Participants were randomized into an exergame group (EG) or a supervised exercise group (SG). Both groups received similar exercise tasks for 4 weeks, with three 30 min sessions per week, during hemodialysis treatment. Depression symptoms were assessed at baseline and the fourth week using the Center for Epidemiologic Studies Depression Scale. Both groups showed a significant reduction in depression score  with no between-group difference for the observed effect (p > 0.050). The EG expressed a positive intradialytic exercise experience including fun, safety, and helpfulness of sensor feedback. Together, results suggested that the virtually supervised low-intensity intradialytic exergame is feasible during routine hemodialysis treatment. It also appears to be as effective as nurse-supervised intradialytic exercise to reduce depression symptoms, while reducing the burden of administrating exercise on dialysis clinics.Regular exercise can reduce depression. However, the uptake of exercise is limited in patients with end-stage renal disease undergoing hemodialysis. To address the gap, we designed a gamified non-weight-bearing intradialytic exercise program (exergame). The intradialytic exergame is virtually supervised based on its interactive feedback via wearable sensors attached on lower extremities. We examined the effectiveness of this program to reduce depression symptoms compared to nurse-supervised intradialytic exercise in 73 hemodialysis patients (age = 64.5 ± 8.7years, BMI = 31.6 ± 7.6kg/m An estimated 2.62 million people worldwide rely on hemodialysis treatment to sustain their lives . DepressAlthough pharmacological treatments, such as antidepressants, are considered effective in treating depression in the general population , its theHowever, due to the poor physical condition and medical complexity of the hemodialysis population, the approach and intensity of exercise should be carefully designed . ConventHemodialysis patients are required to visit dialysis clinics three times per week and spend 4 h each time sitting or lying on a bed to receive the hemodialysis treatment. This facilitates a perfect opportunity to provide low-intensity non-weight-bearing intradialytic exercise for this patient population. Several studies have demonstrated the feasibility and effectiveness of non-weight-bearing intradialytic exercise programs to reduce depression symptoms ,19,20. IRecent advances in wearable technology have opened new opportunities to design virtually supervised exercise which can be applied anytime and anywhere ,25,26. TThis study is a secondary analysis of a clinical trial focused on examining the benefit of intradialytic exercise in adult hemodialysis patients . The clinical trial was offered to all eligible hemodialysis patients who visited the Fahad Bin Jassim Kidney Center  for hemodialysis treatment. To be eligible, the participant should be 50 years or older, be diagnosed with diabetes and end-stage renal disease that requires hemodialysis and have the capacity to consent. Participants were excluded if they had severe uncorrected visual impairment (based on the judgement of the investigator) or severe cognitive impairment , which could limit the ability to interact with the intradialytic exergame interface; had major amputation; were non-ambulatory or had severe gait or balance problems ; had active foot ulcers or active infection; had a major foot deformity ; had changes in psychotropic or sleep medications in the past 6 weeks; had taken any antidepressant agents in the past 6 weeks; were in any active intervention ; had any clinically significant medical or psychiatric conditions; or were unwilling to participate. All participants signed a written consent form approved by the Institutional Review Board at the Hamad Medical Corporation in Doha, Qatar. All participants were randomly assigned into either an exergame group (EG) or a supervised exercise Group (SG). The randomization was done using a computer-generated list (Matlab code) with the ratio of EG vs. SG being 1:1. For the final data analysis, we only included those who had both valid baseline and fourth week depression data. Participants’ demographics and health information including age, sex, height, weight, body-mass-index (BMI), duration of hemodialysis, fall history, and number of prescription medicines were collected. All participants underwent clinical assessments, including a mini-mental state examination (MMSE) , short fDepression symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) Scale . As suggTM, BioSensics, MA, USA) were used to estimate three-dimensional joint angles needed for providing real-time feedback during the intradialytic exercise. Sensors were attached on the top of each foot of the participants in the EG using elastic straps , which were 30 min long, including breaks. Validated inertial sensors  and one target (solid circle) presented on the screen each time B. After The foot rotation and working memory exercise  was a motor–cognitive exercise that requires accurate coordination of foot motion while performing a cognitive task. For this exercise, a total of six circles appeared on the screen: one home circle in white and five target circles in yellow C. The taParticipants randomized into the SG were also receiving hemodialysis for three sessions per week. During each hemodialysis session, a nursing staff instructed the participant in the SG to participate in a 30 min non-weight-bearing foot rotation intradialytic exercise program (including breaks) without any technology. The nurse-supervised intradialytic exercise program contained exercise tasks and intensity similar as the intradialytic exergame. However, it did not provide any game-feature or visual-audio feedback. Instead of the interactive interface, the nursing staff guided the participant throughout the intradialytic exercise program. The nurse-supervised intradialytic exercise program also lasted 4 weeks .We evaluated the user experience of the intradialytic exergame program using a revised technology acceptance model (TAM) suggested by Schwenk et al.  with somd effect size [p < 0.050 was considered to be statistically significant. All statistical analyses were performed using IBM SPSS Statistics 25 .All continuous data were presented as mean ± standard deviation. All categorical data were expressed as counts (percentages). A Shapiro–Wilk test was applied for testing the normality of the data. Between-group differences for continuous demographics and clinical data were compared using an independent t test. Between-group differences for categorical demographics and clinical data were compared using a Chi-square test. The effect of intradialytic exercise on depression symptoms was evaluated using repeated measures comparing the groups’ CES-D scores between pre-  and post-exercise . The effect size to discriminate between pre- and post-exercise was estimated for each group using Cohen’s ect size . The corect size ,41. A twp > 0.050).Eighty-one participants satisfied the inclusion and exclusion criteria of this study. However, the CES-D data was available and valid for only 73 participants at both baseline and 4 weeks. The analysis of demographics and clinical data for the remaining participants was summarized in All participants in the EG and SG completed all exercise sessions of the four-week program. No adverse events related to the intradialytic exergame or foot rotation exercise were reported. n = 11 for pre-exercise; n = 7 for post-exercise), and the number of participants at risk for clinical depression in the SG reduced by approximately 43% . p < 0.001, d = 0.69), and from 16.8 ± 11.0 to 9.9 ± 10.5 in the SG . There was no significant difference in reduction of CES-D score between the EG and SG (p = 0.246).At the baseline of the intradialytic exercise program, 27 participants (37%) were identified at risk for clinical depression (CES-D≥16) in the two groups. At the end of the intradialytic exercise program, the number of participants at risk for clinical depression in the EG reduced by approximately 36% .To our knowledge, this is the first study that used wearable technology to provide a game-based non-weight-bearing intradialytic exercise program for hemodialysis patients. We were able to confirm our hypothesis that the proposed intradialytic exercise program is feasible and practical to be performed during routine hemodialysis treatment inside a regular dialysis clinic. It is acceptable among patients undergoing hemodialysis. In addition, this is the first study that objectively evaluated the effect of the low-intensity non-weight-bearing intradialytic exergame to reduce depression symptoms in hemodialysis patients. We have showed that virtually supervised intradialytic exercise therapy appears to be as effective as nurse-supervised intradialytic exercise therapy to reduce depression symptoms. No requirement for continuous attention of a physical therapist or a trained nursing staff for the intradialytic exergame program is however considered as an advance compared to nurse-supervised intradialytic exercise intervention. This may improve the uptake of routine intradialytic exercise intervention for hemodialysis patients, without adding significant burden to the already overburdened nursing staffs in dialysis clinics.Comparing to the conventional exercise strategies, the advantage of the low-intensity non-weight-bearing intradialytic exercise program is that it can be performed while patients receiving routine hemodialysis treatments in regular dialysis clinics. In order to participate in the conventional physical exercise, hemodialysis patients usually need to visit out-clinic facilities on a non-dialysis day , which gp < 0.001) [Previous studies have demonstrated effects of non-weight-bearing intradialytic exercise, such as ankle rotation, toe flexion & extension, joint warming action, stretching exercise, etc., to reduce depression symptoms. Razaei et al. provided a 35 min non-weight-bearing intradialytic exercise program three times per week for 10 weeks to 25 hemodialysis patients. At the end of the program, the depression score significantly decreased by 53% (< 0.001) . Santhi < 0.001) . Non-sig< 0.001) . In our In this study, the SG also received 4 weeks  of non-weight-bearing foot rotation intradialytic exercise without any technology, game-feature, or visual-audio feedback, but under a supervision by nursing staffs. Comparing to the nurse-supervised intradialytic exercise, wearable and interactive interface technologies enable real-time visual and audio feedbacks in the intradialytic exergame. Hemodialysis patients can visually perceive their performances and errors during the exercise. In the intradialytic exergame, hemodialysis patients need to rotate ankle joint to certain range and achieve certain speed to complete the exercise task. This can standardize the exercise intensity and push the boundary of hemodialysis patients. The intradialytic exergame also includes game-features such as rewarding elements and animations, which could be more attractive than the non-technological foot rotation exercise. Therefore, it has the potential to increase exercise adherence and be more efficient to reduce depression symptoms . FurtherA major limitation of this study is the relatively low sample size, which could be underpowered for the clinical conclusion. This study is a secondary analysis of a clinical trial focused on examining the benefit of intradialytic exergame in gait and balance among hemodialysis patients. We only performed CES-D for depression assessment in the clinical trial. The CES-D is a screening test for depression symptoms but not a sufficient tool to diagnose depression. A future study using comprehensive psychological assessments for evaluating depression is needed. Due to the same reason, we did not have a non-exercise control group in this study. However, the effectiveness of low-intensity non-weight-bearing intradialytic exercise to reduce depression symptoms has been demonstrated in previous studies ,19,20. IThis study demonstrated the feasibility and acceptability of the sensor-based non-weight-bearing intradialytic exergame program to be performed during routine hemodialysis treatment in a regular dialysis clinic. The sensor-based intradialytic exergame program enables delivering a personalized and virtually supervised intradialytic exercise intervention. It also appears to have similar effect as nurse-supervised intradialytic exercise therapy to reduce depression symptoms in hemodialysis patients, especially in those with severe depression symptoms. Its key advantage compared to nurse-supervised intradialytic exercise is that there is no requirement for the continuous attention of a physical therapist or trained nursing staff. It can reduce the burden of implementing exercise intervention during routine hemodialysis treatment.


