The current evidence on an integrative role of the domain-specific early mathematical skills and number-specific executive functions (EFs) from informal to formal schooling and their effect on mathematical abilities is so far unclear. The main objectives of this study were to (i) compare the domain-specific early mathematics, the number-specific EFs, and the mathematical abilities between preschool and primary school children, and (ii) examine the relationship among the domain-specific early mathematics, the number-specific EFs, and the mathematical abilities among preschool and primary school children.Ntotal = 505, n6yrs = 238, and n7yrs = 267). The domain-specific early mathematics as measured by symbolic and nonsymbolic tasks, number-specific EFs tasks, and mathematics tasks between these preschool and primary school children were compared. The relationship among domain-specific early mathematics, number-specific EFs, and mathematical abilities among preschool and primary school children was examined. MANOVA and structural equation modeling (SEM) were used to test research hypotheses.The current study recruited 6- and 7-year-old children (The current results showed using MANOVA that primary school children were superior to preschool children over more complex tests of the domain-specific early mathematics; number-specific EFs; mathematical abilities, particularly for more sophisticated numerical knowledge; and number-specific EF components. The SEM revealed that both the domain-specific early numerical and the number-specific EFs significantly related to the mathematical abilities across age groups. Nevertheless, the number comparison test and mental number line of the domain-specific early mathematics significantly correlated with the mathematical abilities of formal school children. These results show the benefits of both the domain-specific early mathematics and the number-specific EFs in mathematical development, especially at the key stages of formal schooling. Understanding the relationship between EFs and early mathematics in improving mathematical achievements could allow a more powerful approach in improving mathematical education at this developmental stage. Mathematical skills are regarded as an important tool and an integral part of effective functioning in everyday life , 2. ThesResearchers from several disciplines have currently begun to reveal underlying cognitive and brain architectures of our numerical processing abilities e.g., –11). One. One11])Other studies have also alternatively revealed the main roles of executive functions (EFs)  as a cruA multicomponent framework of mathematics highlighting the main role of EFs on domain-specific numerical skills and early numerical abilities as being an indirect and stable relationship from age 8 years through to young adults has been documented . This stMore specifically, the general EFs or EFs in numerical contexts may consist of partially dissociable components in early childhood –40. The Several studies demonstrated the significant connection among specific executive functioning, that is, working memory, inhibition and shifting abilities, and mathematical ability in children , 42. InhThe developmental patterns for the relationship between inhibitory control and shifting/switching abilities with mathematics achievement differed depending on the academic outcomes examined . That isAlthough recent literature support transfer effects from EF interventions to mathematical abilities, the EF trainings have a larger effect in preschool than in school ages –53. FurtIt can be concluded that several studies have focused on numerical and domain-general executive functioning skills , 60. TheThe current study included 511 6- to 7-year-old children (238 or 47.1% for 6-year-old preschoolers and 267 or 52.9% for 7-year-old first graders); six children were excluded because of missing values, thus leaving 505 children  for final analysis. All participants were native Thai and attended 12 public schools in Chonburi province, Thailand and a sample of 12 public schools was drawn using a stratified sampling technique. All public schools used the same set of subjects and standards under the national curriculum for Thailand. The preschoolers and first graders were studying at the same public schools with equal proportions. No participant was clinically referred for learning difficulties (LD) or attention-deficit/hyperactivity disorder (ADHD). The experimental protocols were approved by the Burapha University Research Ethics Committee (BUU 6200/01533). All methods were carried out in accordance with the Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki. Written informed consent was obtained from parents of all participants prior to inclusion.The domain-specific early mathematics is composed of eight paper-and-pencil tests  with Arabic numerals (nonsymbolic vs. symbolic numbers). An Arabic symbolization is required for the development of the mental number line as a representation of magnitude and ordinality to visual space . The dotThe number comparison test was used to examine symbolic numerical magnitudes . The numα was 0.77.The mental number line test was used to assess proficiency in numerical magnitude processes and representations . The menThe numerical inhibition test was used to assess a cognitive inhibition or the ability to automatically inhibit irrelevant responses and adjust control –71 on phThe numerical shifting test was used to assess children’s cognitive flexibility performance or the ability to shift attention on the basis of changing  condition demands . The papThe number sets test was used to assess mathematical abilities in young children . The numThe numerical operation test was adapted and used to assess children’s storage and manipulation of numerical operations , 76. Thiη2 was also calculated to represent the magnitude of difference between groups ).Moreover, the weak correlation among the mental number line and other variables in the same construct may additionally stem from the issues of the test format and the scoring method. A further limitation of this study is that children could have made their comparisons on the basis of continuous extent rather than the number for nonsymbolic stimuli , 96. FutFor practice reasons and practices, the paper-and-pencil based tests were suitable for our settings in terms of distribution and administration of the tests. However, the response time could reflect the automatization during numerical processing of both mathematical and executive functioning skills of the young age . Thus, tThe current study did not compare the relative effects of the domain-specific early mathematics, the number-specific EFs, and the general EFs on mathematical abilities. Further studies should specifically compare common and unique roles of domain-general vs. domain-specific EF on mathematical development. The present findings provide a strong motivation to delineate these factors. Finally, a longitudinal study is needed to support the current findings in regards to the differential effects of the domain-specific early mathematics and the number-specific EFs on the mathematical abilities.The present study yielded two key findings. First, 7-year-old children outperformed 6-year-old children in the overall measures of the domain-specific early mathematics and the number-specific EFs, especially for more sophisticated numerical knowledge and EF subcomponents, namely, symbolic numerical magnitude representations as indexed by the number comparison and the mental number line tests and the numerical inhibitory and shifting abilities as measured by the numerical inhibition and shifting tests. Second, both the domain-specific early mathematics and the number-specific EFs comparably and significantly related to the mathematical abilities for 6- and 7-year-old children, but the domain-specific early mathematics and the number-specific EFs were dominant concerning the mathematical abilities for 7-year-old children.


Hippocampus atrophy is an early structural feature that can be measured from magnetic resonance imaging (MRI) to improve the diagnosis of neurological diseases. An accurate and robust standardized hippocampus segmentation method is required for reliable atrophy assessment. The aim of this work was to develop and evaluate an automatic segmentation tool (DeepHarp) for hippocampus delineation according to the ADNI harmonized hippocampal protocol (HarP). DeepHarp utilizes a two-step process. First, the approximate location of the hippocampus is identified in T1-weighted MRI datasets using an atlas-based approach, which is used to crop the images to a region-of-interest (ROI) containing the hippocampus. In the second step, a convolutional neural network trained using datasets with corresponding manual hippocampus annotations is used to segment the hippocampus from the cropped ROI. The proposed method was developed and validated using 107 datasets with manually segmented hippocampi according to the ADNI-HarP standard as well as 114 multi-center datasets of patients with Alzheimer’s disease, mild cognitive impairment, cerebrovascular disease, and healthy controls. Twenty-three independent datasets manually segmented according to the ADNI-HarP protocol were used for testing to assess the accuracy, while an independent test-retest dataset was used to assess precision. The proposed DeepHarp method achieved a mean Dice similarity score of 0.88, which was significantly better than four other established hippocampus segmentation methods used for comparison. At the same time, the proposed method also achieved a high test-retest precision (mean Dice score: 0.95). In conclusion, DeepHarp can automatically segment the hippocampus from T1-weighted MRI datasets according to the ADNI-HarP protocol with high accuracy and robustness, which can aid atrophy measurements in a variety of pathologies. Dementia has devastating effects on patients as well as their families and care givers . It is nAccurate hippocampus volume measurement requires a robust and accurate segmentation tool. A growing body of research exists aiming to improve the accuracy of hippocampus segmentation for early diagnosis of dementia ,12,13. HSegmentation methods that use machine learning algorithms, such as support vector machines, require many high-quality labelled datasets and a priori feature extraction . Novel dEven though CNN-based hippocampus segmentation methods yield better results compared to traditional segmentation methods, they are often biased by the quality of the ground truth hippocampus labels used for training the CNN. Recently, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) defined the harmonized hippocampal protocol (HarP) for the manual segmentation of the hippocampus from structural MRI, which aims to reduce inter-observer differences ,22. ADNIAccording to protocol, the cut line between the amygdala and hippocampus at the rostral level can be recognized by segmenting gray matter below the alveus and at the caudal level by separating the last grey matter mass inferomedial to the lateral ventricles. The protocol suggests using 2D orthogonal views  for optimal tracings. This recommendation relates to the similarity of tissue intensity of the surrounding tissues, in which case visualization in the different orthogonal views can help to assess the continuity of the structures, aiding segmentation, especially at the medial boundary of the hippocampus, where the grey matter is difficult to delineate based on only voxel intensity information. The ADNI-HarP protocol was agreed upon by a panel of experts from North America and Europe and is accepted as the standard systematic method for hippocampal manual segmentation ,22.The ground truth data include the brain MRI datasets and the corresponding manual hippocampus segmentations by ADNI-Harp experts. Their segmentations have more than 90% agreement .To