Are an annual prostate magnetic resonance imaging (MRI) and potential MRI-guided biopsy cost-effective compared with a transrectal ultrasonographic (standard) biopsy for men with a positive prostate-specific antigen (PSA) test result?In this economic evaluation, annual MRI and potential MRI-guided biopsy for prostate cancer found improved economic value compared with standard biopsy for men with a serum PSA level of 2.5 ng/mL or more beginning at 65 years of age.This study suggests that an annual MRI and potential MRI-guided biopsy are a cost-effective option from the federal payer perspective compared with standard biopsy for men beginning at 65 years of age for a serum PSA level of 2.5 ng/mL or more. Magnetic resonance imaging (MRI) and potential MRI-guided biopsy enable enhanced identification of clinically significant prostate cancer. Despite proven efficacy, MRI and potential MRI-guided biopsy remain costly, and there is limited evidence regarding the cost-effectiveness of this approach in general and for different prostate-specific antigen (PSA) strata.To examine the cost-effectiveness of integrating annual MRI and potential MRI-guided biopsy as part of clinical decision-making for men after being screened for prostate cancer compared with standard biopsy.Using a decision analytic Markov cohort model, an economic evaluation was conducted projecting outcomes over 10 years for a hypothetical cohort of 65-year-old men in the US with 4 different PSA strata  identified by screening through Monte Carlo microsimulation with 10 000 trials. Model inputs for probabilities, costs in 2020 US dollars, and quality-adjusted life-years (QALYs) were from the literature and expert consultation. The model was specifically designed to reflect the US health care system, adopting a federal payer perspective .Magnetic resonance imaging with potential MRI-guided biopsy and standard biopsy.Incremental cost-effectiveness ratios (ICERs) using a willingness-to-pay threshold of $100 000 per QALY was estimated. One-way and probabilistic sensitivity analyses were performed.For the 3 PSA strata of 2.5 ng/mL or greater, the MRI and potential MRI-guided biopsy strategy was cost-effective compared with standard biopsy . Results varied depending on the diagnostic accuracy of MRI and potential MRI-guided biopsy. Results of probabilistic sensitivity analyses showed that the MRI and potential MRI-guided biopsy strategy was cost-effective at the willingness-to-pay threshold of $100 000 per QALY in a range between 76% and 81% of simulations for each of the 3 PSA strata of 2.5 ng/mL or more.This economic evaluation of a hypothetical cohort suggests that an annual MRI and potential MRI-guided biopsy was a cost-effective option from a US federal payer perspective compared with standard biopsy for newly eligible male Medicare beneficiaries with a serum PSA level of 2.5 ng/mL or more. This economic evaluation compares the cost-effectiveness of integrating annual magnetic resonance imaging and potential magnetic resonance imaging–guided biopsy vs standard biopsy as part of clinical decision-making for men after being screened for prostate cancer. The standard for detecting PCa is transrectal ultrasonography (TRUS)–guided biopsy with 12 to 16 cores distributed throughout the prostate (standard biopsy).5 This approach is associated with risks of postbiopsy complications,6 has limited diagnostic accuracy,7 and is performed without visual confirmation of the cancer’s location.8 The primary diagnostic limitations of standard biopsies are overdetection of clinically insignificant lower-grade PCa and underdetection or undergrading of clinically significant PCa.9 There remains substantial controversy regarding prostate-specific antigen (PSA) screening for PCa, particularly its potential to result in overdiagnosis of low-risk disease.10 Despite these concerns, PSA screening remains a commonly used tool, and both American Urological Association and American Cancer Society guidelines continue to include PSA screening for PCa diagnosis.13Prostate cancer (PCa) is the most common noncutaneous cancer among men in the US and the second-highest cause of cancer deaths among men.14 Despite proven efficacy, MRI and potential MRI-guided biopsy remain costly, and there is limited research evaluating the cost-effectiveness of this approach.15Multiparametric MRI can assess which men have regions suspicious for cancer in the prostate, improving detection of clinically significant cancer and potentially avoiding biopsy when no target is evident.16We evaluate the cost-effectiveness of annual MRI and potential MRI-guided biopsy as a screening strategy for PCa detection compared with standard biopsy. We focused on newly eligible male Medicare beneficiaries who are 65 years of age over 10 years to maintain a model consistent with the initial phase of Medicare eligibility to the age limit beyond which PCa screening is generally not recommended.18 while men older than 75 years are less likely to undergo definitive therapy for PCa because they face greater morbidity and mortality risk associated with other health issues.19 The study was conducted using simulated data and does not constitute human participants research and is therefore exempt from institutional review board approval. We followed the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) reporting guideline.In this economic evaluation, a decision analytic Markov model based on current US epidemiologic and clinical data was constructed to evaluate the cost and effectiveness of 2 biopsy strategies: standard biopsy and MRI and potential MRI-guided biopsy in the US . Without loss of generality, the models assume that an individual’s PSA category would not change over the 10-year horizon and have identical structures but with different probabilities of PCa recurrence due to disease progression. The aggressiveness of PCa is described by pathologic grade, stratified to grade groups based on the preponderance of histologic Gleason patterns.22; positive and negative results, as well as false-positive and false-negative results, are recorded. If MRI detects a possible PCa, individuals will receive an MRI-guided biopsy. If the MRI findings are negative, no biopsy is conducted.The model accounts for the sensitivity in detecting clinically significant PCa and specificity of potential MRI-guided biopsy  and standard biopsy  and the sensitivity or specificity of MRI 23 Those with high-grade PCa, however, may require treatment regardless of the presence of comorbidities.24Patients with comorbidities such as diabetes, chronic obstructive pulmonary disease, congestive heart failure, or multiple comorbid conditions that can be exacerbated by treatment may defer PCa treatment out of concern that it would not improve length or quality of life.Descriptive and structural validity was conducted between the economic and clinical authors first and then by the modeling team prior to evaluating final economic outcomes. Using the complete model, internal validity and consistency were checked via multiple sensitivity analyses by assessing the association of varying key parameter values, such as diagnostic test characteristics and cancer progression probabilities, with variation in relative Markov cohort sizes from one cycle to another. Additional model details required to replicate this study are included in the eAppendix in 29 costs, and quality-of-life weights37 associated with each health state in the Markov model . These sources provided transition probabilities,38 We identified the efficient strategy for each PSA group using a standard willingness-to-pay (WTP) threshold of $100 000 per QALY; if the ICER was under $100 000 per QALY and the incremental QALY was positive, the strategy was considered cost-effective.39The incremental cost-effectiveness ratio (ICER) was used to assess cost-effectiveness. ICERs were calculated as the difference in costs divided by the difference in quality-adjusted life-years (QALYs) between the 2 competing strategies. All future costs and QALYs were discounted at a rate of 3% annually.A probabilistic sensitivity analysis was performed using Monte Carlo microsimulation with 10 000 trials to account for simultaneous uncertainty in model parameter values when calculating ICERs, and 1-way sensitivity analyses of key test characteristics (sensitivity and specificity of MRI and MRI-guided biopsy) were evaluated within these simulations. In addition, we generated tornado diagrams to describe the association of uncertainty of input parameters with incremental effectiveness and cost outcomes between strategies. All analyses were performed using TreeAge Pro, version 2021 R.12 (TreeAge Software LLC). Additional detail on primary measures is included in the eAppendix in The costs, QALYs, incremental values, and ICERs comparing the 2 strategies—the MRI and MRI-guided biopsy vs the standard biopsy—for the 4 different PSA strata are summarized in We conducted 1-way sensitivity analyses on the test characteristics of the MRI and potential MRI-guided biopsy. Holding the sensitivity of MRI-guided biopsy constant, QALYs for the MRI and potential MRI-guided biopsy strategy decreased at very high sensitivity values of MRI. No additional incremental QALYs were gained for the MRI and potential MRI-guided biopsy strategy, with sensitivity values for the MRI greater than 0.84 across all PSA strata compared with 0.76 in the base case.There were approximately 0.062 QALYs gained on average throughout the entire range of specificity values of MRI for the PSA stratum greater than 10 ng/mL, while the cost of the MRI and potential MRI-guided biopsy strategy decreased as the specificity of the MRI increased, resulting in an ICER less than $11 000 per QALY for the entire range. For the PSA stratum of 4.1 to 10.0 ng/mL, the ICER stayed below $50 000 per QALY for the entire range as the specificity increased. For the PSA stratum of 2.5 to 4.0 ng/mL, the specificity of the MRI needed to be at least 0.50 for the ICER to be less than $50 000 per QALY.Holding the specificity of the MRI constant, the ICER remained at approximately $6000 per QALY or less for the entire range of specificity values of MRI-guided biopsy for the PSA stratum of more than 10 ng/mL. For the PSA stratum of 4.1 to 10.0 ng/mL and the PSA stratum of 2.5 to 4.0 ng/mL, the ICER stayed below $13 000 per QALY and $22 000 per QALY, respectively. For the PSA stratum of less than 2.5 ng/mL, the ICER decreased as the specificity increased, but it remained between $187 000 and $192 000 per QALY. Additional sensitivity analyses  are provided in eFigure 2A and B in Results from probabilistic sensitivity analysis indicate that the MRI and potential MRI-guided biopsy strategy was cost-effective at the $100 000-per-QALY threshold in a range between 76% and 81% of simulations for each of the 3 PSA strata of 2.5 ng/mL or more . Through35 in addition to its already proven value in decreasing cancer overdiagnosis demonstrated in 2 prospective randomized clinical trials.40 Findings from our study are supported by 2 prior economic evaluations that compared MRI-guided biopsy with alternative strategies, including multiparametric MRI, which also found that MRI-guided biopsy is more cost-effective than the standard of care using TRUS biopsy.42 However, PSA levels were not differentiated in those analyses. Barnett et al35 examined the cost-effectiveness of PCa screening strategies for people with PSA levels above 4 ng/mL and found that MRI and a combined biopsy in which both a standard biopsy and targeted MRI and ultrasonography fusion biopsy are performed is the optimal strategy, with an ICER of $23 483 per QALY. Pahwa et al5 found that a standard biopsy is dominated by the MRI and cognitive-guided biopsy with an ICER of –$8946 per QALY and by the MRI and in-gantry MRI-guided biopsy with an ICER of –$1263 per QALY. Our study stratifies the economic evaluation model by PSA, allowing us to examine MRI and potential MRI-guided biopsy outcomes in the context of this common marker, and we report ICERs using QALYs whose interpretation is broadly applicable. However, 1-way sensitivity analyses demonstrated no incremental QALY gain for MRI and potential MRI-guided biopsy for MRI sensitivity values greater than 0.84. This