Bph36-NIL, through RNA-seq, depicting the differential expression profiles of mRNAs and long non-coding RNAs (lncRNAs) in rice before and after BPH feeding. We observed a proportion of genes (1.48%) and (2.74%) were altered in KW and NIL, respectively, indicating different responses of rice strains against BPH feeding. Nevertheless, we characterized 384 differentially expressed long non-coding RNAs (DELs) that can be impacted by the two strains by alternatively changing the expression patterns of the respective coding genes, suggesting their certain involvement in response to BPH feeding. In BPH invasion, KW and NIL responded differently by modifying the synthesis, storage, and transformation of intracellular substances, adjusting the nutrient accumulation and utilization inside and outside the cells. In addition, NIL expressed stronger resistance by acutely up-regulating genes and other transcription factors related to stress resistance and plant immunity. Altogether, our study elaborates valuable insights into the genome-wide DEGs and DELs expression profiles of rice under BPH invasion by high throughput sequencing and further suggests that NILs can be utilized in BPH resistance breeding programs in developing high-resistance rice lines.Brown planthopper (BPH) is the most devastating pest of rice in Asia, causing substantial yield losses and has become a challenging task to be controlled under field conditions. Although extensive measures have been taken over the past decades, which resulted in the evolution of new resistant BPH strains. Therefore, besides other possible approaches, equipping host plants with resistant genes is the most effective and environment-friendly technique for BPH control. Here, we systematically analyzed transcriptome changes in the susceptible rice variety Kangwenqingzhan (KW) and the resistant near-isogenic line (NIL) KW- Oryza sativa L.) is one of the most important crops in the Asia-pacific region and therefore, is a host to a wide range of insects that feed on it. Among these IPs, brown planthopper  is the most devastating pest of rice, accounting for about 20% to 80% of yield loss and an overall economic loss of around $300 million in Asia annually (Insect pests (IPs) have always emerged as the major agricultural constraint, resulting in significant yield loss and deteriorating grain quality. Among other cereals, rice  developed from wild rice GX2183, which was previously reported to be resistant to BPH. Using backcrossing via marker-assisted selection (MAS) approach, a BPH-resistance locus on the short arm of chromosome 4 was mapped to a 38-kb interval flanked by InDel markers S13 and X48 and then was named Bph36. After evaluating several parameters, Bph36 conferred high levels of antibiosis and antixenosis to BPH and confirmed that Bph36 could be utilized in BPH-resistance breeding programs to develop high-resistant rice lines to facilitate further map-based cloning of resistant genes  have been used to verify and fine-map QTLs in many crops  and are Nowadays, RNA sequencing (RNA-seq) is the most important tool to study differential expression of genes (DEGs) and long non-coding RNAs (DELs), thereby facilitating the ability to know potential physiological changes under distinct conditions. High-throughput sequencing and genome-wide alignment showed that non-coding transcripts account for the vast majority of eukaryotic genomes, most of which are long non-coding RNAs (lncRNAs) . High-thBph36-NIL) that we previously produced , a near-isogenic line, introgressed BPH-resistant gene Bph36 into KW were used as study materials. Rice seeds were germinated in a 10 cm diameter plastic cup and cultured in a greenhouse at 16/8 h day/night photoperiod under 28/25°C day/night temperature. When the rice seedlings reached 3 leaf stage, weak seedlings were removed, leaving 10 plants per cup. Then, put the transparent gauze net bag on the cup and released the 2nd-3rd instar larvae of BPH, ensuring 8 nymphs per seedling on average. Samples were taken at 0h (control), 6h, 24h, and 48h after BPH onset, with three replicates for each treatment. Resistant materials were named as NIL0, NIL6, NIL24, and NIL48 and susceptible samples as KW0, KW6, KW24, and KW48. BPH nymphs were released at different time points, and all materials were sampled at the same time point. Samples were taken from about 5 cm of rice stem, which was eaten by BPH, and immediately put in liquid nitrogen.Kangwenqingzhan (KW), an Indica rice variety developed by Guangdong Academy of Agricultural Sciences, with no resistance genes to BPH, is highly susceptible to brown planthopper (BPH) and KW-Three biological replicates were used for all RNA-seq experiments sampled from each time point. Total RNA was extracted from each sample using TRIzol Reagent (Invitrogen)/RNeasy Mini Kit (Qiagen). Total RNA was quantified and qualified by Agilent 2100 Bio-analyzer , Nano Drop (Thermo Fisher Scientific Inc.) and 1% agarose gel. RNA with RIN value above 7 was used for further sequencing library construction. Preserved samples were sent to UniqueGene Company (Wuhan) for transcriptome sequencing. RNA-seq library was constructed by Illumina sequencing using the removed rRNA method with Ribo-Zero™GoldKits.O. sativa_323_v7.0) and the corresponding annotations were retrieved from the Phytozome database (Version 12.0) (43). After filtering low-quality raw reads with adaptor sequences, clean reads were obtained with FASTX-Toolkit (version 0.0.14) and the purified data with high quality were mapped to the reference genome using HiSAT2  for KW or NIL, determining up-regulated and down-regulated genes.Rice genomic sequence  intergenic transcripts were regarded as novel gene loci and used for lncRNAs identification. Five steps were adopted for the identification of bona fide lncRNAs as previously described : (1) traThe resulting lncRNA transcripts and known transcripts were then merged into non-redundant transcripts, which were further quantified by StringTie for each sample . Differe-ΔΔCt method  (Cat. RR047). qRT-PCR reactions were performed on a LightCycler 480 using TB Green™ Premix Ex Taq™II(Tli RNaseH Plus) (Code No. RR820). The reaction conditions were as follows: 95°C for 1 min followed by 40 cycles at 95°C for 15 s, 60°C for 15s, and 72°C for 28s. All RT-qPCR reactions were performed in triplicates. The results of each reaction were analyzed based on the 2t method . The detBph36-NIL to evaluate the high-quality and complete transcriptome of rice in response to BPH. First, KW and KW-Bph36-NIL (referred to as NIL) were used to perform the resistance identification to BPH feeding. As shown in (Supplementary figure 1), KW was highly sensitive while NIL exhibited high resistance to BPH suggesting the involvement of NIL materials has a vital role in BPH-resistant responses. These results further illustrate the facilitation of the development of BPH-resistant rice varieties.Brown planthopper (BPH) is the most destructive insect pest (IP) of rice, causing direct and indirect damage to the crops. Extensive measures like chemical and biological have been taken for the control of the pest during the past decades which alternatively resulted in increased BPH resistance and risk to our environment. Conversely, equipping host plants with resistant genetic resources is the most effective and environment-friendly approach to managing BPH. Therefore, the present study uses KW as a recurrent parent and the constructed near-isogenic lines KW-In order to validate the findings of these transcripts to determine the reliability of transcriptome in gene expression, we randomly checked six genes that were influenced by BPH treatments in the two strains. Among them, three genes  were up-regulated, and three genes  were down-regulated in terms of relative expression in both KW and NIL in our RNA-seq dataset. Therefore, we further strengthen the reliability of our results by RT-qPCR analysis. Expression patterns of all the examined genes were in agreement with RNA-seq data, further indicating the credibility of our transcriptome dataset for gene exploration  as visualization tool and constructed the putative interactive network of lncRNAs targeting their presumed PCGs  can interact with their related protein-coding genes (PCGs) regulating their expression at functional levels ; . In riSequencing data in the current study were obtained from four individual time points  to provide more comprehensive information on the change in rice during BPH attack. High-throughput sequencing was used to analyze the changes in the response of resistant and susceptible plants to BPH feeding. Through the preliminary analysis of KW, we found that there were more down-regulated genes among DEGs and most of them were related to metabolism. On the contrary, there were more up-regulated genes as to NIL Figure 1The sensitive rice had to reduce its basic metabolism levels to cope with the threat of BPH, while the resistant rice can initiate its defense mechanisms through the role of resistant genes. It is worth noting that a large number of genes were down-regulated in resistant rice at 48h after BPH onset, indicating that NIL was under great threat and could quickly adjust multiple ways to deal with the threat. Functional analysis showed that most of these DEGs were pathogen-related genes and energy metabolism-related genes Figure 3The balance of reactive oxygen species (ROS) in plant cells needs strict regulation to ensure that cells are not damaged. In our study, several DEGs were associated with signal pathways of redox, including catalase (CAT), ascorbate peroxidase (APX), superoxide dismutase (SOD), peroxiredoxins (PrxR), and glutathione peroxidase (GPX) illustrating the main active oxygen scavenging enzymes of KW and NIL changed significantly in each stage. For example, peroxidase was up-regulated in the early, middle, and late stages of KW and significantly changed in the middle stage of NIL. Therefore, we speculate that plant can resist the invasion of BPH by decreasing the accumulation of excessive ROS in cells.Xylanase inhibiting protein can be used as an elicitor to induce plant disease resistance and defense system. Xylanase inhibitors can help plants defense against pathogens by inhibiting the hydrolase effect of xylanases to xylan . At diffTranscription factors (TFs) are another contributor of plant resistance to stresses . SeveralPhytohormones signaling pathways are another crucial stakeholder of plant resistance against stresses . The treCytochrome P450 plays a fundamental role in plant-insect interactions in the detoxification of xenobiotics . In our Long non-coding RNAs (lncRNAs) are emerging as important transcriptional regulators under biotic stresses in plants . Here, tBph36-NIL had the strongest defense response after 48 hours of induction and had the maximum down-regulation of growth and metabolism-related genes following metabolic balance theory. The DEGs and DELs identified in our study can provide abundant resources for studies of BPH-resistant rice in the future.Altogether, this study provides a systematic analysis of DEGs and DELs in response to BPH attacks in rice. To deal with the BPH invasion as effectively as possible, plants have not only up-regulated their basic metabolism level to meet the energy demand of defense response activation but also have down-regulated their growth-related genes to balance metabolic processes. In the present study, resistant strain KW-All the raw reads produced in this study have been deposited in NCBI database with accession number PRJNA910668.RL supervised the research and designed the experiments. YX, JY, XW, NZ, and BQ helped and produced rice NILs. YX carried out phenotypic observation and other experiments. ZD and ZU performed bioinformatics analysis. SM analyzed and interpreted the sequencing data. SM, YX, and YQ drafted the article. SM, WZ, FL, and RL revised the manuscript. All authors read and approved the final manuscript.