date, the majority of hippocampal segmentation tools developed either utilize atlas-based segmentation methods or deep learning-based algorithms, in particular CNNs ,25,26,27Briefly described, the main contributions of this work are: (1) harnessing the combined advantage of atlas- and CNN-based segmentations producing superior accuracies and test-retest precision when compared with other established atlas-based techniques  and deep learning approaches ; (2) incorporating MRI data and corresponding hippocampus segmentations from patients with multiple brain disorders acquired with different MRI scanners and different field strengths (1.5 and 3.0 T) to improve the validity, robustness, and the general application of DeepHarp; and (3) designing an automatic method for automatic hippocampus segmentation following the ADNI-HarP standardization.n = 50; datasets included healthy subjects and patients with various pathologies such as AD, AD with cerebral vascular disease, and MCI) [n = 130) [n = 14) [n = 50) [The T1-weighted MRI datasets included in this study were acquired using various 3T and 1.5T MRI scanners and were collected from four sources: Sunnybrook Health Sciences Centre, Ontario, Canada (and MCI) , Alzheimn = 130) , the Ope[n = 14) , and a f[n = 50) .www.adni-info.org.ADNI was launched in 2003 as a public-private partnership led by Principal Investigator, Michael W. Weiner, MD. The primary goal of ADNI has been to test whether serial MRI, positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer’s disease (AD). For up-to-date information, see Finally, a freely available test-retest dataset of healthy subjects  was used3 resolution with cubic interpolation.The image datasets were acquired on various scanners using distinct imaging parameters. Thus, the image resolution and signal intensities were not directly comparable between the datasets used to train the CNN. To overcome this limitation, the datasets were pre-processed by normalizing the intensity values to a mean of zero with a standard deviation of one and resampling to a 1 × 1 × 1 mmThe pre-processing step of the proposed hippocampus segmentation method aims to detect a volume-of-interest (VOI) that contains the hippocampus within the 3D MRI datasets see . A safetThe CNN architecture  describeThe fully-connected DeepMedic CNN architecture, originally designed for brain lesion segmentation and previously described in detail elsewhere , was optIn the final setup, the number of feature maps started at 20 and increased by increments of five in each layer up to a maximum of 60 in the final layer. For the training stage, a batch size of 20 and 10 epochs were used to train the network by minimizing the cross-entropy loss function. Small 3 × 3 × 3 kernels were applied, which reduces the number of network parameters . A funneADNI-HarP segmentations are specifically harmonized at the most posterior, anterior, and medial anatomical boundaries . HippocaThe non-ADNI-HarP data from the Sunnybrook, OASIS, and the epileptic datasets used in this work were segmented using different manual labeling protocols, which vary based on local manual segmentation protocol. However, these manual labels encompassed most of the hippocampal anatomy included in the ADNI-HarP protocol. Thus, it was assumed that these datasets still provide useful information for training of the CNN-based segmentation model. The ADNI-HarP data that was used in this study was comprised of 130 MRI brain scans, of which 78 were used for training, together with all non-ADNI-HarP datasets see . During Thus, DeepHarp was trained using anatomical segmentation patterns from a combination of the local-protocols and the ADNI-HarP protocol. To improve the generalizability of the CNN model, all training data were augmented by Gaussian blurring using standard deviations of 0.5 and 1.0 .For validation purposes, the hippocampus segmentation results obtained by the DeepHarp model were compared to the segmentation results generated using FSL  and FreeThe precision of the proposed segmentation method was evaluated using two independent MRI scans of the same subject available for each scan session . For a quantitative evaluation, the second MRI of each session was registered to the first image acquisition of the same session, using a rigid transformation with a normalized cross-correlation cost function and linear interpolation. After this step, the previously described preprocessing steps and DeepHarP method were applied to each of the co-registered images for hippocampus segmentation. The two segmentations from each session were compared using the Dice coefficient, and the average Dice coefficient was computed across all sessions. As all scan pairs were acquired from the same subject within one-month, minimal volume changes were expected over this interval, and the Dice similarity metric was hypothesized to be close to 1.0. We additionally performed hippocampus segmentation on these 20 scan pairs using the FSL , Freesurhttps://github.com/snobakht/DeepHarP_Hippocampus/tree/main/DeepHarP.The training of the CNN model was performed using a NVIDIA GTX 1060 GPU and the CUDA 9 toolkit and cuDNN 7.5 with TensorFlow 1.12.1. All pre-processing steps were performed using the visualization toolkit (VTK) and python 2.7. All registrations were performed using the NiftyReg package . Brain eThe quantitative evaluation of the segmentations generated showed that the proposed DeepHarp model achieved an average Dice score of 0.88 ± 0.02 using the 23 test datasets (46 hippocampi segmented from ADNI-Harp data). No significant difference was observed regarding the Dice similarity metrics of the left and right hippocampi.p < 0.001) indicating a high level of accuracy  showed that DeepHarp achieved significantly higher Dice scores . HippoDeep is significantly more robust than DeepHarp  based on Dice scores, while no statistically significant difference was found between HippoDeep and DeepHarp  based on volume differences. DeepHarp and QuickNat have no significant difference based on Dice scores, while QuickNat is statistically more robust than DeepHarp on left hippocampus measurements, but not for the right hippocampus. Overall, DeepHarp, QuickNat, and HippoDeep are comparable in robustness based on the two quantitative metrics, Dice scores and absolute volume differences. p-values.The statistical evaluation on Dice scores and absolute volume difference revealed that DeepHarp is significantly more robust than FSL for the left hippocampus and Freesurfer for the right hippocampus segmentation . Overall, DeepHarp achieves higher accuracy and test-retest precision than commonly used segmentation tools such as FSL and Freesurfer, and achieves more accurate results compared to other deep learning methods ,14.Automation of the ADNI-HarP protocol is necessary to increase efficiency, accuracy, and standardization of hippocampus segmentations within larger studies. Therefore, a major contribution of this work is that the proposed DeepHarp technique achieves highly accurate and precise segmentation results following the ADNI-HarP standard. The proposed model demonstrated high accuracy and precision across different scanners, image resolutions, and pathologies. Due to the limited number of manually segmented datasets from the original ADNI-HarP validation sample, we utilized datasets that were manually segmented by medical experts, using validated protocols with inclusive anatomical definitions. To assure that the final model segments the hippocampus according to the ADNI-HarP guidelines, the trained CNN model was additionally fine-tuned using an independent validation sample selected from the ADNI-HarP dataset, which was then tested using another independent ADNI-HarP sample.Another major advantage of the proposed method is its simplicity, as it only requires an atlas registration and subsequent application of the trained CNN. Although training of a CNN can be time-consuming, the application of a trained network is usually quite fast using modern hardware especially if applied to a small ROI.Excluding the atlas-based segmentation, DeepHarp segments the hippocampus in an MRI dataset in about 6 s. The efficient DeepMedic architecture as well as cropping images using the atlas-based segmentation are key components for fast inference time of DeepHarp. However, the atlas registration can take up to 10 min depending on the implementation and computational resources available. The other two deep learning methods used in this work for comparison (QuickNat and HippoDeep) require less than a minute for a single dataset while FreeSurfer and FSL are considerably slower. However, it needs to be highlighted that there is no clinical decision that requires fast hippocampus segmentation from MRI. What matters most is a reliable, robust, and accurate segmentation for use as an image-based biomarker in clinical decision making and clinical studies.From a technical perspective, the main contribution of this work is the development and evaluation of an advanced method for hippocampus segmentation from T1-weigthed MRI datasets, according to the ADNI-HarP protocol by combining an atlas-based and CNN-based segmentation methods. These two techniques are the two most used general approaches for hippocampus segmentation ,25,26,27However, there are still many interesting avenues to further improve the accuracy of DeepHarp. For example, a recent study by Dill et al.  showed tDeepHarp is based on the DeepMedic architecture  that hasIn our study, the selection of data used for training DeepHarp was very diverse, as demonstrated by the inclusion of MRI scans from patients with multiple brain disorders  and dementia subtypes  ,22,23,28There are several limitations to our proposed method that should be addressed in future work. First, the use of non-linear registration in the pre-processing stages can be time consuming. Future work should investigate if an affine registration might be suitable enough for this purpose. Second, the CNN generates segmentations using T1-weighted data only. Whether the proposed method can be applied/re-trained to other MRI sequences or multi-modal MRI datasets requires further assessment and is beyond the scope of this study. Although our method yielded high accuracy, the reliability of the DeepHarp was significantly lower than the HippoDeep method. This is likely due to the higher number of training sets used in HippoDeep (>20 k). Including auxiliary data (using automated tools) for post training of DeepHarp may improve robustness but likely at the price of reduced accuracy. In this case, robustness is a measure of segmentation consistency across different time points. In other words, for this specific analysis, we mostly investigated if the methods make the same mistakes for the same patients or if the segmentation errors occur at different locations when segmenting the same structure in the same patient in images acquired at multiple time points. This analysis shows that all methods make similar mistakes across different imaging time points, while DeepHarp achieves the highest segmentation accuracy when comparing the different methods. Thus, it is important to consider the accuracy levels found when comparing the robustness between models. In other words, the results suggest that DeepHarp is precise and accurate.From a clinical perspective, DeepHarp improved hippocampus segmentation accuracy is important as it could help to establish an image-based biomarker for early detection of Alzheimer’s disease that can be used in prospective clinical testing of the effects of disease modifying treatments on rates of hippocampus atrophy as a secondary outcome measure.Our findings suggest that the DeepHarp can automatically segment the hippocampus from T1-weighted MRI datasets according to the ADNI-HarP protocol with higher accuracy than four other state-of-the-art methods, while also achieving high precision.