finding can be explained by the potential greater quality-of-life losses associated with early treatment compared with the risks and benefits associated with later treatment. We also account for both comorbidities and different grades of cancer in combination with PSA ranges. To our knowledge, our study is also the first economic evaluation that considered an annual MRI surveillance strategy. Prior studies have assessed the cost-effectiveness of MRI for PCa based on a single instance of screening, not accounting for costs of repeat MRI for patients receiving surveillance that occurs in clinical practice. Also, with increasing surveillance being associated with more frequent detections at lower PSA levels, especially in the 2.5 to 4.0 ng/mL range, there is a concern about the cost-effectiveness of MRI due to the lower likelihood of cancer. However, even for men in this PSA stratum, our results indicated economic value gains for stakeholders.This economic evaluation examined the cost-effectiveness of integrating annual MRI and potential MRI-guided biopsy compared with standard biopsy differentiated by PSA strata after PCa screening in the Medicare-eligible cohort. Results from this study suggest that the MRI and potential MRI-guided biopsy strategy is cost-effective compared with standard biopsy for the detection of PCa from a federal payer perspective among 65-year-old men with a PSA level of 2.5 ng/mL or more at generally accepted WTP levels. Although for these men the initial cost of the MRI and potential MRI-guided biopsy strategy was higher than the cost of standard biopsy, extra costs were offset by higher expected QALYs. Our results are consistent with previous literature on the cost-effectiveness of MRI and potential MRI-guided biopsy strategy as management tools for PCa,41A concern could be raised that cancers detected by MRI strategies could be more indolent than those detected by TRUS biopsy alone, and thus stratification data from TRUS biopsy could overestimate survival benefit from an MRI-guided strategy. However, the PROMIS (Prostate Magnetic Resonance Imaging Study) trial has previously shown that cancers missed by MRI strategies are smaller and lower in grade than those detected and, thus, the opposite is expected to be true.43 and incorporating such trends in economic models is important for research focused on budgetary effects. Future cost-effectiveness analyses of MRI and potential MRI-guided biopsy to screen for PCa should consider emerging treatment options and develop region-specific models that can more accurately project total cost and effectiveness outcomes to better inform local policy makers.As is the case in all simulation studies, this study has a number of limitations. First, in estimating treatment cost, we applied equal proportions of the 3 most common treatment options for PCa. Although changes in the proportion of treatment options will be associated with absolute cost estimates, varying the proportion of treatment will not be associated with the comparative results of the economic evaluation because any variation in cost or effectiveness  due to treatment proportions would be associated with both strategies equally. Furthermore, treatment may vary and change over time (and by region) depending on clinician and patient preferences,44 Furthermore, our study assumes that men will stay in their original PSA stratum, which may not occur naturally with aging. However, because our results provide economic and effectiveness outcomes for each PSA category, concerns regarding dynamic changes in PSA can be addressed by weighting the results of PSA categories to calculate expected values for a model that incorporated those possible variations. We expect that including changes in PSA strata over time would not result in a qualitatively different conclusion because in our analysis the MRI and potential MRI-guided biopsy strategy are optimal in all groups with a PSA level of 2.5 ng/mL or more.45Developing a model necessitates making choices that may affect results and limit generalizability. We chose to use the cost for in-bore MRI-targeted biopsy instead of systematic TRUS fusion biopsy, as the former would detect the higher-risk grade PCa sooner, resulting in an expected increase in short-term costs and potentially decreasing the likelihood of cost-effectiveness. However, these costs may be offset by potential long-term cost reductions due to greater efficacy of treatment when PCa is detected at an early stage, which may be of particular interest to policy makers. Future studies can address the difference in the estimated economic value of these different techniques once reliable longitudinal data are available. In addition, our outcomes may vary for other reimbursement settings and perspectives. A societal perspective, for example, could result in higher time costs for the patient or other costs not covered by Medicare that may differ between the strategies.46 which found that MRI-guided biopsy was optimal compared with standard biopsy in detecting clinically significant PCa among men with a PSA level of more than 5.2 ng/mL. In addition, the likelihood of clinically significant cancer increases with increasing serum PSA value, although this is a multifactorial phenomenon, as prostatic hyperplasia is more likely to result in an elevated PSA, and prostatic hyperplasia would decrease the sensitivity of standard biopsy. For simplicity, this scenario was not incorporated into the model.Our findings represent the widening of the PSA threshold from previous research by Shakir et al,Our study was restricted to the Medicare-eligible cohort starting at 65 years of age for men followed up for 10 years after PSA screening. This cohort is particularly relevant for policy makers not only because of their increased risk of developing PCa but also because economic modeling tends to devalue later-life outcomes , and thus the evaluation of surveillance strategies for PCa will undervalue cost reductions and QALY gains that occur during the age at which the disease burden is highest. Our choice of beginning the simulation at 65 years of age minimized the impact of such time discounting by focusing on the group with the highest incidence rate. Nevertheless, further investigation may be appropriate for younger men, using a model where initial screening costs would be incurred by other payers, and the association with quality of life might extend beyond 10 years. Adjusting for the follow-up frequency, such as every other year rather than annual testing, could also be explored for individuals at low risk of PCa.We did not further stratify our model by other patient characteristics such as family history, ethnic origin, diet, or genetic factors. This would require a markedly different model from the one used here as well as the availability of detailed longitudinal information on such cohorts. Finally, our study assumed a biopsy-naive population at enrollment. Further study is needed to determine optimal screening options for patients with a prior history of PCa or prior negative biopsy results, which would substantially alter the likelihood of receiving a diagnosis of clinically significant cancer.47This economic evaluation of a hypothetical cohort from a federal payer perspective suggests that investments in expanding the capacity to conduct MRI and potential MRI-guided biopsy will provide economic value for stakeholders and improve quality of life for 65-year-old men with a PSA of 2.5 ng/mL or more undergoing screening. Results from this study add to a growing consensus that the use of MRI and potential MRI-guided biopsy is cost-effective compared with standard strategies. These findings are valuable as they can support establishing a new approach for men in active surveillance for PCa. The capacity for all men in the US to receive MRI and potential MRI-guided biopsy has been expanding, but greater adoption of this strategy is contingent on MRI availability and adequate resources and training for the MRI-guided procedures, as well as overcoming fixed cost barriers.


Regular physical activity is important for arthritis self-management and could be promoted through tailoring community leisure and fitness centers’ customer-relationship management (CRM) strategies.This study investigates the influence of two CRM strategies on individuals with arthritis reaching or maintaining two moderate-to-vigorous physical activity (MVPA) thresholds (≥150 and ≥45 minutes/week) from baseline-to-12 months and 12-to-24 months as well as mean changes in total minutes/week of MVPA. It also explores time-dependent variations in the influence of socio-cognitive variables on MVPA outcomes.Only and Incentive+Support) were used. Participants reported measures of physical activity participation, socio-cognitive decision-making, mental and physical wellbeing, friendship, community connectedness, sense of trust in others, and demographics.Survey data from 374 participants with arthritis in a two-year randomized controlled trial (control versus two CRM strategies: Incentive+Support CRM strategy (versus control) increased participants’ likelihood of reaching/maintaining both physical activity thresholds from 12-to-24 months  but not from baseline-to-12 months. However, receiving the IncentiveOnly CRM strategy (versus control) did not predict reaching/maintaining these thresholds. Importantly, socio-cognitive decision-making variables’ influence on reaching/maintaining these MVPA thresholds varied over time, suggesting CRM strategies may require further tailoring based on time-specific profiles. Perhaps because of new facility induced excitement, the mean change in total MVPA minutes/week for the control group significantly increased  from baseline-to-12 months, but subsequently declined by 11.4 minute/week from 12-to-24 months . Mean changes in total MVPA minutes/week were non-significant for those receiving IncentiveOnly content but significant for those receiving Incentive+Support content: baseline-to-12 months  and baseline-to-24-months .Receiving the Incentive Regular physical activity is an important component in self-managing common arthritic conditions including osteoarthritis, rheumatoid arthritis, and psoriatic arthritis , 2, partWhat is less evident in extant literature is the potential for community leisure and fitness centers to also play a role in promoting and encouraging regular physical activity among typically inactive people with arthritis. The protracted nature of arthritic conditions means those impacted are likely to require uninterrupted access to physical activity resources for extended periods of time . Multi-pIn CRM systems, organizations tailor their marketing communications and promotions using data they have collected and collated on current and prospective customers . ResearcIn examining the efficacy of using CRM program content to motivate physical activity it is important to understand the socio-cognitive characteristics of those being targeted, as constructs from socio-cognitive theories  have been shown to explain why some individuals are more likely to enact physical activity behaviors than others , 28. UndIn this study, we draw on the Monitoring and Observing the Value of Exercise (MOVE) two-year randomized control trial , which sought to encourage regular physical activity among those that are typically inactive  located adjacent to the central business district of the city. The PARC facility, developed at a cost of AUD$49.7 million, was designed to meet a diverse range of resident needs and includes a 50-metre indoor lap pool, warm water pool, learn to swim pools, an aquatic playground, gymnasium, group exercise rooms, as well as a spa, sauna and wellness therapies center.The MOVE trial collected data across three timepoints: baseline (prior to participant randomization), 12 months post-baseline, and 24 months post-baseline. The trial was undertaken with the cooperation of the PARC facility, received institutional approval from the Monash University Human Research Ethics Committee (Project IDs: CF14/1148–2014000497 and CF14/2059–2014001074), and is registered with the Australian New Zealand Clinical Trials Registry .Residents of the City of Frankston aged 18–70 years were eligible to participate in the MOVE