Human papillomavirus (HPV) vaccine is a safe and effective strategy for reducing HPV morbidity and mortality. Schools have become an increasingly attractive setting for delivering vaccinations and supporting vaccination health literacy and decisional support. This study assesses the effectiveness of a community-based, physician-led HPV education campaign (starting in 2016) and onsite middle school-based HPV vaccination program across six school districts  in a rural, medically underserved Texas area . Pre- and post-intervention HPV vaccination rates were tracked against the 2016 National Immunization Survey—Teen target rates . Summary statistics were stratified by gender, school district, and grade level. The study reached 19,951 students who received HPV vaccines directly or indirectly through our program  (August 2016–August 2022). Of those, 2145 students  were vaccinated directly through our program. The overall HPV up-to-date (UTD) rates were 58.8%. The overall median age at HPV vaccine initiation and HPV-UTD (range) was 11 years (9–21) and 12 years (9–20). The overall median interval between HPV vaccine doses (range) was 291 days (146–2968). Recommending HPV vaccine initiation at younger ages increases HPV vaccine completion and providing access to HPV vaccines encourages on-time vaccination and completion. Human papillomavirus (HPV) vaccinations have proven to be a valuable, cost-effective public health intervention for reducing HPV morbidity and mortality . HoweverPersonal, community, and provider-level factors may inhibit the translation of the willingness to vaccinate into an actual HPV vaccine update. Acceptance may not be the only precursor of the willingness to vaccinate. The most commonly cited reasons for low HPV vaccination rates in the US are missed clinical opportunities and the lack of strong and consistent vaccine recommendations from healthcare providers . Other kAccording to the National Immunization Survey—Teen ages 13–17), Texas ranks as one of the lowest states in terms of HPV-UTD vaccination rates (47 out of 50 states and the District of Columbia) . In 2016–17, TexaSchool-based vaccination programs are becoming a more widely considered method of delivering HPV immunizations to adolescent populations, with a grade-based vaccination strategy preferred over an age-based vaccination strategy ,22. IntrThis cross-sectional study summarizes multiple projects funded by the Cancer Prevention Research Institute of Texas (CPRIT) to increase HPV vaccine uptake in the RGV (Texas). The goals were to meet the 2016 NIS-Teen HPV vaccination rates  ,28,29. TThe study outcomes included HPV vaccine initiation and HPV-UTD status. For study inclusion, students received at least one HPV vaccine dose either directly (school-based vaccination program) or indirectly  through our program and had parental consent. HPV vaccine initiation was defined as receipt of the first dose of the HPV vaccine series. HPV-UTD was defined as receipt of ≥3 doses if initiated after age 15 years or with immunocompromising conditions, or receipt of 2 doses if initiated before age 15 years, with a minimum interval of 5 months between the first and second dose ,31.Results from a previously published survey were used to develop and strengthen strategies for implementing the two-component intervention to increase HPV vaccine uptake . As descThe physician-led educational events started in August 2016 in Cameron, Hidalgo, and Starr Counties (located in a 15-mile radius encompassing the pilot program in RGCCISD). In all school districts, school-based vaccinations were implemented with the largest student enrollments for the largest impact. Between 2019 and 2022, the school-based vaccination events were implemented in PSJA ISD  . BetweenDuring the school year, the HPV vaccine series was initiated and completed at back-to-school events, progress report nights, and preview events. To ensure on-time vaccination and adherence to the dosing schedule, catch-up vaccination was scheduled by our staff through nearby clinics and planned events for missed doses. Up to 5 reminder letters, texts, and phone calls for subsequent doses were sent to the parents/guardians of children who initiated HPV vaccination. Prior to coronavirus disease 2019 (COVID-19), school-based vaccination events were held in the nurses’ offices, conference rooms, nearby clinics at parents’ requests, and at community events. Adaptations to how vaccinations were implemented were made when the COVID-19 pandemic hit and caused school closures during the first year of the school-based vaccination program in the expanded school districts ,29. We hGiven the transient nature of the student population in this area, the baseline cohort was followed for simplification. HPV vaccination rates are based on the baseline study cohort for each school. The HPV vaccination data was refreshed each quarter using data collected from the vaccine vendor and school immunization records  and reconciled with Immtrac2 (Texas Immunization Registry) ,28,29. TBaseline HPV vaccination rates and demographic information  from the schools’ data processing departments were collected for the study cohort during the study period. The vendor collected student vaccination data  during the vaccine administration. We tracked HPV vaccine administrations that were given directly through our vaccination program  and those given indirectly through collaborating healthcare practices .SAS version 9.4  was used in conducting all analyses. Tables, graphs, and charts were used to perform descriptive analysis and report the frequencies. Logistic regression models were used to examine characteristics associated with HPV vaccine completion (HPV-UTD) using both school-based and non-school-based vaccination delivery modalities. Statistical significance was set at α| = |0.05 (two-sided).A total of 19,951 students received HPV vaccines directly or indirectly through our program . Of the 19,951 students reached by our program, 2145 students  were vaccinated directly (received at least 1 HPV vaccine dose) through our school-based vaccination program . Most wep-value < 0.05). In this study, older age at initiation (1-year increase) was 32% less likely to be HPV-UTD  (1–0.712) . Male st1–0.712) , older ap-value < 0.05).Over the last six years, our community-based education and school-based vaccination program has helped to build and strengthen adolescent health in the RGV ,35. The To our knowledge, our pilot project was one of the first school-based vaccination programs aimed at increasing HPV vaccination rates in RGV and Texas. Results from the pilot project in RGCCISD helped lay the foundation for the program by addressing known barriers affecting HPV vaccine uptake  ,9,10,11.As our results show, middle schools are a feasible, effective setting for increasing HPV uptake. School settings are conducive to active adolescent engagement about HPV and HPV vaccination, promoting adolescent involvement in decision making, reducing needle-related fear and anxiety, and leading to more vaccination-literate adolescents ,26. Our This study had its limitations. First, information on baseline characteristics of students and parents, such as students’ race and ethnicity, socioeconomic status (SES), insurance status, parents’ education, country of birth, or knowledge and confidence in the HPV vaccines, was not collected. Additional comparisons evaluating these important characteristics could not be undertaken. Second, we did not have complete information on other vaccines or confirmation that other providers bundled HPV vaccines with other recommended vaccines. This could be an important future extension of our study. Next, the study population is transient, with some students changing schools during the study period. For simplification, we followed our baseline cohort at each middle school. Last, we are unable to account for all HPV vaccines. Although the vendor and schools shared updated information, it may not capture all vaccines received outside the school setting when parents fail to report vaccinations to the school. Future studies should explore issues, such as inadequate school-based health centers and vaccine billing as barriers to school-based HPV programs. Last, the study may have limited generalizability to Texas and the US. The school districts were not randomized, with implementation occurring in schools with the highest enrollment. There is also no national mandate for HPV vaccination.School-based vaccination programs play an important role in increasing HPV vaccine uptake by reaching underserved adolescent populations who are most at risk for HPV-associated diseases. Through partnership with the RGV community and healthcare providers, our voluntary school-based vaccination program educated the community  about the importance of HPV vaccines, removed access and transportation barriers, developed care coordination between local physicians and the RGV community, bundled HPV vaccines with other required vaccines when provided by our program, and increased HPV-UTD to 58.8%. Recommending HPV vaccine initiation at younger ages increases completion of the HPV vaccine series and providing access to HPV vaccines encourages on-time vaccination and completion. Increasing HPV vaccine uptake has the potential to decrease HPV-associated diseases in the area in the future.


