A high-resolution dataset of digitally scanned railway ballast  is presented, consisting of 108 individual, digitised samples. The ballast samples were sourced from both a railway test track section located on a heavy haul coal export line in South Africa and a local quarry. The sampled ballast from the field installation represent angular, semi-angular and rounded geometric features depending on the sampled location. The fresh ballast sourced from the quarry was iteratively tested using a hydraulic actuator in a small-scale box test which forms part of a separate research project. The ballast samples were scanned before and after every test to ascertain the changes in geometry, in addition to the loss of material due to attrition. The field and laboratory samples were digitised using a high-resolution, commercial  VSLAM-based scanner with a 40-micrometre accuracy. Samples which were fractured by the hydraulic actuator are also included in the dataset. HRSBallast serves as a reference dataset for granular media (GM) simulations utilizing DEM (discrete element method), degradation or wear modelling, digital assets for the creation of synthetic datasets for deep learning applications, embedded railway instrumentation and video games requiring high-resolution geometry. No datasets are readily available with practitioners relying on in-house scanning solutions to generate their own samples 1Railway infrastructure is designed for the economical and safe transportation of passengers and freight. The rail structure with its defined vertical and horizontal alignment, in combination with the various track components, provides the required performance subject to a range of environmental and loading conditions. The response of the granular material supporting the superstructure results from a complex interaction of principal stress rotation •An instrumented section of railway track on the Coal export line near Bloubank, KwaZulu-Natal in South Africa •Fresh ballast  sourced from a nearby quarry in Pretoria, South Africa. These samples were subjected to accelerated testing in a laboratory. These samples  are denoted with a “M”-prefix.For the proposed dataset  installed in the small-scale box test and subjected to 100,000 load cycles by the hydraulic actuator . The sam•Fresh ballast placed in a concrete mixer for 15 min (M0A-M0J). The samples were installed in the small-scale box test and subjected to 100,000 load cycles by the hydraulic actuator. The samples were scanned again after concluding the cyclic loading (M1A-M1J) .Fig. 6Co•Fresh ballast placed in a concrete mixer for 30 min (M0K-M0T). The samples were installed in the small-scale box test and subjected to 100,000 load cycles by the hydraulic actuator. The samples were scanned again after concluding the cyclic loading (M1K-M1T) .The 60 ballast samples obtained from the quarry are subdivided into three categories:The two collections of samples which were pre-treated in the concrete mixer  produced an additional 3 ballast samples  originating from ballast fracturing during the cyclic loading. The fragments which were large enough to be successfully scanned are included as separate fragments . The addition of the sample fragments resulted in a total of 63 scans.1.3HighRes.zip) LowRes.zip) archive The original, high-resolution sample scans are available as a single archive  summarises the following information:•Sample ID);sample identification number (•Vertex count);total number of vertices (•Face count);total number of faces  of every ballast sample are provided in the data repository 2The in-service ballast samples were obtained from the instrumented section of rail track located on the heavy haul Coal export line near Bloubank in the KwaZulu-Natal province of South Africa . This naSOLO Goya TRITON acrylic paint marker 1.4 mm silver) was used to clearly mark every sample with a unique (number of letter) designation across multiple locations on the surface. The acrylic paint is resistant to abrasion and does not compromise the scanning performance. Furthermore, the reflective markings of the paint assist the scanner in accurately aligning the discrete scans. The samples were weighed using a calibrated laboratory scale with a resolution of 10 mg. The mass of every sample, combined with the volume from the scanning process, yields an accurate estimation of the material density.The fresh ballast samples sourced from the quarry were rounded for a predetermined amount of time using a concrete mixer. The inter-particle attrition serves as an efficient method to grind down the edges of the ballast. All the samples presented in this dataset conform to the specifications as required for South African heavy haul railway operating condition medium quality preset, prior to the decimation step. The generated mesh of every ballast sample was decimated , limiting the number of faces to between two and three million for some measure consistency among the various ballast sample sizes. The final mesh was exported as a single STL file and stored on the computer. No scaling factors were applied during the last step of the export procedure, ensuring that the true dimensional scale of the model is retained.A commercially available VSLAM-based EinScan Pro HD  rd party 3D Print add-on tool (enabled in the preferences menu). Once the model is selected in the software, the Volume and Area options of the 3D print tool are selected to calculate and display the volume and surface area of the ballast sample, respectively. Blender also provides a built-in decimation modifier which was used to reduce the density of the point cloud (and corresponding mesh), similar to the post-processing steps required during the scanning process. A decimation factor of 0.01 (1%) reduced the number of vertices and faces substantially, producing the final low-resolution version of the dataset. Blender, the open source animation, graphics, and modelling software suite, was primarily used to measure the sample's volume and surface area. The high-resolution STL file generated by the scanning process is imported into Blender followed by measurements using the 3André Broekman: Conceptualization, Data Curation, Formal analysis, Investigation, Methodology, Project administration, Software, Validation, Visualization, Writing - Original Draft. Jacobus Oostewald Van Niekerk: Conceptualization, Investigation, Project administration, Resources, Visualization, Writing - Review & Editing. Petrus Johannes Gräbe: Funding acquisition, Resources, Supervision, Writing - Review & Editing.The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article.