trial if they did not, at the time of recruitment, attend a leisure/exercise facility 3 or more times per week and were classified as being typically physically inactive using Milton et al.’s  criterioIn this study, we draw on data from 374 individuals enrolled into the MOVE trial who self-reported having an arthritic condition at the baseline data collection point.Once participants had completed the baseline survey, electronic random number generation was used to randomize them on an individual basis (undertaken by author BJS), after which sequential ordering was used to allocate them to the control group or one of the two CRM strategies (undertaken by author JDN). The participants were not blinded to their group. The control group received no CRM related materials; they were, however, exposed to public promotions of the PARC facility .Only) focused on encouraging uptake of physical activity through the provision of a voucher for one free trial visit to use the swimming pools or gymnasium at the PARC facility and an information pack about the facility. CRM Strategy 2 (Incentive+Support) included the voucher and information pack as well as ongoing supportive interactions with PARC in the form of a follow-up telephone call in the first 6 months to encourage trialing of the Centre, PARC-branded supportive messaging, and customer relationship materials. These included hand-written birthday and Christmas cards encouraging participants to achieve their physical activity goals as well as quarterly mailed newsletters designed to encourage physical activity by providing tips on how to overcome common barriers to engaging in physical activity. These types of supportive messaging were selected for trialing because of the ease with which they could be integrated into existing CRM systems and their low ongoing running costs.Drawing on customer relationship methods  and sociThe primary outcome measure for this study is physical activity, which was assessed using the Exercise Recreation and Sport Survey (ERASS) . ERASS hTo develop a profile of those who did (or did not) reach/maintain these two MVPA thresholds, we drew on single-item measures of social and cognitive determinants of physical activity aligned with the Theory of Planned Behavior framework –45. EachTo assess the influence of health-related factors on physical activity, we drew on the single item global self-rated mental health measure  to captuThe trial measures were administered at each data collection timepoint by a trained team via computer assisted telephone interviews. The interviews took approximately 20 minutes and the interviewers were blind to participant group allocation.Among MOVE trial participants reporting an arthritic condition at baseline, 90 were lost to follow-up at 12 months with 109 lost at the 24-month data collection point. Mann-Whitney test and chi-square tests indicated that those who were lost to follow-up did not differ from those retained at 12 months post-baseline and 24 months post-baseline in terms of their physical activity levels (the primary outcome variable), socio-demographic, and socio-cognitive variables at baseline. In line with Bell et al. , the casOnly and Incentive+Support). At each level of specificity, comparisons of the control with the two CRM groups were undertaken. The socio-demographic and socio-cognitive characteristics are described using means (standard deviations) and proportions. Given the exploratory nature of this research and that we were not engaging in hypothesis testing, we used a stepwise logistic regression model with backward elimination to examine baseline predictors of individuals who reached or maintained (i) ≥150 min/wk and (ii) ≥45 min/wk of MVPA from baseline-to-12 months post-baseline. This approach has been used previously in the context of physical activity and health [Only and Incentive+Support) was included as a covariate. This was done to assess whether the type of CRM strategy influenced physical activity levels. Predictors with p<0.1 were included in the final model, with p < .05 considered statistically significant. Next, we undertook analyses using mixed-effects models to examine the changes in total minutes of MVPA per week across the three MOVE trial data collection points among all participants with arthritis and by allocated group. Analyses were undertaken using Stata 16.0.The data analysis plan was developed at two levels of specificity: all participants with arthritis and those with arthritis by group allocation  significantly predicted reaching/maintaining the ≥150 min/wk of MVPA threshold at 12 months post-baseline when compared to the control group.+Support CRM strategy demonstrated a higher likelihood of reaching/maintaining ≥150 min/wk of MVPA at 24 months post-baseline . Reaching or maintaining the ≥150 min/wk threshold at 24 months post-baseline was also more likely among those reporting a positive attitude towards physical activity  and those with a university degree  relative to those with only a primary/high school education.Next, to explore potential changes in predictors of reaching/maintaining the ≥150 min/wk of MVPA threshold over time, we used socio-cognitive data collected at the 12-month timepoint to identify significant predictors of this threshold at 24 months post-baseline. As outlined in Only and Incentive+Support) were predictive for the intermediate threshold of ≥45 min/wk of MVPA at 12 months post-baseline.The results from +Support CRM strategy .To further examine changes in the predictive utility of socio-cognitive variables over time, we drew on data collected at the 12-month timepoint to identify significant predictors of reaching/maintaining the intermediate physical activity threshold ≥45 min/wk of MVPA at 24 months post-baseline. As outlined in +Support strategy, there was a significant mean increase of 45.9 min/wk of MVPA from baseline-to-24 months  among all participants with arthritis and separately for each type of CRM strategy and for the control group. As outlined in Identifying interventions to enhance the physical activity levels of typically inactive individuals with arthritis has important implications for improving their quality of life –5. Yet f+Support CRM strategy was predictive of reaching/maintaining the WHO’s [Taken together, the findings suggest that in the longer term, CRM strategies comprising incentives and ongoing supportive messaging have the potential to influence MVPA/wk thresholds among typically inactive individuals with arthritis. Notably, relative to the control group, receiving the Incentivehe WHO’s  recommen+Support CRM strategy increased significantly from baseline-to-24 months. Notably, while much of this increase appeared to have occurred in the first 12 months, it was maintained through the second year of the trial. This is a positive outcome given that prior research indicates sustained change in physical activity levels can be difficult to achieve in the longer term among individuals with arthritis [+Support condition helped to sustain engagement in physical activity by either keeping the importance of this behavior salient or offering tips for overcoming common barriers to physical activity. These findings warrant further research to determine ways to support and amplify this combined CRM approach. The lack of significant change in mean total MVPA min/wk among those receiving the IncentiveOnly CRM strategy may be attributed to the potential undermining (or crowding out) effect of extrinsic incentives on intrinsic motivation, as suggested by self-determination theory literature [+Support group may have protected against this by boosting intrinsic motivation. This interpretation aligns with recent research suggesting that crowding out can be mitigated when extrinsic incentives are used in combination with intrinsically motivating factors, including supportive emails and resources to enhance personal capacity for physical activity [+Support CRM strategy. Finally, the excitement and publicity around the opening of the new PARC facility is a possible explanation for the significant increase in MVPA min/wk among the control group from baseline to 12 months.Importantly, the findings from our mixed effect models provide insights into mean change in total mins/wk of MVPA across time and reinforce the positive impact of using CRM-driven supportive messaging to encourage MVPA among individuals with arthritis. Specifically, the mean total minutes of MVPA for individuals receiving the Incentiverthritis –59. It mterature . Interesactivity . As noteOur findings also indicate that socio-cognitive drivers of physical activity can differ by MVPA threshold and across discrete timepoints, suggesting a need to consider developing CRM strategies on timepoint specific profiles. For example, the predictive role of intentions and action planning varied across timepoints for the intermediate MVPA threshold, such that baseline intentions were a significant predictor of participants with arthritis reaching/maintaining ≥45 min/wk of MVPA at 12-months post-baseline, whereas intentions measured at 12 months did not significantly predict meeting this threshold at 24-months post-baseline. Conversely, only action planning measured at 12-months post-baseline predicted this threshold at 24-months post-baseline. One potential explanation for these findings is that intentions to engage in physical activity may become crystalized into well-formed action plans with the passage of time, thus increasing the predictive utility of action planning. After all, action planning involves an individual conceptualizing when and where an intended behavior will be enacted . Over tiIn terms of anticipated regret, prior research suggests that this construct is predictive of exercise-related behavior in cross-sectional studies  and acroIndividuals with arthritis are recommended to work towards the upper ≥150 min/wk MVPA threshold . Our finWhile the relationship between social connection and physical activity is under researched in the context of arthritis, prior research from community samples suggest a positive association between levels of social connection and physical activity such that those who are more socially isolated are more likely to have lower levels of physical activity –68. Our Prior research is mixed on the relationship between gender and physical activity among individuals with arthritis, with some studies suggesting no gender differences and others suggesting physical activity is low among women , 70. Our+Support group were general in nature , future research is needed to examine whether additional minutes of MVPA/wk could accrue through incorporating disease-specific elements into the CRM program content. Further research is also needed to explore whether additional CRM elements could be introduced at 12 months post-baseline to boost mean minutes of MVPA/wk in the subsequent year. At a strategic level, exploration of the optimal frequency of delivering CRM program content to system recipients would also be valuable; too much could be perceived as annoying while too little could lessen the effectiveness of the overarching CRM strategy.Given the CRM strategies provided to the IncentiveThe MOVE trial from which the data from the current study were drawn, and indeed the current study, are not without limitations. First, physical activity was measured by self-report at each timepoint rather than device-based measures, such as accelerometers. As such, recall bias and social desirability bias cannot be ruled out. Second, we drew on a subsample of the randomized participants in the MOVE trial who self-reported having arthritis, but we were not able to confirm the type or severity of their arthritis. Third, we applied the missing at random assumption and replaced missing values with LOCF. This may have led to the underestimation or overestimation of some of the associations identified.Our findings show that the use of a CRM strategy delivering incentives and supportive messaging increases mean total min/wk of MVPA among individuals with arthritis. Such a strategy is also helpful in encouraging individuals with arthritis to reach or maintain both the WHO  and an iS1 Appendix(DOCX)Click here for additional data file.S1 Dataset(DTA)Click here for additional data file.