Ovarian hyperstimulation syndrome (OHSS) is a rare but serious complication of controlled ovarian stimulation. Frozen-embryo transfer (ET) is prompted to be performed in the next menstrual cycles after cancellation of fresh-ET after occurrence of OHSS. However, effects of frozen-ET in the second menstrual cycle have never been investigated. Therefore, this study aimed to assess this in the menstrual cycle after OHSS.The OHSS group included 342 women with moderate-severe OHSS who underwent the first frozen-ET in the second menstrual cycle in the First Affiliated Hospital of Anhui Medical University from June 2018 to September 2019. A total of 342 women without OHSS who received frozen-ET in the second menstrual cycle were selected as control group matched by age, body mass index, fertility history, ovulation induction scheme. Uni- and multi-variable conditional logistic regression was used to estimate the association between moderate-severe OHSS and pregnancy outcomes.There were no significant differences in maternal outcomes  and in neonatal outcome  between the two groups in either uni- or multi-variable models.Frozen-ET in the menstrual cycle after OHSS has similar maternal and neonatal outcomes as in women without OHSS. This study indicates that frozen-ET could be performed in the second menstrual cycle in women who recovered from moderate-severe OHSS.The online version contains supplementary material available at 10.1186/s12884-022-05239-0. Ovarian hyperstimulation syndrome (OHSS) is a complication associated with controlled ovarian stimulation (COS) during infertility treatment –3. ModerFrozen embryo transfer (frozen-ET) has been shown to reduce the risk of severe OHSS and has been prompted to avoid deterioration of OHSS , 16–18. From the 10.090 women in the Reproductive Center of the First Affiliated Hospital of Anhui Medical University 5.746 women had the first frozen cycle during the period from June 2018 to September 2019. Among them, 705 (12.3%) had moderate-severe OHSS. Inclusion criteria included women ≤40 years who were at high risk of OHSS , 22 and Inclusion criteria were fulfilled in 342 (48.5%) women allocated to the OHSS group. The control group consisted of 342 women, who conceived via the first Frozen-ET cycle during the same time period and did not develop OHSS, matched by age, body mass index (BMI), etiology, fertility history and ovulation induction scheme. The flowchart of the study is summarized in Fig. Moderate and severe OHSS was classified according to the American Society for Reproductive Medicine criteria . Moderatth day after ET were assessed to determine biochemical pregnancy. Clinical pregnancy was defined as a sac visible by ultrasonography with a fetal heartbeat at 7 weeks after ET. Miscarriage with positive heart activity was used to define loss of clinical pregnancy.Data on pregnancy outcomes related to mother and neonate were extracted from the Electronic Medical Records. Maternal outcomes included biochemical pregnancy, clinical pregnancy, ectopic pregnancy, early pregnancy, abortion rate, successful childbirth and pregnancy complications rate . Neonatal outcomes included gestational age at birth, birth-weight and body length, congenital defects rate, jaundice rate and neonatal mortality. Serum human chorionic gonadotropin (HCG) levels on the 142, prolactin, luteinising hormone, testosterone and total dosage of gonadotropin). On trigger day, the following data were extracted: number of follicles, retrieved oocytes, transplantable embryos, high-quality embryos and sex hormone values . The information of implantation included transfer interval, endometrial thickness on transfer day, number of transferred embryos, clinical pregnancy rate and ectopic pregnancy rate.Demographic and clinical data of the women were retrieved from the Electronic Medical Records including age, years of infertility, types of infertility, number of pregnancies, causes of infertility, BMI, basic sex hormone levels .Continuous data were presented as mean ± standard deviation and count data were described using frequencies and percentages. Normality tests of continuous data were performed by visual inspection of the histogram and distribution curve. Comparison of continuous variables between the groups was conducted using Student’s t-test and analysis of variance. Chi-squared or Fisher exact test were used for comparison of categorical variables as appropriate. Multivariable regression was used to determine the association of moderate-severe OHSS with maternal and neonatal outcomes after controlling for confounders. Potential confounders with P < 0.05). On trigger day, serum levels of estradiol2 and progesterone were significantly higher and the number of removed oocytes and transplantable embryos were significantly greater in the OHSS group than in the control group (P < 0.05). Regarding perinatal outcomes, 123/304 (40.5%) successful births in the moderate OHSS group, 15/38 (39.5%) in the severe group and 149/342 (43.6%) in the control group . Similarly, gestational age at birth, preterm birth rate or caesarean section rate in OHSS group were not statistically different from matched controls. Moreover, none of the maternal and neonatal outcomes were associated with moderate-severe OHSS in either univariable or multivariable regression models.Rates of biochemical pregnancy, clinical pregnancy, extrauterine pregnancy and early abortion were similar in both groups Table . Rates oP < 0.05). Additionally, numbers of both left and right ovary follicles in severe OHSS were higher than in controls (P < 0.001). Estradiol2 and progesterone levels on trigger day in moderate OHSS were significantly higher than those in the control group (P < 0.001). Hormone levels in severe OHSS were higher than that in control group, however, lower than in moderate OHSS. The number of transplantable and high-quality embryos in severe OHSS was highest compared with the other groups. Supplementary Table Comparisons of women’ characteristics among the moderate OHSS, severe OHSS and control group are shown in Supplementary Table To the best of our knowledge, this is the first study investigating the effect of frozen-ET in the menstrual cycle after oocyte retrieval on pregnancy outcomes among women with OHSS. We found that there are no differences in the odds of pregnancy outcomes between frozen-ET among women with moderate-severe OHSS compared with controls, and this persisted among women with moderate OHSS, severe OHSS and controls. These findings indicate that frozen-ET in the subsequent menstrual cycle after OHSS has comparable pregnancy outcomes with women without OHSS regardless of the severity of OHSS.2 on trigger day in both severe and moderate OHSS groups were higher than controls, which is consistent with the theory that circulating high estradiol2 levels could be of predictive value for the occurrence of OHSS [HCG used in COS stimulates the secretion of vascular endothelial growth factor (VEGF). Over-secretion of VEGF, however, increases the capillary permeability resulting in the clinical symptoms of OHSS related to systemic vascular endothelial dysfunction and micro-thromboembolism in GDM and PIH –30. Trea of OHSS , 37.Fresh-ET in women with OHSS has been shown to increase the rate of loss of pregnancy, preterm birth, GDM and PIH compared with women conceived via IVF and did not develop OHSS, whilst we did not find difference in the odds of pregnancy outcomes between women with OHSS and without OHSS –40. ThisThis study found no differences in pregnancy outcomes of the first frozen-ET cycle between women with moderate-severe OHSS and those without OHSS. This suggests that once women are recovered from OHSS in the next menstrual cycle, frozen-ET could be performed for anticipated conception. This study provides supportive evidence for the clinical treatment strategy of performing frozen-ET in the menstrual cycle after OHSS.Additional file 1: Supplementary Table 1. Basic data of moderate-severe OHSS group and matched ControlAdditional file 2: Supplementary Table 2. Ovulation induction and transplant information of moderate-severe OHSS and control.


Cardiovascular disease is prevalent in idiopathic pulmonary fibrosis (IPF), yet the extent of left-sided heart failure (HF) burden, whether this has changed with time and whether HF impacts mortality risk in these patients are unknown. The aims of this study were therefore to determine the temporal trends in incidence and prevalence of left-sided HF in patients with IPF in England and compare these to published estimates in the general population and those with comparable chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD), as well as determine the risk of all-cause and cause-specific mortality in patients with comorbid left-sided HF and IPF at population-level using electronic healthcare data.Clinical Practice Research Datalink (CPRD) Aurum primary-care data linked to mortality and secondary-care data was used to identify IPF patients in England. Left-sided HF prevalence and incidence rates were calculated for each calendar year between 2010 and 2019, stratified by age and sex. Risk of all-cause, cardiovascular and IPF-specific mortality was calculated using multivariate Cox regression.From 40,577patients with an IPF code in CPRD Aurum, 25, 341 IPF patients met inclusion criteria. Left-sided HF prevalence decreased from 33.4% (95% CI 32.2–34.6) in 2010 to 20.9% (20.0–21.7) in 2019. Left-sided HF incidence rate per 100 person-years (95% CI) remained stable between 2010 and 2017 but decreased from 4.3 (3.9–4.8) in 2017 to 3.4 (3.0–3.9) in 2019. Throughout follow-up, prevalence and incidence were higher in men and with increasing age. Comorbid HF was associated with poorer survival (adjusted HR (95%CI) 1.08 (1.03–1.14) for all-cause mortality; 1.32 (1.09–1.59) for cardiovascular mortality).Left-sided HF burden in IPF patients in England remains high, with incidence almost 4 times higher than in COPD, a comparable lung disease with similar cardiovascular risk factors. Comorbid left-sided HF is also a poor prognostic marker. More substantial reduction in left-sided HF prevalence than incidence suggests persistently high IPF mortality. Given rising IPF incidence in the UK, this calls for better management of comorbidities such as left-sided HF to help optimise IPF survival.The online version contains supplementary material available at 10.1186/s12890-022-01973-5. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease resulting in irreversible lung scarring. Due to diagnostic challenges, evolving diagnostic criteria as well as differences in study methodologies, estimates of IPF disease burden show substantial heterogeneity, ranging from a prevalence of 0.57–4.51 per 10,000 persons in Asia, 0.33–2.51 in Europe, and 2.40–2.98 in North America . For insHowever, while the high burden of CVDs such as IHD , pulmonaWhile there is evidence that IPF and left-sided HF co-exist, there are few population-level studies examining the epidemiology of left-sided HF in IPF patients, with generalizability of findings from existing studies made challenging by use of small cohorts from registries or single centres, frequent study of HF in only hospitalised patients, and lack of clear HF case definition . FurtherThe aim of this study was therefore to investigate temporal trends in incidence and prevalence of left-sided HF in IPF patients in England, compare this to published estimates in the general population and those with comparable chronic respiratory conditions such as chronic obstructive pulmonary disease (COPD), as well as explore the risk of all-cause, cardiovascular and IPF-specific mortality in England using population-level electronic healthcare data. This is the first European study to explore temporal patterns of the burden of left-sided HF in IPF and one of few studies to date to investigate left-sided HF epidemiology in IPF using nationally representative population-level data.Data were obtained from the Clinical Practice Research Datalink (CPRD) Aurum, a nationally- representative database of de-identified primary care electronic healthcare records (EHR) covering approximately 19% of the UK population . Use of CPRD Aurum data for eligible patients registered in England was linked to secondary care data from Hospital Episode Statistics (HES), mortality data from Office of National Statistics (ONS) and socioeconomic data from the 2015 Index of Multiple Deprivation (IMD). Data linkage between sources was conducted by NHS Digital, a statutory trusted third party.https://github.com/NHLI-Respiratory-Epi/IPF_HF_codelists.Consistent with previous studies exploring IPF epidemiology by means of diagnostic codes in EHR , 36, we st January 2010–31st December 2019). For each patient, start of follow-up was defined as the latest of: 12 months post registration date with a general practice, start of study, patient’s 40th birthday or date of IPF-CS diagnosis. The end of follow-up was defined as the earliest of: transfer out of practice, end of study, last data collection date or patient’s date of death.We used a retrospective cohort study design with rolling entry and a 10-year study period  and based on previously published work were used to identify baseline covariates. Smoking, alcohol status and body mass index (BMI) were determined closest to start of follow-up. BMI data in the 3 years prior to start of follow-up was used, with BMI values calculated from height and weight data closest to start of follow-up, where available, in event of missing BMI data. Presence of baseline cardiovascular comorbidities and left-sided HF risk factors were determined at any point prior to start of follow-up, while cardiovascular medication use was defined as at least one prescription in the 12 months preceding start of follow-up. All codelists used, including those for ascertaining outcomes below, are accessible at: Codelists were also used to identify prevalent and incident left-sided HF. Codes denoting right HF were excluded.Cause of death was ascertained from ICD-10 codes using the derived cause of death field in linked ONS records. All-cause mortality was defined as death from any cause, with cardiovascular mortality defined as death due to myocardial infarction, ischaemic stroke or HF.Baseline characteristics are presented as absolute numbers and frequencies (%) for categorical data and medians with interquartile ranges [IQR] for non-normally distributed continuous variables. Proportions of missing data are described as frequencies (%) for each covariate.Left-sided HF prevalence and crude incidence rates were calculated annually for the 10-year study period, stratified by age  and sex. Incidence rates are reported per 100 person-years at risk, with associated 95% confidence intervals (CI).p < 0.05 level of statistical significance was used in all analyses. All analyses were conducted in Stata v16.0 .Multivariate Cox regression was used for mortality analyses. Covariate inclusion in the multivariate models was based on directed acyclic graphs (DAGs) created using clinical knowledge and existing literature to identify possible confounders  removing patients from the cohort diagnosed with IPF-CS post 1st September 2018 when ATS/ERS/JRS/ALAT IPF diagnostic guidelines changed (2) removing patients with non-specific IPF-CS diagnostic codes such as fibrosis of lung, pulmonary fibrosis, diffuse pulmonary fibrosis, Hamman-Rich syndrome, O/E-fibrosis of lung; (3) removing patients if they had evidence of another cause for pulmonary fibrosis or interstitial lung disease other than IPF, based on ICD-10 codes denoting an autoimmune condition, occupational lung disease, hypersensitivity pneumonitis or sarcoidosis in mortality data; and (4) removing patients diagnosed with IPF-CS when younger than 50 or 60 years old to exclude possible hereditary or familial IPF cases.For mortality analyses, ethnicity and IMD were also added as possible confounders in the multivariate models for all-cause and cardiovascular mortality.25,341 IPF-CS patients from 1379 general practices in England were included in the cohort  had HF diagnosed prior to IPF-CS, 3.7% were diagnosed concurrently with IPF-CS and 38.9% following IPF-CS.Those with comorbid IPF-CS and left-sided HF were more likely to be older, male, more socioeconomically deprived, have a higher BMI, be an ex-smoker, have a history of CVD or HF risk factors and be on cardiovascular medications at start of follow-up Table .Table 1BLeft-sided HF incidence rate per 100 person-years (95% CI) remained relatively stable between 2010–2017 but decreased modestly from 4.3 (3.9–4.8) in 2017 to 3.4 (3.0–3.9) in 2019  in 2010 to 20.9% (20.0–21.7) in 2019  than COPD patients [ref] and having comorbid HF is poor prognostic marker which increases risk of both all-cause and cardiovascular mortality, with a comparatively higher risk of the former than the latter.The modest reduction in HF incidence could reflect improved management of cardiovascular risk factors over time. Indeed, prescriptions for CVDs increased by 78% in England between 1991 and 2014 . By contWe were unable to ascertain from the data whether IPF patients with HF had HFrEF or HFpEF, although this would be useful to characterise. While HF prevalence has been noted to be increasing globally, many studies show a stable or decreasing HF incidence. An increasingly ageing population and improved HF survival due to treatment advances may explain increased prevalence while better treatment of acute coronary syndromes due to the advent of revascularisation therapies may explain reduced incidence of HF . FurtherAs discussed earlier, the treatment landscape of IPF has changed significantly in the last decade and it is unclear how these changing treatment patterns have influenced the burden of comorbidities such as left-sided HF in IPF. As antifibrotics are prescribed in tertiary care, we did not have access to antifibrotic use data in CPRD Aurum and therefore were unable to explore this potential association. Interestingly however, antifibrotics have been shown to have cardioprotective properties within the context of HFpEF, albeit this has not been explored specifically in the context of comorbid IPF and HF , 29. To Our HF incidence estimates are significantly lower than those reported by a US study, the only other population-based study which has explored the burden of left-sided HF in an IPF patient population. Using claims data between 2001 and 2008 for over 9000 patients, this study reported an incidence rate of 67.5 cases per 1000 person-years . Given tBy contrast, our prevalence estimates are higher than those from smaller cohort studies which range from 8 to 23% , 23–26. Consistent with other studies, male gender was found to be a significant risk factor for having a higher HF burden . AlthougBased on our estimates, left-sided HF prevalence is approximately 30-fold higher and incidence is almost 12-fold higher in IPF patients than in the general UK population . AssuminOur all-cause mortality estimates are in-keeping with two studies showing an increased mortality risk with comorbid IPF and HF, although our estimates are 29% lower than those in an Italian study , and thrWhile this study cannot explain why left-sided HF burden is so high in IPF relative to COPD patients, there are several possible theories. Shared risk factors such as smoking and ageing or shared pathological mechanisms such as telomere dysfunction and molecular and cellular fibrosis in both IPF and HF may contribute , 31. AltStrengths of this study include use of nationally representative population-level data linked to national mortality and secondary care data to explore left-sided HF epidemiology in IPF patients. This contrasts previous studies to date which have largely explored cohorts from single centres or registries. Although there is recognised heterogeneity in IPF coding terms in electronic healthcare records, left-sided HF incidence and prevalence estimates remained robust despite several sensitivity analyses optimising IPF case ascertainment. While there is potential risk of case misclassification due to dependency on codes entered in primary care, we draw confidence in the validity of ascertainment of both our exposure and outcome due to high positive predictive values (82–95%) of both HF and IPF diagnoses in primary care records , 34.Nevertheless, this study has several limitations. The cohort was predominantly Caucasian with patients residing in England, limiting generalisability of findings to other populations. Almost 80% of patients in the cohort also had non-specific codes for pulmonary fibrosis and although we used proxy measures in the sensitivity analyses to optimise IPF-CS case ascertainment such as exclusion of those with evidence of a potential non-idiopathic cause for pulmonary fibrosis based on mortality data, there is nonetheless a possibility that some cases were misclassified. A more comprehensive study of the validity of IPF codes in CPRD Aurum is currently in progress and would inform confidence in the results from this study. Furthermore, we did not have access to imaging data to determine IPF disease severity. This is important to ascertain as studies have shown IPF patients with a rapid disease course were more likely to be diagnosed with HF post IPF diagnosis . FurtherLastly, there was a significant proportion of missing data for alcohol intake, ethnicity and BMI. As missing data for these variables has been shown to not be missing at random in CPRD Aurum, we conducted a complete-case mortality analysis, but acknowledge this may have introduced some bias. For instance, patients with missing alcohol or BMI data are more likely to not have engaged with healthcare providers as often and by extension may have been less compliant with their medications or monitoring investigations for their IPF or HF. Therefore, it is possible that the patients excluded from the mortality analyses due to missing data may have generally been less healthy and may have had more severe disease severity of both their IPF and HF. The exclusion of these patients due to missing data may have therefore underestimated the risk of all-cause and cause-specific mortality in those patients with comorbid IPF and HF.This study shows temporal changes in both incidence and prevalence of left-sided HF in IPF patients in England, with modest reduction in incidence possibly reflecting improved screening and management of cardiovascular risk factors. However, despite decreasing incidence and prevalence, left-sided HF burden is considerably higher in IPF patients than in patients with other comparable chronic respiratory diseases and confers a higher mortality risk. Further studies are needed to explore HF phenotypes in IPF patients, whether there is a temporal relationship between the two diseases, what the aetiological mechanisms driving this association are, what drives the noted gender differences and whether HF treatment modifies the mortality risk.Additional file 1.Supplementary material.


