,20The aim of the study is therefore to determine the influence of neuropathic-like symptoms, adjusted for multiple important influential covariates, on joint-specific function and HRQoL in a hip and knee OA patient cohort.For this cross-sectional observational study a cohort of 603 patients was obtained from hospital registration lists and invited by mail to fill out a questionnaire. All were adult patients (age >18 years) that were diagnosed with primary hip or knee OA by their treating orthopedic surgeon and visited the orthopedic outpatient clinics of University Medical Center Groningen, Martini Hospital Groningen or Medical Center Leeuwarden, all in the Netherlands, between July 2013 and May 2014. The responders were subsequently checked for additional exclusion criteria. Exclusion criteria were inflammatory arthritis (e.g. rheumatoid arthritis), hip/knee surgery within the last six months, chronic conditions of the nervous system, cognitive or psychiatric disorders, no joint pain during the past week, and inadequate understanding of the Dutch language. Patients were also excluded if they showed no sign of radiographic degeneration as defined by the Kellgren-Lawrence [KL] classification grade <1 on the anteroposterior radiograph. The typical radiographic OA severity cutoff point (KL≥2) was not used, due to the known discordance between radiographic severity and pain . FurtherRadiographic severity was determined from the most recent anteroposterior radiograph. These radiographs were all taken as part of the patient’s usual care within one year prior to the questionnaire survey. Radiographs were rated by a single observer (T.B.) using the KL grade classification (I-IV) . Rating Gender, age, height and weight, family status , highest level of education, duration of joint pain (in months), awaiting joint replacement (index-joint), previous surgery index-joint area, number of significant painful joint/body regions , comorbidities  . It is cAverage pain intensity in the past week within the index joint was obtained by an 11-point NRS, with 0 representing “no pain” and 10 representing “pain as bad as you can imagine”. The NRS showed to be highly reliable in rheumatic patients (r = 0.95–0.96) . For conParticipants completed the Hip disability and Osteoarthritis Outcome Score (HOOS)  and kneeThe RAND 36-item Health Survey (RAND-36) is a generic health status questionnaire. It consists of 36 questions organized into eight multi-item scales: physical functioning (PF), role-physical (RP), bodily pain (BP), general health (GH), vitality (VT), social functioning (SF), role-emotional (RE) and mental health (MH). Each raw scale score is transformed into a linear 0–100 scale (worst to best). The higher the score, the less disability. The Dutch-language version was proven to be practical, reliable and valid .Statistical analyses were conducted by using IBM SPSS (V.23). Analyses were conducted separately for hip and knee OA patients. Descriptive statistics were used to describe the study sample. Differences between the unlikely NP phenotype and the possible NP phenotype were analyzed in case of continuous variables with a Student t-test. A Mann-Whitney U-test was performed in cases of skewness . Fisher’s exact test was used for non-continuous data. To estimate the influence of neuropathic-like symptoms on joint-specific function (WOMAC) and health-related quality of life (RAND-36) an ANCOVA analysis was performed, enabling adjustment for the potential influences of the multiple covariates. After a check for basic assumptions like collinearity (variance inflation factor) and homoscedasticity three separate stepwise models were created. Model 1 added the three basic variables of age, sex and BMI to the crude data. Model 2 added severe or persistent back disorder (Yes/No), painful joint/body regions (/13), comorbidities (/9) and previous surgery in index-joint (Yes/No) to Model 1. Model 3, the fully adjusted model, added pain intensity and analgesic usage (Yes/No) to Model 2, to gain insight into the influence of basic pain intensity and analgesic usage on neuropathic like-symptoms. Dependent variables in the ANCOVA analyses were separate WOMAC and RAND-36 domains. A p-value <0.05 was considered statistically significant.The definitive study sample consisted of 255 subjects, 117 primary hip OA and 138 primary knee OA patients. Patient characteristics are displayed in The crude data showed statistically significant differences between the two pain phenotypes  displayed statistically significant differences between the two pain phenotypes  significantly differed, namely the physical functioning domain (18.5 points) and the role-physical domain (15.4 points). Basic adjustment for age, sex and BMI (model 1) only retained the statistically significant difference in the physical functioning domain (15.7 points). This difference was retained after adjustments made in models 2 (14.6 points) and 3 (9.6 points).The aim of this study was to determine the sole influence of neuropathic-like symptoms on joint-specific function and HRQoL, in both hip and knee OA patients, while adjusting for multiple known influential covariates. We found that the presence of neuropathic-like symptoms does not interfere with a hip OA patients’ joint function, but does deteriorate the subjective rating of pain-related quality of life. By contrast, knee OA patients who experience neuropathic-like symptoms encounter clinically relevant diminished joint-related function  and moreThe major additional value of this study compared to previous ones in this field is that extensive adjustments for relevant covariates have been made. The effect of adjusting was especially visible in the hip OA group. Without adjusting, deficits on joint function were apparent. However, as these effects were no longer apparent after adjusting, the found deficits in joint-related function were explained by other covariates.As indicated, our study is the first to extensively adjust for multiple relevant known covariates, therefore results can only be compared with previous studies to a limited extent. Furthermore, studies on this specific topic are lacking in hip OA patients, so no comparison with previous studies was possible at all for hip OA results. When comparing our findings to previous knee OA studies that did not adjust for relevant covariates , we found comparable large differences in our unadjusted analyses on the WOMAC between the possible and the unlikely NP phenotype group ,19,20. AIn this study neuropathic-like symptoms were quite prevalent among hip and knee OA patients; respectively 37% and 46% experienced at least a possible NP phenotype (m PDQ>12), which is in line with previous research –11. The Strengths of this study are that it focused solely on a general secondary care hip and knee OA population with few exclusion criteria, which benefits external validity. In contrast to most studies, we used the modified version of the painDETECT questionnaire (mPDQ), which is joint- and population-specific and forces OA patients to think about their specific joint within a delimited timeframe, enhancing face and content validity . This isUnfortunately, to date there is no gold standard to detect definitive neuropathic pain in OA. The International Association for the Study of Pain (IASP) requires a demonstrable lesion or disease that satisfies established neurological diagnostic criteria  . In dailIn conclusion, experiencing neuropathic-like symptoms seem to be associated mainly with diminished physical functioning in knee OA patients. In hip OA patients this only deteriorates the subjective rating of pain-related quality of life. Overall, neuropathic-like symptoms seem to be related to more signs of central pain sensitization. OA patients could benefit from pain phenotype screening and a more customized treatment for their underlying pain mechanism . Future longitudinal RCTs are needed to determine whether such treatment enhances function and quality of life in OA patients with neuropathic-like symptoms.S1 Dataset(SAV)Click here for additional data file.


