Point-of-care (POC) technologies in resource-limited settings can circumvent challenges of centralized laboratory testing, improving clinical management. However, higher device costs and uncertain indications for use have inhibited scaling up POC modalities. To address this gap, we investigated the feasibility and cost of targeted near-POC viral load (VL) testing in 2 large HIV clinics in Lilongwe, Malawi.VL testing using GeneXpert was targeted for patients suspected of treatment failure or returning to care after a previously elevated VL (>1000 copies/mL). Descriptive analysis of retrospective clinical and cost data is presented.Two thousand eight hundred thirteen near-POC VL tests were conducted. One thousand five hundred eleven (54%) tests were for patients for whom results and reason for the test were documented: 57% (794/1389) of tests were to confirm a previously high VL, and 33% (462/1389) were due to clinical indications. Sixty-one percent (926/1511) of patients had a high VL, of whom 78% (719/926) had a recorded clinical action: 77% (557/719) switched to second line antiretroviral therapy, and 15% (194/719) were referred for intensive adherence counseling. Eighty-two percent (567/687) of patients received a clinical action on the same day as testing. The “all-in” cost was $33.71 for a valid POC VL test, compared with an international benchmark for a centralized VL test of $28.62.Targeted, near-POC VL testing was feasible and consistently enabled prompt clinical action. The difference between the “all-in” cost of near-POC VL and centralized testing of $5.09 could be further reduced in an optimized national program by combining targeted near-POC testing and centralized testing. Ninety-one percent of PLHIV on ART in South Africa had at least one VL performed in 2015,7 whereas only 53% of PLHIV on ART in Malawi met their monitoring milestone by the end of 2016.8 Enabling routine access to VL testing to ensure viral suppression is necessary to reduce the HIV burden and associated morbidity and mortality,10 but testing coverage is only impactful if results are used appropriately to differentiate patients to the model of care that meets their condition.11 In many countries, PLHIV on ART for at least 1 year with a suppressed VL (<1000 copies/mL) are considered stable and eligible for a less intense model of care, which could include decreased dispensing frequency or participation in a community-based adherence club. Conversely, PLHIV with an unsuppressed VL (>1000 copies/mL) require more intensified care that includes adherence counseling and subsequent regimen change if the VL does not resuppress with time.12 Despite these recommendations, many stable patients unnecessarily remain in more intense models of care,13 and the rates of ART regimen switch to second line do not correspond well to the estimated rates of unsuppressed VL, despite the known risk of poor outcomes.15The WHO guidelines recommend VL testing at 6 and 12 months after ART initiation, and then annually thereafter.16 These tests can be operated outside of conventional laboratory settings by laboratory or nonlaboratory personnel and closer to locations where patients are receiving care, either in the facility or the community. POC tests range from device-free rapid HIV or pregnancy tests to device-based near-POC technologies, such as the GeneXpert . By enabling testing on-site, near-POC technologies can remove the need for specimen transport to centralized laboratories that lead to long TAT between sample collection and result availability—nearly 7 weeks in some settings.7 However, decentralized testing brings additional challenges, including the need for decentralized quality control, equipment maintenance, supply chain, and waste management.17 In addition, there is a perception of increased expense because the cost for POC proprietary commodities and devices may be higher than those for centralized laboratory machines while the throughput may be substantially lower.18One proven approach to increase access to testing services and rates of clinical action is point-of-care (POC) technologies—tests that have rapid turnaround times (TAT) that enable result availability and clinical action in the same visit.19 Similarly, POC testing for early infant diagnosis (EID) has been shown to increase rates of ART initiation for HIV-positive infants across several countries in sub-Saharan Africa.22 Evidence is emerging on how near-POC testing could benefit VL testing programs. A recently completed study in South Africa replaced centralized testing with near-POC VL within a package of services for adult clients newly initiating efavirenz-based ART. The combination intervention increased the proportion of patients achieving viral suppression, retained in care, and referred into community-based care.23 In addition, a recent project in Malawi demonstrated that routine POC VL testing decreased overall TAT, time to intensified adherence counseling, and a shorter time to switch to second line for patients with a VL >1000 copies.24Despite these challenges, the evidence that near-POC testing improves the management of PLHIV continues to grow. Near-POC CD4 testing has been successfully rolled out in resource-limited settings for the past decade, resulting in increased ART initiations and retention in care.25 and nearly 70% are receiving 3 monthly refills13 so typically receive their VL result on their next visit or are called by phone if the test result is unsuppressed.In the resource-limited setting of Malawi, we hypothesized that an optimal testing program for nonpregnant or breastfeeding patients would combine (1) high-volume centralized testing for most patients requiring routine VL assessments with (2) targeted near-POC VL testing on low throughput machines for patients whose management requires the same day result, specifically patients suspected of treatment failure or returning to care after a previously elevated VL (>1000 copies/mL). The strategy was predicated on the evidence that most patients on ART are effectively managed through centralized VL testing, despite extended TAT for results. National data show that 91% of PLHIV on ART are virally suppressedTo improve the management of those who were at high risk for being unsuppressed, we provided targeted near-POC VL testing to eligible patients at 2 high-volume facilities in Lilongwe and assessed the process and cost implications in a programmatic setting.25 During the time of this project, the country guidelines recommended VL monitoring at 6 months and at 2 years after ART initiation and every 24 months thereafter, which differs from the WHO recommendations.12 The decision to reduce the frequency of treatment monitoring in Malawi was driven by a desire to maximize coverage while minimizing costs.26 This guidance was changed to annual VL monitoring in 2019. In addition, the national ART guidelines recommend regimens based on 2 nucleoside reverse transcriptase inhibitors (NRTIs), combined with a non-NRTI, mainly efavirenz as first-line ART. As second-line ART, a combination of 2 NRTIs with ritonavir-boosted protease inhibitors are recommended. Confirmed treatment failure occurs after a targeted or repeat VL is >1000 copies/mL, with good adherence in the previous 3 months. After a switch to second-line or third-line ART, patients reset their clock for routine VL monitoring.12The prevalence of HIV infection among adults aged 15–64 years in Malawi is estimated at 10.6%, and 67.6% of all PLHIV are virally suppressed. The Lighthouse (LH) Trust is a public trust and a WHO-recognized Center of Excellence for integrated HIV prevention, treatment, care, and support partly funded through the Malawi Ministry of Health but receives significant supplemental funding from the President’s Emergency Plan for AIDS Relief through the Centers for Disease Control and Prevention. LH operates 2 large urban patient-centered HIV clinics in Lilongwe: one at the Kamuzu Central Hospital (LH-KCH) with a current cohort of 10,729 patients, and the second called the Martin Preuss Center (LH-MPC) with 21,701 patients.From January to December 2017, the GeneXpert HIV-1 VL assay was available at the 2 LH facilities for nonpregnant adult and adolescent clients who met the following criteria: clinically suspected of ART failure or advanced HIV disease, such as those with WHO stage 3 and 4 diseases or those with low CD4 counts; in need of follow-up because of previous high VL; and switched to second-line ART 6 months previously, regardless of clinical status. Clinicians were trained on testing guidelines for VL monitoring and failure management in January 2017.One GeneXpert platform with 4 modules was placed in each clinic and was primarily operated by nurses. A laboratory technologist also operated the GeneXpert platform at LH-KCH and assisted with supply chain management and technical support for both sites. At LH-KCH, most tests were for VL , and at LH-MPC, the majority of tests were for VL .27 is approved by the European Union and WHO Prequalification Program. The GeneXpert technology enables the automated quantitation of HIV VL, requiring 1 mL of plasma in 10427 minutes. The assay has been validated in lower resourced clinical settings and detects virological failure (>1000 copies per mL) with 94% sensitivity and 99% specificity.29The Xpert HIV-1 VL test, which is run on the GeneXpert platform Near-POC VL testing and results data were extracted from the POC laboratory registers and POC VL request forms. LH clinics serve both patients within their primary cohort on-site and referral patients. VL results for referred patients are returned directly back to the patient without maintaining documentation at LH facilities; therefore, the data analysis was restricted to the primary cohort. Demographic and clinical data were abstracted from the electronic medical record system. Process outcomes from the targeted near-POC testing included accuracy of pretest risk assessment of treatment failure, time to clinical action, and costs to implement the targeted near-POC VL testing. Data were analyzed using Stata 14.2.As the targeted POC VL testing was implemented concurrently with an aggressive process to ensure all LH patients received at least one VL test, an excess number of routine centralized VL tests among LH patients occurred during the study period. Comparisons of the targeted approach with a routine testing approach within the same cohort were therefore not possible.P > 0.5). There were also no associations between categorical variables and missingness.Missing values were evaluated using Little's missing completely at random test and did not show any systematic patterns in missing data . Where exact figures were not available, estimates from similar contexts were used. The study reported costs in the United States Dollar.The following equipment was purchased for the purpose of