Background: To investigate quantitative ultrasound (QUS) based higher-order texture derivatives in predicting the response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC).1), which were further processed to create texture derivatives (80 QUS-Tex1-Tex2). Patients were classified into responders and non-responders based on clinical/pathological responses to treatment. Three machine learning algorithms based on linear discriminant (FLD), k-nearest-neighbors (KNN), and support vector machine (SVM) were used for developing radiomic models of response prediction.Materials and Methods: 100 Patients with LABC were scanned before starting NAC. Five QUS parametric image-types were generated from radio-frequency data over the tumor volume. From each QUS parametric-image, 4 grey level co-occurrence matrix-based texture images were derived  calculated for KNN predicted responders and non-responders using QUS-Tex1-Tex2 model were comparable to RFS for the actual response groups.Results: A KNN-model provided the best results with sensitivity, specificity, accuracy, and area under curve (AUC) of 87%, 81%, 82%, and 0.86, respectively. The most helpful features in separating the two response groups were QUS-TexConclusions: We report the first study demonstrating QUS texture-derivative methods in predicting NAC responses in LABC, which leads to better results compared to using texture features alone. Breast cancer is the second most common cancer globally in terms of incidence, comprising 11.6% of all new cancers and is the 5th leading cause of mortality attributed to 6.6% of all cancer deaths –4. The r1) features like contrast (CON), energy (ENE), correlation (COR), and homogeneity (HOM). Earlier studies have evaluated baseline QUS parameters and texture analysis extracted from the tumor to predict the response to systemic therapies [Radiomics is an emerging field in medicine and oncology, which has been made possible through advanced computer-based image analysis, often combined with machine learning algorithms for data interpretation –9. Radioherapies , 15.1-Tex2) have been determined from pretreatment QUS data for patients with LABC undergoing NAC to predict treatment response. To the best of our knowledge, this is the first study to demonstrate the effectiveness of texture derivatives applied to any form of imaging data, leading to the improvement of classifier performances.In the study here, higher-order imaging features in the form of QUS texture-derivatives .Patient and treatment-related features are summarized in 1 features using Fisher’s linear discriminant (FLD), k-nearest neighbors (KNN), and radial-basis-function support vector machine (SVM) classifiers were 62%, 69%, and 69%, respectively. Selecting from 105 features inclusive of the texture derivatives, accuracy improved to 67%, 82%, and 69% for FLD, KNN, and SVM, respectively. Amongst all the models, KNN classification resulted in the best performances. The sensitivity, specificity, accuracy, and area under curve (AUC) for the best classifier was 87%, 81%, 82%, and 0.86, respectively. The comparison of the performance using QUS+QUS-Tex1 and QUS-Tex1-Tex2 is shown in Representative ultrasound B-mode images, MBF parametric images and MBF-CON, MBF-ENE, MBF-COR, and MBF-HOM texture images corresponding to three responding and three non-responding patients are displayed in The best-selected features for model development are summarized in 3, T4) or advanced nodal involvement  or both [Locally advanced breast cancer encompasses stage III breast cancer, denoting a higher disease burden, either with an extensive primary disease  analyzing clinic-pathological factors, found that the presence of microcalcifications on baseline imaging was associated with predicting residual disease as opposed to patients with pCR . Radioge1) and, finally, 80 higher-order texture derivatives (QUS-Tex1-Tex2). Each spectral parameter reflects different aspects of underlying cellular biology; MBF, ASD, and AAC can be related to microstructure and cellular organization, scatterer size, and scatterer number density.The clinical application of QUS spectral and texture analysis to identify a subset of patients likely to respond to NAC as early as four weeks  or even before the initiation of treatment (baseline imaging) , 32, 33.In our previous work involving comparative analysis of QUS parameters from pretreatment and intra-treatment scans, the most evident changes were noticed in mean values of MBF and SI, suggesting microenvironment changes in response to NAC . Here, tAs expected, clinical outcomes were distinctly different between the responders and non-responders as defined by the clinical-pathological criteria and demonstrated in survival plots. This reflects the strong influence of response to neoadjuvant treatment on tumor biological behavior and outcomes depicted by a relapse of breast cancer. It is essential to note although the sensitivity of the three models was comparable , the speThe early identification of patients not responding to NAC does have potentially significant clinical implications. Alternative chemotherapy regimens or upfront surgery should be considered in patients who are refractory to the standard protocols rather than continuing with the ineffective regimens. In a phase 2 randomized study involving HER2+ breast cancer, PET was used for response assessment before the 1st and 2nd cycles of neoadjuvant therapy with docetaxel and trastuzumab. Predicted non-responders were randomly assigned to 4 cycles of the same treatment or the addition of bevacizumab. The addition of bevacizumab for predicted non-responders resulted in better pathological complete response rates . Other shttp://ClinicalTrials.gov identifier NCT04050228). In that work, the goals are the identification of biological non-responders as soon as the first cycle of chemotherapy to modify the protocol early and avoid unnecessary treatments; the identification of pathological complete responders to possibly avoid surgical procedures.Based on the results from previous observational studies, the clinical utility of QUS-radiomics is being evaluated in a randomized clinical trial, where patients predicted to have inadequate response can have modifications made to their NAC  of QUS in predicting treatment response to NAC involving 100 patients with LABC. The work provides a framework for using QUS-radiomics in clinical practice to choose appropriate chemotherapy regimens or other treatment modalities like upfront surgery (in predicted chemo-resistant tumors), leading the way towards personalized oncology.http://ClinicalTrials.gov (NCT00437879). Patients accrued between January 2009 and January 2017 were included in the current analysis. Written informed consent was obtained from patients before accrual to study. Patients with LABC receiving NAC were considered eligible for the study. All patients were required to have a histological diagnosis of primary breast malignancy before initiation of any treatment with documentation of pathological and molecular information like hormonal receptor or HER 2 status. The choice regarding the NAC regimen and timing was at the discretion of the treating medical oncologist, with almost all patients receiving anthracycline and taxane-based chemotherapy regimens. Also, patients receiving HER 2 targeted therapies in addition to neoadjuvant chemotherapy were allowed in the study.All the patients included in this report were obtained from a prospective study approved by the Sunnybrook Health Sciences Centre research ethics board and registered with in-situ < 1%), with all other patients being considered as non-responders (NR).Following surgery, surgical specimens were evaluated by a board-certified pathologist for the assessment of histological characteristics and tumor response. Patients were classified into responders and non-responders based on the combined clinical and pathological evaluation. This modified response grading system was based on combined radiological and pathological assessment, and had been described in our previous studies , 15, 37.As a part of this study, ultrasound RF data was acquired using a Sonix RP clinical research system  with a linear array transducer  having a central frequency of 7 MHz (bandwidth 4–9 MHz). Imaging was conducted before the initiation of NAC. The sampling frequency of 40 MHz was considered for digital acquisition of ultrasound data with a 16-bit resolution. The tumor was scanned at intervals of 1 cm across the breast to cover the entire range of the primary tumor, with the transducer focused towards the center of the tumor. For the determination of QUS features, the region of interest (ROI) was manually drawn corresponding to the edge of the tumor in all image planes. A recent publication had shown the effects associated with different clinical ultrasound systems, or other factors related to image acquisition can be overcome with appropriate normalization techniques . All theQuantitative ultrasound parametric maps, including MBF, SS, SI, ASD, and AAC, were determined using quantitative ultrasound techniques described in previous studies . A refer1 features from the QUS parametric maps. Corresponding color-coded QUS-texture feature maps for each QUS parametric map were constructed by making a spatial map of the texture values computed over all the sub-ROI. Subsequently, a second-pass texture analysis using the QUS parametric maps as input was applied to create QUS-Tex1-Tex2 features (texture-of-texture features)  were determined from ultrasound data for each tumor.For individual QUS features, mean values were determined by averaging QUS values obtained from all the sub-volumes. Four texture features, including CON, ENE, COR, and HOM, were evaluated using a GLCM method to generate QUS-Texeatures) . A total1, QUS-Tex1-Tex2) between the two response groups were compared. A Shapiro-Wilk normality test was undertaken on feature-based data to determine its distribution. An unpaired t-test was completed for normally distributed data; otherwise, a Mann-Whitney test was used. The distribution of categorical variables between the two response groups was studied using the Pearson chi-square test and Fisher’s exact test as indicated. The continuous variables  were compared using an unpaired t-test or the Mann-Whitney test as appropriate. A value of p < 0.05 was considered to be statistically significant. In this study, three multi-feature machine learning classifiers were used to classify patients into the two response groups. These included FLD, KNN, and SVM analyses. Classification analyses were performed using two data sets independently; (i) QUS means, and QUS-Tex1; or (ii) QUS means, QUS-Tex1 and QUS-Tex1-Tex2. Receiver operating characteristics (ROC) were determined for each classifier-based algorithm (responders versus non-responders) to obtain the AUC, and other indices like sensitivity, specificity, and accuracy were also calculated. Tumor segmentation, QUS data extraction, and classification analyses were performed using MATLAB R2016B . Before performing class analyses, the class imbalance problem was circumvented by subsampling the original data into seven subsets, such that each unit had an equal number of responders and non-responder selected randomly. The feature selection was performed based on a sequential-forward selection method. Analyses permitted a maximum of 3 features in the classification model to avoid overfitting of the model given the number of samples in the cohorts used. Leave one out cross-validation was adopted to test the reliability of the classifiers. Survival analysis was done using a Kaplan Meier product-limit method with the factors compared using a log-rank test.The mean values for all features (QUS, QUS-TexIn summary, the work here reports ultrasound radiomics can detect tumor response before neoadjuvant chemotherapy with high accuracy using texture derivative analysis of parametric images using a machine learning approach. The use of quantitative ultrasound-texture derivative biomarkers can serve as pretreatment survival-linked surrogates of response to cancer-targeting therapies leading the way towards personalized medicine and facilitate in selecting appropriate treatment regimen on an individual patient basis.