Digital mobile technology presents a promising medium for reaching young adults with smoking cessation interventions because they are the heaviest users of this technology.The aim of this study was to determine the efficacy of an evidence-informed smartphone app for smoking cessation, Crush the Crave (CTC), on reducing smoking prevalence among young adult smokers in comparison with an evidence-informed self-help guide, On the Road to Quitting (OnRQ).A parallel, double-blind, randomized controlled trial with 2 arms was conducted in Canada to evaluate CTC. In total, 1599 young adult smokers (aged 19 to 29 years) intending to quit smoking in the next 30 days were recruited online and randomized to receive CTC or the control condition OnRQ for a period of 6 months. The primary outcome measure was self-reported continuous abstinence at the 6-month follow-up.21(N=845)=1.6, P=.23. Furthermore, OnRQ participants reported significantly higher levels of overall satisfaction , perceived helpfulness , and frequency of use  compared with CTC participants.Overall follow-up rates were 57.41% (918/1599) and 60.48% (967/1599) at 3 and 6 months, respectively. Moreover, 45.34% (725/1599) of participants completed baseline, 3-, and 6-month follow-up. Intention-to-treat analysis (last observation carried forward) showed that continuous abstinence (N=1599) at 6 months was not significantly different at 7.8% (64/820) for CTC versus 9.2% (72/779) for OnRQ . Similarly, 30-day point prevalence abstinence at 6 months was not significantly different at 14.4% (118/820) and 16.9% (132/779) for CTC and OnRQ, respectively . However, these rates of abstinence were favorable compared with unassisted 30-day quit rates of 11.5% among young adults. Secondary measures of quit attempts and the number of cigarettes smoked per day at 6-month follow-up did not reveal any significant differences between groups. For those who completed the 6-month follow-up, 85.1% (359/422) of young adult smokers downloaded CTC as compared with 81.8% (346/423) of OnRQ, χCTC was feasible for delivering cessation support but was not superior to a self-help guide in helping motivated young adults to quit smoking. CTC will benefit from further formative research to address satisfaction and usage. As smartphone apps may not serve as useful alternatives to printed self-help guides, there is a need to conduct further research to understand how digital mobile technology smoking cessation interventions for smoking cessation can be improved.ClinicalTrials.gov NCT01983150; http://clinicaltrials.gov/ct2/show/NCT01983150 (Archived by WebCite at http://www.webcitation.org/6VGyc0W0i) Tobacco use among young adults remains a global public health issue as young adults continue to maintain high prevalence rates . For exaYounger age groups have the highest quit attempt rates, which decline with age , indicatA promising new direction for reaching and engaging young adults in smoking cessation interventions is the use of mobile phones, particularly smartphone apps. Smartphone ownership among young adults aged 18 to 34 years in both the United States and Canada is almost ubiquitous at 92% and 94%, respectively . It is nThe advanced processing capabilities, global reach, and unmatched accessibility of smartphones render them ideal channels for delivering health-related interventions . In addiAlthough there is a growing body of evaluative evidence on the efficacy and effectiveness of smartphone-based technologies for smoking cessation, this has largely been through small pilot studies. Although most evaluative evidence consists of studies of short message service (SMS) text-messaging-based interventions for smoking cessation ,21, the A systematic review of 8 studies found mixed evidence regarding the effectiveness of smoking cessation apps and observed that user engagement and adherence to app features influenced quit rates and that larger sample size studies are needed . Two of One recent RCT examined the effect of an evidence-informed decision-aid app on continuous abstinence at 1, 3, and 6 months among adults aged 18 years and older who were motivated to quit . The autOur aim was to conduct a large and methodologically rigorous evaluation of smartphone cessation technology to address the identified gap in the published literature. We compared the effects of an evidence-informed smoking cessation mobile phone app known as Crush the Crave (CTC) with a self-help booklet on reducing smoking prevalence among young adult smokers after 6 months. The mobile phone app was hypothesized to yield higher rates of continuous abstinence, 30-day point prevalence abstinence (PPA), 7-day PPA, quit attempts, and reduction in consumption of cigarettes. This is the first full-scale and long-term study that we are aware of to assess the efficacy of a quit smoking app that specifically targets young adults.The study was a 6-month, 2-arm, parallel RCT conducted in Canada with participants assigned with an equal probability to the mHealth intervention, CTC, or to the self-help booklet. Investigators, data collectors, and participants were blinded to the group assignments. Follow-up was conducted at 3- and 6-months post randomization. A superiority trial design was used  and the Participants were eligible if they were between the ages of 19 and 29 years, smoked cigarettes daily, resided in Canada, were considering quitting smoking in the next 30 days, had an Android (Version 2.0 to 5.0) or iPhone (Version 4.0 to 7.0) smartphone, were able to provide informed consent, were able to comprehend English, and were not referred to the study by an existing study participant—a friend or family member already participating in the study—to avoid possible contamination bias.Recruitment sources were primarily Web-based media and included 72% from Facebook advertisements, 24% Google advertisements, and 4% from other sources . Interested young adults were referred to a website describing the study. Potential participants were screened at the entry webpage where their eligibility was determined, informed consent was sought, and registration for the study conducted. Participants who met the inclusion criteria and consented to participate completed the Web-based baseline questionnaire and were then randomly allocated to either the control or intervention arm and were sent a computer-generated email confirming registration and containing instructions for downloading their randomly assigned quit smoking program see . ParticiThe intervention group received a comprehensive and evidence-informed smoking cessation smartphone app, CTC version 2.1. CTC was developed in early 2012 by a team of population health researchers, social media experts, and computer programmers as an evidence-informed quit smoking smartphone and social media app for young adults aged 19 to 29 years ). Furthermore, there was no difference in the number of quit attempts between groups  and in the number cigarettes smoked per day between groups .Secondary measures of quit attempts and the number of cigarettes smoked per day at 6-month follow-up for those who had not quit smoking at 6 months (n=671) did not reveal any significant difference between the groups. Moreover, 94.3% (249/264) of OnRQ participants and 91.4% (265/290) of CTC participants had made at least 1 quit attempt (χP=.06). Similarly, higher cessation outcomes favored the OnRQ condition for those reporting high levels of social support , the sub-group analysis for prespecified variables included gender, age, education, heaviness of smoking, self-confidence to quit, level of social support, use of a smoking cessation aid at baseline, and frequency of assigned intervention use. No statistically significant subgroup effects were found when comparing continuous self-reported abstinence between the intervention (CTC) and control (OnRQ) conditions see . Althoug21(N=845)=1.6, P=.23). Furthermore, OnRQ participants reported significantly higher levels of overall satisfaction  and perceived helpfulness , as well as higher levels of frequency of use, confidence in using, ease of use, and perceptions of the intervention being well laid out as compared with the CTC participants  is 5% (95% CI 4%-6%) among adult smokers based on a large sample size (n=4355) population-based longitudinal cohort study of Ontario smokers . AccordiCTC was not superior to the control condition OnRQ. Rather, the primary outcome and secondary outcome measures at 6 months favored the self-help booklet control condition. However, the continuous abstinence rate and 30-day abstinence rate for CTC is comparable with previous research on smoking cessation smartphone apps ,26 and iIt is interesting that those with higher education and those with low social support favor the CTC app and that some populations may prefer alternative low-intensity evidence-informed interventions such as self-help guides. In addition, men’s interest in using CTC is noteworthy. In our recently published qualitative work, it was found that men were particularly receptive to CTC’s ability to present personalized and relevant information in relation to their smoking behavior and engage them in autonomous behavior change . That meDespite the independent and positive assessment of Ubhi et al  regardinThis study has several limitations. Despite a rigorous process for encouraging participants to complete follow-up, an overall response rate of 60.48% at 6-month follow-up is considered suboptimal. However, this level of follow-up response is similar to other Web-based cessation intervention studies such as BecomeAnEX with a 3-month follow-up rate of 59% . DespiteAlthough it was demonstrated that the rates of continuous abstinence and 30-day PPA for the CTC intervention condition were comparable with the few trials of smoking cessation apps to date, an important limitation of this study is the lack of a no intervention control group. However, it is often difficult to avoid attrition bias when conducting trials with inactive controls , and inaAlthough participants were blinded, both interventions were potentially available to any participant, implying a risk of contamination. However, we took measures to minimize this through ensuring unique IPs at recruitment and only 2.2% reported use of a self-help guide and 3.2% use of a smartphone app at 6-month follow-up in groups not allocated to these interventions.Recall bias with regard to the self-reported use of interventions is possible. Although the automated recording of the use of CTC is possible as reported elsewhere , it was Finally, the lack of biochemical validation of smoking abstinence is a limitation that may have resulted in an overestimation of smoking abstinence . HoweverThis study reached a large sample of Canadian male and female young adults from various ethnicities, education, and income groups, including unemployed and low-income young people, who owned smartphones and were motivated to quit smoking. The inclusion criteria of understanding, reading, and speaking English resulted in a lack of representation from young adult francophone smokers. French is the mother tongue of approximately one-fifth of the Canadian population, most of whom live in Quebec. Therefore, the study sample is limited to English-speaking Canada, and the findings may not be generalizable to young adult smokers with smartphones in other settings.CTC did not show a significant difference from a usual care self-help guide. Despite the rates of quitting being comparable with other smoking cessation app interventions, research into improving the overall satisfaction and helpfulness of CTC is needed before practitioners may recommend an evidence-informed mHealth app, such as CTC, to smokers willing to quit. In addition, the widespread reach that cessation apps, such as CTC, can have, particularly for hard-to-reach populations, supports the relevance and need for mHealth cessation interventions. For example, among 18- to 29-year-old people, smartphone ownership is nearing saturation among all socioeconomic groups , and as To date, the effects of smartphone apps for smoking cessation are largely unknown and this study is one of the very few trials that have been undertaken. A number of larger RCTs are underway to assess the effect of smartphone apps for smoking cessation -61. In tCTC was feasible for delivering cessation support but was not superior to a self-help guide in helping motivated young adults to quit smoking. Both conditions in this trial are considered low-intensity self-help interventions and achieved rates of continuous abstinence comparable with other mHealth studies for smoking cessation. As smartphone apps may not serve as useful alternatives to printed self-help guides, there is a need to conduct further research to understand how smartphone apps for smoking cessation can be improved and become better in supporting population health efforts to reduce the overall prevalence of smoking.