this study: Cepheid GeneXpert IV device, service contract, centrifuge, and uninterrupted power supply. The total cost to set up a testing site for laboratory equipment was $22,316, with the majority $17,000 comprised the POC GeneXpert device. During the study, testing activities were conducted by 3 cadres of health workers who worked full time, senior nurses, junior nurses, and laboratory technicians. The model was populated with corresponding salary information, inclusive of benefits, for each cadre of health worker in a top-down costing approach. The materials required to run each test were GeneXpert HIV VL test cartridges; gloves, syringes, and EDTA tubes for specimen collection; and paper and toner for printing results. The prices for gloves, syringes, and EDTA tubes were reported from invoices from the study. The GeneXpert HIV VL cartridge was benchmarked to manufacturer's ex-works pricing. Toner and paper were assumed to be purchased at typical benchmark prices. There were additional costs incurred for freight, clearing and duty to import the test cartridges, consumables, and equipment; there was one initial training and one refresher training  conducted during the study period; waste management costs were incurred for the disposal of GeneXpert HIV VL, which contains guanidinium thiocyanate, a toxic substance. It was not possible to collect study-specific overhead data, so a fixed percentage of 15% was used across all other components of the all-in cost per test. There were assumed to be 20 working days in a month after accounting for weekends and holidays.Targeted POC VL testing was provided for as routine care and followed the national guideline protocols; therefore, no informed consent was required. The protocol was approved by the Human Research Ethics Committee of the National Health Science Research Committee of Malawi.During the study period, a total of 2813 VL tests were run on the GeneXperts at the 2 study sites, with an error rate of 4% (59/1364) at LH-KCH and 6% (87/1449) at LH-MPC.P > 0.5) (Table Of the 2813 POC VL tests conducted across both LH-KCH (n = 1364) and LH-MPC (n = 1449), 54% (1511) tests were for patients who received their primary HIV care at LH and thus had documented results, with the remainder testing volume for referred patients. Fifty-seven percent (n = 794/1389) of LH primary patients had a previous high VL, 33% (462/1389) patients had a clinical indication of advanced HIV disease, 3.6% (n = 50/1389) patients were being monitored after switching to second line, 6% (n = 83/1389) patients for other reasons, and 8% (n = 122/1511) patients were missing a reason for testing on their sample referral form and assumed to be missing completely at random  patients were women with a mean age of 32 years. Seventy-eight percent (719/926) patients had a documented clinical action captured in the register: 77% (557/719) patients were switched to second line, whereas 15% (104/719) of patients were referred to intensified adherence counseling  of the cost per test. The remaining 53% of the test cost comprised staff, equipment, other, and overhead. The other category includes freight, clearing and duty, initial training of device users, refresher trainings, and waste management, the largest of which is clearing and duty at $6.35 per test. The scale-up costs assumes 75% device utilization, whereas including estimates for costs not incurred in the study, such as external quality assurance and connectivity to enable remote monitoring of device performance. A sensitivity analysis shows that in the best-case scenario, the all-in cost per patient result could be as low as $21.03 and in a worst-case scenario as high as $60.15 per result. The primary driver of lower costs would be full utilization of the devices, running more tests than were observed during the study period. The main driver of increased cost in the worst-case scenario are primarily due to higher human resources cost from health workers not multitasking while assays are in the analyzer for 104 minutes and lower device utilization.The implementation of near-POC testing for targeted VL monitoring proved feasible at 2 high-volume urban clinics in Malawi. Near-POC VL testing enabled prompt and effective clinical management for nonpregnant adult and adolescent patients on ART who were suspected of treatment failure. Among patients deemed eligible for targeted testing, clinicians documented that 57% had a previously elevated VL and 33% had clinical signs or symptoms consistent with advanced disease or a serious coinfection such as tuberculosis. Sixty-one percent of patients tested using GeneXpert were found to have an elevated VL that required clinical attention, adherence counseling, or switch to second line. Across both clinics, 78% of patients with an elevated VL result had a documented clinical action, 82% of which happened on the same day as testing and 92% within 2 days of testing.30 in the same year 6% of VL tests performed nationally were >1000 copies/mL.31 Although not a one-to-one comparison and not all patients with an elevated VL should be switched to second line, the proportion of patients on second line is much lower than the proportion who have an elevated VL. In our study using GeneXpert for targeted POC VL testing, most patients with an elevated VL received a clinical action; 60% patients were switched to second line and 11% patients initiated adherence counseling, indicating the impact that rapid, immediate testing can have on effective clinical decision making in a nonresearch setting. Third, the same day clinical action not only benefits patients' health but also may reduce their out-of-pocket cost of returning to collect their test results at subsequent visits.These findings illustrate several potential advantages of near-POC VL testing, particularly prompt data-driven clinical action. First, had patients perceived to be failing been presumptively switched to second line without the use of VL testing up to 39% (585/1511) may have been unnecessarily switched, indicating that the access to on-site VL testing enables more appropriate clinical action. Second, although only 2% of ART patients were receiving a second-line (protease inhibitor based) regimen at the end of 2017 throughout Malawi,Assuming 240 working days per year, the average daily number of VL tests run was 5.7 at LH-KCH and 6.0 at LH-MPC; the average daily utilization during the study period was 6 tests, compared with a total theoretical throughput of 28 per day based on the 11-hour workday 5 days per week observed at the study sites. Comparing the cohort sizes, at LH-KCH, 1 near-POC VL was performed per 7.9 ART patients per year, and at LH-MPC, the ratio was 1 near-POC VL per 15.0 ART patients per year. With targeted testing in our cohort in high-volume centers of excellence, we reached only 32% utilization of the testing capacity of the GeneXpert devices, leaving plenty of capacity for other types of urgent near-POC testing that could be performed.The cost per test was $33.71 and cost per result, accounting for test errors, increased to $35.46. With 68% remaining capacity, economies of scale dictate the cost per test can continue to be reduced.32 or children and adolescents. Finally, near-POC VL testing would be useful in a remote or difficult-to-access location, which may not be part of routine sample transportation routes.In this study, the POC VL was mainly targeted to patients who had either a previous elevated VL, were suspected of advanced disease, or required a follow-up VL after switching to second line. In addition to these priority populations, the POC VL can be further expanded to other targeted populations, for example, pregnant and breastfeeding women33 Indeed, a large fleet of GeneXpert devices already exists in many resource-limited settings mostly for TB testing,35 which could be leveraged for targeted VL testing to benefit more patients living with HIV on ART, without requiring large capital investments in new devices.Several test types can be performed on the GeneXpert, such as EID, tuberculosis (TB), and human papillomavirus (HPV). Multidisease testing on GeneXpert across HIV VL, EID, and TB has been shown feasible in Zimbabwe.There are several limitations of our study, including that this is an observational study with no concurrent comparator in the project facilities. The implementation of the study in routine settings was intentional for purposes of assessing feasibility and process outcomes; however, record keeping was not optimal; we were only able to collect data for 54% of all POC VL test of interest. There is no reason to assume that the patients without test process documentation were systematically different from those with documentation. In addition, during the time of implementation, patient files without recent VL tests were actively flagged for testing, which likely led to overall increases in testing coverage during the study period, but may have not influenced testing among the targeted population substantially.The most encouraging findings of this intervention were the reduced time between VL sample collection and management actions for patients eligible for a targeted near-POC VL, with most clinical decisions occurring on the same or next day as sample collection as well as the very high proportion of at-risk clients who had a documented clinical action after their VL testing. Even at very high-volume centers of excellence, the less than 10 at-risk patients were identified each day—well within the testing capacity of a 4 module GeneXpert.This study shows the potential benefit of providing targeted near-POC VL technology for people in need of urgent clinical management, whereas most patients who require more routine clinical decisions receive centralized testing. Because of economies of scale, centralized VL testing is lower cost and may provide more consistent quality results and fewer operational challenges. It offers a valuable option for VL testing for most people on ART in lower resource settings who are stable and virally suppressed. Patients at risk of advanced disease, however, can feasibly be provided with and benefit from access to near-POC VL testing. The higher costs and facility resource required by near-POC testing are minimized by only using the intervention for the patients who will most benefit from prompt clinical action, including appropriate switch to a virally suppressing regimen. These costs can be further amortized by expanding the eligibility criteria for near-POC VL or using GeneXpert machines for additional purposes such as TB diagnoses. Therefore, targeted near-POC VL testing for the facilitation of high-quality patient care was both affordable and feasible. Further evaluation of how best to optimize use of near-POC VL with centralized VL testing, especially in the context of a multidisease testing program, is warranted.


