Healthcare systems globally were shocked by coronavirus disease 2019 (COVID-19). Policies put in place to curb the tide of the pandemic resulted in a decrease of patient volumes throughout the ambulatory system. The future implications of COVID-19 in healthcare are still unknown, specifically the continued impact on the ambulatory landscape. The primary objective of this study is to accurately forecast the number of COVID-19 and non-COVID-19 weekly visits in primary care practices.This retrospective study was conducted in a single health system in Delaware. All patients’ records were abstracted from our electronic health records system (EHR) from January 1, 2019 to July 25, 2020. Patient demographics and comorbidities were compared using t-tests, Chi square, and Mann Whitney U analyses as appropriate. ARIMA time series models were developed to provide an 8-week future forecast for two ambulatory practices (AmbP) and compare it to a naïve moving average approach.Among the 271,530 patients considered during this study period, 4,195 patients (1.5%) were identified as COVID-19 patients. The best fitting ARIMA models for the two AmbP are as follows: AmbP1 COVID-19+ ARIMAX, AmbP1 nonCOVID-19 ARIMA, AmbP2 COVID-19+ ARIMAX, and AmbP2 nonCOVID-19 ARIMA.Accurately predicting future patient volumes in the ambulatory setting is essential for resource planning and developing safety guidelines. Our findings show that a time series model that accounts for the number of positive COVID-19 patients delivers better performance than a moving average approach for predicting weekly ambulatory patient volumes in a short-term period. The weeks that followed included several modifications to the original state of emergency to minimize the spread of the virus.Healthcare systems were globally shocked by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the resulting disease, coronavirus disease 2019 (COVID-19). In response to the growing pandemic, ChristianaCare Health Services, Inc. (ChristianaCare), which serves the majority catchment area of Northern Delaware and the most populous county in the state, followed suit with its own measures to mitigate spread, postponing all elective procedures in hospitals and all ambulatory practices effective March 17, 2020 to adhere to state and CDC guidelines. The ambulatory services at ChristianaCare adjusted the delivery of healthcare services by reducing the number of in-person visits to minimize the risk to patients and healthcare providers, redirecting patients to telehealth when appropriate. This resulted in a decrease of patient volumes throughout the ambulatory system. With the uncertainty that COVID-19 presented then, the Phase 1 reopening that occurred on June 1, 2020, and the exponential rise in cases occurring now, it is essential to understand how the ambulatory setting will continue to be affected in order to develop proper guidelines.12 SIR models have also been applied to inpatient settings to predict hospital capacity regarding admissions, ICU beds, and ventilators.14 In addition to SIR models, the current literature on predicting patient volume varies from descriptive statistics to advanced time series models, with most of the studies that have used time series forecasting models focusing on emergency department and hospital admissions.To understand the impact of the novel virus, scientists rely on community spread models to predict possible transmission. The popular susceptible, infected, and recovered (SIR) epidemiologic model and variations of this model have been used to gauge community spread of a variety of infectious diseases such as influenza and dengue fever.22 The most used method for time series forecasting is the Box-Jenkins method otherwise known as the AutoRegressive Integrated Moving Average (ARIMA) model.23 The ARIMA model has been used for its simplicity and flexibility in capturing linear patterns in a time series.22Time series forecasting in ambulatory visits prior to the COVID19 pandemic have been described in a few reports.The future implications of COVID-19 in healthcare are still unknown, specifically how it will continue to affect the ambulatory landscape. This work aims to inform COVID-19 and nonCOVID-19 ambulatory resources allocation as well as guide ambulatory practices reopening for in-person visits as in-person care might have been delayed. We propose an ARIMA time series model to capture the changes in ambulatory patient volumes as a result of COVID-19.The primary objective of this study is to accurately forecast the number of COVID-19 and nonCOVID-19 weekly visits in primary care practices. The ability to forecast patient volumes in primary care locations by accurately evaluating the dynamic changes in patient visits and fitting these data to a statistical model is useful for the appropriate allocation of human and material resources for future planning. With the uncertainty that COVID-19 presents, healthcare systems have been adapting their ambulatory practices to adhere to state guidelines and prepare for state reopening phases. Therefore, we developed a time series model that provides an 8-week future forecast for ambulatory practices and compared it to a naive moving average approach.24 We selected the patients’ records from the two practices that had the highest historical patient volumes among all clinics affiliated with ChristianaCare. Our study population included (1) COVID-19 patients who had prior family medicine ambulatory services within ChristianaCare in 2019 and had been previously hospitalized and discharged or were self-monitoring at home and had not been hospitalized for the disease. (2) Any patient who utilized ambulatory services from the same practices during the same time period and were not diagnosed with COVID-19. COVID-19 patients currently hospitalized were excluded from the population.This retrospective study was conducted in a single health care system in Delaware (ChristianaCare), serving the primary catchment area of New Castle County. New Castle County is in the northernmost region of Delaware and as of 2019 has an estimated population of 558,753, accounting for nearly two-third of the entire state population.25 Patient-level data were used for characterizing the study population. Ambulatory practice-related data were primarily used for our time series models. For model development, we used one year of data between January 2019 and December 2019, and for model validation data from January 2020 until the most recent data available (July 2020).We extracted all patients’ records from our electronic health records system (EHR) from January 1, 2019 to July 25, 2020 and built two datasets. One included patient-level data .Patient demographics and comorbidities were compared using t-tests, Chi square, Mann Whitney U analyses as appropriate according to the distribution.11 The framework for ARIMA is displayed in A time series is a sequential set of data points, measured typically over successive times. The ARIMA model was created for auto-correlated and non-stationary time series data.Most patients were seen by clinicians in the Department of Family Medicine, with 28% of COVID-19 patients and 26% of non-COVID-19 patients primarily utilizing family medicine services. The forecasting method used is a non-seasonal ARIMA, and ARIMA with exogenous variables (ARIMAX) to predict COVID-19 and nonCOVID-19 weekly patient volumes for Ambulatory Practice 1 (AmbP1) and Ambulatory Practice 2 (AmbP2). The COVID-19 models included an exogenous variable, the weekly number of positive COVID-19 patients, and were significant at p-value < 0.05. When incorporating the exogenous variable to the nonCOVID-19 models, we found them to be insignificant. The complete dataset was split, 75:25 for training and validation sets. The individual models were trained on weekly patient volume data from each location and validated on the most up-to-date 2020 practice volume data available at the time of model development. The validity of our models was evaluated using the difference between the forecasted patient volume and the actual patient volume beyond the period on which the model was trained. For each model out-of-sample forecast errors were assessed by calculating the Root Mean Square Error (RMSE) and mean absolute percentage errors (MAPE) as follows:n represents the total data points, yi represents the observed values at time i and <mi> represents the forecasted value at time i. Once we evaluated the models performance by computing the RMSE and MAPE, the  parameters was used to forecast the next 8-week patient volumes for both populations in each location.Where statsmodels.The model selection was performed using the Python 3.8.3 software package The protocol was approved by Expedited Review by the Christiana Care Health System Institutional review board (IRB). Informed consent was waived by Christiana Care IRB in accordance with the Office for Human Research Protections (OHRP) regulations 45 CFR 46.116(d).Among the 271,530 patients considered during this study period, 4,195 patients (1.5%) were identified as COVID-19 patients. The COVID-19 patients were younger, and majority were non-white compared to the COVID-19 negative patients. Both COVID-19 positive and negative patients had multiple comorbidities such as obesity, diabetes and hypertension despite the COVID-19 patients being younger. Details of the patient demographics and comorbidities for the study population are provided in The novelty of the COVID-19 virus created a conundrum, not only for the inpatient world, but for the ambulatory outpatient clinical environment as well. While many people were being hospitalized due to complications from the virus, an overwhelming majority were being evaluated and treated in the outpatient setting, either by urgent care or by their primary care provider. At the height of the pandemic, prediction models only existed for hospitals to anticipate the need for staffing, personal protective equipment (PPE), equipment and other resources as the cases surged, which made it very challenging to anticipate staffing, equipment and logistical needs for primary care practices. There were many questions/scenarios to consider such as designating specific practices to care for COVID-19 infected patients, estimating the number of staffing and PPE necessary at each practice site for in person care vs delivering telehealth care; redeployment of staff to our Ambulatory COVID-19 treatment center (in person care for non-emergent patients with COVID-19) and to our Virtual COVID-19 primary care practice, which monitored moderately ill patients infected by the disease via video visits and secure texting, based on ambulatory patient volumes. Development of the ambulatory COVID-19 model provided the opportunity to identify volume trends and anticipate the need to modify our care delivery models based on the estimates.We found that the ARIMA/ARIMAX forecasting models considered in this study outperformed more traditional modeling approaches such as the moving average-based approach. Although a MAPE of < 10% is considered an accurate forecast, the COVID-19 ARIMA models we generated provided a more dynamic prediction than the moving average forecast. Our model accounted for the number of weekly positive COVID-19 cases.Our findings support the use of such models by health care system administrators to forecast patient volumes and make prospective resource adjustments.26 This convergence has the potential to yet again overwhelm healthcare systems especially the ambulatory environment, which is often the first point of contact during respiratory virus season. It is thought that the possible resurgence of COVID-19 would lead to tighter social distancing measures which would lessen flu transmission.27 However, in absence of that certainty, having an ambulatory prediction model to project patient volumes is crucial.Data utilized for the test set prediction included the time period from March 1, 2020 – July 25, 2020 and was not inclusive of the months during which flu season typically occurs. The impending flu season brings much uncertainty in relation to COVID-19 for both inpatient and ambulatory settings because the two infections may overlap in the winter season. COVID-19 and the flu share clinical characteristics, therefore differentiating between the illnesses is paramount.The current study is limited to retrospectively using electronic health records and positive COVID-19 results from only one hospital system. Our results may not be generalizable to other hospital systems, particularly those who serve patients with different characteristics. Other forecasting methods may be appropriate for different hospitals due to the differences in organizational structure and resources. Our study period is limited to one year of historical data, ignoring potential factors such weather and seasonal affects that could possibly improve forecasting accuracy. However, due to the unpredictable nature of COVID-19 our regular volumes and trends were disrupted. Therefore, using volumes from more years might not actually give us any more accurate prediction since our system is in a transient state, especially during the time of this study. Also, our weekly predictions did not differentiate between in-person and virtual volumes. In future studies, dividing the volumes between in-person and virtual could improve accuracy and provide additional information to healthcare providers for resource planning. Lastly, our models are short-term forecasts. Long-term forecasts can be generated, although the error rate will increase as the prediction period increases.Accurately predicting future patient volumes in the ambulatory setting is essential for resource planning and developing guidelines for safely providing appropriate in-person visits. This study contributes to the exploration of time series modeling to forecast ambulatory patient volumes in ChristianaCare during the COVID-19 pandemic. We compared the forecasting accuracy of a moving average approach and ARIMA. Our findings show that a time series model that accounts for the number of positive COVID-19 patients delivers better performance for predicting weekly ambulatory patient volumes in a short-term period. This improved forecasting ability can be used to aid health systems administrators develop guidelines for clinic operations.


Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiologic agent of COVID-19 pandemic  is the receptor that SARS-CoV-2 uses to enter host cells. ACE2 is highly expressed in lung but widespread distribution of ACE2 provides potential for infection of other organs. ACE2 is a member of the renin-angiotensin system (RAS) that plays an important role in the homeostasis of the cardiopulmonary system. The RAS consists of a vasoconstrictive, pro-inflammatory, and pro-fibrotic axis that includes angiotensin converting enzyme, angiotensin II and angiotensin type 1 receptor. Actions of this axis are balanced by the vasoprotective axis of the RAS that includes ACE2, angiotensin-(1-7) and MAS). Protective effects of ACE2 against cardiorespiratory diseases have been explored for 20 years . It will be imperative to better understand whether SARS-CoV-2 infection increases the incidence of, or predisposes to, neurological and neurodegenerative disorders like cognitive impairment and dementia. We need to understand whether the risk applies only to patients with neurological symptoms during initial infection or to all infected patients. This is of concern because while only 11% of rats infected with a related coronavirus exhibited neurological symptoms, 40% of animals without clinically recognized neurological signs had pathological brain lesions 8-months after infection (Nagashima et al., In conclusion, we believe that not only is there is an urgent need for effective therapies to minimize systemic effects of SARS-CoV-2 and its pro-inflammatory profile, but also to mitigate its CNS effects that are potentially long-term. Minocycline has effective mechanisms to protect the CNS, it attenuates neuroinflammation, counteracts the cytokine storm, modulates gut microbiome, and might inhibit viral replication. If confirmed, our hypothesis may represent an important contribution to prevent neurological impacts of infection and improve COVID-19 management.AO contributed substantially to the conception, design, and writing the opinion letter. ER contributed to the writing and provided critical revision. MK contributed to the final figure. CP revised it critically for important intellectual content. MR contributed the draft and revised it critically for important intellectual content. All authors read 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.


This study examined whether physical activity is associated with better mental health and well-being among very preterm (≤32 weeks) and term born (≥37 weeks) adolescents alike or whether the associations are stronger in either of the groups. Physical activity was measured with accelerometry in children born very preterm and at term in two cohorts, the Basel Study of Preterm Children  and the Millennium Cohort Study . In both cohorts, emotional and behavioral problems were mother-reported using the Strengths and Difficulties Questionnaire. Subjective well-being was self-reported using the Kidscreen-52 Questionnaire in the BSPC and single items in the MCS. Hierarchical regressions with ‘preterm status × physical activity’-interaction effects were subjected to individual participant data (IPD) meta-analysis. IPD meta-analysis showed that higher levels of physical activity were associated with lower levels of peer problems, and higher levels of psychological well-being, better self-perception/body image, and school related well-being. Overall, the effect-sizes were small and the associations did not differ significantly between very preterm and term born adolescents. Future research may examine the mechanisms behind effects of physical activity on mental health and wellbeing in adolescence as well as which type of physical activity might be most beneficial for term and preterm born children. Children and adults born very preterm or with very low birth weight have an increased risk of neurodevelopmental and mental health problems ,2. DurinPhysical activity has been suggested to promote mental health and well-being among children and adolescents in the general population ,8,9. FurVery preterm children tend to have more physical and motor limitations ,16 and sThe objective of the current study was to examine three competing explanatory models regarding how physical activity may impact on very preterm born adolescents’ mental health and well-being . The firSD = 1.1). In total, 40 children and adolescents born very preterm (≤32 weeks and 0 days of gestation) had sufficient days of valid accelerometry recordings to be included . The control sub-sample included 59 term born participants, who were originally recruited through official birth notifications  as an age and sex matched comparison group in the first wave of the BSPC when children were 8 years old on average [The Basel Study of Preterm Children (BSPC) is a cohort study of very preterm children and term born controls. The very preterm sub-sample was recruited from an initial cohort of 260 prematurely born children, who were treated at the University Children’s Hospital of Basel, Switzerland, between June 2001 and December 2006, and for whom gestational age was retrieved from hospital records . Cross-s average .SD = 0.3). Data of twins and triplets were included in the analysis. Detailed analysis of sociodemographic data and a flow chart of study participation of different gestational age groups have been published before [x2(1) = 0.13, p = 0.72)).The Millennium Cohort Study (MCS) is a representative longitudinal study of 18,818 infants born in the UK . A randod before . In totaSample characteristics of very preterm and term born adolescents are shown in Ethical approval from the respective ethic committees  were obtained and participants gave written informed consent.In the BSPC, physical activity was measured over seven consecutive days with triaxial accelerometers  worn on the wrist of the non-dominant hand throughout the day. ActiLife software 6.13.3 (ActiGraph LLC) was used for the initialization of accelerometers, download, and processing of collected data. Prior to analyses, wear time validation was performed with the Troiano and colleagues′  algorithp < 0.001) with moderate to vigorous physical activity defined as bouts of 5-min windows with 80% of time spent in moderate-vigorous physical activity). To calculate a weekly average, weekday physical activity was multiplied by 5 and weekend physical activity was multiplied by 2 before summing the two values. To use physical activity in cross-cohort analysis, the variable was z-standardized.In the MCS, objective physical activity was measured using GENEActiv Original accelerometer devices worn on the wrist of the non-dominant hand on one day during the week and one weekend day calculating Euclidean Norm Minus One (ENMO). Total number of minutes are indicated summing up 1-min epochs with ENMO > 100 mg . This vanot true) to two (certainly true). The overall score and the sub-scores for the four domains of emotional symptoms (five items), conduct problems (five items), hyperactivity and inattention (five items), and peer problems (five items) were used in analyses. Higher scores correspond to more severe behavioral and emotional problems. Reliability coefficients (α) are shown in Mothers reported on behavioral and emotional problems in both the BSPC and the MCS using 20 items of the Strengths & Difficulties Questionnaire (SDQ) . The respsychological well-being , self-perception , peer relations , school related well-being . The overall well-being scale involved all Kidscreen52 items in the BSPC and a mean score of the MCS-single item scales. The Kidscreen-52 included five-point Likert scales, while the MCS-single items included a seven-point Likert scale ; all scales were coded such that higher values denoted higher levels of well-being.Positive well-being was self-reported with the Kidscreen-52  in the BThe following covariates were included in the analysis: participants’ age at the assessment of the outcomes, sex, neurosensory impairment, ethnic minority group membership, and parental education. Neurosensory impairment was defined as parent-reported severe visual impairments, hearing deficits, or motor impairments , or cognitive ability scores of at least three SDs below the population average. Cognitive ability scores were assessed with the Wechsler Intelligence Scale for Children-IV in BSPC, at an average age of 10 years (during the second study wave of the BSPC), and with the British Ability Scales (Picture Similarity and Pattern Construction) in the MCS, at the age of 5 years. Ethnic minority group membership was measured with adolescents’ first language, which was used as a proxy  in the BSPC, and with parent-reported ethnic minority status  in the MCS. Parental education was defined by the highest educational level of either parent .Preliminary analyses were conducted separately for both cohorts and involved comparing physical activity, behavioral and emotional problems, and well-being between very preterm and term born adolescents as well as examining Pearson’s correlations between physical activity and covariates. This was followed by random-effects meta-analysis to compare pooled means of physical activity, behavioral and emotional problems, and well-being of very preterm and term born adolescents across the two cohorts.As the main analysis, two-step individual participant data (IPD) meta-analysis was conducted. In the first stage, following the procedure of Aiken and West , hierarcQ statistic and quantified by the I2 value. Low heterogeneity was defined as an I2 value of 0–25%, moderate heterogeneity as an I2 of 25–75%, and high heterogeneity as an I2 of 75–100%. Two-stage random-effects IPD meta-analysis was conducted using the ‘ipdmetan’ command [p = 0.05/10 = 0.005).In the second stage, two separate sets of meta-analyses were conducted for main effects of physical activity  and interaction effects . Pooled effects and 95% confidence intervals (CIs) were computed using the random-effects method with DerSimonian and Laird technique . In all  command  in STATAWe further conducted two sensitivity analyses. In the first sensitivity analysis, we repeated all analyses excluding those who were twins/triplets (as including these participants this could have resulted in skewed findings). In the second sensitivity analysis, we used propensity score matching using the ‘psmatch2′ command in STATA in the MCS cohort, where there was a large difference in the number of participants between the very preterm and term born groups, and repeated the regression analysis. Using propensity score matching has advantages including that it provides a more precise treatment effect by creating a balanced data set .p = 0.03; Participants′ characteristics are presented in p < 0.001) but not with sex, neurosensory impairment, ethnic minority group membership, and parental education . In the MCS sample, physical activity was associated with sex , ethnic group , and parental education , indicating lower physical activity among girls, participants with ethnic minority background, and with parents with lower educational levels, but was not correlated with age.In the BSPC sample, physical activity correlated significantly with age , the associations between physical activity and hyperactivity/inattention and emotional problems were non-significant. No statistically significant heterogeneity existed between the study cohorts in the analyses of the main effects . Findings remained the same in the sensitivity analysis repeating the analysis without the twin/triplet participants . For both domains, the heterogeneity was indicative of increased well-being among very preterm adolescents with higher physical activity in the BSPC sample, but of an inverse relationship for the MCS.In the IPD meta-analysis of interaction effects the only significant association was between the physical activity × preterm status interaction and hyperactivity/inattention , which became nonsignificant after correction for multiple comparisons. Apart from this association, there were no significant physical activity × preterm status interactions with any of the outcome variables. There was significant heterogeneity between the two samples in general and psychological well-being, which were not explained by female sex, minority ethnicity, and university level parental education  are displayed in IPD meta-analysis for the two cohorts revealed that higher levels of physical activity were associated with lower levels of peer problems reported by mothers. Similarly, higher levels of physical activity were associated with higher overall well-being, psychological and school-related well-being and better self-perception and body image as reported by adolescents themselves. The association of physical activity with behavioral and emotional problems and well-being was not found to be different between very preterm born and term born adolescents. Thus, consistent with the first of the three competing explanatory models (“(A) Universal Protective Effect”), physical activity is similarly associated with behavioral and emotional problems and well-being among all adolescents. Very preterm adolescents were neither more vulnerable nor more susceptible to the effects of physical activity. However, the observed effect sizes were small.It has been suggested that physical activity may have a positive effect on mental health and well-being among adolescents, as it may evoke positive social feedback and recognition from peers, which in turn improves self-image and decreases social inhibition and anxiety . Very prFinally, the findings are consistent with studies indicating that during adolescence, those born very preterm show similar levels of physical activity as their term born counterparts ,19,20, wThe following limitations of the study need to be mentioned. First, preliminary analyses only showed significant mean differences between very preterm and term born adolescents regarding emotional problems, while no further significant differences in behavioral and emotional problems and well-being were found in both cohorts. However, there is a large body of evidence suggesting that differences regarding attention difficulties and peer problems exist as well ,38,39. IIn conclusion, this study suggests that physical activity is associated with improved mental health and well-being for all adolescents, whether born full term or very preterm, although the effect size is small. It remains a task for future studies to determine whether distinct types and aspects of physical activity have a greater influence among very preterm or term born adolescents.