In Sub-Saharan Africa, the rising rates of cerebrovascular and cardiovascular diseases (CBD/CVD) are intersecting with an ageing HIV-infected population. The widespread use of antiretroviral therapy (ART) may confer an additive risk and may not completely suppress the risk associated with HIV infection. High-quality prospective studies are needed to determine if HIV-infected patients in Africa are at increased risk of CBD/CVD and to identify factors associated with this risk. This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent herpesvirus infections, lead to increased CBD/CVD risk in Malawian adults aged ≥35 years.We will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected controls in Blantyre, Malawi. Patients and controls will be recruited from government ART clinics and the community, respectively, and will be frequency-matched by 5-year age band and sex. At baseline and follow-up visits, we will measure carotid intima-media thickness and pulse wave velocity as surrogate markers of vasculopathy, and will be used to estimate CBD/CVD risk. Our primary exposures of interest are cytomegalovirus and varicella zoster reactivation, changes in HIV plasma viral load, and markers of systemic inflammation and endothelial function. Multivariable regression models will be developed to assess the study’s primary hypothesis. The occurrence of clinical CBD/CVD will be assessed as secondary study endpoints.The University of Malawi College of Medicine and Liverpool School of Tropical Medicine research ethics committees approved this work. Our goal is to understand the pathogenesis of CBD/CVD among HIV cohorts on ART, in Sub-Saharan Africa, and provide data to inform future interventional clinical trials. This study runs between May 2017 and August 2020. Results of the main trial will be submitted for publication in a peer-reviewed journal.ISRCTN42862937. This is one of the first large-scale studies in Sub-Saharan Africa to explore the relationship between HIV infection, latent herpesviruses, inflammation, and cardiovascular and cerebrovascular diseases, immediately after starting antiretroviral therapy (ART).Clinical events and death will be comprehensively reviewed through an endpoint review committee using strict diagnostic criteria for events based on those used in the INSIGHT  network or validated verbal autopsy for death with limited data.Because of the recent roll-out of ART in asymptomatic patients, there will be an absence of ART-naïve population, limiting our ability to explore the impact of ART.Approximately one-third of strokes will be asymptomatic and we anticipate not capturing some of these; however, multiple cerebral infarcts without a focal neurological deficit will manifest as cognitive impairment, which we will screen for and corroborate with MRI in a small number of symptomatic cases.Two-thirds of myocardial infarction will be silent and could potentially be missed, and in a nested group we will use digital ECG to evaluate this further.The growing epidemic of cerebrovascular disease  and cardiovascular disease ) now intersects with the HIV epidemic.There are reports of geographical differences in the distribution of CVD risk factors, supporting the argument that evidence derived from high-income countries cannot be applied to Sub-Saharan (SSA).In addition to HIV, there is compelling evidence that reactivation of latent herpesviruses may be an important cause of vasculopathy. In HIV-uninfected elderly populations from high-income settings, latent cytomegalovirus (CMV) infection drives dysregulation of cell-mediated immunity,The involvement of herpesviruses in the mechanistic pathway for CBD/CVD is compelling and may offer additional therapeutic avenues, especially for CMV and VZV. However, our understanding is incomplete, and its population impact is yet to be defined. It is important to determine if, in addition to ART, there is a role for other pharmacological interventions targeting latent viral infections or downstream inflammatory pathways to reduce vasculopathy in HIV-infected patients on ART. Previous work from North America supports the potential of treating reactivated herpesviruses.This study will test the hypothesis that immune activation and dysfunction, driven by HIV and reactivation of latent CMV/VZV herpesvirus infections, lead to increased CBD/CVD risk in adults aged ≥35 years in SSA. We will address this through the following objectives:To determine if progression of the surrogate marker of CBD/CVD or occurrence of new-onset vasculopathy is higher in adults aged ≥35 years with HIV infection on ART compared with those without HIV.To determine if progression of surrogate markers of CBD/CVD or occurrence of new-onset vasculopathy is higher in adults aged ≥35 years with HIV/herpes viral antigenaemia or chronic immune activation compared with those without HIV/herpes viral antigenaemia or chronic immune activation. Specifically, we will determine if progression of surrogate markers or new-onset vasculopathy is higher in the following:In ART patients with reactivated latent herpes viral infection, compared with those without reactivated latent herpes viral infection.In ART patients with the highest 25% of markers for immune activation, inflammation or endothelial activation compared with the bottom 25%.In ART patients with incomplete virological suppression or virological resurgence of HIV, compared with those with suppressed HIV plasma viral load.The secondary study objectives are to determine if viral antigenaemia or chronic immune activation increases the occurrence of the following clinical events: (1) stroke, (2) MI, (3) angina (excluding MI), (4) peripheral vascular disease (PVD), (5) all-cause death/vascular-related death and (6) immune reconstitution inflammatory vasculopathy.To address objective 1, we will conduct a single-centre, 36-month, prospective cohort study in 800 HIV-infected patients initiating ART and 190 HIV-uninfected adults aged ≥35 years. HIV-infected and HIV-uninfected participants will be frequency-matched by 5-year age band and sex. On a 6-monthly basis, we will measure markers of viral infection, inflammation and endothelial function along with surrogate markers for CBD/CVD .This study will recruit consecutive ART patients from the ART clinic of Queen Elizabeth Central Hospital (QECH) and ART clinics in several Blantyre City community health centres (CHCs). These clinics collectively initiate over 100 HIV-infected patients aged ≥35 years onto ART each month. HIV-uninfected adults will be selected from pre-ART counselling sessions, and from randomly selected households in the community by two-stage random sampling  from a previously enumerated sampling frame in the CHC catchment areas.Study inclusion criteria will be (1) age ≥35 years and (2) resident of Blantyre. HIV-infected patients must further be (3) ART-naïve or initiated ART <10 days prior to enrolment and (4) initiating standard first-line ART. Adult controls must further be (5) HIV-uninfected. Study exclusion criteria are (6) clinical history of CBD/CVD, (7) pregnancy, (8) critical illness or symptomatic anaemia at baseline, and (9) enrolment in an intervention study. At the analysis stage abnormal pulse wave velocity (PWV) at baseline  will be stained with anti-CD45 PerCP CY5.5, anti-CD3 AF700, anti-CD4 BV421, anti-CD8 PE Dazzle, anti-CD38 BV605, anti-HLA-DR APC CY7, anti-CD57 APC, anti-PD1 PE CY7, anti-CTLA4 PE and anti-CD223 FITC  to determine the expression of these markers on the surface of T cells. In addition, 2×106 PBMCs stained with anti-CD16 BV421, anti-CD14 PE, anti-HLA-DR PerCP CY5.5, anti-CD45 AF700, anti-CCR2 BV605, anti-CD11b APC, anti-CX3CR1 PE Dazzle and anti-CD38 FITC  will be used for monocytes. Dead cells, CD3+ T cells and CD56+ Natural Killer cells will be excluded using LIVE/DEAD Fixable Aqua Dead Cell Stain , anti-CD3 BV503 and anti-CD56 BV503 , respectively. Stained cells will be acquired on a BD LSRFortessa flow cytometer , and data will be analysed using FlowJo V.10.0 software . For each stained sample analysed, the median fluorescence intensity for each parameter will be normalised to its respective unstained control.Immunophenotyping will be used to characterise peripheral blood mononuclear cells (PBMC) isolated from blood samples of HIV-uninfected and HIV-infected ART initiators. PBMCs will be harvested by density centrifugation using Lymphoprep . PBMCs (2×10A custom-made multiplex assay will be used to assess soluble markers of monocyte activation (CD163), systemic inflammation (IL-6) and endothelial activation (intracellular adhesion molecule 1) in plasma, isolated from blood samples of HIV-uninfected and HIV-infected ART initiators. Following isolation, plasma will be aliquoted and stored at −80°C until further use.Quantitative VIDAS CMV IgG and IgM  and VZV glycoprotein IgG Low-Level Enzyme Immunoassay Kit (VaccZyme EIA) will be used to determine exposure to these viruses using a commercial ELISA platform. These kits will detect VZV antigen to a sensitivity and specificity of 97.8% and 96.8% and for CMV, 97.2% and 100% for IgG, and 100% and 97.4% for IgM, respectively.HIV infection will be diagnosed using two rapid