Kaplan-Meier survival analysis revealed a significantly lower 90-day mortality  in obese patients compared to non-obese patients. Additional analyses of baseline characteristics, disease severity, and microbiological findings outlined further statistically significant differences among the groups. Multivariate Cox regression analysis estimated a significant protective effect of obesity on 90-day mortality after adjustment for confounders. An understanding of the underlying physiologic mechanisms may improve therapeutic strategies and patient prognosis.Septic shock is a frequent life-threatening condition and a leading cause of mortality in intensive care units (ICUs). Previous investigations have reported a potentially protective effect of obesity in septic shock patients. However, prior results have been inconsistent, focused on short-term in-hospital mortality and inadequately adjusted for confounders, and they have rarely applied the currently valid Sepsis-3 definition criteria for septic shock. This investigation examined the effect of obesity on 90-day mortality in patients with septic shock selected from a prospectively enrolled cohort of septic patients. A total of 352 patients who met the Sepsis-3 criteria for septic shock were enrolled in this study. Body-mass index (BMI) was used to divide the cohort into 24% obese (BMI ≥ 30 kg/m A worldwide increasing incidence of sepsis and septic shock has had a noticeable and challenging effect on the everyday routine in intensive care units (ICUs) . DespiteAccording to the revised definition in 2016, sepsis is defined as an inadequate host immune response to infection, and the pathology of septic shock can be considered a severe subclass of sepsis ,6. Pulmo2, obesity is associated with a number of other concomitant comorbidities, such as hypertension, cardiovascular diseases, diabetes mellitus type 2, non-alcoholic fatty liver disease, sleep apnea, and cancer [The clinical phenotype and outcome of septic shock are multifactorially affected by exogenous and endogenous factors. Exogenous factors such as diagnostic procedures or antibiotic treatment strategies are still up for discussion and are often inconsistent ,9. Likewd cancer ,19.Despite predominantly negative associations, previous studies have also suggested obesity as a possible protective factor in sepsis and septic shock ,21. BiolThe present study, therefore, investigated a cohort of Caucasian patients with septic shock according to the current definitions and guidelines to reveal the effect of obesity on mortality and the course of disease. The primary outcome was 90-day mortality risk, whereas 28-day mortality, analyses of detailed clinical parameters, disease severity, microbiological findings, and an adequate adjustment for confounders served as secondary endpoints. Based on previous investigations, it was hypothesized that obesity could lead to better outcomes, more precisely, a favorable 90-day mortality in patients with clinically defined septic shock.The present study was performed at the University Medical Center Goettingen, Germany. All investigations were approved under the ethical project identification code 1/15/12 by the institutional ethics committee of the University of Goettingen, Germany. The study was performed in accordance with the provisions, relevant guidelines and regulations of the Declaration of Helsinki. Written informed consent was obtained from all patients or their legal representatives.2) or obese (BMI ≥ 30 kg/m2) according to the WHO definition of obesity. Patient recruitment took place at three surgical ICUs of the University Medical Center Goettingen. All adult Caucasian patients admitted to the three ICUs were screened daily for septic shock according to the current guidelines and definitions. Eligible patients were added to the study database and followed for 28 days with daily data acquisitions. Mortality within 90 days was recorded by either individual telephone follow-up or official written request at the local registry. No patient was lost to follow-up. Non-eligible patients were excluded from the study according to the following exclusion criteria: (I) immunosuppressive therapy  or cancer-related chemotherapy, (II) myocardial infarction within six weeks before enrolment, (III) human immunodeficiency virus (HIV) infection, (IV) congestive heart failure classified as level IV by the New York Heart Association (NYHA), (V) end-stage incurable disease with a reduced probability of surviving the following 28 days, (VI) pregnancy or breastfeeding, (VII) age below 18 years, (VIII) “Do Not Resuscitate” (DNR) or “Do Not Treat” (DNT) order, (IX) persistent vegetative stage , (X) participation in interventional studies, and (XI) familial relationship with a member of study team.A total of 352 patients who met the International Consensus Sepsis-3 definition criteria for septic shock were selected from a prospectively enrolled cohort of 686 patients with sepsis. For the purpose of the present study, the remaining 334 patients with sepsis but not in septic shock were withdrawn from the study. All patients were classified as either non-obese  and organized in the GENOSEP database, a database that was previously described and primarily used for genetic association studies with the clinical phenotype of sepsis . Collectp-values ≤ 0.05 were considered statistically significant. The significance for continuous variables was calculated using the Mann-Whitney U-test or Kruskal-Wallis test, if applicable. Categorical variables were examined using the Pearson chi-square test or the two-sided Fisher’s exact test. Furthermore, time-to-event data were compared with the log-rank test in the Kaplan-Meier survival analysis. A multivariate Cox regression analysis was applied to the observed time-to-event survival data in order to estimate proportional hazard ratios and adjust for relevant confounders. A power calculation was conducted using the Statistica 13 software package for power analysis considering a probability of a type I error  of 0.05.All statistical analyses were performed using Statistica 13 software . Tables in this paper show continuous variables presented as the mean values ± the standard deviations or as median and interquartile ranges (IQRs) and categorical variables as absolute numbers or percentages as marked in the respective columns. The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.2) and 86 obese patients . Illustrated in p = 0.023; p = 0.0206; p = 0.0358; p = 0.0342; A total of 352 adult Caucasian patients met the criteria for septic shock and were enrolled in the study. The cohort included 266 non-obese  in obese patients was also observed.Kaplan-Meier 90-day survival analysis was performed to obtain the primary outcome. Obese patients showed a significantly lower 90-day mortality  over the observation period. Creatinine levels were, on average, higher , the urine output was lower , and the average number of cumulative days with renal replacement therapy was almost doubled  in obese patients compared to non-obese patients. The average inflammatory, liver, central nervous, and coagulation parameters are presented in To examine patient disease severity, the average SOFA score, organ-specific SOFA subscores and organ support, inflammatory, kidney, liver, central nervous, and coagulation parameters were compared . Obese pEnterococcus faecalis infections . As a secondary observation, 17% of obese patients died within the first 28 days, whereas 31% of non-obese patients did not survive this period (p = 0.0159). To the best of our knowledge, this investigation is the first to present both a favorable short-term 28-day mortality as well as a favorable 90-day mortality in obese patients within a cohort of Caucasian patients in septic shock conforming with the 2016 Sepsis-3 definitions [p = 0.01) and 28-day mortality  after adjusting for relevant baseline characteristics and significant confounders .The primary finding of this investigation was that obese patients with septic shock had a significantly better 90-day mortality rate compared to non-obese patients. In our cohort of 352 patients in septic shock, 90-day mortality was 31% for obese patients sustaining septic shock compared to 43% in non-obese patients sustaining septic shock . Further research is necessary to investigate the assumption that obese patients in septic shock might be less vulnerable to secondary nosocomial infections, such as Enterococcus faecalis, due to a stronger immune response compared to non-obese patients. It has been suggested that an increased risk of infection is associated with reduced levels of leptin, e.g., in malnourished individuals [Another finding that can be obtained from the microbiological analyses performed in this investigation was that obese patients had significantly fewer ividuals .While the relatively large cohort of patients with septic shock, the prospective data collection, and the large number of recorded clinical parameters are strengths of this investigation, there are certainly some limitations to this study. The monocentric study design and the entirely Caucasian septic shock study population are limitations of the present investigation; the results may be limited in their generalizability, especially for other ethnicities. It is of interest to assess the observed effects in cohorts of other ethnicity to allow generalization of the clinical relevance of our findings. Similarly, the studied cohort consists of critical ill surgical patients, so that some of the observations may not be representative for other ICUs . Thus, our findings should be further verified in cohorts from other ICUs and centers. Furthermore, a power calculation to determine a sample size with adequate power could not be conducted at the beginning of the investigation, because the effect size of obesity on the 90-day mortality in patients with septic shock according to the Sepsis-3 definition criteria was unknown. However, a performed post-hoc power analysis revealed a power of 0.86 considering the observed 90-day mortality rates of 31% and 43% among the obese and non-obese patients, respectively. Thus, our sample size was sufficiently large to adequately address the present study’s objective. The presented results are associations and do not imply causality. The physiological and molecular mechanisms behind the presented findings should be further investigated. As this study only dichotomously investigated the differences between obese and non-obese patients, a more detailed categorization of BMI  would be helpful to reveal potential underlying correlations in future investigations.Our investigation provides important evidence for obesity as an independent prognostic variable for the survival of Caucasian patients with septic shock. In the studied cohort, the condition of obesity was independently associated with a favorable 90-day and, secondarily, 28-day outcome. We suggest using an adequate categorization of obese versus non-obese patients for risk stratification of patients in septic shock. The revealed associations need to be validated in other cohorts, and the underlying physiological mechanisms need to be revealed. The understanding of how obesity improves survival in septic shock could affect therapeutic strategies and prognosis for many patients.


Cytokines predominate the inflammatory pathways in diseases like rhinitis, asthma, and atopic dermatitis. Corticosteroids and immunosuppressants are presently the mainstays of treatment for patients with moderate-to-severe disease, but often accompany a poor side effect profile. In this review, we attempt to consolidate current data on various interleukins (IL) that participate in the pathogenesis of atopic dermatitis (AD) to further improve therapeutic strategies. For now, dupilumab is the most accepted biologic to be registered for treatment for moderate-to-severe disease. Recently, IL-37, IL-13, IL-26, IL-17 & IL-31/33 axis as well as proteins like thymic stromal lymphopoietin (TSLP) show promising results as future therapeutic targets because of their important role in the pathogenesis of AD. However, further studies are required to clarify the safety and efficacy of these interventions compared to current treatment modalities but it is worthwhile to pursue research into biologics as a more successful treatment option for moderate-to-severe AD. Atopic dermatitis (AD) is a recurrent, chronic inflammatory skin disease . It is cT-helper (Th) 2 cells predominate the initial phase of AD which involves interleukin (IL)-4 and IL-13, followed by Th1 response . InfantiThe multifactorial nature of AD, both environmental and genetic, as well as chronic relapse of the disease has made it difficult to establish an effective treatment strategy and justifies the need to search for novel and optimum solutions. Topical emollients, antihistamines, and glucocorticoids, along with calcineurin inhibitors, are the mainstay of treatment for mild disease but only offer temporary relief . Thirty-Therefore, it becomes pertinent to pursue an investigation on developing treatments that focus on other immunological targets like IL-37, IL-13, IL-26, IL-17 & IL-31/33 axis as well as proteins like thymic stromal lymphopoietin (TSLP). Such immunological factors have been gaining more importance over the past few years due to their critical roles in the initiation as well as progression of AD. In this article we attempt to consolidate data on various cytokines as well as introduce other molecular players that promote inflammation in AD in the hopes to achieve more targeted immunological benefits for patients suffering with moderate-to-severe disease. These biologics may evidently prove to be superior in efficacy while also maintain a tolerable side effect profile as compared to current immunosuppressants.MethodA search was conducted using PubMed and Google Scholar database of articles with restrictions of English language, free articles, articles published in the last 10 years (2010-2020), and we included both human and animal studies. Abstracts and full-text articles containing the keywords “atopic dermatitis AND inflammation; atopic dermatitis AND interleukins AND inflammatory response; eczema AND treatment AND cytokines." Following this, of the 261 articles, 42 were used for the final review.ResultsVarious cytokines were analyzed that are presently serving as a mode of treatment or currently being studied to become potential treatments, as seen in Table DiscussionIL-31/IL-33 axisBoth IL-31 and IL-33 are members of the alarmins family. Cytokines in this family contain several endogenous peptides and proteins that are involved in cellular damage, apoptosis along with adaptive and long term immune memory . IL-33 fIL-4 & IL-13IL-4 and IL-13 gene expression is greater upregulated in pediatric and adult AD skin lesions compared with those with healthy skin . Both ILIL-13 & OVOL1To maintain skin barrier integrity, expression of FLG and other epidermal proteins is known to play a key role . Ovo-likIL-17 & Thymic Stromal LymphopoeitinIL-17 has been known to be a proinflammatory cytokine, mostly involved in inflammatory diseases like psoriasis, arthritis, and inflammatory bowel disease but in recent years has also been known to predominate in patients with intrinsic AD . IL-17 iIL-37IL-37 is considered a natural suppressor of inherent processes of inflammation and immune-mediated responses with both intracellular and extracellular properties . Along wLimitationsThe review presented here has potential limitations. The review is by no means an exhaustive list of the cytokines and proteins involved in mediating inflammation in AD due to the filters applied in the search engines and only using data from abstracts and free articles. Further addition of references and sources may have added valuable information to expands upon cytokines presented in this article as well as discuss other cells and players that may prove to be superior targets than the cytokines discussed. With additional references, more emerging trials and interventions being studied could have been compared for safety and efficacy. Another essential limitation is that animal studies, specifically data from mouse models were used to prove the involvement of cytokines in AD. Even though animal research provides a rationale for conducting human trials, responses seen in animal studies may not translate into human research and thus may not be used to extrapolate human response.Future ConsiderationsEnormous benefit exists in pursuing these cytokines as therapeutic agents. More organized studies will undoubtedly uncover the valuable potential of these cytokines in the pathogenesis of AD. The additional knowledge and treatment modalities will also prove to be advantageous for treating other diseases like psoriasis and rheumatoid arthritis due to cytokines like IL-37 and IL-17 also being heavily involved in this inflammatory process as well ,11. AnalThe effects, demographics and pathogenesis of AD is complex and thus emphasizes the need to individualize treatment specially for those with moderate-to-severe disease. Patients with AD suffer from barrier dysfunction and are susceptible to environmental triggers and pathogens which leads to a poor quality of life. Inflammation is predominantly mediated by Th2/Th22 whereas Th1 and Th17 mediate the progression of AD. After much deliberation and efforts by the scientific community, dupilumab, a biologic against IL-4, was registered as a treatment in the United States. More recent data show promising results when it comes to IL-31/IL-33, IL-13, IL-17, IL-37, and TSLP. IL-26 seems more promising for the pediatric population. Larger scale human-based studies still need to be conducted to prove the safety and efficacy of these cytokines as treatments for moderate-to-severe AD.