Computer-aided diagnosis in low-dose (≤ 3 mSv) computed tomography (CT) is a potential screening tool for lung nodules, with quality interpretation and less inter-observer variability among readers. Therefore, we aimed to determine the screening potential of CT using a radiation dose that does not exceed 2 mSv.We aimed to compare the diagnostic parameters of low-dose (< 2 mSv) CT interpretation results using a computer-aided diagnosis system for lung cancer screening with those of a conventional reading system used by radiologists.We conducted a comparative study of chest CT images for lung cancer screening at three private institutions.A database of low-dose (< 2 mSv) chest CT images of patients at risk of lung cancer was viewed with the conventional reading system (301 patients and 226 nodules) or computer-aided diagnosis system without any subsequent radiologist review .The numbers of detected and solid nodules per patient (both P < 0.0001) were higher using the computer-aided diagnosis system than those using the conventional reading system. The nodule size was reported as the maximum size in any plane in the computer-aided diagnosis system. Higher numbers of patients  and nodules  were diagnosed with cancer using the computer-aided diagnosis system.The computer-aided diagnosis system facilitates the diagnosis of cancerous nodules, especially solid nodules, in low-dose (< 2 mSv) CT among patients at risk for lung cancer. In China, the computed tomography interpretation systems for the management of lung cancer vary among institutions. Moreover, the experiences of radiologists have an impact on computed tomography interpretation. Therefore, standardized computed tomography interpretation and management of nodule screening is crucial.Low-dose computed tomography is an effective imaging modality to reduce mortality in patients at high risk of lung cancer. The European Society of Radiology and European Respiratory Society recommend computer-aided diagnosis of lung cancer nodules. The investigated computed tomography scans were considered low dose at 3 mSv or less; however, the requirement for low-dose computed tomography is actually < 2 mSv. However, computer-aided diagnosis in computed tomography can miss lung cancer nodules that are detected by radiologists. A computer-aided diagnosis system has less sensitivity for ground-glass nodules than the conventional reading system. Computer-aided diagnosis systems often miss lesions that are large, endobronchial, and inseparable from the mediastinum or perihilar. In addition, computer-aided diagnosis is typically used to aid radiologists in screening trials; therefore, both methods are used in clinical practice. Hence, the feasibility and efficacy of computer-aided diagnosis in computed tomography for lung cancer nodules should be investigated in detail.Computer-aided diagnosis is reportedly a potential measurement tool for screening lung nodules, with quality interpretation and fewer variabilities among readers.In this retrospective study, we aimed to compare the diagnostic parameters of low-dose (< 2 mSv) computed tomography interpretation results using a computer-aided diagnosis system for lung cancer screening with those of a conventional reading system by radiologists.The present study involved chart reviews from a database (of lung cancer diagnosis) of chest computed tomography images of patients at risk for lung cancer. Therefore, the requirements for ethics approval from The First Affiliated Hospital of Nanchang Medical College Review Board, consent to participate, consent to publish, and registration in the Chinese Clinical Trial Registry were waived by Xianyang Cai-Hong Hospital (China), Hospital of Shaanxi University of Chinese Medicine (China), and Jiangxi Provincial People’s Hospital Affiliated with The First Affiliated Hospital of Nanchang Medical College (China). from the radiology departments of Xianyang Cai-Hong Hospital, Hospital of Shaanxi University of Chinese Medicine, and The First Affiliated Hospital of Nanchang Medical College from December 8, 2019, to January 1, 2021 were included in the analyses. Patients without nodules were excluded from this study. A flowchart of the patient selection is shown in Low-dose (< 2 mSv) chest computed tomography images of patients at risk of lung cancer according to the risk prediction model, including demographics and metabolic markers for lung cancer,The detailed protocols for chest computed tomography were based on individual institutional guidelines; there were no differences between the image acquisition protocols and basic characteristics of each center. The basic configuration comprised a computed tomography scanner with at least 16 detector rows. A whole thoracic scan was performed with a one-breath hold at full inspiration. The slice thickness was 1.5 mm, and the image acquisition settings were 80–120 kVp, 22 mA, and the lowest possible collimation on the scanner; the radiation dose was less than 2 mSv.™, MeVis Medical Solutions AG, Bremen, Germany), including semi-automated segmentation and measurement of the nodules .The AVIEW LCS Lung Cancer Screening SW system  was available at the three institutions. All chest computed tomography scans were uploaded to the cloud included with the software. All participating radiologists interpreted the chest computed tomography scans irrespective of the availability of the software. Interpretations of the chest computed tomography scans were based on a computer-aided diagnosis system for lung nodules  were accessible to the radiologists, who had a minimum of three years of experience in thoracic imaging, at each hospital. The nodule diameters were measured manually using an electronic caliper . The software displays the Lung-RADS category results. The predictions of the different Lung-RADS categories are presented in The chest computed tomography scan interpretations were based on the Lung Imaging Reporting and Data System (Lung-RADS) Version 1.1.U test, unpaired t-test with Kolmogorov-Smirnov test, or one-way analysis of variance. Categorical data were compared using the chi-square test for independence (for comparisons of more than two classes) or Fisher’s exact test (for comparisons of two classes). Tukey-Kramer multiple comparisons tests  were performed for post hoc analysis. McNemar’s tests were used to compare diagnostic parameters between the two systems. P values less than 0.05 were considered statistically significant.InStat 3.01  was used for statistical analysis. Continuous data were compared using the Mann-Whitney A database of 1,245 patients was retrospectively reviewed. Among them, a database of 301 patients was viewed using the conventional reading system with the radiologists unaware of the computer-aided diagnosis system data. In addition, the data of 944 patients were viewed using a computer-aided diagnosis system without any subsequent review by a radiologist. Details of the participants’ characteristics are presented in A total of 20 (7%) and 102 (11%) patients were diagnosed with cancer using the conventional reading and computer-aided diagnosis systems, respectively. The computer-aided diagnosis system detected a higher number of patients with cancer than the conventional reading system . If nodules were measured in a transverse plane, there were no significant differences between the two systems in the number of patients diagnosed with cancer . However, if nodules were measured in any maximum plane with the computer-aided diagnosis system, a higher number of patients with cancers were detected than with the transverse plane measurement using the conventional reading or computer-aided diagnosis systems. The details of the per-patient Lung-RADS category distribution screening results for lung cancers are presented in A total of 17 (8%) and 154 (15%) nodules were diagnosed using the conventional reading and computer-aided diagnosis systems, respectively . If nodules were measured in a transverse plane, there were no significant differences between the two systems in the number of nodules diagnosed with cancer . However, if nodules were measured in any maximum plane with the computer-aided diagnosis system, then higher numbers of cancerous nodules were detected compared with the transverse plane measurement using the conventional reading or computer-aided diagnosis systems. The details of the per-nodule Lung-RADS category distribution screening results and lung cancers are presented in Sensitivity and positive predictive values were higher if nodules were measured in any maximum plane of the computer-aided diagnosis system compared with that measured in any plane of any system. The sensitivity, specificity, and positive predictive values did not differ between the transverse plane in the conventional reading and computer-aided diagnosis systems, transverse plane in the conventional reading system, and maximum orthogonal plane in the computer-aided diagnosis system. The details of the diagnostic parameters for the imaging interpretation systems for lung cancer are presented in  Small nodules missed using a conventional reading system can be detected by the computer-aided diagnosis system. The computer-aided diagnosis system facilitates the diagnosis of cancerous nodules in patients at risk of lung cancer.This study revealed that the sensitivity and positive predictive values were higher if nodules were measured with the computer-aided diagnosis system than those measured with the conventional reading system. The diagnostic parameter results of the current study are consistent with those of previous retrospective studies.We found that the specificity and negative predictive values were the same when nodules were measured with the computer-aided diagnosis or conventional reading systems. There was a difference in nodule sizes measured by the two systems. The radiologists did not measure oversized nodules, and the computer-aided diagnosis system did not measure undersized nodules. Nodule size and the risk of lung cancer are separate issues that require investigation. The increased diagnosis of small nodules with cancer resulted in a higher per patient Lung-RADS screening rate. Moreover, the increased diagnosis rate of small nodules significantly changed the per-nodule Lung-RADS screening rate. The use of data from more than one institution, heterogeneity of the patients, and higher numbers of involved radiologists may explain the contradictory results between imaging interpretation systems for lung cancer in the current study and those of other retrospective studies. A computer-aided diagnosis system is a more accurate tool for lung cancer screening among at-risk patients.In this study, we found that the Lung-RADS screening rate per patient was higher with the computer-aided diagnosis system than that of the conventional reading system. In addition, the Lung-RADS screening rates per nodule differed between imaging interpretation systems for lung cancer. The per patient and per nodule Lung-RADS screening rates in the current study were inconsistent with those of retrospective studies. Lung cancer can be missed by radiologists using computer-aided diagnosis systems. Lung-RADS does not recommend any specific plane in computed tomography imaging for the measurement of nodules, although Lung-RADS Version 1.118 is validated in the transverse plane. However, nodules measured in the transverse plane cannot reflect the actual nodule size. Low-dose noncontrast computed tomography images are also responsible for insignificant results. Further research is required to overcome missed lung cancer nodules, and clear instructions are required for the specific planes in computed tomography imaging for the measurement of nodules in lung cancer screening.We found that the diagnostic parameters did not differ between the transverse plane in the conventional reading and computer-aided diagnosis systems, transverse plane of the conventional reading system, and maximum orthogonal plane of the computer-aided diagnosis system. The results of the different planes using the computer-aided diagnosis system in the current study were consistent with those of a previous retrospective study. A computer-aided diagnosis system has less sensitivity for ground-glass nodules than that of the conventional reading system. Solid nodules that can be detected by a computer-aided diagnosis system are sometimes missed by radiologists. The conventional reading system is recommended for pure-ground nodules, whereas computer-aided diagnosis systems are recommended for solid nodules in lung cancer screening among at-risk patients.The current study revealed significantly fewer pure ground nodules and significantly more solid nodules among patients evaluated by the computer-aided diagnosis system compared with patients evaluated by the conventional reading system. The pure-ground and solid nodule results observed in the current study were consistent with those of other retrospective studies. The conventional reading system showed comparable performance to the computer-aided diagnosis system for part-solid nodules.We also found insignificant differences in part-solid nodules between patients evaluated with the computer-aided diagnosis and conventional reading systems. The performance results of the imaging systems for the detection of part-solid nodules in the current study were consistent with those of a prospective multicenter study. When comparing radiologist interpretations and computer-aided diagnoses it is critical to use the same images. Given that there were two different image sets in this study, it was not possible to validate their performance because there were many different variables between the two groups. Therefore, the increased diagnosis of lung cancer using a computer-aided system may also reflect differences in underlying risks among patients.This was an interesting study on a highly relevant topic that included a large database with follow-up data on malignancy diagnoses. This study had some limitations, mainly its retrospective design  and lack of cross-sectional analysis. It may be more valuable to compare the performance of both systems using the same dataset. However, the gold standard  has not yet been described. This study noted that the data were organized according to a local “risk prediction model” established for a single institution. This is problematic as it did not translate to other universally standardized classifications (United States Preventive Services Task criteria). There was an apparent difference between the small number of cases (n = 301) read by radiologists and an entirely different large (n = 944) set of cases read by the computer. Consequently, this study included the two separate, albeit overlapping, issues of diagnosis and measurement. This might be responsible for the overall differences between the radiologists’ and computer’s results. A possible justification for this is that the study included clinical features, which showed broad similarities between the patients diagnosed by radiologists and patients diagnosed by computer (P > 0.05). This study used size in maximum length rather than volume, which is not conventionally used when screening populations in the United Kingdom. The possible justification for this is that nodule diameter or volume can be used for lung cancer screening.This study validates a commercial computer-aided diagnosis system (Lung-RADS) in a clinical setting, tackling an important question on the utility of computer-aided diagnosis of nodules in the evaluation of computed tomography scans. Use of a computer-aided diagnosis system in low-dose computed tomography (< 2 mSv) for lung cancer screening resulted in higher per-patient and per-nodule Lung-RADS screening rates among patients at risk of lung cancer. Therefore, we recommend a computer-aided diagnosis system for lung cancer screening with low-dose (< 2 mSv) computed tomography, especially for solid nodules. In addition, clear instructions are required regarding the specific plane measured in computed tomography imaging for lung cancer nodule screening. Further investigation of diagnosis rates and measurement accuracy in ultra-low-dose computed tomography (< 1 mSv and < 0.5 mSv) may be of interest.