By multivariate logistic regression analysis, trans-carotid access was associated with a higher all stroke rate at 30 days ; p = 0.001). Conclusions: In this national registry-based study, patients treated for BAV vs. TAV stenosis had no significant difference in all-cause mortality at 30 days, but trans-carotid access was associated with a higher all stroke rate after TAVR at 30 days.Background: This study aims to compare the outcomes of transcatheter aortic valve replacement (TAVR) with self-expandable valves for bicuspid aortic valve (BAV) vs. tricuspid aortic valve (TAV) stenosis patients who are at low surgical risk. Methods: Participants were enrolled from 36 centers in China between January 2017 and December 2021. The primary endpoint event was all-cause mortality and all stroke at 30 days. Results: Among 389 patients at low surgical risk that underwent TAVR, 229 patients were BAV stenosis . There was no significant difference in the rate of all-cause death between two populations at 30 days. However, the rate of all stroke was significantly higher in the BAV group at 30 days , 0.97 , 0.94 to 0.99);  Since Cribier and colleagues reported the first case of transcatheter aortic valve replacement (TAVR) in 2002 , TAVR haCompared with Western countries, Chinese AS patients have the characteristics of a high proportion of BAV and high calcium burden ,8. Of paThe National Transcatheter Valve Therapeutics Registry (NTCVR) database was co-initiated by National Clinical Research Center for Interventional Medicine and Chinese Cardiovascular Association, which is the largest database that includes TAVR procedures performed in China . In this2. All consecutive patients undergoing TAVR with self-expandable THVs  from 36 centers in China between January 2017 and December 2021 were evaluated in this study . BaselinSelf-expandable THVs were used in all severe AS patients, including two domestic self-expanding THVs: Venus A  and the VitaFlow valve . Venus A and Vitaflow were the first-generation self-expanding THVs in China . We perft-tests for continuous covariates. To identify independent predictors of all stroke after TAVR, candidate variables for the multivariable logistic regression model were required to have clinical relevance and a p-value < 0.05 in the univariate analysis, which included all available baseline clinical, echocardiographic, and procedural data. All p values were two-sided, and p < 0.05 was considered significant for all tests.All statistical analyses were performed using SPSS version 25 . Categorical data are presented as the number of events and frequencies, and continuous data are presented as mean ± SD. Comparisons between the two groups were performed using the Chi-square test or Fisher’s exact test for categorical variables, and independent Between January 2017 and December 2021, a total of 475 patients at low surgical risk who underwent TAVR for aortic stenosis with self-expandable THVs at 36 institutions in China were included in the primary analysis. Some 86 patients were excluded because of unknown anatomy or other unknown reasons. A total of 389 patients at low surgical risk (229 with BAV and 160 with TAV) were included in the final analysis . Baseline characteristics of the BAV group and TAV group are shown in p > 0.05). Procedural details are presented in p = 1.00). There was no significant difference in the rates of all-cause death or stroke between the BAV and TAV group at 30 days ; p = 0.053). However, the rate of all stroke was significantly higher in the BAV group both at discharge ; p = 0.045) and at 30 days ; p = 0.044). In the secondary clinical outcomes, there were no significant differences in the rates of major vascular complications, major bleeding, myocardial infarction, new-onset atrial fibrillation, new PPM implantation, or moderate/severe paravalvular leak (PVL) between the two groups, both at discharge and at 30 days .Clinical outcomes are shown in p-value < 0.05 in the univariate analysis. Interestingly, trans-carotid access and BAV were predictors of all stroke on univariate analysis. However, on multivariate logistic regression analysis, the BAV was not significantly different (p = 0.001).A total of 359 patients (213 with BAV and 146 with TAV) completed a 30-day follow-up. The rate of all stroke in the entire population was 1.9%. The candidate variables for the univariate logistic regression analysis for predictors of all stroke are shown in ifferent . By multIn this national registry-based study of AS patients at low surgical risk who had undergone TAVR with self-expandable THVs in China, the primary results were as follows: (1) BAV patients had a low 30-day all-cause mortality (0.9%); (2) compared with TAV patients, BAV patients had higher rates of in-hospital and 30-day all stroke. However, there were no significant differences in all-cause mortality, the rates of major vascular complications, major bleeding, myocardial infarction, new-onset atrial fibrillation, new PPM implantation, or moderate/severe PVL between BAV and TAV patients both at discharge and at 30 days; (3) by multivariate logistic regression analysis, trans-carotid access was associated with a higher all stroke at 30 days after TAVR.This is the first report from the NTCVR database on outcomes of TAVR in patients at low surgical risk in China. There are limited randomized clinical trials of TAVR vs. surgical aortic valve replacement (SAVR) for the treatment of BAV stenosis. Low surgical risk patients with BAV stenosis are often considered more suitable for SAVR. In the present study, BAV patients account for 58.9% of all low surgical risk TAVR patients, which was significantly higher than a recent study based on the western registry . The prep = 0.001). The lack of cerebral protection during TAVR may contribute to the increased risk of all stroke in patients with trans-carotid TAVR in our study. Due to the superficial and less calcified carotid arteries, trans-carotid TAVR is an easier technique compared with trans-femoral TAVR. It has also been shown that trans-carotid TAVR has similar clinical outcomes compared with the trans-femoral TAVR regarding mortality and morbidity ,26. HoweFor BAV stenosis patients with low surgical risk, the selection of TAVR or SAVR should be carefully considered combined with the anatomical suitability, coronary artery access for future interventions, feasibility of repeated TAVR or SAVR, pacemaker incidence, and valvular thrombosis to optimize the lifetime management of treatment. Although the rate of 30-day all stroke was significantly higher in the BAV group, this difference disappeared after multivariate logistic regression analysis in the present study. In the future, prospective randomized clinical studies comparing TAVR vs. SAVR with long-term follow-up data are needed to guide the optimal management of BAV stenosis in young low surgical risk patients.In this national registry-based study, patients receiving TAVR with self-expandable valves treated for BAV vs. TAV stenosis had no significant difference in all-cause mortality at 30 days. However, the rate of all stroke was significantly higher in the BAV group at 30 days. By multivariate logistic regression analysis, trans-carotid access was associated with a higher all stroke rate after TAVR at 30 days.


The development of mobile technology with substantial computing power  has enabled the adaptation of performance-based cognitive assessments to remote administration and novel intensive longitudinal study designs . Although an “ambulatory” cognitive assessment paradigm may provide new research opportunities, the adaptation of conventional measures to a mobile format conducive to intensive repeated measurement involves balancing measurement precision, administration time, and procedural consistency.Across 3 studies, we adapted “complex span” tests of working memory capacity (WMC) for ultra-brief, smartphone-based administration and examined their reliability, sufficiency, and associations with full-length, laboratory-based computerized administrations.In a laboratory-based setting, study 1 examined associations between ultra-brief smartphone adaptations of the operation span, symmetry span, and rotation span tasks and full-length computerized versions. In study 2, we conducted a 4-day ecological momentary assessment (EMA) study (4 assessments per day), where we examined the reliability of ultra-brief, ambulatory administrations of each task. In study 3, we conducted a 7-day EMA study (5 assessments per day) involving the ultra-brief rotation span task, where we examined reliability in the absence of extensive onboarding and training.r=0.4 to r=0.57. Results of study 2 and study 3 suggest that reliable between-person estimates of operation span, symmetry span, rotation span, and latent WMC can be obtained in 2-3 ultra-brief administrations . The results of study 3 replicated our findings, showing that reliable between-person estimates of rotation span may be obtained in as few as 2 ultra-brief administrations in the absence of extensive onboarding and training. In addition, the modification of task parameterization for study 3 improved the estimates of reliability of within-person change.Measurement models in study 1 suggest that comparable estimates of latent WMC can be recovered from ultra-brief complex span task performance on smartphones. Significant correlations between the ultra-brief tasks and respective full-length versions were observed in study 1 and 2, ranging from Ultra-brief administration of complex span tasks on smartphones in a measurement burst design can generate highly reliable cross-sectional estimates of WMC. Considerations for future mobile cognitive assessment designs and parameterizations are discussed. The proliferation of mobile technology with substantial processing power has enabled a significant leap forward for intensive longitudinal study designs aiming to examine psychological and behavioral processes under naturalistic circumstances. This active area of research is often referred to as ecological momentary assessment (EMA) and leverages pervasive mobile technology  to study how these processes, which have most often been well studied under controlled laboratory conditions, unfold over the course of daily life ,2. RecenWMC describes an individual’s ability to maintain information in short-term memory while processing ongoing or new information . WMC is Recent applied research also suggests that WMC may play an important role in goal-directed behavioral processes. For example, in laboratory-based experiments, individuals with higher WMC have been shown to exhibit more successful self-regulation . In Intensive longitudinal study designs commonly used in EMA research, such as the “measurement burst design,” involve sampling multiple times per day over multiple days to generate a rich description of contexts, behavior, or experiences under study ,24. ThisThe measurement advantages associated with EMA may also extend to ambulatory performance-based cognitive assessments. Aggregation of data over many ambulatory cognitive assessments can mitigate the influence of a single episode of poor or inspired performance, which may otherwise misrepresent an individual’s overall average ability . The inThe paper is organized into 3 studies. In the first study, we describe the results of a laboratory-based study designed to examine the degree to which scores on ultra-brief adaptations of the operation span (OSpan), symmetry span (SSpan), and rotation span (RSpan) tasks, administered on smartphones, are correlated with full-length, computerized versions and determine whether latent estimates of WMC can be recovered from performance on ultra-brief tasks. In the second study, we describe the results of a measurement burst design study in which we assessed the reliability of the 3 ultra-brief tasks and composite WMC across intensive repeated administrations occurring over 4 days. In the third study, we describe the results of an EMA field study involving the ultra-brief Rotation Span task to illustrate task psychometrics in a context in which participants received minimal in-laboratory practice and training with the task procedures.In study 1, we conducted a cross-sectional study of performance on automated full-length OSpan, SSpan, and RSpan tasks and delayed performance on smartphone-based ultra-brief adaptations of each task (an average of 3 days later in a separate session). We examined correlations between ultra-brief and full-length task performance for each complex span task, the fit of confirmatory measurement models, and criterion correlation with a Gf factor indicated by performance on 2 reasoning tasks.A total of 132 younger adults  participated in this study. Participants were recruited from the psychology undergraduate research pool at the Pennsylvania State University.All the participants provided written informed consent and received course credit for their participation. All experimental procedures were approved by Pennsylvania State University’s institutional review board for the ethical treatment of human participants (reference number STUDY00003499).Participants completed 3 full-length, automated complex span tasks  and 2 reasoning tasks  in a 90-minute laboratory session. Tasks were administered in a fixed order across all participants to control for potential crosstalk between tasks: OSpan, SSpan, RSpan, RAPM, and Letters. Following the initial laboratory session, participants were scheduled to return to the laboratory for a brief session, an average of 3 days later (range 2-4), where ultra-brief versions of the OSpan, SSpan, and RSpan tasks  were administered on a smartphone provided by the laboratory .OSpan involves memorizing a single letter at a time while performing interleaved arithmetic