Despite the advances in screening protocols and treatment options, hepatocellular carcinoma (HCC) is still considered to be the most lethal malignancy in patients with liver cirrhosis. Moreover, the survival outcomes after failure of first-line therapy for unresectable HCC is still poor with limited therapeutic options. One of these options is immune checkpoint inhibitors. The aim of this study is to comprehensively review the efficacy and safety of immune checkpoint inhibitors for patients with HCC. Hepatocellular carcinoma (HCC) is still the most common and most lethal malignancy in patients with liver cirrhosis, despite the advances in screening programs, chemoprophylaxis for high-risk patients and treatment options ,2. With Despite the recent advances in systemic therapy for unresectable HCC, patients who progress on first-line multikinase inhibitors, namely sorafenib  ,7,8 and The tumor microenvironment of the HCC is infiltrated with different types of immune cells, mainly T-cells , natural killer cells and myeloid cells (myeloid-derived suppressor cells and tumor-associated macrophages). Due to the chronic inflammation and cirrhosis present in most HCC patients, the tumor ecosystem gets complicated affecting the behavior of the tumor and response to treatment. These changes are due to complex interactions between immune cells and tumor cells in the tumor microenvironment conveyed through cytokines and signaling pathways leading to exhaustion of pro-inflammatory immune cells and the dominance of the regulatory leukocytes hindering the anti-tumor response. A study by Yu et al.  concludeAvoiding immune destruction is one of the hallmarks of cancer. The PD-1/PD-L1 pathway plays a pivotal role in this escape mechanism . StudiesOne of the well-known mechanisms of resistance to anti-PD-1 therapy is FcɤR1 mediated macrophage antibody-dependent phagocytosis  Figure . TherefoCTLA-4 is expressed on T regulatory cells regulating the early immune response after the primary stimulation by antigens mainly in lymphoid organs whereas PD-1 is expressed mainly on activated T cells in the tumor microenvironment regulating late immune response. Moreover, inhibition of the CTLA-4/B7 signal in lymph nodes increases activated CD8+ cells which will subsequently infiltrate the tumor and be part of the microenvironment ,33. BaseVascular endothelial growth factor (VEGF) has been linked with the development and progression of HCC ,39. MoreThe landmark IMbrave 150 trial comparing atezolizumab  plus bevacizumab  versus sorafenib found a better objective response rate and survival for patients treated with the combination therapy . MoreoveSangro et al. recruited 21 patients with hepatitis C virus who had progressed on previous lines of treatment for HCC. The treatment was tremelimumab at a dose of 15 mg/kg IV every 90 days. The drug showed a safe profile with a partial response rate of 17.6% . InteresThe progression-free survival, overall survival and response rates were found to be better for patients treated with anti-PD-1/PD-L1 compared to placebo . HoweverInitial results of a single-arm study examining a combination between durvalumab and tremelimumab in patients with or without hepatitis infection. Out of 40 patients treated, 6 (15%) had an objective response rate with an acceptable safety profile  Table 2Table 2.Two studies evaluated the combination of biologic therapy with immunotherapy. The first evaluated ramucirumab plus duravalumab revealing an objective response rate of 11% and progression-free survival of 4.4 months . The othImmunohistochemical detection of PD-L1 has been studied in clinical trials as a predictor of response. It has been found that the expression of PD-L1 is associated with better overall response and survival outcomes ,23. A hiOne of the main concerns while treating patients with immune checkpoint inhibitors is immune-related adverse events which can be irreversible and even fatal ,57,58. TSeveral retrospective studies and case reports evaluated the safety profile of immune checkpoint inhibitors for patients with cancer and concomitant autoimmune disease ,66,67,68In summary, the immune-related side effects seem to be higher in patients with pre-existing autoimmune disease. Active disease and female gender are independent risk factors for immune-related side effects. Although immune-related side effects in patients treated with immune checkpoint inhibitors with a pre-existing autoimmune disease can be fatal, most cases are managed successfully without permanent discontinuation of the immune checkpoints. Nevertheless, these observations are derived from case reports and small retrospective studies and a well-designed large scale trial still represents an unmet need. Moreover, data about patients with HCC carcinoma specifically and hepatobiliary autoimmune diseases is still sparse.Patients suffering from inflammatory bowel disease (IBD) usually suffer from other hepatobiliary diseases such as drug-induced liver injury (about 30% of patients with IBD), primary sclerosing cholangitis (1.4% to 7.5% of patients with IBD), autoimmune hepatitis, primary biliary cirrhosis and nonalcoholic steatohepatitis . These fThe combination of biologic therapy, especially bevacizumab, with immune checkpoint inhibitors in patients with IBD is of particular importance. Indeed, in patients not suffering from IBD, the intestinal perforation rate after using bevacizumab is about (1.5 to 2.5%) and severe bleeding is about 3% ,81. ImpoOverall, the use of atezolizumab with bevacizumab in patients with IBD carries a risk for intestinal perforation, gastrointestinal bleeding and the safety profile is still lacking in the literature.With the recent advances in the immunotherapeutic mechanisms, novel immunotherapies have gained popularity. Different therapeutic targets have been evaluated such as lymphocyte activation gene 3 (LAG-3). LAG-3 is first described by Triebel et al. and thereafter it was found to be overexpressed on the activated T cytotoxic and T regulatory cells with a negative impact on T helper cells. Therefore, during tumorigenesis, cancer cells use this pathway to escape from the immune system. Therefore, immunoglobin against LAG-3 has been investigated in different clinical trials . SeveralOne other therapeutic target is the killer immunoglobulin-like receptor (KIR) which has an inhibitory effect on the NK cells. Therefore, Lirilumab, a KIR antibody, is under investigation in combination with immune checkpoint inhibitors in clinical trials .Overall, the novel immunotherapies’ investigation in HCC is still restricted to being a part of evaluation of their role in solid tumors in general. Therefore, a better understanding of these pathways and their contribution to the HCC microenvironment is needed.Hepatocellular carcinoma treatment represents a real challenge in patients with cirrhosis and several pharmacological ,73,74,75


Timely allocation of medical resources for coronavirus disease (COVID-19) requires early detection of regional outbreaks. Internet browsing data may predict case outbreaks in local populations that are yet to be confirmed.We investigated whether search-engine query patterns can help to predict COVID-19 case rates at the state and metropolitan area levels in the United States.We used regional confirmed case data from the New York Times and Google Trends results from 50 states and 166 county-based designated market areas (DMA). We identified search terms whose activity precedes and correlates with confirmed case rates at the national level. We used univariate regression to construct a composite explanatory variable based on best-fitting search queries offset by temporal lags. We measured the raw and z-transformed Pearson correlation and root-mean-square error (RMSE) of the explanatory variable with out-of-sample case rate data at the state and DMA levels.r=0.69, 95% CI 0.51-0.81; median RMSE 1.27, IQR 1.48) and DMA levels , using search data available up to 10 days prior to confirmed case rates. They fit case-rate activity in 49 of 50 states and in 103 of 166 DMA at a significance level of .05.Predictions were highly correlated with confirmed case rates at the state (mean Identifiable patterns in search query activity may help to predict emerging regional outbreaks of COVID-19, although they remain vulnerable to stochastic changes in search intensity. Early detection of regional coronavirus disease COVID-19) outbreaks is essential for efficient medical resource allocation, public health messaging, and implementation of infection prevention and control strategies 9 outbrea,3. HowevInternet browsing data, such as search-engine query results, can provide a real-time indication of symptoms in a population and have been used extensively to predict and model outbreaks like influenza and dengue -7. Such COVID-19 case rates display significant regional heterogeneity that requires locally tailored containment strategies. Google search trends, encompassing a majority of internet queries in the United States and publicly available through Google Trends (GT), provide a powerful resource for systematic comparison of browsing behavior between US regions. We hypothesized that keyword libraries could be screened for specific terms whose aggregate activity would reflect regional differences in COVID-19 case rates, as has been demonstrated for influenza . While sWe obtained confirmed case data for US states and counties from the New York Times (NYT) data set from January 21, the date of the first confirmed US case, to April 2, 