The relationship between speaking rate and burst amplitude was investigated in plosives with differing oro-laryngeal timing: long-lag voice-onset time (VOT) (North American English) and short-lag VOT (Indian Tamil). Burst amplitude  was hypothesized to decrease in pre-vocalic plosive syllables with the increase in speaking rate, which imposes temporal constraints on both intraoral pressure buildup behind the oral occlusion and respiratory air flow. The results showed that decreased vowel duration (which is associated with increased speaking rate) led to decreased burst amplitude in both short- and long-lag plosives. Aggregate models of bilabial and velar plosives (found in both languages) suggested lower burst amplitudes in short-lag stops. Place-of-articulation effects in both languages were consistent with models of stop consonant acoustics, and place interactions with vowel duration were most apparent with long-lag English stops. The results are discussed in terms of speaking rate and language-internal forces, contributing to burst amplitude variation and their implications for speech perception and potential to affect lenition phenomena. For example, velars generally have a mid-frequency prominence as a result of a relatively long oral cavity. Indeed much of the literature does not examine burst variation directly, but rather intraoral pressure , models of Po for voiceless stops suggest that it is not straightforwardly affected by the temporal constraints imposed by increased rate. Po in voiceless stops has a rise time on the order of 50 ms , which is potentially sufficient time to achieve Po maxima in speeded speaking rate conditions where closure duration at fasts rates are generally greater than 50 ms (Po is indeed correlated with speaking rate. In a study of Swedish aspirated “pa” spoken by a single speaker at different rates (1–3 syllables/s), Po, which decreased by approximately 4–5 cm H2O at fast speaking rates. Po in three speakers’ productions of English CVCs in monologues  and citation contexts. For all three speakers, Po for voiceless stops was at least 1 cm H2O lower in monologue than citation contexts. Speaking rate also affects physiological properties of respiration. Lung volumes in speeded speaking tasks are lower than in slow speech  and tissue compliance have been shown to slow the buildup of Po during stop closure, and are highly variable both within and across speakers, thereby contributing to the complex effects on burst amplitude  and airflow at consonant release  and resonances . Place oplitudes . Importaplitudes .Po and burst amplitude. The faster initiation of vocal fold oscillation in short-lag VOTs suggests that Po is sufficiently low to promote enough of a trans-glottal pressure differential for the rapid onset of phonation. This would be manifested in lower burst amplitude. The study focuses on consonants broadly classified as “voiceless,” that is, consonants where the primary acoustic and perceptual characteristic is VOT. Previous research on speaking rate, Po, and burst amplitude was conducted in languages (English and Swedish), where pre-vocalic word-initial voiceless plosives are necessarily aspirated. The present study examines the relationship between relative burst amplitude and speaking rate in speakers of North American English (Indo-European) and Indian Tamil (Dravidian), a language which lacks phonemic voicing and exhibits short-lag VOT word-initial plosives  test the hypothesis that burst amplitude in CV syllables decreases with the increase in speaking rate, (2) examine whether such speaking rate effects are more or less evident at various places of articulation, and (3) explore the interaction between speaking rate and oro-laryngeal synchronization  on burst amplitude. It is hypothesized that burst amplitude is related to VOT, with long-lag VOT being associated with high plosives .F0 perturbation; Po variability which might potentially obscure the effects of VOT on burst amplitude. These phonetic characteristics associated with English have not been reported for short-lag Tamil plosives, where there is no phonological contrast. Given that the hypothesized mechanism affecting burst amplitude variation in the current study is Po constrained by time in speeded conditions, the short-lag series from Tamil, rather than the phonologically voiced English series, was considered a more appropriate comparison with the long-lag English series. Language differences are, therefore, explained in terms of the effects of VOT type on burst amplitude.In comparing short-lag (Tamil) and long-lag (English) plosives, the present study addresses the contribution of speaking rate and oro-laryngeal timing dynamics to observed burst amplitude effects. Short-lag plosives from Tamil are examined instead of English short-lag stops (the voiced series /b d g/ [b° d° g°]) to avoid aerodynamic and acoustic characteristics of phonologically voiced stops  and extra-linguistic (speaking rate), and directions for future study examining potential perceptual effects of burst amplitude variation are offered.The speech of 12 North American (Canadian and American) English speakers , aged 36–45 years, and 10 Indian Tamil speakers , aged 24–44 years, was analyzed. All participants were native speakers of their respective languages, with no reported speech or hearing disorders. Participants were recruited via email solicitation and through various social media platforms.Due to restrictions to laboratory access during the global pandemic, participants were asked to record themselves in a quiet room at their respective residences . Participants were instructed to use a wired microphone (either ear-bud or closed-ear gaming style) along with recording software (such as Audacity or Praat) installed on their home computer. English-speaking participants were instructed to make three recordings, one each for the monosyllables “pa,” “ta,” and “ka.” For each recording, participants were asked to repeat the syllable at four self-paced speaking rates  for approximately 5 s per rate. Instructions for Tamil-speaking participants were identical but with recordings for four places of articulation, bilabial ([pa]), dental ([t⊓a]), velar ([ka]), and retroflex ([ʈa]). Instructions included an example audio file of the syllable “pa” (American English as recorded by the author) modeling the rate manipulation and providing a general structure of the recording. Participants made recordings with sampling rates at or above 22 kHz and saved as .wav or .aiff files. Given the nature of the instructions (5 s per rate) participants produced more fast-rate tokens than slower rate tokens. There was some concern that amplitude measurements would be affected by the variety of microphones and recording interfaces employed by the participants. No post hoc scaling was performed on raw amplitude measurements (burst) as difference measures (between the burst and adjacent vowel) served as dependent variables (see Section 2.3).All measurements were made by hand using Praat speech processing software by trained phoneticians. Two temporal measurements were made: duration of consonant release/burst (VOT), and vowel duration. The onset of consonant release was identified at the first appearance of broadband transient noise, which was often followed by a burst of frication noise. Both transient and frication were considered the “burst.” Burst offset was identified at the zero-crossing before the first glottal cycle of the following vowel. The vowel onset (coinciding with the burst offset) was indexed by the first low-amplitude periodic oscillation. The end of the vowel (in the CV syllables) was marked by three co-occurring events: (1) a dramatic change in amplitude in the waveform, (2) a change in the energy in the formants accompanied by a change in complexity in the waveform indicating a loss of energy in F2 and F3, and (3) the onset of aperiodicity.AvF1, or the average amplitude of F1 in the vowel; (2) MaxHi, or the maximum spectrum amplitude in the burst above 3 kHz  and 3.5 kHz ; and (3) MaxMid, or the maximum spectrum amplitude in the burst in the F2/F3 range. Following HiDiff (AvF1-MaxHi), and mid-frequency MidDiff (AvF1-MaxMid) burst amplitudes. Relational measures of burst amplitude have been used in other studies examining strength . To confirm this assumption, the relationship between subjective speaking rate and vowel duration was examined. The raw vowel duration data according to speaking rate and language are shown in Although some literature on speaking rate follows from a controlled implementation of speaking rate regulation procedures, where participants are instructed to synchronize their production with a metronome ensuring a consistent implementation of rate e.g., , much ofA linear mixed-effects model (nlme) was fit to the vowel duration data with rate  crossed with language  as predictors. The model was fit with random slopes and intercepts for rate by subject. Model coefficients are given in The model suggests that subjectively implemented speaking rate adjustments affect vowel duration in the direction predicted, increasing with the decrease in subjective rate. The interaction between rate and language reflects the longer mean vowel duration for slow rate in English speakers than Tamil speakers, which flips the more general trend in the data, where vowel durations in Tamil are longer than in English in normal, fast, and very fast rates.To determine the effectiveness of incremental speaking rate increases in each language, separate linear models were built for English and Tamil. Pairwise comparisons of rate effects on vowel duration in English speakers showed significant differences between all rates, suggesting shortening with each successive increasing rate. The difference in vowel duration between slow and normal rates in Tamil speakers was small and not significantly different, whereas all other rates showed significant differences in the expected direction.Vowel duration was used as a stand-in for speaking rate in all of the following analyses. Linear mixed-effects models were fit to examine (1) short-lag (Tamil) and long-lag (English) VOT differences in the effect of vowel duration on MidDiff and HiDiff across all places of articulation and (2) the language-specific interaction effects of vowel duration and place of articulation on MidDiff and HiDiff. All models were fit with random slopes and intercepts for vowel duration by subject.t = 1.58, p = 0.12) than long-lag (English) burst amplitudes. Model coefficients for both MidDiff and HiDiff are given in The results confirm the hypothesis that temporal constraints on articulation negatively affects the amplitude of release bursts in word-initial stops—with the increase in vowel duration, the difference in amplitude between the consonant burst and the following vowel decreases, or put another way, with the increase in vowel duration consonant bursts increase in amplitude. Model estimates also suggest that short-lag Tamil burst amplitude may be lower than in long-lag English plosives, especially for the high-frequency prominence at vowel durations longer than 200 ms where confidence intervals no longer overlap. The language/VOT difference may be obscured by the differing consonant inventories in English and Tamil. To explore the possible language/VOT differences on burst amplitude, the next section models the effect of vowel duration on a subset of the data where English and Tamil share consonant places of articulation—bilabial and velar plosives.To tease apart possible differences between short-lag (Tamil) and long-lag (English) plosives, a subset of the full data with only bilabial and velar stops was analyzed (shared by both Tamil and English). Fully crossed models (Vowel Duration × POA × Language) of MidDiff and HiDiff were fit to the bilabial-velar data with random slopes and intercepts for vowel duration by subject. t = 2.02, p = 0.05; HiDiff: t = 1.91, p = 0.07). The effect of vowel duration on burst amplitude is comparable to the models including all places of articulation in Section 3.2.The model coefficients suggest that short-lag (Tamil) burst amplitudes  are lower , suggests the effect of vowel duration on the relationship between bilabials and velars is different in the two languages .In the HiDiff model, the effect of vowel duration (across both POAs) on burst amplitude was different in short-lag (Tamil) relative to long-lag (English) plosives. The model also shows that the relationship between bilabial and velar was different in short-lag (Tamil) relative to long-lag (English). There was a significant interaction between POA and vowel duration suggesting that vowel duration has a different effect on velar burst amplitude than bilabial burst amplitude across both laryngeal specifications (English and Tamil). Finally, the three-way interaction term suggests differing effects of vowel duration on the relationship between bilabials and velars in the two languages/laryngeal specifications.The effect of vowel duration on the various places of articulation in the two languages (with language-specific models) is explored in the next section.Place-of-articulation effects in English and Tamil were analyzed separately to account for their differing stop-consonant inventories. Although both languages share bilabial and velar places, coronal places vary—Tamil with two, dental ([t⊓]) and retroflex ([ʈ]). Linear models of burst amplitude were fit with place of articulation and vowel duration as predictors and the same random-effects structure as the aggregate models above.The effects of vowel duration and place of articulation on MidDiff and HiDiff in English are given in All fixed effects and interactions were significant as were the vowel duration interactions with alveolar and velar places of articulation . That is, the effect of vowel duration on the burst amplitudes of alveolars and velars is different from vowel duration effects on the burst amplitudes of bilabials. These interactions are evident in the model estimates shown in Po given in The overall effect of place of articulation on burst amplitude measures are consistent with those given in Velars have a high-amplitude mid-frequency prominence (MidDiff = 23.43 dB) and a high-frequency prominence that is between bilabials and alveolars in amplitude (HiDiff = 34.5 dB). Alveolars have a mid-frequency amplitude higher (MidDiff = 28.85 dB) than bilabials, and a high-amplitude, high-frequency prominence (HiDiff = 24.05 dB).The effects of vowel duration and place of articulation on MidDiff and HiDiff in Tamil are given in ret = 38.80 dB, HiDiffden = 38.50 dB), again consistent with All fixed POA effects were significantly different from the reference bilabial. Similar to the long-lag English data, and consistent with t =−0.70, p = 0.48), retroflex stops showed a significantly steeper increase in amplitude with the increase in vowel duration relative to bilabials.To better understand the oro-laryngeal timing differences in burst amplitude as a function of speaking rate, the relationship between VOT and vowel duration was modeled in the two languages. The results of the VOT model are given in laryngeal realism literature, suggesting that phonetic cues to phonological categories decrease in duration as speech rate increases , while the long-lag VOT status in English allows for a more flexible oro-laryngeal timing. Given the relative immutability of VOT in short-lag Tamil plosives, does it contribute to burst amplitude variability? The effect of VOT on burst amplitude measures were modeled separately in both languages.Mixed-effects models of MidDiff and HiDiff were fit to the data with VOT as a predictor and random intercepts and slopes for VOT by subject. Model coefficients are shown in The results show that VOT is correlated with burst amplitude in both the mid-frequency and high-frequency prominences. Similar to vowel duration, with the increase in VOT, burst amplitude increases (difference measures decrease).t =−1.83, p = 0.07) in the high-frequency prominence.Mixed models were likewise fit to the Tamil short-lag burst amplitude data, with VOT as a predictor and random slopes and intercepts for VOT by subject. The overall temporal constraining of the Tamil syllable  primarily affects the mid-frequency burst amplitude. That is, the effects of VOT are comparable to the effects of vowel duration on Tamil short-lag burst amplitudes (Section 3.4).Linguistic factors such as syllable structure  and phraPo buildup. Conversely, short-lag stops have lower burst amplitudes than English (suggesting lower Po), with less pronounced effects of speaking rate. However, the automatic relationship between short-lag VOT and burst-amplitude need not necessarily follow in a way exemplified in the present data. For example, Korean fortis stops show high Po and have burst energy comparable to lenis stops despite having short-lag VOTs  than in long-lag (English) plosives; the effect was smaller for velars. These differences were unpacked by examining the association between vowel duration and VOT. Consistent with the extant literature, long-lag VOT is more tightly associated with vowel duration when intended speaking rate increases or decreases. Although there is a relationship between vowel duration and VOT in short-lag plosives (as a function of rate adjustments), it is considerably more shallow. This suggests that the differing oro-laryngeal timing in the two types of plosives may be responsible for the burst amplitude variation. Long-lag VOT is strongly correlated with vowel duration as well as higher overall burst amplitudes than in short-lag plosives. When coupled with the general tendency for voiceless aspirated stops to have long closure durations , it can lag VOTs . This suWe can conclude from this study that speaking rate, as manifested in vowel duration, affects the burst amplitude of preceding consonants, and that VOT interacts with that effect. These results are very much in line with a growing phonetics literature focused on rate variability and its contribution to phonological lenition , which hWhile the outcome of fast speech in the intervocalic consonant literature is a non-phonologized synchronic lenition in production, directions for future research building upon the present results might consider how the acoustic variability  in consonant bursts contribute to both our understanding of (1) general consonant perception and (2) listener-driven diachronic patterns in languages.From a purely speech processing perspective, we might ask about the extent to which the phonetic association between vowel duration and burst amplitude is represented in the listener, that is, does a listener expect an association between vowel duration (rate-conditioned or otherwise) and reduced burst amplitude? If so, how does a listener’s language experience affect their perception of this trading relationship ? Would tA second line of inquiry considers the laryngeal-timing and place effects observed in the present study as contributing to our understanding of diachronic lenition processes. Although burst characteristics are part of a larger constellation of acoustic cues utilized by the listener in determining consonant identity, disruption of burst cues results in a greater reliance on formant transitional cues in perception . When coIn this way, the study of naturally conditioned variation in stop consonant burst amplitude may allow us to better understand the nature of listener knowledge as well as how that knowledge potentially affects historical phenomena.


Plant-microbe interaction has always been the focus of agricultural life science and has continuously increased the knowledge of human cognition about the nature. However, previous efforts in this regard have mostly focused on “one-to-one” binary relationships, such as the most classical plant-pathogen interaction “zigzag” model proposed by Jones and Dangl . HoweverZhang et al. in their article “Co-infection of Fusarium aglaonematis sp. nov. and Fusarium elaeidis causing stem rot in Aglaonema modestum in China” obtained multiple Fusarium isolates from the diseased A. modestum, and determined F. aglaonematis and F. elaeidis belonging to different Fusarium species complex as the pathogens. Co-infection of the two species enhanced the disease severity of the host compared to single inoculation. Similar examples of synergistic interactions of pathogen-pathogen in plants that lead to increased disease severity have often been reported. For instance, co-infection of F. oxysporum f. sp. medicaginis and Rhizoctonia solani resulted in more severe disease incidence and growth reduction in commercial alfalfa production compared to a single infection   reveals hypersensitive responses to Plasmopara viticola” revealed that the resistant grape variety “Kober 5BB” has significantly different gene expression profiles from the susceptible variety “Zitian Seedless”, and Caspase-like proteases mediating plant hypersensitive response (HR) cell death is the key strategy in the process of grape defense against downy mildew. Besides HR, reactive oxygen species (ROS) and plant hormones like salicylic acid (SA) and jasmonic acid (JA) have been reported to be involved in plant defense  silencing pathways in regulating the expression of effectors in pathogenic oomycetes.The complexity of the pathogen-host interaction is not only reflected in the change of the composition of the pathogen mixture at different stages on the same plant, but also in the different gene expression profiles of the resistant and susceptible plant varieties responding to the same pathogen. In conclusion, this special issue focusing on pathogen co-Infections of plant diseases highlights the importance of the interactions between multiple pathogens and plant-pathogen and calls for future endeavors in this area. The underlying mechanisms resulting from pathogen co-infection that can lead to complex disease epidemiology are important topics for investigation and for the development of novel disease management approaches.JZ, SK, and XZ contributed to the manuscript preparation and finalizing. All authors contributed to the article and approved the submitted version.