The dysregulated release of cytokines has been identified as one of the key factors behind poorer outcomes in COVID-19. This “cytokine storm” produces an excessive inflammatory and immune response, especially in the lungs, leading to acute respiratory distress (ARDS), pulmonary edema and multi-organ failure. Alleviating this inflammatory state is crucial to improve prognosis. Pro-inflammatory factors play a central role in COVID-19 severity, especially in patients with comorbidities. In these situations, an overactive, untreated immune response can be deadly, suggesting that mortality in COVID-19 cases is likely due to this virally driven hyperinflammation. Administering immunomodulators has not yielded conclusive improvements in other pathologies characterized by dysregulated inflammation such as sepsis, SARS-CoV-1, and MERS. The success of these drugs at reducing COVID-19-driven inflammation is still anecdotal and comes with serious risks. It is also imperative to screen the elderly for risk factors that predispose them to severe COVID-19. Immunosenescence and comorbidities should be taken into consideration. In this review, we summarize the latest data available about the role of the cytokine storm in COVID-19 disease severity as well as potential therapeutic approaches to ameliorate it. We also examine the role of inflammation in other diseases and conditions often comorbid with COVID-19, such as aging, sepsis, and pulmonary disorders. Finally, we identify gaps in our knowledge and suggest priorities for future research aimed at stratifying patients according to risk as well as personalizing therapies in the context of COVID19-driven hyperinflammation. Accumulating evidence suggests that patients with severe COVID-19 develop a dysregulated release of cytokines also known as a “cytokine storm” or “cytokine storm syndrome.” The cytokine storm produces an excessive inflammatory and immune response, especially in the lungs, leading to acute respiratory distress (ARDS), pulmonary edema and multi-organ failure. In these situations, an overactive, untreated immune response can be deadly, suggesting that mortality in COVID-19 cases is likely due to this virally driven hyperinflammation. While the risk factors and phenotype profiles that cause otherwise healthy individuals to become critically ill still remain unknown, preliminary evidence suggests that other inflammatory processes such as aging or permanent lung damage may make one predisposed to a poorer prognosis. In this review, we summarize the latest data available about the role of the cytokine storm in COVID-19 disease severity as well as potential therapeutic approaches to ameliorate it. We also examine the role of inflammation in other diseases or conditions often comorbid with COVID-19, such as aging, sepsis, and pulmonary disorders. Finally, we identify gaps in our knowledge and suggest priorities for future research aimed at stratifying patients according to risk as well as personalizing therapies in the context of COVID19-driven hyperinflammation.Inflammation is a vital phenomenon of a healthy immune response. However, dysregulated inflammation can result in severe damage, multisystemic organ dysfunction or even death. Rampant inflammation plays a central role in several pathologies such as sepsis, rheumatoid arthritis, respiratory diseases, cancer, and aging. Below we briefly review the role of inflammatory responses in several of these pathologies or conditions, which have been found to be aggravating factors in COVID-19.As we age the effectiveness of the innate and adaptative immune response declines, and this results in reduced protection against external pathogens, decreased ability to vaccination and increased susceptibility to infection, and limited repair capacity of damaged cells and tissues. This process is called “immunosenescence”  and it lSepsis is a life-threatening clinical process characterized by the dysregulation of homeostasis and the presence of a systemic inflammatory response syndrome. Sepsis is caused by an infection  and leads to multiorgan dysfunction . ConsequSepsis survivors are immunosuppressed, which makes them easy targets for viral infections such as COVID-19 . LikewisInflammation also plays a central role in respiratory diseases such as chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. In allergic asthma, epithelial cells respond to the presence of the allergen by producing cytokines such as IL-25 and IL-33 . In turnMuch can be learned about the role of inflammation in the course of the infections from previous respiratory coronaviruses. SARS-CoV-2, the severe acute respiratory disease coronavirus (SARS-CoV-1) and the Middle Eastern Respiratory Syndrome coronavirus (MERS-CoV) infect the lower respiratory airways and can cause severe pneumonia. During the first 9 days the patient shows flu-like symptoms such as cough and fever, often accompanied by diarrhea . During The production of chemokines by immune cells plays a central role in coronavirus-related hyper-inflammation. For example, infection of human monocyte-derived macrophages with SARS-CoV resulted in a very low production of IFN-γ but successfully induced the expression of CXCL10/IFN-inducible protein 10 and CCL2/monocyte chemotactic protein 1 . ChemokiThe origin of the dysregulated release of cytokines in these infections has been ascribed to diverse factors . It is aThe dynamic interplay of factors involved in the cytokine storm generated by coronavirus infections makes it complicated to design therapies to halt its progression. For example, treatment with corticosteroids has been found to be mildly beneficial, not beneficial at all, or even deleterious in different studies –36. ThesA recent paper published in Lancet was the first to report the epidemiological, clinical, laboratory, and radiological characteristics, treatment, and clinical outcomes of 41 laboratory-confirmed cases infected with SARS-CoV-2  is strongly associated with the levels of IL-6 in COVID-19 patients . The levThe serial detection of IFN-γ-induced protein 10 (IP-10), monocyte chemotactic protein-3 (MCP-3) and IL-1ra in 14 severe cases showed that the continuous high levels of these cytokines were associated with disease deterioration and fatal outcome . The autSeveral studies have also reported that the activation of coagulation pathways , during the immune response to COVID-19 might also lead to an overproduction of proinflammatory cytokines leading to multiorgan injury and death .In summary, early reports show a correlation between the cytokine storm syndrome and severity leading to a poor prognosis in COVID-19.Below we also review early therapeutic attempts at relieving this hyperinflammatory state with available drugs at the time of the pandemic.Currently, the preferred therapeutic approach to COVID-19 seems to be a multimodal treatment combining antibiotics, antiviral , and anti-inflammatory drugs with support therapies for the respective organic failures , 61. AntEmerging evidence indicates that there are potential benefits when managing the cytokine storm in COVID-19 patients by administering steroids, IL-6/IL-6-receptor (IL-6R) blocking antibodies, TNF inhibitors, IL-1 antagonists, and Janus kinase inhibitor (JAK) inhibitors . SteroidTocilizumab is an FDA-approved immunosuppressive drug targeting IL-6R that is commonly used for the treatment of rheumatoid arthritis (RA) . TocilizWu and Yan  suggest Hydroxychloroquine (HCQ), an anti-malarial drug which exhibits an antiviral effect similar to that of chloroquine, could mitigate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation . HCQ hasAzithromycin is an antibacterial agent (macrolide) that is also being used to treat COVID-19 patients in combination with other drugs such as hydroxychloroquine. It has a well-known immunomodulatory effect and could be an important element of multimodal treatments, even in seriously ill patients .n = 3) merits more investigation  in COVID-19 patients , 73.To date, no available FDA drug or therapy has demonstrated 100% efficacy for patients with COVID-19. The high percentage of critically ill patients in the COVID-19 pandemic has forced some ICUs to take desperate measures. In this context, it is imperative to identify biomarkers for predicting disease severity and prognosis in order to make more efficient choices regarding the use of limited resources in ICUs as to avoid their oversaturation. According to early reports depicted in There is a need to better understand the disease, its pathophysiology, temporal evolution, prognostic clinical and analytical parameters, the immunity (or not) generated, and the real impact of the proposed treatments that are being evaluated in different clinical trials at this moment. Lessons learnt from other hyperinflammatory syndromes such as sepsis and the cytokine storm responsible for the poor outcomes in SARS and MERS show a strong time dependence between cytokine levels and disease progression. We propose that measuring inflammation biomarkers frequently over time is the best strategy to characterize the evolution of the cytokine storm, since it provides a personalized biomarker profile for each patient. In turn, this could be used for guiding the timing and dosage of anti-inflammatory treatments, as well as to assess their effectiveness. Point-of-care diagnostic devices will likely be crucial to enable these kinetic biomarker measurements without collapsing central diagnosis laboratories –77.Young individuals or people with no associated morbidities typically have mild symptoms or remain asymptomatic, while the elderly experience substantially more severe symptoms and lethality. Prevention and screening strategies should be implemented to manage COVID-19 disease . Older pFinally, there is an urgent need to develop rehabilitation treatments for COVID19 survivors. Patients with respiratory symptoms who survive the virus might be probably left with chronic problems, such as lung fibrosis, lower lung function, and kidney damage , 79. IntRR, MB and MG-F contributed to develop the content of the manuscript and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The global pandemic of coronavirus disease 2019 (COVID-19) rapidly spread worldwide during the first few months of 2020. Most industrialized countries had to adopt so-called “suppression strategies” against COVID-19, aiming to greatly reduce virus transmission and to limit deaths and the demand for critical care services. These suppression strategies have required substantial reductions in the rate of human-to-human contact, sometimes via legally binding countermeasures including “lockdown” policies in urban areas [2) emissions were instantaneously reduced for a certain duration of time [2 emissions levels. Nevertheless, the impact of COVID-19 on climate change comprises both positive and negative elements because many COVID-19 countermeasures have had severely negative economic impacts. Moreover, plans for mitigation as well as adaptation are also considerably affected by the “new normal” lifestyles. Under the direction of the Ministry of the Environment, Japan, the Environmental Restoration and Conservation Agency of Japan (ERCA) has launched a strategic financial support program, the Environment Research and Technology Development Fund, to support “Integrated Research on Climate Change Impact Assessment and Adaptation Plans” , beginning in the fiscal year 2020. The project aims to provide up-to-date scientific evidence to assist decision-making regarding governmental policies for adaptation planning that also address climate change. As life under the new normal conditions progresses worldwide, our strategic research program should also be flexibly set to measure the scientific features of the relationship between COVID-19 and climate change. In this editorial, we aim to discuss the research agenda regarding this particular relationship.Such drastic and artificial changes in societies around the world have provided an unprecedented opportunity for the scientific community to study climate change. Global air pollution and carbon dioxide CO emissionr = −0.31, p < 0.01; Two issues must be debated regarding the impact of climate change on COVID-19. First, we have begun to understand how temperature levels could have a direct impact on human-to-human transmission of COVID-19 and how cold weather increases secondary transmission of SARS-CoV-2. At the moment, it is very likely that cold weather could increase the spread of COVID-19 . This epSecond, more broadly, the COVID-19 pandemic offers a unique research opportunity to investigate the increasing frequency of emerging infectious diseases over time . Most no2 emissions during 2020, which represents a crucial moment in terms of countermeasures that can mitigate climate change. The global population has directly experienced reduced CO2 emissions and improved air quality. However, decreases in CO2 emissions owing to the COVID-19 pandemic account for only a small proportion of the planned reduction target [2 emissions should be encouraged. Additionally, the post-pandemic period presents an important opportunity to implement adaptation measures, to recover public trust. People are now better able to understand the seriousness of global warming; therefore, preparedness against the adverse impacts of climate change can be strengthened during this window of opportunity.Reverse causal effects  during the aftermath of the COVID-19 pandemic have yielded both positive and negative impacts. A critically important positive impact is the resulting reduced levels of COn target , requiriThere are numerous possible negative impacts of the COVID-19 pandemic on climate change. Importantly, we must remember that people with underlying comorbidities and those with lower incomes are disproportionately affected by both COVID-19 and climate change. Thus, the physical impact of the COVID-19 pandemic together with climate change is more intense in socioeconomically underdeveloped countries and populations. Global society should protect these vulnerable populations from this double burden by maintaining solidarity with these countries. The financial impact of COVID-19 on climate change has been huge, and it has become clear that the global economy is not very resilient. This is bad news for continuing and additionally implementing responses to climate change because these include many costly measures, such as transformation to renewable energy sources, electrification of transportation systems, and other clean technologies. At minimum, policy leaders in industrialized nations should aim to take action toward climate-resilient recovery during the post-pandemic period. It is also vital to remember that social changes owing to COVID-19 can lead to complications with respect to future adaptation. For instance, the time and frequency that care workers spend with elderly people has been greatly reduced, to avoid unnecessary close contact in confined spaces. However, this situation can lead to lower levels of care and monitoring in elderly populations aimed to avoid problems such as heat stroke, where older people may need to be reminded to drink water and use air conditioning. Such critical points should be thoroughly explored over the course of the pandemic.We have briefly described the research agenda surrounding the COVID-19 pandemic in terms of climate change. Owing to the pandemic, climate change studies in 2020 have partly stagnated with researchers forced to work remotely. However, taking advantage of the heightened awareness of the mutual impact of the COVID-19 pandemic and climate change, important modifications have taken place owing to physical, financial, and social conditions being altered during the pandemic. Concerted research efforts on this subject are called for.


The amount of erythrocyte-derived microRNAs (miRNAs) represents the majority of miRNAs expressed in whole blood. miR-451, miR-144, and miR-486, which are abundant in red blood cells (RBCs), are involved in the process of erythropoiesis and disease occurrence. Moreover, erythrocyte-derived miRNAs have been reported to be potential biomarkers of specific diseases. However, the function and underlying mechanisms of miRNAs derived from erythrocytes remain unclear. Based on a review of previously published literature, we discuss several possible pathways by which RBC miRNAs may function and propose that RBCs may serve as repositories of miRNAs in the circulatory system and participate in the regulation of gene expression mainly via the transfer of miRNAs from erythrocyte extracellular vesicles (EVs). In the whole blood, there are still other important cell types such as leukocytes and platelets harboring functional miRNAs, and hemolysis also exists, which limit the abundance of miRNAs as disease biomarkers, and thus, miRNA studies on RBCs may be impacted. In the future, the role of RBCs in the regulation of normal physiological functions of the body and the entire circulatory system under pathological states, if any, remains to be determined. Extensive evidence has shown that miR-451 and miR-144 are crucial to erythropoiesis and are located within the same gene cluster and regulated by the erythrocyte-specific transcription factor GATA1 (Research studies conducted in the past decades have shown that that microRNAs (miRNAs) play key roles in the process of erythropoiesis. or GATA1 . In addior GATA1 . Interesor GATA1 .Transfusion showed that prolongation of the RBC preservation period alters the expression patterns of RBC-derived miRNAs  participate in parasite pathogenesis, host defense, and the evolution of host polymorphisms driven by host interactions with these parasites  nephropathy , 2017. KPrevious studies have shown that the characteristics of erythrocytes are influenced by the tumor environment . PritchaAlthough multiple miRNAs derived from leukocytes and platelets in whole blood have been reported to be inextricably linked with the disease , RBCs asin vitro  sequence of target genes to form RNA-induced silencing complexes that influence protein synthesis by regulating gene transcription or degrading cytoplasmic messenger RNAs (mRNAs) . Early sIt is presumed that any residual translation in RBCs can be regulated by these miRNAs. As mentioned earlier in this review, researchers have studied the potential of miR-4732-3p in regulating Smad2 and Smad4 in RBCs, which show that miR-4732-3p overexpression inhibits SMAD4-mediated transcriptional activity . AlthougThe large circulating erythrocytic pool may be the source of miRNAs associated with protein (miRNPs), which are transported to recipient cells where these reprogram mRNA translation. Argonaute 2 (Ago2) binds and protects miRNAs from degradation in the circulatory system. As a basic functional unit, Ago2 directs the complex to specific targets on the regulated mRNA .Previous studies have demonstrated the existence of multiple intracellular Ago2-bound miRNAs in RBCs that are stored for 24 h. Among these Ago2-bound miRNAs, miR-16-5p, miR-451a-5p, miR-486-5p, and miR-92a-3p are the most abundant miRNAs. Functional enrichment analysis of mRNA targets of major miRNAs identified molecules that are related to various diseases, biofunctions, and toxicity functions such as cardio-, hepato-, and nephrotoxicity . It has Another study evaluated protein-bound miRNAs in RBC supernatants and showed that these induce monocyte suppression  which inExtracellular vesicles are the main miRNA carriers in the circulatory system . Under nP. falciparum) between the donor cells and recipients, which is involved in the development of parasite infection  and downregulated its expression  mature RBCs may absorb exogenous miRNAs or release internal ones through the circulatory system , and (2)LS, DW, and BN composed the manuscript. LS and YY edited and revised the manuscript and the figure.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


An increasing number of subjects are recovering from COVID-19, raising the need for tools to adequately assess the course of the disease and its impact on functional status. We aimed to assess the construct validity of the Post-COVID-19 Functional Status (PCFS) Scale among adult subjects with confirmed and presumed COVID-19.Adult subjects with confirmed and presumed COVID-19, who were members of an online panel and two Facebook groups for subjects with COVID-19 with persistent symptoms, completed an online survey after the onset of infection-related symptoms. The number and intensity of symptoms were evaluated with the Utrecht Symptom Diary, health-related quality of life (HrQoL) with the 5-level EQ-5D questionnaire, impairment in work and activities with the Work Productivity and Activity Impairment questionnaire and functional status with the