2020, comprising county-specific, lab-confirmed COVID-19 case reports compiled daily from local and state health authorities . We usedWe compared the z-transformed correlation of each query’s search activity with an in-sample data set comprising daily confirmed national cases rates for days through March 10 with >100 new cases per day. Each query’s search activity was offset by temporal lags of between 0 and 14 days, generating a list of best-fitting queries and their associated optimal lag times. To focus on terms with early predictive power, we excluded queries whose optimal lag was less than 9 days. We selected the five best-fitting queries and constructed a single explanatory variable by summing the lag-adjusted, relative activity levels of each query. Finally, we linearly fit the explanatory variable to national data through March 10 to generate a single scalar coefficient.We measured the correlation of state-specific activity levels for our explanatory variable with daily reported case levels in individual states using out-of-sample data from March 11 through April 2. We also measured how well the explanatory variable explained out-of-sample case rates in 166 designated market areas (DMA), which are collections of approximately 15 counties each constituting the highest-resolution regional data available on GT. Means and confidence intervals for correlation coefficients were calculated using the inverse z-transformation of the averaged z-transformed coefficients. The strength of model predictions over time was measured using a partial correlation of first confirmed case dates with z-transformed correlation coefficients in all regions with >100 cases, controlling for regional population. We used root-mean-square error (RMSE) as an additional measure of model performance. Model predictions were adjusted for regional population and internet access . All datQueries incorporated into the final explanatory variable were highly correlated with national case data, with correlation coefficients ranging from 0.996 to 0.999 on the in-sample data. The optimal temporal lags for incorporated queries were from 11 to 12 days, indicating a prediction horizon of up to 10 days (assuming that a day’s full GT query results become available on the subsequent day). The final variable, the linear sum of weighted, lag-adjusted activity levels for the five best-fitting terms from the 463-term library, fit the in-sample data with a correlation of 0.998.Characteristics of additional screened queries validated our methodology. For instance, acute topics like medical care and testing had smaller associated lag times with confirmed case rates, as would be expected for urgent inquiries . QueriesP<.001) for out-of-sample data and 0.83 (P<.001) for all available data. The predictions were also well correlated at the state level in nearly all cases, fitting case data in 49 of 50 states at a significance level of α=.05 and 41 of 50 states at α=.005 , suggesting that predictive search behaviors may precede new cases regardless of the timing of a regional outbreak  of regions at α=.05, or 79% (84/107) excluding DMA with fewer than 100 cases (mean outbreak C and D. outbreak , even inThese data suggest that specific patterns of internet search behavior, which can be curated automatically from libraries of search terms, precede and correlate with regional case rates of COVID-19. Such patterns, which we captured using a single explanatory variable, remain correlated with case rates in regions with a broad range of populations, locations, and outbreak times, making aggregate search trends a useful tool for estimating regional COVID-19 outbreaks in the days preceding confirmed case reports. Correlation strengths were not significantly associated with the date of onset of regional outbreaks, making it unlikely that a single national event, such as a press release, could explain the strength of model predictions in all regions. Furthermore, search queries explicitly related to COVID-19 have more predictive power than unrelated keywords, and acute queries, such as those concerning testing or medical care, have smaller associated lag times.Taken together, these results suggest that systematic screening of key term libraries can identify search queries reflecting real-time health-seeking behaviors at the regional level, expanding the suite of “infoveillance” methods that may assist in monitoring COVID-19 cases. This type of approach does not directly depend on either regional testing capacity or local media reports, making it particularly relevant in areas with small populations, limited medical infrastructure, or low case numbers. Such information can supplement traditional epidemiological approaches, such as estimates based on a compartmental framework, to guide community health interventions in the early days of an outbreak.Several aspects of query-based approaches to case estimation, such as this work, must be further characterized for COVID-19. First, while correlations were statistically strong across most US regions, elevated RMSE indicated lower accuracy for predictions in the New York City and New Orleans areas, both regions with major outbreaks. However, comparable losses in accuracy were not observed for other major outbreak sites, such as Philadelphia, Los Angeles, or Chicago. This may reflect region-specific differences in both internet browsing behavior and patterns of community infection and may be a limitation of query-based models using fixed terms. As evidenced by previous attempts to predict influenza outbreaks based on search data, browsing behavior will also likely change as public understanding evolves over the course of disease spread . Therefo


Physical activity can help to protect against cognitive decline in older adults. However, little is known about the potential combined relationships of time spent in sedentary behavior (SB), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) with indices of cognitive health. We examined the cross-sectional associations of objectively-determined sedentary and physically-active behaviors with an indicator of cognitive function decline (CFD) in older adults.A randomly-recruited sample of 511 Japanese older adults  wore a tri-axial accelerometer for 7 consecutive days in 2017. Cognitive function was assessed by interviewers using the Japanese version of Mini-Mental State Examination, with a score of ≤23 indicating CFD. Associations of sedentary and physically-active behaviors with CFD were examined using a compositional logistic regression analysis based on isometric log-ratio transformations of time use, adjusting for potential confounders.Forty one (9.4%) of the participants had an indication of CFD. Activity compositions differed significantly between CFD and normal cognitive function (NCF); the proportion of time spent in MVPA was 39.1% lower, relative to the overall mean composition in those with CFD, and was 5.3% higher in those with NCF. There was a significant beneficial association of having a higher proportion of MVPA relative to other activities with CFD. LPA and SB were not associated with CFD when models were corrected for time spent in all activity behaviors.Larger relative contribution of MVPA was favorably associated with an indicator of CFD in older adults. The combined relationships of time spent in SB and intensity-specific physical activity with cognitive health remain to be examined.Physical activity can help in preventing the onset of dementia and decline of cognitive function. However, some studies have identified protective effects,14,15 For example, if time spent in MVPA increases or decreases, this can influence the time spent in SB and LPA. Findings obtained using basic statistical adjustment for physical activity have differed from those of studies using CoDa.14,16 Conventional statistical models can be misleading, with some effects being over- or under-estimated. To date, no previous study has investigated a role of each activity behavior with indices of cognitive health when time spent in other activities is taken into account.Time is finite during the day, and activity behaviors are not independent. Compositional data analysis (CoDa) allows the examination of co-dependence of time spent in all behaviors arising within a day or part of the day.We examined the associations of objectively-determined SB, LPA, and MVPA with cognitive function in community-dwelling older adults using the CoDa approach. We also explored relationships of bout-length specific MVPA with an index of cognitive function.17 Participants were community-dwelling older adults without long-term care in Tokamachi city, Niigata Prefecture, Japan. Tokamachi is a rural city located in the southernmost region of Niigata Prefecture . A total of 1,346 residents (aged 65–84 years) were selected from a resident registry using stratified random sampling. In the fall of 2017, we conducted a questionnaire survey and health examination to 527 participants who agreed to enroll in NEIGE study, and at the same time they were asked to wear an accelerometer. Detailed methods have been reported elsewhere.17This cross-sectional study was a part of the Neuron to Environmental Impact across Generations (NEIGE) study.The University Ethics Committee  granted ethics approval. Written informed consent was obtained from all participants.18–20 that provides data comparable to the devices most commonly used in studies conducted in Western countries.21,22 Its algorithm has been explained in detail elsewhere.18,19 No acceleration signal