Hernia repair is one of the most common surgical procedures; however, the long-term outcomes are seldom reported due to incomplete follow-up.The aim of this study was to examine the use of a mobile app for the long-term follow-up of hernia recurrence, complication, and quality-of-life perception.A cloud-based corroborative system drove a mobile app with the HERQL  questionnaire built in. Patients who underwent hernia repair were identified from medical records, and an invitation to participate in this study was sent through the post.The response rate was 11.89% (311/2615) during the 1-year study period, whereas the recurrence rate was 1.0% (3/311). Causal relationships between symptomatic and functional domains of the HERQL questionnaire were indicated by satisfactory model fit indices and significant regression coefficients derived from structural equational modeling. Regarding patients’ last hernia surgeries, 88.7% (276/311) of the patients reported them to be satisfactory or very satisfactory, 68.5% (213/311) of patients reported no discomfort, and 61.1% (190/311) of patients never experienced mesh foreign body sensation. Subgroup analysis for the most commonly used mesh repairs found that mesh plug repair inevitably resulted in worse symptoms and quality-of-life perception from the group with groin hernias.The mobile app has the potential to enhance the quality of care for patients with hernia and facilitate outcomes research with more complete follow-up. Hernia repair is one of the most common surgical procedures performed each day worldwide, which can be traced back to the era of ancient Egypt . With thWith reduced herniorrhaphy failures, outcomes research of hernia surgery should concentrate on postoperative quality of life and complications such as chronic pain ,12. The To understand treatment outcomes, several quality-of-life instruments specific to hernia disease, such as the Carolinas Comfort Scale (CCS), the Hernia-Related Quality-of-Life Survey, the European Abdominal Wall Hernia Quality-of-Life Scores, the Core Outcome Measures Index adapted for patients with hernia, the Inguinal Pain Questionnaire, and the Brief Pain Inventory, have been developed and reported -20. In tThe HERQL questionnaire targets both abdominal wall and inguinal hernias, traditional open and minimally invasive surgeries, and various mesh materials ,22. One As previously mentioned, low compliance and high loss-of-follow-up rates among patients with hernia heavily compromised outcome evaluation of herniorrhaphy, especially when long-term outcomes were pursued. Indeed, there remains an unmet need to understand the true recurrence rate of hernia surgery, as well as the associated complications and subjective well-being . To overWe invited patients who completed hernia repair at our hospital to participate in this study. Index cases were identified from medical records. Both groin and abdominal hernias were eligible, with the latter comprising primary ventral and incisional hernias. The latest hernia surgery should have been performed at least 1 year prior to the starting date of the study. The enrollment period was between April 1, 2016, and March 31, 2017. Identified cases were contacted through the post using addresses from the medical charts.A preset combination of a unique ID and password was sent to each invitee concurrently, and electronically signed informed consent was obtained with the mobile app through the built-in signature module (see Mobile App section). A copy of the informed consent document was sent to the email address provided by each invitee for reference.The HERQL questionnaire has been described elsewhere . In briePain and activity restriction due to pain or discomfort were rated on an 11-point Likert-type scale, ranging from 0 to 10, for each item, while symptomatic and functional domains  were evaluated using a 5-point Likert-type scale. An auxiliary postoperative module, also equipped with 5-point Likert-type scales, was designed for potential complications following hernia repairs; these items included mesh foreign body sensation, severity of complications, overall satisfaction with hernia repair, confidence that hernia will not recur, and quality-of-life improvement by hernia repair. All scales were arranged with higher values representing compromised functionality or worse symptoms. The causal and indicator variables model proposed by Fayers et al ,25 and BSummative pain score measures pain and discomfort resulting from rest or mild, moderate, or heavy activities:11-point Likert-type scaleQ01, Q03, Q04, and Q05 (Q: question)Activity restriction due to pain or discomfort:11-point Likert-type scaleQ09Symptomatic domains:5-point Likert-type scaleHernia protrusion: Q02Analgesic use: Q08Functional domains:5-point Likert-type scaleHernia’s impact on health: Q11Economic burden: Q12Subjective quality-of-life/global health perception: Q13Postoperative module:5-point Likert-type scaleMesh foreign body sensation: Q15Severity of complications: Q17Overall satisfaction with hernia repair: Q18Confidence that hernia will never recur: Q19Quality-of-life improvement by hernia repair: Q20The mobile app version of the HERQL questionnaire assessing patients’ quality of life was ready for log-on for index cases identified from medical records, and an invitation was sent by post to those who had undergone hernia repairs at our institute at least 1 year before the study began. Both Android and iOS platforms were supported; a URL that linked to an online Google Docs–based questionnaire was provided as an alternative for those not equipped with a smartphone but who had internet access . Figure The mobile app was driven by a cloud-based corroborative system. The system comprised a data management and storage subunit, as well as a security information subunit. Patients with hernia could administer HERQL, to report their quality-of-life and outcomes following hernia repair. The platform provided an easy and efficient way for patients to report any discomfort to their surgeons, which was designed to enhance the long-term follow-up and compliance of patients with hernia. A built-in signature module was developed to facilitate acquisition of electronically signed informed consent , the adjusted GFI (>0.80), the standardized root mean square residual (<0.1), the comparative fit index (>0.9), and the root mean square error of approximation . All variances for latent factors were determined to be the ones used for model identification purposes.Human subject research ethics review and approval was in accordance with the regulation of the Institutional Review Board of Cathay General Hospital (protocol number: CGH-P102069). Written informed consent using electronic signatures was obtained from all participants, and all study subjects were compensated by post with a remuneration of 200 New Taiwan Dollars (approximately US $7 in 2016). Analyses were conducted after all data were anonymized for privacy and confidentiality protection.During the 1-year study period, 2615 patients who had their hernia repaired at our institute were invited to participate in the study via the post. Among them, 2245 (85.85%) were male and 370 (14.15%) were female. The mean age was 60 (SD 15) years . The response rate was 11.89%: 311 patients followed the instructions, with successful log-on, and completed the HERQL survey. There were 93 (29.9%) abdominal wall  hernias, 202 (65.0%) groin hernias, and 16 (5.14%) patients had both. The earliest hernia repair took place more than 13 years ago . Most responders were within 5 years of hernia repairs. χ2/df=3.3) was slightly deviated from a good fit of the hypothesized construct to the experimental data. In large data sets with hundreds of samples, this deviation is not uncommon and was acceptable. Other indices supported the concept of the HERQL questionnaire for long-term follow-up of patients with hernia, with slight deviations of GFI (0.89) and RMSEA (0.09). Most importantly, the causal relationship between the summative pain score and the quality-of-life latent factor was indicated by a significant –0.22 regression coefficient, whereas the significant and positive 0.71 regression coefficient was reported for the causal relationship between the quality-of-life and postoperative satisfactory latent factors.The overall recurrence rate among 311 participants was 1.0% , and 88.7% (n=276) of participants rated their last hernia repair as satisfactory or very satisfactory (Q18). Approximately 70% of invitees  reported no discomfort with their hernia repair (Q16), and 61.1% (n=190) never experienced mesh foreign body sensation (Q15). Quality-of-life improvement following hernia repairs was ascertained in 90.4% (n=281) of enrolled subjects (Q20).Comparisons were conducted between 77 patients with mesh plugs and 57 patients with the Prolene Hernia System (PHS) or the Ultrapro Hernia System (UHS) for groin hernia repair. Patients with mesh plug hernia repairs reported higher analgesic usage than those with PHS or UHS , worse impact on health , economic burden , foreign body sensation , discomfort severity , less satisfaction in herniorrhaphy , less confidence in hernia repair , and compromised quality-of-life improvement .In this study, we reported the development of a mobile app to facilitate the long-term follow-up of patients with hernia and ascertained the feasibility of the app. The cloud-based system eliminated the need for return visits by subjects who had undergone hernia repairs as early as a decade ago, which, in turn, enhanced the long-term follow-up and outcomes research. Hernia is a type of surgically treated disease with compromised long-term follow-up, as there is neither periodic surveillance nor medication prescription once the defect has been repaired. As well, patients with recurrent disease may seek a second opinion and receive further operations from surgeons in addition to the one resulting in failed repair ,14. TherFor these reasons, we sent invitation letters by post to subjects who had their hernia repaired at our institute more than 1 year ago, with index cases identified from medical records. With an enclosed preset ID and password, invitees could easily download the iOS or Android version of the mobile app, complete the quality-of-life survey, and provide their electrical signature for informed consent within a few minutes. For those not familiar with mobile apps or not equipped with a smartphone, a Google Forms survey provided an online alternative. The response rate was 11.9%, or slightly more than one-tenth of the identified candidates. The majority of the 311 responders were diagnosed with groin hernias, reflecting the clinical scenario of the hernia population.From our study, the long-term recurrence rate was less than 1%, with 3 patients reporting hernia recurrence. Most of the 311 patients  reported that they were satisfied or very satisfied with their last hernia repair, 68.5% of patients (n=213) reported no hernia-related discomfort, and 61.1% (n=190) never experienced mesh foreign body sensation. We also compared patients with groin hernias receiving either mesh plug repairs or PHS or UHS repairs and found that those with mesh plugs inevitably experienced more analgesic usage, worse health impaction, economic burden, foreign body sensation, discomfort severity, less satisfaction, less confidence in hernia repair, and compromised quality-of-life improvement. Most importantly, 90.3% of the participants experienced an improvement in quality of life following hernia surgery, indicating that elimination of hernia-related symptoms might be the main contributor to such improvement.The conceptual structure of the HERQL questionnaire with the postoperative module displayed satisfactory model fit indices , furtherOur study was not the first to perform outcomes research for hernia outside a hospital. Heniford et al  conducteIn our previous study, 192 patients who had groin hernias repaired with mesh plugs were compared with 234 patients who had PHS repairs. Postoperatively, the group who had mesh plug repairs had a higher incidence of chronic nondisabling groin pain . In thisThere were some limitations of this study. First, the retrospective design inevitably introduced