The management of patients with hematological malignancies including chronic myeloid leukemia (CML) can be challenging in the era of the coronavirus disease-19 (COVID-19) pandemic ,3, so, hThe Ministry of Health of the Republic of Turkey has been recording every test for SARS-CoV-2 in the public health records, which are accessible to physicians. We identified 243 adult chronic-phase CML patients currently receiving medical care from our institution and acquired their public health records for SARS-CoV-2 polymerase chain reaction analysis from nasopharyngeal swab specimens. Sixteen of our patients had undergone testing for SARS-CoV-2 by 7 July 2020, and five patients  tested positive. The eleven patients who tested negative for COVID-19 were contacted by telephone. Five of them had been asymptomatic and were tested due to contacts. Two patients were tested during the evaluation of symptoms of the upper respiratory tract, from which they recovered without a complicated course. One patient was tested while being evaluated for diarrhea and another while being prepared for a cystoscopy. Two patients were tested before travel. All of these eleven patients were in good health when they were interviewed.CML can present unique problems during a SARS-CoV-2 infection . Drug-drThree (60%) of our five patients had lung involvement according to a chest CT scan. This rate seems to be high. However, two of these patients underwent chest CT only because they were assumed to be in a high-risk group due to CML and had no signs or symptoms related to the lungs. Thus, comparing the rate of lung involvement in our CML cohort with the rate of pneumonia in the general population may be misleading as the imaging indications are biased and the number of infected patients in our cohort is small.The papers by Li et al.  and BrecIn conclusion, we report five CML patients with COVID-19, all of whom recovered without the need for intensive care. CML patients may have disease-related or treatment-related factors that place them at a higher risk of complications during SARS-CoV-2 infection. A diligent and individualized approach is necessary. Documentation of this growing experience is necessary to optimize the care for these patients.


Are mindfulness-based interventions associated with decreased anxiety in adults with cancer?In this systematic review and meta-analysis of 28 randomized clinical trials with 3053 participants, mindfulness-based interventions were associated with reductions in the severity of anxiety in adults with cancer up to 6 months after delivery of mindfulness sessions compared with usual care, waitlist control, or no intervention; a concomitant reduction in the severity of depression and improvement in health-related quality of life was also observed. None of the trials used mindfulness-based interventions in children with cancer.Mindfulness-based interventions were associated with a reduction in anxiety and depression in adults with cancer. This systematic review and meta-analysis of 28 randomized controlled trials examines the effectiveness in mindfulness-based interventions in reducing anxiety and depression in adult patients with cancer. Mindfulness-based interventions (MBIs), grounded in mindfulness, focus on purposely paying attention to experiences occurring at the present moment without judgment. MBIs are increasingly used by patients with cancer for the reduction of anxiety, but it remains unclear if MBIs reduce anxiety in patients with cancer.To evaluate the association of MBIs with reductions in the severity of anxiety in patients with cancer.Systematic searches of MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and SCOPUS were conducted from database inception to May 2019 to identify relevant citations.Randomized clinical trials (RCTs) that compared MBI with usual care, waitlist controls, or no intervention for the management of anxiety in cancer patients were included. Two reviewers conducted a blinded screening. Of 101 initially identified studies, 28 met the inclusion criteria.Two reviewers independently extracted the data. The Cochrane Collaboration risk-of-bias tool was used to assess the quality of RCTs, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Summary effect measures were reported as standardized mean differences (SMDs) and calculated using a random-effects model.Our primary outcome was the measure of severity of short-term anxiety (up to 1-month postintervention); secondary outcomes were the severity of medium-term (1 to ≤6 months postintervention) and long-term (>6 to 12 months postintervention) anxiety, depression, and health-related quality of life of patients and caregivers.I2 = 76%). The association of mindfulness with short-term anxiety did not vary by evaluated patient, intervention, or study characteristics. Mindfulness was also associated with the reduction of medium-term anxiety . No reduction in long-term anxiety was observed . MBIs were associated with a reduction in the severity of depression in the short term  and the medium term  and improved health-related quality of life in patients in the short term  and the medium term .This meta-analysis included 28 RCTs enrolling 3053 adults with cancer. None of the trials were conducted in children. Mindfulness was associated with significant reductions in the severity of short-term anxiety (23 trials; 2339 participants; SMD, −0.51; 95% CI, −0.70 to −0.33; In this study, MBIs were associated with reductions in anxiety and depression up to 6 months postintervention in adults with cancer. Future trials should explore the long-term association of mindfulness with anxiety and depression in adults with cancer and determine its efficacy in more diverse cancer populations using active controls. The results of these trials are conflicting about the effect of mindfulness on anxiety.23Mindfulness is a technique whereby a person becomes purposefully cognizant of the present moment and learns to address their thoughts, feelings, and sensations in a nonjudgmental manner.27 These reviews did not explore the association of mindfulness with anxiety in other cancer types and did not examine different types of mindfulness-based interventions, such as mindfulness-based cognitive therapy (MBCT) or mindfulness-based cancer recovery (MBCR).27 Since the publication of these systematic reviews, several RCTs have been performed. These trials evaluated the effect of various mindfulness-based interventions in patients with cancer.Previous systematic reviews have evaluated the associations of mindfulness-based stress reduction (MBSR), a widely used mindfulness-based intervention, with psychologic symptoms and HRQoL among patients with breast cancer.In light of the growing literature on the use of mindfulness-based interventions for the reduction of anxiety and depression among patients with cancer, we conducted this systematic review and meta-analysis to synthesize the existing evidence. Our primary objective was to determine whether mindfulness-based interventions were associated with reductions in the severity of anxiety in adults and children with cancer. Our secondary objective was to determine whether these associations varied by cancer type, intervention, or methods of the study.28 The search strategy is presented in eTable 1 in the PRISMA) reporting guideline.Our systematic review was conducted according to an a priori protocol. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, CINAHL, PsycINFO, and SCOPUS from database inception to May 2019 to identify relevant citations of published RCTs, using individualized systematic search strategies for each database. The search strategy was developed by a health sciences librarian and peer reviewed by a second librarian using the Peer Review of Electronic Search Strategies checklist.We included RCTs comprised of a patient population of adults (≥18 years) or children (<18 years) with cancer or who were undergoing hematopoietic stem cell transplant as a treatment for cancer (≥80% of the study population). Enrolled patients were randomized to mindfulness-based interventions or usual care, waitlist, no intervention, or sham control groups for the management of anxiety. We excluded observational, quasi-randomized, crossover, or cluster-randomized trial designs and trials that did not report any outcomes of interest to this review. We did not restrict inclusion by language or date of publication.Two reviewers (S.O. and J.Y.) independently evaluated the titles and abstracts. The full text of any citation considered potentially relevant by either reviewer was retrieved and assessed for eligibility. The inclusion of trials in this meta-analysis was determined by agreement of the 2 reviewers with discrepancies resolved by a third reviewer .We extracted data from included trials using standardized data extraction forms. Study-level variables included the year of publication and enrollment, country of study, age of participants (adults vs children), cancer diagnosis , cancer stage , the timing of intervention , selective enrollment of palliative care patients (author defined), presence of anxiety as an eligibility criterion for recruitment (author-defined threshold), characteristics of the intervention and control groups, and anxiety, depression, and HRQoL scores up to 1 month, between 1 and 6 months inclusive, and from 6 months up to 1 year postintervention. We decided a priori to include overall or global HRQoL scores for the data synthesis. General health HRQoL scores were extracted from the studies that did not provide global or overall HRQoL scores.Incorporating recommendations from patients and stakeholders, our primary outcome was self-reported short-term (≤1 month postintervention) severity of anxiety measured by any anxiety assessment scale. For studies that used more than 1 type of anxiety assessment scale, we defined a hierarchy of anxiety assessment scales based on the most prevalent scale used among the included trials to use in the primary analysis  that use mindfulness as the foundation of a therapeutic intervention instead of as an ancillary component.14 Interventions that include mindfulness as 1 of many elements  were not included because it is difficult