tests in parallel  and Uni-Gold HIV , and EIA rapid tests will be used as a tie-breaker. HIV-1 RNA levels in plasma will be measured using the Abbott RealTime HIV-1 assay with a lower limit of detection of 150 copies/mL , according to the manufacturer’s instructions. CD4+ T cell count measurements will be performed using BD FACSCount machine (Partec platform).Carotid-femoral PWVThe primary outcomes are the progression of surrogate markers of CBD/CVD, namely PWV and CIMT, as well as the occurrence of new-onset vasculopathy defined by threshold values outlined in The secondary outcomes are the following clinical events: (1) stroke, (2) MI, (3) unstable angina, (4) PVD, (5) all-cause death/vascular death and (6) immune reconstitution inflammatory syndrome (IRIS) vasculopathy . Changes10.1136/bmjopen-2018-025576.supp1Supplementary dataThe exposure for primary objective 1 will be HIV status. Yearly HIV rapid tests in HIV-uninfected adults will be performed to exclude those with new HIV infections .Potential confounding and mediating factors will be recorded in study participants. This will include demographic factors, lifestyle and behavioural factors , chronic comorbidities , and cardiometabolic, renal and haematological factors . Blood pressure will be measured at all study visits. Although vascular IRIS  will be For objectives 2a–2c, markers of herpes and HIV viral antigenaemia and immune inflammation will be measured according to the outline in For primary objective 2b, markers of immune activation, inflammation and endothelial activation will be measured . QuantitFor primary objective 2c, incomplete viral response and viral rebound of HIV will be measured by quantitative PCR in patients on ART.The two-stage screening will be conducted to find and recruit potential study participants. A trained fieldworker will first screen to assess eligibility for criteria 1–3 in pre-ART counselling sessions and in individuals from randomly selected households in the community. Eligible participants will then be referred to the QECH to complete screening for criteria 4–9, and if eligible consented to participate in the study. At study visits, a tablet-based, standardised Open Data Kit case report form will be administered in one-on-one interviews by a study nurse to capture demographic and clinical data. Study data will be collected as outlined in The required sample size for the study’s primary objectives is 800 HIV-infected patients and 190 HIV-uninfected adults using standard, normal distribution approximation sample size formulas for comparing proportions in two groups of unequal size and based on the following assumptions: (1) of HIV-infected study participants, 18.4% have abnormal PWV at baseline. We will exclude these participants from analysis. The 18.4% figure is informed by our ongoing studies of vasculopathy in HIV-infected patients, where this is the percentage of participants aged ≥35 years who have a PWV (>12 m/s). (2) Of both HIV-infected patients and HIV-uninfected adults, 20% will be lost to follow-up, including by death and HIV seroconversion.The reporting of this study will be prepared in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.There will be three analysis time points: (1) after recruitment has finished and baseline data are available for all participants ; (2) once every participant has completed 6 months in the study ; and (3) at 36 months, when each participant has completed 24 months in the study .2 or Fisher’s exact tests (depending on contingency table cell counts) for binary and categorical variables. Adjusted analyses will be conducted using generalised linear models (GLMs).The baseline analysis will largely consist of descriptive statistics on participant characteristics and data recorded at baseline. Simple regression models will also be used to investigate relationships between exposure and outcome variables measured at baseline. Unadjusted analyses will consist of paired t-tests or Wilcoxon signed-rank tests  for continuously measured variables, and χThe 6-month analysis will be limited in scope and serves two purposes: (1) characterise new-onset vasculopathy in HIV-infected participants who have initiated ART treatment at baseline (vascular IRIS) and (2) define vasculopathy outcomes for the final analysis. The main analysis of the study data will be conducted at the final analysis time point.For objective 1 we will develop three regression models. Two GLMs will be developed to compare mean progression of arterial damage from baseline in HIV-infected ART patients and HIV-uninfected adults. These models will regress change from baseline PWV and CIMT, respectively, on HIV status. We will develop a third model to estimate the RR and population-attributable fraction of new-onset arterial damage in HIV-infected patients compared with HIV-uninfected adults.For objective 2a, a set of GLMs will be developed to compare mean progression of vasculopathy in HIV-infected ART patients with and without reactivated latent herpes viral infection. These models will regress PWV and CIMT, respectively, on, on two log-transformed variables for antibody titres of CMV and VZV.For objective 2b, we will again fit a set of GLMs, with change from baseline in PWV as response variable, this time to investigate if, in HIV-infected ART patients, there is an association between progression of vasculopathy and immune activation and inflammation biomarkers . Specifically, for each marker, we will regress PWV on marker quantiles. After having built models for each marker, we will then develop comprehensive multiple regression models for PWV and CIMT with multiple independent markers as predictor variables.For objective 2c, we will proceed as for objective 2a, but comparing HIV-infected ART patients with incomplete virological suppression or virological resurgence of HIV with those with suppressed HIV plasma viral load.In addition to these analyses, given the repeated measurements for PWV, immune activation and inflammation markers, we will extend the GLMs for PWV to linear mixed models taking full account of the longitudinal nature of the data. Mixed models will also handle deviations from the visit schedule in a principled fashion and use all available data for dropouts. If a log link function is required for PWV in the GLMs, we will fit marginalised models using Generlaised Estimating Equations [GEE] instead of Linear Mixed Models [LMMs].For the secondary study objectives, we will use univariate methods to assess the frequency of clinical events within exposure strata. If there are sufficient numbers of clinical events, we will develop Poisson or negative binomial regression models (depending on model fit) for each clinical event type to compare exposure-defined participants.We will also use time-to-event models, specifically Cox proportional hazard models, to investigate associations between all-cause mortality and exposures.As part of exploratory analyses, we will aim to identify risk groups that are potentially incompletely captured with the measured exposure variables. We will perform unsupervised group-based multitrajectory modelling of multivariate longitudinal patient trajectories to confirm any associations we have found using more traditional approaches.All efforts will be made to collect complete data on all study participants. However, there will inevitably be missing data due to dropouts and a variety of other reasons. All primary analyses will be performed using multiple imputation. For sensitivity analyses, we will use all available cases, direct likelihood and fully Bayesian models, and for GEE models weighted GEE. If the number of missingness patterns is sufficiently small, we will also use pattern mixture models which can be used under the general missing-not-at-random setting but make additional identification assumptions.The global burden of HIV-associated CBD and CVD has tripled over the last two decades with the greatest impact in SSA. CBD and CVD are a priority for patients in Malawi as HIV infection is endemic and the population are living for longer. Knowledge of this informed our research question with the aim of understanding the mechanisms and thus direct targeted novel therapies to reduce this burden. Patients will be involved in the recruitment of the study, but not in the design. Patients and their advisors will be thanked for contributing to the study.Written informed consent will be obtained from all study participants, either written or witnessed verbal consent with thumbprint if the participant is non-literate. Study data will be maintained in an encrypted and password-protected database to which only study staff will have access. Study participants who develop a clinical event will be managed, using the hospital guidelines, by our study clinician alongside the hospital doctor. Clinical data will be anonymised using unique identifying code. Study data will be kept for 10 years and then destroyed with a record, as recommended by good clinical practice guidelines. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.African regions continue to bear the brunt of HIV infection. In 2013, an estimated 8.5 million adults were receiving ART.