operations. After memorizing a set of letters and completing the interleaved arithmetic operations, the participants were asked to recall all of the letters memorized throughout the current trial in order. Trials randomly varied in set-size. Set-sizes  ranged from 3 to 7, with 3 repetitions of each set-size throughout the task. The total number of item operation pairs was 75.SSpan involved memorizing the highlighted locations in a 4×4 matrix one at a time while performing interleaved symmetry judgments on 8×8 mosaic pattern stimuli that were either symmetrical or nonsymmetrical along the vertical axis. After memorizing a set of locations and completing the interleaved symmetry judgments, participants were asked to recall all spatial locations from the 4×4 matrices memorized throughout the current trial in order. Trials randomly varied in set-size. Set-sizes  ranged from 2 to 5, with 3 repetitions of each set-size throughout the task. The total number of location symmetry pairs was 42.RSpan involved memorizing oriented arrows one at a time while performing interleaved mental rotation judgments on letter stimuli that were either forward or backward facing if oriented back to standard typeface orientation. Study arrows were oriented at 45° increments around an invisible clock face and were either short or long in total length, allowing for 16 possible orientation-length combinations. After memorizing a set of arrows and completing the interleaved mental rotation judgments, participants were asked to recall all of the oriented arrows memorized throughout the current trial in order. Trials randomly varied in the set-size. Set-sizes  ranged from 2 to 5, with 3 repetitions of each set-size throughout the task. The total number of arrow rotation pairs was 42.Each automated task contained self-guided instructions, practice, and timing parameters customized to the participant . Participants were given 10 minutes to complete as many matrices as possible before the assessment timed out. The number of correct responses obtained over the course of 10 minutes served as the RAPM score.Letters evaluated 5 groups of 4 letters each with a pattern or rule governing the association among 4 of the 5 groups. For every set of letters, participants were asked to select the group that violated the pattern or rule implied by the other 4 groups. Participants were given 10 minutes to complete as many sets as possible before the assessment timed out. The number of correct responses obtained over the course of 10 minutes served as the Letters score.Ultra-brief, smartphone-adapted versions of the full-length, automated complex span tasks used in study 1 were programmed using Qualtrics survey software  and administered using the Qualtrics “Offline Surveys” smartphone app  installed on the investigator-provided Samsung Galaxy S5 phones. The ultra-brief tasks were presented in a fixed order across participants, consistent with the order of the full-length task presentation in the first session: amb-OSpan, amb-SSpan, and amb-RSpan. The participants completed 3 trials for each task, one at each set-size. Set-sizes for the amb-OSpan task ranged from 4 to 6, and set-sizes for the amb-SSpan and amb-RSpan tasks ranged from 3 to 5. The scale of set-sizes selected for the ultra-brief tasks  was set to reflect the scale of the full-length tasks. The ultra-brief tasks contained no practice phase and included only an instruction screen that reminded the participants of the respective task procedures. Owing to limitations in the degree to which set-size randomization could be achieved using Qualtrics, within each task, set-sizes were presented in a pseudorandomized and counterbalanced order across all participants. Participants logged their responses using a touch screen . The totConfirmatory factor analyses and structural equation modeling analyses were performed using the Mplus software package . Generally, ultra-brief tasks were significantly correlated with nonmatching domain full-length tasks . However, a marginal correlation was observed between OSpan and amb-SSpan .Means, SDs, and first-order correlations for each task are shown in 218=25.5, P=.01; RMSEA=0.056, 90% CI 0.000-0.103; SRMR=0.049; CFI=0.967 and Model 2: χ216=24.2, P=.08; RMSEA=0.062, 90% CI 0.000-0.110; SRMR=0.049; CFI=0.964). The factor loading for the amb-RSpan task in Model 1 was consistent with that for the full-length task. Loadings for amb-OSpan and amb-SSpan were lower than those for the respective full-length tasks. Consistent with previous research, WMC was highly associated with Gf in both models  on a common latent WMC factor. Model 2 included a hierarchical factor representation where 2 latent factors (lab-WMC and amb-WMC) were indicated by full-length in-laboratory tasks and ultra-brief phone-based tasks, respectively. In model 2, lab-WMC and amb-WMC were modeled as latent indicators of a superordinate WMC factor. Model 2 was fit to determine the relative contribution of each modality-specific WMC factor (lab- and amb-WMC) to the criterion correlation with a latent reasoning factor. In each model, a latent reasoning (Gf) factor was included, as indicated by RAPM and Letters, and correlations between Gf and the highest-level WMC factors were estimated. Both models exhibited good fit to the data . Factor loadings and correlations between WMC and Gf in the revised model were highly consistent with model 1 .Participants were most accurate on the lowest set-size trials for each ultra-brief task . Participants accurately responded to 93% of all set-size 4 trials for the amb-OSpan task, 74% of all set-size 3 trials for the amb-SSpan task, and 70% of all set-size 3 trials for the amb-RSpan task. Performance on higher set-size trials yielded less skewed distributions. The inclusion of low set-size trials was consistent with standard procedures for the automated full-length tasks. Given our goal of developing assessments that are as brief as possible, following the method used by Oswald et al , we refiThe results of study 1 suggest that estimates of complex span task performance obtained via ultra-brief assessments on smartphones correlate with full-length, computerized administrations. The results of the confirmatory measurement models suggest that latent estimates of WMC can be recovered from performance on ultra-brief complex span tasks . Consistent with previous studies, a strong association between latent WMC and Gf was observed. The results of the sensitivity analysis suggest that estimates of latent WMC may be obtained in as few as 3 minutes of administration on smartphones . Building on this observation, in study 2, we examined the psychometric properties of 2-trial, ultra-brief complex span tasks in the context of a measurement burst study design.N administration of ultra-brief tasks . Incremental estimates of between-person reliability would be useful to prospectively determine the number of administrations necessary to power projects and analyses focused on individual differences in WMC. Estimates of between-person reliability are often calculated based on data collected from the same individual at multiple occasions. However, between-person reliability is distinct and statistically independent of estimates of within-person reliability . Applied research over the past 30 years has demonstrated that individual differences in WMC are strongly associated with important domains of higher order cognition, development, and behavior, including Gf and reasoning ability ,11, contWe shifted to a single-indicator approach for study 3 in response to the same forces that are at play in studies involving in-person data collection and full-length task administration, namely participant burden, time, and study resources. Our goal was to deploy a version of the ultra-brief rotation span task parameterized to improve sensitivity to short-term within-person variation. The results of study 3 suggest that these changes do improve the reliability of within-person changes in complex span task performance. We selected the ultra-brief task that the results of study 1 indicated as the strongest indicator of latent WMC. However, the effect of shifting from a multi-indicator, domain-general approach to estimating WMC using a single indicator should not be overlooked. The measurement models from study 1 demonstrated that latent WMC substantially contributes to ultra-brief rotation span task performance. Yet, task- or domain-specific abilities are also present in the manifest scores. The degree to which this affects the interpretation of future applied research using a single-indicator approach needs to be considered in context . Future development research will be needed to determine whether the principles applied in study 3 to increase within-person reliability can be applied to other indicators and deployed as a multi-indicator battery to the same effect.when WMC predicts behavior . We assume that although individuals with higher WMC may excel at criterion tasks in the laboratory or under experimental conditions, they may not always engage in such successful patterns of behavior. Moreover, it seems unreasonable to assume that individuals with lower WMC would infrequently or never exhibit successful patterns of behavior. Moment-to-moment and day-to-day variation in cognitive function may be driven by a wide range of contextual factors, including, but not limited to, stress, fatigue, pain, and negative affect [whether, how, and when short-term variation in WMC affects behavioral processes and the potential mechanisms through which higher or lower WMC confers an advantage.The validation of ultra-brief complex span tasks suitable for repeated administration represents an important step toward examining the role of intraindividual variation in WMC in psychological and behavioral processes that unfold under naturalistic circumstances. Goals for future research in these areas will need to include a description of e affect ,21,54-56The current set of studies leveraged a new mobile platform under development and sponsored by the NIH and National Institute on Aging. The M2C2 platform is part of the NIH Mobile Toolbox project, and is currently undergoing development, validation, norming, and testing across a wide range of use cases and populations. An early prototype of the M2C2 platform was used to conduct study 2 and study 3, which was validated in other studies involving middle-aged and older adult samples .The complex span tasks developed for these studies deviated in a few ways from the most widely distributed automated tasks . Choice This study involved college-aged younger adults; thus, the results and task parameterization may not be generalizable to other populations. Complex span tasks have, generally, been used to study basic cognitive processes, such as the mechanisms underlying executive control, and less frequently  as a clinical marker. The necessarily complicated instructions and procedures may make them less appropriate for use in clinical studies involving samples with suspected impairments. Validation studies involving middle-aged and older adults are underway to examine whether similar task parameters as those used here might be appropriate for use with older, cognitively unimpaired participants.Finally, the strength of the correlations observed between the laboratory and ambulatory administrations may raise several questions about how well the ambulatory administrations replicate what is observed in the laboratory. Although there are several potential sources of imprecision in ambulatory testing that may drive down correlations , it stands to reason that similar issues apply to the laboratory-based context. The participants are asked to sit in quiet, controlled laboratory environments for more than an hour, focusing their attention on repetitive procedures, managing fatigue, changes in motivation, and internal distractions throughout the testing period. Although the laboratory-based procedures are well established and validated enough to be considered the “gold standard,” the question of which contextual factors are at play and how much they obscure or enhance measures of cognitive ability or performance in each testing context warrants further consideration and future research.Given the attempt to create an optimal  testing context in the laboratory, laboratory-based scores may be assumed to reflect close to the ideal, or maximum ability level. Whether this score reflects the actual capability brought by individuals to face everyday problem solving and decision making remains unknown. A person’s WMC may be immutable, and each measure may more or less accurately reflect one’s underlying ability. However, another view is that laboratory and ambulatory task scores are equally “valid” measures of WMC, simply reflecting WMC under different contextual constraints . Our results indicate that there is systematic variation in WMC that occurs over time. Although this is likely due to various contexts over which participants completed the task administrations, it nonetheless points toward a view of cognitive ability that may be situationally constrained by everyday contextual factors. Which aspect of WMC  is a better predictor of real-world outcomes should be the focus of future research.The results of these studies suggest that reliable estimates of WMC can be obtained via ultra-brief adaptations of computerized complex span tasks, in a measurement burst design, via smartphones, under naturalistic circumstances. These findings present a new avenue for research on the role of WMC in psychological and behavioral processes that unfold over the course of daily life. Future work should also focus on the optimization of ambulatory cognitive assessments for detecting short-term intraindividual variation in cognition.