to determine the effect of mindfulness in the setting of the physical movement. The control groups in the trials were usual care, waitlist, no intervention, or sham control.Mindfulness was defined as a technique in which a person learns to focus attention in the present to become mindful of thoughts, feelings, and sensations and observes them in a nonjudgmental way to achieve greater calmness, physical relaxation, and psychologic balance.29 This tool categorizes the overall risk of study bias and consists of 6 domains . Each domain is rated low risk, unclear risk, or high risk. Information regarding the risk of bias was used to guide sensitivity analyses and explore sources of heterogeneity. Discrepancies in assessments between the 2 reviewers were resolved by consensus or by a third reviewer (A.M.A-S. or L.S.), as required.We assessed the internal validity of included trials using the Cochrane Collaboration Risk of Bias tool.29 Weighted mean difference (WMD) was used to synthesize data for analyses concerning specific anxiety and depression scales. A summary effect estimate less than 0 indicates that the mean score was lower  in the mindfulness group compared with the control group. The generic inverse variance method was used to weight the effects. A random-effects model was used for all analyses. We assessed statistical heterogeneity between trials using the I2 statistic.30We used the standardized mean difference (SMD) to synthesize data across studies, which measured anxiety, depression, or HRQoL using a variety of scales.31 In the event of potential publication bias, the trim-and-fill technique was used to determine the effect of potential bias using Comprehensive Meta-analysis software, version 2 (Biostat).32 Meta-analyses were conducted using Review Manager, version 5.3.5 (The Cochrane Collaboration). All tests of statistical inference reflect a 2-sided α < .05.For the primary outcome, we evaluated potential publication bias using funnel plot analysis and visual inspection of the forest plot.P value for interaction.We evaluated the following factors in subgroup analyses: (1) type of cancer , (2) cancer stage , (3) timing of intervention , (4) mindfulness-based intervention type , (5) group vs nongroup or individual delivery setting, (6) number of weeks of intervention (<8 weeks vs ≥8 weeks), (7) sequence generation , and (8) allocation concealment (low vs unclear or high risk of bias). We determined whether the mindfulness-based intervention effect varied by subgroups using the 54 We included 1 additional trial identified through hand searching. One trial by Compen et al21 randomized patients to in-person MBCT, internet-based MBCT, and usual care cohorts and thus represented 2 separate analyses, for an overall total of 29 mindfulness-based comparisons (3053 participants). All trials were published as full-text articles in English. These trials were conducted in 13 countries from 4 continents  and MBCT . Trials used usual care  and waitlist  equally as comparators. The median duration of intervention was 8 weeks . Anxiety assessment scales used across all included trials are listed in eTable 2 in the The risk of bias assessment is presented in eFigure 1 in the I2 = 76%) (I2 = 32%) or STAI scales . On sensitivity analysis, the effect estimate was reduced  when the trial by Lorca et al35 was excluded because of the very short duration of the intervention (50-60 minutes). Examination of the funnel plot for the primary outcome showed the potential absence of small-size studies showing no effect of mindfulness; however, no statistically significant evidence of publication bias was present using trim-and-fill methods  . SimilarI2 = 66%) (I2 = 68%) (Mindfulness-based interventions reduced the severity of medium-term (1 to 6 months postintervention) anxiety  . Mindful2 = 68%) .I2 = 86%) (I2 = 91%) (I2 = 54%). Mindfulness was not associated with a reduction in the severity of depression in the long term    and medi2 = 91%) . The lis2 = 97%) .I2 = 82%) and medium term . The included HRQoL assessment scales are listed in eTable 4 in the Mindfulness-based interventions were associated with improved overall HRQoL scores in the short term  associated with HADS-A and STAI has not been identified for patients with cancer in the literature. The reported MCID for HADS-A among patients with chronic obstructive pulmonary disease is 1.5.58 If we extrapolate the MCID of the HADS-A scale from patients with chronic obstructive pulmonary disease to patients with cancer, the observed reduction in short-term anxiety on the HADS-A scale (1.03) is lower than the clinically meaningful threshold. Similar to anxiety, the observed short-term association of mindfulness with depression could not reach a clinically significant threshold. However, it should be noted that behavioral therapies, recommended by American Society of Clinical Oncology as 1 of the modalities for the treatment of anxiety and depression in adults with cancer, are associated with small to moderate effect sizes, similar to mindfulness-based interventions.59 Furthermore, mindfulness-based interventions also positively affect other symptoms, such as fatigue, distress, and pain in patients with cancer.61 Therefore, we suggest that mindfulness-based interventions should be considered an effective treatment option for reducing short-term and medium-term anxiety among adults with cancer. Comparing mindfulness-based interventions with other effective interventions for anxiety, such as drugs and behavioral therapies, should be the focus of future research in adults with cancer.An SMD of 0.51 suggests a moderate reduction in short-term anxiety associated with mindfulness.We also demonstrated that, in the longer term, mindfulness-based interventions were associated with little or no benefit on anxiety, depression, or quality of life. Our confidence in the long-term effects of mindfulness-based interventions is low because only 2 trials reported the long-term effects of mindfulness. It is plausible that the absence of booster or follow-up sessions after an initial 8 to 12 weeks of intervention might have diminished the durability of effect. As mindfulness is a skill-building approach, booster sessions may provide participants with the opportunity to master difficult skills and to generalize the mindfulness skills to newly encountered situations in life.37 The longer-duration group sessions can be challenging for patients who either have complications related to cancer or are on active treatment. Young adults with cancer who are well connected with technology may also prefer shorter mindfulness sessions delivered by telehealth, video-interface, or a mobile application.62 Our findings suggest that individually delivered or shorter duration mindfulness-based interventions can be offered to the patients with cancer who cannot commit to group sessions or 8 weeks of intervention due to their illnesses or other barriers.The effect of mindfulness on short-term anxiety did not differ by the assessed patient, intervention, and study characteristics. Specifically, the short-term benefits of mindfulness on anxiety were dependent neither on the type of cancer nor on the treatment phase. These results suggest that examined mindfulness-based interventions could result in the reduction of short-term anxiety of adults regardless of cancer type or stage of treatment. Furthermore, the association of mindfulness with reductions in short-term anxiety was not restricted to studies providing 8 weeks or more of mindfulness and group sessions; instead, the reduction in anxiety was marginally higher when mindfulness was delivered in the individual setting. In clinical practice, mindfulness-based interventions are typically offered in a group setting during an 8-week period.53 and 43% of included trials were done in patients with breast cancer who had completed curative treatment. The effect size for men in the gender-inclusive trials was not reported separately.53 The only trial that exclusively enrolled men with advanced prostate cancer did not show any reduction in anxiety.37 Men may be less receptive and responsive to mindfulness because of their different coping mechanisms than women.63 Therefore, further investigation of how gender affects the efficacy of mindfulness is warranted. There was also no representation of patients in palliative care or undergoing hematopoietic stem cell transplant in the included trials. None of the included trials were conducted in children or in patients with metastatic disease exclusively. Consequently, the results of this meta-analysis may not be generalizable to all cancer populations and settings. Most included trials did not use standardized tools to measure the total time spent practicing mindfulness per week or reported changes in the mindfulness. These factors may explain the heterogeneity in the measured effect, which subgroup analysis did not demonstrate. Other unmeasured patient characteristics in the included trials may also have contributed to the heterogeneity. Finally, imprecision, related to the small sample size, limited our confidence in the long-term effects of mindfulness-based interventions on the studied outcomes.Our systematic review has limitations that deserve comment. We cannot be certain that the observed treatment gains were exclusively due to the mindfulness intervention and not because of the facilitator’s attention, group support, and social interaction, given that none of the trials included an attention control group that matched the intervention group on all of these elements. These nonspecific factors are inherent components of the mindfulness intervention and can potentially affect the outcome. Women were overrepresented in the trials with mixed cancer populations,In this study, mindfulness-based interventions were associated with short-term and medium-term reductions in anxiety and depression along with improved quality of life among adult patients with cancer. Future studies should assess the efficacy of mindfulness in different settings, include diverse cancer populations such as children and men, and compare mindfulness with other effective interventions for anxiety and depression.