being detected for longer than 60 consecutive minutes was defined as “non-wear”, and records from participants wearing the accelerometer for at least 10 hours per day were considered valid.23 Participants with 4 or more valid wear days were included in the analyses.24,25 We used 60-second epoch data and obtained estimated metabolic equivalents (METs) values using analysis software. METs-based criteria was used to determine each intensity of activities: ≤1.5 METs for SB, 1.6–2.9 METs for LPA, and ≥3.0 METs for MVPA.26,27 MVPA was further classified according to bout length: sporadic MVPA and bouted MVPA.28 Bouted MVPA was defined as 10 or more consecutive minutes above the moderate intensity threshold, with allowance for interruptions of 1 or 2 minutes per 10 minutes below the threshold.25 Sporadic MVPA was calculating by subtracting bouted MVPA from total MVPA. The analysis included the sub-compositions of activity behaviors that constitute accelerometer wearing time .Participants were instructed to wear an accelerometer, the Active style Pro HJA-750C , over the waist on an elasticated belt for 7 consecutive days while awake, except during water-based activities . Active style Pro is a validated accelerometer29,30 MMSE has been commonly used for screening dementia and mild cognitive impairment (MCI). MMSE-J was used as a total score (range 0–30) and also divided into the following sub-domains: orientation (score 0–10), working memory (score 0–3), attention (score 0–5), delayed memory (score 0–3), and language (score 0–9). Based on previous research, a total score of ≤23 as cognitive function decline (CFD).29 This 23/24 cut-off value classified into a normal cognitive impairment/MCI group and an Alzheimer disease (AD) group with 0.86 sensitivity and 0.89 specificity.29Cognitive function was assessed by interviewers using the Japanese version of the Mini-Mental State Examination (MMSE-J).2) measured using a body composition analyzer MC-780A .Residential area (city side/countryside) was obtained from residential registry of Tokamachi city. Participants reported their age, gender, living arrangement , working status (workers/non-workers), educational attainment (<13 years/≥13 years), smoking (smokers/non-smokers), and alcohol use (yes/no). Medical doctors asked participants to report their past history of stroke  and the use of medication for hypertension, dyslipidemia, and diabetes. Body mass index (BMI) was calculated from height and weight  was used to perform all statistical analyses. We used R package ‘compositions’, ‘robCompositions’, and ‘zCompositions’ for CoDa approach. Statistical significance was set at t-test was performed to compare participant characteristics between those who with CFD and normal cognitive function (NCF). We adopted a CoDa approach, as detailed in previous research.14 Variability in the data, in terms of variability of each behavior relative to the variability of other behaviors, was described through a variation matrix.14,31 A log-ratio expectation-maximization algorithm was used to impute zeros in compositional data sets, since zero does not allow for log-ratio transformation.32 One participant (0.2%) and 138 (27.0%) participants had no time spent in MVPA and bouted MVPA, respectively. We graphically described the difference of activity behaviors by cognitive status to initially appraise the relative differences between these groups. To support the graphical interpretation, we used multivariate analysis of variance (MANOVA) to test whether the activity compositions significantly differed overall between CFD and NCF.The chi-square test, Fisher’s exact test, or 33,34To investigate associations of activity behaviors with CFD, a compositional multiple logistic regression analysis using isometric log-ratio (ilr) transformations of time-use composition was applied, adjusting for potential confounders. We present results for the first ilr transformations for SB, LPA, and MVPA. When analyzed the associations of bout-specific MVPA with CFD, we reworked the ilr transformations using four activities . Model 1 was unadjusted. Model 2 was adjusted for gender and age. Model 3 was additionally adjusted for socio-demographic and behavioral factors, including residential area, educational attainment, working status, living arrangement, and BMI. Model 4 was additionally adjusted for past history of stroke and the use of medication for hypertension, dyslipidemia, and diabetes. If activity behaviors were found to be significantly associated with CFD, we estimated percent change in being CFD when fixed durations of time were reallocated from one part of a particular composition to another, while the remaining parts were kept constant.n = 13), hospitalization (n = 2), and accelerometer system error (n = 1). The final analytic sample was 511 in this study.Of the 527 older adults who agreed to wear an accelerometer (response rate: 39.2%), 16 were excluded for: not meeting accelerometer wearing time criteria  was favorably associated with an index of cognitive function decline in our sample of community-dwelling older adults, even when time spent in other activity behaviors was taken into account. However, the proportion of time spent in bout-specific MVPA, LPA, and SB relative to the other behaviors were not associated with CFD when models were corrected for time spent in all activity behaviors. The current study adds novel evidence to the emerging body of research on physical activity and cognitive health using CoDa.35,36 Physical activity intensity (peak counts), as measured by accelerometry, was found to be associated with better cognitive performance in older Australian adults.35 A study with older Japanese adults with MCI found device-based moderate physical activity but not LPA to be associated with hippocampal volume.36 Findings from randomized trials suggest that moderate-intensity exercise increases hippocampal perfusion37 and the size of hippocampus38 among healthy older adults. Although LPA makes much larger contribution to energy expenditure than MVPA in the older population,28 higher intensity of physical activity may be needed for maintaining cognitive health.In this study, MVPA but not LPA had a significant association with CFD. These results are in line with previous studies indicating that intensity of physical activity may be of importance for better cognitive function.9,10 while others have suggested no associations.11,39 This inconsistency could be partly due to the differences of statistical approach. Most previous studies did not accurately control for time spent in other activities  when analyzing the effect of SB. Sufficient levels of MVPA may attenuate associations of SB with cognitive health.11 Another potential reason is that different types of SB have different impacts on cognitive function.40,41 A prospective cohort study with a large sample of United Kingdom adults showed television viewing and driving time to be unfavorably associated with cognitive decline, whereas non-occupational computer use was found to be favorably associated.40 There is also evidence that higher volumes of time spent in computer use and lower volumes of television viewing time can be related to better cognitive performance.41 Domain-specific SB, as distinct from overall sedentary time, should thus be considered in examining relationships with cognitive health.To date, the associations of SB with cognitive function have been inconsistent; some have suggested unfavorable associations,42,43We have reported novel findings on the relationships of older adult’s sedentary and physically-active behaviors with an indicator of CFD, through an explicit consideration of the co-dependence of time-use domains. Also, we conducted objective assessments of both sedentary and physically-active behaviors and cognitive function. Compared to self-report which involves reporting bias, device-based assessment using accelerometers can provide more accurate and reliable understanding of activity behaviors.44 Although evidence of decline in cognitive function was objectively assessed using MMSE-J, which is valid and commonly used to screen dementia, further research using medical diagnose are needed to more accurately detect those who with dementia. There is also the need to consider selection bias. Accelerometry responders can be healthier and more active than non-responders,45 which would influence the generalizability of the present findings.The most important limitation in our study was the cross-sectional design, which does not allow us to infer any causal relationship. Longitudinal studies using CoDa approach are required to establish the links of sedentary and physically active behaviors with cognitive health. Another limitation was that the Active style Pro device cannot detect sleep, which can be associated with cognitive impairment.In conclusion, objectively measured time spent in MVPA, taking into account SB and LPA, was favorably associated with cognitive function in community-dwelling older adults. On the other hand, time spent in bout-specific MVPA, LPA, and SB relative to time spent in other behaviors were not associated with cognitive function when our models controlled for time spent in all activity behaviors. The shift of time from any behavior toward any form of MVPA (bouted or sporadic) is therefore likely to be beneficial for cognitive health. Our findings also suggest intensity of physical activity may be important for preventing cognitive decline. Further research using CoDa are needed to confirm our conclusions.