Background: The Academic Research Consortium has identified a set of major and minor risk factors in order to standardize the definition of a high bleeding risk (ACR-HBR). Oral anticoagulation is a major criterion frequently observed.Aims: The objective of this study is to quantify the risk of bleeding in patients on oral anticoagulation with at least one additional major ACR-HBR criteria in the Cardio-Fribourg Registry.Methods: Between 2015 and 2017, consecutive patients undergoing percutaneous coronary intervention were prospectively included in the Cardio-Fribourg registry. The study population included patients with ongoing long-term oral anticoagulation (OAC) and planned to receive triple antithrombotic therapy. Patients were divided in two groups: patients on OAC with at least one additional major ACR-HBR criteria vs. patients on OAC without additional major ACR-HBR criteria. The primary endpoint was any bleeding during the 24-month follow-up. Secondary bleeding endpoint was defined as Bleeding Academic Research Classification (BARC) ≥3.Results: Follow-up was completed in 142 patients at high bleeding risk on OAC, of which 33 (23%) had at least one additional major ACR-HBR criteria. The rate of the primary endpoint was 55% in patients on OAC with at least one additional ACR-HBR criteria compared with 14% in patients on OAC without additional ACR-HBR criteria . Patients with additional major ACR-HBR criteria also experienced significantly higher rates of BARC ≥ 3 bleedings (39% at 24 months).Conclusion: The presence of at least one additional ACR-HBR criterion identifies patients on OAC who are at very high risk of bleeding after percutaneous coronary intervention. Dual antiplatelet therapy (DAPT) is mandatory after percutaneous coronary intervention (PCI) . Of the Oral anticoagulation is a major criterion frequently observed in patients undergoing PCI. This study was conducted to (a) estimate the incidence of bleeding in patients under TAT after PCI, (b) assess whether the presence of at least one additional bleeding risk factor according to the ARC-HBR classification further increases bleeding risk in patients on TAT, and (c) measure the ischemic risk in HBR patients.The Percutaneous Coronary Intervention Registry FRIBOURG (CARDIO-FR) registry is a single-center prospective registry enrolling all consecutive patients undergoing PCI between May 2015 and May 2017 at the University & Hospital Fribourg . The exclusion criteria are the inability to provide written informed consent and the unwillingness to participate in clinical follow-up. The present analysis included patients with ongoing long-term OAC planned to receive DAPT.The indication for PCI was based on established European guidelines . PCI wasA prospective clinical follow-up by phone or clinic visit was completed for all patients up to 24 months. The study complied with the Declaration of Helsinki, was approved by the local ethics committee (003-REP-CER-FR), and is registered at clinicaltrials.gov (NCT04185285). Written and informed consent for prospective follow-up was obtained from every patient.Patients and the public were not involved in the design and conduct of this research.The primary endpoint was any bleeding during the 24-month follow-up. The secondary bleeding endpoint was defined as Bleeding Academic Research Classification (BARC) ≥3 , which cTwo groups were defined for the primary analysis: patients on OAC with additional major HBR criteria  vs. patients on OAC as the only major HBR criteria .t-test or the Wilcoxon rank-sum test according to their distribution. Categorical variables were compared using chi-square or Fisher exact test as appropriate. Furthermore, clinical outcomes were reported as Kaplan-Meier failure estimations. Hazard ratios were derived from univariate Cox regression. To account for between-group differences in baseline characteristics and in prognostic variables with regard to the primary endpoint, we performed a Cox regression analysis. All relevant variables  were forced into the model. Likewise, we performed a multivariable Cox regression to provide an adjusted hazard ratio for one of the bleeding secondary endpoint (major bleeding). Given the low number of events (n = 17), we performed a backward stepwise regression to identify the strongest predictors and finally retained two variables (diabetes mellitus and age) while forcing group membership into the model.Categorical variables are reported as count and percentages; continuous variables are reported as mean ± SD or median (25–75% interquartile range). Normality was assessed by visual inspection of histograms and the computation of Q–Q plots. Continuous variables were compared using the Student's Secondary analysis included bleeding outcomes in relation to prescribed TAT duration by an individual patient-level analysis performed after cessation of TAT in each patient. Statistical analyses were performed with Stata version 14.0 .p < 0.01).A total of 187 patients on OAC (17.3% of the cohort) underwent PCI during the inclusion period, of which 45 were excluded, as they received OAC and only single antiplatelet therapy . Of the p = 0.35). The indication for OAC was mainly atrial fibrillation in both groups (Vitamin K antagonist (VKA) were prescribed in 76 patients (54%), and 66 patients (46%) received a direct oral anticoagulant (DOAC). DAPT with aspirin and clopidogrel were prescribed in 123 patients (87%). The median duration for TAT was 1 month for both groups (h groups .n = 18) of patients in the OAC with additional ARC-HBR group and in 14% (n = 15) in the OAC without additional ARC-HBR group (p < 0.01) (p < 0.01) (n = 13) of patients in the OAC with additional ARC-HBR group and in 4% of patients (n = 4) in the OAC without additional ARC-HBR group   , Table 4 < 0.01) . The rat < 0.01) . Interes < 0.01) .n = 4) in the OAC with additional ARC-HBR group vs. 15% (n = 16) in the OAC without additional ARC-HBR group .The secondary combined ischemic endpoints at 24 months are provided in In this study, we observed that OAC is frequent in an all-comers registry of patients undergoing PCI. The main findings regarding OAC and bleeding risk are the following: (a) bleeding rates are high among patients on TAT; (b) in patients on TAT, the presence of at least one additional major ARC-HBR criteria is associated with a 3.9-fold increase in bleeding at 2-year clinical follow-up; (c) this difference persists after TAT cessation; and (d) there was no statistically significant difference in ischemic events in patients on OAC with additional HBR criteria compared to patients on OAC without additional ARC-HBR patients.We observed an overall incidence of any bleeding of 23% and major bleeding of 12% in 142 high-risk patients at 2 years. Several clinical trials have assessed bleeding events in TAT among participants with atrial fibrillation who underwent PCI. The incidence of bleeding in the major trials assessing TAT in patients with atrial fibrillation undergoing PCI was similarly high, although they varied depending on the type and duration of triple therapy, and patient characteristics. Overall bleeding rates range from 18 to 31% and severe bleeding of 1–6% in studies with 1 year of follow-up [the percentage of any bleeding outcome and severe bleeding were, respectively, 18 and 1% in PIONEER AF-PCI , 31 and According to the ARC-HBR, the risk of a bleeding complication following PCI is defined by a number of major and minor criteria. This definition is dichotomous; in other words, a patient is declared as high bleeding risk or not. However, the interaction between each criterion is unknown, and thus, clinical validation is required. Natsuaki et al.  demonstrHowever, the definition of bleeding events reported by Cao et al. diverges from the BARC type 3–5 criteria.The present study focuses on the risk of bleeding in patient under OAC as a sole major criterion and addresses the relevance of additional ARC-HBR criteria. Indeed, the incremental risk is magnified in our registry . In addition, our analysis provides a glimpse into off-label strategies such as triple therapy with more potent P2Y12 inhibitors, as 13% of patients received a TAT with prasugrel or ticagrelor.As recently demonstrated in a large meta-analysis including most TAT trials with DOAC, TAT cessation and switch to double antithrombotic therapy (DAT) significantly reduced the risk of bleeding . HoweverOverall, ACR-HBR patients may be at increased ischemic risk, as some risk factors present in the ARC-HBR definition are also global ischemic factors such as advanced age, renal failure, and active malignancy. If some HBR criteria are also ischemic risks, with shorter antithrombotic therapy duration in some patients, the ischemic risk could be expected to increase. This was partly observed in the WOEST study, where TAT was associated with an increase in the combined ischemic events of death, MI, TVR, stroke, and stent thrombosis. It has been hypothesized that this may be due in part to the interruption of the TAT due to bleeding complications . In the This study had several limitations. First, the number of patients was small, and the study was based on a single-center experience. The type and duration of triple therapy was not predefined but was individualized according to physician judgment; our findings, nonetheless, reflect real-world practice. Triple therapy duration was reported according to prescription at hospital discharge and was not consistently recorded. Possible triple therapy discontinuation has not been measured. Unmeasured confounders  have not been determined.In a high-risk population with triple therapy and PCI, an incremental risk of major bleeding was detected with the addition of major-HBR criteria, up to 39% of major bleeding at 24 months. Patients with two or more ARC-HBR major criteria should be regarded as extremely high risk for major bleeding.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Local Ethics Committee of canton Vaud (CER-VD). The patients/participants provided their written informed consent to participate in this study.All the authors have made substantial contributions to the conception and design of the study, the data acquisition, data analysis, and interpretation, the writing of the paper and critical review for important intellectual content, and the final approval of the version to be submitted.Data collection was supported by an unrestricted grant from the Fonds Scientifique Cardiovasculaire .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.


Planarians are flatworms capable of whole-body regeneration, able to regrow any missing body part after injury or amputation. The extraordinary regenerative capacity of planarians is based upon the presence in the adult of a large population of somatic pluripotent stem cells. These cells, called neoblasts, offer a unique system to study the process of stem cell specification and differentiation in vivo. In recent years, FACS-based isolation of neoblasts, RNAi functional analyses as well as high-throughput approaches such as single-cell sequencing have allowed a rapid progress in our understanding of many different aspects of neoblast biology. Here, we summarize our current knowledge on the molecular signatures that define planarian neoblasts heterogeneity, which includes a percentage of truly pluripotent stem cells, and guide the commitment of pluripotent neoblasts into lineage-specific progenitor cells, as well as their differentiation into specific planarian cell types. Some of the main challenges in regenerative medicine are related to the capacity to control stem cell self-renewal and differentiation, as well as to try to induce and/or improve our limited regenerative abilities as mammals. Planarians are one of the few animal models that combine two amazing features: They can regenerate the whole body from a tiny piece of them, and they do it because they maintain a population of adult pluripotent stem cells throughout their lives, referred to as neoblasts ,2. NeoblIt is now clear that neoblasts constitute a heterogeneous cell population that includes real pluripotent stem cells as well as a large number of lineage-committed progenitors . By idenIn this review, we summarize our current knowledge on some of these questions, as well as on the molecular signatures that define planarian neoblasts’ heterogeneity and guide the commitment of pluripotent neoblasts into lineage-specific progenitors first and mature cells later.piwi-1 ..zfp-1 anhnf-4 and gata4/5/6 in piwi-1-expressing cells [gata4/5/6 but not hnf4 causes defects in gut regeneration and maintenance [gli-1 and the ras-responsive element binding protein 2 (rreb2) for the regeneration and maintenance of goblet cells, respectively [ceramide synthase gene -like molecule fgfrL-1 [ets-1, foxF-1 and fgfrL-1 play an important role in early pigment progenitor specification, while albino may act at later stages of the pigment cell lineage  that diversify their function through the reversible or irreversible alteration of their structure and properties through biochemical reactions including phosphorylation, glycosylation, ubiquitylation, methylation and acetylation . PTMs, tChromatin is important because in addition to compacting DNA it regulates how and when specific molecules such as repair, replication and transcription factors access to the DNA to undertake their function. Thus, gene expression will be mainly regulated through the capacity of these activating and repressing factors to bind their specific DNA targets. Histones undergo many distinct PTMs, including methylation and acetylation . HistoneIn recent years significant progress has been made in order to understand the role of PTMs and epigenetic modifications on planarian regeneration ,126. Strhuwe1 results in an increase in apoptosis and regeneration inhibition despite also inducing an increase in cell proliferation [Ubiquitylation and SUMOylation have been shown also to be important for planarian regeneration . Thus, fferation . Similarferation .mcm5 [In addition, several factors involved in chromatin formation and remodeling have been shown to play a role in neoblast function. Thus, a homologue to heterochromatin protein 1 (HP-1) seems to be required to maintain neoblast self-renewal and promote proliferation probably by inducing the expression of mcm5 . Other imcm5 . The silmcm5 . The MLLmcm5 ,137,138.mcm5 .cbp-2 appears to be required for stem cell maintenance and planarian survival, as after its silencing, the animals show a significant reduction in the number of neoblasts and proliferative cells and die after a few days of treatment [cbp-3 appears to be mainly involved in neoblast differentiation, although some differences are reported in both studies that might be explained by the different RNAi experimental set up as well as the long-term effects of its silencing. Most invertebrates have just one CBP homologue, and a duplication at the base of the vertebrate lineage seems to be the origin of the p300 gene in that phylum [S. mediterranea possess five CBP homologues as a consequence of possible duplication events specific to the phylum Platyhelminthes [cbp-2 and cbp-3 appear to play quite complementary functions. Thus, the silencing of cbp-2 leads to the absence of the first mitotic peak associated with the wound response together with a significant decrease in the number of +piwi-1 cells. In contrast, cbp-3 RNAi results in a significant increase in the first mitotic peak, as well as of the +piwi-1 population [cbp-2(RNAi) animals show a decrease in the number of gut progenitors, whereas an increase is observed after silencing cbp-3 [Recently, two different studies have uncovered the function of the planarian CREB-binding protein (CBP)/p300 family in neoblast biology ,140. Thereatment ,140. On t phylum . Remarkalminthes ,140. Evelminthes . Intereslminthes ,146. Howlminthes . Remarkacbp-2 and cbp-3 could have complementary functions is that concerning the neuroectodermal lineage. It has been shown recently that a SoxB1 homologue is expressed in a common neuroectodermal lineage that will give rise to either epidermal or neural cells [SoxB1-positive cells co-express either cbp-2 or cbp-3 [Another process in which al cells . Remarkaor cbp-3 , which sor cbp-3 .The fine molecular characterization of the planarian neoblasts has uncovered their high level of heterogeneity and a complex hierarchical organization. Through the combination of FACS-based neoblast isolation, single neoblast transplantations and single-cell sequencing, the planarian stem cell compartment has been shown to be constituted by truly pluripotent stem cells that become specialized into multiple lineage progenitors. These distinct cell lineages have been characterized by the expression of specific transcription factors and other genes required for their final differentiation. Importantly, recent studies have started to characterize the onset of neoblast differentiation in relationship to the cell-cycle and their symmetric or asymmetric division. Thus, for example, specialized lineage progenitors show a certain degree of plasticity that allows them to step back towards a pluripotent state and switch cell fate in particularly challenging contexts. Although advances have been made in terms of characterizing the early signals that trigger regeneration , how these signals regulate neoblasts behavior remains to be fully understood. Similarly, the muscle fibers provide multiple signals required to regulate the proper patterning during regeneration. How some of these signals act on neoblasts to regulate their proliferation and differentiation is something that requires further studies. In this same line, the possible role of the ECM and the gut as putative niches for neoblasts deserves further investigation. Recent efforts have been made to establish consistent neoblast culture conditions which might be pivotal for the future gene editing of neoblasts as well as to implement transgenesis in these animals ,149,150.