Studies on serological responses following coronavirus disease-2019 (COVID-19) have been published primarily in individuals who are moderately or severely symptomatic, but there are few data from individuals who are mildly symptomatic or asymptomatic.We measured IgG, IgM, and IgA to the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by using enzyme-linked immunosorbent assay in mildly symptomatic (n = 108) and asymptomatic (n = 63) on days 1, 7, 14, and 30 following RT-PCR confirmation in Bangladesh and when compared with pre-pandemic samples, including healthy controls (n = 73) and individuals infected with other viruses (n = 79).Mildly symptomatic individuals developed IgM and IgA responses by day 14 in 72% and 83% of individuals, respectively, while 95% of individuals developed IgG response, and rose to 100% by day 30. In contrast, individuals infected with SARS-CoV-2 but who remained asymptomatic developed antibody responses significantly less frequently, with only 20% positive for IgA and 22% positive for IgM by day 14, and 45% positive for IgG by day 30 after infection.These results confirm immune responses are generated following COVID-19 who develop mildly symptomatic illness. However, those with asymptomatic infection do not respond or have lower antibody levels. These results will impact modeling needed for determining herd immunity generated by natural infection or vaccination. Coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 in Wuhan, China . The WorInfection with SARS-CoV-2 can cause a range of symptoms, ranging from mild illness to severe pneumonia; symptoms of the disease include fever, cough, sore throat, myalgias, headaches, diarrhea, and anosmia. In severe cases, difficulty in breathing, need for mechanical ventilation, and death can occur . The virSerological responses in COVID have been reported in moderately or severely symptomatic individuals in China , Europe To address this, we studied IgG, IgM, and IgA immune responses in individuals infected with SARS-CoV-2 in Bangladesh who were either only mildly symptomatic or asymptomatic, and followed these individuals over the subsequent 30 days; we utilized the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as an antigen for the detection of immune responses. The novel coronavirus SARS-CoV-2 has four main structural proteins, the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins . The S pWe enrolled patients with COVID-19 infection, with or without symptoms, from in and around Dhaka using the surveillance and outbreak platform of the IEDCR. Patients with COVID-19 infection, who were confirmed by RT-PCR of nasopharyngeal or oropharyngeal swabs were recruited for this study. Asymptomatic individuals were detected either in screening programs or through contact tracing. We collected serial blood specimens from infected patients on days 1, 7, 14, and 30 following the confirmation of infection, either in the clinic or during home visits.We included a variety of controls to determine cross-reactivity to the SARS-CoV-2 antigen in the enzyme-linked immunosorbent assay (ELISA). These included 152 single time-point plasma specimens from healthy controls (n = 73), patients with influenza A (n = 59), or specimens from the Japanese encephalitis (JE) surveillance platform (n = 20) (collected between January 2015 and November 2019 in previous studies prior to the current pandemic). All specimens from COVID-19 patients were collected through public health surveillance conducted by the IEDCR as part of the country’s response to the disease. WHO guidelines were followed to categorize illness severity . The stuSARS-CoV-2 RNA was detected in nasopharyngeal/oropharyngeal swabs of patients by RT-PCR using Nucleic Acid Diagnostic Kits (PCR- Fluorescence Probing), supplied by the Directorate General of Health Services to IEDCR and performed as per the manufacturer’s instructions. The classification of patients as symptomatic versus asymptomatic was determined by the presence or the absence of symptoms consistent with COVID-19  at the time of RT-PCR testing. Symptoms were documented by phone calls and also by home visits during follow up days. Asymptomatic patients did not have any symptoms at the time of collection of the nasal swab nor in the 30 days after collection; data were not available on the symptoms in the 1–2 months prior to testing.g for 15 min. Serum was separated from blood and kept frozen (−80O C) until the time of laboratory analysis.Blood (5 ml) was collected initially 2–3 days after individuals tested positive and this was designated as study day 1. In addition, blood was collected on study days 7, 14, and 30. Blood was transported to the laboratory at 2 °C–8 °C. Vacutainers were centrifuged at 700× The RBD component is a part of the spike protein-binding domain of SARS-CoV-2, which binds specifically to the cell receptor ACE2 . The SARThe distribution of antibody responses in symptomatic and asymptomatic cases was compared by the Wilcoxon’s rank-sum test. The accuracy of the RBD ELISA was assessed by receiver-operating characteristic area under the curve (AUC) analyses. All analyses were performed using the GraphPad Prism 6.0 and STATA software version 15.In this study, we analyzed data from 171 patients positive for SARS-CoV-2 by RT-PCR. Based on WHO criteria, our data set contains only mildly symptomatic patients (n = 108) and asymptomatic individuals (n = 63). Of the 108 symptomatic patients, none met criteria for moderate or severe disease  ; we had blood samples from all 4 time points from 20 individuals. The asymptomatic individuals were contacts of suspected or confirmed positive cases, frontline workers such as police and related individuals referred for routine testing or staff at IEDCR tested in screening programs.Antibody responses to the SARS-CoV-2 RBD are shown in In mildly symptomatic individuals, IgA antibody titers to RBD were positive in 36% : 26% and 49%) of patients on study day 1 after the detection of infection. Seropositivity increased further on study days 7  and 14 , but then declined by study day 30  . IgM antWe compared immune responses in the mildly symptomatic and asymptomatic patients , to asseSARS-CoV-2, a human beta coronavirus, is the cause of COVID-19, which was first identified in December 2019 in Wuhan, China . This diRT-PCR of respiratory secretions has been shown to be both sensitive and specific for the diagnosis of COVID-19 early in illness . SerologWe analyzed serological results in 108 mildly symptomatic patients with COVID-19 and 63 asymptomatically infected individuals, and compared these to 152 control subjects both healthy individuals and those with documented infection with influenza A or Japanese encephalitis prior to the pandemic. We used the recombinantly produced RBD of the spike protein of SARS-CoV-2 as our antigen, as this has been used in previous immunoassays for the detection of serological responses and shown to have high sensitivity and specificity. In our study, we found a small number of patients with influenza or Japanese encephalitis who had low positive serological responses to the RBD of SARS-CoV-2. In our analysis of individuals infected with SARS-CoV-2 with mild symptoms, 72% (95% CI: 60% and 86%) symptomatically infected individuals had significantly lower response rates and titers in all three antibody isotypes.These previous studies included mostly patients with moderate and severe symptoms of COVID-19 who were hospitalized. Our results in mildly symptomatic patients with COVID-19 in Bangladesh are similar to these previous studies, although our rates of seropositivity are slightly lower than some of these studies, particularly for IgM and IgA. This may relate to the fact that the immunoassays used by other investigators sometimes included more than one antigen and may be more sensitive than the technology used in the ELISA reported here. Nevertheless, our results are overall similar in mildly symptomatic individuals to those reported previously.Overall, the results of this ELISA utilizing recombinant RBD of the spike protein of SARS-CoV-2 as the detecting antigen, show that the vast majority of patients with COVID-19 infection and even mild symptoms show a serological response to infection by 2 weeks or more after diagnosis. Serology may be useful in diagnosing cases suspected of COVID-19 infection, but later in the course of illness when RT-PCR may be negative, at least in upper respiratory secretions. Serology also may be useful for identifying asymptomatic infections in close contacts if RT-PCR is either not available or these individuals were exposed in the more remote past, although the sensitivity of serology in these individuals is substantially lower than in symptomatically infected individuals. Sensitive and specific serology may also be useful for estimating the prevalence of COVID-19 infection in a population to determine the level of herd immunity, either following infection in that population or vaccination.Prospective studies will need to be done to determine the relationship between the serological responses to COVID-19 seen by ELISA and protection against subsequent infection, and how long that protective response may persist after infection or vaccination. Future studies should investigate the development of memory B cells to SARS-CoV-2 antigens following infection and whether these, in addition to or in place of circulating antibody, may mediate protection against subsequent infection, as seen in other infectious diseases . Lastly,Our study has several limitations. We did not examine for cross-reactivity of our immunoassay with the RBD of SARS-CoV-1, MERS coronavirus or other human coronaviruses that circulate and infect humans. In the studies cited above, cross-reactivity of the RBD of SARS-CoV-2 was not seen with MERS or other human coronaviruses, but was seen with the RBD of SARS-CoV-1. Secondly, patients in our study were enrolled when they tested positive, and data on the dates of symptom onset prior to that testing were not available in the database of public health authorities. Therefore, our results are presented as days following positive testing rather than after symptom onset, as many other studies have utilized. We did not correlate our ELISA titers with neutralization activity against SARS-CoV-2, as has been done in other studies that showed that an IgG titer to RBD correlated with neutralization titers against SARS-CoV-2 . We haveDespite these limitations, this is the first serological study of immune responses to SARS-CoV-2 in a substantial number of mildly symptomatic and asymptomatic individuals in South Asia utilizing an easily available ELISA platform for detecting immune responses to SARS-CoV-2 infection. Our results suggest that this assay can be highly sensitive and specific for recent symptomatic SARS-CoV-2 infection. These data will be very useful for seroepidemiological studies as well as for vaccine trials when they will be rolled out in the future.None declared.10.13039/100004423World Health Organization, Fogarty International CenterTW005572, and Emerging Global Leader Award; K43 TW010362, US NIH/NIAID R01: AI130378, the Fondation Merieux, and the Bill and Melinda Gates Foundation (BMGF). This study was carried out with the support of the United States Agency for International Development (USAID)under the terms of USAID’s Alliance for Combating TB in Bangladesh: activity cooperative agreement no. CA # 72038820CA00002. Views expressed herein do not necessarily reflect the views of the US Government or USAID.