Lipid emulsions (LEs), an integral component in parenteral nutrition (PN) feeding, have shifted from the primary aim of delivering non-protein calories and essential fatty acids to defined therapeutic outcomes such as reducing inflammation, and improving metabolic and clinical outcomes. Use of LEs in PN for surgical and critically ill patients is particularly well established, and there is enough literature assigning therapeutic and adverse effects to specific LEs. This narrative review contrarily puts into perspective the fatty acid compositional (FAC) nature of LE formulations, and discusses clinical applications and outcomes according to the biological function and structural functionality of fatty acids and co-factors such as phytosterols, α-tocopherol, emulsifiers and vitamin K. In addition to soybean oil-based LEs, this review covers clinical studies using the alternate LEs that incorporates physical mixtures combining medium- and long-chain triglycerides or structured triglycerides or the unusual olive oil or fish oil. The Jaded score was applied to assess the quality of these studies, and we report outcomes categorized as per immuno-inflammatory, nutritional, clinical, and cellular level FAC changes. It appears that the FAC nature of LEs is the primary determinant of desired clinical outcomes, and we conclude that one type of LE alone cannot be uniformly applied to patient care. Fundamental knowledge in lipid science is well elucidated in terms of the fat molecule’s contribution to total caloric needs, metabolic pathways of energy production, utilization, and storage in the human system. Further, the differentiation of fats based on chemical structure has led to an understanding on metabolic risks associated with atherogenecity in the non-critical status . On the n-6 linoleic acid (LA) in its total fatty acid (FA) profile. But side effects related to the high LA content added to a higher oxidative stress burden in critically ill patients  molecules is determined by the type of FA esterified to the glycerol backbone and the stereospecificity of the linkage . Althougs varies , with 4 s varies . Thus, iThe melting point of saturated oils used in LEs increase with increasing FAs chain length . Physicaet al. (2012) has noted information on these additives may not be declared on the LE product label depending on country availability and local regulation.Other microcomponents in LEs such as phytosterols, α-tocopherol, emulsifiers, and vitamin K further confer functional characteristics. In practice, Vanek et al. (1993) reported occurrence of cholestatic liver disease, likely attributed to the 100% uptake of phytosterols into systemic circulation. In this situation, liver metabolism favors the conversion of sterols to bile salts, which been less soluble than cholesterol, is likely to be precipitated. The accumulation of sterol precipitates within liver cells is the hallmark of cholestasis  content.In animal models, some vitamin E isoforms show benefit in prevention of hepatic injury. LEs consist of two immiscible liquid phases, oil in water. Phospholipids play the role of emulsifying agent to allow the dispersion of fat droplets in the aqueous phase . Main soWith excess emulsifier, liposomes are generated in vesicular form termed as phospholipid-rich particles, forming a bilayer in the aqueous phase of LE. The liposome content is greater in LEs with a lower percentage of oil due to the higher phospholipid:oil ratio . The grePhylloquinone or vitamin K1 is important for normal blood clotting, and a deficiency would prolong the clotting time . The dieFAs introduced intravenously bypass the intestinal lumen and directly enter blood circulation. This means bypassing digestion by lipases, solubilization by bile, uptake into intestinal enterocytes, or packaging into chylomicrons compatible for circulatory transport to target organs. Lipids infused intravenously are already packaged into artificial chylomicrons ready for transport to target organs . LE chylLE chylomicrons are hydrolyzed to yield FAs by lipoprotein lipase, and then transported to the liver to provide energy substrate similar to the fate of natural chylomicrons . DiffereTransported long-chain FAs are activated at the outer mitochondrial membrane by adenosine tri-phosphate to form acyl-adenylates before catalysis by acyl-CoA synthase. The sulfhydryl group of CoA reacts with the acyl-adenylate to form acyl-CoA. Aided by carnitine, the activated long-chain FAs then get transported into the mitochondrial matrix. The acyl carnitine formed from the reaction of acyl-CoA with the hydroxyl group of carnitine diffuses into the inner mitochondrial membrane. The acyl group of acyl-CoA reacts with the hydroxyl group of carnitine to form acyl-carnitine which enables diffusion into the inner mitochondrial membrane. Once inside the mitochondrial membrane, the acyl group will be transferred back to acyl-CoA and carnitine is released. These transacylation reactions are catalyzed by fatty acyl-CoA:carnitine FA transferase .Medium-chain FAs been saturated and having shorter carbon chains generate energy faster, as the route of its fat oxidation differs from the longer FAs. These FAs promote passive movement across the mitochondrial double membrane, independent from carnitine allowing for direct oxidation . Metabolsn-1 and sn-3 positions of the glycerol backbone would facilitate faster hydrolysis by lipoprotein lipase (As regards structured triglycerides (STG), symmetrical TAGs formed by medium-chain FAs esterified at the n lipase . This fan lipase .n-3 or n-6 PUFAs is competitive depending on their concentration and incorporating desaturation and chain elongation , ~23% oleic acid, and ~8% α-linolenic acid (n-6 PUFA compared to n-3 PUFA with ratio of 7:1 (Soybean oil-based LEs (SOLEs) were the primary LEs in PN therapy, formulated with the objective of preventing the development of essential FA deficiency , as wellnic acid . About 8nic acid . SOLEs ho of 7:1 . Commerc intestinal failure associated liver disease in home PN patients  and Kagawa et al. (2012) suggested LE infusion is dose-dependent and the infusion rate at 0.09–0.12 g/kg/h does not alter human immune function  is lower compared to soybean oil (~320 mg/100 g) with β-sitosterol contributing ~70%, followed by stigmasterol ~18% and campesterol ~11% . The α-tn-6 PUFA  which fulfills the desired functionality of rapid hydrolysis compared to LCTs  and long-chain FAs (from soybean oil) are randomly reassigned on the glycerol backbone, generating new TAG molecular species . In STG-position . The choposition . Additio to LCTs .vice versa for 6 days with lipid dose-dependence while maintaining amino acids and dextrose concentrations  and surgical patients (n = 17) concluded short-term administration of STG-LE (5 to 7 days) was significantly associated with improved nitrogen balance, increased plasma proteins, reduced plasma triglycerides, improved liver function parameters, and reduced adverse events and length of hospital stay compared to physical mixture MCT/LCT LEs .STG-LEs do not show any influence on the reticuloendothelial system, unlike the inhibition of reticuloendothelial system function shown by LCT .A lower α-tocopherol (6.9 mg/L) content adds to greater lipid peroxidation risk and higher phytosterols (~350 μg/ml) compared to MCT/LCT LE (~280 μg/ml), therefore adding to liver toxicity risk . Naber an-6 PUFAs is with olive oil as a principal component by 80% replacement of soybean oil. The FA composition of olive oil reflects ~80% of the nonessential n–9 oleic acid with lesser proportions of the essential n–6 LA ~7% and the saturated palmitic acid ~10%  blending ~20% soybean oil with ~80% olive oil in volume is commercially available  who studied 30 home PN patients receiving a combination of olive oil (80%) and soybean oil (20%) for 3 months at five times a week, reported their patients did not develop essential FA deficiency  from the Ministry of Higher Education, (MOHE) Malaysia. BS is a recipient of a PhD study scholarship from Universiti Kebangsaan Malaysia and BK is a PhD Zamalah scholar under the Vice Chancellor of UKM. SS is a recipient of mybrain scholarship from MOHE.Co-author KS is employed at the Malaysian Palm Oil Council. He has published widely in lipid science.The remaining 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.


Syrian refugees residing in Germany often develop posttraumatic stress as a result of the Syrian civil war, their escape, and postmigration stressors. At the same time, there is a lack of adequate treatment options. The smartphone-based app Sanadak was developed to provide cognitive behavioral therapy–based self-help in the Arabic language for Syrian refugees with posttraumatic stress.The aim of this study was to evaluate the effectiveness and cost-effectiveness of the app.In a randomized controlled trial, eligible individuals were randomly allocated to the intervention group  or control group . Data were collected during structured face-to-face interviews at 3 assessments . Using adjusted mixed-effects linear regression models, changes in posttraumatic stress and secondary outcomes were investigated as intention-to-treat (ITT) and per-protocol (PP) analysis. Cost-effectiveness was evaluated based on adjusted mean total costs, quality-adjusted life years (QALYs), and cost-effectiveness acceptability curves using the net benefit approach.P=.52) and after 4 months . The same was true for PP. Regarding secondary outcomes, ITT indicated a treatment effect for self-stigma: after 4 weeks  and after 4 months , the IG showed significantly lower values in self-stigma than the CG. ITT showed no significant group differences in total costs and QALYs. The probability of cost-effectiveness was 81% for a willingness-to-pay of €0 per additional QALY but decreased with increasing willingness-to-pay.Of 170 screened individuals (aged 18 to 65 years), 133 were eligible and randomized to the IG (n=65) and CG (n=68). Although there was a pre-post reduction in posttraumatic stress, ITT showed no significant differences between the IG and CG after 4 weeks (Posttraumatic Diagnostic Scale for DSM-5, Diff –0.90, 95% CI –0.24 to 0.47; Sanadak was not more effective in reducing mild to moderate posttraumatic stress in Syrian refugees than the control condition nor was it likely to be cost-effective. Therefore, Sanadak is not suitable as a standalone treatment. However, as the app usability was very good, no harms detected, and stigma significantly reduced, Sanadak has potential as a bridging aid within a stepped and collaborative care approach.German Clinical Trials Register DRKS00013782; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013782RR2-10.1186/s12888-019-2110-y According to the United Nations Refugee Agency in 2019, the unprecedented number of 26 million individuals worldwide have been seeking shelter as refugees . For exaCurrent guidelines on PTSD treatment by the German Association of the Scientific Medical Societies indicate that trauma adaptive psychotherapy should be offered in a timely manner . HoweverResearch suggests that treatment of PTSD is effective ; howeverThe study design is detailed in the study protocol, published elsewhere . The triAfter screening for eligibility, study participants were randomly allocated (1:1) to the intervention group (IG) or control group (CG), which received a psychoeducational brochure. In order to test short- as well as medium-term treatment effects, 3 face-to-face interviews were scheduled with the study participants: baseline (T0: pre), immediately after the intervention , and 4 months after baseline (T2: follow-up).The trial was approved by the ethics committee of the Medical Faculty of the University of Leipzig, Germany (ID: 111-17-ek) and adheres to the Declaration of Helsinki and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guidelines for good clinical practice. All participants were informed about the study aims, including clarification about data protection measures and data security according to latest legal standards. Participation was only allowed after written informed consent.By using a multistrategic approach to recruit Syrian refugees residing in the urban areas of Leipzig, Halle/Saale, and Dresden in Germany, potential study participants were attracted. This included bilingual posters and brochures, building contact with specific multipliers and institutions, a snowball sampling approach, and use of social media and personal contacts of the native Arabic-speaking study personnel. Recruitment strategies have been described in detail elsewhere . EligibiParticipants in the IG had the opportunity to use the self-help app via person-specific log-in data (to avoid group contamination) for 4 weeks on demand. They were advised to use the app regularly and work through the modules. Participants in the CG received psychoeducational reading material in the Arabic language covering traumatization and posttraumatic stress .In addition to sociodemographic characteristics such as age, gender, and family status, information on residence status, employment, religious beliefs, and escape-related information were collected during standardized interviews at baseline.The primary outcome was posttraumatic stress, measured by the PDS-5 . SecondaFor the cost-effectiveness analysis, health service utilization was assessed retrospectively over 4 months at T0 and T2, using an adapted and shortened version of the German Client Socio-Demographic and Service Receipt Inventory . The queIn the IG, we furthermore assessed information on app usability . FurtheLast, a standardized assessment at T1 and T2 was implemented to monitor potential harms due to trial participation. Harms/negative effects were defined as adverse events (AE) and severe adverse events (SAE). AE comprised an increase in target symptoms , occurrence of novel psychological or physical symptoms, any negative events, all of which may or may not be associated with trial participation in both IG and CG. SAE were defined as events that require some form of high-intensity treatment  or fatality, including suicide.d=0.5), a significance level of α=.05 (1-sided), and a statistical power of 1–β=0.80, optimal sample size for estimating a significant treatment effect is n=102. Considering attrition due to different circumstances , a dropout rate of approximately 20% may be expected, suggesting a sufficient baseline sample size of n=128 participants.The sample size was calculated based on recent evaluations regarding the efficacy of telemedical-based treatment of PTSD symptoms . Given aAfter participants were found to be eligible for participation, they were randomly assigned to IG or CG using a 1:1 ratio using randomized permuted blocks of 6, stratified by age and sex, which ensured both balance in sample size across groups and control of important covariates. An external, independent statistician generated the randomization block lists with a respective computer program .The study coordinator (SR), responsible for individual group allocation, remained blind to the randomization list strata identity. Moreover, the data analyst (AP), who conducted the primary analysis concerning the hypothesized group differences (IG vs CG) in primary and secondary outcome measures (see above), was blind to group assignment.With regard to interview assessments, deidentified data entry took place immediately after each interview using the statistical software SPSS Statistics version 24 (IBM Corp), generating a password-protected and locally stored file with access granted only to study personnel who had signed data protection wavers. Concurrently, data completeness and consistency checks were conducted to ensure data integrity. With regard to data on app use, anonymous log-file data were collected during participant interaction with the app, stored at the app developer’s secured server, and collectively transferred upon completion of all intervention periods to the study investigator using Secure Sockets Layer technology to ensure data encryption and protection. In fact, specific arrangements regarding data protection  were prespecified in a data protection concept. The data protection concept detailed data handling of all collected data  with the purpose to ensure compliance with the General Data Protection Regulation (GDPR) of the European Union. The GDPR specifies the lawful processing of personal data. The data protection concept was composed with and approved by an external lawyer specializing in data protection.As an additional measure of data quality, auditing took place in the form of independent source data verification, performed by commissioned external statisticians. Specifically, 5% of the questionnaires at T0, T1, and T2 (source data) were randomly drawn and inspected regarding their degree of matching with the electronic data file.Quality checks on baseline data revealed missing information on both outcome variables and covariates. Frequency of missing values was low  for all variables but high for education (24/133 cases) and summed up to 27.8% for the set of baseline characteristics. Since sensitivity analysis showed that missing values were not completely at random, a complete case analysis was inappropriate. Therefore, we multiple-imputed missing baseline data using the algorithm of chained equations implemented in Stata (StataCorp LLC) with all sociodemographic variables and baseline assessments of outcome variables as predictors. The resulting pooled estimates of 25 imputed datasets were used for all analyses.Primary analysis of trial data was intention-to-treat (ITT) as outlined in the guidelines of the CONSORT statement and its supplement for reporting eHealth trials . In ordeFor sensitivity analysis, we performed a per-protocol (PP) analysis by excluding participants who had not used the intervention as indicated by deidentified log-in data. Mixed-effects linear regression models for both primary and secondary outcomes were also used on that restricted sample following the same procedure outlined above. The above described analyses were repeated with regard to subgroups .To analyze the cost-effectiveness of Sanadak compared with receiving psychoeducational reading material on trauma and PTSD only, adjusted total costs, QALYs, and differences in total costs and QALYs between the IG and CG were calculated using mixed-effects linear regression models with robust standard errors adjusted for age, sex, costs, EQ-5D-5L indices, and PDS-5 indices at baseline. Furthermore, cost-effectiveness acceptability curves of Sanadak based on the net benefit approach were calculated accordingly by multilevel mixed-effects linear regressions based on the net monetary benefit for different willingness-to pay (WTP) thresholds .d) using adjusted mean scores from the mixed models. All analyses were performed using the Stata 16.1 SE software package (StataCorp LLC). A P value of <.05 was considered statistically significant.Descriptive data are presented as number of observations with percentages or means with corresponding standard deviations or 95% confidence intervals. Results of the mixed-effects regression models are presented as adjusted mean differences and 95% confidence intervals in primary and secondary outcome scores between the treatment groups at both follow-ups. We also report standard effect sizes of treatment on all study outcomes at follow-up  of the participants were lost to follow-up at the end of 4 weeks (T1). In all cases, participants refused further participation. Another 6.8% (9/133) of the sample did not complete assessments at T2. Two of those refused further participation; in 7 cases, repeated contact attempts failed. Total attrition was 12.8% (17/133). There were no significant differences between participants that did and did not complete any of the follow-up interviews nor were there significant differences between conditions in participating at T1 and T2.P=.52) and after 4 months  nor after 4 months . A significant difference was found for self-stigma (SSMIS-AG and SSMIS-AP). After 4 weeks  and after 4 months , the IG showed significantly lower values in self-stigma than the CG .P=.38). Mean adjusted QALYs were 0.29 in the IG and 0.29 in the CG, with the difference not being statistically significant  and in mean adjusted QALYs  between the IG and CG were not statistically significant. The probability for cost-effectiveness at a WTP of €0 per additional QALY was 81% (67%) in the intention-to-treat analysis . For a WTP of €50.000 per additional QALY, the probability for cost-effectiveness was 20%  and €484 in the CG , with th20% 18%; .At T1, participants in the IG were asked to rate the usability (SUS) of the app; 89.2% (58/65) of participants completed the SUS, indicating a mean usability score of 78.9 .Across the intervention and follow-up period, one AE occurred with relation to the trial participation. The participant self-reported increased anxiety at T1 which, however, was not quantified by the GAD-7 scores comparing baseline and T1. The participant wanted to remain in the trial. Follow-up at T2 showed that the AE had resolved. No SAE occurred.Across all assessment waves, 36 paper-and-pencil questionnaires (source data) were randomly drawn and compared with the electronic data file. For each questionnaire, up to 16 case report forms were inspected. Altogether, 7837 items were checked and 56 errors identified. This cumulated in a total error rate of 0.71%.The smartphone-based app Sanadak, a self-help intervention in the Arabic language, was primarily developed for reducing posttraumatic stress in Syrian refugees residing in Germany as there is a gap of timely and culturally appropriate treatment. Its effectiveness was evaluated in an RCT with 133 Syrian refugees aged 18 to 65 years. Although symptom severity decreased, Sanadak was not superior in reducing mild to moderate posttraumatic stress in Syrian refugees in the short-term (4 weeks) and midterm (4 months) compared with the CG, who received psychoeducational reading material on trauma and PTSD. Likewise, the app showed no effectiveness regarding secondary outcomes, including depressive symptoms, anxiety, somatization, posttraumatic growth, general self-efficacy, social support, social isolation, health-related quality of life, and health state. However, there was a significant treatment effect for aspects of self-stigma: stereotype agreement as well as stereotype application reduced significantly in the short-term and midterm in the IG compared with the CG. Moreover, Sanadak is unlikely to be cost-effective. The app showed a small but insignificant reduction in total costs compared with the CG. As the number of QALYs tended to be (insignificantly) higher in the CG than in the IG, the probability of cost-effectiveness decreased with increasing willingness to pay per additional QALY, reaching only 20% at a WTP of €50.000. In a model-based economic evaluation, self-help without support also showed a small reduction in total costs of £235 (€199) compared with no treatment and was unlikely to be cost-effective compared with other treatment options, with a probability of cost-effectiveness of only 42% for a WTP of £20.000 (€23.624) per additional QALY .Although evidence-based treatments are available for mild to severe PTSD and cognitive-behavioral therapies are among the recommended treatments , findingThe literature provides more evidence regarding the effectiveness of interventions for posttraumatic stress in refugees delivered via internet or face-to-face. For example, in a web-based psychotherapy for war-traumatized Arab patients (focused on Iraq), posttraumatic stress was significantly reduced from baseline to posttreatment in the IG compared with the CG and effects sustained at 3-month follow-up . RegardiThe question is why treatment for posttraumatic stress may be less effective if delivered via apps compared with internet-based or face-to-face treatments. Due to the small number of studies, this remains to be investigated. However, it is likely that brief intervention periods, the self-management approach without clinical expert guidance or support, and the use of self-report measures are explaining factors . For exaOn a positive note, the SUS usability score of Sanadak was found to be above average, indicating very good usability. There were no harms associated with the use of Sanadak, and pre-post comparisons indicated a significant reduction in posttraumatic stress, even though not more than in the control condition. Moreover, Sanadak significantly reduced self-stigma regarding mental health relative to the CG. This aspect should not be underestimated. Mental health stigma has been named a key barrier to help seeking in refugees with posttraumatic stress . By reduThe study has several strengths: a robust RCT design to determine effectiveness, adequate power, midterm follow-up assessment and low attrition, monitoring for potential harms as well as rigorous data quality control and imputation strategies for missing values, which decrease risk of bias in determining trial results. There are also limitations to consider. First, the multistrategic recruitment that heavily relied on snowball sampling techniques may limit generalizability of our findings to other traumatized populations. Moreover, the control condition which saw the provision of psychoeducational reading material in the Arabic language may not have been ideal in determining the app’s treatment effect as building awareness on posttraumatic stress symptoms in the CG may been associated with symptom severity reduction. Potentially, a mere waiting list condition would have led to differential results. Moreover, assessments heavily relied on self-report assessments. There were no in-depth clinically diagnostic interviews to assess outcomes. As service use was assessed retrospectively over 4 months using an adapted and shortened version of a service receipt inventory, it is possible that health care services utilization was not completely assessed and a potentially delayed effect of Sanadak on total health care costs could not been identified.Sanadak, an interactive self-help app in the Arabic language, showed reductions in posttraumatic stress in Syrian refugees residing in Germany in a pre-post comparison but was not superior to the control condition. This is in line with similar studies evaluating apps for posttraumatic stress, although targeting different populations. In addition, Sanadak is unlikely to be cost-effective. Future studies that investigate reasons for the limited effectiveness of respective apps are warranted to allow for improved app development and delivery modes. However, there were no harms associated with the use of Sanadak, and importantly, we found a significant and sustained treatment effect for reducing self-stigma. Consequently, Sanadak cannot be recommended as a standalone treatment for posttraumatic stress in refugee populations, but trial results indicate potential usefulness as a bridging aid, particularly as the usability was found to be very good, for the uptake of more effective internet-based or face-to-face treatments within a stepped and collaborative care approach.


There is mounting evidence supporting that patients with kidney diseases are particularly vulnerable to coronavirus disease-2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The review was conducted to examine the risk and complications of COVID-19 among patients with confirmed cases of underlying kidney disease. A search of Google Scholar, PubMed and Science direct databases to August 2020 was conducted using search terms pertaining to kidney diseases, renal insufficiency, kidney injury, angiotensin receptors, hemodialysis, and kidney transplant. We briefly reviewed COVID-19 in the context of kidney diseases. A significant proportion of hospitalized patients for COVID-19 have acute kidney injury, which further deteriorates their prognosis. COVID-19 increases morbidity and mortality among people already diagnosed with kidney disorders and obesity due to multiple organ injury caused by the SARS-CoV-2. This review supports the need for clinicians to carefully manage and monitor all patients with renal disorders in order to minimize acute kidney injuries. Although some therapeutic drugs have been suggested by some studies, treatment should be administered cautiously not to worsen the condition of the kidney. Further studies are required to highlight the efficient management of patients with underlying kidney diseases, who are infected with SARS-CoV-2. With proactive systematic screening and triaging, close monitoring and prompt management of coexisting other infections, the COVID-19 disease burden among these patients could be reduced. In late December 2019, cases of pneumonia of unknown origin were identified in Wuhan, the capital city of Hubei province in central China. The causative pathogen has since been identified as a severe acute respiratory syndrome coronavirus-(2) (SARS-CoV-2) due to the phylogenetic similarity to the previously isolated SARS-CoV .The coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has been declared as a pandemic and has infected ~21.2 million people that caused over 761,000 deaths across countries and territories globally as at August 2020 , 5. ThesCo-morbidities are linked to severe and critical cases of the COVID-19, with hypertension, diabetes mellitus, and cardiovascular diseases being the main causes . StudiesThis review aims to examine risk and complications of COVID-19 among confirmed cases with underlying kidney conditions to guide clinical practice and management decisions.A search was conducted on studies published from first January to tenth June 2020 in Google Scholar, PubMed, and Science Direct databases. Search terms such as “COVID-19,” “SARS-CoV-2,” “SARS2,” “kidney diseases,” “renal insufficiency,” “kidney injury,” angiotensin receptors,” “hemodialysis,” and “kidney transplant” were used with no language restriction introduced in the search. The reference list of each selected study was checked to ensure that no relevant study was missed. Eligible studies were those that described and reported on the risk, complications, and management of COVID-19 disease among people with underlying kidney diseases. Additionally, some unpublished reports found online were also included. Studies excluded from the review were those that reported on other co-morbidities but not kidney diseases as well as duplicated studies and news articles. A total of 260 published articles were reviewed, but only 87 were included after a careful review.The RAAS plays a cardinal role in human renal and cardiovascular physiology and pathophysiology. Briefly, angiotensinogen released by the liver, is transformed to angiotensin I by the action of renin. Angiotensin I is converted to angiotensin II (AII) through removal of two C-terminal residues by the angiotensin-converting enzyme (ACE). Besides the well-described role of ACE, which is homologous to ACE protease, ACE2 has also been discovered. ACE2 is mainly located in the membrane cell, or found as circulating forms, and it degrades AII to Ang –7, and tSince the emergence of COVID-19 in December 2019, it has attained a worldwide distribution , 18. AltClinical manifestations include cough, shortness of breath, muscle ache, confusion, headache, sore throat, rhinorrhea, and chest pain among others , 8. A syDirect cellular injury due to the virus or sepsis leading to a cytokine storm syndrome are thought to be possible mechanisms connected to the SARS-CoV-2 disease. Recently, some studies show that the kidney is one of the target organs for SARS-CoV-2. The vulnerability of patients with diagnosed kidney conditions to SARS-CoV-2 is now known with its associated complications , 21, 23.Kidney impairment has been found to occur in some COVID-19 patients. About >50 % of patients admitted at the ICU present with acute kidney injury (AKI) characterized by elevated serum creatinine, reduced urine output, or both as a result of multiple factors . EarlierAnother retrospective study shows that SARS-CoV-2 directly affects the kidney tubules resulting in acute tubular damage and cytotoxicity, and thus, acute renal failure in COVID-19 patients especially among the aged and co-morbid . AdditioIn a postmortem study on 26 patients who died from SARS-CoV-2 in China, by using ultrastructural and immunostaining assessment, “diffused acute proximal tubular injury with loss of brush border and non-isometric vacuolation” was found. This depicts a direct virulent nature of the novel virus . The autper se already at an early stage (Thus, several mechanisms have been described through which SARS-CoV-2 can lead to acute and chronic kidney damage, such as via acute tubular necrosis, interstitial inflammation, injuries in renal vasculature and collapsing glomerulopathy. Endothelial dysfunction is a key characteristic of CKD ly stage  and endoly stage . Of notely stage , and thely stage . Endothely stage , since tly stage . Kidney ly stage . Indeed ly stage . As the ly stage .Viruses are the main cause of opportunistic infections post-transplant among kidney transplant recipients leading to increased morbidity and mortality . FactorsThe susceptibility of end-stage kidney failure patients on dialysis to COVID-19 disease due to their immune suppressed state is high , 40, 41.The cornerstone of successful treatment in this context is early detection of renal abnormalities, and avoidance of nephrotoxic agents. Further, it is essential to adhere to the recommended treatment guidelines to manage COVID-19 patients with kidney disorders. Drug management has aimed at targeting ACE2 in humans, which serves as a receptor for the virus . HoweverObesity is an independent risk factor for development of CKD . The incD hypovitaminosis is a common characteristic of patients with renal insufficiency and is associated with over activation of RAAS . PreviouIn conclusion, this review revealed the current studies on patients with underlying kidney diseases infected with SARS-CoV-2. The COVID-19 increases morbidity and mortality among people already with kidney disorders due to multiple organ injury caused by the virus. There is a call on all clinicians to carefully manage and monitor all patients with renal disorders to minimize acute kidney injuries. Although some therapeutic drugs have been suggested by some studies, there is a need to tread cautiously not to worsen the condition of the kidney. Further studies are required to bring new information about the efficient management of patients with underlying kidney diseases infected with SARS-CoV-2.PD: conceptualization. PD and CT: methodology, investigation, and writing—original draft. PD, ER, DM, and RB: writing—review and editing. PD and DM: supervision and project administration. All authors contributed to the article and approved the submitted version.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.