Chest wall metastasis at biopsy site (CWM) is still an unsolved problem in malignant pleural mesothelioma (MPM) due to its aggressive invasiveness. Here we investigated the incidence and risk factor of CWM using our institutional cohort. Consecutive 262 patients who underwent curative-intent surgery following neoadjuvant chemotherapy for MPM were enrolled in this retrospective cohort study. Of 262, 237 patients were eligible. CWM was evaluated radiologically (r-CWM) and pathologically (p-CWM). Radiological examination showed r-CWM in 43 patients (18.1%), while pathological examination showed p-CWM in 135 patients (57.0%). The incidence of p-CWM was significantly higher in the patients who received pleurodesis after pleural biopsy . Multivariate logistic regression analysis for p-CWM revealed that pleurodesis is an independent risk factor of p-CWM.To investigate the incidence and risk factors of chest wall metastasis (CWM) at biopsy sites in patients with malignant pleural mesothelioma (MPM). This retrospective cohort study was conducted in 262 consecutive MPM patients who underwent multimodal treatment in which including neoadjuvant chemotherapy (NAC) and curative-intent surgery, from August 2009 to March 2021. CWM was evaluated radiologically (r-CWM) and pathologically (p-CWM). We also investigated the risk factors of p-CWM and the consistency between r-CWM and p-CWM. Of 262 patients, 25 patients were excluded from analysis due to missing data or impossibility of evaluation. Of the eligible 237 patients, pleural biopsy was performed via video-assisted thoracoscopic surgery in 197 (83.1%) and medical thoracoscopy in 40 (16.9%). Pleurodesis was performed after pleural biopsy in 74 patients (31.2%). All patients received NAC followed by curative-intent surgery. Radiological examination showed r-CWM in 43 patients (18.1%), while pathological examination showed p-CWM in 135 patients (57.0%). The incidence of p-CWM was significantly higher in the patients who received pleurodesis after pleural biopsy . Multivariate logistic regression analysis for p-CWM revealed that pleurodesis is an independent risk factor of p-CWM . CWM at the biopsy site was pathologically proven in more than half of the patients (57.0%) who received NAC followed by curative-intent surgery, which was higher than the numbers diagnosed by radiological examinations (p-CWM: 57.0% vs. r-CWM: 18.1%). Pleurodesis after pleural biopsy is an independent risk factor of p-CWM. Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm arising from the parietal pleura. The treatment of MPM is still challenging due to its diffuse growth with considerable invasiveness ,2. IpsilSince MPM easily infiltrates into surrounding organs due to its invasiveness, chest wall metastasis (CWM) is highly frequently observed at the biopsy site or drainage tract ,10,11. CThe institutional review board at the Hyogo College of Medicine (number 3925) approved this study on 25 November 2021. Due to the retrospective cohort study, the requirement for written informed consent for study participation was waived by the institutional ethics committee. Instead, participants were given an opportunity to opt-out if they did not want their information to be used in this study. This study was conducted in accordance with the principles of the Declaration of Helsinki.We conducted a historical cohort study to investigate the incidence and risk factors associated with CWM in MPM patients who underwent curative-intent surgery following neoadjuvant chemotherapy (NAC). Between August 2009 and March 2021, 262 consecutive patients with histologically proven MPM, who underwent multimodal treatment (MMT) at the Hyogo College of Medicine Hospital were enrolled in this study. All patients were histologically diagnosed as MPM through pleural biopsy. The pleural biopsy was basically performed via video-assisted thoracoscopic surgery (VATS) or medical thoracoscopy. Patients without pathological evaluation of the biopsy sites and those diagnosed by needle biopsy were excluded from analysis, the latter due to the impossibility of identifying the biopsy site.As mentioned in the therapeutic guidelines , curativOverall, NAC was performed in all patients who met the inclusion criteria prior to curative-intent surgery. After the completion of NAC, radiological examinations such as contrast-enhanced computer tomography (CT) and/or positron emission tomography–computer tomography (PET–CT) were performed to evaluate the response to NAC on the basis of the modified Response Evaluation Criteria in Solid Tumors (mRECIST) . CurativAn en bloc resection, including the biopsy site, was routinely performed ,15,16 whWe evaluated the presence of CWM through not only radiological examinations but also pathological examinations. Radiological CWM at the biopsy site (r-CWM) was radiologically evaluated prior to curative-intent surgery using contrast-enhanced CT and/or PET. We defined r-CWM as the following situations: on contrast-enhanced CT images, lesions were diagnosed when an apparent tumor nodule was detected at the biopsy site. On PET–CT images, lesions were diagnosed when abnormal focal fluorodeoxyglucose uptake relative to the uptake in comparable normal structures or surrounding tissue—observed on PET–CT images—corresponded to an abnormal mass on CT. The diagnosis of r-CWM was performed by a diagnostic radiologist (KK).Pathological CWM at the biopsy site (p-CWM) was evaluated using hematoxylin-eosin stain and immunohistochemical stains A–E. We cMedical records of all enrolled patients, including operation notes, radiological findings, and pathological findings, were collected. Clinical and pathological stages were determined using the Eighth Edition of Tumor Node, Metastases Classification, proposed by the International Mesothelioma Interest Group and the International Association for the Study of Lung Cancer ,19,20. OThe primary endpoint of this study was to investigate the incidence of CWM at the biopsy site in MPM patients who underwent curative-intent surgery following NAC. The secondary endpoints were to investigate the risk factors of CWM and investigate the consistency between r-CWM and p-CWM.p values < 0.05 were considered statistically significant.Fisher’s exact test was employed to compare between the two groups. Logistic regression analysis was utilized to estimate the associations of the patients’ baseline characteristics with p-CWM. Survival was analyzed using the Kaplan-Meier method, and comparison of the survival rates between the 2 groups was performed using the log-rank test. All statistical analyses were performed using EZR , which is a graphical user interface for R . Two-tailed Two hundred and sixty-two consecutive patients were enrolled in this study. Of 262 patients, 14 patients were excluded from analysis due to the absence of pathological examination of the biopsy site, and 11 patients were excluded due to diagnosis through needle biopsy. Therefore, the analyses of this study were performed in the remaining 237 patients. Patient characteristics are shown in Radiological examination through contrast-enhanced CT and/or PET–CT showed r-CWM in 43 patients (18.1%), while pathological examination showed p-CWM in 135 patients (57.0%). The correlations between radiological findings and p-CWM are shown in p = 0.09), on the right side , and was diagnosed through VATS pleural biopsy . Significant correlation with p-CWM was observed in patients who received pleurodesis after pleural biopsy . The results of multivariate logistic regression analysis for p-CWM are shown in p ≤ 0.001). The correlations between patient characteristics and p-CWM are shown in p < 0.05). In multivariate analyses, p-CWM tended to be correlated with poor prognosis.The median follow-up duration was 30.9 months among 237 patients. Median survival time in this cohort was 40.8 months. As shown in This cohort study revealed two insights into CWM in patients who underwent curative-intent surgery following NAC. First, the incidence of p-CWM was higher than r-CWM (57.0% vs. 18.1%). Second, pleurodesis was an independent risk factor associated with CWM, a finding, to our knowledge, of the first investigation analyzing the risk factors for CWM.The incidence of CWM in this study was higher than that shown in previous reports ,22,23,24Given the higher incidence of CWM found in this study, the diagnostic procedure have to be considered with its risk and benefit. Although it is preferable to obtain a sufficient amount of material, an all-layer pleural biopsy should be done only at the incision site. Several literature reports reveal that loco-logical recurrence is the most frequent recurrence pattern in MPM patients who underwent curative-intent surgery ,27. Accop = 0.07). An analysis of only patients who received talc pleurodesis revealed that the incidence of T-stage upstaging was significantly higher in patients with talc pleurodesis . Several inflammatory cytokines such as interleukin 6, tumor necrosis factor-β, and vascular endothelial growth factor could induce tumor growth of mesothelioma [Surprisingly, this study revealed that pleurodesis is an independent risk factor of CWM. As recommended by the guidelines, pleurodesis is commonly performed in patients with malignant pleural effusion (MPE) . Pleurodthelioma ,37,38. Tthelioma , pleurodTalc pleurodesis is the most standardized therapeutic strategy in patients with MPE . HoweverProphylactic radiation therapy (RT) to the chest wall after diagnostic or therapeutic interventions has been widely performed to prevent the development of CWM ,40,41,42Bölükbas and colleague showed the presence of CWM was significant poor prognostic factor in patients who underwent curative-intent surgery . RichardSeveral limitations have to be considered in this study design. First, this study was a single-institution retrospective study with selected patients who had undergone MMT. In our therapeutic strategy, curative-intent surgery was not indicated for patients with apparent tumor progression after NAC. Since MMT was not indicated for most of the MPM patients, the incidence of CWM should be investigated in histologically proven MPM patients regardless of their tumor status. Second, the procedure of pleural biopsy could not be standardized due to the retrospective nature of the study. Third, although this study revealed that pleurodesis was an independent risk factor of CWM, the indication and the agents used were also not standardized. Therefore, a prospective study must be conducted to evaluate the association between tumor progression and pleurodesis. Fourth, the grading of p-CWM according to size were not evaluated in pathological examination. It might be caused survival impact of CWM was not observed in this study.We investigated the incidence and risk factors of CWM. CWM was pathologically proven in more than half of the patients, which was higher than the number diagnosed by radiological examinations (57.0% vs. 18.1%). Pleurodesis was found to be an independent risk factor of CWM after pleural biopsy. Further investigation must be conducted to clarify the correlation between pleurodesis and tumor progression.