Coxiella Burnetti) and Whipple disease (Thropheryma Whipplei). Hydroxychloroquine has also been effectively administered in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis and sarcoidosis with skin manifestations and refractory hypercalciuria. Hydroxychloroquine acts through increase of lysosomal pH in antigen-presenting cells and as an inhibitor of autophagy . Anti-viral properties were also attributed to a mechanism involving interference with glycosylation of angiotensin-converting enzyme- (ACE)-2, the cellular receptor of SARS-CoV   .p = 0.001). Interestingly, its effects were enhanced by azithromycin which was co-administered in 6 patients to prevent bacterial co-infection. All of these patients (100%) exhibited virological clearance compared to 57% of patients in the single-drug group. Intriguingly, one patient who was still positive following 6 days of hydroxychloroquine administration of azithromycin resulted in negative PCR 3 days after. Notably, two patients receiving hydroxychloroquine were asymptomatic. The study was underpowered and included non-severe cases of COVID-19, meaning non-ventilated patients. These findings were corroborated by a second study of the same group enrolling 1,061 patients with COVID-19. Combination of hydroxychloroquine and azithromycin, started immediately after diagnosis, led to a mortality rate of 0.5% in elderly patientsIn China, a panel of experts recommended chloroquine phosphate, administered orally at a dose of 500 mg twice per day for 10 days for patients diagnosed as mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine . RegardiResults are encouraging but should be treated with caution. Perhaps hydroxychloroquine could be effective in combination with other drugs  in most moderate and severe cases. TheHydroxychloroquine represents a cheap, relatively safe and potentially effective therapeutic option for COVID-19 respiratory tract infections. Its synergistic effect with azithromycin, another potent immunomodulatory agent which has shown effectiveness in Zika and Ebola viruses, requires further investigation. Future large randomized placebo-controlled clinical trials are eagerly awaited to prove this concept. Avoidance of irrational use by asymptomatic or mild-symptomatic non-hospitalized non-confirmed COVID-19 cases should be aggressively pursued.AT wrote the initial manuscript. TK and DB were involved in article modification and offered intellectual contribution for the latest data in the context of COVID-19. All authors offered significant intellectual contribution and approved the final form of the 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.


Sarcoidosis is a multisystemic disease histologically characterized by non-caseating epithelioid granulomas and multinucleated giant cells; the etiology is still uncertain, and likely related to a complex interplay between environmental and genetic factors. The genitourinary system is affected in fewer than 0.2% of all clinically diagnosed cases of sarcoidosis and in 5% of those identified in autopsy studies. In this report, we describe a case of a 42–year-old male with one hypoechoic lesion per testis on B-mode evaluation; contrast-enhanced ultrasound (CEUS) on both lesions was carried out. During the early phase, the masses showed a hypovascular appearance as compared to the surrounding testicular tissue, maintaining the hypo-enhancement in the late phase. Tissue biopsy for pathological evaluation confirmed testicular sarcoid involvement, showing non-caseating granulomas. Allowing visualization of testicular microvascularisation, CEUS may play an important role in excluding malignancy, avoiding unnecessary aggressive treatment for benign conditions, such as sarcoidosis. A review of the literature of reported cases since 2004 of sarcoidosis involving the testis is also included. Sarcoidosis is a multisystemic disease that usually affects patients in the fifth decade of their life with a variable incidence rate depending on countries and ethnic group . A recenSarcoidosis is histologically characterized by non-caseating epithelioid granulomas and multinucleated giant cells. Its etiology is still uncertain, and likely related to a complex relationship between environmental and genetic factors –9.Sarcoidosis is characterized by bilateral chest hilar lymphadenopathy and/or reticulonodular pulmonary infiltrates in the vast majority of cases (>90%). However, this systemic pathology can involve any organ : among tTesticular sarcoid presentation can vary from testicular swelling to painless or painful unilateral or bilateral masses , 13. EspUsually the achievement of a correct diagnosis of sarcoidosis with genitourinary and in particular testicular involvement relies on the association between clinical and imaging findings . The mosNew and non-invasive imaging techniques, such as contrast-enhanced US (CEUS), have recently been refined and adopted in many guidelines , 16. HowA very rare case of testicular sarcoidosis is herein reported together with a detailed review of the literature highlighting the role of CEUS to confidently achieve the final diagnosis excluding other possible differential diagnoses, such as testicular tumor masses.A 42–year-old Caucasian male was admitted to our Hospital referring a 4-month history of gradually increasing upper left quadrant pain. His medical history included bladder neck sclerosis, cholecystectomy, diabetes insipidus, hypogonadotropic hypogonadism, allergic asthma, and a smoking history until 10 months before this admission. The medical examination did not show any relevant features and, therefore, the subsequent diagnostic work-up continued with abdominal US.18F-Fludeoxyglucose (18F-FDG) PET/CT was performed, showing increased 18F-FDG uptake  max=17 at the chest hilar lymphadenopathies level) in all the lesions revealed on CT  with a high frequency (4–14 MHz) linear transducer. The US demonstrated, using the B-mode evaluation, a hypoechoic lesion of 20 mm with ill-defined margins in the left testis  was performed on the chest hilar lymphadenopathies, showing non-caseating granulomas, consistent with sarcoidosis. Stains for acid-fast bacilli and polymerase chain reaction (PCR) in specimens were negative. The final diagnosis was sarcoidosis with multiorgan involvement. A testicular US evaluation was carried out using a Canon-Toshiba Aplio 500t testis  correspot testis . Therefot testis , maintait testis . FinallyThe patient was treated with corticosteroids and then with a second-line therapy (methotrexate), thus achieving a reduction of the SUVmax in all of the sarcoid lesions (SUVmax = 2.6 at the testicular level) at 6- and 12-month PET/CT follow-up.According to our review , from 20Testicular masses may have many differential diagnoses including malignancies and, very rarely, benign processes such as traumatic or infective/inflammatory lesions including sarcoidosis which incidence is increasing , 35. US 18F-FDG uptake was detected only in the left testis (not in both testes) and the max SUV of the left testicular lesion (SUVmax = 11.6) was different from the sarcoid lesions involving the other organs. All these findings could not allow the exclusion of a testicular tumor.However, a question remains unsolved: what is the correct diagnosis of the left testicular lesion? In fact, the testicular sarcoid involvement is very rare, and an association between testicular cancer and sarcoidosis has been reported . Moreove18F-FDG-PET scan has high sensitivity in detecting lesions having an increased glucose uptake, but it is unable to differentiate an inflammatory process such as sarcoidosis from malignancy .All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Mechanical chest compression devices deliver high-quality chest compressions. Early data suggests that mechanical devices may be superior to manual chest compressions in adults following an in-hospital cardiac arrest patients. To determine the feasibility of undertaking an effectiveness trial in this population, we undertook a feasibility randomised controlled trial.We undertook a multi-centre parallel group feasibility randomised controlled trial (COMPRESS-RCT). Adult in-hospital cardiac arrest patients that were in a non-shockable rhythm were randomised in a 3:1 ratio to receive mechanical CPR  or ongoing manual CPR. Recruitment was led by the clinical cardiac arrest team.The primary study outcome was the proportion of eligible participants randomised in the study during site operational recruitment hours. Patients were enrolled under a model of deferred consent. We report data using descriptive statistics, point estimates and 95% confidence intervals.Over a two-year period, we recruited 127 patients across five UK hospitals. We recruited 55.2% (95% CI 48.5%–61.8%) of eligible study participants in site operational recruitment hours. Most participants were male  with a mean age of 72 (95% CI: 69.9–74.9) years. Median arrest duration was 18 (IQR 13−29) minutes. In patients randomised to mech-CPR, median time from CPR start to device deployment was 11 (IQR 7−15) minutes. ROSC was achieved in 27.6% (n = 35) participants and 4.7% (n = 6) were alive at 30-days.COMPRESS-RCT identified important factors that preclude progression to an effectiveness trial of mechanical CPR in the hospital setting in the UK. Findings will inform the design of future in-hospital intra-arrest intervention trials.ISRCTN38139840, date of registration 9th January 2017. In the UK, there are approximately 35,000 in-hospitals cardiac arrests per year with an overall hospital survival of 18.4%.5Mechanical chest compression devices (mech-CPR) deliver high-quality CPR.Based on evidence of mech-CPR use at in-hospital cardiac arrest and uncertainty regarding its effectiveness, we identified a need for a clinical trial to evaluate the effect of the routine use of mech-CPR, compared with man-CPR in adults that sustain an in-hospital cardiac arrest.We conducted a multi-centre parallel group randomised controlled feasibility trial across five UK hospitals. We randomised in a 3:1 ratio to either mech-CPR or man-CPR. The trial objective was to assess how feasible it would be to deliver an effectiveness mech-CPR trial in the in-hospital cardiac arrest population.The trial was approved by the West Midlands – Coventry and Warwickshire Research Ethics Committee (16/WM/0299). The Health Research Authority Confidentiality Advisory Group approved the processing and transfer of data without consent, under The Health Service (Control of Patient Information) Regulations 2002 (16/CAG/0088). We prospectively registered the trial with the ISRCTN Trial Registry (ISRCTN08233942). We published the protocol in an open-access journal.We conducted in accordance with Medical Research Council (MRC) Good Clinical Practice guidelines, national legislation and University of Warwick Clinical Trials Unit Standard Operating Procedures. The University of Warwick sponsored the trial.During the trial, we amended the primary outcome from proportion of eligible patients randomised to proportion of eligible patients randomised during operational recruitment hours. This change was made on 21st March 2018  due to the challenges experienced by some sites in recruiting 24/7. Our ISCTRN registration records this change.Adults (age ≥18) that sustained an in-hospital cardiac arrest were eligible for inclusion if the cardiac arrest was attended by an emergency team trained in the use of mech-CPR