Few studies have investigated the real-life outcomes of interdisciplinary multimodal pain rehabilitation programs (IMMRP) for chronic pain. This study has four aims: investigate effect sizes (ES); analyse correlation patterns of outcome changes; define a multivariate outcome measure; and investigate whether the clinical self-reported presentation pre-IMMRP predicts the multivariate outcome. To this end, this study analysed chronic pain patients in specialist care included in the Swedish Quality Registry for Pain Rehabilitation for 22 outcomes  on three occasions: pre-IMMRP, post-IMMRP, and 12-month follow-up. Moderate stable ES were demonstrated for pain intensity, interference in daily life, vitality, and health; most other outcomes showed small ES. Using a Multivariate Improvement Score (MIS), we identified three clusters. Cluster 1 had marked positive MIS and was associated with the overall worst situation pre-IMMRP. However, the pre-IMMRP situation could only predict 8% of the variation in MIS. Specialist care IMPRPs showed moderate ES for pain, interference, vitality, and health. Outcomes were best for patients with the worst clinical presentation pre-IMMRP. It was not possible to predict who would clinically benefit most from IMMRP. Pain is an unpleasant experience with complex interactions between sensorimotoric, affective, and cognitive brain networks. As such, pain, especially chronic pain, is influenced by and interacts with physical, psychological, social, and contextual factors ,2,3. OneUnlike single/unimodal interventions, interdisciplinary multimodal pain rehabilitation programs (IMMRPs) for chronic pain—an interdisciplinary treatment according to the International Association for the Study of Pain (IASP)—distinguish themselves as well-coordinated complex interventions. Typically, IMMRPs are based on cognitive behavioural therapy (CBT) models  and are administered over several weeks to months ,10,11,12Systematic reviews (SRs) have generally reported higher efficacy both on a general level and for specific outcomes of IMMRP compared with single-treatment or treatment-as-usual programs ,21,22,23Complex interventions such as IMMRP should have several outcomes measured at multiple levels and strategies for handling multiple outcomes ,30. IMMRTo investigate the outcome effect sizes of IMMRP immediately post-IMMRP and at 12-month follow-up.To analyse the multivariate correlation patterns of changes in outcomes of IMMRP: pre-IMMRP versus post IMMRP and pre-IMMRP versus 12-month follow-up.To define a multivariate outcome measure of IMMRP.To investigate if the clinical self-reported presentation pre-IMMRP can predict the multivariate outcome measure.The above knowledge gaps motivated this PBE study of chronic pain patients based on patient reported outcome measures (PROMs) from the Swedish Quality Registry for Pain Rehabilitation (SQRP) . This reThe SQRP, recognised by the Swedish Association of Local Authorities and Regions, receives data from all specialist care units in Sweden . The SQRThis study included SQRP data from women and men ≥18 years old with complex chronic (≥3 months) non-malignant pain who were referred to specialist pain and rehabilitation units  between 2008–2016. These patients can be characterised as complex, as their health profiles included psychiatric comorbidities such as depression and anxiety, low levels of acceptance, high levels of kinesiophobia, decreased working life and participation in social activities, and/or did not respond to routine pharmacological/physiotherapeutic treatments delivered in a monodisciplinary fashion. Strict inclusion and exclusion criteria for inclusion in the registry is not available, since this is a registry study of patients with complex chronic pain conditions referred from mainly the primary care to specialist care in Sweden. A minority of patients were referred from other specialist clinics e.g., orthopedic and rheumatology clinics. The following general inclusion criteria for IMMRP were used: (i) disabling chronic pain (on sick leave or experiencing major interference in daily life due to chronic pain); (ii) age 18 years and above; (iii) no further medical investigations needed; and (iv) written consent to participate and attend IMMRP. General exclusion criteria for IMMRP included severe psychiatric morbidity, abuse of alcohol and/or drugs, diseases that did not allow physical exercise, and specific pain conditions with other treatment options available .The proportions of patients within primary health care with chronic pain conditions are not exactly known, but 10–20% are estimates ,33. FurtThe study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice and approved by the Ethical Review Board in Linköping (Dnr: 2015/108-31). All the participants received written information about the study and gave their written consent.Background variables that were collected pre-IMMRP and symptom-related self-reported variables that were collected at all three times  were used in the analyses. The variables and instruments used are mandatory for the units registering their data with the SQRP.The following background variables were collected: age (years), gender (man or woman), education level, and country of birth. Education level was dichotomised into university and the other alternatives ; this variable was labelled as University. Country of birth was dichotomised as from Europe and outside Europe and labelled as Outside-Europe. In addition, self-reported pain duration (days), persistent pain duration (days), and number of days off work (Days no work) were obtained.Pain distribution was registered using 36 predefined anatomical areas (18 on the front and 18 on the back of the body) and the patients registered the areas with pain: (1) head/face, (2) neck, (3) shoulder, (4) upper arm, (5) elbow, (6) forearm, (7) hand, (8) anterior aspect of chest, (9) lateral aspect of chest, (10) belly, (11) sexual organs, (12) upper back, (13) low back, (14) hip/gluteal area, (15) thigh, (16) knee, (17) shank, and (18) foot. The number of areas with pain (range: 1–36) were summed, and the obtained variable was denoted as the Pain Region Index (PRI).For reports of the psychometric aspects of the self-reported measures, the reader is referred to other studies summarising these ,34,35,36Pain intensity average during the previous seven days was registered using a 0–10 (0 = no pain and 10 = worst possible pain) numeric rating scale (NRS)—NRS-7days.MPI is a 61-item self-report questionnaire that measures the psychosocial, cognitive, and behavioural effects of chronic pain ,38. PartSymptoms of anxiety and depression were registered using the Hospital Anxiety and Depression Scale (HADS) ,41. ThisThe Short Form Health Survey (SF36) attempts to represent multidimensional health concepts and measurements of the full range of health states, including levels of well-being and personal evaluations of health . Scores The European Quality of Life Instrument (EQ-5D) captures a patient’s perceived state of health ,44,45. TThe patients post-IMMRP and at the 12-month FU estimated the degree of positive change in pain (Change-pain) and in their ability to handle life situations in general (Change-life situation). The Change-pain item was rated on a five-point Likert scale from markedly increased pain (0) to markedly decreased pain (4). The Change-life situation item was rated on a five-point Likert scale from markedly worsened (0) to markedly improved (4). All the statistics were performed using the statistical package IBM SPSS Statistics (version 24.0) and SIMCA-P+ . A probability of <0.001 (two-tailed) was accepted as the criteria for significance due to the large number of subjects. t-test for unpaired observations, analysis of variance (ANOVA with post hoc test if significant difference), and Chi square test. Effect sizes  for within-group analysis were computed using a calculator when appropriate (https://webpower.psychstat.org/models/means01/effectsize.php). Hedges’ g, which provides a measure of effect size weighted according to the relative size of each sample, was used for between ES using a calculator (https://www.socscistatistics.com/effectsize/default3.aspx). The absolute effect size was considered very large for values ≥ 1.3, large for values between 0.80–1.29, moderate for values between 0.50–0.79, small for values between 0.20–0.49, and insignificant for values < 0.20 [The text and tables generally report the mean value ± one standard deviation (±1 SD) together with a median and range of continuous variables. Percentages (%) are reported for categorical variables. The detailed analyses also report 95% confidence intervals (95% CI). SQRP uses predetermined rules when handling single missing items of a scale or a subscale; details about this have been reported elsewhere . To comps < 0.20 .Common methods such as logistic regression (LR) and multiple linear regression (MLR) can quantify the level of relations of individual factors but disregard interrelationships among different factors and thereby ignore system-wide aspects . MoreoveHence, using SIMCA-P+, we applied advanced Principal Component Analysis (PCA) for the multivariate correlation analyses of all investigated variables and Orthogonal Partial Least Square Regressions (OPLS) for the multivariate regressions. These techniques do not require normal distributions of the included variables . Note tht-scores) can also be used (score plot), and each subject receives a score (t) for each of the significant components. The t-score was used to calculate a Multivariate Improvement Score (MIS). R2 describes the goodness of fit—the fraction of sum of squares of all the variables explained by a principal component [2 describes the goodness of prediction—the fraction of the total variation of the variables that can be predicted using principal component cross-validation methods [2 and distance to model in the X-space. No extreme outliers were detected. PCA extracts and displays systematic variation in the data matrix. All the variables were log transformed before the statistical analyses if data were skewed. Using PCA, we analysed the multivariate correlation pattern for the changes in the 22 outcome variables for all the subjects. Note that changes in outcomes are calculated so that a positive value indicates an improvement. A cross-validation technique was used to identify nontrivial components (p). Variables loading on the same component p were correlated, and variables with high loadings but with opposing signs were negatively correlated. Variables with high absolute loadings were considered significant. The obtained components are per definition not correlated and are arranged in decreasing order with respect to explained variation. The loading plot reports the multivariate relationships between variables. A corresponding plot reporting the relationships between subjects  [2, Q2, and the p-value of a cross-validated analysis of variance (CV-ANOVA). SIMCA-P+ uses the Non-linear Iterative Partial Least Squares (NIPALS) algorithm to handle missing data: maximum 50% missing data for variables/scales and maximum 50% missing data for subjects. OPLS was used for the longitudinal multivariate regression analyses of the ne data) . The varne data)  p(corr) ne data) . Thus, at-scores of the PCA mentioned above, we performed hierarchical clustering analysis (HCA). Based on the identified clusters (subgroups) defined by HCA, we performed partial least squares discriminant analysis (PLS-DA). In addition, we applied a bottom–up HCA to the principal component score vectors using the default Ward linkage criterion to identify relevant subgroups of patients. HCA can find subtle clusters in the multivariate space. In the resulting dendrogram, clusters were identified and, based on these groups, we performed PLS-DA using group belonging as the Y-variable and the psychometric data as predictors (X-variables). The PLS-DA model was computed to identify associations between the X-variables and the subgroups. Based on the HCA defined clusters, traditional inferential statistics (ANOVA including post hoc tests when appropriate) were computed using SPSS. To identify clusters based on the 2 = 43.437, p < 0.001), and fewer men had university education . Continuous background variables are shown in p < 0.001) and reported more spreading of pain according to PRI . The other variables in There were 14,666 chronic pain patients registered in the SQRP that fulfilled the inclusion criteria: chronic pain; >18 years of age; and completed the SQRP questionnaire before and on at least one of the two time points after the IMMRP. More than half (60%) of the patients answering the questionnaires pre-IMMRP and post-IMMRP also answered the questionnaires at 12-m FU. Most of the patients (76.3%) were women, 25.2% had studied at university, and 10.4% were born outside of Europe. More men were born outside Europe  were performed for pre-IMMRP versus post-IMMRP and pre-IMMRP versus 12-month FU. Significant models were achieved for both analyses . SimilarAt 12-month FU, the PCA also identified two additional components . The sect-score) for each significant component. Patients with high positive t-scores on the first component show prominent changes in the important variables constituting the first component, whereas patients near zero do not benefit, and patients with negative t-scores (located to the left in the score plot) deteriorate in the multivariate context. Hence, the t-score of the first component of both analyses can be considered as a Multivariate Improvement Score, in the following denoted MIS-post-IMMRP and MIS-12-month FU. The loading plot  is shown in 2 = 0.35; Q2 = 0.35; CV-ANOVA p < 0.001; n = 14,666). Using a similar approach, we performed an HCA based on MIS-12-month FU. This analysis identified three subgroups/clusters. Based on the HCA, a PLS-DA model with two predictive components was obtained with group belonging as the Y-variable .An HCA based on MIS-post-IMMRP was performed. Three subgroups/clusters were identified. Based on the HCA, a PLS-DA model with two predictive components was obtained with group belonging as the Y-variable (Rt-score) showed clear positive values  for cluster 1 and negative scores  for cluster 3  and in management of life (Change-life situation) were not included in the PCAs and thus not included in the calculations of MIS. However, these estimations showed a similar pattern: the most prominent positive changes were in cluster 1, and the least positive changes were in cluster 3 . In the next step, the identified three clusters of both analyses were compared for their pre-IMMRP values . For the2 = 0.08 in both analyses). Hence, most of the variations in the two MIS were not possible to predict.The outcome data at baseline (pre-IMMRP) together with the background variables were used to regress MIS-post-IMMRP and MIS-12-month FU . For botSimilar analyses for each of the clusters  revealedModerate long-term ES were found for pain intensity (MPI Pain severity and SF-36 bodily pain), interference in daily life (MPI Interference), and state of health (EQ-5D-index); most other variables showed small ES. Vitality also displayed moderate effect sizes immediately after IMMRP but fell slightly under cut-off for moderate change at 12-month follow-up. The majority of the 22 investigated outcomes were significantly improved.Significant intercorrelations between changes in pain intensity, interference, control, psychological distress, and mental health were confirmed. The changes in 22 outcomes reflected one (pre-IMMRP versus post-IMMRP) or three (pre-IMMRP versus 12-month follow-up) latent components (groups of variables).The outcomes were best for patients with the worst self-reported clinical presentation pre-IMMRP. Based on a defined multivariate improvement score (MIS), three clusters were identified. Cluster 1—overall, the worst situation pre-IMMRP—showed positive multivariate improvements in outcomes. Cluster 3—deteriorated—showed negative scores. Cluster 2, the intermediate cluster, was associated with overall slightly positive multivariate improvements.Certain variables  pre-IMMRP were associated with improvements according to MIS both post-IMMRP and at 12-month FU. However statistically significant, the pre-IMMRP situation could only explain a small part of the variation in MIS (8%); therefore, for clinical use, it was not possible to predict those who would benefit most from IMMRP.The major findings of the present large PROM study from SQRP are listed below:The outcome variables mandatory in SQRP and presented in the present study are in good agreement with the BSP model of chronic pain and the outcome domains presented by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) ,52 and tThe present study was not primarily designed to evaluate the efficacy of IMMRP, which requires RCTs and SRs/meta-analyses. However, our results for the repeated measurements  of chronThe present study reported medium ES for two of three pain intensity variables both post-IMMRP and at 12-month FU ; the third pain intensity variable had effect sizes near medium ES. These results contrasted some SRs reporting of no evidence for efficacy with respect to pain intensity ,11. HoweSRs of IMMRP report that it is an effective intervention with small to moderate effects for patients with chronic pain conditions ,12,62,63The number of outcomes in IMMRPs in RCTs are generally high, which reasonably reflects the broad goals of the complex intervention. The present study used 22 outcomes that are mandatory in SQRP measured on up to three occasions . PCA was applied to handle the pattern of changes in potentially intercorrelated outcomes as suggested by the Medical Research Council of the United Kingdom . From thindependent comparisons [t-scores for the most relevant latent factor (component). Hence, we defined an objective Multivariate Improvement Score , which on an individual patient level defines the multivariate improvement; a positive MIS indicates multivariate improvements because of IMMRP. The presented PCAs also highlight that it may be possible to reduce the number of outcome variables, since several of these appear to measure similar aspects of the chronic pain condition. The fact that 22 outcomes were analysed  may raisparisons . The latparisons , but reqparisons , but thiparisons . Howeverparisons . We usedThree clearly separated clusters based on MIS were identified. On a group level, clusters 1 and 2 were associated with various degrees of improvements, whereas cluster 3 showed negative MIS, indicating deterioration. Although the greater improvement in cluster 1 can be interpreted as a sign of regression to the mean and that these patients did not benefit from IMMRP more than cluster 2, this cluster still improves from IMMRP at least as well as those with e.g., less severe psychological distress symptoms (clusters 2 and 3). This may seem unexpected, but it is important to recognise that addressing psychological symptoms with CBT is an important component of IMMRPs. The patients at post-IMMRP and 12-month follow-up estimated the degree of positive change in pain  and the ability to handle life situation in general . Most patients reported improvements according to both the Change-pain and Change-life situations . RelativN > 35,000) that identified clusters based on the clinical presentation at assessment (decision not taken about participation in IMMRP); the study found that patients with the most severe clinical situation who later participated in IMMRP had the most prominent improvements in six investigated outcomes [We found that cluster 1, which had high MIS values , had a more severe clinical picture at baseline/pre-IMMRP than those with lower MIS . These results agree with another SQRP study (outcomes . Althougoutcomes , both thoutcomes  indicateThe longitudinal regressions of MIS using background variables and pre-IMMRP data as regressors were significant . A blendOutcomes of IMMRP in real-life practice settings agree with the conclusions from SRs. Partly in contrast to SRs, this registry study of patients managed within specialist care found that pain intensity was positively affected because of IMMRP. It was also obvious that not all patients benefit from IMMRP. Hence, there is a need to develop better matching between clinical presentation and participation in MMRP in real-life practice settings. Moreover, the intercorrelations of most changes in outcomes also opens up the possibility of reducing the number of outcome variables and hereby reduce the burden upon patients included in the SQRP. This study’s strengths include a large number of patients with complex chronic pain conditions with a nation-wide representation. However, these patients were referred to specialist clinics and thus represent a selection of the most difficult cases, so our results cannot be generalised to other settings. Another strength was the use of MVDA methods such as PCA and OPLS to handle correlation patterns, repeated measures, and regressions when there were obvious risks for multicollinearity. Changes in the social context may have changed and influenced the longitudinal analyses; however, we used validated and well-known instruments. Repeated evaluations using PROM questionnaires in treatment studies may be problematic . Thus, tThis large-scale study of IMMRPs in real life practise settings demonstrates significant outcome changes in almost all measures. Most short-term and long-term effect sizes were small, but interestingly, moderate long-term effect sizes were demonstrated for pain, pain interference in daily life, and perceived health. In addition, patients reporting higher levels of perceived disability and suffering displayed greater improvement.