Air filtration in various implementations has become a critical intervention in managing the spread of coronavirus disease 2019 (COVID-19). However, the proper deployment of air filtration has been hampered by an insufficient understanding of its principles. These misconceptions have led to uncertainty about the effectiveness of air filtration at arresting potentially infectious aerosol particles. A correct understanding of how air filtration works is critical for further decision-making regarding its use in managing the spread of COVID-19. The issue is significant because recent evidence has shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can remain airborne longer and travel farther than anticipated earlier in the COVID-19 pandemic, albeit with diminishing concentrations and viability. While SARS-CoV-2 virions are around 60-140 nm in diameter, larger respiratory droplets and air pollution particles (>1 µm) have been found to harbor the virions. Removing particles that could carry SARS-CoV-2 from the air is possible using air filtration, which relies on the natural or mechanical movement of air. Among various types of air filters, high-efficiency particle arrestance (HEPA) filters have been recommended. Other types of filters are less or more effective and, correspondingly, are easier or harder to move air through. The use of masks, respirators, air filtration modules, and other dedicated equipment is an essential intervention in the management of COVID-19 spread. It is critical to consider the mechanisms of air filtration and to understand how aerosol particles containing SARS-CoV-2 virions interact with filter materials to determine the best practices for the use of air filtration to reduce the spread of COVID-19. Evidence is mounting that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can remain suspended in the air for extended periods. A fraction of airborne SARS-CoV-2 virions remains viable for at least 3 hours following aerosolization . PolymerThe diameter of SARS-CoV-2 virions is around 60-140 nm . NonetheRemoving particles that could harbor SARS-CoV-2 from the air using specialized air filtration equipment and using masks or respirators is an essential intervention in managing the COVID-19 spread. However, the effective deployment of air filtration has been hampered by a poor understanding of how air filtration works and misconceptions about the concept of filtration efficiency for aerosol particles of different sizes. It is critical to consider the mechanisms of air filtration and to understand how aerosol particles containing SARS-CoV-2 virions interact with filter materials to determine the best practices for the use of air filtration in managing the spread of COVID-19.For air filtration, efficient particulate air (EPA) filters, high-efficiency particle arrestance (HEPA) filters, and ultra-low penetration air (ULPA) filters have been widely used in various industries and applications for many decades . HEPA fiOften, the abbreviation HEPA is interpreted as “high-efficiency particulate air.” Both versions of the underlying term are used extensively, and there is no difference between them. The United States Department of Energy and the United States Environmental Protection Agency (EPA) define HEPA based on a minimum efficiency of 99.97% when tested with an aerosol of 0.3 µm diameter . The UniHEPA filters are recommended to be installed on the outflow from the ventilators used in intensive care of people infected with SARS-CoV-2 . StationAntiviral properties can be imparted to the filter materials. However, once aerosol particles are collected on the filter fibers, virtually none detach and pass through the filter during or after proper use , so the The mechanisms of aerosol particle filtration in the gas phase—inertial impaction, diffusion, interception, electrostatic deposition, and sieving ,19—have It is known that some respiratory infections arise more frequently when people breathe more polluted air and that the recovery process and outcomes of certain respiratory infections are adversely affected by air pollution, based on numerous published studies. An association of higher COVID-19 mortality with the level of long-term particulate air pollution has already been shown . BreathiThis paper is a perspective, so it did not need ethical approval.


Pulmonary arterial hypertension-congenital heart disease (PAH-CHD) is characterized by systemic to pulmonary arterial shunts and sensitively responds to volume overload and stretch of the vascular wall leading to pulmonary vascular remodeling. We hypothesized that the responses of pulmonary artery smooth muscle cells (PASMCs) to mechanical stress-associated volume overload may promote vascular remodeling in PAH-CHD. Here, we show that significantly increased collagen was in the PA adventitial layer by trichrome staining in PAH-CHD patients and an aortocaval fistula (ACF) rat model in which chronic vascular volume overload induced-PAH. We assessed the gene expression profiles of SMC markers, extracellular matrix, and collagen in isolated SMCs from pulmonary and thoracic vessels with cyclic stretch-triggered responses by real-time PCR analysis. The data corresponded to collagen deposition, which modulated pulmonary vascular remodeling in clinical and experimental PAH-ACF cases as well as in cyclic stretch-triggered SMCs in an in vitro model. We observe that collagen I A2 (COLIA2) is expressed in the control rat, but collagen I A1 (COLIA1) and Notchs remarkably increase in the lungs of ACF rats. Interestingly, closing the left-to-right shunt that leads to a reduced blood volume in the PA system of ACF rats (ACFRs) decreased the expression of COLIA1 and increased that of collagen I A2(COLIA2). This study contributes to the stretch-induced responses of SMCs and provides important future directions for therapies aimed at preventing abnormal matrix protein synthesis in volume overload-induced pulmonary hypertension (PH). The pulmonary circulation is a relatively low pressure system (approximately 14 mm Hg at rest) compared to the systemic circulation (approximately 100 mmHg at rest) because the pulmonary arteries (PAs) are not as muscularized as their systemic counterparts. In the systemic circulation, the artery is able to tolerate over 100 mmHg pressure, but in the pulmonary circulation, an arterial pressure increase to 20 mmHg can cause pulmonary vascular remodeling. Patients with congenital heart disease (CHD) have a central shunt between the systemic and pulmonary circulation , leading to volume overload and stretching of the pulmonary circulation. More than 90% of these patients are subjected to percutaneous or surgical repair early in life for a simple, noninvasive diagnostic evaluation ,4. HowevFurthermore, PAH is characterized by increased PVR and caused by remodeling of the PAs ,8. CliniElastin and collagen are proteins for elasticity and play an important role in the regulation of vascular tone. Elastic fibers are an abundant and integral part of many extracellular matrices, in which they provide resilience and deformability to tissues ,19,24. THowever, the role of the dynamic stretch link with ECM regulation is still not clear in the vascular biology of PA remodeling and vascular tone. Although advances in our understanding of the pathophysiology and the management of pulmonary hypertension , signifiIn PA tissues of non-PH, PAH-CHD, and idiopathic pulmonary arterial hypertension (IPAH) patients, we investigated PA remodeling and the regulation of ECM . A histology experiment detected abundant collagen distribution in the medial layer and in the adventitia layer of PAH-CHD patients but not in IPAH patients. In contrast, collagen was less detectable in the PAs of the non-PH patients than in those with PH diseases a. We alsIn the systemic circulation, artery is able to tolerate over 100 mmHg pressure, but in pulmonary circulation, artery increase to 20 mmHg can caused the pulmonary vascular remodeling ,4. ExperBased on the gene profile of SMC markers, ECM and collagen, we observed these markers in SMCs. To better understand the mechanisms underlying the regulation of ECM assembly in the vascular stiffness of PAH in the dynamic increased blood flow of systemic and pulmonary circulation, we isolated and maintained arterial SMCs (TASMCs and PASMCs) to observe gene regulation response to the vascular pressure change and stretched the vascular wall by using the cyclic mechanical stretch model a. We aimp < 0.05 versus controls)  c. Collagontrols) d. ConsisArteries have more collagen and elastin than veins . An advePatients with CHD have simple communications between the systemic and pulmonary circulation, atrial and ventricular septal defects, or patent ductus arteriosus that induce flow overloading and vascular stretch stress, leading to PA remodeling and stiffness. PAH-CHD is an early phase in which arteriopathy can generally be reversed by closing communication between the systemic and pulmonary circulation to reduce volume-overload stress. In this study, we propose to observe and study the pathophysiological and molecular mechanisms in clinical PAH-CHD and establish an ACF animal model, as well as a dynamic stretch in vitro model. These studies elucidate the relative importance of downstream signaling pathways underlying the dynamic stretch effects of collagen signaling transduction. Moreover, it is of interest to profile the downstream target factors due to the dynamic volume-overload stretch effect in the ECM assembly of vascular SMCs under investigation to clarify the pathology of PAH-CHD. In this study, a PAH-CHD patient had significantly increased collagen accumulation in the adventitial layer than an IPAH patient. We further confirmed collagen deposition in the PA wall through an ACF model in which chronic vascular volume overload induced PAH. The data relate to collagen deposition in clinical and experimental ACF-PAH as well as in a cyclic stretch-triggered SMC in vitro model. We show the overexpression of collagen I (COLIA1) and Notchs in the lungs of ACF rats. Interestingly, closing the left-to-right shunt that leads to a reduced blood volume in the PA system of ACF (ACFR) decreased the expression of COLIA1 and increased COLIA2. This study contributes to the stretch-induced responses of SMCs and provides important future directions for therapies aimed at preventing abnormal matrix protein synthesis in volume overload-induced PH.Recent studies state survival in PAH as disease stability rather than disease reversal. In idiopathic PAH, the trigger cannot be removed, and vascular morphology is normalized. However, this unique type distinguishes PAH-CHD from other groups of PH, and arteriopathy can generally be reversed by closing the communications between the systemic and pulmonary circulation to reduce volume-overload stress and result in full disease regression ,37. In PHowever, the arteriopathy of PAH-CHD can generally be reversed by closing the communication shunt between the systemic and pulmonary circulation to reduce the volume-overload stress and result in full disease regression. COLIA1 and COLIA2, the relative proteins that respond to flow-induced vascular overloading, reflect a dynamic adjustment in response to the stress of volume overload but not of tropoelasin. COLIA2 was expressed primarily in the normal vascular environment. Upon dynamic stretch overload, COLIA1 and Notch1-3 were increased in ACF rat. Closing the left-to-right shunt that leads to a reduced blood volume in the PA system (ACFR rats) decreased Notchs and decreased COLIA1 but increased COLIA2. For the first time, we report a dynamic switch in the COLIA2 and COLIA1 isoforms in response to flow-overload stress stretching in vivo. There is an adventitial layer outside the SMC layer of large vessels, and this layer extends beyond the external elastic laminae and interstitial matrix that contains fibrillar type I and III collagen, chondroitin sulfate and dermatan sulfate proteoglycans, fibronectin, and many other ECM proteins . COLIA1 In the systemic circulation, the artery is able to tolerate over 100 mmHg pressure, but in the pulmonary circulation, a