and the patient was in a non-shockable rhythm at the point of the study eligibility assessment. Key exclusion criteria included known pregnancy, prisoners, known previous study participation, and cases where mech-CPR was contraindicated  or required as part of routine clinical care .We defined in-hospital cardiac arrest to exclude events in the emergency department. We excluded patients in a shockable rhythm due to a finding of harm associated with mech-CPR use in this patient group in the PARAMEDIC trial.17For a team to be considered trained in the use mech-CPR, at least two clinicians were required to be competent in device use. This safeguard was implemented as previous research has highlighted that mechanical chest compression device deployment can be associated with prolonged chest compression pauses.Following confirmation of cardiac arrest, all patients received man-CPR. Following randomisation, the cardiac arrest team deployed the mechanical chest compression device (mech-CPR- intervention group) or continued to deliver manual CPR (man-CPR- control group). All other treatments were delivered in accordance with Resuscitation Council (UK) guidelines.A LUCAS-2 or LUCAS-3 mech-CPR device  was deployed as soon as possible following randomisation in participants randomised to mech-CPR. Teams were trained using a pit-stop approach to minimise pauses in chest compression delivery during device deployment through use of a two-stage deployment process.In patients randomised to the man-CPR arm, participants continued to receive manual chest compressions. If available, teams were permitted to use a real-time audiovisual feedback device to guide man-CPR delivery.The primary outcome was the proportion of eligible patients randomised during site operational recruitment hours.Secondary outcomes included a range of measures, grouped as study feasibility outcomes, patient outcomes, process outcomes, and safety outcomes . Our patient follow-up included an assessment of survival, neurological outcome and quality of life at six-months. Patient outcomes were selected to comply with the Core Outcome Set for Cardiac Arrest (COSCA) statement.We designed the trial to facilitate recruitment 24-h a day by the hospital cardiac arrest team.On arrival of the mechanical chest compression device at the cardiac arrest event, a trained clinician assessed patient trial eligibility. Eligible patients proceeded to randomisation. We used a sequentially numbered sealed opaque tamper-proof envelope randomisation system. A single envelope was stored with each trial device. We randomised eligible patients on an individual basis in a 3:1 ratio in favour of the use of the mech-CPR.We used an unequal randomisation ratio to increase clinician’s potential exposure to mech-CPR use as this would better correlate with exposure if devices were implemented in practice. Our expectation was that this would help to optimise the deployment process and safeguard participants against the potential harm associated with prolonged chest compression pauses during mechanical chest compression device deployment.At the point that an envelope was opened, we categorised the participant as being randomised for the intention-to-treat analysis. One randomisation envelope was stored with each mechanical device. Following envelope use, the next sequentially numbered envelope was allocated to that device. The study statistician generated the randomisation sequence, using the centre as strata and random block sizes to ensure that a 3:1 allocation was maintained for each strata. A staff member at the trial co-ordinating centre, who was independent of the study team, packed the envelopes.We ensured allocation concealment through the use of an opaque envelope system. We were unable to blind the clinical team as they were required to deliver the clinical intervention. We did not specifically seek to blind all site research teams as the randomisation details were recorded in the patient’s medical record, but requested that a blinded researcher support the participant to complete discharge questionnaires. We also did not blind staff at the trial co-ordinating centre as knowledge of allocated intervention was required for monitoring of compliance. Participants were initially blinded as they would be unconscious due to cardiac arrest. We measured blinding success through study questionnaires in which survivors were asked if they were aware of their allocated treatment intervention.Patients were enrolled in the trial under a deferred consent model, as approved by a Research Ethics Committee, in accordance with English law. We approached participants, or a surrogate decision maker, at the earliest reasonable opportunity following the cardiac arrest event to seek consent for ongoing data collection.We planned to recruit for a period of two-years or until we reached 330 participants, whichever came first. Feasibility trials typically recruit 25–50 patients per study arm.For our statistical analysis, we describe categorical data as frequency and percentage and continuous data as mean and standard deviation or median and interquartile range, depending on normality of the data distribution. In our statistical plan, we described plans to compare group outcomes, as we would for an effectiveness trial, by describing risk ratio and 95% confidence interval or mean difference and 95% confidence interval, as appropriate. In addition, for the outcome of 30-day survival, we planned to compare groups using an 80% one-sided confidence interval, as described above. Analyses are undertaken on an intention-to-treat basis.Over a two-year period (February 2017 to February 2019), COMPRESS-RCT ran at five UK hospitals, of which three hospitals recruited patients on a 24/7 basis. Sites screened a total of 936 cardiac arrests, of which 662 occurred during site operational recruitment hours (figure one). After excluding 432 events for patient reasons, we randomised 127  out of 230 potentially eligible patients in cardiac arrest.The proportion of patients randomised during operational recruitment hours was 55.2% . In total, 38.6% participants were randomised outside normal office hours and 74.8% participants had analysable CPR quality data (The mean age of participants was 72 (95% CI: 69.9–74.9) years and 59.8% (n = 76) were male , Table 3Median arrest duration was 18 (IQR 13−29) minutes, with median time from CPR start to randomisation of 6 min (IQR 4−10). In patients randomised to mech-CPR, median time from CPR start to device deployment was 11 (IQR 7−15) minutes. In the 99 patients randomised to mech-CPR, 71.7% (n = 71) received mechanical chest compressions. The main reason for not using mech-CPR was return of spontaneous circulation prior to deployment .Fig. 1TrData on mechanical device deployment were available for 62.9% (n = 44) patients that received mech-CPR . Mean tiROSC was achieved in 27.6% (n = 35) participants . SurvivaFour device adverse events were reported, of which none were categorised as serious. In two cases, the device did not start and both events were attributed to human error. In one case, the device did not restart after a rhythm assessment. Following an investigation by the manufacturer and Medicines and Healthcare products Regulatory Agency, a device-related cause could not be identified. In all three cases, manual CPR was immediately recommenced. In the fourth case, skin breakdown at the device compression point was noted.There were a number of protocol deviations during the study, including the 28 participants randomised to mech-CPR who did not receive the intervention . Three pIn this randomised feasibility trial comparing mech-CPR with manual-CPR in the hospital setting, we recruited 127 patients over a two-year period across five hospitals. We recruited 55% of potentially eligible patients. We observed effective deployment of mech-CPR devices and delivery of high-quality CPR across both study arms. Overall, 30-day survival was 4.7%. Due to lower than planned recruitment, we decided that it would not be informative to either statistically compare groups or make use of the Cocks and Torgerson approach.Our rationale for undertaking a feasibility trial reflects limited experience in both the UK and internationally of undertaking trials of intra-arrest interventions in the setting of in-hospital cardiac arrest, and the challenge of implementing a new health technology.Our trial demonstrated the feasibility of 24/7 recruitment to a randomised controlled trial of an intra-arrest intervention across three hospital sites. In the remaining two sites, 24/7 recruitment was precluded by frequent changes in cardiac arrest team composition and the associated need to train a large number of individuals in device use and trial procedures. This is an important finding that will inform the design of future in-hospital trials.In the specific context of a mech-CPR trial, we identified three key challenges that would likely preclude progression to an effectiveness trial, namely patient outcome; CPR quality; and overall recruitment. Firstly, for patient outcome, we observed a lower than expected hospital survival rate. Study recruits were patients in a non-shockable rhythm that had not responded to initial resuscitation measures. The implication of a low event rate is marked inflation of the sample size required to reliably detect a difference between study arms. For example, based on a baseline 30-day survival rate of 4.7%, a sample size of over 20,000 patients would be required to detect a small 1% difference in 30-day survival at 90% power and a significance level of 0.05.Our original survival projection was based on registry data which reported a hospital survival rate of approximately 10% in patients that present in a non-shockable rhythm, compared with 45% in patients in a shockable rhythm.Recruitment of patients earlier in their cardiac arrest would have resulted in a higher survival rate.In this trial, recruitment of patients earlier in the arrest would have been challenging to achieve and reduced the reduced the trial’s external validity. Our approach was to strategically locate 2–3 devices across each study site to best reflect practice in hospitals that already use mechanical chest compression devices. Arrival of the device at the arrest was required for randomisation. Our median reported time to randomisation was six minutes, although, as this was based on clinician recollection of events, this likely reflects a best-case estimate.Secondly, the primary process by which it is proposed mechanical chest compression devices might improve outcome in cardiac arrest is through the optimisation of chest compression delivery. This reflects evidence that delivery of in-hospital CPR is often sub-optimal.Thirdly, our overall recruitment was lower than anticipated. This was attributable to a number of system and patient factors, including the challenge of delivering 24/7 recruitment at two of our sites, the incidence of patients in shockable rhythm, and the decision to require two clinicians present trained in device use. These are important issues to consider when designing future trials.Our study has a number of limitations. Firstly, despite the efforts of site teams, we were unable to achieve our planned sample size. This precluded key planned analyses, although we were able to base our decision that an effectiveness trial is not feasible on other findings. Secondly, we pragmatically selected study sites based on their willingness to participate. We do not know how representative these sites are of other UK hospitals. Across these sites, there was variability in use of real-time audiovisual feedback and previous experience with mech-CPR, which reflects variability across UK hospitals.In this multi-centre feasibility randomised controlled trial, we identified specific challenges that preclude progression to an effectiveness trial of mech-CPR. These challenges were predominantly attributable to the challenge of implementing a new technology safely in the context of a clinical trial. Our findings demonstrate that recruitment to a randomised controlled trial of an intra-arrest intervention is feasible and highlight key issues that will require consideration in designing trials of other interventions.NIHR Post-Doctoral Research Fellowship (PDF 2015-08-109). A funding condition was the use of an unequal randomisation ratio. Otherwise, the funder had no role in the design of the study, data collection, data analysis and interpretation, or the writing of the manuscript. GDP is supported as an NIHR Senior Investigator and by the NIHR Applied Research Centre (ARC) West Midlands, UK. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.This research is funded by an Some equipment support was provided by the manufacturer  of the LUCAS mechanical chest compression device. The company had no role in the design of the study, data collection, data analysis and interpretation, or the writing of the manuscript.GDP is an editor of Resuscitation. The remaining authors have no conflicts of interest to declare.Keith Couper: Conceptualization, Methodology, Investigation, Writing - original draft, Writing - review & editing, Funding acquisition. Tom Quinn: Conceptualization, Methodology, Investigation, Writing - review & editing, Funding acquisition. Katie Booth: Investigation, Formal analysis, Writing - review & editing. Ranjit Lall: Conceptualization, Methodology, Investigation, Formal analysis, Writing - review & editing, Funding acquisition. Anne Devrell: Conceptualization, Methodology, Investigation, Writing - review & editing, Funding acquisition. Barry Orriss: Investigation, Writing - review & editing. Scott Regan: Project administration, Writing - review & editing. Joyce Yeung: Investigation, Writing - review & editing. Gavin D. Perkins: Conceptualization, Methodology, Investigation, Writing - review & editing, Funding acquisition.


Supplemental Digital Content is available in the text. Disabling anxiety affects a quarter of stroke survivors but access to treatment is poor. We developed a telemedicine model for delivering guided self-help cognitive behavioral therapy (CBT) for anxiety after stroke (TASK-CBT). We aimed to evaluate the feasibility of TASK-CBT in a randomized controlled trial workflow that enabled all trial procedures to be carried out remotely. In addition, we explored the feasibility of wrist-worn actigraphy sensor as a way of measuring objective outcomes in this clinical trial.We recruited adult community-based stroke patients (n=27) and randomly allocated them to TASK-CBT (n=14) or relaxation therapy (TASK-Relax), an active comparator (n=13).In our sample , remote self-enrolment, electronic signature, intervention delivery, and automated follow-up were feasible. All participants completed all TASK-CBT sessions (14/14). Lower levels of anxiety were observed in TASK-CBT when compared with TASK-Relax at both weeks 6 and 20. Mean actigraphy sensor wearing-time was 33 days (±15).Our preliminary feasibility data from the current study support a larger definitive clinical trial and the use of wrist-worn actigraphy sensor in anxious stroke survivors.https://www.clinicaltrials.gov. Unique identifier: NCT03439813.URL:  Remotely delivered CBT by internet, email, telephone, mobile text messaging, or video calling (telemedicine) makes it possible to centralize resources for staff, training, quality monitoring, and cross coverage of large geographic areas, reducing cost and improving access. Meta-analyses have demonstrated guided internet-based CBT is superior to waitlist control and as efficacious as face-to-face CBT in treating anxiety disorders or depression in adults without stroke.10 We co-produced a telemedicine guided self-help CBT intervention with patients with anxiety after stroke (TASK-CBT).11 Additionally, we planned to use a wrist-worn actigraphy sensor (noninvasive method of monitoring rest and activity cycles) to obtain longitudinal data, offering potentially novel insights into daily living aspects of stroke survivors in community studies. Anxious stroke survivors showed higher levels of avoidant behavior across a range of situations, for example, going out alone, social situations, physical exertion compared with those who were not anxious.3 Sleep disturbances are clinical features in both anxiety and depression. Actigraphy offers the potential of gathering objectively measured data with minimal participant effort in clinical trials.Extra barriers to accessing face-to-face CBT for patients with stroke include physical immobility, the fear of going out alone, the fear of going to places full of people,In this study, we aimed to demonstrate that it is feasible to (1) recruit and follow up remotely, (2) deliver CBT remotely, and (3) use an actigraphy sensor to collect continuous data in community-dwelling patients with stroke/TIA with anxiety.The data that support the findings of this study are available from the corresponding author on reasonable request as per the journal’s Transparency and Openness Promotion Guidelines.11 and registered (20/2/2018) at ClinicalTrials.gov (NCT03439813). Favorable opinion was obtained from local research ethics committee (South East Scotland 17/SS/0143). All participants provided written informed consent using a web-form.The TASK RCT protocol was publishedThe TASK feasibility trial was a parallel 2-armed RCT comparing TASK-CBT with relaxation control  patients who were anxious (at least one positive response on our 6-item anxiety screening questions)www.task4stroke.org12 and complete informed consent with an electronic signature securely on this website, which uses the HIPAA-compliant Research Electronic Data Caputre (REDCap) application.13 We sent postal invitations to eligible participants identified from the National Health Service Lothian Stroke Audit register and previous observational studies. No financial incentives were offered. In addition, we offered trial information to stroke and TIA patients during their 1-month telephone follow-up.Potential participants could view project information at 14 7-item generalized anxiety disorder,15 modified fear questionnaire,16 patient health questionnaire-2,17 and EuroQol-5D5L.18We verified eligibility with electronic health records. Baseline data were collected remotely including age, sex, stroke/TIA diagnosis, past history of, or medications for anxiety or mood; a telephone verbal fluency test (words beginning with F in one minute), modified Rankin Scale score,The TASK-CBT intervention was delivered remotely via the telephone, a treatment website, email, and mobile text. Participant allocated to TASK-CBT received 6 weekly telephone sessions (35–45 minutes each), delivered by the TASK therapist—a stroke physician (Dr Chun) trained in CBT with supervision from a consultant neuropsychiatrist (Dr Carson) using an electronic TASK therapist’s manual. Each week, the TASK-CBT participant received an online task to practise between sessions and was prescribed one or more of the psycho-educational videos on the TASK-CBT treatment website. Telephone sessions were audio-recorded for further validation of intervention fidelity.Participants allocated to TASK-Relax had one introductory telephone session only. They were instructed to watch an introductory video and do 5 following online relaxation tasks: (1) audio and visually guided breathing exercise, (2) relaxing imagery and sounds, (3) music for relaxation, (4) audio-guided progressive muscle relaxation, and (5) a selection of sounds of nature. Participants selected a favorite task to practise daily for 5 minutes.To promote adherence and completion of follow-up surveys, participants of both arms received weekly mobile text reminders and a participant record card. All participants were aware that they would be offered access to the treatment website given to the other group after completion of their final follow-up survey at 20 weeks. Data collection was carried out at 6 and 20 weeks post-randomization using automated electronic self-completed surveys via emailed links.19 which records 3-dimensional acceleration (actigraphy), light, and wrist-temperature. Participants could wear the sensor on either wrist. After the first 2 months, the duration of the sensor’s rechargeable battery life, and with the participant’s agreement, a second sensor was sent to the participant to wear for the rest of the trial. All sensors were sent and retrieved by post.All participants were invited to wear the GENEactiv sensor,We assessed participants recruited per month, completion of electronic consent forms, time taken for remote eligibility confirmation (date of randomization—date of sign up and consent form received) and completion of electronic follow-up. We assessed adherence to TASK-CBT and intervention fidelity with (1) % completion of each online task, (2) aggregate web usage data from Google Analytics, and (3) review of audio-transcripts. We prespecified lack of feasibility as recruitment number of fewer than 2 participants per month; >50% of TASK-CBT patients dropping out after fewer than 3 telephone sessions; >10% noncompletion of follow-up surveys at 20 weeks, participants reporting unwanted effects from the intervention.Treatment relevant outcomes included the modified Rankin Scale score, 7-item generalized anxiety disorder, modified fear questionnaire, patient health questionnaire-2, EuroQol-5D5L, and a single question about concurrent treatment for mood or anxiety. An online user feedback survey automatically followed the 20-week online follow-up survey. We assessed the feasibility of obtaining useable recording for at least 14 days for each sensor worn.We aimed to recruit 40 participants in this feasibility RCT. We did not perform a statistical sample size calculation.13 and was inaccessible to the TASK researcher enrolling participants. On randomization, baseline data were collected remotely and participants were given their allocated treatment website. Participants allocated to TASK-CBT also received an appointment for their first telephone session.A researcher not involved in conducting the TASK trial generated a computerized permuted block randomization sequence with random block sizes. The sequence was uploaded to the in-built randomization module within the trial’s web-based data management application—REDCapThe unblinded TASK researcher delivered the allocated intervention. We partially blinded participants by informing them they would be allocated to an anxiety treatment website. They were not aware of the contents of the intervention given to the other group.20 for measuring aggregate web usage.We used descriptive statistics to summarise patient characteristics, feasibility, and clinical outcomes. We used Google analytics23 at week 6 and week 20 post-randomization. We computedWe used standard algorithms to mine the actigraphy data and computed activity and sleep