Introduction:Three-dimensional finite elemental analysis (FEA) is a contemporary research instrument for the numeric simulation of a real physical system’s mechanical process. FEA can be used as a very effective tool to analyze and compare various aspects of rapid palatal expanders and to determine the stress distribution in maxillofacial bones and displacement and the biomechanical effects it has on the circummaxillary sutures. This study evaluates the effects of different modes of rapid palatal expansion on maxillary protraction as a treatment modality in skeletal Class III malocclusion by determining the stress and displacement along the circummaxillary sutures using the FEA. appliance , (B) tooth-borne HYRAX (hygenic rapid expander) appliance , and (C) bone-borne modified MARPE appliance , was transferred to ANSYS WORKBENCH, 2020 R1 software , and three finite element models with each appliance were prepared. A protraction force of 500g was applied to the occlusal plane that is directed 20 degrees inferiorly. The tensile stress, compressive stress, and the amount of displacement on the circummaxillary sutures were assessed and compared in all the three appliances. Young’s modulus (kg/mm2) and Poisson’s ratio (V) were used to calculate the stress and displacement in sutures adjacent to the maxilla in different aspects.Materials and methods: Initially, a three-dimensional finite element simulation of the maxillofacial skeleton and sutures was obtained by Mimics software  from the cone-beam computed tomography  images of a 30-year-old adult with normal occlusion. A geometrical preparation of the three expansion appliances, (A) hybrid MARPE Results: On analyzing the stress distribution, the tensile stress was found to be maximum in the medial aspect of the frontomaxillary suture of the bone-borne modified MARPE appliance (C), and the minimum tensile stress was found in the lateral aspect of the sphenozygomatic suture in hybrid MARPE (A). Again, the compressive stress distribution was found to be maximum in the medial aspect of the frontomaxillary suture in all three simulations and the minimum compressive stress in the superior aspect of the internasal suture in hybrid MARPE (A) along with the frontonasal suture at its medial aspect for tooth-borne HYRAX (B) and bone-borne modified MARPE (C). Displacement of the maxilla in all the planes was observed to be the largest for the bone-borne modified MARPE (C) appliance. On the contrary, the minimum displacement was found in the tooth-borne HYRAX (B) appliance. Conclusion: The findings reveal that all three modes of rapid palatal expanders produced stress and displacement along the circummaxillary sutures on the application of protraction force with bone-borne modified MARPE being more effective in treating posterior crossbites thereby correcting the skeletal Class III malocclusions successfully. Maxillary protraction with face mask therapy is a significant treatment modality for skeletal Class III malocclusion with maxillary deficiency at growing age. The protractive force should be applied to the maxilla as a single unit for it to be effective . The extOne of the effective ways to treat transverse deficiency in Class III malocclusion is rapid palatal expansion (RPE) . The forVarious studies have assessed and compared these rapid palatal expanders and their effects on the circummaxillary sutures , 3, 5, 6First, a three-dimensional finite element simulation of the maxillofacial skeleton and a physical model of the sutures were established. For that, a cone beam computerized tomography of an adult of 30 years with normal occlusion and no temporomandibular disease was chosen. Finally, a three-dimensional finite element model of the maxillofacial skeleton and sutures was obtained by Mimics software .Three-dimensional coordinate axis distribution as well as displacement in the maxillary suturesX denotes the transverse plane, Y denotes the anteroposterior plane, and Z the vertical plane. The positive values on these planes show forward, outward, and downward displacements of the maxilla. The physical properties of the materials used are shown below Table  11]..11].Design of the RPE Appliances: In the study, three diverse modes of rapid palatal expanders are used: hybrid MARPE  appliance , tooth-borne HYRAX (hygenic rapid expander) appliance , and bone-borne modified MARPE appliance . The rapid palatal appliance was designed in such a way as to open the palate in the sutural region at a rate of 1mm per side.Hybrid MARPE Appliance (Simulation A): The MARPE appliance includes a HYRAX screw with the extension attached to the first molars and first premolars. The bands for molars are meshed with shell elements. A tied interface connects it to the teeth and is then attached with a 0.9mm stainless steel wire on the palatal sides [al sides .Tooth-Borne RPE Appliance (Simulation B): The tooth-borne expander used in this study is HYRAX type. Here, bands are attached to the premolars and first molars. Two-dimensional images of the appliance are used to simulate the first model as tooth-borne RPE [orne RPE .Bone-Borne or Modified MARPE Appliance (Simulation C): A two-dimensional Micro-4 HYRAX appliance, with four palatal miniscrews and the arms of the HYRAX screw bent to fit into the collar design, was used for the bone-borne appliance to simulate the three-dimensional finite element model for bone-borne rapid palatal expander [expander .2) and Poisson’s ratio (V) were used to calculate the stress and displacement in sutures adjacent to the maxilla in different aspects [After the completion of the design of the rapid palatal expanders, a geometrical preparation of the three appliances, (A) hybrid MARPE appliance, (B) tooth-borne HYRAX appliance, and (C) bone-borne modified MARPE appliance, using Auto CAD  and CREO  software was done. All these components were transferred to ANSYS WORKBENCH, 2020 R1 software , and three finite element models with each appliance were prepared. A protractive force of 500g was directed 20 degrees below the plane of occlusion. That means the force is directed around the Z axis at approximately -20 degrees inferiorly in all three models, according to Oppenheim . The thr aspects .The tensile stress, compressive stress, and the amount of displacement on the circummaxillary sutures were assessed and compared in all the three appliances, hybrid MARPE (A), tooth-borne HYRAX (B), and bone-borne modified MARPE (C).The stress distribution was assessed and compared in the following circummaxillary sutures: (i) frontomaxillary , (ii) nasomaxillary (superior and inferior), (iii) zygomaticomaxillary , (iv) zygomaticotemporal , (v) zygomaticofrontal , (vi) frontonasal , (vii) internasal (inferior and superior), (viii) sphenozygomatic , and (ix) pterygomaxillary sutures (inferior and superior).The amount of three-dimensional displacement was measured using the ANSYS software at the points: (i) anterior nasal spine (ANS), (ii) point A, (iii) prosthion (Ps), and (iv) posterior nasal spine (PNS) .The three RPE appliances (i) hybrid MARPE (A), (ii) tooth-borne HYRAX (B), and (iii) bone-borne modified MARPE (C) were evaluated for the stress distribution at each suture and the displacement to the forces applied.Comparison of the tensile stress distribution produced by hybrid MARPE (A), tooth-borne HYRAX (B), and bone-borne modified MARPE (C)On analyzing the tensile stress distribution, it was found to be maximum in the medial aspect of the frontomaxillary suture for bone-borne modified MARPE appliance (C) and the minimum tensile stress was found in the lateral aspect of sphenozygomatic suture in hybrid MARPE (A). In tooth-borne HYRAX (B) and bone-borne modified MARPE (C) appliances, the stresses appeared to be that of a wide range in the medial aspect of the frontomaxillary suture, and it got narrower in the medial aspect of the sphenozygomatic suture Table .Comparison of the compressive stress distribution between hybrid MARPE (A), tooth-borne HYRAX (B), and bone-borne modified MARPE (C)On analyzing the appliances, the compressive stress was found to be highest in the medial aspect of the frontomaxillary suture in all three simulations, a minimum stress distribution was observed in the superior aspect of the internasal suture in hybrid MARPE (A), and for the frontonasal suture, it appears medially with the tooth-borne HYRAX (B) as well as bone-borne modified MARPE (C) Table .Comparison of the range of displacement at the sutures between hybrid MARPE (A), tooth-borne HYRAX (B), and bone-borne modified MARPE (C)The displacement was calculated and determined separately with the help of reference points of ANS, PNS, Ps, and point A on the three axes X, Y, and Z. The transverse (X-axis), antero-posterior (Y-axis), and vertical (Z-axis) displacements of the maxilla are the largest for bone-borne modified MARPE (C) appliance when compared to hybrid MARPE (A) and tooth-borne HYRAX (B) appliance. On the contrary, the minimum displacement was found in the tooth-borne HYRAX (B) appliance Table .Among the three appliances, the bone-borne modified MARPE appliance (C) has the largest displacement of 1.16mm, whereas the tooth-borne HYRAX appliance (B) has the least displacement of 0.5557mm. Also, the largest amount of displacement was found to be at point Ps of bone-borne modified MARPE appliance, and the least amount of displacement was found to be at point PNS for hybrid MARPE appliance (A). However, the amount of displacement at point PNS for hybrid MARPE (A) and tooth-borne HYRAX (B) is coinciding.The management modalities and time of treatment in skeletal Class III malocclusions have remained controversial among clinicians. These are mostly related to the factors such as skeletal dental discrepancies, age, and residual growth. The transverse deficiency should be corrected as soon as it is diagnosed since it is mandatory for establishing normal occlusion. Baik analyzed the effects of maxillary advancement in children. After maxillary protraction, the maxilla as well as the maxillary dentition moved forward and downward similar to our study .In a study done by Gautam et al., the application of maxillary protraction forces produced maximum stress at the sphenozygomatic suture followed by the zygomaticomaxillary and zygomaticotemporal sutures . HoweverBaik evaluated the effect of protraction force on the maxilla at the craniofacial bones . He founRPE remodels the circummaxillary sutures and is effective for maxillary protraction. Hass observed forward and downward tipping of the maxilla along with the inferior and backward rotation of the mandible . FEA is Kambara reported that postero-anterior traction produced changes in the maxillary tuberosity and circummaxillary sutures . This inIn a FEM study by Miyasaka-Hiraga et al., in order to find out the effects of the direction of maxillary protraction forces on biomechanical changes in the craniofacial complex, it was observed that a force directed 30 degrees inferiorly produced a stress distribution that was more uniform at the various transverse planes whereas in our study, a 20-degree protraction force, unique to the occlusal plane, produced a non-uniform stress distribution in all three simulations . Hence, In a study evaluating the distribution of stress and displacement at the craniofacial sutures with rapid maxillary expansion (RME), the maximum tensile stress was found along the frontomaxillary suture, which is similar to our study . Our obsThe rate of growth of sutures is increased by tension as well as compression, and it is an important factor for the development of the suture. The tensile stress initiates the separation of the cranial sutures and the sutural growth . In a clThe limitation of the study includes that a more advanced study with clinical identification is needed since the impacts on the muscles of the face and other soft tissues also need to be examined.In conclusion, the most effective mode of producing RPE among the three appliances used in the study on the application of maxillary protraction force, by using the three-dimensional FEA, is the bone-borne modified MARPE appliance (C) followed by the hybrid MARPE appliance (A) and the least effective being the tooth-borne HYRAX appliance (B) based on the amount of displacement each appliance produces. At the same time, the amount of stress produced was also in a wide range for the bone-borne appliance when compared to the other appliances. The maximum tensile and compressive stresses were produced at the frontomaxillary suture for the bone-borne modified MARPE (C) appliance. The amount of displacement was also greater for the bone-borne modified MARPE appliance (C) followed by the hybrid MARPE appliance (A). However, the tooth-borne HYRAX appliance measured the least amount of displacement.The findings reveal that all three modes of rapid palatal expanders produced stress and displacement along the circummaxillary sutures on the application of protraction force with bone-borne modified MARPE (C) being more effective in treating posterior crossbites thereby correcting the skeletal Class III malocclusions successfully.


The impact of the intrinsic curvature of in-plane orientationally ordered curved flexible nematic molecules attached to closed 3D flexible shells was studied numerically. A Helfrich-Landau-de Gennes-type mesoscopic approach was adopted where the flexible shell’s curvature field and in-plane nematic field are coupled and concomitantly determined in the process of free energy minimisation. We demonstrate that this coupling has the potential to generate a rich diversity of qualitatively new shapes of closed 3D nematic shells and the corresponding specific in-plane orientational ordering textures, which strongly depend on the shell’s volume-to-surface area ratio, so far not predicted in mesoscopic-type numerical studies of 3D shapes of closed flexible nematic shells. Particularly intriguing are mechanisms which have the potential to generate a rich pallet of qualitatively different configurations, could be sensitively tuned, and exhibit universal features applicable to various physical systems. Different morphologies in general provide different functionalities, and such properties are, among other things, essential for complex systems to adapt to changes in their environments.It is of strong interest to identify and master generic mechanisms that drive 3D changes in geometrical shapes of diverse condensed matter systems17, elastomers18 or liquid crystalline (LC) bodies7. For instance, by varying the volume-to-surface area ratio, erythrocytes and liposomes transform among qualitatively different shape classes22. LC drops and shells24 could exhibit morphological changes by varying the surface tension strength and LC elasticity forces8. Via this mechanism, LC bodies could exhibit either a spherical, undulated, “flower”-like or filamentous structure. Furthermore, in elastomers one could trigger shape changes mechanically or remotely by appropriate external fields18.Of particular recent interest are mechanisms triggering 3D shape changes of soft matter objects, such as biological membranes26 exhibiting an in-plane structural order28 embedded in a 3D Euclidian space. There exist diverse experimentally accessible effectively thin flexible 2D ordered systems, for instance biological membranes or LC shells24. Furthermore, due to the relative simplicity of 2D flexible shells embedded in 3D space, several well established mathematical approaches modelling their behavior are available.Convenient model systems to study 3D shape changing mechanisms are closed 2D flexible shells30 are inevitably formed in closed flexible shells exhibiting an in-plane order for nontoroidal topologies. They correspond to localized field distortions and are characterized by the winding number m31, which is a conserved value. Commonly, TDs carrying positive and negative values of m are referred to as defects and antidefects, respectively. According to the Gauss-Bonnet and Poincare-Hopf theorems34 the total winding number within a closed flexible shell equals 2 for spherical topology.Topological defects (TDs)V and surface area A is their relative/reduced volume A and radius v. In previous related studies on the effect of orientational ordering of membrane attached curvature-inducing nematogens on nematic vesicle 3D shapes35, the relative volume v was not fixed in simulations. By contrast, in our study the value of v plays a key role in the determination of different 3D flexible shell shape classes.In our study we consider 3D shapes of closed 2D flexible thin shells with attached curved nematic rod-like molecules exhibiting a nematic orientational order (flexible nematic shells). We use a modified Landau-de Gennes-Helfrich model, where we introduce an additional term, which couples the curvature of flexible rod-like nematic molecules with the shells’s curvature field. We show that this term could generate a rich pallet of qualitatively different 3D shapes of flexible nematic shells with attached curved nematic molecules. The crucial geometric parameter of the 3D closed shapes of these nematic shells with volume 24 and biological membranes14.We study the interplay between equilibrium shapes and the in-plane nematic orientational ordering of closed axially symmetric flexible shells with attached curved rod-like nematic molecules. The local geometry and order at the mesoscopic level of such nematic shells are described by the curvature field and nematic order parameter field of the nematic shell. Our model could describe diverse 2D curved manifolds exhibiting an in-plane nematic-type orientational order. Prototypical examples are nematic LC shellsThe local curvature of the flexible nematic shell’s surface is described by the curvature tensor37Orientational ordering on the surface is described by the surface order tensor 40. This term aims to minimise the isotropic bending energy of the flexible shell, where In our model it is assumed that curved nematic molecules are homogeneously distributed throughout the flexible shell surface, but they can locally change their in-plane orientation. The total free energy functional of such curved nematic surface T is the temperature37.The condensation term Eq.  enforces41. This term enforces a spatially homogeneous nematic order and is locally minimised when neighbouring curved nematic molecules are parallel to each other. In this study the nematic order parameter correlation length The intrinsic elastic (direct interaction) term Eq.  is weigh43 to study the influence of curved rod-like proteins (e.g. BAR proteins44) attached to biological membranes, where direct interactions between proteins were not taken into account. In Eq.  of the investigated shell. We study the 3D shapes of closed 2D axisymmetric surfaces (flexible thin nematic shells) exhibiting a spherical topology.In this section we present numerical results designed to study the interplay between the equilibrium 3D shapes and in-plane orientational ordering of closed thin and flexible nematic shells for different values of the relative volume. All lengths in the paper are scaled to R. We predicted three qualitatively different classes of shapes  for different 47; therefore, the sequence in Fig. First we describe the influence of the intrinsic curvature of nematic molecules mentclass2pt{minimmentclass2pt{minimmentclass2pt{minimv48  at lower values of v, plays a crucial role in determining equilibrium shapes. Oblate-stomatocyte-prolate shape transformations  to the highly curved protrusions45. If the molecules were not distributed over the entire surface, the costly TDs could also be avoided, which would reduce the energy penalty given by the energy terms described by Eqs.  curvatures as previously suggested in42. We show that the spiral organization of curved nematic molecules is possible also when the molecules are rod-like  shapes due to rod-like proteins and different orientations of differently curved proteins on the tubes were predicted also in45. In Fig. v of the shape is assumed to remain constant in the process. Curved nematic molecules with 45 for the case of closed membrane shapes containing curved BAR proteins, but without considering the direct interaction term  in both solutions, the relative volume v of the closed membrane (vesicle) is fixed for the given osmotic conditions in the system58.The coupling between the 3D equilibrium shapes of 2D closed shells and their 2D in-plane nematic orientational ordering was studied theoretically. We assumed strong adhesion of curved flexible nematic molecules on the flexible shell support. In addition to the free energy terms associated with in-plane orientationally ordered curved nematic rod-like molecules, we included in the total free energy functional also the isotropic bending energy of the flexible shell as supporting material for the attached curved nematic molecules  orientation of curved nematic molecules. In the present study, such an in-plane orientational ordering configuration was theoretically predicted also for prolate shapes in the absence of an external stretching force . Increasing the temperature above the phase transition temperature could therefore lead to the formation of thin necks and consequently to the fission of the shell into separate compartments.Lastly, we have shown that temperature-driven shape reconfigurations when moving from ordered (nematic) to disordered (isotropic) phase can lead to the formation of undulated shapes with extremely thin disordered necks Fig.  that areR in our study) would lead to quantitatively different content shown in Fig. 61. Therefore, we expect a significantly quantitatively different behavior of the system just by varying the temperature. Moreover, there are several indications (see62 and references therein) that the proximity of the phase transition temperature in biological membranes is evolutionarily beneficial. Therefore, significant changes in the configuration of the membrane energy landscape are expected by varying the temperature, and this is also the focus of our planned future study. In addition, the relative strength of intrinsic (D) curvature may also strongly influence the placement of TDs and thus the stability diagram of competing membrane structures. Moreover, the character of the order-disorder phase transition might depend on the membrane thickness62. Namely, in 3D bulk system, the isotropic-nematic phase transition is discontinuous because the condensation free energy term , defined by the unit vectors (41:z(s) are the coordinates of the profile curve in the s is the arc length of the profile curve. On a surface of revolution, the parallels and meridians are lines of principal curvature. We establish that the principal directions s is constant), respectively.We conducted simulations on two-dimensional (2D) closed axisymmetric shells with spherical topology. These shells are assumed to have a surface of revolution with rotational symmetry about the mentclass2pt{minim65:65:N Fourier modes  and mean curvature (H) through the following expressions:41:37:The parameterization for the nematic order tensor (defined in Eq.  see Eq.  can be dJ(s)  and volume (V) of the shell to establish a fixed value for the relative volume of the shell (v).In numerical simulations, we obtain the equilibrium shapes of closed shells and their corresponding nematic ordering textures. The equilibrium nematic textures are computed using the standard Monte Carlo method, where the shell surface in the coordinates J(s) Eq. . The equThe parameterization for all the shapes is the same. The different calculated shapes are given by different sets of Fourier amplitudes mentclass2pt{minimSupplementary Information.