recall bias, especially for those with longer follow-up periods. This study evaluated the feasibility of mobile app–based outcomes research, and further study is warranted to eliminate this bias with a more uniform follow-up interval. Second, not all clinical and demographic data were available through chart reviews, such as BMI and fascia defect size, which could hamper post hoc and multivariate analysis considerably. Third, some older adult patients might not be able to complete the survey without an assistant, and there was no printed questionnaire available in the event that the mobile app was not properly installed. Fourth, no further reminder letters were sent by mail and no further phone calls were attempted if there was no response from the initial invitation letter, which inevitably compromised the response rate.Knowledge gained from this study can translate into the design of future hernia outcomes research. For example, an updated hernia registry could be established that includes a novel mobile app to enhance the follow-up of patients with hernia, and a cloud-based database could be established for surgeons as well as patients with hernia. A corroborative database would be useful for surgeons to collect clinical and operative details from hernia surgeries, and this would provide a platform for real-time communication between patients with hernia and surgeons and to enhance postoperative follow-up and outcomes assessment. Surgeons could enter the clinical and operative data immediately after completion of hernia repairs using mobile devices, whereas sensitive clinical data would be secured and restricted to authorized personnel. In addition, patients with hernia could review their clinical and operative details in a well-designed and self-explanatory manner. Patients with hernia could also record postoperative events, such as results from a visual analog pain scale, wound condition, and complications, and they could complete the HERQL questionnaire periodically in order to assess the outcomes of hernia repair. Finally, the instant message communication feature can be established to provide an easy and efficient way for patients to report any discomfort to their surgeons, and a proper response from the latter could enhance the long-term follow-up compliance rate of patients with hernia.The establishment of the mobile app could enhance the quality of care for patients with hernia and facilitate outcomes research for hernia disease with a more comprehensive and complete follow-up, and the feasibility is ascertained herein. The knowledge gained from this project could extended to other common surgical procedures ,35. This


Walking behavior is positively associated with physiological and mental health as much evidence has already shown. Walking is also becoming a critical issue for health promotion in urban environments as it is the most often used form of active mobility and helps to replace carbon dioxide emissions from motorized forms of transport. It therefore contributes to mitigate the negative effects of climate change and heat islands within cities. However, to promote walking among urban dwellers and to utilize its health-enhancing potential, we need to know more about the way in which physical and social environments shape individual experiences during walking episodes. Such person-place interactions could not adequately be analyzed in former studies owing to methodological constraints.This study introduces walking-triggered e-diaries as an innovative ambulatory assessment approach for time-varying associations, and investigates its accuracy with 2 different validation strategies.The walking trigger consists of a combination of movement acceleration via an accelerometer and mobile positioning of the cellphone via GPS and transmission towers to track walking activities. The trigger starts an e-diary whenever a movement acceleration exceeds a predetermined threshold and participants' locations are identified as nonstationary outside a predefined place of residence. Every 420 (±300) seconds, repeated e-diaries were prompted as long as the trigger conditions were met. Data were assessed on 10 consecutive days. First, to investigate accuracy, we reconstructed walking routes and calculated a percentage score for all triggered prompts in relation to all walking routes where a prompt could have been triggered. Then, to provide data about its specificity, we used momentary self-reports and objectively assessed movement behavior to describe activity levels before the trigger prompted an e-diary.g in 58.4% vs 19% of these situations).Data of 67 participants could be analyzed and the walking trigger led to 3283 e-diary prompts, from which 2258 (68.8%) were answered. Regarding accuracy, the walking trigger prompted an e-diary on 732 of 842 (86.9%) reconstructed walking routes. Further, in 838 of 1206 (69.5%) triggered e-diaries, participants self-reported that they were currently walking outdoors. Steps and acceleration movement was higher during these self-reported walking episodes than when participants denied walking outdoors  lead to changes in accuracy. Walking with low to moderate intensity is associated with physiological health such as all-cause and cardiovascular mortality , obesityTo analyze such person-place interactions between the individuum within its environment, we need time-varying associations, which previous studies mostly do not provide. The goal of this study is to introduce walking-triggered e-diaries as an innovative ambulatory assessment approach to overcome this methodological constraint.A plethora of studies and reviews investigated associations between the built or physical environment and physical activity . They indicated that high-quality walking infrastructure, access to recreational facilities, as well as parks, trails, or new infrastructure for walking are associated with increased levels of physical activity ,19. RegaIn recent years, some research groups in the field of urban development and city planning extended assessment ideas and collected momentary data of mental health or subjective environmental experiences during everyday life. These study designs combined mobile geographic location technologies  to assess precisely the space where participants spend their time outdoors. Time-based assessments via daily diaries resulted in geographically explicit ecological momentary assessments  but rather operationalized activity using time-space patterns of the GPS. In addition, most GEMA designs struggled with the disadvantages of “time-based” assessments because prompts to answer the web-based questionnaires were usually triggered at regular time intervals. With such a sampling scheme, self-reports during rare events  are likely to be missed, which impedes the analysis of person-place interactions. A currently published study protocol of a GEMA study attempted to overcome this restriction . This GThe purpose of this study is to introduce walking-triggered e-diaries as an innovative ambulatory assessment approach to overcome the methodological shortcomings mentioned above. It combines movement acceleration, time, and distance assessments (GPS) to trigger an e-diary. The aim of this study is to examine its accuracy through 2 different approaches. First, we reconstructed walking routes (using a GPS) and examined on how many walking routes the walking trigger prompted an e-diary (sensitivity). Second, we describe activity levels (movement acceleration and number of steps) immediately before the prompt, and used self-reports to identify “false positive” walking-triggered e-diaries; that is, a participant received a triggered e-diary, but denied walking outdoors (specificity).g and with a sampling frequency of 64 Hz. Move3 has been validated for documenting movement acceleration and different body positions [Triggered e-diaries (or triggered EMAs) have previously been employed to assess data during physically active and inactive episodes , as wellositions ,34.g for at least 1 minute) and the participants’ location changes beyond a radius of 100 m. If these conditions are met, a walking-triggered e-diary (main) is prompted. Furthermore, participants receive follow-up walking-triggered e-diaries on their walking trip with a repeat interval of 420 seconds and a randomization time of 300 seconds for as long as the trigger conditions are met (repeated). For each e-dairy, participants need approximately 1 minute for responding.Taken together, the walking trigger consists of a combination of movement-acceleration and mobile positioning of the cellphone via GPS and transmission towers to identify walking episodes. The walking trigger prompts an e-diary between 6 AM and10 PM whenever an individual is walking outdoors. This is achieved by distinguishing between 2 states: stationary and nonstationary. The trigger state switches to nonstationary whenever a movement acceleration exceeds a predetermined threshold  available at the manufacturer’s website home page . All datIn a final step, spatial information and data on environmental features  were added for further analyses. Data fusion of the e-diary and accelerometer data with GIS information require that GPS data are linked to the concomitant e-diary via a unique ID composed of the participant ID and the time stamp of the e-diary or accelerometer data.For participant recruitment, 3000 letters were distributed to preselected urban households with an invitation to participate in a web-based, cross-sectional questionnaire. The data collected in the survey were used for purposes not emphasized in this study, except for the final step of the web-based questionnaire. Individuals, who want to and who fit the inclusion criteria could join the walking-triggered e-diary assessment. Inclusion criteria were for individuals to understand the German language (as the questionnaires were in German), to be older than 18 years, to live in an urban or suburban area, and to have no mental or physical health conditions that would restrain them from being physically active . Furthermore, participants were offered a profile of their activity pattern during the duration of the assessment and an incentive of €50 (US $51.86) if they provide data on at least 7 days. Potential participants received information regarding the study and the procedure and instructions on how to wear and use the sensors and smartphones before written consent was obtained. In addition, a video was provided with the same information for further clarification.After a confirmatory phone call, participants were equipped with a smartphone and a sensor via a mailed package. In the cases where no questions came up, the participants were able to start the study by themselves. Participants were consecutively recruited from July to December 2020 (no lockdown conditions during this time owing to COVID-19 restrictions in Germany). The study period per participant lasted 10 consecutive days with an option to extend the study voluntarily. During the assessed time period, between 6 AM and 10 PM, participants received walking-triggered prompts, requesting them to answer short e-diaries that were shown on their smartphones. In addition, they randomly received 3 further e-diaries over the course of the day . After completing the study, the participants returned the smartphone-sensor combination via prepaid mail packages.The study received full ethical approval from the University of Konstanz .Two different approaches were used to evaluate the accuracy of the walking trigger algorithm. First, we assessed accordance between walking routes and walking-triggered e-diaries (sensitivity). To reconstruct as many walking routes as possible, we used all recorded GPS signals, with the following conditions: GPS signals with a time span of 60-120 seconds, each GPS-signal has an accuracy of at least 30 m, mean speed of the total route is less than 10 km/hour, and a minimum walking distance of 100 m.We modeled the walking routes with the statistical analysis software R and the OpenRouteService routing system (HeiGIT gGmbH). The reconstructed walking routes are calculated independently from the walking-triggered e-diaries and were used as reference data. We checked for how many walking routes were e-diaries triggered .Furthermore, we compared how many trigger-based versus time-based prompts started an e-diary during a walking route to give an impression of the added value of using the walking-triggered approach instead of a time-based approach. In the next step, we focused on the specificity of the walking trigger approach and verified whether a participant was walking outside immediately before a walking-triggered e-diary was prompted (only main e-diaries were used). For this purpose, we used the self-reports of the main e-diaries. In addition, we compared steps and accelerometer data before main e-diaries were triggered between situations in which participants self-reported that they were or were not walking outdoors.We could analyze data of 67 of 79 recruited participants . The excluded participants (n=12) did not differ significantly in age  and sex (sex distribution of the excluded participants was 50% each for women and men) from the included participants. The included participants (N=67) had a mean age of 41.0 (SD 14.6) years, and 50.7% were female. 82.1% of participants had a high school certificate, and the average BMI was 23.9 (SD 3.8). Participants provided a total of 632 days of sensor data . At least 1 e-diary was triggered on 452 days, which yielded an average of 6.7 (SD 2.9) diaries per day. The walking-trigger produced 3283 e-diary prompts within the study period . Of a total of 3283 prompts, 2258 (68.8%) were answered, including 1206 of 1840 main e-diaries  and 1052 of 1443 repeated e-diaries . The resulting compliance rates were 65.5%  and 72.9% , respectively. In addition, participants received 1955 randomly prompted e-dairies . Of a total of 1955 randomly prompted e-diaries, 1479 (75.6%) were completed .main or main and repeated) was triggered during or immediately after a walking route (maximum 2 minutes). This yielded an overall accuracy of 86.9%  situations, the participants indicated via self-report that they were (currently) walking outdoors .g in 82.0% and ≥0.2 g in 58.4% of these situations. GPS records were present 783 out of 838 (93.4%) times. However, in 368 of the 1206 (30.5%) situations, participants indicated via self-report that they were not (currently) walking outdoors. In the 2 minutes before these triggered e-diaries, an average of 32 (SD 39) steps were taken, and in 64.9% and 19.0% of cases, the acceleration was >0.1 g and ≥0.2 g, respectively. GPS records were present 307 times . Unanswered main questionnaires amounted to a total of 634. The following movement data for these situations can be reported: an average of 104 (SD 89) steps were recorded in these situations, and in 70.7% and 50.6% of cases, the acceleration was at least 0.1 g and ≥0.2 g, respectively. GPS records were present 508 out of 634 (80.1%) times.In these 838 situations, an average of 106 (SD 81) steps were taken in the 2 minutes before the e-dairy, and the acceleration was >0.1 This study introduces walking-triggered e-diaries as an innovative measurement approach for walking behavior and evaluates its accuracy for this purpose. This new method allows for the analysis of time-varying associations to deepen our understanding of person-place interactions. It can potentially assess data of the person  as well as the social and physical environment  during the very situations in which a person walks outdoors.g. Detection of gait velocity or inclusion of steps in the algorithm of the walking trigger potentially mitigate this inaccuracy.According to the results of the reconstructed walking routes about sensitivity, in 86.9% of these walking episodes, participants received a triggered e-diary. This finding shows that walking-triggered e-diaries had high accuracy in capturing data during episodes of walking outdoors. Compared to a time-based assessment, which was usually used in previous studies , the walking trigger is more sensitive and leads to a relevant higher number of e-diaries during episodes of walking outdoors . Nevertheless, there are some reconstructed walking routes where participants did not receive a triggered e-diary. As the trigger depends on movement acceleration and not explicitly on gait velocity, it is possible that the participant's movement acceleration had been lower than the set threshold value of 0.1 The assessment approach of walking-triggered e-diaries extends former studies, which have already shown that, for instance, more green space during active episodes is associated with lower stress levels . Howeverg , but the person did not interpret the movement as walking outdoors. Overall, our findings emphasize the importance of assessing participants' interpretations and behavior patterns apart from objective measures of physical activity. Furthermore, the histograms in g; 32 steps) than that in situations where participants confirmed activity . This observation leads to the conclusion that an increase in the activity threshold to 0.2 g of movement acceleration would help reduce false positive e-diaries but would also reduce sensitivity .The second analysis was related to the specificity of the walking trigger assessment. It used participants' self-reports to provide an impression of false positive triggered e-diaries and used movement acceleration and step counts to estimate activity levels immediately before the e-diary was triggered. However, participants reported, in 30.5% of the walking-triggered e-diaries, that they were currently not walking outdoors. According to the objectively measured activity data during these situations, there had been sufficient movement acceleration, and the accelerometer identified on average 32 steps per person during the last 2 minutes immediately before the prompt. Thus, owing to the objectively measured activity levels, the walking trigger algorithm’s prompt was accurate. Participants, however, did not actively indicate these movements as outdoor walking behavior. A possible explanation is that a person was strolling around his or her home or performed some leisure time activities such as slow roller-skating or slow bicycling. Such activities can lead to a nonstationary movement acceleration greater than 0.1 Our study design with walking-triggered e-diaries reveals acceptable compliance rates of 65% for the triggered main e-diaries and 72% for the repeated ones. These numbers are in line with those of other studies assessing walking triggers . HoweverAlthough the data set included 632 days of sensor data, at least 1 walking-triggered e-diary was triggered on only 452 days. We therefore have 180 days of no data on outdoor walking activity (an average of 2.7 days per participant during a 10-day assessment period). This number seems quite high. Part of the explanation is, however, that data assessments have been conducted during a time where COVID-19 restrictions imposed heavy constraints on participants to meet other people, and working from home was recommended or even mandatory for some employees. Several studies showed that physical activity levels and walking activities were reduced during this time [The strength of our new measurement approach of walking-triggered e-diaries is 2-fold: first, it incorporates accelerometers to assess physical activity directly and combines activity level and mobile positioning of the cellphone via GPS and transmission towers to identify walking outdoors. Second, it uses these identified outdoor walking episodes to start an e-diary. Such a design expanded existing activity-triggered assessments because it can differentiate between indoor activities or stationary outdoor activities and walking behavior. Thus, person-place interactions with the physical and social environment, participants’ walking behavior, and how these constructs might moderate health-enhancing effects can be examined exactly in those situations in which a person is walking outdoors. This design also minimizes the burden for participants, since they receive questionnaires predominantly in situations in which a relevant behavior occurs. In addition, this study highlights the importance of assessing participants’ interpretation of their current behavior when assessing and analyzing person-place interactions.Nevertheless, walking-triggered e-diaries do face some challenges. First, the topography of cities limits the accuracy of GPS signals because buildings restrict their transmission to satellites . Second,In future studies, ambulatory assessments with walking-triggered e-diaries could be enriched with further sensor-based data  to enhance knowledge about different momentary exposures, experiences, and behavior during active mobility . FurtherThis study presents an accuracy analysis for a new method in ambulatory assessments. Our results reveal that walking-triggered e-diaries are suitable to collect different data of individuals' current experiences  during episodes of walking outdoors. Analyzing time-varying data during these predefined situations provides new insights into person-place interactions; that is, how physical and social environments shape individual experiences when walking outdoors. Based on the increasing interest in the design of health-promoting urban environments in recent years, such a design can offer substantial methodological progress. However, analyzing person-place interactions requires expert knowledge on data handling  and the management of intensive longitudinal studies in interdisciplinary teams.


Radiomics features were extracted from the B mode and Kupffer phase of S-CEUS images. Maximum relevance minimum redundancy (MRMR) and least absolute shrinkage and selection operator (LASSO) were used for feature selection, and a stepwise multivariate logit regression model was trained for prediction. Model accuracy, sensitivity, and specificity in both training and testing datasets were used to evaluate performance. Results: The prediction model derived from Kupffer phase images (CE-model) displayed a significantly better performance in the prediction of stage III HCC patients, with an area under the receiver operating characteristic curve (AUROC) of 0.908 in the training dataset and 0.792 in the testing set. The CE-model demonstrated generalizability in identifying HCC patients with elevated Ki-67 expression (>10%) with a training AUROC of 0.873 and testing AUROC of 0.768, with noticeably higher specificity of 92.3% and 80.0% in training and testing datasets, respectively. Conclusions: The radiomics model constructed from the Kupffer phase of S-CEUS images has the potential for predicting Ki-67 expression and histological stages in patients with HCC.Objectives: Histopathological tumor grade and Ki-67 expression level are key aspects concerning the prognosis of patients with hepatocellular carcinoma (HCC) lesions. The aim of this study was to investigate whether the radiomics model derived from Sonazoid contrast-enhanced (S-CEUS) images could predict histological grades and Ki-67 expression of HCC lesions. Methods: This prospective study included 101 (training cohort:  Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver, with a 5-year survival rate of less than 20% . CurrentPrevious studies showed that histological grade, which represents the biological behavior of tumors, is one of the significant prognostic factors that correlates with the recurrence of HCC after surgery . CompareMoreover, concerning the prognosis of patients with HCC lesions, Ki-67 protein expression level is another independent indicator of tumor growth rate and poor prognosis in HCC . Those wClinically, the accurate prediction of Ki-67 protein expression level and histological grade of the tumor may help in the selection of appropriate and personalized treatment. For example, preoperative transhepatic arterial chemotherapy and embolization (TACE) treatment is always recommended in highly aggressive HCC patients , which fAs a noninvasive, convenient, and real-time imaging method, ultrasound is recommended as the first-line imaging tool for the detection and diagnosis of liver tumors. Sonazoid is a hepatic-specific contrast agent with a long Kupffer phase. Contrast-enhanced ultrasound (CEUS) with Sonazoid may be helpful for better characterizing focal liver lesions . StudiesCurrent radiomics approaches based on ultrasound images involve numerous advanced, quantitative, high-throughput features. Previous studies have reported that tumor characteristics at the genetic and cellular levels can be reflected by predictive, diagnostic, and prognostic models developed with radiomics signatures ,15,16. SThe purpose of our study was to construct preoperative and noninvasive radiomic models based on the Kupffer-phase features of Sonazoid enhanced CEUS images and to predict histopathological grade and Ki-67 protein expression level of HCC lesions.In this prospective study, we constructed radiomics models based on Kupffer-phase features from Sonazoid CEUS (S-CEUS) images . Two setThis prospective study was approved by the institutional review board of our institution . Informed consent was waived before the ultrasound examination. The procedure followed was in accordance with the Declaration of Helsinki.The inclusion criteria were: (1) patients diagnosed with focal liver lesions and suspected to be HCC; (2) patients who underwent preoperative B mode ultrasound (BMUS) and S-CEUS examinations one week before surgery; (3) patients with no previous treatment, such as radiofrequency ablation, microwave ablation, chemotherapy treatment, etc.; and (4) patients’ final diagnosis were confirmed by surgical resection and histopathological results.The exclusion criteria were: (1) patients with suspected hepatic lesions that could not be clearly visualized on BMUS scan; (2) patients who were under 18 years, pregnant, or had a contraindication to Sonazoid contrast agent; (3) patients with incomplete clinical information or lack of final immunohistochemical diagnosis; and (5) patients with multiple focal liver lesions.Patients were sorted by admission dates and assigned to training and testing datasets with a ratio of 7:3; the training dataset consisted of patients admitted earlier than those in the testing dataset.S-CEUS examinations were performed by 2 radiologists with at least 10 years of liver CEUS experience, with a Siemens Acuson Sequoia machine  equipped with a 5 C-1 convex array transducer. All patients fasted for at least 8 h before S-CEUS examinations. The BMUS scan was first performed to locate the suspected HCC lesion. Then, a dose of 0.5 mL of Sonazoid was injected as a contrast agent, followed by a 5 mL saline solution flush. CEUS enhancement features were recorded and analyzed according to current WFUMB guidelines . S-CEUS The histopathological examination was performed by an experienced pathologist with more than 15 years of experience, who was blinded to the clinical and radiological results. The resected specimens were fixed with 10% paraformaldehyde solution, embedded in paraffin, and cut into 4 μm thick sections for either hematoxylin–eosin (HE) staining or immunohistochemical identification of Ki-67 protein expression. Ki-67 protein expression was considered positive when the cell nuclei were stained brown to yellow. Immunoreactive cells were classified as low Ki-67 expression (≤10% immunoreactivity) or high Ki-67 expression (>10% immunoreactivity) [Kupffer-phase CEUS and BMUS images of HCC lesions with pixel values transformed from RGB pseudo-colored to grayscale were collected for quantitative radiomic analysis. Normalization and denoising algorithms were applied to adjust for interpatient variations in CEUS examinations and to remove image noise. The ultrasound imaging system used in this study produced images that simultaneously displayed CEUS and BMUS modes. HCC lesions were manually segmented on either CEUS or BMUS depending on the visibility of the lesion using 3DSlicer  by ultrasound radiologist 1 with 5 years of experience; then, the segmentation was copied to the other half using a symmetry-based algorithm. This ensured that the tumor’s shape-related features in CEUS and BMUS were identical for a single patient. Initial tumor segmentations were confirmed by ultrasound radiologist 2 with more than 15 years of experience. In the case of an unclear tumor–liver boundary, the tumor was recorded with an ‘unclear boundary’ and the consensus reached by both radiologists was used as the final segmentation of that tumor. Both radiologists were blinded to the pathological results at the time of segmentation and confirmation.To evaluate the radiomic features’ segmentation-dependence, images from 20 randomly selected patients were resegmented by radiologist 1, and feature extraction was repeated. Radiomic signatures in the repetition were tested against features in the original extraction using the intraclass correlation coefficient (ICC). Test/retest analysis using concordance correlation coefficient (CCC) was calculated to evaluate feature stability. Features that suffered poor reproducibility or stability  were omitted from further analysis.Quantitative radiomic features were extracted using the open-source PyRadiomics package according to IBSI standards. Histogram-based gray level co-occurrence matrix (GLCM), gray level dependency matrix (GLDM), gray level size zone matrix (GLSZM), neighboring gray tone difference matrix (NGTDM), and gray level run length matrix (GLRLM) features were extracted from the Laplacian of Gaussian, wavelet transform, and local binary pattern filter-derived images. A bin width of 2 was used for histogram-based feature extraction. Two sets of radiomic features were extracted from each patient: (1) radiomic features of the grayscale image and (2) radiomic features of the Kupffer CEUS image. Z-score normalization was applied to the training dataset, then to the testing set, using the mean and standard deviation of the training data.The model was developed on the training dataset and then tested for performance on the testing dataset. For simplicity of prediction, HCC stages were further classified into an advanced group consisting of stage III patients and a mild group consisting of the rest.To coarsely narrow down the scope of valuable features, a subset of features having the most relevance with the prediction target and least correlation among themselves was identified by applying the minimal redundancy maximum relevance (MRMR) algorithm, which is a filter-based feature selection method that ranks feature relevance and intrafeature correlation using F statistics and Pearson’s correlation coefficient. The MRMR-selected subset of features was fitted to the prediction target using multivariate logistic regression. To optimize the prediction performance of the logistic regression, L1 regularization was applied to attenuate the feature coefficients, with its penalizing factor tuned with five-fold internal cross-validation. By setting the coefficient of feature least contributing to the final prediction to zero, L1-regularized logistic regression achieved further feature selection. Ten-fold cross-validation was applied in the training dataset to finalize candidate features.The finally selected features were applied in a stepwise multivariate logistic regression minimizing the Akaike information criterion (AIC) to formulate the final prediction model.Based on the modality of the images from which the radiomic features were extracted, two models were constructed: (1) BM-Model using radiomic features from B-mode images, and (2) CE-model using radiomic features from Sonazoid contrast-enhanced images.The area under the receiver operating characteristic curve (AUROC) was used to evaluate each predictive model’s performance. Diagnostic metrics such as accuracy, sensitivity, and specificity were measured at the point on the ROC curve with maximum Youden’s index in the training dataset, and threshold probabilities corresponding to the point in the training dataset were used to measure the model’s diagnostic performance in the testing dataset.t-test, Mann–Whitney U-test, and chi-squared test when appropriate. We calculated 95% confidence intervals (CIs) for the model’s performance metrics with the bootstrapped method. For comparison of model performance, Delong’s test was used for AUROC comparison, and the McNemar chi-squared test was used to compare accuracy, sensitivity, and specificity. A p-value less than 0.05 was considered statistically significant.All statistical analysis and radiomics0related model development were performed on Python (version 3.8.8) using ‘SciPy’ and ‘sklearn’ packages. Descriptive statistics are presented as the median with interquartile range or mean with standard deviation depending on the normality of statistical distribution. The normality of observations was determined using the Shapiro–Wilk test. Missing values and outliers were filled with mean or median values. Group differences were compared using Student’s n = 78), with a mean age of 59 years ± 10. Baseline characteristics were not significantly different between the training and validation cohorts   .There were significant differences in prediction accuracy  and specificity .p = 0.972). However, in the testing dataset, CE-model achieved a higher and more significant AUROC of 0.768 compared to 0.712 achieved by BM-model; the difference of AUROC was significant with Delong p < 0.05.We selected 7 and 13 radiomic features for BMUS and S-CEUS images, respectively. There were no significant differences between the AUROCs of the two models in the training dataset  (There was a noticeable difference in specificity between the two models . CE-modectively) .Previous studies have demonstrated that imaging features are potentially helpful for predicting prognosis-related factors of HCC lesions, such as tumor grade, microvascular invasion, pathological subtype, and Ki-67 expression level ,19. In rRecently, Ki-67 protein expression level has been regarded as a proliferation-associated marker. The nuclear antigen was found only in proliferative cells. High Ki-67 protein expression level indicates an active status of cell proliferation. HCCs with lower Ki-67-positive tumor cell nuclei expressed high levels of VEGF, whereas those with higher Ki-67-positive tumor cell nuclei had a lower expression of VEGF . Severalp < 0.05) and sensitivity  on the differentiation of stage I and II versus stage III HCC patients in the training set, which showed the potential to assist in the diagnosis of HCC stage during ultrasound scans. A higher sensitivity was found over higher specificity because 9 out of 41 patients (22%) in the testing group were pathologically confirmed stage III HCC.In this study, we analyzed the relationships between radiomics features and HCC stages, and used radiomics features to identify the more advanced stage of HCC (stage III). The developed radiomic models established a mathematical relationship between ultrasound radiomic features and pathological results. The CE-Model was constructed using quantitative radiomic features from Kupffer-phase images of Sonazoid CEUS, which display unique tissue characteristics after contrast agent uptake, to differentiate HCC at different stages. Compared with the BM-Model, which was based on regular BMUS scans, CE-Model presented a higher AUROC . Interpreting the complex associations between the biological processes and radiomics features remains an enormous challenge, although it aligns with the current trend toward precise and personalized medicine [Moreover, the CE-Model demonstrated good generalizability on new tasks such as the classification of Ki-67 expression of HCC tumors , while the BM-Model displayed weaker classification ability . Both models displayed no significant differences in accuracy and sensitivity. Still, a higher specificity was observed for the CE-Model , which was preferable due to there being fewer patients with lower Ki-67 expression levels in the entire study group (medicine ,29.The main limitation of this study is that it is a single-centered, prospective study with a limited patient sample. In the future, a multicenter study with an extended population size and balanced patient distribution is necessary. The diagnostic values of the arterial, portal venous, and late phases images of CEUS also remain to be investigated.The radiomic model constructed from the Kupffer phase of S-CEUS images has potential for predicting Ki-67 expression in patients with HCC. Moreover, it can provide valuable information to differentiate the histologic stages of HCC lesions.