characteristicsMaximum average activity over 10 consecutive hours in a 24-hour day and is a measure of diurnal daily activity (M10),Least average activity over 5 consecutive hours in a 24-hour day (L5),Relative amplitude, takes into account M10 and L5: Inter-daily stability: expresses the stability of activity across days,Intradaily variability: complementary to inter-daily stability, characterizing variability across days,Mean diurnal activity during the 24 hours when the participant is not sleeping,Mean nocturnal activity, mean activity during bedtime,Percentile sleep activity, where we compute the 5th, 25th, 50th, 75th, and 95th activity percentile during bed time,Sleep duration.We screened 1481 patients with a diagnosis of stroke or TIA and randomized 27 participants into TASK-CBT (n=14) and TASK-Relax (n=13) at a recruitment rate of 12 participants per month between January 27, 2018 and April 9, 2018  completed an electronic consent form and the remainder by post. Confirming eligibility remotely took 1 day (IQR 3) from receiving consent to randomization. Hundred percent (27/27) completed follow ups at baseline, 6 weeks, and 20 weeks post-randomization.All 14 participants allocated to the TASK-CBT group completed all 6 telephone sessions.In the TASK-CBT group, online TASK completion was good for the first 3 online tasks but decreased over time Table . AverageData Supplement).Median modified Rankin Scale score was one in both groups at 6 and 20 weeks post-randomization. Lower levels of anxiety were observed at 6 and 20 weeks in the TASK-CBT group compared with the TASK-Relax group on the 7-item generalized anxiety disorder and FQ-agoraphobia . Most participants allocated to TASK-CBT found the website easy to use. Participants reported accessing the treatment website at least 2 days a week. Most users reported finding the online videos and written information useful. Most participants reported the TASK-CBT treatment was helpful in overcoming their anxiety. No unwanted effects were reported. One participant felt slightly isolated.Participant feedback on their experience of using TASK-CBT was positive (Supplement II in the Data Supplement). Reasons for declining to wear the sensor included wrist strap being too small, skin irritation, too bulky to wear, and already wearing another activity tracker. Data were not recorded in one sensor.All 27 participants consented to wrist-worn actigraphy sensor for 2 months. 19/27 (74%) agreed to wear a second sensor. Useable recording was available for at least 14 days in 25/27 (93%) participants on the first sensor and 17/19 (89%) on the second sensor. Mean wearing time was 33 days (SD 15) on the first sensor and 35 days (SD 16) on the second  for a randomly selected participant, presented as an actogram, a standard approach for visualizing actigraphy data in circadian biology Figure .In this feasibility RCT of anxious stroke and TIA patients, we demonstrated it is feasible to conduct a clinical trial remotely for the delivery of telemedicine CBT for anxiety after stroke.24 Telephone verbal fluency was included as an easy-to-administer screen of language and fluid-intelligence. Further assessment of expressive and receptive language and written communication should be considered in future studies.Participants were relatively young, with mild disability, and could use the internet. Our sample size was small, and there were expected imbalances between the groups. Participants allocated to TASK-CBT took more antidepressants, were less disabled, and had less previous stroke/TIA than the TASK-Relax group, which could have biased the effect in favor of TASK-CBT. With wider adoption of home broadband by older people, populations who can use this intervention might increase.Screening the local stroke registry manually for eligible participants was time-consuming, thus limiting the number of patients contacted and generalizability of the study findings. Automation of the screening process and generation of study invitations could potentially overcome this challenge. Prospective recruitment was feasible but initial contact was opportunistic and made at the discretion of the stroke clinician during first presentation at clinic. A well-publicised online platform for use by stroke survivors to self-screen and self-recruit to research studies may help widen access to research studies. Lack of telephone sessions in TASK-Relax could have reduced adherence, which could be improved in a future trial with more telephone contact with these participants. Reviewing audio-recorded transcripts was not feasible given the time and funding constraints in this study. Google Analytics provided only aggregate but not individual web usage data so would not be a suitable tool as a measure of intervention fidelity. The automated data capture of online task completion by each participant offered a simple and feasible measure of intervention fidelity. We had a small sample size (14 in TASK-CBT and 13 in TASK-Relax) in this feasibility study with insufficient statistical power to draw conclusions on our clinical outcomes.Our remote trial design could be applied to other remote-delivered interventions, for example, guided or unguided self-management. A remote trial design offers the potential to centralize trial staff and processes even in a large RCT. Screening with the local stroke registry was time-consuming, though verifying eligibility with electronic health records was feasible in one site and may be performed with national registers. Sending electronic proof of identity and eligibility to the research centre, for example, digital photograph, electronic clinic letter via a secure email, or form submission system are potential future options for national recruitment.25 Phobic anxiety, rather than generalized anxiety is the predominant subtype poststroke.3 Online relaxation therapy is popular, free, and widely used, making it a suitable comparator in a pragmatic RCT. RCTs of psychological therapy typically use treatment as usual as control condition which is known to exaggerate treatment effect.26TASK-CBT is designed as a low-intensity guided self-help CBT intervention delivered by appropriately trained and supervised stroke nurses or rehabilitation therapists. A telemedicine model could overcome the barriers in accessing psychological therapy by treating stroke patients remotely. We used relaxation as an active comparator, a therapy that may have benefit for generalized anxiety but has consistently been shown to be inferior to CBT-based intervention for panic, phobic, posttraumatic stress disorders in RCTs.This study demonstrated the feasibility of using wrist-worn sensors in a stroke and TIA cohort and longitudinal use of the device to objectively assess therapy effects. A wrist-worn sensor is a convenient way to measure actigraphy data from which we can infer potentially clinically useful characteristics regarding a person’s activity and sleep patterns. These data could be clinically relevant in assessing anxiety after stroke. Passive collection of objective outcome measures throughout an entire RCT requires minimal participant effort, which in turn could minimize bias by reducing attrition, reliability, and inter-rater variability problems related to patient-reported outcome measures or observer-rated measures.28; these findings tentatively support the argument that sleep characteristics might need to be further explored in association with CBT effects and anxiety management. This exploratory analysis paves the way for considering the use of wrist-worn actigraphy sensors in similar longitudinal studies both to assess inherent subject variability, potentially seasonality effects, therapeutic effects, and group cohort comparisons. Future work may investigate the association between objectively extracted information from actigraphy signals and patient-reported outcome measures or clinical assessments. Our small sample size limits further analyses of the actigraphy data.We provided indicative plots for how data might be presented to visually assess patterns and have also extracted a number of known actigraphy measures to characterize long-term activity and sleep variability. We have also illustrated how the computed characteristics can be used to compare groups (TASK-CBT versus TASK-Relax in this study). We found that there is no obvious difference in terms of the extracted activity patterns during the daily activities, but there seems to be some noticeably different patterns in terms of the sleep characteristics computed using mean nocturnal activity and median sleep activity. We postulate the sleep patterns presented in Figure Telemedicine-delivered CBT is a feasible model to treat anxiety after stroke/TIA. A remote clinical trial workflow was feasible and will enable a definitive study. Wrist-worn actigraphy sensors could help collect objective outcomes in future stroke trials.We thank Surgical Informatics team at the Centre for Medical informatics, Usher Institute, University of Edinburgh, for their assistance with REDCap. All authors conceived the idea and contributed to the design of the current study. Dr Chun designed all study websites and the web-enabled trial procedures. She wrote all drafts and the final version of the manuscript with input from Drs Carson, Dennis, Tsanas, Mead, and Whiteley. Dr Calabria analyzed and wrote up the patient feedback data. Dr Tsanas developed the algorithms and conducted the analysis for the GENEActiv data. The study sponsor and funders had no role in the design or the reporting of the results of this study.Chief Scientist Office of Scotland Clinical Academic Fellowship (CAF/15/07) provided funding for the study and Dr Chun, a stroke physician . Lindsay Bequest and Reid Trust Grant funded some of the actigraphy sensors in this study (2017). Stroke Association’s Princess Margaret Research Development Fellowship supported HYC’s research training (2014–2015). Dr Whiteley is supported by the Chief Scientist Office of Scotland Senior Clinical Fellowship (CAF/17/01). The study was supported by Health Data Research UK, which receives funding from Health Data Research UK Ltd (HDR-5012) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), the British Heart Foundation, and the Wellcome Trust.www.neurosymptoms.org and www.headinjurysymptoms.org. He is a holder of a Health Technology Assessment grant in the United Kingdom to develop an app to deliver cognitive behavioral therapy after mild traumatic brain injury. This grant is shared with commercial partners. He has given independent testimony in Court on neuropsychiatric topics including anxiety after stroke. He has published and has been involved in a range of studies on the use of cognitive behavioral therapy for neurological diseases. He has received no personal payments from this but his research group benefits from high profile publications. Dr Mead reports royalties from Later Life Training and Elsevier outside the submitted work. She receives grants from the Stroke Association, Chief Scientist Office of Scotland, National Institute of Health Research, Chest Heart & Stroke Scotland outside the submitted work. She is a paid editor of Cochrane Stroke Group. Dr Whiteley reports grants from Chief Scientist Office of Scotland, Alzheimer’s Society and Stroke Association outside the submitted work.Dr Carson is a paid associate editor of Journal of Neurology, Neurosurgery, and Psychiatry and is involved in 2 not-for-profit websites: