To investigate the relationship between baseline clinicopathological and laboratory variables especially hematological parameters and lymphovascular invasion (LVI) in patients who underwent radical prostatectomy (RP).We retrospectively evaluated 348 prostate cancer (PCa) patients who underwent RP in our center between May 2018 and June 2021. We divided them into non-LVI and LVI groups based on LVI status, and compared clinicopathological characteristics between non-LVI and LVI groups. Clinicopathological parameters including age, body mass index (BMI), history of hypertension and diabetes mellitus, neoadjuvant hormonal therapy (NHT), pathological stage T (pT) and lymph node status (pN), ISUP  grade, positive surgical margin (PSM) rate, and hematological parameters containing prostate-specific antigen (PSA), whole blood parameters and inflammatory indexes were collected. The association between the clinicopathological parameters and the presence of LVI was identified by multivariate logistic regression analysis.The pathological results of the RP specimen consisted of 53 (15.2%) patients with LVI and 295 (84.8%) cases without LVI. The level of PSA, percentages of advanced pT and grade, pN1, and PSM were significantly higher in the LVI group when compared with the non-LVI counterpart . Among the whole blood parameters, only red cell distribution width (RDW) was significantly different . Multivariate regression analysis demonstrated that RDW and NHT were negatively correlated with the presence of LVI , while PSA, ISUP, and pT were positively correlated with the presence of LVI  after adjusting for confounding factors.RDW rather than other whole blood parameters was independently and negatively associated with the presence of LVI in PCa patients, suggesting that RDW might play an essential role in PCa invasion. Worldwide, prostate cancer (PCa) represents the second most common solid tumor in men. There were over 1414000 estimated new cases of PCa worldwide in the year 2020, with an age-standardized rate (ASR) incidence of 31 per 100000. Besides, there were over 375000 estimated deaths worldwide, and the overall mortality ASR was 7.7 per 100000 . We havewww.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocoltemplates). For PCa, LVI is reported in up to 21.5% of RP specimens (www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancerprotocoltemplates), and the presence of LVI at time of RP is recognized as an adverse pathological feature , white blood cell (WBC), and platelet (PLT), provide basic elements to conceive the immune and inflammatory TME, which consists of distinct immune cell populations highly associated with the antitumor immunological state in tumor islets . MoreoveTherefore, our objective was to systematically and comprehensively evaluate the association of the clinicopathological parameters especially the whole blood parameters with the presence of LVI of RP specimen in the Chinese patients with PCa.The current study included patiens who underwent laparoscopic RP and pelvic lymph node dissection in our center between May 2018 and June 2021. The exclusion criteria of the study were the presence of hematologic diseases, anemia, acute or chronic infection, severe hepatic and/or renal insufficiency, hypersplenism, hyperthyroidism, cardiovascular disease, other malignant tumors or a history of other malignancies, preoperative radiotherapy or chemotherapy. Finally, a total of 348 cases were included.All demographic and clinicopathological data were collected from the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College information system.www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocoltemplates).The data included age, body mass index (BMI), hypertension, diabetes mellitus, prostate-specific antigen (PSA), neoadjuvant hormonal therapy (NHT), operative time, blood loss, transfusion, preoperative whole blood parameters, and postoperative pathological results including pathological stage T (pT) and lymph node status (pN), ISUP  grade, PSM. The assessments of cancer pT, pN, and grade were performed as we previously reported . The patRoutine preoperative whole blood tests were performed, and included WBC, neutrophils (%), neutrophil counts, lymphcytes (%), lymphocyte counts, monocytes (%), monocyte counts, eosinophils (%), eosinophil counts, basophils (%), basophil counts, RBC, hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RDW-standard deviation (RDW-SD), PLT, mean PLT volume (MPV), PLT-large cell ratio (P-LCR), PLT distribution width (PDW), and plateletcrit. Based on peripheral blood cell counts, systemic inflammation markers were calculated as follows: N/L=neutrophil counts/lymphocyte counts, P/L=platelet counts/lymphocyte counts, SII=(neutrophil counts *platelet counts)/lymphocyte counts, L/M=lymphocyte counts/monocyte counts, SIRI=neutrophil counts×monocyte counts/lymphocyte counts.Data were expressed as means ± SD or median with interquartile range for continuous variables and number (percentage) for categorical variables. The differences between continuous variables were analyzed by unpaired t-tests or Mann-Whitney U tests as appropriate. Categorical variables were analyzed by χ2-test.n= 93); the second quartile group , n =82); the third quartile group ; n= 92); the fourth quartile group ; n= 81). Significant clinicopathological risk factors for LVI were analyzed by multivariate logistic regression analysis in 4 models step by step. Model 1 was unadjusted; Model 2 corrected for covariates including age, BMI, and comorbidities.; Model 3 additionally corrected for PCa specific risk factors including PSA, ISUP grade, and stage based on Model 2; Model 4 further corrected for NHT, the intervention before RP surgery, based on Model 3. All tests were two-sided and a p-value <0.05 was considered significant. The statistical analyses were performed with SPSS version 22.0 software .All PCa subjects were divided into two groups according to LVI status: non-LVI and LVI groups, and clinicopathological variables especially hematological parameters were compared between the two groups. The RDW was stratified into quartiles as following: the first quartile group , The clinicopathological characteristics including whole blood parameters of the non-LVI and LVI groups were shown in We performed multivariate logistic regression analysis to evaluate the correlations of RDW and other clinical variables with LVI. As shown in Our current study firstly investigated the correlation between clinicopathological parameters and LVI in PCa patients who underwent RP, and demonstrated that PSA, stage, and grade were independent risk factors for LVI,while RDW was independently and negatively associated with the presence of LVI among all whole blood parameters. The results have clinical implications for the prediction of PCa aggressiveness using routine blood tests.www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocoltemplates). It is reported that LVI exists in 5%-41.7% of RP specimens , National Natural Science Foundation of China (Grant No. 81972400), The Capital Health Research and Development of Special Funding (Grant No. 2022-1-4021), the CAMS Initiative for Innovative Medicine (Grant No. 2021-I2M-1-015), and Beijing Hope Run Special Fund of Cancer Foundation of China (no. LC2019B02)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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Key features include guidance to set goals, self-monitor and assess achievements, and experiential learning via the connected activity trackers which allows for continuous steps recording during the program. iEngage was implemented in two schools over 5 weeks with 10–12 years old adolescents (n = 57) and PA outcomes compared to control group (n = 26). Results show that adolescents successfully set goals and self-assessed achievements during the program, progressing toward higher physical activity (PA) levels as shown by the 30% increase in daily steps through the program  with boys increasing goals and achievements faster than girls. The consistency in days totalling at least 11,000 steps/day increased from 35% at the start to 48% at the end of the program. The increase in PA is confirmed through the assessment of MVPA during schooldays pre- and post- program via research grade wrist accelerometers in both iEngage and control participants. Contrasting with the control group, MVPA was increased in the week following the program  in short bouts, particularly during lunch time, recess and after school. This study shows that a digital program integrating activity trackers data, health education, goals setting and self-monitoring of PA, helped young adolescents enhance PA goals, improve achievements and increase MVPA.iEngage is a modular health education and behavioural change program designed to help adolescents increase moderate to vigorous physical activity (MVPA). The program is delivered through the iEngage app which integrates activity trackers data (Misfit Ray Physical activity (PA) is a major component of health and wellbeing across the lifespan and contributes to reducing all-cause mortality. However, current evidence from large population cross-sectional surveys indicates that 81% of children and adolescents globally do not participate in sufficient amounts of PA . SurveysBecause low participation in PA is a risk factor for the development of overweight and obesity in young people, leading to adverse cardiometabolic profiles, there is an urgent need to identify approaches and interventions that are effective , 6. For Numerous interventions have attempted to enhance participation in PA and MVPA in children and adolescents; most of them showing no or small changes in PA behaviour in response to interventions, indicating that changing PA behaviour in adolescents is challenging . School-In this article, we present our approach to designing and implementing iEngage, an educational and behavioural change program tailored to 10–12 years old adolescents. Building on an initial work , the proWe hypothesised that iEngage, combining experiential learning and behavioural change techniques, delivered via a user-friendly digital environment with integrated activity trackers, will be able to help adolescents enhance PA behaviour.We present the original design approach of the iEngage program and report on its effectiveness for enhancing PA goals and achievements and increase MVPA in daily life of 10–12-year-old Australian adolescents.iEngage is an evidence-based health education and behavioural change program designed to help young adolescents increase MVPA. The program is supported by a digital environment that includes the iEngage app connected to activity trackers. Using live data from these trackers and digital health education modules, iEngage aims to drive behavioural change through experiential learning, goal setting and self-assessment of achievements. The program and companion app were co-designed with experts in physical education, exercise science, data science and mobile health industry experts. A few short sessions were organised to gather feedback from adolescents.Topics such as health, intensity of PA, MVPA, sedentary behaviours (SB), physical fitness, physical effort, exertion, mode of exercise or the impact of PA on body functions are explained through a series of 10 digital modules  while aciEngage also aligns with the Australian Physical Literacy Framework. Physical literacy is described as the skills, knowledge and behaviours that help us lead active lives , 17, 18.amount of daily steps and MVPA they aim for  and (2) choosing a mission from four suggestions . To facilitate the quantitative goal, the app proposes a finite list of increasing commitments to choose from, with increasing boundaries throughout the program. Step choices from modules 1 to 10 are: 5,000 to 7,000 steps in module 1; 6,000 to 10,000 steps in module 2 and so on. MVPA choices start from module 6 and increase from 20 min to 60-min daily of MVPA as follows: 9000 steps/day and 20 min of MVPA, 10000 steps/day and 30 min of MVPA, 11,000 steps/day and 40 min of MVPA, 12000 steps/day and 60 min of MVPA. The maximum number of steps is based on studies estimating that performing 12,000 steps/day is possible only if adolescents engage in at least 45 minutes of MVPA [The process for personalised goal setting and assessment of achievements is designed as follows: in each module, the adolescent must set two types of goals for the next 3 days through two tasks: (1) choosing the The missions encourage adolescents to engage with the program through diverse activities with their parents or siblings, as research shows the importance of family, friends and community in driving behaviour change in adolescents . Example(C)) in the iEngage app; 2) reporting achievements in the app, 3) providing a self-assessment of achievements by answering a quiz and 4) reporting on completion of their mission. It is made clear in module 1 that iEngage focuses on progressing and achieving individual goals. iEngage has no component involving ranking the adolescents’ achievements and it has no competitive aspect. This is aligned with studies showing that competition and performance-based ranking can lead to adverse outcomes in adolescents [In each module but the first one, the adolescent assesses their achievements against their individual goals. This involves: 1) reading the number of steps recorded daily via the activity trackers . They signal the start of a specific activity, thus helping the transition between activities  to 2H. Aarphones .The research protocol and consent procedures were approved by The University of Sydney Human Research Ethics Committee (2017/272) and by the NSW Department of Education State Education Research Applications Process (2017151).The study was conducted in 2017 and 2018 with a sample of one control class (26 students) and 2 intervention classes (57 students) in schools located in the Sydney inner city area. To avoid information contamination, the study groups were conducted in two different schools and years. Written consent was obtained from the principals, class teachers, parents and students. All participants were consenting students attending a Year 5/6 class and were able to withdraw from the study at any time. The 2017 and 2018 studies were conducted over the same month (November) of each year and the data were combined for analysis. The program was delivered over 5 consecutive weeks. The research team attended the school to supervise the delivery of the program in the morning, usually between 9AM and 11AM. The control class received no program over the 5 weeks.The participants’ MVPA was objectively measured prior the program and after completion of the last iEngage module using a research grade accelerometer validated in young adolescents (GENEActiv) . The GEN© activity tracker continuously for the 5-week duration of the program on the non-dominant wrist. Misfit Ray© is a commercial tracker well tolerated by children and adolescents. Daily step counts were provided to the participant via the iEngage app during each module. In addition, raw data, averaged over 1 min periods were downloaded at the end of the program to allow analysis of daily steps consistency rate as previously described [For the iEngage classes participants wore a Misfit Rayescribed . Goals, Data analysis are presented for twenty-six control participants and fifty-seven iEngage participants. Seventy-one participants were included in the iEngage group. Fourteen were excluded from the analysis because they missed at least 3 modules due to absences, injury, or attendance to special study programs. No student dropped-out or asked to stop the program. Anthropometric, fitness and PA data from the activity tracker (daily steps collected at each module for 5 weeks) as well as GENEActiv data (collected and averaged over 3 school days before and after the iEngage program) are presented as mean +/- standard deviation (SD). Goals and achievements are presented as a percentage of students choosing or achieving a particular goal or PA level. To assess goal achievement for the whole cohort, data was aggregated over the 3 days preceding each module .There was no statistical difference between control and experimental groups at baseline for anthropometric data, physical activity or physical fitness . Most paP < .001, On average, participants progressively and significantly increased their daily steps goals from 6,153 ± 774 steps/day in M2 to 9,153 ± 1317 in M6 and finally 10,461 ± 760 in M10  = 91.1, P = 0.045, While participants could select 12,000 steps/day from module 8, 17% of participants set this goal in M8 compared to 27% in M10, with a marked difference between girls (7%) and boys (48%) . Across Within each module, students entered the daily steps recorded by the activity tracker for each of the previous three days. Results showed that students met or surpassed goals in the 3 days preceding modules M2, M3, M4, M6, M9 and M10 while they missed out on achieving goals in M5 and M8 . The proWe assessed participants’ satisfaction with the program with a simple question at the end of each module ("did you have fun in completing the module") using a Likert scale (1 to 5). The average score for the whole program was 4.3 ± 0.99.© activity trackers during the program showed that both female and male participants increased their daily steps over time (P < .001). Comparing the first 4 with the last 4 days of program showed that daily steps increased by 2,647 steps/d . Boys tended to increase MVPA more than girls  and after school, about one hour after school until 7PM . After sThis study is the first to report on the implementation and outcomes of a fully integrated mobile health program in primary school context, using both participant’s self-reported data and continuous monitoring of PA during the program. It shows that a digital health education and behaviour change program integrating activity tracker successfully guided adolescents to effectively progress PA goals and achievements. Data indicate that the program led adolescents to increase PA and MVPA in daily life through short bouts of activity during recess, lunch and after school. We show that the iEngage app can be used as a research platform to study how adolescents engage and respond to health education or behaviour change interventions.iEngage was based on BCTs, the Australian physical literacy framework and WHO recommendations for adolescents , 18, 29.Recent systematic reviews and meta-analysis found interventions using diverse degree of mobile health technologies targeting the promotion of healthy behaviours in schools, however none used mobile health , 32. NonMVPA can only be assessed through research grade accelerometers which do not provide information to the user on their PA. This was done before and after the program in the iEngage group and before and after a 5-week period in the control group over the same weeks of the school term. At baseline, daily MVPA in all participants was on average ~50 min /day with higher MVPA engagement in boys (~63 min) compared to girls (~43 min), and only 32% of the cohort achieving 60-min/day MVPA on average . Our datWhen analysing PA post- versus pre-intervention, previous systematic reviews and meta-analysis found no or little effect of school-based interventions, with no significant differences between those using or not web-based technology , 31. OurOne study  found thAdolescent boys and girls differed from each other with regards to both PA levels and the way they responded to the program. While all students developed competences in setting goals, girls tended to be less ambitious with setting daily step goals during the whole program, progressing goals slightly slower than boys. This indicates that, although they were exposed to the same program, the pace at which girls were willing to progress was slower than for the boys. This attitude toward goals setting cannot be explained by physical capacity since girls in the program had similar or slightly better performance across all baseline fitness tests. However, we cannot exclude the impact of perceived fitness or social norms on goal setting . While gWhile both girls and boys increased daily PA, boys were more successful than girls in increasing MVPA following iEngage. The greater enhancement of PA in boys compared to girls aligns with previous studies on school-based PA interventions including either single (PA) or combined (PA and nutrition) components  and with© activity tracker and to synchronise weekly with the app once the program is completed could encourage sustaining the behaviour over longer periods.One limitation of this study is the relatively small cohort however our results were consistent across the two schools. In each school, all year 5 and 6 students were included indicating that a whole class can participate in the program. iEngage is a short program with 10 modules delivered over 5 weeks. While this allows for strong focus and facilitates sustained motivation, a slower pace may be envisaged to enable progression and maintenance at slower rates, which may be more suitable for female adolescents. This study specifically focused on PA changes during the program and immediately after, however allowing the adolescents to keep the Misfit RayDelivered through a tailored digital environment, iEngage combines health education, experiential learning, interaction with peers and behavioural change theory. It enables individual goal setting, self-monitoring and self-assessment. In addition, iEngage provides researchers with a powerful tool to study how adolescents respond to information, activities and goals setting through continuous recording embedded in the app. In the future, iEngage could be considered to help adolescents maintain or increase PA in situations such as pandemic-induced lockdown and remote school activities but also in paediatric populations in which PA behaviour is important.


It is often challenging to determine which variables need to be included in the g-computation algorithm under the time-varying setting. Conditioning on instrumental variables (IVs) is known to introduce greater bias when there is unmeasured confounding in the point-treatment settings, and this is also true for near-IVs which are weakly associated with the outcome not through the treatment. However, it is unknown whether adjusting for (near-)IVs amplifies bias in the g-computation algorithm estimators for time-varying treatments compared to the estimators ignoring such variables. We thus aimed to compare the magnitude of bias by adjusting for (near-)IVs across their different relationships with treatments in the time-varying settings.After showing a case study of the association between the receipt of industry payments and physicians’ opioid prescribing rate in the US, we demonstrated Monte Carlo simulation to investigate the extent to which the bias due to unmeasured confounders is amplified by adjusting for (near-)IV across several g-computation algorithms.In our simulation study, adjusting for a perfect IV of time-varying treatments in the g-computation algorithm increased bias due to unmeasured confounding, particularly when the IV had a strong relationship with the treatment. We also found the increase in bias even adjusting for near-IV when such variable had a very weak association with unmeasured confounders between the treatment and the outcome compared to its association with the time-varying treatments. Instead, this bias amplifying feature was not observed  by adjusting for near-IV when it had a stronger association with the unmeasured confounders .It would be recommended to avoid adjusting for perfect IV in the g-computation algorithm to obtain a less biased estimate of the time-varying treatment effect. On the other hand, it may be recommended to include near-IV in the algorithm unless their association with unmeasured confounders is very weak. These findings would help researchers to consider the magnitude of bias when adjusting for (near-)IVs and select variables in the g-computation algorithm for the time-varying setting when they are aware of the presence of unmeasured confounding.The online version contains supplementary material available at 10.1186/s12874-022-01563-3. In most epidemiologic studies, there is a dilemma between including only true confounders or all possible confounders. It is often believed that including as many covariates as possible would reduce the bias due to unmeasured confounding between the treatment and outcome. However, as suggested in prior literature, this is not always true, and conditioning on variables that are associated with the outcome only through the treatment, called instrumental variables (IVs), can increase the bias of treatment effect estimates in the point-treatment settings under the presence of unmeasured confounding –5. This G-computation, which is the computational algorithm of g-formula, is one of the methods to estimate the causal effect of time-varying treatments accounting for time-varying confounders that are affected by the treatment –9. In prThe goal of our study is to compare the magnitude of bias due to the adjustment of IV or near-IV across different relationships between (near-)IV and treatments in the time-varying settings. After describing a case study of industry marketing payments and prescriptions of opioid products, we conducted Monte Carlo simulation studies to investigate the extent to which the bias due to unmeasured confounders is amplified by adjusting for IV or near-IV . Our study will guide readers to consider the possible magnitude of bias due to adjustment for potential IVs, and thus help them to select covariates in their g-computation algorithms under the time-varying setting in future epidemiological research.Physician Payment Sunshine Act which requires the pharmaceutical industry to publicly report data on all payments and ownership interests made to licensed physicians and teaching hospitals in 2013  – E , 4.3 for E  – E , and − 4.0 for E  – E . The biases generally increased  when additionally adjusting for IV 3B) in the g-computation algorithm when X3B had a very weak association with unmeasured confounder X1 (β1 = 0.01 or 0.05) compared with its association with T1 and T2 (OR = 10) , we rather found the bias reduction by adjusting for X3B (as a proxy of an unmeasured confounder X1). This trend was observed in all estimates; E  – E , E  – E , and E  – E .In scenario B, we found the bias amplification for all estimates by adjusting for near-IV XB in the 1 for E  – E , T2 for E  – E , and both T1 and T2 for E  – E ). Of note, we found the increase in bias even adjusting for near-IV when such variable had a very weak association with unmeasured confounders between the treatment and the outcome. Instead, the bias decreased after adjusting for near-IV when it had a stronger association with the unmeasured confounders . Our findings were not stable with a small sample size (N = 500), indicating the importance of additional consideration for small sample bias.Our simulation study showed that adjusting for IV of time-varying treatments in the g-computation algorithm increased bias due to unmeasured confounding, particularly when the IV has a strong relationship with the treatment of interest  and a very weak association with the outcome . This net bias reduction is expected to be larger when the relationship between the near-IV and the unmeasured confounders gets stronger. Conducting analysis both with and without adjusting for the variable would also be an option to transparently convey the results , 28. BecIn our case study, consistent with prior findings –21, we fnon-opioids) than Model 2 (model with adjustment for the receipt of industry payments for non-opioids). If we assume there is no relationship between unmeasured confounders  and the receipt of industry payments for non-opioids, Model 1 would be preferred to Model 2. However, given that the association between the receipt of industry payments for non-opioids and the above-mentioned unmeasured confounders may not be very weak in reality, we assume that the estimated effects in Model 2 would be less biased estimates than those in Model 1 based on our simulation study.We also found that the estimated effects were generally larger in Model 1 IVs and select variables in the g-computation algorithm for the time-varying setting when they are aware of the presence of unmeasured confounding.Additional file 1.


AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in  AT-rich interaction domain 1A (ARID1A), a component of the chromatin remodeling SWI/SNF complex, affect DNA damage repair in tumor cells. First, we briefly review the diverse key cellular functions of ARID1A. Next, we highlight the therapeutic potential by targeting the ARID1A synthetic lethal phenotype with inhibitors of PARP, ATR, or other agents in ARID1A-mutated tumors. We will also provide our insights into the promises and challenges in developing therapeutic strategies to treat cancers with ARID1A mutations.Targeting the DNA damage response (DDR) for cancer therapy has gained significant attention in recent years. This promise reflects the fact that many malignant neoplasms are defective in their DNA damage repair machineries, most commonly a result of molecular genetic alterations, either somatic or inherited, in genes critically involved in various repair pathways. The recent success of PARP inhibitors in treating homologous recombination-deficient ovarian high-grade serous carcinomas champions such endeavors and encourages basic scientists and oncologists to explore novel anti-cancer strategies on a basis of synthetic lethality , 2. Thossaccharomyces cerevisiae in 1984 [The SWItch/Sucrose Non-fermentable (SWI/SNF) was originally identified in  in 1984 . The hum in 1984 . These s in 1984  AT-rich interaction domain 1A (ARID1A) is one of the chromatin remodeling proteins belonging to the SWI/SNF complex. The cBAF complex contains several subunits within which ARID1A and ARID1B are mutually exclusive  [Arid1a transcripts and protein levels are highly increased during all stages of mouse embryonic development and its ablation leads to the loss of pluripotency, self-renewal of mouse embryonic stem (ES) cells, and severe developmental arrest [In humans, germline #614607) . In rodel arrest .ARID1A as a tumor suppressor gene was made more than a decade ago by two sequencing-based studies. Both studies analyzed whole exomes and global mRNAs in rare subtypes of epithelial ovarian cancer, clear cell carcinoma, and endometrioid carcinoma and identified a high frequency of  inactivating mutations occurring diffusely in ARID1A with resultant loss of protein expression, a characteristic of a tumor suppressor. The mutations lead to truncated proteins that are rapidly degraded, and thus, ARID1A is functionally inactivated. Subsequently, inactivating ARID1A mutations have been detected in a wide variety of human cancers, highlighting the epigenomic roles of ARID1A in cancer development [The discovery of elopment , 19.ARID1A promoter hypermethylation [Loss of ARID1A expression can also be a result of hylation , and it hylation . Occasiohylation .ARID1A. Some of the cancer types showing the highest incidence of ARID1A inactivating mutations and loss of expression are clear cell ovarian cancer (~ 50%), endometrial cancers (~ 37%), gastric cancers (20–30%), bladder cancers (~ 20%), hepatocellular cancers (~ 14%), melanomas (~ 12%), colon cancers (~ 9%), and lung cancers (~ 8%) [ARID1A mutations have also been studied for their potential role as biomarkers for predicting clinical outcomes in cancer patients [Approximately ~ 6% of human cancers harbor inactivating mutations in s (~ 8%) –23. ARIDpatients .In vitro cell models and genetically engineered mouse models have provided cogent evidence to support the functional role of ARID1A in tumor suppression , 25–29. PIK3IP1 [SLC7A11 [CDKN1A, TGF-β receptor [SMAD3 [ARID1A-mediated transcriptional regulation is mainly attributed to its chromatin accessibility role. ARID1A can increase or decrease chromosome accessibility histone marks at the promoter regions of genes and regulate their expression. ARID1A-mediated chromatin remodeling regulates transcription positively as well as negatively . GeneralPIK3IP1 , SLC7A11[SLC7A11 , CDKN1A,receptor , and SMAr [SMAD3  among seHDAC6, AURKA, and TERT [On the other hand, ARID1A depletion promotes expression of the deubiquitinating enzyme USP9X. Mechanistically, ARID1A recruits HDAC1 to the promoter of USP9X where it downregulates its expression by removing the acetyl group from histone. Conversely, depletion of ARID1A causes an increase in the acetylation level H3K9 and H3K27 at the USP9X promoter, thereby increasing its expression . Similarand TERT  associatand TERT .ARID1A is inactivated. DNA damage and replication stress initiate DDR through activities of two signaling proteins that detect these aberrant events: ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-Related). ATM is generally activated by a double-strand DNA break (DSB) whereas ATR is activated by a single-stand break (SSB), DNA replication stress [In recent years, the emerging roles of ARID1A in the DNA damage response (DDR) have been established Fig. . These nn stress , and DNAn stress . DNA DSBARID1A-containing SWI/SNF complexes also allow DNA repair proteins to effectively access DNA damage sites . InactivARID1A is also involved in repairing damaged DNA through homologous recombination (HR) repair. Mechanistically, ARID1A is recruited to DNA DSB sites through interacting with the upstream kinase, ATR. ARID1A also helps recruit the ATPase subunit of the SWI/SNF complex to DNA damage sites. Loss of ARID1A also impairs the G2/M DNA damage checkpoint. Overall, ARID1A facilitates DSB end resection and also helps maintain checkpoint signaling . Thus, AMSH2, MSH6, MLH1, and PMS2 or their combination in the mismatch repair (MMR) pathway contributes to DNA MMR deficiency, especially in endometrial and colorectal carcinomas. When the MMR pathway is defective, tumors show a high microsatellite instability (MSI-H) phenotype, producing up to thousands of somatic mutations in the genome, including many that encode neo-antigens which potentially trigger immune responses. ARID1A mutations have been found enriched in MSI-H neoplasms including endometrial carcinomas [ARID1A mutations are simply the result of the unstable hyper-mutated phenotype. There is some evidence supporting the former. In endometrial and colorectal cancer, ARID1A loss is associated with MLH1 silencing resulting from promoter hypermethylation [Alterations that lead to loss of expression of any genes such as rcinomas –49, ovarrcinomas , gastricrcinomas , 52, colrcinomas , 54, andrcinomas . It remahylation . As wellhylation . These fCD274, which encodes PD-L1, is transcriptionally repressed by ARID1A [Many ARID1A-mutated endometrial and colorectal carcinomas harbor the MSI-H phenotype. This finding is of significant clinical interest as the MSI-H phenotype provides a biomarker relevant to immunotherapy based on anti-PD1/PD-L1 drugs . ARID1A y ARID1A . As a rey ARID1A  via actiy ARID1A , 60. TheReplication stress characterizes cancer and is associated with incessant and uncontrolled cell replication . ReplicaR-loops are three-stranded hybrid nucleic acid structures formed during a normal transcription process Fig. . PhysiolAnother source of replication stress is DNA catenation, an intermediate product of DNA replication. It is formed when two replication forks collide and DNA topoisomerase II removes these structures (known as decatenation) . MechaniApurinic/apyrimidinic sites (AP sites), also known as abasic sites, are DNA repair intermediates that act as roadblocks to replication fork progression . These lBRCA1/2 mutated ovarian cancer [Synthetic lethality is a phenomenon where the simultaneous loss of function of both genes causes cell death, whereas the inactivation of any one of two genes independently has no impact on cell survival. The idea of synthetic lethality in cancer has been expanded to include pairs of genes, where the inactivation of one gene through deletion or mutation and the pharmaceutical inhibition of the other results in the death of cancer cells, whereas normal cells are spared they do not have the fixed genetic alteration . Since iIt has become clear that loss of ARID1A impairs genome stability after DNA damage. Since genomic stability is essential for normal cells to survive, several repair pathways have evolved to protect the genome. It is not surprising that upon ARID1A loss, other pathways will compensate for its loss of function. Thus, targeting those complementary pathways holds promise in developing new cancer therapies in ARID1A deficient neoplasms. The role of ATR, PARP1, and TOP2A in maintaining genome integrity is pivotal as discussed in the previous section. To reiterate, after ARID1A loss, ATR signaling is activated as a result of replication stress due to transcription-replication conflicts, aberrant R-loop formation, defective decatenation process, and DNA damage. Thus, inhibition of ATR can theoretically eliminate ARID1A-deficient cancer cells. In fact, ATR inhibitors have been reported to act in a synthetic lethal way in ARID1A-deficient cancer . ATR inhIn addition to ATR inhibition , TOP2A aIn addition to PARP and ATR, there are several existing (reviewed in: –88) and ARID1A knockout cells exhibit altered mitochondrial biogenesis showing a higher number of globular mitochondria, increased oxidative phosphorylation, and increased oxygen consumption without increased ATP production. Interestingly, PLK1 is localized at mitochondria, and this may explain why PLK1 inhibition is associated with exaggerated mitochondrial oxygen consumption and membrane depolarization, leading to apoptosis. To further explore the therapeutic potential of targeting PLK1 in the context of ARID1A deficiency, PLK1 inhibition may be combined with chemotherapeutic agents and PARP inhibitor. To this end, PLK1 is reported to increase the temozolomide sensitivity in glioma stem cells [Polo-like kinase 1 (PLK1) belongs to the serine-threonine kinase family. PLK1 plays a critical role in advancement of the cell cycle to mitosis by promoting mitotic spindle assembly, cell division, DNA-damage response, and maintenance of genomic stability. Overexpression of PLK1 has been reported to enhance proliferation rate and enhance tumorigenicity. Conversely, its inhibition causes reduction of proliferation and apoptosis in cancer cells but not in normal cells, suggestive of a potential role as a cancer therapeutic agent . Howeverem cells . Recentlem cells .USP9X (ubiquitin-specific peptidase 9 X-linked) is a deubiquitinase which regulates the protein levels of its substrates through proteasomal degradation. USP9X is involved in cancer initiation and development , 94, andRecently, the role of USP9X in ARID1A-deficient hepatocellular carcinoma was reported to involve a synthetic lethal interaction between ARID1A deficiency and inactivation of adenosine 5′-monophosphate-activated protein kinase (AMPK) . Thus, aARID1A, a tumor suppressor gene, has been shown to have significant prognostic value in several malignancies, gastric cancer [PIK3CA, TP53, EZH2, KRAS as in ARID1A-deficient gynecological cancers that impact the prognosis in these cancers. Moreover, it is rare for a single gene to serve as a significant prognostic marker. Instead, a group of markers may serve better for this purpose. For instance, ARID1A, p53, and β-Catenin in combination may have a better prognostic potential in ovarian clear cell and endometroid subtypes [Synthetic lethality-based targeting vulnerabilities of ARID1A deficiency exploits the high mutational burden in many malignancies. Thus, ARID1A deficiency has the potential as a biomarker for precision medicine in various cancers. Loss of c cancer –105, lunc cancer , hepatocc cancer –109, brec cancer , osteosac cancer , clear cc cancer , 113, anc cancer . ARID1A c cancer ). In gync cancer , 117, enc cancer . Conversc cancer –123. Thesubtypes .ARID1A has emerged as one of the major tumor suppressor genes in many types of human cancer, especially those arising from the endometrial epithelium. Somatic mutations of ARID1A have been shown to alter the chromatin landscape and to affect several fundamental cellular functions including transcription, DNA hypermethylation, DNA synthesis, and DNA damage response. In recent years, ARID1A mutation has been explored for synthetic lethal targeting, and certain epigenetic drugs and inhibitors in the DNA damage repair have shown promise for treating ARID1A-mutated tumors. Immune checkpoint blocking is also currently being evaluated for efficacy in controlling ARID1A-mutated cancers. Despite the promise, several challenges need to be overcome before ARID1A-based precision oncology becomes a reality.Foremost, the functional difference between the SWI/SNF complex in the presence and absence of ARID1A remains to be fully determined. Because of the mutually exclusive nature of subunits ARID1A and ARID1B, when ARID1A is missing, ARID1B can substitute for ARID1A in SWI/SNF complexes in maintaining DNA accessibility to various nuclear proteins. The knowledge whether ARID1A-containing complex and ARID1B-containing complex show different specificity to bind to DNA loci or the subunit alter the chromatin remodeling activity is important to understand the pathogenesis in tumor cells losing ARID1A, and help discover the synthetic lethal strategies.ARID1A mutation or loss of expression can be an ideal tissue biomarker, but clinical validation is required to affirm this conclusion. It is uncertain if monoallelic inactivation  share some phenotypes as bi-allelic inactivation. Other biomarkers involved in various DNA damage repair pathways can also be explored for outcome correlations in ongoing and future clinical trials.Second, identification and validation of biomarkers to predict treatment outcomes using synthetic lethal drugs like EZH2 inhibitor and PARP inhibitor is important for development of effective targeted therapies. Intuitively, ARID1A-mutated malignancies.Third, despite the well-described clinical benefits of targeted cancer therapy, drug resistance to monotherapy is inevitable due to the expansion of tumor clones that are refractory to the targeted therapeutic agent under an ever-changing tumor microenvironment. Combinational therapy provides a possible solution for this significant clinical problem but increased adverse effects can become more apparent. A better dosing and scheduling strategy in a well-defined clinical setting is warranted to deliver effective therapy to


Research has identified the benefits and challenges of creating multigenerational classrooms for the purpose of intergenerational learning in higher education. However, much less is known about the systems of support needed at the organizational level to promote intergenerational learning within lifelong learning initiatives. With a focus on formal and informal organizational structures, this session describes insights from faculty who opened their courses to older adults as part of a college-wide course auditing initiative. Many did not understand their own role in the program and offered suggestions to address these issues. Recommendations include ways to acknowledge the work of faculty who participate in the program, and to engage more professors and older adults in the community to ensure program success. To create an age-inclusive, and age-friendly university, formal structural change led from the top-down is as important, if not more important, as creating informal networks that start at the faculty level.