This systematic review aims to collect evidence regarding the impact of the SarsCov-2 pandemic on people affected by eating disorders (EDs) targeting the following variables: psychopathology changes, mechanisms of vulnerability or resilience, and perception of treatment modifications during the pandemic.Since the beginning of the pandemic, a mental health deterioration has been detected in the general population and especially in people affected by pre-existing psychiatric conditions. Furthermore, mental healthcare has moved toward online treatment.ED people showed a trend toward worsening of ED-specific psychopathology and impairment in general psychopathology. The most common vulnerability mechanisms were social isolation and feelings of uncertainty, while heightened self-care and reduced social pressure were resilience factors. The online treatment, although raising many concerns related to its quality, was considered the best alternative to the face-to-face approach. These findings may support the idea that stressful events contribute to the exacerbation of ED psychopathology and highlight the relevance of internalizing symptoms in EDs. The identification of putative risk and resilience variables as well as of subjective factors affecting online treatment perception may inform healthcare professionals and may promote more personalized approaches. The coronavirus disease-2019 (COVID-19) pandemic has worldwide affected human physical and mental health , and theThe COVID-19 pandemic is a traumatic event, which encompasses several types of stressors, including fear of contagion, worries for relatives’ health, social distancing and isolation, disruption in routine activities and in everyday life, and change in the economic status . It coulPeople affected by eating disorders (EDs) have been considered at high risk during the COVID-19 pandemic •. IndeedThis systematic review aims to gather evidence from studies regarding the impact of the COVID-19 pandemic on people affected by EDs exploring (1) changes in ED-specific and general psychopathology; (2) mechanisms of vulnerability and resilience to the COVID-19 pandemic exposure; and (3) change in treatment delivery service, in terms of the patients’ perception of online treatment, potential barriers and/or advantages of this method, and its effectiveness.The PRISMA guidelines were followed to select and assess published articles .In order to perform a systematic review of the literature, the following search keys were used in PubMed: “(COVID) AND (((eating) AND (disord*)) OR (anorexia) OR (bulimi*) OR (bing*))”. Bibliographies from relevant papers were inspected to identify studies not yielded by the initial search.Articles were selected according to the following inclusion criteria: the paper (1) was a peer-reviewed research article published in English; (2) included samples of people with a current or lifetime diagnosis of any ED; and (3) was published between January 1st, 2020, and April 30th, 2021. Review papers, meta-analyses, commentary, study protocols, and case reports were excluded.The literature search identified 696 papers, which were screened against the inclusion criteria. Fifty-two full-texts were assessed. Thirty studies were excluded because they did not meet the eligibility criteria: fifteen were editorial/commentary/letter, six were interview of healthcare providers or caregivers, three were study protocols, three were case series, and three were conducted on general population. This resulted in the inclusion of 22 studies in the qualitative synthesis. Figure All the studies were conducted during the first wave of SarsCov-2 pandemic.Most studies 14 of 22) were quantitative studies, 4 showed a quantitative–qualitative design, and 4 were qualitative studies. The main characteristics , the assessed outcomes, and the main findings of quantitative studies are reported in Table 4 of 22 wAll the selected studies, except those by Schlegl et al. •, 27•, LSeven studies reported the prevalence of SarsCov-2 infection among patients with EDs ranging from 0 to 5%.Most studies •, 38• idWhen differences between the main ED diagnoses were investigated, a greater concern about food restriction was found in AN individuals, while more frequent binge eating was detected in the BN ones, suggesting that differences between the ED diagnoses are consistent with diagnostic characteristics •. DifferOnly two studies ••, 35 coLimitations of these studies need to be acknowledged. First, except for Schlegl et al.’s study •, differChanges in general psychopathology during the lockdown were assessed in 11 studies. Three of them focused on specific psychopathology variables and revealed an increase in anxiety , 37• andThe quality of life perception was evaluated in three studies through a quantitative assessment •, 32. RePredictors of symptom change during the COVID-19 lockdown period were evaluated in three studies adopting a quantitative design •, 43. TwThe factors related to the COVID-19 psychopathology worsening were assessed in 8 qualitative studies –42, 44. The main limitation of the qualitative studies is their small sample sizes. Furthermore, a few studies have evaluated the effects of personality-related characteristics and of theoretically suggested variables  that may contribute to explain the observed variation in psychopathology trajectories.The main COVID-19-induced treatment change was a reduced access to in-person treatment , 42, 45.This systematic review assessed the impact of the COVID-19 pandemic on people with EDs. A trend toward worsening of ED-specific psychopathology with respect to the pre-pandemic period was observed as well as an impairment in general psychopathology. Feeling of uncertainty was the putative common mechanism promoting mental health deterioration in individuals with EDs, although resilience mechanisms such as supporting interpersonal relationships and heightened self-care emerged. The treatment has largely moved toward online delivering strategies that, despite being considered by patients as the best alternative to the face-to-face approach, were affected by concerns about the quality of the online therapy. A wide variation in both psychopathology changes and perception of the quality of treatments has been observed among individuals with EDs.Regarding the effects of the COVID-19 pandemic on psychopathology, it is worth noting that ED-specific symptoms deterioration was often observed, although data were even more consistent when referring to the general psychopathology  worsening. No differences across the main ED diagnoses were identified, although they were not deeply investigated. These data are corroborated by the increase in urgent and routine referrals of individuals with EDs and their relatives  as well It is worth noting that studies reported that some individuals with EDs remained stable in their symptoms during the lockdown, while others even improved. The inconsistency of these findings may be the result of the heterogeneity of the study methodologies: most of them included mixed ED samples with patients at different illness phases  or different treatment conditions  and different diagnostic evaluation processes . However, these findings also highlight the variability of the patients’ response to such an acute challenge and provide interesting data regarding mechanisms of resilience or illness deterioration. Although causal interpretation may be limited by the correlation nature of most of the study results, the high number of qualitative studies included in this review contributes to overcome this issue. The lack of interpersonal relationships providing security feelings and support as well as negative emotions and uncertainty feelings was the most common mechanisms making individuals with EDs more vulnerable to the COVID-19 pandemic. They were promoted from the disruption in routine activities  associated with the COVID-19-related restrictions. Unlike other psychiatric conditions • and iniThe effects of the COVID-19 pandemic were observed also on the treatment. In addition to the well-known transition to the online treatment that involved all psychiatric disorders , this syThe COVID-19 pandemic induced several psycho-social stressors in people with EDs. Despite exacerbation of ED-specific symptomatology and deterioration of general psychopathology have been observed during this period, great variability exists among people affected by these illnesses. In this line, the identification of factors promoting variability in psychopathological change as well as in the perception of online treatment may inform researchers and healthcare professionals. Clinicians are advised to target interpersonal and emotion regulation difficulties of people with EDs and their subjective response to stressful events as well as to consider the patient’s experience of online treatments and to identify his/her potential barriers to this approach. These findings may meet the suggested need –73 for a


With the recent advancements in molecular biology research, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have emerged as excellent therapies for patients with EGFR-mutant cancers. However, these patients inevitably develop cross-acquired resistance to EGFR-TKIs. Transformation to small-cell lung cancer (SCLC) is considered a rare resistance mechanism against EGFR-TKI therapy. Here, we report a case of TKI resistance due to SCLC transformation and demonstrate its mechanisms and clinical features.A 54-year-old Chinese man with a history of smoking for 40 years complained of an intermittent cough in March 2019.Transbronchial lung biopsy was performed on the basal segment of the left lower lobe, which confirmed lung adenocarcinoma. In January 2020, repeat biopsy was performed, and the results of immunohistochemistry (IHC) staining showed TTF-1 (+), CK7 (+), napsin A (+), syn (+), and CD56 (+), with a Ki-67 (+) index 80% of small cell carcinomas. Infiltrating adenocarcinomas and small cell carcinomas were observed.Icotinib (125 mg thrice daily) was administered as a first-line treatment from June 2019. We subsequently administered a chemotherapy regimen consisting of etoposide  plus cisplatin  every 3 weeks for 1 cycle after recurrence. As the patient could not tolerate further chemotherapy, he continued taking icotinib orally and received whole-brain radiotherapy 10 times to a total dose of 30 Gy after brain metastases.The patient relapsed after successful treatment with icotinib for 9 months. A partial response was achieved after 4 cycles of chemotherapy, and despite the brief success of chemotherapy, our patient exhibited brain metastasis and metastases of the eleventh thoracic spine and the second lumbar vertebra with pathological fracture. The patient eventually died of aggressive cancer progression.Our case highlights the possibility of SCLC transformation from EGFR-mutant adenocarcinoma and the importance of repeat biopsy for drug resistance. Serum neuron-specific enolase levels may also be useful for detecting early SCLC transformation. Similarly, transformation to SCLC has been defined as a rare mechanism occurring in approximately 3.5% of patients. Here, we report a case of TKI resistance due to SCLC transformation, and demonstrate its mechanisms and clinical features.Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC). However, these patients inevitably develop resistance to EGFR-TKIs after a median time of approximately 6 to 8 months.2A 54-year-old Chinese man with a history of smoking presented to our department in March 2019 complaining of intermittent cough. Computed tomography (CT) revealed a 4.0 × 3.5 cm mass in the left lower lobe and enlarged mediastinal lymph nodes  was administered as first-line treatment in June 2019, and the best response was partial response according to the Response Evaluation Criteria in Solid Tumors guidelines Fig. . After r3–9 A number of mechanisms of acquired resistance to EGFR-TKI therapy in EGFR-mutant lung adenocarcinoma have been described, including the EGFR T790M mutation, EGFR amplification, MET gene amplification, PIK3CA mutation, and transformation to SCLC.,11 However, the potential mechanism underlying SCLC phenotype conversion after TKI therapy remains unclear.SCLC transformation is 1 resistance mechanism associated with first-generation EGFR-TKIs, and is more frequent in lung adenocarcinomas with EGFR-activating mutations than in EGFR wild-type tumors. Therefore, SCLC and adenocarcinoma cells could originate from the same cancer stem cells or progenitor cells. Second, SCLC can result from the dedifferentiation of a previously well-defined cancer, which is similar to a mechanism known to occur in prostate cancer,,14 while the majority of transformed SCLCs retained the original EGFR-activating mutation, supporting this mechanism. Third, it is possible that the initial tumor consisted of the combined histology of NSCLC and SCLC. As the number of NSCLC cells decreased due to treatment, the SCLC component of the initial tumor became dominant. Consequently, it is possible that the 2 components are both present at the initial diagnosis, but the material available for analysis was limited in our case. This phenomenon emphasizes the importance of repeat biopsies in the clinical design of treatment regimens.We postulated 3 mechanisms that could account for the switch between NSCLC and SCLC. First, adenocarcinoma is believed to develop from alveolar type II cells located in the alveolar surface area, whereas SCLC is derived from the neuroendocrine cells of the central airways. Several studies have shown that alveolar type II cells may be common precursors of both lung adenocarcinoma and SCLC.–17 In our case, the remarkable increase in serum levels of NSE highlighted the necessity for repeat biopsy and suggested SCLC transformation. Moreover, pro-gastrin releasing-peptide (pro-GRP) during EGFR-TKI treatment is also an indication of transformation from NSCLC to SCLC.–20 However, little attention has been paid to the NSE and pro-GRP levels in serum, as there are no routine clinical tests for NSCLC patients. Therefore, routine and dynamic tests of NSE and pro-GRP levels in the serum may be helpful for screening patients with SCLC transformation before invasive biopsies.A rapid increase in serum NSE may be a useful indication of transformation from adenocarcinoma to SCLC in cases that are resistant to EGFR-TKI therapy.In summary, we report a case of EGFR-mutant NSCLC that transformed to SCLC during treatment with EGFR-TKIs. Transformation from adenocarcinoma to SCLC may originate from a minor preexistenting SCLC cell population under the selective pressure of EGFR-TKI treatment. A secondary biopsy was important for the evaluation of genetic and histological changes and the selection of an appropriate treatment following TKI resistance. Measuring serum NSE levels in serum may be useful for early detection of SCLC transformation.The authors thank the patient's consent for this case report to be published.All authors made a significant contribution to the work reported, whether that is in the conception, case collection, execution, acquisition of figures, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.Data curation: Yiqian Jiang, Leyi Shou, Yanhong Bao, Xiaoping Xu, Suhong An, Jianfeng Lu.Supervision: Yiqian Jiang, Qingmin Guo.