pressure increase in the artery to 20 mmHg can cause pulmonary vascular remodeling ,4. ExperThe normal contractile type of SMCs can adjust myogenic tone, to control blood pressure, and response to blood flow within the blood vessel . ConversThe disturbance of collagen features is a typical part of PAH-CHF pathophysiology. This work was derived from studies in ACF rat models to understand the role of volume overload in PAH (ACF-induced PAH) and to understand the mechanisms of collagen regulation in the phenotype of pulmonary vascular cell walls and vascular remodeling. According to the literature data and our own results, this study contributes to the stretch-induced responses of SMCs and shows that vascular stiffness by COLA1 accumulation and elastic laminae degradation are still in the PAs and have a long-term impact on the development of PAH-CHD. This study provides important future directions for therapies aimed at preventing abnormal matrix protein synthesis in volume overload-induced PH.Human lung tissues were received from non-PH patients and patients with IPAH or PAH-CHD undergoing lung surgery at National Taiwan University Hospital. Informed consent was obtained from all individuals. The protocol for tissue collection was permitted by the Human Research Ethics Committee at National Taiwan University Hospital  and Chang Gung Memorial Hospital , and the study was conducted in accordance with the principles of the Declaration of Helsinki.An ACF model  was deveAdult male SD rats (200–250 g in body weight) received either a subcutaneous injection of 60 mg per kg body weight of crotaline  or saline alone to induce PAH and RV hypertrophy after 4 weeks . All insl-glutamine , and 10% fetal calf serum and incubated at 37 °C in 5% CO2-95% air. The medium was changed then and thereafter every 2–3 days. To characterize SMCs, we used the smooth muscle cell–specific gene markers α-smooth muscle actin  and desmin . Desmin was down-regulated at passage 3. Therefore, PASMCs were used before passage 2 for all of the in vitro experiments. The SMCs were studied from passages one to two. SMCs were characterized by immunocytochemical staining for α-smooth muscle actin and desmin.The SMCs were isolated from SD rats, as described previously ,48. To o2-95% air atmosphere at 37 °C. Cells were subjected to stretch/relaxation for a variable duration up to 24 h as indicated.Cyclical stretch-relaxation was applied for cultured PASMCs and TASMCs. Cells were grown to 80% confluence and cultured in DMEM with 0.5% fetal bovine serum on six-well silicone elastomer-bottomed culture plates  that had been coated with collagen type I. After incubating for 48 h in the quiescent medium, cells were subjected to cyclical stretch/relaxation using the Flexercell Strain Unit FX-4000 (Flexcell). This unit a is a moThe technicians obtained 6 samples from each pulmonary artery. The sampling should target different areas within the arteries to obtain an adequate representation of the whole tissue. For all histological procedures, the tissue was fixed with 10% neutral buffered formalin, immersed in formalin overnight, and then embedded in paraffin. Sections (4 μm thick) were stained with hematoxylin and eosin or Masson’s trichrome stain or modified Verhoeff elastin stain for morphometric analysis. The staining was processed according to the manufacturer’s instructions .http://bioinfo.ut.ee/primer3/) . Complementary DNA was synthesized using 1 mg total RNA in a 20 μL volume RT reaction mix . Primers for quantitative real-time RT-PCR were designed with the Primer3 program (rimer3/) . QuantitFor the isolation of proteins from arterial tissues, the samples were lysed by the addition of SDS-PAGE sample buffer followed by homogenization. After transfer to PVDF membranes , proteins were incubated with primary antibodies using anti-collagen I , NOTCH1, 2, and 3 . Secondary antibodies specific for peroxidase-conjugated anti-mouse IgG  or anti-rabbit IgG  were used as needed. Blots were visualized using an enhanced chemiluminescence detection system . Samples were normalized to GAPDH  and quantified by densitometry.p ≤ 0.05 was considered statistically significant.Data are defined as the mean and standard error (SE). Differences between two groups were determined by an unpaired t-test. For multiple groups, one-way ANOVA with Bonferroni’s post hoc test was applied to compare the data. A value of


The human T cell leukemic/lymphotropic virus type 1 (HTLV-1), discovered several years ago, is the causative agent for a rapid progressive haematological malignancy, adult T cell leukemia (ATL), for debilitating neurological diseases and for a number of inflammatory based diseases. Although the heterogeneous features of the diseases caused by HTLV-1, a common topic concerning related therapeutic treatments relies on the use of antiretrovirals. This review will compare the different approaches and opinions in this matter, giving a concise overview of preclinical as well as clinical studies covering all the aspects of antiretrovirals in HTLV-1 infection. Studies will be grouped on the basis of the class of antiretroviral, putting together both pre-clinical and clinical results and generally following a chronological order. Analysis of the existing literature highlights that a number of preclinical studies clearly demonstrate that different classes of antiretrovirals, already utilized as anti-HIV agents, are actually capable to efficiently contrast HTLV-1 infection. Nevertheless, the results of most of the clinical studies are generally discouraging on the same point. In conclusion, the design of new antiretrovirals more specifically focused on HTLV-1 targets, and/or the establishment of early treatments with antiretrovirals could hopefully change the perspectives of diseases caused by HTLV-1.  The human T cell leukemic/lymphotropic virus type 1 (HTLV-1) . It has HTLV-1 is the etiological agent of a rapid progressive malignancy, Adult T cell leukemia (ATL), which develops in 5% of infected people, as well as a debilitating neurological disease, HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), which develops in 4% of HTLV-1 positive individuals. In addition, a number of inflammatory HTLV-1 associated diseases such as uveitis, Hashimoto’s thyroiditis and Graves’ disease, HTLV-1 associated pulmonary disease, infective dermatitis associated with HTLV-1, HTLV-1 associated inflammatory myositis, and HTLV-1 associated arthritis have been reported . AlthougZidovudine , a nucleoside analogue acting as competitive inhibitor of reverse transcriptase was the first effective antiretroviral used in HIV infection . The potAn HTLV-1 associated neuromyelopathy, originally named tropical spastic paraparesis (TSP), was first uncovered in the Caribbean area. A similar neurological disorder was then described in Japan and named as HTLV-1 associated myelopathy (HAM). The two diseases were then recognized to be identical and here we refer to this neurological disease, occurring in HTLV-1 infected patients, as HAM/TSP. First clinical trials using AZT in HTLV-1-infected HAM/TSP patients provided conflicting reports. An open study conducted for six months on five patients (1 g/day) affected by HAM/TSP observed no effect of AZT on the encephalomyelopathy and therefore no clinical benefit . ConversObviously, since HAM/TSP is caused by HTLV-1 infection, the assessment of the effect of antiretroviral therapy on viral load could highlight the possible influence of inhibition of reverse transcription on the clinical response. However, in vivo response to AZT was variable, and therefore, studies with other nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) were performed. In particular, it was reported in observational studies that treatment with lamivudine  for 24 weeks was able to reduce HTLV-1 viral load in five out of five patients with HAM/TSP, but with oscillation rising toward the baseline, accompanied by parallel variation in CTL precursor frequency and CD25 expression. These data pointed out an effect of therapy towards reverse transcription and the return to base line proviral DNA was interpreted as a failure in drug phosphorylation within the cell or emergence of viral variants with less susceptibility to 3TC inhibition . MoreoveOne alternative strategy for the use of NRTIs in HAM/TSP could be a combination treatment including compounds acting on different targets from viral replication. Such a possible alternative approach was the investigation of the effects of a combination treatment of NRTIs with the epigenetic regulator valproic acid (VPA). Asymptomatic baboon naturally infected with STLV-1, almost identical to HTLV-1 in humans, were treated with a combination of AZT plus VPA resulting in a reduction of proviral load by 5–12-fold in 50% of the animal tested at early stage of infection. The treatment with VPA was shown to be associated to a transient rise in the proviral load early in the first week of treatment while combination with AZT prevented the rebound of the viral load. Given that the decrease of viral load in VPA/AZT treatment was accompanied by an increase of CD8+ effector-cell cytotoxic activity, it was hypothesized that the decrease in viral load was owed to the reactivation of the immune response against the virus facilitated by AZT-mediated inhibition of viral transmission. On the other hand, the rebound of viral load following interruption of the combined treatment might be due to virus production by reservoirs not affected by the therapy, similar to what is observed in HIV infection. On the basis of the results obtained in STLV-1 infection, the combination treatment with VPA and AZT could be potentially transferred to HAM/TSP patients if treated at an early stage of the disease .Taken together, studies carried out until now on NRTIs in HAM/TSP provide conflicting results, but it seems that there is no opinion excluding their potential effect at least at some stage of the disease. Accordingly, attention has been recently paid to a novel generation of NRTIs anti-HIV drugs, i.e., the acyclic nucleoside phosphonates (ANP). In particular, prodrugs of the already mentioned TFV, also named as PMPA [9-R-(2-phosphonomethoxypropyl)adenine], were investigated in a new model of HTLV-1 infection in vitro using as recipient cells LTR luciferase reporter Jurkat T-cells . InteresThus, clinical studies concerning antiretrovirals in HTLV-1 induced neurological disorders provide, at the moment, insufficient evidence to support the use of antiretroviral therapy for the treatment of HAM/TSP as asserted in a recent systematic review and consensus-based recommendations . NeverthIn contrast to HAM/TSP, NRTIs were fruitfully used to treat ATL caused by HTLV-1 infection. This choice was due to the poor therapeutic options for treating ATL which was resistant to the classical cytotoxic chemotherapy. One of the first reports about the use of antiretrovirals was done by Gill et al. in 1995 when AZT was combined with interferon alpha (IFNa) . This coThe above reported studies highlighted the need to elucidate whether AZT+IFNa combination exerted a direct antiretroviral effect. Actually, an indirect antiretroviral effect by AZT+IFNa combination was recently hypothesized as the consequence of an impact towards dendritic cells or macrophages in which viral replication occurs and that provide growth factors and cytokines useful for the survival of ATL cells . InteresTransplantation has been recently recognized as a potentially efficacious HTLV-1 transmission route. The lack of routinely screening of organ donors for HTLV-1 makes difficult to precisely state that the transplant is actually responsible for ATL or HAM/TSP development in the recipient. Some scattered case reports were reported in the literature regarding HTLV-1 transmission through organ transplantation in France, Spain, and United States ,45,46,47Beside NRTIs, only two other classes of antiretroviral agents were translated from HIV experience to possible anti-HTLV-1 drugs. They belong to the classes of integrase and protease inhibitors. No study on anti-HIV non-nucleoside reverse transcriptase inhibitors in HTLV-1 infection has been reported.Several integrase strand transfer inhibitors (INSTIs) have been developed and its use has been introduced in HIV treatment . UnfortuRegarding protease inhibitors, only one recent evidence for the effect of an already used anti-HIV agent belonging to this class has been reported in . RitonavCollectively, the reported data suggest that antiretroviral therapy in HTLV-1 infection could provide benefit although there is not a common protocol to be suggested. The preclinical studies, have clearly demonstrated that antiretroviral therapies based on drugs translated by the HIV experience efficiently repress HTLV-1 infection, with exception of 3TC owe to a natural resistance of the virus. Nevertheless, the clinical results are still relatively discouraging. Different aspects could account for this discrepancy. The first, as reported, is the scarce reliability of known anti-HIV drugs capable to exert any activity towards the vertical spread of HTLV-1 through clonal expansion of already infected cells. Another related point that might be taken into consideration, based on 3TC experience, is that not all the drugs utilized in HIV infection should exert their optimal activity in HTLV-1 infection. Therefore, the still limited results of antiretrovirals in HTLV-1 might depend, at least in part, on the lack of compounds specifically designed and developed towards HTLV-1. Another aspect that should be taken into consideration is that HTLV-1 preferentially infects through cell-to-cell transmission rather than in a direct virus-to-cell way. Thus, in vitro experimental models might have some limitations owing to this fact. Nevertheless, recent results on new anti-HIV integrase inhibitors and on anti-HIV protease inhibitors in HTLV-1 infection could open new scenarios on usage of antiretrovirals in diseases caused by the virus. Relevant to the later, another aspect to be considered is that antiretroviral compounds could be also endowed with properties displaying activities that exert beneficial effects towards diseases caused by HTLV-1 independently on their antiviral activity and/or in addition to it . Finally


A distributed data network approach combined with distributed regression analysis (DRA) can reduce the risk of disclosing sensitive individual and institutional information in multicenter studies. However, software that facilitates large-scale and efficient implementation of DRA is limited.This study aimed to assess the precision and operational performance of a DRA application comprising a SAS-based DRA package and a file transfer workflow developed within the open-source distributed networking software PopMedNet in a horizontally partitioned distributed data network.We executed the SAS-based DRA package to perform distributed linear, logistic, and Cox proportional hazards regression analysis on a real-world test case with 3 data partners. We used PopMedNet to iteratively and automatically transfer highly summarized information between the data partners and the analysis center. We compared the DRA results with the results from standard SAS procedures executed on the pooled individual-level dataset to evaluate the precision of the SAS-based DRA package. We computed the execution time of each step in the workflow to evaluate the operational performance of the PopMedNet-driven file transfer workflow.−12), and DRA model fit curves were identical or similar to those obtained from the corresponding pooled individual-level data analyses. All regression models required less than 20 min for full end-to-end execution.All DRA results were precise (<10We integrated a SAS-based DRA package with PopMedNet and successfully tested the new capability within an active distributed data network. The study demonstrated the validity and feasibility of using DRA to enable more privacy-protecting analysis in multicenter studies. Distributed regression analysis (DRA) is a suite of methods that perform multivariable regression analysis in multicenter studies without the need for pooling individual-level data ,2. Data However, DRA is not widely used in practice due to the operational challenges in implementing the approach . The modIn our previous work, we enhanced PopMedNet, an open-source distributed networking software currently used by several large national distributed data networks (DDNs), to enable an automatable and iterative file transfer workflow for routine implementation of DRA . This woDespite the appealing theoretical properties of DRA, applications designed to perform the analysis can still be inoperable or produce biased results in real-world settings due to unappreciated factors . Evaluating the precision of DRA applications compared with the pooled individual-level data analysis and the feasibility of performing the analysis in reasonable execution times in real-world settings is needed to demonstrate DRA as a practical and valid analytical method. In this study, we demonstrate the feasibility of using the SAS-based DRA package and PopMedNet-driven file transfer workflow to perform DRA in a real-world horizontally partitioned DDN. Specifically, we quantify the precision of the SAS-based DRA package and the operational performance of the PopMedNet-driven file transfer workflow.Funded by the US Food and Drug Administration, the Sentinel System is an active surveillance system designed to monitor the safety of approved medical products using longitudinal, regularly updated electronic health data from a network of 18 health plans and health care delivery systems ,17. SentSentinel uses PopMedNet to facilitate file transfers between the data partners and the Sentinel Operations Center . The SenThere are numerous algorithms  for DRA in horizontally partitioned DDNs, environments where each data partner holds information about distinct patient cohorts ,22. In oWe provide a brief overview of the distributed iteratively reweighted least squares and the Newton-Raphson algorithms used to implement the SAS-based DRA package for distributed linear, logistic, and Cox proportional hazards regression analysis using the Sentinel Operations Center as the analysis center in Both the distributed iteratively reweighted least squares and Newton-Raphson algorithms in the SAS-based DRA package utilize a master-worker process, where the analysis center directs the iterative DRA computations and the data partners execute these computations on their individual-level data with input  from the analysis center. Thus, an iterative file transfer workflow is required to transfer the highly summarized intermediate statistics and the updated regression parameter estimates between the data partners and the analysis center until the model converges or the analysis reaches a prespecified maximum number of iterations.DRA-adapter, into PopMedNet to allow the DataMart Client to upload files automatically and iteratively from and download files to prespecified folders at the data partners and the analysis center. We also developed functionalities for folder monitoring and trigger file creation and deletion in the DataMart Client to integrate the PopMedNet workflow with the two interlinked SAS packages of our SAS-based DRA package. A full description of the PopMedNet workflow and its integration with the SAS-based DRA package is available elsewhere [We previously enhanced PopMedNet to create an iterative and automatable file transfer workflow to facilitate routine DRA . In brielsewhere ,13. We cA typical DRA includes 3 major steps [2 in the year before surgery, and have at least one height and weight measurement in the year after surgery. We excluded patients with any bariatric procedure during the 1-year period before the index bariatric surgery. We also excluded patients with gastrointestinal cancer or a revised bariatric surgery procedure on the day of surgery. For each regression analysis, follow-up started on the day of the index bariatric surgery and continued until the occurrence of the outcome of interest (see below), death, end of health plan enrollment, or end of the study period. For distributed linear regression analysis, the outcome was a change in BMI within 1-year postsurgery, defined by subtracting the BMI measurement closest to the end of the 1-year postsurgery date from the last BMI measurement before surgery. For logistic regression, we created a binary outcome variable indicating 1 if the patient had weight loss ≥20% within 1-year postsurgery, and 0 if otherwise. For Cox regression analysis, we computed the time to weight loss ≥20% within the 1-year post-surgery period (We used the CIDA tool (version 3.3.6) to assemble a harmonized individual-level analytical dataset of adult patients aged 18-79 years who received sleeve gastrectomy or Roux-en-Y gastric bypass in any care setting between January 1, 2010 and September 30, 2015 at 3 Sentinel data partners. To be eligible for cohort inclusion, patients must be continuously enrolled in a health plan with medical and drug coverage for at least 1 year before the index bariatric surgery, have at least one weight and height measurement that corresponded to a BMI ≥35 kg/my period .We assembled 3 separate SAS-based DRA packages to perform distributed linear, logistic, or Cox regression analyses and assessed the association between bariatric procedure (sleeve gastrectomy vs Roux-en-Y gastric bypass) and weight loss within 1-year postsurgery, adjusting for prespecified confounders . For Cox, (3) specify the file path to the SAS-based DRA package, and (4) execute the SAS-based DRA package in batch mode. Similarly, we instructed the Sentinel Operations Center to (1) initiate the automated PopMedNet workflow, (2) manually place the SAS-based DRA package for the analysis center in a prespecified local directory, (3) specify the file path to the SAS-based DRA package, and (4) execute the SAS-based DRA package in batch mode. Full details of these packages and examples of their execution have been previously described [We distributed each SAS-based DRA package to the 3 data partners through PopMedNet (version 6.7). We instructed the data partners to (1) initiate the automated PopMedNet workflow, allowing the DataMart Client (version 6.7) to automatically download and unzip the SAS-based DRA package to a prespecified local directory, (2) manually place the individual-level analytical dataset created in step 1 in a prespecified local folderescribed ,13.Once the data partners and the analysis center executed their SAS-based DRA package, the package ran continuously, awaiting input files  and DRA computation directions  from the Sentinel Operations Center. We used the PopMedNet workflow to transfer input files and computation directions iteratively and automatically between the data partners and the Sentinel Operations Center.2R, Akaike information criterion (AIC), Sawa’s Bayesian information criterion (BIC), and Schwarz BIC to the statistics obtained from a PROC REG run with the pooled individual-level data. For distributed logistic regression, we compared the model fit statistics log-likelihood, AIC, and Sawa’s BIC to the statistics obtained from a PROC LOGISTIC run with the pooled individual-level data. For distributed Cox proportional hazards regression, we compared the model fit statistics log-likelihood, AIC, and Schwarz BIC to the statistics obtained from a PROC PHREG run with the pooled individual-level data. We considered the integration successful if the DRA parameter estimates and SEs and model fit statistics were precise to the results from the corresponding pooled individual-level data analyses (10−6).We requested all data partners to securely transfer their deidentified individual-level analytical datasets to the Sentinel Operations Center. We assessed the precision of the SAS-based DRA package by comparing the DRA parameter estimates and SEs to those obtained from the pooled individual-level data analyses using standard SAS procedures. For distributed linear regression, we compared the model fit statistics For distributed logistic regression, we also compared the receiver operating characteristic (ROC) curve and the area under the ROC curve with the corresponding curve