Communities of Practice are formed by people who interact regularly to engage in collective learning in a shared domain of human endeavor. Virtual Communities of Practice (VCoP) are online communities that use the internet to connect people who share a common concern or passion. VCoPs provide a platform to share and enhance knowledge. The Policy Circle is a VCoP that connects mid-career professionals from across Canada who are committed to improving healthcare policy and practice. We wanted to understand the perceived value of the VCoP.We used qualitative and quantitative survey research to explore past and current Policy Circle members’ thoughts, feelings, and behaviours related to the program. Our research was guided by the Value Creation Framework proposed by Wenger and colleagues. Three surveys were created in collaboration with stakeholders. Data were analyzed within cohort and in aggregate across cohorts. Qualitative data was analyzed thematically, and quantitative data was analyzed using descriptive statistics .Survey participation was high among members . Participants came from a variety of disciplines including medicine, health policy, allied health, and nursing, with most members having a direct role in health services research or practice. The program was successful in helping participants make connections ; variances in both qualitative and quantitative data indicated that levels of enthusiasm within the program varied among individuals. Members appreciated the access to resources; quarterly meetings (n = 11/11), and a curated reading list (n = 8/11) were the most valued resources. Participants reported the development of a sense of belonging (mean = 2.29) and facilitated knowledge exchange (mean = 2.43). At the time of this study, participants felt the program had minor impact on their work (mean = 3.5), however a majority of participants (50%) from Cohort 2 planned to acknowledge the program in their professional or academic endeavours. Through reflective responses, participants expressed a desire for continued and deeper professional network development.The Policy Circle was successful in facilitating knowledge exchange by creating a community that promoted trust, a sense of belonging and a supportive environment. Members were satisfied with the program; to promote further value, the Policy Circle should implement strategies that will continue member participation and networking after the program is finished.The online version contains supplementary material available at 10.1186/s12961-022-00897-0. Virtual Communities of practice (VCoPs) are an increasingly common way to connect individuals with a common interest to share knowledge and network; insufficient evidence exists to support the development and maintenance of VCoPs.We introduce facilitators and barriers to successful virtual collaboration between healthcare professionals that can be adopted to increase efficacy of communication for healthcare professionals and the success of VCoPs.We offer insight into what mechanisms support the success of a VCoP. Our recommendations will help with the development and support of effective communication online for healthcare professionals. Our findings support an increased understanding and implementation of best practices, current research, and better patient care.We identify key indicators for the evaluation of VCoPs that can support future evaluations and cross-program comparisons.Building a Virtual community of practice: Experience from the Canadian Foundation for Healthcare Improvement’s Policy Circle.The concept of Communities of Practice (CoP) was first popularized in the 1990s by Etienne Wenger . CoPs arVirtual Communities of Practice (VCoP) are online communities that use the internet to connect people that share a concern or passion and provide a platform where they can share and enhance their knowledge . VCoPs gDespite the benefits of VCoPs there are some limitations that need to be considered including members fading back or withdrawing from the community . This caInspireNet in British Columbia reported that nurses and allied health professionals who rated themselves as computer literate still required mentoring and support to adapt to a virtual environment [Trust and justice have been found to be an important foundation for the success of a VCoP –12. Trusironment .Leadership plays an important role in ensuring that CoPs and VCoPs develop and achieve a clear vison. VCoP leaders ultimately influence the structure and help shape a common vision , 17. ThiTwo commonly cited models to support the development or maintenance of VCoPs in the healthcare sector are the Integrated VCoPs Success Model  and the VCoPs are very similar to online learning environments. In his work on web-based learning environments, Renaud  discusseEvaluations of VCoPs should be done using a range of indicators and a combination of qualitative and quantitative methods . FramewoThe Value Creation Framework developed by Wenger et al.  is an evThe main objective of most VCoPs is to facilitate knowledge sharing between members. However, achieving a continuous exchange of knowledge is a challenge of VCoPs in health . In thisWe set out to evaluate a VCoP and to explore the facilitators and barriers to its success. The Policy Circle, a part of the former Canadian Foundation for Healthcare Improvement (CFHI), now Healthcare Excellence Canada (HEC), connects mid-career professionals from across Canada who are committed to improving healthcare policy and practice . The cenAs the program concluded its second year in 2021, we wanted to explore what, if any, value the CFHI Policy Circle created as a social learning activity. Our main objective in reviewing the Policy Circle were to identifying barriers and facilitators, to determine the level of the program’s impact over the past two years, and to improve the program for future cohorts. In order to achieve our objectives, we sought to determine whether each of the values introduced by Wenger and colleagues  were creWe used a mix of qualitative and quantitative survey research, guided by the Value Creation Framework , to explThe first cohort of the CFHI Policy Circle (PC-C1) ran its inaugural year with six participants from April 2019 to March 2020. This cohort was surveyed retrospectively in February 2021. The second cohort (PC-C2) (April 2020–March 2021) had 11 members that were asked to complete a similar survey at two time points: mid-way and at program completion. For both cohorts, Policy Circle members applied to the program through an online application. Each application was reviewed by a pair of reviewers drawn randomly from a pool of four internal reviewers and two external reviewers. Based on reviewer results and recommendations, CFHI’s CEO made the final selection of Policy Circle members. Participants came from a variety of disciplines including medicine, health policy, allied health, and nursing. Participants' primary work was varied, with most members having a direct role in health services practice or research. Demographics for Policy Circle members from both cohorts are presented in Survey development was collaborative, and based on the Value Creation Framework ; questioIn addition, the PC-C2 survey included aggregate and ranking responses based on the midpoint evaluation findings. This allowed us to explore shared goals as well shifting perspectives over time  for PC-C2 was sent out in November 2020 and the exit survey (PC-C2-E) was sent to members after the last quarterly meeting (March 2021), each with a reminder email sent out after two weeks.Data was analysed in within cohort and in aggregate across cohorts using indicators that represented each of the values presented by Wenger and colleagues . QualitaFour out of six members from Cohort 1 responded to the retrospective survey (67% response rate). From Cohort 2, nine out of 11 members provided responses for the midpoint survey (81.8% response rate) and seven responded to the exit survey (63.6% response rate).n = 8/11) attended three or more times (PC-C1: 2/4 (50%), PC-C2-E: 6/7 (86%)) and the remainder attended one to two times . Six members (55%) participated in the mentorship meetings (PC-C1: 2/4 (50%), PC-C2-E: 4/7 (57%)). Making new connections was a key goal of the program with a mean score of 2.43 (SD = 1.5) (PC-C2).Looking at both cohorts, all members indicated that they had attended quarterly meetings; 73% of all respondents , with two out of seven members answering 1 . In personal reflections from both cohorts, member statements included, “my expectations were fairly high entering the program; I believe those expectations were met.” One individual said it declined, while another reported an increase stating, “the groups enthusiasm was contagious.”In comparing the number of individuals from Cohort 2 who took advantage of the program’s opportunities at midpoint versus at exit, there was no change aside from an increase for IHI open school (Table n = 6/9) participated in the journal club and 33% (n = 3/9) volunteered to participate in an additional opportunity offered by the CFHI. On exit, all seven respondents participated in the journal club and four participated in an additional opportunity. Only two members from either cohort (one from each cohort) attended a conference.The Policy Circle program gave members access to numerous opportunities and resources Tables , 2. FollWhen measuring potential value we asked members in PC-C2-E if the program was successful in facilitating increased knowledge and skills, on a scale from 1  to 5 . All members either answered 1, 2 or 3 with a mean score of 2.43 (SD = 0.73). Further, “ability to advance knowledge” was reported as the third most important strength of the program.I liked being connected to like-minded professionals in a similar stage of career outside my institution”, “those connections and conversations at meetings were professionally and personally rewarding” and “the policy circle members were great in providing advice.” We asked participants in PC-C2-E to rate whether the program helped them achieve a sense of belonging along the same scale. The mean rating was 2.29 (SD = 1.03). Some members also added descriptively, “I felt this group provided a safe space to share ‘work challenges’” and that the Policy Circle program “created a sense of community when we were all relatively isolated” .All members answered either in the affirmative or neutral when asked if they are proud to tell others they are a Policy Circle member (100% of PC-C2 answered yes and 50% from PC-C1 answered yes) . Members also expressed trust in their colleagues' abilities, stating, “new group of researchers” and helping form “a more national network of people to assist with my work.” Five respondents described some barriers to realizing an impact including, “no opportunities have arisen”, “I haven’t been able to connect with my assigned mentor”, and that many external colleagues are unaware of the program which “made it hard to share.”We asked PC-C1 and PC-C2-E if their work was positively impacted by their participation in the Policy Circle , nearly half said at least somewhat with the mean response of 3.5 (SD = 1.35) and one of 11 members (9%) answered “yes, significantly.” In open ended responses participants described ways in which work was impacted including connecting with a “n = 2) of respondents from PC-C1 said they acknowledge their Policy Circle experience in their current work through informal means such as including it in their LinkedIn profile. Nearly all respondents to PC-C2-E  planned to acknowledge the program in their current or future work by listing it on their CV, promoting and referring the program to others, and continuing to connect with the CFHI (now HEC).Half , networking was rated as the most important strength by members, followed by the program coordinator for the Policy Circle , ability to advance knowledge  and mentorship .PC-C2-M asked members openly what could be done to improve the program. For PC-C2-E, we summarized answers and had members rank them from most to least important . Adding face-to-face meetings was most commonly ranked first  and inviting a guest speaker that members would not get regular access to was rated most important . Secondly, having a formal contribution to policy that members can work on together throughout the year, with a mean of 3.14 (SD = 1.73), followed by extra optional meetings that focus on a specific topic . Other improvement suggestions in order of ranking are having a collective goal from the start , more structure and linkages to different Canadian sector leaders in order to facilitate cross context engagement , and providing more information on how to access opportunities .We asked members for ideas on continuing support as a Policy Circle alumni. Participants most commonly cited having opportunities to continue to engage with the CFHI (now HEC) and current, past, and future Policy Circle members to facilitate networking and collaboration. Members suggested annual meetings or get togethers that include an overlap between cohorts. Other suggestions included setting clear objectives for the gathering at future meetings and having continued access to resources like the IHI open school.Microsoft Teams). According to McLoughlin et al. [Participation in the activities of the program  were high. This finding can possibly be attributed to the use of familiar and reliable technology by the Policy Circle  can also be attributed to the successful networking that occurred within the program. According to literature, networking has been found to be motivator for participation in knowledge sharing as it can lead to career advancement and enhancement of professional reputation –36. Overn = 7, 100%) by the time they exited the program indicated participants wanted more frequent meetings outside of current quarterly meetings.Members took advantage of the opportunities offered by the Policy Circle program, suggesting that some level of information and skills were acquired by members. A high percentage of Cohort 2 participants attending journal club , we believe this is limitation was mitigated. Due to the small sample size, we did not consider the role of the participant’s demographics in their responses. This may be considered a limitation as age or gender may impact how the participant responded, however the small sample size did not allow for any statistically significant analyses based on disaggregated demographic data. In addition, since the Policy Circle application process does not consider age or gender, this analysis would not significantly affect the results in terms of quality improvement. The time frame of this study occurred during the COVID-19 pandemic, however since Cohort 1 ran before the pandemic the impact of the pandemic was not considered in all aspects of our analysis. Finally, while we cannot state the direction of the relationship between facilitating variables and success, we can state that a relationship exists, and it should be considered in VCoP success.Our evaluation of the Policy Circle determined that the program was successful in facilitating knowledge exchange and network development among its members. This is partially due to the presence of trust, a sense of belonging, and a supportive environment within the program. Participants felt that there was the possibility to create deeper connections with other members and the organization during and after the program. As the Policy Circle continues to mature, stakeholders should implement strategies that facilitate VCoP impact on the practice. Strategies to keep members involved beyond the one year should also be considered; especially initiatives that foster leadership by current members. We recommend that the program facilitates cross-cohort collaboration with past and future participants, as well as health policy leaders. Our recommendations our consistent with Li et al.’s suggestion to focus on specific characteristics, such as support for member interaction, knowledge sharing and building a sense of a belonging, that facilitate interventions that support relationship building to optimize the function of these groups .Our findings demonstrate the value of the different components of the Policy Circle program, and describe factors that have contributed to its success. The CFHI (now HEC) can use these findings in the development of future Policy Circle programs to help achieve HEC’s goals of fostering the growth of future healthcare leaders and a greater impact on improvements in healthcare. Further, during the creation of similar programs, our recommendations can help stakeholders identify which factors should be implemented and what possible barriers there may be. We provide a real-life example that supports the current literature on VCoPs and adds to existing evidence of evaluations of VCoPs. We identify appropriate indicators based on a recognized framework that measure the value produced; these indicators can support future evaluations as well as cross program comparisons. This study highlights the current limitations known about VCoPs as well; moving forward future research on the appropriate duration of VCoP Cohorts and the impact of member demographics  on a VCoP should be conducted to ensure that optimal outcomes are being achieved. As well, research on methods of communication and the difference in achieving successful outcomes between virtual and in person communities should be conducted.Additional file 1. Data reports.Additional file 2. Reporting standards checklist.


E) was computed. Stiffness was associated with the initial slope of enhancement on DCE-MRE , reflecting active disease, but lacked association with CEUS parameters. For structural imaging parameters, inflammation and stricture stiffness were associated with prestenotic dilatation on US  but not with MRE . Strictures identified by US were stiffer, 16.8 (14.0–20.1) kPa, than those graded as no or uncertain strictures, 12.6 (10.5–15.1) kPa, p = 0.02. MRE global score (activity) was associated with E . Elastography did not correlate with circumferential stiffness. We conclude that increasing activity defined by the initial slope of enhancement on DCE-MRE and MRE global score were associated with stricture stiffness. Prestenotic dilatation on US could be a potential biomarker of CD small intestinal stricture stiffness.Strictures and abdominal pain often complicate Crohn’s disease (CD). The primary aim was to explore whether parameters obtained by preoperative contrast-enhanced (CE) ultrasonography (US) and dynamic CE MR Enterography (DCE-MRE) of strictures associates with biomechanical properties. CD patients undergoing elective small intestinal surgery were preoperatively examined with DCE-MRE and CEUS. The excised intestine was distended utilizing a pressure bag. Luminal and outer bowel wall cross-sectional areas were measured with US. The circumferential stricture stiffness (Young’s modulus  The natural course of Crohn’s Disease (CD) usually evolves from active inflammation to stricturing and penetrating disease ,2. ActivStrictures are defined from cross-sectional imaging and endoscopy as localized, persistent lumen narrowing with or without prestenotic dilatation ,10,11. SConventional imaging inadequately separates strictures with active inflammation, mixed inflammation with fibrosis, and fibrosis without significant inflammation ,17,24. MMechanical properties of the gastrointestinal tract are essential for both normal and abnormal organ function, and well-established accurate and reproducible methods for assessment in vitro exist ,13,14,15The present study aimed to explore which parameters obtained by preoperatively CEUS and DCE-MRE of small bowel CD are associated with the biomechanical properties of the strictures. Our primary hypothesis was that strictures with low perfusion on CEUS and DCE-MRE are stiffer than those with high perfusion, as the former would be fibrotic and the latter inflammatory ,26.The present study was a GCP-monitored blinded prospective observational study. Patients were 18 years or older and had small intestinal inflammation or stricture on US, as described in a previous publication . A flowc®; Bracco Imaging, Milan, Italy). Time-intensity curves were analyzed in VueBox® 5.1 . The mean values of three ROIs from each of the two injections were used to compare biomechanical parameters since this has been shown to achieve the best repeatability [The preoperative imaging procedures have previously been described in detail ,33. In b®; Boehringer Ingelheim, Ingelheim, Germany) were injected intravenously before scanning non-dynamic sequences. This was repeated immediately before dynamic contrast sequences. In addition to the DCE-MRE analysis, components of the MR enterography global score (MEGS) [MRE is performed routinely in our department using 4 h fast and ingestion of 1 L Mannitol solution. Patients lie in the prone position throughout the scan. 20 mg of Hyoscine butyl bromide (Buscopane (MEGS)  and MR ie (MEGS)  were incAll patients included in the study had bowel wall thickness >3 mm. No clear definition exists for strictures ,22,23. F2 1 L/min. The Krebs solution included 118 mmol/L NaCl, 4.7 mmol/L KCl, 25 mmol/L NaHCO3, 1.0 mmol/L NaH2PO4, 1.2 mmol/L MgSO4, 2.5 mmol/L CaCl2-H2O, 11 mmol/L glucose, and 0.11 mmol/L ascorbic acid [®, Crospon, Galway, Ireland) was inserted from the anal side of the bowel segment. The bag was slightly distended, and we utilized a HI VISION Preirus US machine with a EUP-L73S probe  to obtain b-mode images to determine the most stenotic part of the specimen by measuring the lumen diameter [2O pressure.Immediately after surgical resection, the bowel specimen was opened at the stapled ends, rinsed in lukewarm water, and placed in a water tank containing 37 °C buffered Krebs Solution with 100% Obic acid . The watdiameter . The bow®  for further analysis.We only analyzed the narrowest and stiffest part of the inflammation/stricture since this is the primary determinant of flow through a stricture . US imagC) and luminal areas (LA) of inner and outer surfaces. At each location, the circumferential Green strain (θε) and circumferential Kirchhoff stress (θS) for each distension pressure were calculated as [The bowel segments were assumed to be straight cylinders. The ultrasound images were analyzed for circumference , outerLA), and α and β are material constants, and α relates to the wall stiffness. The circumferential Young’s modulus (E) was thus calculated as:Circumferential Kirchhoff stress:E for 2.5 < θS < 5 kPa was calculated, assuming linearity.In this paper, 10 (AIU) = dB. Spearman’s correlation (ρ) was computed between E and CEUS or DCE-MRE parameters. Furthermore, spearman’s correlation was used for associations between E and MEGS, MaRIA. For ordinal categorical variables, including the degree of prestenotic dilatation, MRE mural edema, and enhancement pattern, Kendall’s τb was computed. Categorical variables were examined with one-way ANOVA before the investigation of pairwise differences. Finally, the difference in E was tested with Students t-test for dichotomous variables such as the presence of strictures and ulcers. A p-value < 0.05 was regarded as significant.Descriptive statistics were used for all demographic variables. These included means, standard deviations, and ranges for continuous variables and frequencies and percentages for categorical factors. Several parameters did not follow the Gaussian distribution. Young’s Modulus was log-converted for further analysis, and CEUS intensity parameters (expressed as arbitrary intensity units (AIU)) were converted to dB using the equation 10 × logAmong 25 patients included , distensn = 11) or US (n = 10), the stress-strain curves from stenotic segments were located to the left of those from non-stricture segments, illustrating the stiffer wall of the strictures. A strong association was found between E and DCE-MRE Initial slope of enhancement  but not by MRE  kPa, than those classified as “no” or “uncertain,” E: 12.6 (10.5–15.1) kPa, p = 0.022. No such difference was found between the certainty of strictures on MRE and E: 15.4 (12.5–19.0) kPa for “certain” strictures and 13.8 (11.4–16.7) kPa for “uncertain/no stricture” (p = 0.42). By defining stricture as prestenotic dilation >25 mm, the difference was more considerable for US, ρ = 0.48, p = 0.045). Patients with large ulcers on US had a trend toward a stiffer bowel wall, E: 15.9 (13.5–18.7) kPa than those with no ulcers, E: 12.1 (9.6–15.3) kPa, p = 0.057. Normal (layered) versus disturbed bowel wall stratification on US was not associated with E, p = 0.62. MRE bowel edema was also not associated with E of the stricture . Compound MRE scores were without agreement. No correlation was found between E and MaRIA . In contrast, there was a moderate association between MEGS and E  when assessed before surgery by US . For predicting strictures, there was a non-significant difference between no strictures 1.75 (1.21–2.29) m/s and “certain” strictures 2.09 (1.23–2.95) m/s. There was a moderate but insignificant association with E  for calprotectin, whereas CRP showed a moderate but significant association . Most patients 14/18 (78%) reported severe pain before surgery. No correlation was found between the stricture stiffness and the degree of self-reported pain , HBI , or CDAI .Elastography was only possible in 11 out of the 18 patients. There was no correlation between elastography and biomechanical stiffness, We aimed to explore the association between imaging parameters and stiffness of small intestinal inflammation or strictures in CD. Such associations would support the clinical use of specific imaging methods to evaluate CD inflammation and strictures and potentially guide therapy. The stricture stiffness was associated with prestenotic dilatation or “certain” strictures on US but not MRE. In contrast, both DCE-MRE initial slope of enhancement and MEGS were moderately and directly associated with stricture stiffness, whereas CEUS was not. This contradicts our hypothesis since we expected an inverse correlation between relative perfusion and stricture stiffness. However, inflammation and fibrosis may co-exist, and the classification of strictures should probably be more detailed than just inflammatory, compound, and fibrotic ,38. FibrIt is well known that clinical symptoms correlate poorly to objective signs of mucosal inflammation in CD . LikewisStidham et al. utilized strain elastography to predict bowel wall elasticity in a rat model of colitis and later in seven CD patients undergoing surgery for intestinal strictures . The elaAll the studies mentioned above either investigated tissue elastography or longitudinal stress-strain relationship for a section of the intestine. The more important circumferential wall stress was not studied. We found no statistically significant associations between shear wave elastography and circumferential wall stress or presence vs. absence of a stricture. These negative findings could result from a small sample size with high standard deviations. However, numerous issues with shear wave elastography assessment in the intestines may hamper any meaningful association with true stiffness or even histological composition. First, the success rate of the modality was low, with a high SD of the ten measurements. Secondly, fitting the ROI inside the bowel wall may be difficult when the bowel is only moderately thickened. In addition, reproducibility is affected by the depth of measurement and the absolute stiffness of the examined element ,50. The E than luminal inflammation or uncertain strictures, and this was not the case for MRE. Although oral contrast consumption before an US scan may be superior to non-contrast intake [Strictures, defined by US, had a significantly higher t intake , we belit intake  and the t intake  using >2t intake ,52. Our study has limitations. The distension was not performed in vivo and without the standard hormonal and neurogenic feedback mechanisms. Thus, we studied passive mechanical properties, which is advantageous since the structure is made of passive elements such as collagen. Active contraction of smooth muscle cells within a stricture will increase wall stiffness. Our study could theoretically have been conducted intra-operatively, and however, this would have increased surgery duration and the risk of contamination during the procedure. In vitro and ex vivo studies can use classical biomechanical methods, including imaging with US having high accuracy ,13,14,15In the analysis of both DCE-MRE and CEUS, we did not take the arterial input function into account . This maWe reported data from in vivo imaging and studied their association with the circumferential stiffness of bowel inflammation and strictures in CD. Surprisingly, direct correlations were found between the stricture stiffness and several indicators of active inflammation, such as the initial slope of enhancement on MRE, the MEGS, and CRP. Stiffness also correlated well with prestenotic dilatation on US without oral contrast agents, potentially a new biomarker.


Dromedaries can be integrated efficiently into an intensive production environment.Intensive camel milk production requires a significant initial investment, however, it also offers a number of advantages.happy and healthy” animals.A Herd Health Management program and compliance with statutory requirements guaranty the production of good quality and safe raw camel milk from “No undesired effects associated with intensification such as the emergence of zoonotic diseases and antibiotic resistance were detected.Assisted reproductive technologies are important to enhance the efficiency of a selective breeding program.SDGs) to ensure development of the world as a whole in the coming years. Among those, SDG-2 aims to “end hunger, achieve food security and improved nutrition and promote sustainable agriculture” through determining targets and indicators ; this is a 5-fold increase over the 60-yr period. With this quantity, camels are the fifth most important dairy animals, following cattle, water buffalo, goat, and sheep (The number of camels has been continuously increasing in the last few decades and has reached approximately 40 million head of Bactrian and dromedary camels and this number is expected to increase to above 60 million in 25-years’ time . In parand sheep . Howevernd sheep . In addind sheep . MoreoveEICMP) with processing and distribution facilities has also been established during this period  together with the solid data generated by the operations have provided an unprecedented opportunity for developing, monitoring, and improving an intensive camel milk production system for dromedaries. Here, we focus mainly on animal health, welfare, and management as well as on assisted reproduction.The aim of this paper is to review our experience on the present status and challenges related to the intensification of camel farming. The large pool of animals at EICMP and Camel Reproduction Centers (n = 47) in Saudi Arabia. In contrast, the production potential of Maghrebi camels (n = 10) in Egypt was lower, with an average production of 1612 ± 710 liters during 353 ± 152 d lactation period (n = 8) was an average 2,642 ± 523 liters for 390 d of lactation (n = 95) it was 1,388 ± 575 liters for 11 mo of lactation  and good veterinary practices (GVP). The role and responsibilities of international organizations such as the Codex Alimentarius Commission (CAC), World Organization of Animal Health (OAI), and Food and Agriculture Organization (FAO) are to set standards and give recommendations on various aspects of agricultural production . These standards have been integrated by the International Organization for Standardization (ISO) into a comprehensive food safety management system (FSMS) that can be applied voluntarily at farm level (ISO22000: PRPs) need to be established. The currently existing PRPs on food safety of farming are detailed in a separate standard  occurs at a much later stage (7 to 12 mo). Frequently, camels have a reputation as being aggressive and bad-tempered, and as being difficult and dangerous to handle. However, if trained and handled properly camels can become companion animals attached to their caretakers and they can equally adapt to a nonpersonal, large-scale husbandry system. This is due to the supposed aptitude, high cognitive function, sophisticated mental capacity, and learning ability of the species. This statement is based on our personal experience and is not supported by actual research data in this species. However, cognitive capacity in other livestock species has been already demonstrated and is a new area of research for animal welfare and for improving livestock management .2 paddock space for a lactating dromedary of which approximately 30% (15 m2) is shaded . However, irrespective of the available technology, the milking stand should be safe and comfortable for both animals and people. Milkers should have easy access to the udder and the flooring of the parlor should be nonslippery to avoid injury of the animals . It is ahappy and healthy” camels are able to produce good quality milk close to the maximum of their genetic potential. In order to reach this aim, a comprehensive so-called Herd Health Management program has been implemented and is in practice at EICMP. This program has three main elements which include an animal health and biosecurity program, an animal welfare or well-being program, and a breeding and reproductive management program. These elements are not independent of each other, rather they are very much interlinked sometimes are overlapping, and could not be managed successfully on their own without the other elements. For example, whilst it is easy to understand that the good, healthy condition of pregnant camels cannot be guaranteed without proper reproductive management and animal welfare activities, it is also the case that any diseases in dromedary herds compromise their welfare.The underlying concept of our intensive production system is that only “TVC) and Coliform counts (CC) below 10,000 cf/ml and 10 cf/ml, respectively, and the milk free from antibiotic residues.The Animal Health and Biosecurity programs ensure that most camels remain healthy at any given time, the occurrence of new diseases is prevented and sick animals are recognized quickly, and treated efficiently. In a large-scale system, the emphasis is more on prevention rather than on treatment, but looking after individual animals is still an important part of the veterinary service. The Bio-security program is designed to prevent and control any bio-security hazard from entering the premises and spreading on the farm in order to protect the health status of not only the animals, but also of the people. It consists of controlled movement of animals, including quarantine procedures, separation of sick animals, handling of carcasses, cleaning, disinfection, and sanitation of various places on the farm, pest control , training and healthcare for staff, and the control of movement of people, including visitors and vehicles, into and out of the premises. The Animal health program focuses on three major areas: on infectious disease control, on milking hygiene and mastitis control, and on general animal health which also includes multifactorial or noninfectious diseases and ecto-parasite control. The OAI Terrestrial Animal Health Code  describeBrucella melitensis bacteria, is the most important zoonotic infectious disease of dromedaries and in certain countries, the seroprevalence can reach as high as 40% (RBT) and milk ring test (MRT). In case of a positive reaction, confirmatory laboratory tests are carried out in the nearby veterinary laboratory according to OAI guidelines in order to exclude false positive animals. Although, over the years there have been sporadic, individual cases of Brucellosis, only one confirmed abortion was detected and the seroprevalence of the herd remained below 0.1% , digestive and alimentary tract problems (12.5%), reproductive disorders including abortions, perinatal mortality, postpartum problems (12.5%), and generalized infections with fever (11.7%). Injuries (8.7%), lameness (3.5%), and respiratory tract conditions (2.2%) occur less frequently and the remaining miscellaneous diseases (5.6%) include eye and ear infections, generalized oedema, tympani, foot cancer, neurological syndromes, camel pox, Trypanosomiasis, and snake bites. We also want to mention that common metabolic conditions in dairy cows such as milk fever, ketosis, and fatty liver disease are not observed in dairy camels.The most important measurable criteria to evaluate the health status of a livestock production system are the mortality and morbidity rates . At EICME. coli infection, Clostridiosis, colon fecal impaction, and gastric ulcer. The distribution of the various diseases both in adults and calves is changing from year to year and these figures are difficult to compare due to lack of information in the literature. In pastoral, extensive systems most of these data are not recorded and the focus is mainly on infectious diseases  at EICMP has been an integral part of the Herd Health Management program and it is in line with OAI recommendations (BCS) of all age groups , treatments, washing for ecto-parasite control, nail trimming, and delivery assistance when individual handling and various degrees of restraint are required. This may cause temporary discomfort to the animal but it is necessary both for the safety of the camel and staff. We also have to emphasize that the intensity of vocalization is not always in proportion with the severity of the procedure or the restraint. In traditional management, the movement of animals is frequently restricted by ropes or hobbles on the front and/or hind legs . If thesThe early recognition of diseased animals both at herd and individual level is an important animal welfare issue. Camels are known to have high pain tolerance and show limited clinical signs even in serious, live threatening conditions (like intestine torsion). Therefore, the proper and continuous training of staff and the regular and frequent daily health monitoring routine are essential.The genetic progress of milk production has been slow in this species due to lack of proper recording, selective breeding, and low reproductive efficiency. The latter is due to a delay in the onset of puberty , a short breeding season (November–March), a long gestation period of 13 mo producing one calf per pregnancy, and a long period of lactation and calving interval. This has led to increased research into assisted reproductive techniques, such as embryo transfer and artificial insemination, to enhance reproductive efficiency, and increase the number of progeny per animal, per season. The efficiency of a genetics improvement program that includes identification and phenotypic characterization, milk data collection and analysis, reproductive data recording, and establishment of an inhouse studbook can be greatly increased by the use of assisted reproductive technologies .Under natural mating conditions camels have singleton pregnancies, twins are extremely rare and, if they do go to term, they are generally born weak and under-developed. Embryo transfer therefore has several advantages as multiple progenies can be produced from desirable combinations of sire and dam in one season. Embryos can also be transported much more easily than live animals thereby diversifying the genetics worldwide, and can be stored cooled, or frozen thus preserving the genetics for many years. There are certain prerequisites for a successful embryo transfer program, namely stimulation of the donor to produce multiple follicles and synchronization of the recipients with the donor. Donors can be treated hormonally with either equine chorionic gonadotrophin , with or without porcine FSH  , 2004. AIn camel industries, there is often a considerable spatial and temporal separation of recipient and donor necessitating the need to freeze embryos so that they can be transported and transferred to recipients in a different location. Attempts to freeze camel embryos started in the late 1990’s with the first successful pregnancies reported in 2004/2005 . The prihappy and healthy” animals. The experience at EICMP clearly demonstrates that intensive camel milk production is sustainable, a better than average animal health status can be maintained and the welfare requirements of the animals can also be fulfilled. In addition, no undesired effects associated with intensification such as the emergence of zoonotic diseases and antibiotic resistance were detected. Intensification also comprises the continuous improvement of milk production potential of the herd through a selective breeding program. The efficiency of this program can be substantially enhanced by the intensive use of assisted reproductive technologies.The milk production potential of dromedaries has not been exploited to its full capacity until recently, despite the fact that camels are an important food source in arid and semiarid regions. Camel milk has been produced exclusively by hand milking in traditional, extensive, or semiintensive farming systems, was mainly consumed locally without further processing and only a fraction of the production reached urban markets. The intensification of the camel dairy industry started 15 to 20 yr ago but such production systems are not widespread, although, it is expected to grow in the coming decades. Intensive camel milk production requires a significant initial investment, which has to include a continuous water and electricity supply, a regular and reliable feed source, as well as well-trained professionals and veterinary service, a processing facility, and reliable access to markets. Unfortunately, today these requirements are difficult to meet in most countries where camels are kept naturally. If the above conditions are available, dromedaries can be integrated efficiently into an intensive production environment. However, such a system requires the implementation and the strict execution of a Herd Health Management program and the compliance with statutory requirements in order to produce good quality and safe raw camel milk from “