Social distancing and stay-at-home orders are critical interventions to slow down person-to-person transmission of COVID-19. While these societal changes help contain the pandemic, they also have unintended negative consequences, including anxiety and depression. We developed StayWell, a daily skills-based SMS text messaging program, to mitigate COVID-19–related depression and anxiety symptoms among people who speak English and Spanish in the United States.This paper describes the changes in StayWell participants’ anxiety and depression levels after 60 days of exposure to skills-based SMS text messages.t tests to detect changes in PHQ-8 and GAD-2 scores from baseline to follow-up measured 60 days later.We used self-administered, empirically supported web-based questionnaires to assess the demographic and clinical characteristics of StayWell participants. Anxiety and depression were measured using the 2-item Generalized Anxiety Disorder (GAD-2) scale and the 8-item Patient Health Questionnaire-8 (PHQ-8) scale at baseline and 60-day timepoints. We used 2-tailed paired The analytic sample includes 193 participants who completed both the baseline and 60-day exit questionnaires. At the 60-day time point, there were significant reductions in both PHQ-8 and GAD-2 scores from baseline. We found an average reduction of –1.72 (95% CI –2.35 to –1.09) in PHQ-8 scores and –0.48 (95% CI –0.71 to –0.25) in GAD-2 scores. These improvements translated to an 18.5% and 17.2% reduction in mean PHQ-8 and GAD-2 scores, respectively.StayWell is an accessible, low-intensity population-level mental health intervention. Participation in StayWell focused on COVID-19 mental health coping skills and was related to improved depression and anxiety symptoms. In addition to improvements in outcomes, we found high levels of engagement during the 60-day intervention period. Text messaging interventions could serve as an important public health tool for disseminating strategies to manage mental health.ClinicalTrials.gov NCT04473599; https://clinicaltrials.gov/ct2/show/NCT04473599RR2-10.2196/23592 The COVID-19 pandemic is a significant public health crisis that has caused devastating physical illness and concurrent mental health challenges ,3.Societal changes to contain the COVID-19 pandemic have caused significant psychological distress worldwide in people of various backgrounds -6. StudiWhile the prevalence of anxiety and depression has increased in the general population, certain groups are at a higher risk of mental health disorders. Individuals with a greater risk for depression during the pandemic include those from lower socioeconomic backgrounds with insufficient economic resources, inadequate social support, and greater exposure to social stressors, such as pandemic-related job loss . FurtherText messaging is a promising tool to deliver interventions that address the detrimental mental health effects of the COVID-19 pandemic -15, espeIncorporating cognitive behavioral therapy (CBT) and skills-based text messaging interventions have proved feasible and acceptable among a diverse group of patients with affective disorders . A signiIn April 2020, we initiated the StayWell at Home intervention , a 60-day skills-based daily text messaging program in accordance with principles of CBT . This paStayWell is a fully remote trial and has various designs: (1) a pre-post comparison, in which we assessed depression and anxiety symptoms for all patients before and after the intervention and (2) a randomized controlled trial with two groups: Uniform Random (UR) messaging and a Reinforcement Learning (RL) messaging. Owing to a coding error in the algorithm, all participants received messages randomly (UR condition). Therefore, we altered the study’s main aims by focusing on the pre-post effects of participating in StayWell on depression and anxiety symptoms. The institutional review board of the University of California (UC) Berkeley reviewed and approved all study procedures.Participants were enrolled in the StayWell trial using the HealthySMS platform—an automated text messaging platform developed by the authors ,24. HealParticipants received messages uniform randomly , where Adult Spanish and English speakers aged 18 years and older who had a mobile phone were recruited via web-based media advertisements on Facebook, Craigslist, and university websites (UC Berkeley and UC San Francisco) to participate. Data were collected through a web-based Qualtrics survey and HealthySMS. Participants were excluded if they used a web-based text messaging app or were outside of the United States. Web-based text messaging apps are more prone to scams on the internet and facilitate the creation of multiple phone numbers for 1 participant. The study lasted from April to December 2020. The CONSORT  flow diagram for data collection is shown in We designed web-based advertisements to target vulnerable populations, including low-income groups and people of color, who are disproportionately impacted by the COVID-19 pandemic in the United States. Using a user-centered design, we created 16 user personas. A persona is a fictional characterization of a user, which includes specific characteristics and demographics found in the target population . The percaptcha. Eligible participants were then sent a unique weblink to a baseline assessment. Using a different Qualtrics survey, participants consented and answered demographic questions and other measures of interest. Upon completion, participants were enrolled in an automated text messaging intervention for 60 days. On day 61, participants were sent an exit assessment where they were asked the measures of interests originally asked at baseline. Participants were paid US $20 at the end of the study for completing study questionnaires. To prevent web-based scams and fraud, interested subjects were sent to a Qualtrics survey to assess eligibility criteria and human identity through a built-in Our primary outcomes, including the 8-item Patient Health Questionnaire 8  and the Secondarily, we were interested in assessing engagement in the intervention by measuring response rates to mood rating messages and calculating how many participants stopped the text messaging.We will conduct a pre-post comparison among all participants. The depression score measured using the 8-item Patient Health Questionnaire (PHQ-8) and the anxiety score measured using the 2-item Generalized Anxiety Disorder (GAD-2) scale will be improved over the 60-day study.d=0.5), a sample size of 64 participants is required to detect an improvement of either the depression or anxiety score from baseline to 60-day at 80% power and 5% level of significance. The sample size of this study was 193 participants, which is based on the secondary aim. The secondary outcome focuses on the proximal effect of daily improvement on the mood rating. However, the analysis will be presented in a separate manuscript.The sample size calculation was performed in a previous protocol paper , which it tests. The normality assumptions for the change in each score are validated by their corresponding histogram plots, which are relatively symmetric. The goodness of fit to normal distribution was validated using the Anderson-Darling test, while skewness for normality was validated using the Shapiro-Wilk skewness test [To detect the change in depression (PHQ-8) and anxiety (GAD-2) scores from baseline to follow-up measured 60 days later, we used 2-tailed paired ess test .We used simple linear regression analysis to model the change in PHQ-8 and GAD-2 scores as a function of participants’ response rates  to determine whether the improvements in depression and anxiety are predicted by engagement with the intervention. Furthermore, to determine whether any other covariates predict the effects of the StayWell intervention, we used multivariable linear regression analysis to model the change in PHQ-8 and GAD-2 scores  as a function of demographic predictors, response rates, self-rated health, and the change in COVID-19 weekly rolling average case rates in each participants’ county of residence. Demographic predictors include education , age, gender , language (English or Spanish), and employment . Self-rated health includes poor/fair, good, very good, and excellent. The weekly rolling average of daily new confirmed cases per 100,000 population is calculated for the day in which participants enroll and exit the program by averaging the values of that day, 3 days prior, and 3 days thereafter. We then used the change in COVID-19 case rates at 60-day follow-up from the baseline date for each participant.A total of 303 people entered the study and received text messages. Of these, 12 were recruited via ClinicalTrials.gov, 75 via Craigslist, 184 via Facebook, and 32 by texting the StayWell phone number. We show the distribution of baseline characteristics in bGAD-2: 2-item Generalized Anxiety Disorder.P>.05) in clinical parameters between people who only responded to the baseline survey and those who responded to the baseline and 60-day assessment. This suggests that the mental health burden was similar between our study sample and individuals who did not complete the 60-day survey.To evaluate the generalizability of our data in terms of anxiety and depression prevalence and symptoms in our baseline samples, we compared the clinical parameters between participants who only responded to the baseline survey versus those who responded to both the baseline and 60-day surveys  and 4. LP=.001) and –0.78 points (P=.01), respectively.To determine whether the changes in PHQ-8 and GAD-2 scores remain constant after accounting for participants’ engagement in the intervention, we used a simple linear regression model  with parP=.01) among males, adjusting for all other covariates; this suggests that males experienced relatively lesser improvement in depression symptoms. Having very good self-rated health was associated with less improvement in anxiety symptoms  at 60 days from baseline compared to those with poor health and adjusting for covariates.To assess the influence of other factors  on GAD-2 and PHQ-8 score improvements, we conducted a post hoc exploratory analysis . This anF2,190=4.106; P=.02). This suggests that there are true differences in the average improvement in PHQ-8 scores among male- and female-identifying participants. However, the mean change in GAD-2 scores did not differ between self-rated health categories . Thus, we cannot conclude that there are differences in the average improvement in GAD-2 scores by self-rated health.As a sensitivity analysis, we conducted 2 separate 1-way analysis of variance to assess the differences in the average change in PHQ-8 scores between genders and explore the association between self-rated health and the average change in GAD-2 scores. Our results show that gender had a significant effect on the change in PHQ-8 scores at 60 days from baseline . We also found that participants’ response rates are not significant predictors of improved PHQ-8 and GAD-2 scores (The results in 2 scores . In Tabl2 scores . TherefoParticipants answered the mood text messages on average 60.0% of the time (ranging from 0% to 100%). Furthermore, 21 people did not respond to any mood-related messages, and 13 participants opted out of text messaging by texting “STOP” to our system. The 303 baseline participants were in the study for a range of 2 to 72 days (mean 59 days). Seventy participants went beyond the 60-day time frame owing to a system glitch; these participants were in the study for an average number of 63 days.Participants who received the StayWell text messaging program showed improved depression and anxiety symptoms at completion of the program (60 days) on average. These results are similar to those of previous studies utilizing text messaging as a public mental health intervention to counteract the deleterious emotional and mental health effects of the COVID-19 pandemic in Canada -15. AddiIt was important to assess whether other factors  influenced the positive outcomes; however, we found that improvements in GAD-2 scores were not related to other measured variables. We found a greater improvement in PHQ-8 scores for female-identifying participants, but improvements held despite local infection rates or other demographic factors. These findings suggest that women may experience greater benefits in their depression symptoms from participating in the StayWell program. Nonetheless, it is particularly notable that weekly local infection rates were not related to changes in outcomes. For example, it is possible that decreases in symptoms could be influenced by reductions in local infection rates and accompanying lowered concerns of infection or reduction in policies such as stay-at-home orders. However, improvements in PHQ-8 scores persisted after accounting for changes in weekly infection rates and other covariates, suggesting that the intervention improved symptoms beyond the influence of any change in the severity of the COVID-19 pandemic in participants’ area of residence.P<.001). Despite no significant differences in baseline mood ratings, PHQ-8, or GAD-2 scores between completers and noncompleters, those who completed the final assessment had increased daily mood ratings , whereas those who did not complete the final assessment reported decreases in mood ratings . Therefore, it is possible that people with worsening symptoms respond less often or that less engagement is related with worse outcomes. It is possible that the study outcomes are biased on the basis of the mood rating post hoc analyses (attrition bias); however, this is in contrast with significant differences in outcomes remaining after controlling for the response rate. Ideally, we would be able to assess any differences in primary outcomes (PHQ-8 and GAD-2 scores), but we do not have those data for participants who dropped out of the study. This provides a mixed picture but suggests that it is more likely that participants experiencing worsening symptoms drop out of the study more often.Over a third (36.3%) of participants did not complete the final assessment, and we took steps to assess how noncompletion impacted our results. First, we assessed whether reductions in depression and anxiety symptoms remained after controlling for participants’ response rates, and our findings suggest that the intervention may be beneficial overall even if participants do not respond. It is possible that reading messages can be beneficial even if participants do not respond to subsequent mood ratings. On average, participants who completed the study had a significantly higher response rate to mood rating messages  than those who dropped out  . Considering technical difficulties, we could not randomize participants into the distinct conditions, and all participants received the same intervention (random message condition). To prevent technical errors, future studies using RL should incorporate pilot work before commencing the trial to check for errors; however, we were unable to do so because we needed a quick roll-out during the pandemic. Further studies are needed to compare the effectiveness of personalizing messages using a reinforcement learning algorithm to that of a random message condition. Other studies in progress may be better suited to answer questions related to the impact of reinforcement learning models’ utility for improving personalization .This study had a racially/ethnically diverse sample in the United States, which included 11.3% of Spanish speakers. On average, participants entered the study with mild/moderate symptoms of depression, which improved to mild symptoms at the end of the intervention period. While reductions in PHQ-8 and GAD-2 were not large, the low-intensity intervention approach is highly scalable and can accommodate a large number of people. This study also shows that participants are open to receiving 2 messages per day, including one mood response, while maintaining a high response rate (60%). Lastly, the longitudinal data collected provides opportunities for further inquiry into daily mood ratings and response rates.The main limitation of this study is the lack of a control group with no or an inactive intervention. Given the impacts of the COVID-19 pandemic on mental health, the study team felt that it was unethical to withhold mental health support at this time. In addition, we were interested in assessing whether the intervention might be improved by applying a reinforcement learning algorithm to personalize messages, but technical errors prevented us from examining this. Lastly, a significant portion of the sample did not complete the final assessment, which may result in attrition bias, and further exploration of the engagement-outcome relationship is merited.Our study provides support for low-intensity text messaging interventions to improve mental health at the population level. Our data show the feasibility of sending 2 messages a day and asking for daily mood responses. Texting and other mobile interventions could serve as ways to identify individuals in need of more intensive intervention on the basis of reported daily mood ratings. Future studies should continue to assess the impacts of text messaging and related mobile health interventions for mental health and continue to assess methods including machine learning to improve personalization.Participation in a CBT-based text messaging program focused on COVID-19 cognitive flexibility, and behavioral activation and acceptance were related to improved depression and anxiety symptoms. In addition to improvements in outcomes, this study reported high levels of engagement during a 60-day intervention that sent 2 messages per day. Text messaging interventions could serve as an important public health tool to disseminate strategies for managing mental health.


Chronic exertional compartment syndrome (CECS) of the forearm is a rare but important cause of morbidity amongst athletes involved in strenuous upper limb activities. The diagnosis remains challenging due to the absence of objective, reproducible diagnostic studies.To assess and quantify signal intensity (SI) changes of involved muscles in patients with CECS of the forearm compared to healthy control subjects competing in similar sporting disciplines. Also, to objectively measure MRI SIs within muscle compartments when using a pre- and post-exercise regime and calculating a signal intensity ratio (SIR) between post- and pre-exercise studies.The study retrospectively examined MRI scans of patients treated for CECS of the forearm and compared these to the MRI scans of asymptomatic high-level rowers. A specific, reproducible pre- and post-exercise MRI scanning protocol was utilised in both patient and control subjects between 2011 and 2020. Signal intensities were evaluated pre- and post-exercise in involved muscle groups and ratios were calculated.p = 0.0010). The extensor carpi radialis, flexor digitorum profundus and flexor digitorum superficialis muscles were most commonly involved.A total of 86 SIs were measured (43 pre- and 43 post-exercise) in nine study participants (five patients and four controls). After post:pre-exercise comparisons, a statistically significant difference was found between control and patient groups (This study confirms that significant SI changes are apparent in patients with CECS of the forearm when making use of a standardised pre- and post-exercise MRI protocol. Furthermore, SIR may be used to accurately diagnose CECS of the forearm. Symptoms include pain, paraesthesia, cramping, a ‘stiff’ feeling of the involved compartment as well as loss of grip strength.15 The pathophysiology of the condition remains incompletely understood but is based on the premise of raised intra-compartmental pressures within a relatively rigid fascial compartment, causing reduced tissue perfusion and subsequent ischaemia.20Chronic exertional compartment syndrome (CECS) of the forearm is a rare entity with the first case only being described in 1983.19 Patients with CECS have relatively greater increases in pressure and these pressures also take longer to return to normal after cessation of exercise.21 Furthermore, there is evidence that patients with CECS have relatively low levels of oxygenation within muscle compartments during exercise and recovery, as well as deoxygenation early on in exercise, before intra-compartmental pressures rise significantly.18 This points to altered oxygen extraction from the blood by affected muscles as well as altered muscle metabolism, likely because of a chronic state of low-grade ischaemia during exercise.18During exercise, it is normal for intra-compartmental pressures to rise; however, this increased pressure does not usually cause symptoms or altered tissue oxygenation as in patients with CECS.23 Currently, the most widely used method is based on intra-compartmental pressure testing and the values proposed in 1990.21 These values were proposed for lower leg CECS, and various modifications of the values have been suggested for diagnosis of forearm CECS; however, none are universally accepted.24 Various studies confirmed that a significant proportion of patients with clinical and surgically responsive CECS may be misdiagnosed with the use of current intra-compartmental pressure values.24 Moreover, there is an ever-changing variation in the proposed ‘normal’ compartmental pressure values of the forearm.25 Furthermore, the invasive nature of testing, the associated risks and the lack of an accepted testing technique make intra-compartmental pressure manometry a far from ideal diagnostic tool.26Despite the growing amount of available literature on CECS, controversy remains on how best to diagnose the condition, as well as what diagnostic parameters to use within each specific modality.26 Additionally, MRI can accurately exclude other conditions that may mimic CECS, for example, tendonitis, muscle tears and nerve impingements. MRI scanning has been utilised for the past 30 years in the diagnosis of CECS, with numerous studies and case reports published at testing to its usefulness.29MRI in chronic compartment syndrome is based on the premise that ischaemic muscle will become oedematous and thus exhibit a more intense T2-weighted (T2W) signal compared with normal muscle.30 Furthermore, in the absence of T2W mapping software, signal intensity (SI) is graded subjectively, presenting the possibility for greater inter-observer variations.6 The ever-increasing competitiveness and demands faced by top-level and professional athletes require that timeous and accurate diagnosis of any sporting-related symptoms is paramount to the longevity and success of an athlete. In our setting, several rowers have been treated for CECS, necessitating the need for future accurate, reproducible and reliable diagnostic methods.Despite the relatively strong evidence for the use of a pre-post exercise MRI protocol in CECS, no standardised methods regarding exact exercise protocols and imaging acquisition have been published.This study aimed to quantify SI changes in patients with CECS of the forearm and compare them with healthy control subjects participating in similar sporting disciplines. A further aim was to objectively measure MRI SI within muscle compartments when using a pre- and post-exercise regime and calculate a signal intensity ratio (SIR) between post- and pre-exercise studies.The study makes use of a cross-sectional descriptive pilot study design. Study findings in a CECS patient group were compared to a control group.31 in Pretoria, South Africa, which is a high-level specialist sporting centre and served as training base for all our control subjects. Patients were assessed by an experienced upper limb orthopaedic surgeon in private practice.A private radiology practice based at both the Life Groenkloof Hospital (part of Pretoria MR Trust) and the Sport, Exercise Medicine and Lifestyle Institute (SEMLI), University of Pretoria, South Africa was the setting for this study. Sport, Exercise Medicine and Lifestyle Institute is located at the High-performance Centren = 5) included in the study all received fasciotomy surgery for treatment of CECS of the forearm, with symptoms improving or resolving after surgery. Patients who underwent concurrent nerve release surgery, had a history of additional previous surgery to the forearm, or who had a history of significant trauma to the forearm, were excluded Patients all underwent MR imaging at the above centres between 2009 and 2020.Patients (n = 4) were athletes enrolled in the University of Pretoria Rowing Team and included individuals who were symptom-free when rowing, did not undergo any previous forearm surgery and had not previously sustained significant trauma to the forearms. Control subjects were screened for eligibility by completing a questionnaire that excluded any of the above conditions.32The control subjects  at rest. They were then asked to do a repetitive exercise , after which the forearm(s) was immediately scanned again.Patient scans were performed on either a 1.5-T MRI scanner (1.5T) or a 3-T MRI scanner (3T). Control subjects were scanned on a 3T scanner. Both 1.5-T and 3-T scanners were used because of the equipment changes during the research period, as well as different machines being used at the different imaging sites.The patient group was imaged using fat-sensitive T1-weighted (T1W) sequences as well as fluid-sensitive T2W sequences with fat-suppression short-tau inversion recovery (STIR).Control subjects only underwent fat-suppressed T2W (STIR) imaging both before and after exercise. As a result of the time constraints in the MRI suite, the control group had their forearms scanned simultaneously. This resulted in differing imaging parameters and a modest decrease in image resolution. The sequences used are listed in Anonymous MRIs were evaluated using dedicated radiological workstations and AGFA picture and archiving system (PACS) for both patient and control subjects. Muscles that exhibited an increase in STIR signal on post-exercise contrast imaging were further investigated by placing a circular region of interest (ROI) within the respective muscles for both the post-exercise and the corresponding pre-exercise STIR images. Region of interests used were either 10 mm or 5 mm in diameter depending on the size of the area suitable for measurement. Tendons, vascular structures, nerves and surrounding fat were excluded from the ROI. Absolute SI was measured both pre- and post-exercise, and results were entered into an Microsoft Excel data table alongside the corresponding arm, age and sex of the participant.Muscles involved were also recorded and included extensor carpi radialis (ECR), extensor carpi ulnaris (ECU), extensor digitorum (ED), brachioradialis (BR), supinator (Sup), abductor pollicis (AP), flexor digitorum profundus (FDP), flexor digitorum superficialis (FDS), flexor pollicis longus (FPL) and flexor carpi radialis (FCR). Findings were validated by a musculoskeletal radiologist with more than 20 years of experience.Moreover, the pre- and post-exercise SI of involved muscles was compared, and a post:pre-exercise SIR was calculated. This ratio was obtained by dividing the measured SI of the post-exercise study by the measured SI of the pre-exercise study.Demographic data including age and sex of participants were analysed as were the arms and muscles affected. Descriptive statistics included measurements such as mean, standard deviations, frequencies and proportions to describe the results. Tabulated and graphical representations were made where applicable to assist in visualising aspects of the data. The Shapiro–Wilk test was used to determine whether the data were normally distributed, followed by the independent t-test that investigated whether a significant difference existed between the SIR values in the control and patient groups. All significance tests were performed at a 5% level of significance.The participant group consisted of a total of four (44.4%) males and five (55.6%) females. Demographics of all study participants, as well as the arm(s) that exhibited SI changes on post-exercise imaging, are detailed in n = 27; 62.8%) and patient  groups was measured. Muscle SI values were collected in the right arm  and the left arm  of males  and females .A total of 86 SIs were collected (43 pre-exercise and 43 post-exercise measurements). The SI in 43 different muscles across the control , FDP  and FDS . In the patient group, the ECR  followed by the FDP was mostly involved. In the control group, FDP and FDS were equally involved  followed by ECR .The number of specific muscles involved are listed in p = 0.0010) in the SIR between the control (1.30 ± 0.18) and patient (1.57 ± 0.25) groups. Examples of pre- and post-contrast imaging studies in both control (The post:pre-exercise SIR measurements are depicted in  control  and pati control  groups ap = 0.001).This study confirms that there are objectively measurable SI changes in the forearm muscles of both control and patient subjects when making use of a pre- and post-exercise imaging protocol. Furthermore, the study illustrated a statistically significant difference in SIR when utilising a pre- and post-exercise MRI protocol in patients with confirmed CECS compared with normal control subjects , FDP (25.6%) and FDS (23.3%). These muscles were the dominant muscles affected in both the patient and the control groups. Repetitive concentric hand squeezes were undertaken by both the patient and control groups as part of their imaging protocols, which logically explain the involvement of the two large flexor muscle groups; however, the frequent involvement of the ECR muscle was a surprising finding. We believe that this may be because of the continual opposition forces applied by this extensor muscle in maintaining wrist and hand position and stability in the presence of strong flexor forces.30 As all study participants did the same forearm exercise actions as part of their imaging protocol, it is unclear whether this distribution of muscular involvement is specific to the disease process or simply to the exercises performed. Further studies utilising different methods of exerting patients between pre- and post-exercise studies are necessary to evaluate patterns of muscle involvement.To a smaller degree, the BR (4.7%), AP (4.7%), ECU (2.3%), ED (2.3%), flexor pollicis longus (2.3%) and supinator (4.7%) muscles were occasionally involved. The muscles affected in this study correlate well with the muscles affected in the available literature.30 Further research in this area is necessary to determine whether true differences exist between muscle physiology in male and female athletes. As this study evaluated retrospective data collected over 9 years, differences in equipment and imaging protocols can be expected. The control group also had their forearms scanned simultaneously because of the time constraints in the MRI suite used. We believe that as we were comparing pre- and post-exercise studies performed on the same day with the same machines and protocols, this should have no significant outcome on our results. The control group was all investigated on a 3-T MRI machine. To our knowledge, there are no studies comparing the accuracy between 1.5T and 3T in diagnosing muscle oedema. The 3T machines can lead to higher signal-to-noise ratios, shorter scanning times and thinner slices, all of which should not make a difference in detecting muscle oedema.33The main limitation of this study is the small sample size. The rarity of the condition as well as our strict inclusion and exclusion criteria limited the number of candidates eligible for the study. Secondly, the control group consisted only of female athletes. This was a complete chance occurrence because of potential male candidates not fulfilling the eligibility criteria. To our knowledge, only a single previous study compared differences in male and female athletes, and the differences reported between the sexes were of dubious significance.This study confirms that SI changes are present in the forearms of both patients confirmed with CECS of the forearm as well as in healthy control subjects who partake in similar high-intensity forearm activities. In patients in whom CECS of the forearm is clinically suspected, we suggest a pre- and post-exercise MRI protocol as part of the patient work up. By calculating the SIR when using a post:pre-exercise imaging protocol, we were able to identify a statistically significant, objectively measured difference between patients and controls. We propose calculation of a SIR to assist in diagnosis of CECS. Further studies with a larger sample size are required to determine specific inclusion and exclusion values.Future research in the field should include studying a larger number of patients and control subjects to further validate these results. The inclusion of study subjects participating in a greater variety of forearm activities will augment the relevance of our findings.