and area obtained from a PROC LOGISTIC run with the pooled individual-level data. We considered the integration successful if the ROC curves were similar in likeliness and if the areas under the curves were comparable. To offer better privacy protection, we summarized individual-level predicted values for the distributed logistic regression analysis in bins of 6. Full details of this approximation method can be found elsewhere . For disWe extracted time stamps of status changes from PopMedNet and computed the average download, upload, SAS execution, and transfer time at the data partners and the analysis center to evaluate the operational performance of the DRA application. We also reported the average iteration time for each regression model type, and the time required to perform an end-to-end DRA in our test case.We executed all SAS-based DRA packages in SAS versions 9.3 or 9.4, on a Windows desktop or server routinely used to perform Sentinel queries. All machines used to execute the SAS-based DRA packages and DataMart Client instance operated on a Windows 7 platform, with multiple Intel core processors ranging from 2.3 to 3.4 GHz, and 8 to 16 GB of RAM .1=1706, n2=2728, and n3=1018). Of these, 981 patients received sleeve gastrectomy, whereas 4471 patients received Roux-en-Y gastric bypass during the study period. Within 1-year postsurgery, the BMI decreased on average by 9.8 kg/m2 in sleeve gastrectomy patients and 18.7 kg/m2 in Roux-en-Y gastric bypass patients. Five-hundred eighty-two of the 981 (59.3%) patients who had undergone sleeve gastrectomy and 3617 of the 4471 (80.10%) patients who had undergone Roux-en-Y gastric bypass had a weight loss ≥20% within the 1-year postsurgery period. The median time to a weight loss ≥20% was 223.9 days for patients who had undergone sleeve gastrectomy and 196.2 days for patients who had undergone Roux-en-Y gastric bypass.We identified 5452 eligible patients among the 3 participating data partners , followed by logistic regression (95.0 s) and linear regression (91.5 s). Overall, distributed linear regression analysis with our bariatric surgery test case required 440.7 s to complete, whereas logistic and Cox proportional hazards regression analysis required 925.5 and 1016.0 s, respectively.We have successfully integrated a SAS-based DRA package with PopMedNet, an open-source distributed networking software, and performed DRA in select data partners within a real-world DDN. Our application was able to compute regression parameters, SEs, model fit statistics, and model fit graphics of 3 regression model types  that were within machine precision or similar in likeliness to those produced using standard SAS regression procedures, without the need to share any individual-level data, in under 20 min. The study demonstrated the feasibility and validity of performing multivariable regression analysis in a multicenter setting while limiting the risk of disclosing sensitive individual or institutional information.−12) results compared with the results from the pooled individual-level data analysis. However, information on the operational performance (computation and file transfer time) of DRA algorithms or workflows is scarce. The closest experience to our DRA application is a Web-based DRA software developed by the SCAlable National Network for Effectiveness Research (SCANNER) [Previous studies have used simulated or relatively well-controlled distributed environments to demonstrate the ability to perform DRA with only summary-level information -8. TheseSCANNER) . This soSCANNER) . The autOur DRA application required significantly more time for model convergence than the SCANNER software. However, this additional time for model convergence may be considered marginal in practice, where other aspects of a multicenter study are typically more time-consuming. For example, developing a study protocol and analysis plan or assembling an analytical dataset at each participating data partner for DRA may require considerably more time than the time required to perform DRA. There are also several key differences between our application and the SCANNER software that may explain the difference in operational performance. Specifically, the SCANNER software requires users to install a virtual machine and open ports to the master node hosting the SCANNER hub. This design may have shorter file upload, transfer, and download times between the execution nodes, as files are only transferred between homogeneous virtual machines on the server and not subject to impediments such as firewall security protocols, additional workload, and upload, transfer, and download speeds.The operational performance of the SCANNER software makes it a desirable option for DRA in networks that are amenable to installing the required software and applications. We previously found that most Sentinel data partners were unwilling to install new software or make modifications to their existing hardware configurations to perform DRA . We chosOur study is not without limitations. First, DRA requires infrastructure and processes beyond the algorithms and technology described in this paper. For example, DRA with our application requires harmonized individual-level datasets. Since its inception, Sentinel has continuously enhanced its common data model, routine analytical tools, and data quality assurance processes. Thus, Sentinel data partners can rapidly create harmonized analytical datasets for DRA. Research networks and investigators without the same infrastructure may not be able to perform DRA with our application as easily, even if data partners are willing to use PopMedNet as their data-sharing software.Second, we tested the DRA application with only 3 Sentinel data partners, and all tests were completed in a Windows version of SAS (desktop or server). It is possible that different hardware configurations not found at these data partners or different versions of SAS (Linux or Unix) could change the precision and operational performance or even inhibit the execution of our DRA application. However, we previously found only 3 different configurations of the required hardware components  among Sentinel data partners [Third, our precision and operational performances were based on a small sample of successful end-to-end executions of our DRA application. These executions were limited to regression models with 23 variables and analytical datasets ranging from 1000 to 3000 patients distributed among 3 data partners. Future work should include more end-to-end executions, regression models with more variables, datasets of larger sample sizes, and more data partners. However, we found that 89% of the iteration time was attributed to file transfer time, which was largely driven by the number of files, size of the files transferred, and network conditions . Because the files contain highly summarized information, increasing the number of variables or patients will not increase the number of files or substantially increase the size of the files to be transferred. In this study, each file transfer process transferred files that were less than 1 MB. Our internal testing of analyses with more variables, patients, and data partners did not result in file sizes larger than a few MBs or increased the iteration time. Thus, we do not anticipate DRA with more variables, patients, and data partners in a real-world setting to have a considerable impact on the operational performance of our DRA application. In addition, network conditions at each data partner can vary depending on the workload. We could not vary network conditions at each data partner to formally analyze its impact on the operational performance. However, we did complete our experiments with 3 Sentinel data partners, with machines that are routinely used to fulfill Sentinel query requests. Thus, our results on precision and operational performance likely represent what potential users of DRA will experience in practice.Fourth, our bariatric surgery test case was relatively simplistic and not as sophisticated as an actual clinical or epidemiologic study. For example, we did not include all the potential confounders. Therefore, the results of our analysis did not have any causal interpretation.Finally, although DRA uses the intermediate statistics at each data partner to perform multivariable regression analysis, the risk of reidentifying specific individuals is not 0. Under certain conditions , there could be leakage of personal information that could be used to infer or identify specific individuals . To furtWe have successfully developed and integrated a SAS-based DRA package with an iterative and automatable PopMedNet-driven file transfer workflow to create a DRA application and conduct DRA in select data partners within a real-world DDN. The application produced results that were within machine precision to the results from the pooled individual-level data analyses using standard SAS regression procedures. The end-to-end execution times were reasonable, demonstrating that DRA can be a practical and valid analytical method in real-world settings.


Topological magnetic structure possesses topological stability characteristics that make it robust against disturbances which are a big advantage for data processing or storage devices of spintronics; nonetheless, such characteristics have been rarely clarified. This paper focused on the formation of chiral soliton lattice (CSL), a one-dimensional topological magnetic structure, and provides a discussion of its topological stability and influence of thermal fluctuation. Herein, CSL responses against change of temperature and applied magnetic field were investigated via small-angle resonant soft X-ray scattering in chromium niobium sulfide ( On the other hand, the chiral magnetic configuration in the 1D system has been considered as the chiral magnetic soliton lattice (CSL). The formation of CSL has been experimentally demonstrated in chiral magnets, such as 2  state.Magnets with chiral crystal structure provide a good platform for exploring non-trivial spin textures due to Dzyaloshinskii-Moriya (DM) interaction which comes from the spin-orbit interaction and the lack of inversion symmetry of crystals. In these years, spin textures with topological features in the chiral magnets have been intensively investigated because of their promising potential for developing novel spintronics devices. For example, skyrmions, topological magnetic structures, show a triangle crystallization of the stable magnetic whirls that emerge in the 2D or 3D magnetic systemz along the helical axis (z axis). The helix is caused by the isotropic FM interaction (J) and the anisotropic DM interaction  started to broaden. Below y direction) kept its low temperature values. These results suggest that the short-range order (SRO) of helical magnetic state survives even above 18. This indicates the strong ferromagnetic interaction within the ab plane, which satisfies the longer correlation length for i.e. 16. However, our diffraction experiments have not observed any higher-order reflections that are evidence for forming CSL, thus we can identify it as a helical or a fan-like magnetic state with the short-range order.Temperature dependence of the full-width-half-maximum (FWHM) of fundamental magnetic diffraction  to 28. The critical fields for transition from one topological number to another with a larger number are determined the energy crossing points. The energy barrier to change the topological number, relating the topological protection, depends on the magnetic field and the topological number itself28. Based on the discussion of hysteresis, the existence of the surface barrier  would result to the topological number change at greater than 1. Transitions from the n-th topological sector to the m-th one will occur at the magnetic field where the energy difference between these two states  and right-handed circularly polarization (RCP) with a beam size of 0.6 mm (H) Small-angle RSXS measurements were carried out at a soft X-ray beamline BL-16A in Photon Factory, KEK, Japan, that was equipped with a vacuum chamber having a background pressure of