Chemotherapy-induced neutropenia is a common result of myelosuppressive chemotherapy treatment. Infections such as febrile neutropenia (FN) are sensitive to the duration of neutropenia as well as the depth of absolute neutrophil count (ANC) at nadir. Filgrastim, a granulocyte colony stimulating factor (G-CSF), can stimulate the function of mature neutrophils. Pegfilgrastim, a long-acting form of filgrastim, has been shown to reduce FN to a greater extent compared to filgrastim. G-CSF agents have been recommended for prophylactic administration with chemotherapy. Apotex developed a proposed pegfilgrastim biosimilar. This study was conducted to confirm that no clinically meaningful efficacy or safety differences exist between Apotex’s proposed biosimilar and its reference product.589 breast cancer patients were randomized and dosed with the proposed pegfilgrastim biosimilar, US-licensed pegfilgrastim reference product, or EU-approved pegfilgrastim reference product. The primary endpoint assessed was the duration of severe neutropenia (DSN) and secondary endpoints included rate of FN and ANC nadir.As Treated arm had a 95% confidence interval within the equivalence range for the proposed pegfilgrastim biosimilar with the US-licensed and EU-approved pegfilgrastim reference products. Secondary endpoints, which included depth and peak of ANC nadir, time to ANC recovery post-nadir and rates of FN, also showed similarity between the three different treatment groups. The adverse event incidence was similar across treatment arms and there were no unexpected safety events.Data showed that the mean DSN, the primary endpoint measured, was comparable across all three treatments. The Overall, these results show that the proposed pegfilgrastim biosimilar is similar to Amgen’s US-licensed and EU-approved pegfilgrastim reference products with regard to the clinical efficacy and safety endpoints assessed.Trial registration EMA: European Union Clinical Trials Register:  Eudract # 2011-002678-21 Registered: 01/10/2012 Myelosuppressive chemotherapy treatment commonly results in chemotherapy-induced neutropenia (CIN), a complication associated with a high risk of morbidity, mortality, and hospitalization . After aFilgrastim, a granulocyte colony stimulating factor (G-CSF), stimulates hematopoietic cells, promoting growth, proliferation, differentiation, and maturation of neutrophil precursors. Filgrastim also enhances the function of mature neutrophils by increasing phagocytic activity and antibody-dependent cell-mediated cytotoxicity , 5.The addition of a polyethylene glycol moiety to filgrastim results in the long-acting form of pegfilgrastim, which requires only once-per-cycle administration for CIN management. Pegfilgrastim retains the same biological activity as filgrastim and binds to the same G-CSF receptor. In both experimental animals and healthy human volunteers, pegfilgrastim showed decreased renal clearance and increased plasma half-life compared with unpegylated filgrastim, allowing pegfilgrastim a sustained pharmacological effect . In clinSeveral international clinical guidelines  recommend prophylactic administration of G-CSF (filgrastim or pegfilgrastim) with chemotherapy associated with a high risk (> 20%) of FN and supportive G-CSF therapy with chemotherapy regimens associated with intermediate frequency (10–20%) of FN when additional predisposing factors exist for the patient  of FN, or advanced stage of disease).®, marketed by Amgen, Inc. State-of-the-art analytical techniques previously demonstrated analytical similarity between the proposed pegfilgrastim biosimilar and the US-licensed pegfilgrastim reference product . The two-sided 95% CIs were derived from a one-way ANOVA model accounting for the treatment effect. For statistical analyses, treatment groups were defined as follows:Full analysis set (FAS)-As Randomized included all enrolled subjects who were randomized, received at least one dose of active treatment, and who had any follow-up data for the primary endpoint variables. Treatment assignment for subjects was based on the treatment they were randomized to . FAS-As Randomized represents the prespecified primary analysis set used for efficacy endpoints.FAS-As Treated included all enrolled subjects who were randomized and received at least one dose of active treatment, and who had any follow-up data for the primary endpoint variables. Treatment assignment for subjects was based on the treatment they received in each cycle instead of the treatment they were randomized to receive.Safety analysis set, sensitivity included all subjects who received at least one dose of active treatment. All subjects who received APO-Peg at any time during the treatment period (regardless of randomized treatment group) were included in the APO-Peg group for this data set. Subjects who did not receive APO-Peg at any time were assigned to their randomized treatment group.Per protocol (PP) analysis set included all enrolled subjects who were randomized and received at least one dose of active treatment, and who had any follow-up data for the primary endpoint variables. Subjects with protocol deviations that impacted the integrity of the primary endpoint data and the safety/well-being of the subject in Cycle 1 were excluded from the PP (Cycle 1) analysis for the primary endpoint. Additionally, subjects with protocol deviations affecting the integrity of the data and the endpoint of the efficacy/safety analysis and well-being of the subject during Cycles 2–6 were excluded from the PP (All Cycles) analyses.A total of 595 patients were randomized from 56 investigational centers in 11 countries. All subjects were suitable for neoadjuvant TAC treatment . Patient demographics and breast cancer history were consistent across the treatment arms  was similar between treatment arms with the highest incidence occurring in Cycle 1 (as expected) and decreasing in subsequent treatment cycles (Table 9/L (day 3.1–3.4); overall mean ANC nadir of 0.5 × 109/L (day 7.1–7.3), and recovery of ANC ]  reported at least one AE in the treatment phase  and nausea  . None of these events were related to the study drug. The incidence of immunogenicity was low and similar across treatment arms, including no apparent clinically meaningful effects associated with anti-drug antibodies (ADAs) or neutralizing antibodies (data not shown).biosimilarity, defined in section 351(i) of the Public Health Services (PHS) Act [The term PHS) Act , means tPHS) Act . A demonBuilding on prior work demonstrating that the Apotex/Intas proposed biosimilar pegfilgrastim is analytically highly similar to US-licensed pegfilgrastim , as wellAs Randomized population was slightly outside the pre-defined equivalence margin of ± 0.5 days, prior data suggest that this range is very conservative. An equivalence range of ± 1 day, consistent with the usual daily sampling of ANC, has commonly been used in other similar studies [The proposed biosimilar showed comparable mean DSN in Cycle 1 to both the US-licensed and EU-approved pegfilgrastim reference products, and the data are consistent with the published data for these reference products. While the 95% CI of the difference in mean DSN in Cycle 1 for the  studies , 14. GivThe mean DSN in the absence of G-CSF in breast cancer patients treated with doxorubicin and docetaxel is expected to be 6–7 days , while pSimilarity between the proposed pegfilgrastim biosimilar and the US-licensed and EU-approved pegfilgrastim reference products was also supported by the results from all secondary efficacy analyses including the depth and peak of ANC nadir in Cycle 1, the time to ANC recovery post-nadir in Cycle 1, the rates of FN by cycle and across cycles, and the ANC time profile in Cycle 1.The AE incidence was similar across treatment arms and there were no unexpected safety events for the proposed pegfilgrastim biosimilar. The incidence of immunogenicity was low and similar across treatment arms, including no apparent clinically meaningful effects associated with anti-drug antibodies (ADAs) or neutralizing antibodies. Overall, these results contribute to the totality of the evidence collected to support a conclusion of biosimilarity between the proposed biosimilar pegfilgrastim and the reference product. Just like originator biologics, post marketing surveillance data, from the countries where the product is approved, is being continually monitored and the results are no different from those found with other pegfilgrastim products.This head-to-head, randomized, clinical confirmatory study of a proposed pegfilgrastim biosimilar demonstrates that the proposed pegfilgrastim is similar to Amgen’s US-licensed and EU-approved pegfilgrastim reference products, with regard to safety and efficacy, in the treatment of chemotherapy-induced neutropenia in breast cancer patients receiving myelosuppressive chemotherapy.


Spatial navigation involves multiple cognitive processes including multisensory integration, visuospatial coding, memory, and decision-making. These functions are mediated by the interplay of cerebral structures that can be broadly separated into a posterior network  and an anterior network (dedicated to memory and navigation planning). Within these networks, areas such as the hippocampus (HC) are known to be affected by aging and to be associated with cognitive decline and navigation impairments. However, age-related changes in brain connectivity within the spatial navigation network remain to be investigated. For this purpose, we performed a neuroimaging study combining functional and structural connectivity analyses between cerebral regions involved in spatial navigation. Nineteen young  and 22 older  participants were examined in this study. Our analyses focused on the parahippocampal place area (PPA), the retrosplenial cortex (RSC), the occipital place area (OPA), and the projections into the visual cortex of central and peripheral visual fields, delineated from independent functional localizers. In addition, we segmented the HC and the medial prefrontal cortex (mPFC) from anatomical images. Our results show an age-related decrease in functional connectivity between low-visual areas and the HC, associated with an increase in functional connectivity between OPA and PPA in older participants compared to young subjects. Concerning the structural connectivity, we found age-related differences in white matter integrity within the navigation brain network, with the exception of the OPA. The OPA is known to be involved in egocentric navigation, as opposed to allocentric strategies which are more related to the hippocampal region. The increase in functional connectivity between the OPA and PPA may thus reflect a compensatory mechanism for the age-related alterations around the HC, favoring the use of the preserved structural network mediating egocentric navigation. Overall, these findings on age-related differences of functional and structural connectivity may help to elucidate the cerebral bases of spatial navigation deficits in healthy and pathological aging. Spatial navigation represents one of the most fundamental activities of daily life and it requires the integration of multiple processes. These processes include the perception of spatial information from a variety of sensory cues, the creation and maintenance of spatial representations in memory, and the manipulation of these representations to guide navigational behavior  is a useful tool for non-invasively studying the age-related differences in functional and structural connectivity between regions within the navigation network. Functional connectivity can be probed using resting-state functional MRI, which measures the correlation between low-frequency spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal across brain regions in the absence of an explicit stimulus . In addition, considering the crucial role of vision for human spatial navigation, we additionally included the projection into the visual cortex of central and peripheral visual fields in our navigation network analysis. We anticipated age-related differences in the spatial navigation network in functional and structural connectivity. We hypothesized that there would be heterogeneous connectivity changes between key regions of interest within our spatial navigation network, and that such changes would be associated with spatial cognition, in particular regarding navigational strategies.Among the 41 healthy participants initially enrolled in the study, two older participants were excluded due to anatomical abnormalities, which resulted in failure of the normalization procedure. The participants were part of the French cohort population SilverSight (~350 subjects) established and followed-up ever since 2015 at the Vision Institute—Quinze-Vingts National Ophthalmology Hospital, Paris. All participants were native French speakers, and they gave their written informed consent to participate in the study. All screening and experimental procedures were in accordance with the tenets of the Declaration of Helsinki and they were approved by the Ethical Committee “CPP Ile de France V” . All participants had normal or corrected-to-normal vision, and they had no history of neurological or psychiatric disorders, or sensorimotor dysfunctions. Older participants had a score of 26 or higher on the Mini Mental State Examination . For the functional localizer scans of scene-selective regions and low-visual areas, 364 and 304 volumes respectively of 64 slices were acquired using a T2*-weighted SMS-EPI sequence .Images were acquired using a 3T Siemens Magnetom Skyra whole-body MRI system  with a 64-channel head coil at the Quinze-Vingts National Ophthalmology Hospital in Paris, France. Resting-state functional magnetic resonance imaging (fMRI), diffusion-weighted imaging and an anatomical image were acquired for all participants, followed by two additional functional localizer runs. The anatomical volume consisted of a T1-weighted, high-resolution, three-dimensional MPRAGE sequence . For the resting-state functional scan, 304 volumes of 60 slices were acquired using a T2*-weighted simultaneous multi-slice echo planar sequence . Diffusion-weighted images were acquired along 128 gradient directions  and the projection into visual cortex of central and peripheral visual fields . A block fMRI paradigm, adapted from Ramanoël et al.  was thenTo define ROIs for CVF and PVF regions, we used a blocked eccentricity mapping experiment adapted from Chang et al. . Two rinProcessing of localizer data was performed using SPM12 release 7,487 ]. CVF and PVF areas were mapped using the contrasts (Center > Periphery) and (Periphery > Center), respectively. Significant voxel clusters on individual t-maps were identified using false discovery rate correction (FDR) for multiple comparisons  to control for the overall false-positive rate. Sphere ROIs (5 mm radius) were created at individual peaks of activation in each scene-selective and low-visual region and in each cerebral hemisphere  for each pair of ROIs and each hemisphere (14 × 14).The resulting parameters were used to reconstruct the distribution probability of tract locations using probabilistic tractography (PROBTRACKX). This approach considers crossing-fiber pathways and it provides maps of the probability of the presence of a fiber in a voxel ]. Similarly to the functional connectivity analysis, gender was included as a covariate and effect sizes were evaluated with Hedges’ g score. Mean diffusion parameters were not averaged across tracts however using two regions as seed and target  were assessed using a two-sided two-sample Wandell, . This alN = 19; 10 females; mean age ± SD: 27 ± 4.3 years; age range: 21–37 years) and an older group . All subjects had visual, oculomotor, and audio-vestibular faculties in between or above normative age-dependent limits. In MRI data were analyzed from 39 participants divided into two age groups: a young group  between groups . We founWe then examined the co-variation of fractional anisotropy, the mean and radial diffusivities between age groups. Results revealed differences in structural connectivity only between both hemispheres in the navigation network . We founThe magnitude of the effects for structural results reported here was between 1.1 and 2.2 (> 0.8 considered large).r = −0.87) for the 3D-Rotation test between the R-CVF and the R-OPA; and a positive correlation (r = 0.80) for the FGT (long) between the R-OPA and the R-RSC [p-values were Bonferroni-corrected for multiple comparisons: p = 0.05/(12 × 12 × 6)].We conducted correlational analyses between cognitive scores obtained from the neuropsychological evaluation  and connectivity measures  for the older group only. We found no significant association between functional connectivity and cognitive scores. By contrast, for structural connectivity, we showed a significant correlation between fractional anisotropy values and two pairs of ROIs within our navigational network. More precisely, we found a negative correlation  typically seen in normal aging Owsley, , 2016 anConversely, the functional connectivity was higher for older compared to young participants in the anterior part of the spatial navigation network, between the left OPA and left PPA. The role of PPA in spatial navigation has previously been described in relation to the representation of landmark-based navigation . The patients/participants provided their written informed consent to participate in this study.SR, CH and AA: conceived the study. SR, EY, MP and KL: data acquisition. SR, EY and MP: data processing. SR, EY, MP and AA: manuscript writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.