Thrombocytopenia and platelet dysfunction commonly occur in both dengue and COVID-19 and are related to clinical outcomes. Coagulation and fibrinolytic pathways are activated during an acute dengue infection, and endothelial dysfunction is observed in severe dengue. On the other hand, COVID-19 is characterised by a high prevalence of thrombotic complications, where bleeding is rare and occurs only in advanced stages of critical illness; here thrombin is the central mediator that activates endothelial cells, and elicits a pro-inflammatory reaction followed by platelet aggregation. Serological cross-reactivity may occur between COVID-19 and dengue infection. An important management aspect of COVID-19-induced immunothrombosis associated with thrombocytopenia is anticoagulation with or without aspirin. In contrast, the use of aspirin, nonsteroidal anti-inflammatory drugs and anticoagulants is contraindicated in dengue. Mild to moderate dengue infections are treated with supportive therapy and paracetamol for fever. Severe infection such as dengue haemorrhagic fever and dengue shock syndrome often require escalation to higher levels of support in a critical care facility. The role of therapeutic platelet transfusion is equivocal and should not be routinely used in patients with dengue with thrombocytopaenia and mild bleeding. The use of prophylactic platelet transfusion in dengue fever has strained financial and healthcare systems in endemic areas, together with risks of transfusion-transmitted infections in low- and middle-income countries. There is a clear research gap in the management of dengue with significant bleeding. The exponential spread of COVID-19 that started early in 2020 resulted in one of the worst global pandemics of our lifetime, leading to a gauntlet of clinical challenges, including responding to unique patterns of coagulation anomalies. The COVID-19 outbreak has further added to clinical challenges in tropical and subtropical regions of the world, where dengue fever, caused by dengue virus (DENV) is also endemic. Similarities in clinical manifestations of COVID-19 and dengue fever often create diagnostic dilemmas in dengue-endemic countries with limited resources, often leading to delayed or even incorrect diagnosis. Furthermore, there are growing concerns of cross-reactivity due to pre-existing DENV-antibodies that potentially can enhance COVID-19 antibody-dependent immune responses . There aDENVs are the most important human arboviruses worldwide. Transmission of dengue occurs via Aedes mosquitoes, producing four antigenically distinct serotypes (DENV-1 to DENV-4). Clinical presentations range from mild to more severe infections, with significant morbidities and mortalities in endemic areas. It is estimated that there are currently 50–100 million cases of dengue infections worldwide annually, with more than 500,000 reported cases of severe forms of dengue infections such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) .DENV is a single-stranded RNA virus of the Flaviviridae family. Each of the four DENV serotypes vary in their epidemiological patterns, but some countries may have hyperendemicity with more than one serotype actively circulating at the same time , as in tThe gold standard test to confirm dengue is by reverse transcriptase-PCR (rt-PCR) targeting regions within the genome of DENV. Resource-limited countries rely on detecting DENV IgG and IgM. The serology tests could cross-react with other flaviviruses; hence the mainstay is testing for active viremia by rt-PCR . AntigenCOVID-19 is caused by SARS-CoV-2, of the order Nidovirales within the family Coronaviridae. It is an enveloped, positive-sense single-stranded RNA (+ssRNA) virus of dimension between 65 and 125 nm . Cell meNew sub-variants of SARS-CoV-2 have emerged with varying clinical significance, including transmission rates and susceptibility to vaccination ,12. As aDengue is the second most diagnosed cause of fever after malaria in travelers returning from low- and middle-income countries. The global incidence of dengue continues to grow, even though most cases are asymptomatic or mild and self-managed, suggesting that case numbers are likely under-reported. Many cases are also misdiagnosed as other febrile illnesses . Dengue The largest recent outbreak of dengue was in 2019, when all the World Health Organization (WHO) Regions were affected. The Region of the Americas alone reported 3.1 million cases, with more than 25,000 cases classified as severe . Dengue Aedes aegypti mosquitoes. Most of the mosquito-control efforts directed at adult mosquitoes in the early 1970s used expensive methods that were largely ineffective. Changing human lifestyles creates more larval habitats, thus facilitating dengue transmission by increasing mosquito populations in areas with crowded human habitation [Lifestyle changes and globalisation place severe limitations on the control of mosquito vectors to reduce dengue viral infections, in part due to rapid urbanisation in many counties. The increasing use of containers for water storage, such as automobile tyres and plastic containers, creates ideal sites for oviposition and larval habitats for bitation .COVID-19 was first described in Wuhan province (China) in December 2019. It quickly spread throughout the world and was designated a Public Health Emergency of International Concern (PHEIC), the WHO’s highest level of alert, on 30 January 2020. The resultant pandemic created dramatic lockdown measures across the globe that affected international and local travel. There were over 541 million confirmed COVID-19 cases and 6.3 million deaths reported to the WHO as of 4 July 2022 [SARS-CoV-2 is believed to have crossed the species barrier to humans from an animal reservoir, most likely from bats . TransmiThe incubation period is variably reported to be between 2 and 14 days ,23. The The spectrum of COVID-19 severity varies from asymptomatic to life-threatening/fatal infection. Risk factors for severe infection include advanced age and presence of comorbidities  Table 2Table 2. At the time of writing, the global outbreak of COVID-19 is largely receding, with the last peak recorded in January 2022 [The risk of dengue infection in various patient groups is summarised in Severe dengue most commonly occurs in infants and adults with secondary dengue infections . The most widely cited hypothesis for this is antibody-dependent enhancement (ADE) of disease, which occurs when non-neutralising anti-DENV antibodies bind to, but do not neutralise, an infecting DENV. This virus-antibody complex allows for enhanced viral entry into host cells  and the virus replicates and generates higher viral titers in blood than when the anti-DENV antibody is not present, resulting in a ‘cytokine storm’ and exacerbating the disease.Infants in dengue-endemic areas have anti-DENV IgG antibodies at birth. Anti-DENV IgG antibodies are passed from a mother to foetus (IgM does not cross placenta). This passively transferred maternal anti-DENV IgG can protect the infant for a few months after birth, which can explain why the occurrence of dengue in infants under 4 months of age is unusual. However, as the maternal anti-DENV IgG titer falls 4–6 months after birth, ADE outweighs neutralisation, and the infant is at higher risk for severe disease even with a primary DENV infection. Children aged one year or more are not at increased risk.9 platelets/L blood [Platelets play an integral part in primary haemostasis by forming a thrombus at the site of vascular injury; new platelets are produced daily to maintain a platelet count of 150–400 × 10/L blood ,31,32. A/L blood .2+, resulting in the generation of thrombin [Platelets activate neutrophils, monocytes and lymphocytes to form platelet-leukocyte aggregates, and thus participate in immune responses. It is possible that platelet surface receptors such as toll-like receptors (TLRs) and glycoprotein V1 play roles in immune responses . A haemothrombin . The semthrombin ,38.9/L and haematocrit (HCT) > 50 L/L  is associated with bleeding symptoms in adults, though a study of 245 dengue patients showed there is no clear correlation between clinical bleeding and platelet count, whereas 81 non-bleeding patients had a platelet count of <20 × 109/L [9/L [Thrombocytopenia remains a potential indicator of clinical severity of dengue infection as per WHO guidelines, with the most recent WHO guidelines (from 2009) describing rapid decreases in platelet count, or a count of less than 150,000 per microliter of blood . Coagula × 109/L , while a9/L [9/L .9/L without haemorrhage. It is also advised that platelet transfusion should be considered in patients with bleeding manifestations when platelet count is below 50 × 109/L. However, the efficacy of platelet transfusions in dengue viral infection remains a matter of debate. A study involving 106 children with DSS who had thrombocytopenia and coagulopathy indicated no significant differences in bleeding manifestations between children who received platelets or not. Patients who received platelet transfusions had more transfusion-associated pulmonary oedema and longer hospital stays [Most clinical guidelines recommend that platelet transfusions should be given to patients who develop serious haemorrhagic symptoms or when platelet count is below 10–20 × 10al stays .Severe thrombocytopenia and the secondary effects of hypoxia due to prolonged shock resulting in acidosis can trigger disseminated intravascular coagulation (DIC) and major haemorrhagic manifestations in some patients. Despite less severe bleeding and some minor abnormalities of basic clotting tests, all major pathways of the coagulation cascade are changed in children with DSS. Levels of proteins C, S and antithrombin are reduced secondary to leakage through the vascular endothelium, and correlate with the severity of shock in critical dengue infections. Direct activation of fibrinolysis by DENV may be secondary to raised levels of TF, thrombomodulin and plasminogen activator inhibitor 1 (PAI-1) which can then activate endothelial cells, platelets and monocytes.The details of the pathogenesis of thrombocytopenia and bleeding are poorly understood, with many hypotheses offered on the pathogenesis, such as that DENV directly or indirectly affects bone marrow progenitor cells by inhibiting their function and reducing proliferative capacities , as suppOther comorbidities increase the risk of severity of dengue; for example, allergy or diabetes increase the risk of DHF by 2.5 times, and hepatitis also increases the risk of complications. Increases in viral infections, hyperferritinaemia and the activation of coagulation and fibrinolytic systems occur in children with dengue compared to those without hyperferritinaemia. Other contributing factors to thrombocytopenia include cytokines, coagulation mediators, adhesive molecules and proteins, which encourage inflammatory response promoting cell interactions between platelets, immune cells and the endothelium. In addition, thrombocytopenia resulting from decreased bone marrow production and increased peripheral destruction of platelets, causes immune thrombocytopenia (ITP).NS1 correlates well with levels of viremia, and is particularly high in patients suffering from DHF. Several mechanisms have been proposed by which NS1 contributes to the coagulopathy seen in DHF, such as proinflammatory cytokine release via activation of macrophages, and activation of complement, whilst expressed on the surface of infected cells and when released into the surrounding plasma, both of which contribute to endothelial damage and increase permeability, leading to DHF . Anti-NSThrombotic thrombocytopenia syndrome (TTS), a complication of COVID-19 vaccines, involves thrombosis and thrombocytopenia with infrequent arterial thrombosis. TTS appears to mostly affect females aged between 20 and 50 years old, with no predisposing risk factors conclusively identified so far. Cases are characterised by thrombocytopenia, higher levels of D-dimers than commonly observed in venous thromboembolic events (VTE), inexplicably low fibrinogen levels and worsening thrombosis. Hyper-fibrinolysis associated with bleeding can also occur. Antibodies that bind platelet factor 4, like those associated with heparin-induced thrombocytopenia, have also been identified but in the absence of patient exposure to heparin treatment. TTS is an extremely rare but increasingly recognised serious adverse event related to thromboembolism at unusual sites, such as cerebral venous sinus thrombosis (CVST) or abdominal thromboses , all of which are associated with thrombocytopenia. ‘CVST with thrombocytopenia’ is a rare subtype of cerebrovascular accident, with an incidence of 5.0 per million in those receiving Vaxzevria (manufactured by AstraZeneca) and 4.1 per million in those receiving mRNA-based vaccines, and the prevalence is three times greater in younger to middle aged women (mean age 35). Several countries have suspended the use of adenovirus-vectored vaccines for younger individuals. The prevailing opinion is that the risk of developing COVID-19 disease, including thrombosis, far exceeds the extremely low risk of TTS associated with highly efficacious vaccines. Mass vaccination should continue but with caution. Vaccines that are more likely to cause TTS  should be avoided in younger patients for whom an alternative vaccine is available . The onlThe clinical manifestation and magnitude of coagulopathy varies greatly in patients with dengue due to differences in viral virulence, routes of exposure and host conditions . Minor bShock can also occur in COVID-19. Multisystem inflammatory syndrome in children (MIS-C) and multisystem inflammatory syndrome in adults (MIS-A) are rare post-infectious complications characterised by fever, systemic inflammation, abdominal pain and cardiac involvement. The symptoms usually occur late, while the sudden onset of severe systemic inflammation with shock is reminiscent of toxic shock syndrome in bacterial infections. The aetiology of MIS-C and MIS-A is uncertain, but derangement of the autoimmune reaction is a possibility . Increas9/L); and (4) evidence of plasma leakage manifested by haemoconcentration (>20% increase in hematocrit) or pleural effusion [Systemic viral infection also induces an acute inflammatory and hypercoagulable state, causing DIC that increases the risk of multiorgan failure and death. However, except for Ebola and Marburg, bleeding in haemorrhagic fevers is rarely a direct cause of death . Coaguloeffusion .The clinical features of coagulation disorders are quite different in COVID-19 and dengue see . COVID-1It is possible that prior exposure to DENV could provide some degree of cross-protection to SARS-CoV-2 infection, rendering it less severe in regions where dengue is endemic, as supported by a report from Singapore where a man and a woman (both aged 57 years) were originally COVID-19 virus-positive and false-positive in serological tests for dengue, including DENV-IgM and IgG . ReportsMinor bleeding such as that in the nose, gums and gastrointestinal tract is occasionally observed in children without shock . MucosalExaggerated inflammatory reactions occur during the advanced stages of COVID-19, including progression to acute respiratory distress syndrome (ARDS) and multi-organ failure, ultimately leading to shock, and the development of DIC . The proSeveral coexisting factors predisposing to increased thrombosis are observed throughout the progression of a COVID-19 infection and may manifest as thrombotic events such as myocardial infarction, pulmonary embolism or cerebrovascular disorders, with the highest rates reported among severe cases, particularly those needing ICU admission . Howeverp < 0.001). Of the 12 positive cases, nine had IgM positivity, two had IgG IgM positivity and one had both IgM and IgG IgM positivity. ELISA testing for dengue was positive in two additional subjects using envelope protein-directed antibodies but negative by lateral flow rapid testing. Out of 95 samples obtained from patients diagnosed with dengue before September 2019, SARS-CoV-2 serology targeting the S protein was positive/equivocal in 21 (22%)  versus 4 positives/equivocal in 102 controls (4%) (p < 0.001). Subsequent in silico analysis revealed possible similarities between SARS-CoV-2 epitopes in the HR2 domain of the spike protein and the dengue envelope protein. This finding supports possible cross-reactivity between DENV and SARS-CoV-2, which can lead to false-positive dengue serology among COVID-19 patients and vice versa—which has important therapeutic and public health implications [It is often difficult to distinguish between COVID-19 and dengue owing to their shared clinical and laboratory features, including possible cross-reactivity. Failing to consider COVID-19 due to false-positive dengue serology can have serious implications and vice versa. In a report published from Israel using clinical data and serum samples from 55 individuals with COVID-19, dengue-specific antibodies were detected by lateral-flow rapid tests and enzyme-linked immunosorbent assay (ELISA) in 12 (21.8%) COVID-19 patients compared to zero positive cases in a control group of 70 healthy individuals  in COVID-19, but instead lays out recommendations for general prophylactic management.Anticoagulation should not be commenced routinely in patients with mild, early symptoms, as the risk of coagulation disorders is the lowest in these patients who can be treated at home . ApproprA risk–benefit analysis should be conducted for patients with other co-morbidities that can increase coagulation risk. Anticoagulation should be continued in those already on anticoagulant therapy . However, there are specific considerations concerning the suitability of treatment in light of their current infection status, such as safe access to international normalised ratio (INR) clinics if a patient’s warfarin dosing is unstable, in which case an alternative anticoagulant may be more appropriate.In patients with a COVID-19 syndrome severe enough to be admitted to hospital, management of thrombotic risk requires a more proactive approach. Close monitoring is recommended for signs of either developing a VTE or coagulation abnormality and anticoagulation is recommended in the first instance, with or without mechanical prophylaxis.Specific agents and dosing will differ, and these should be sought from local or national guidelines related to the place of treatment, and at the discretion of the clinician treating the patient. For instance, the National Institute of Clinical Excellence in the UK currently recommends that prophylactic low molecular weight heparin be offered to all COVID-positive patients without contraindications, unless already receiving a suitable prophylaxis agent, with several considerations for escalating to a short-term therapeutic dosing regimen ; howeverMonitoring of biochemical markers is recommended for inpatients, not only for disease progression, but for signs of coagulopathy. Raised D-dimer levels are associated with increased morbidity and mortality ,78 and sSevere COVID-19, as with many other critical conditions, represents an increased risk of developing DIC . Close cThere are three phases of clinical presentations of dengue infections: febrile, critical (leakage) and convalescence . The con3 [The use of an early tourniquet when diagnosing DHF and DSS is very helpful, where blood pressure is measured using an appropriately sized cuff. Cuff pressure is increased to a value that is mid-way between systolic and diastolic pressure for 5 min, and the cuff is then released. Results can be obtained after 1 min, or once normal skin circulation is noted. The test is regarded as positive if there are ≥310 petechiae/mm3 . ParacetShock or impending shock should be suspected in dengue patients with narrow pulse pressure (≤20 mmHg), hypotension, those with clinical signs of shock ), thrombocytopenia and raised haematocrit (320%), leukopenia, which can be related to a poor appetite, clinical deterioration or significant bleeding during defervescence. Any patient with shock or impending shock needs urgent hospitalisation for intensive monitoring of vital signs and prompt management .The risk of clinically significant bleeding in dengue is unpredictable and often contributes to adverse outcomes. A large systematic review of 11 studies on prophylactic and therapeutic interventions for bleeding in dengue failed to identify any effective intervention in preventing or treating clinically significant bleeding in dengue .3 platelets/µL) without prior bleeding, of which 188 received platelet transfusions. Subsequent bleeding, platelet increases, and platelet recovery times were similar between patients either receiving or not receiving platelet transfusions. Prophylactic platelet transfusion did not prevent bleeding in adult patients with dengue infection [n = 188) or control (n = 184) groups. The intention-to-treat analysis shows clinical bleeding by day 7 or at hospital discharge occurred in 40 (21%) patients in the transfusion group and 48 (26%) patients in the control group  −15.08 to 5.34); relative risk 0.81 (95% CI 0.56 to 1.17); p = 0.16); however, significantly more adverse events occurred in the transfusion group (5.81% (95% CI –4.42 to 16.01) versus 6.26% (95% CI 1.43 to 27.34); p < 0.01). No deaths were reported. The authors concluded that prophylactic platelet transfusion was not superior to supportive care in preventing bleeding in adult patients with dengue and thrombocytopenia, and could be associated with adverse events [A retrospective study evaluated 256 patients with dengue infection who developed thrombocytopenia (platelet count, <20 × 10nfection . Anothere events .Prophylactic platelet transfusion should not be routinely prescribed based on low platelet counts in patients with dengue and no bleeding.Therapeutic platelet transfusion should not be routinely prescribed in patients with dengue with thrombocytopaenia and mild bleeding.There is insufficient evidence to support or refute the use of platelet transfusion in patients with severe bleeding in dengue.There is a need for further, well-designed RCTs to evaluate the role of platelets and plasma transfusion in patients in both the prevention of bleeding and in the setting of clinically significant bleeding in dengue infection.There is currently insufficient evidence regarding the role of rFVIIa, anti-D globulin, Ig or tranexamic acid in the prevention or treatment of bleeding in dengue infection and there is a need for further research on these therapeutic agents.Some treatment recommendations are outlined below :ProphylaSignificant coagulation abnormalities, including thrombocytopenia, are common in both dengue and COVID-19 infections. This review discusses their common pathogenesis, clinical features including potential serological false positivity, and diagnostic challenges especially in dengue-endemic areas. We also review the importance of not transfusing platelets routinely as this can further stress already stretched services globally.There are multiple complex mechanisms responsible for coagulation disturbances, thrombocytopenia and platelet dysfunction in dengue and paradoxical thromboembolism in COVID-19. The important aspects of treating COVID-19-induced immunothrombosis associated with thrombocytopenia are anticoagulation with or without aspirin. However, aspirin, nonsteroidal anti-inflammatory agents and anticoagulants are contraindicated in dengue infections.The importance of recognising the similar clinical presentations of both diseases and excluding COVID-19 in the differential diagnoses in the setting of a dengue pandemic is paramount in preventing potential serious consequences in the current management of DENV-induced thrombocytopenia. While both dengue fever and COVID-19 infections can result in thrombocytopenia and coagulopathy, their clinical manifestations and management are quite different. Prevention and control strategies combined with vaccinations are key to controlling disease burden. While successful vaccinations for dengue currently remain largely ineffective, COVID 19 vaccinations have largely been successful.


Evidence on health-related quality of life (HRQoL) outcomes is limited for new antiretroviral therapies (ART). Dolutegravir-based treatment is being rolled out as the preferred first-line treatment for HIV in many low- and middle-income countries. We compared HRQoL between treatment-naïve pregnant women randomized to dolutegravir- or efavirenz-based ART in a clinical trial in Uganda and South Africa.We gathered HRQoL data from 203 pregnant women of mean age 28 years, randomized to either dolutegravir- or efavirenz-based ART. We used the medical outcomes study-HIV health survey at baseline, 24 and 48 weeks between years 2018 and 2019. Physical health summary (PHS) and mental health summary (MHS) scores were the primary study outcomes, while the 11 MOS-HIV subscales were secondary outcomes. We applied mixed model analysis to estimate differences within and between-treatment groups. Multivariate regression analysis was included to identify associations between primary outcomes and selected variables.At 24 weeks postpartum, HRQoL scores increased from baseline in both treatment arms: PHS  and MHS  for dolutegravir-based ART; PHS  and MHS  for efavirenz-based ART. Increased scores for all secondary outcomes were significant at p < 0.0001. At 48 weeks, improvements remained significant for primary outcomes within group comparison. Estimated difference in PHS were higher in the dolutegravir-based arm, while increases in MHS were more for women in the efavirenz-based armat 24 and 48 weeks. No significant differences were noted for corresponding PHS scores at these time points compared between groups. Differences between arms were observed in two secondary outcomes: role function , p = 0.034 and physical function outcomes , p = 0.001. In the multivariate analysis, internet access was associated with higher PHS scores while owning a bank account, using the internet and longer treatment duration were associated with an increase in MHS scores.We found no important differences in HRQoL outcomes among HIV-positive women started on dolutegravir relative to efavirenz in late pregnancy. Increases in HRQoL in the first year after delivery provide additional support for the initiation of ART in HIV-positive women presenting late in pregnancy.Trial Registration Clinical Trial Number: NCT03249181 When treatment is initiated in the third trimester of pregnancy, dolutegravir-based antiretroviral therapy (ART) results in greater viral load suppression (less than 50 HIV RNA copies per ml of blood plasma) at delivery compared with pregnant women taking efavirenz-based ART . DolutegHRQoL is a patient outcome measure that focuses on addressing multidimensional aspects of health that include patients’ social role, physical status, emotional status, cognitive functioning, and a sense of general satisfaction with life , 3. In aProlonged use of ART is associated with adverse effects that can potentially impair overall HRQoL , 18. TheWe assessed HRQoL as part of the DolPHIN-2 Study  that randomized pregnant women initiating ART in the third trimester at the Infectious Diseases Institute and the University of Cape Town in Uganda and South Africa, respectively. We compared the change in HRQoL for women started on dolutegravir- versus efavirenz-based therapy before and after delivery. This knowledge is important to facilitate health policy considerations in programming newer interventions for HIV within sub-Saharan Africa.This study is part of the DolPHIN-2 clinical trial that focused on the treatment efficacy of dolutegravir-based versus efavirenz-based ART initiated in late pregnancy. DolPHIN-2 was a randomized, open-label trial, that recruited pregnant women in South Africa and Uganda aged at least 18 years, living with HIV but are treatment naive and an estimated gestation of at least 28 weeks, initiating ART in the third trimester. Participants were randomly assigned (1:1) to dolutegravir-based or efavirenz-based ART between the years 2018 and 2019. 268 treatment-naïve pregnant women were enrolled in the study. Ethical review committees in South Africa, Uganda, and the UK approved the study. Full details of the clinical outcome study are accessible elsewhere [We used the HIV Medical Outcomes Survey (MOS-HIV) to assess HRQoL in trial participants. HRQoL data were collected at three study visits; 4 weeks pre-partum, and at 24 and 48 weeks postpartum. The MOS-HIV is a comprehensive health status measure designed to assess HRQoL in patients living with HIV/AIDS , 21. We STATA 13  and SAS 9.4 (SAS Institute) were used for data analysis. Permuted block randomization (block size of 4), stratified by country was employed and baseline variables were balanced as indicated in Table Two hundred and three HIV-positive pregnant women with HRQoL information were included in this analysis. 84% (171 out of 203) had baseline socioeconomic and demographic data  and MHS  in the dolutegravir group while PHS  and MHS  in the efavirenz group  and severe birth outcome (10.7% vs. 11.3%) among women using dolutegravir versus efavirenz . AlthougBetween-group differences in secondary endpoints were significant for role function and physical function at 24 weeks postpartum. Participant HRQoL outcomes reflect treatment effectiveness and disease progression . The absIn the SPRING-1 , 205 treatment naïve adult patients were randomized to dolutegravir 10, 25, or 50 mg versus efavirenz 600 mg dose. At 96 weeks, findings revealed that dolutegravir safety profile was more favorable with no dose–response relationship with adverse events; drug tolerance was also generally better with dolutegravir-based dose compared with efavirenz-based dose . PrimaryIn the multivariate analysis, we found a negative association between CD4 count and MHS scores. This is surprising since we expect HRQoL to rise with the increase in CD4 count. One African study showed that, although CD4 increased, the quantitative impact on HRQoL changes was minimal in PLHIV . We founUsing the internet and watching television was associated with better PHS and MHS scores. Qualitative studies in Uganda and Kenya showed that avoidance and distraction were common copying techniques used by youth living with HIV to prevent poor health outcomes, among these included chatting with friends, watching television, and listening to music , 42. A rOur study used recent data collected as part of the DolPHIN-2 clinical trial study and benefited from robust central data management and statistical team and onsite quality assurance and quality control that ensured accurate collection of data. More than 80% of women entered into this sub-study had at least one HRQoL follow-up assessment. Our study had some limitations. A small sample size could be a limitation when we assess the effects of many covariates on the outcomes. The MOS-HIV is a generic tool for measuring HRQoL in HIV, this may limit its validity in specific HIV diagnostic groups such as pregnant women, and future research should consider using specific tools available. We did not collect information on pregnancy-related covariates and cannot assess whether they are balanced between the treatment arms. As a result, our findings could be subject to possible confounding due to imbalances in some unobserved covariates. Additionally, we gathered and analyzed data in a typical trial environment, we anticipate that some trial-based confounders such as protocol-based HIV care could have biased our findings. However, our study teams received training and study sites designed to minimize any form of bias, we are confident of minimal trial effects on our findings.In conclusion, we found no important differences in HRQoL outcomes among women living with HIV, who were started on dolutegravir-based versus efavirenz-based therapy in the last trimester. Increases in HRQoL scores in the first year after delivery provide additional support for the initiation of ART in HIV-positive women presenting late in pregnancy.


Immunity is governed by fundamental genetic processes. These processes shape the nature of immune cells and set the rules that dictate the myriad complex cellular interactions that power immune systems. Everything from the generation of T cell receptors and antibodies, control of epitope presentation, and recognition of pathogens by the immunoediting of cancer cells is, in large part, made possible by core genetic mechanisms and the cellular machinery that they encode. In the last decade, next-generation sequencing has been used to dissect the complexities of cancer immunity with potent effect. Sequencing of exomes and genomes has begun to reveal how the immune system recognizes “foreign” entities and distinguishes self from non-self, especially in the setting of cancer. High-throughput analyses of transcriptomes have revealed deep insights into how the tumor microenvironment affects immunotherapy efficacy. In this Review, we discuss how high-throughput sequencing has added to our understanding of how immune systems interact with cancer cells and how cancer immunotherapies work. The role of genetics in determining cancer immunotherapy response is born from two fundamental principles: (a) cancer is at its core a genetic disease, and (b) genetic mechanisms underlie the ability of the immune system to recognize diverse targets. These concepts evolved alongside the growing capabilities of next-generation sequencing (NGS) technologies that were increasingly used to identify targetable oncogenic driver mutations with the intent to expand the utility of genetic profiling in the clinic. The enthusiasm for this approach in immuno-oncology was amplified by the observation that the expression of the immune checkpoint inhibitor targets alone — i.e., PD-1, PD-L1, and CTLA-4 — was really quite insufficient to optimally identify patients with cancer who do or do not respond to immune checkpoint blockade (ICB) .The hypothesis that tumor genetics can influence immunotherapy response in patients with cancer was first observed in the setting of anti–CTLA-4 therapy for metastatic melanoma . It was Clinically, immune checkpoint inhibitors (ICIs) have improved outcomes in oncology, including prolonging the survival of patients across various cancers whether alone or in combination with other agents . DespiteTMB most commonly refers to the number of nonsynonymous single-nucleotide variants (nsSNVs) in a tumor. It can be assessed by multiple NGS techniques, including whole-exome sequencing (WES), whole-genome sequencing, or NGS panels that sequence predetermined sets of cancer-related genes, such as MSK-Impact, Tempus xT, and the FoundationOne CDx panel. Our group first discovered that the presence of high TMB or mutations in DNA damage repair genes is likely to respond better to ICI treatment , 5–8. HiAs larger cohorts of patients are treated with ICIs, it is becoming evident that the prognostic utility of TMB is context dependent; ICI-treated patients have a better outcome with high TMB, whereas non-ICI-treated patients could potentially have worse prognosis with high TMB . InteresIHC measurement of tumoral PD-L1 is one of the most commonly used clinical tests in guiding the use of anti–PD-1 and anti–PD-L1 therapy. Several conflicting studies reported both positive correlation and no correlation between PD-L1 expression and ICI response, potentially owing to variable PD-L1 staining , 18–25. Tumor neoantigens are somatic mutation–generated peptides presented on the surface of tumor cells and are absent from normal tissues . These nNeoantigenic immunogenicity requires MHC-neoepitope complex presentation and subsequent T cell recognition. Currently, a considerable challenge stems from our inability to distinguish the neoantigens that will trigger a significant T cell immune response from those that bind to MHC without a T cell response. Multiple issues contribute to this challenge. First, immunogenic neoantigens might only be expressed by a minority of tumor cells. Single-cell sequencing techniques might be able to dissect heterogeneous tumor neoantigen expression more precisely . This isIn contrast, contemporary approaches to prediction of MHC-binding potentials are increasingly relying on state-of-the-art artificial intelligence algorithms, such as neural networks (NetMHC and ConvMHC), random forest classifiers (ForestMHC), and natural language processing techniques (HLA-CNN) –46. MHC POLE/POLD1 mutations result in hypermutability due to their role in DNA proofreading and fidelity during replication . APOBEC mutational signatures have also been reported to be predictors of ICI response in urothelial cancer, NSCLC, and head and neck cancer  . Similarlication . MMR deflication . Becausek cancer –53. APOBresponse .+ CRC  have been shown to be associated with worse outcomes after ICI treatment . More remelanoma . Using amelanoma .BRAF suppresses intratumoral T cells via overexpression of IL-1α and IL-1β by tumor cells, leading to overexpression of PD-L1 and PD-L2 in tumor-associated fibroblasts  compared with patients receiving the converse sequence (52%) (In patients with melanoma with ce (52%) .KRAS is the most frequently mutated oncogene in lung adenocarcinomas. KRAS-mutated lung adenocarcinomas can be subdivided into STK11/LKB1-comutated or TP53-comutated subtypes (STK11/LKB1 comutation had significantly lower objective response rates (7.4% vs. 28.6%), median PFS (1.8 vs. 2.7 months), and median OS (6.4 vs. 16.1 months) compared with the KRAS-mutated, LKB1 wild-type patients. STK11/LKB1 alterations were also significantly associated with PD-L1–negative status in lung adenocarcinomas with intermediate to high TMB. In addition, patients with positive PD-L1 also had worse outcomes if they had an STK11/LKB1 alteration  is suggested to decrease T cell infiltration via overexpression of immunosuppressive cytokines in a melanoma preclinical model , which contains PBRM1, ARID2, and BRD7, as frequently mutated genes across cancer types  after VHL and is a component of SWI/SNF chromatin remodeling complexes  lead to contrasting outcomes of ICI treatment  treating prostate cancer with nivolumab and ipilimumab validated previous observations on the effects of homologous recombination repair deficiency on ICI response . The HLA gene family is the most polymorphic set of genes in the human genome  be feasible for use in clinical settings, (b) be able to be efficiently measured using cost-efficient means, and (c) provide useful information for decision making in medical practice. Multiple large studies have now clearly shown that, among genomic biomarkers, TMB and a few other factors provide the largest pan-cancer predictive value for ICI response , 67. Oth+ cohort demonstrated that at least 80% of the significant biomarkers by tumor type were also significant in the overall pan-cancer cohort and that there were differential predictive potentials of each biomarker by tumor type, such as TMB between melanoma and urothelial carcinoma and loss of 9q34 between RCC and the rest of the cohort  tumor-associated macrophages in RCC; (b) tissue-resident macrophages contributing to remodeling of the microenvironment during ICI treatment in lung cancer; (c) distinct neoantigen-specific TILs with specific transcriptional states; and others  has shown promise for the ability to monitor response to ICI after initiation of treatment. Still, there remain substantial challenges to clinical implementation of dynamic circulating biomarker profiling, including lack of harmonization of reporting metrics, varying kinetics of response from study to study, and varying levels of sensitivity between different assay technologies , 155. ImThe current state of biomarker development for cancer immunotherapy is excellent, with an ongoing data deluge of considerable potential and ever-improving technologies. Tumor-agnostic FDA approvals for immunotherapy have been achieved, which is a notable achievement in oncology. However, there is still work to do to improve predictive strategies for identifying responders and nonresponders to ICIs, especially in the setting of combination therapies. As discussed above, we are on a path toward understanding the interplay of relevant mechanisms intrinsic to the tumor, the host, and the interaction between tumor and host and how different processes may vary in a context-specific manner. Biomarker models need to be feasible for clinical use and require technological improvements that may be assisted by advances in artificial intelligence and machine learning. Our field’s understanding of immuno-oncology and immunotherapy response has come a long way very quickly, and there is no sign that it will be slowing down anytime soon.


Infectious agents have been implicated in the pathogenesis of autoimmune disorders for decades. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is no exception. This became evident as the pandemic evolved. Once considered a respiratory pathogen only, SARS-CoV-2 is now linked to a variety of autoimmune rheumatic disorders such as rheumatoid arthritis, systemic lupus erythematosus, reactive arthritis, spondyloarthropathies, vasculitis, and inflammatory myopathy. Although the exact cause for muscle injury in the setting of coronavirus disease 2019 (COVID-19) is not established, autoimmune inflammatory damage is the most accepted mechanism. Moreover, SARS-CoV-2 can cause direct muscle damage and indirectly through a cytokine storm. Inflammatory polymyositis in relation to COVID-19 has seldom been reported in developing countries.Here, we report a unique case of inflammatory polymyositis in a 52-year-old lady. The patient presented with muscle weakness, generalized body aches, and fatigue occurring four months after recovering from mild COVID-19. She had muscle weakness of Medical Research Council (MRC) grade 3/5 involving the shoulders and pelvic girdle with elevated muscle enzymes. Electromyography revealed an active irritable myopathic process consistent with inflammatory polymyositis. She underwent magnetic resonance imaging-guided muscle biopsy from the right thigh which revealed findings consistent with inflammatory myopathy. She was offered prednisolone and azathioprine. After four weeks of treatment, she had a remarkable improvement in her muscle strength to MRC grade 5/5. Viruses have been linked to the initiation and modulation of immune responses in various autoimmune rheumatic illnesses. However, the processes by which viruses and autoimmune disorders interact remain unknown . CoronavThe effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the immune system and cytokine profiles are unclear. Several reports have been published describing the immunological alterations seen with COVID-19. These range from a maladaptive immune response and abnormal cytokine production to hyperactivation of T cells and increased numbers of activated monocytes and macrophages .Antinuclear antibodies (ANA), anti-Sjogren syndrome-related antigen A antibody (anti-SSA), rheumatoid factor (RAF), lupus anticoagulant, and antibodies to interferon are found in 35.6%, 25%, 19%, 11%, and 11% of cases of COVID-19, respectively .The leading causes of muscle involvement in COVID-19 include idiopathic inflammatory myositis, dermatomyositis, necrotizing autoimmune myositis, anti-synthetase syndrome-overlap myositis, and inclusion body myositis . The mosSo far, nine cases of inflammatory polymyositis/dermatomyositis following COVID-19 have been reported. Of the nine cases, four have been reported from Europe and two each from the United States and Asia. Out of nine cases, five were female with a mean age of 55.6 years; most (seven cases) of them recovered . MoreoveA 52-year-old hypertensive lady presented with complaints of shortness of breath, muscle weakness, generalized body aches, and fatigue for the last four months. The shortness of breath was gradual in onset but recently worsened to the extent that she could hardly perform her daily activities. There was no history of orthopnea, paroxysmal nocturnal dyspnea, and chest pain. The muscle weakness had started gradually four months ago and was predominantly in the proximal muscles. It was accompanied by body aches and fatigue. There was no diurnal variation in the muscle weakness. She had difficulty placing heavy objects on the shelf, combing her hair, rising from a sitting position, and walking up and down the stairs. There was no history of joint pain, swelling, stiffness, Raynaud’s phenomena, dysphagia, and skin rashes.She had a reverse transcriptase-polymerase chain reaction-confirmed COVID-19 infection four months ago. The severity of COVID-19 was mild as per the World Health Organization (WHO) criteria. She received appropriate treatment and had an uneventful recovery.She had no significant relevant medical or surgical history, and she was not taking any regular medications except paracetamol. Her travel history was not significant. She was not vaccinated against COVID-19.On examination, her pulse was 80 beats per minute with a blood pressure of 120/70 mmHg, temperature of 98°F, respiratory rate of 14 breaths per minute, and oxygen saturation of 97% on room air. She had weakness involving proximal muscle groups of upper and lower limbs bilaterally, Medical Research Council (MRC) grade 3/5. There was no rash on the hands or face. The rest of her examination was unremarkable. She was admitted to the medical unit of Hayatabad Medical Complex Peshawar, Pakistan for further workup. Her initial investigations are summarized in Table Her autoimmune profile including ANA, RAF, and anti-cyclic citrullinated peptides was negative. A further autoimmune screen could not be performed as the facilities were not available locally. She underwent a nerve conduction study and electromyography which showed an active irritable myopathic process consistent with inflammatory polymyositis. She was started on tablet prednisolone 60 mg per day along with calcium and vitamin D supplements. Azathioprine 50 mg twice a day was added to her regimen as a steroid-sparing agent. She underwent contrast-enhanced computed tomography of the chest, abdomen, and pelvis which showed enlarged fatty liver and atrophic left kidney. Given the electromyography findings, she underwent magnetic resonance imaging of the shoulder and hip muscles which revealed inflammatory changes in the muscles of the shoulder and pelvic girdle, chest, and anteromedial and lateral compartments of the thighs Figures -3.She underwent a muscle biopsy from the right thigh. The histopathology report revealed lymphocytic infiltrate in the muscle, atrophy of the muscle fibers with the splitting of the fibers, vacuolization of cytoplasm, and internalization of nuclei, suggestive of inflammatory myopathy. The inflammatory cells were positive for cluster of differentiation 3 (CD3) and replacement of muscle fibers by fibro-adipose tissue Figures , 5.The patient was assessed daily during her in-patient stay for muscle power and vital capacity. On day 10, the power in her upper and lower limbs improved to the extent that she could walk without support. The changes in her laboratory parameters throughout her stay are summarized in Table The patient was discharged and advised to follow up in the medical outpatient clinic to assess her respiratory and motor system and titrate the steroid accordingly. After four weeks, she was reviewed in the outpatient clinic. She had a remarkable improvement in muscle strength of 5/5 on the MRC scale. Her creatinine phosphokinase (CPK) was 115 U/L. She was booked for a dual-energy X-ray absorptiometry scan as a baseline. The prednisolone was tapered to 50 mg daily aiming to reduce it to a 20 mg maintenance dose within four months.As the COVID-19 pandemic unfolds, SARS-CoV-2 is behaving like a chameleon. Once thought to be a respiratory pathogen, it is now associated with a variety of systemic manifestations. COVID-19 is associated with extrapulmonary involvement, including autoimmune rheumatic disorders, for which an exact immunological mechanism needs to be determined. The initial assumption that COVID-19 is a stand-alone pulmonary infectious disease has significantly changed .Only one case of COVID-19-related inflammatory polymyositis was documented in the literature by July 2020. Since then, multiple case reports and series have been published describing virus-induced inflammatory polymyositis linked to COVID-19. The involvement of muscles might range from asymptomatic muscle enzyme elevation to severe rhabdomyolysis . It was A systematic review by Gracia-Ramos et al. from December 2019 to September 2021 identified 99 patients who fulfilled the specific diagnostic criteria of rheumatic autoimmune disease. In total, 17 patients had inflammatory myopathies, and nine fulfilled the Peter and Bohan criteria. The mean age of the patients was 55.6 years (ranging from 38 to 77 years), and two-thirds of the cases were female. The time interval between COVID-19 and the development of inflammatory polymyositis varied from ten days to three months. The majority of cases (55.5%) had critical and severe COVID-19 [A review by Saud et al. in 2021 found 23 cases of inflammatory polymyositis, with most cases reported in males, in contrast to Gracia-Ramos et al. The age ranged from 33 to 87 years . A mini-In our case, a female aged 50 years developed inflammatory myositis four months after mild COVID-19. Even though idiopathic inflammatory polymyositis is more common among females, there is inconsistent evidence for the gender predilection of inflammatory polymyositis following COVID-19 . The cliCOVID-19 is no longer an acute illness limited to the respiratory system. It may involve other systems at the time of the initial illness, several months after recovery from the acute infection, and even after vaccination for COVID-19. It can lead to fatality even if the person survives the acute infection. Physicians should be vigilant to look for multisystemic involvement during COVID-19 illness. Moreover, all COVID-19 patients should be educated and followed for a long time after recovery lest they develop late multisystemic manifestations.