Through assessing the accuracy of DIR-based auto-propagation for generating IGTVs, this study aimed to identify erring characteristics associated with the process to enhance RT targeting in LA-NSCLC.Respiratory motion of locally advanced non-small cell lung cancer (LA-NSCLC) adds to the challenge of targeting the disease with radiotherapy (RT). One technique used frequently to alleviate this challenge is an internal gross tumor volume (IGTV) generated from manual contours on a single respiratory phase of the 4DCT 4DCTs of 19 patients with LA-NSCLC were acquired using retrospective gating with 10 respiratory phases (RPs). Ground-truth IGTVs (GT-IGTVs) were obtained through manual segmentation and union of gross tumor volumes (GTVs) in all 10 phases. IGTV auto-propagation was carried out using two distinct DIR algorithms for the manually contoured GTV from each of the 10 phases, resulting in 10 separate IGTVs for each patient per each algorithm. Differences between the auto-propagated IGTVs (AP-IGTVs) and their corresponding GT-IGTVs were assessed using Dice coefficient (DICE), maximum symmetric surface distance (MSSD), average symmetric surface distance (ASSD), and percent volume difference (PVD) and further examined in relation to anatomical tumor location, RP, and deformation index (DI) that measures the degree of deformation during auto-propagation. Furthermore, dosimetric implications due to the analyzed differences between the AP-IGTVs and GT-IGTVs were assessed.ps > 0.90); MSSD and ASSD differed significantly by tumor location in the central–peripheral and superior–inferior dimensions (ps < 0.0001) while only in the central–peripheral dimension for PVD (p < 0.001); DICE, MSSD, and ASSD significantly correlated with the DI . Dosimetric assessment demonstrated that 79% of the radiotherapy plans created by targeting planning target volumes (PTVs) derived from the AP-IGTVs failed prescription constraints for their corresponding ground-truth PTVs.Findings were largely consistent between the two algorithms: DICE, MSSD, ASSD, and PVD showed no significant differences between the 10 RPs used for propagation (Kruskal–Wallis test, In LA-NSCLC, errors in DIR-based IGTV propagation present to varying degrees and manifest dependences on DI and anatomical tumor location, indicating the need for personalized consideration in designing RT internal target volume. Non-small cell lung cancer (NSCLC) presents with locally advanced disease in approximately one-third of cases . For patThe respiratory motion of lung tumors adds to the challenge of targeting disease with RT while minimizing the dose to the nearby organs at risk (OARs) . ContourTo generate an ITV, lung tumor motion is characterized with a four-dimensional CT (4DCT) scan. The 4DCT is based on three-dimensional CT (3DCT) images correlated with the breathing cycle and a sorting algorithm that reconstructs the 4DCT by dividing the 3DCT images into a fixed number of respiratory phase (RP)-based bins . In one To our knowledge, little research has been done to assess erring patterns associated with DIR-based IGTV auto-propagation in LA-NSCLC. Given the paucity of data, this study aimed to evaluate the accuracy of commercially available commonly accepted DIR-based auto-propagation algorithms for generating IGTVs in LA-NSCLC for to identify erring characteristics associated with the process that might have implications for RT targeting.The study cohort consisted of patients accrued within the 4D-lung data collection for which imaging is publicly available from The Cancer Imaging Archive (TCIA) . The locThe dataset included GTVs already delineated on each of the 10 respiratory phases for all 19 patients by radiation oncologists with expertise in treating thoracic malignancies. To repurpose the accompanying contouring data for ITV propagation, as was of interest in the current study, the GTV contours were further reexamined and revised, if necessary, according to the most updated guidelines  by a rad® v7.1.3  and Velocity™ oncology imaging informatics system v4.1 . For every patient, DIR-based IGTV propagation was carried out for each of the GT-GTVs from all 10 phases, resulting in 10 separate auto-propagated IGTVs (AP-IGTVs) for each software platform. As of the entire cohort, there were 190 AP-IGTVs for each software and 380 AP-IGTVs in total. The DIR algorithm adopted in MIM Maestro® for IGTV auto-propagation is the VoxAlign Deformation Engine®, and it employs a coarse-to-fine multi-resolution approach in the search for the best corresponding locations in the target image for the predefined control points on the source image , esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body . IGTVs n100% ≥ 95%) and maximum dose less than 120%. The following OAR constraints were used: spinal cord maximum dose of 50.5 Gy, total lung volume receiving 20 Gy (V20Gy) less than 37% and mean dose less than 20 Gy, esophagus mean dose less than 34 Gy, heart volume receiving 60 Gy (V60Gy) less than 33%, volume receiving 45 Gy (V45Gy) less than 66%, and volume receiving 40 Gy (V40Gy) less than 100%. Plans were normalized so that 95% of the AP-PTV received 60Gy . The plans were reviewed to ensure meeting constraints. Dosimetric analysis of VMAT plans was performed on the GT-PTV for each patient, and dose volume histograms (DVHs) were generated. Specifically, V100% was assessed of the GT-PTV with a value ≥ 95% considered sufficient for meeting the prescription constraint.To characterize the dosimetric implications of differences in AP-IGTVs from the GT-IGTVs, a dosimetric analysis was performed. RT plans were created in Eclipse treatment planning software v16.1  using the contouring guidelines and dose constraints in the RTOG 0617 protocol . For eac® Version 16  statistical software package. DICE, MSSD, ASSD, and PVD of the AP-IGTVs relative to their corresponding GT-IGTVs were examined to see if they differed between respiratory phases and between anatomical locations by the Kruskal–Wallis H omnibus test with the null hypothesis being that they remained invariant spatially and temporally . Likewise, the inferiorly located tumors had higher MSSD and ASSD values compared to superior tumors (ps < 0.0001). The MSSD and ASSD findings were consistent in both DIR algorithms. With MSSD and ASSD emphasizing differences in surface morphology between AP-IGTVs and their corresponding GT-IGTVs, this implies that on geographically small scales there might exist a certain degree of spatial dependence in DIR-based auto-propagation of the GTV. Furthermore, it was also observed that the centrally located tumors differed significantly from the peripherally located ones with a significantly higher PVD (p < 0.001). Coupling this with the results regarding MSSD and ASSD, this may suggest that caution should be exerted in using DIR-based auto-propagation to generate an IGTV for centrally located LA-NSCLC tumors.The obtained data on measures of accuracy between AP-IGTVs and their corresponding GT-IGTVs were also pooled according to respiratory phase and anatomical tumor location to examine whether there existed any temporal or spatial dependences associated with DIR-based auto-propagation of IGTVs. ps < 0.0001). These results substantiate the notion that the accuracy of auto-propagated IGTV deteriorates as the amount of deformation required to register the tumor between different respiratory phases increases.Scatter plots with superimposed linear regression showing the trend of correlations between the studied accuracy metrics and the deformation index are illustrated in 100% of the GT-PTVs as a function of deformation index of the corresponding AP-IGTVs used for planning. Although all the VMAT plans satisfied the prescription constraints of V100% ≥ 95% for the AP-PTVs, GT-PTVs in only 4 out of the 19 (21%) patients met this constraint, namely, that 79% of the GT-PTVs (dots labeled in red below the blue dashed line) failed to meet the prescription constraint.To evaluate the dosimetric consequences of the erring patterns described, VMAT plans were made, as mentioned above, to target the AP-PTV derived from the AP-IGTV that had DI closest to the overall median DI among all the AP-IGTVs created by both DIR algorithms for each patient. All VMAT plans created met the RTOG 0617 prescription constraints to the targets and nearby OARs . DVHs ofOutcomes following definitive chemoradiation therapy for LA-NSCLC are poor with a median progression-free survival under 1 year highlighting the urgent need for treatment advances for this disease . Immunot® v7.1.3  and the elastic B-spline deformation algorithm from Velocity™ oncology imaging informatics system v4.1 , two of the most frequently applied commercially available DIR-based IGTV auto-propagation algorithms, were adopted to generate IGTVs using manual GTV contours from each RP of all 19 individual patients. Spatial incoherencies between the resultant AP-IGTVs and their corresponding GT-IGTVs as measured with respect to spatial overlap (DICE), surface deviation (MSSD and ASSD), and volume difference (PVD) for each of the acquired 3DCT scans were pooled by respiratory phase, anatomic tumor location, and deformation index, with each being examined for whether and to what extent it impacts IGTV propagation accuracy. One important finding gleaned from the present study was the observation that DICE, MSSD, and ASSD are all significantly correlated with the deformation index with both the MIM DIR algorithm  and the Velocity DIR algorithm . These highly statistically significant relationships, especially the one between MSSD and the deformation index, bear important clinical implications. MSSD is of particular importance for target volume design as it determines the maximum margin of error by selecting the largest of all calculated distances between the surfaces of one AP-IGTV and its corresponding GT-IGTV. This finding, therefore, implies that AP-IGTVs with a high deformation index ensuing from the great motion envelope of their pertaining GTVs may need larger safety margins or closer physician review to avoid RT target miss or overdosing normal tissues. In other words, the deformation index may have the potential to be a predictor of accuracy for DIR-based IGTV auto-propagation and thereby could be used to personalize the internal margin design for planning radiotherapy in LA-NSCLC. This observation of the current study also corresponds to previous investigations  has been shown to be less reliable in generating ITVs for more advanced tumors compared to early-stage tumors . FurtherFor patients with LA-NSCLC, errors in DIR-based IGTV auto-propagation are present to varying degrees and exhibit dependencies on the deformation index and intrathoracic tumor location. Interestingly, the respiratory phase used to initialize AP-IGTV propagation was found not to correlate significantly with analyzed differences with the GT-IGTV. These findings may allow for the formation of new hypotheses toward achieving robust and more accurate RT targeting in LA-NSCLC.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by BR, BS, and FY. The first draft of the manuscript was written by BR and FY. All authors commented on previous versions of the manuscript. All authors reviewed and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.