PCFS Scale.1939 subjects were included in the analyses  about 3 months after the onset of infection-related symptoms. Subjects classified as experiencing ‘slight’, ‘moderate’ and ‘severe’ functional limitations presented a gradual increase in the number/intensity of symptoms, reduction of HrQoL and impairment in work and usual activities. No differences were found regarding the number and intensity of symptoms, HrQoL and impairment in work and usual activities between subjects classified as experiencing ‘negligible’ and ‘no’ functional limitations. We found weak-to-strong statistical associations between functional status and all domains of HrQoL (r: 0.233–0.661). Notably, the strongest association found was with the ‘usual activities’ domain of the 5-level EQ-5D questionnaire.We demonstrated the construct validity of the PCFS Scale in highly-symptomatic adult subjects with confirmed and presumed COVID-19, 3 months after the onset of symptoms. As of January, 12th 2021, more than 88.3 million confirmed cases of the corona virus disease 2019 (COVID-19) causing approximately 1.900.000 deaths were reported globally . Previouhttps://osf.io/qgpdv/ (CC-BY 4.0). To date, however, no study has investigated any measurement property of the PCFS Scale in post-COVID-19 subjects.Klok and colleagues proposed the “Post-COVID-19 Functional Status (PCFS) Scale” to be used as a patient-reported outcome measure to evaluate the consequences of COVID-19 and their effect on functional status . The PCFThe aim of the present study was, therefore, to assess the construct validity of the PCFS Scale among adult subjects with confirmed and presumed COVID-19 by testing the hypothesis that this simple tool is associated with the number and intensity of symptoms, HrQoL and impairment in work and usual activities due to health.www.coronalongplein.nl) received a web link with an invitation to fill out questionnaires.This cross-sectional, survey study was conducted in the Netherlands and Flanders (Belgium) between June 4th and June 11th 2020. Members of two Facebook groups for COVID-19 subjects with persistent complaints , 13 and Subjects were asked one-off to provide information regarding anthropometric/sociodemographic characteristics and medical history . Subjects were stratified into four groups according to the type of COVID-19 diagnosis: (1) hospitalized with confirmed COVID-19 ; (2) non-hospitalized with confirmed COVID-19 (based on reverse transcription polymerase chain reaction (RT-PCR) test and/or computed tomography (CT) scan of the thorax); (3) non-hospitalized with symptom-based diagnosis of COVID-19 ; and (4) non-hospitalized with presumed COVID-19 .The medical ethics committee of Maastricht University stated that the Medical Research Involving Human Subjects Act (WMO) does not apply for this study and that an official approval of this study by the committee was not required (METC2020-1978). The medical ethics committee of Hasselt University formally judged and also approved the study (MEC2020/041). All subjects gave digital informed consent at the start of the survey. Data from this study on persistent symptoms and care dependency have been published before –16.The present study adopted the definition of one of the three domains of validity  described in the COSMIN study—which aimed to clarify and standardize terminology and definitions of measurement properties that are relevant and should be evaluated for health-related patient-reported outcomes (HR-PRO) . ConstruTo assess the level of impairment in functional status subjects were asked to fill in the PCFS Scale . The PCFP < 0.05.Continuous variables are presented as mean and standard deviation or median and interquartile range, as appropriate. Categorical variables are presented as absolute and relative frequency. The comparisons of continuous variables between subjects with different levels of impairment in functional status were performed with Kruskal–Wallis test, as the dependent variables were not normally distributed for each group of the PCFS Scale. The comparisons of categorical variables between subjects with different level of impairment in functional status were performed with a Chi-square test of independence or Mantel–Haenszel test of trend, as appropriate. The tests were followed by Bonferroni adjustments for multiple comparisons. An ordinal logistic regression was performed to determine which of the baseline characteristics were associated with a higher odd of being in a higher grade of the PCFS Scale. Statistics and visualization were performed using SPSS  and GraphPad Prism 9.0 . A priori, the level of significance was set at 2) were included in the analyses. The general characteristics of these subjects are presented in Table From the initial 2159 respondents, 15 were excluded because of ICU admission during the infection, 22 were excluded because of reported onset of symptoms before January 1, 2020 or within the previous 21 days, and 183 were excluded due to incomplete surveys. Therefore, a total of 1939 subjects : 25.2[22.6–28.8]kg/mThe gender distribution, type of COVID-19 diagnosis, presence of self-reported pre-existing comorbidities and marital status were different among the PCFS Scale categories. Interestingly, no differences in the proportion of smoking status were presented  presented lower BMI compared to all other groups Table . NotablyThe most intense symptoms reported were fatigue, muscle weakness and sleeping problems while the least were fever, nausea and dysphagia. Subjects classified as experiencing slight, moderate and severe functional limitations presented a gradual increase in the number and intensity of symptoms Table . No diffr: 0.233–0.661; P < 0.01)  while no differences between subjects with no functional limitation (grade 0) and negligible functional limitation (grade 1) were found when comparing these outcomes, although a lack of power to detect small but meaningful differences among the latter groups might have affected these results.i.e. non-hospitalized during the infection), the majority of them (85%) report slight-to-moderate functional limitations during course of COVID-19, 3 months after the onset of symptoms, supporting the existence of a ‘post-COVID-19 syndrome’ [The majority of the included subjects was not formally tested during the infection 78%), whereas a minority was hospitalized with confirmed diagnosis of COVID-19 (5%). These findings are expected, as early data showed that the proportion of critical cases of COVID-19 is 5%  and the %, whereayndrome’  which maOf note, one of the strong points of the scale is that it intentionally does not specify why subjects are functionally impaired, i.e. if the impairment is caused by dyspnoea, fatigue, pain, anxiety or otherwise. This is crucial for the scale to be useful in a condition that may cause symptoms in many organ systems. However, it does not rule out the fact that the reported functional limitations are (partly) pre-existent. This is no issue when the scale is measured repeatedly or used as outcome measure in studies comparing two or more groups, especially in randomized controlled trials. The manual to the scale describes the possibility to assess pre-COVID-19 functional status, which would allow for determination of the causality of functional impairment in observational studies . ImportaAs most of the included subjects in our study were highly symptomatic and the PCFS Scale has shown to be associated with number and intensity of symptoms, the groups of subjects stratified as presenting no functional limitations (grade 0) and negligible functional limitations (grade 1) were relatively small  likely due to a selection bias arising from the self-selection nature of the data. Also, the lack of statistically significant differences between these groups could be a direct consequence of this limited number of subjects. It is also possible that there is, in fact, not a clinically relevant difference in outcomes between these two grades of the PCFS Scale, future studies with inclusion of less symptomatic subjects are necessary to investigate this issue. After all, both a scale grade of 0 and 1 indicate no functional limitations. The clinical relevance between the 2 grades is possibly to differentiate full recovery (grade 0) from incomplete recovery and persistent symptoms (grade 1).The groups of subjects stratified as presenting slight and moderate functional limitations (grade 2 and 3) present similar baseline characteristics, however with a gradual increase in number/intensity of symptoms, reduction in HrQoL and impairment in work and usual activities. Despite presenting significantly lower BMI, the relatively small group of subjects with severe functional limitations (grade 4) was found to be highly symptomatic and presenting worse HrQoL. This could be partially explained by the higher proportion of subjects with multimorbidity included in this group, since previous studies have found that multimorbidity is an independent factor associated with HrQoL , 25. FurThe main limitation of the present study is the inclusion of a self-selected sample of subjects with confirmed and presumed COVID-19 who are still symptomatic after the infection, it is possible that the frequency and intensity of symptoms reported by non-hospitalized subjects is overestimated due to selection bias and due to the inclusion of a relatively high proportion of women, who usually report more symptoms than men . MoreoveIn conclusion, we demonstrated the construct validity of the PCFS Scale in highly-symptomatic adult subjects with confirmed or presumed COVID-19 3 months after the onset of symptoms. The fact that the PCFS Scale can be easily used is a major advantage of the scale, potentially facilitating its widespread implementation. We propose that this tool could be used to discriminate between subjects with higher number and intensity of symptoms which is related with reduced HrQoL and impairment in work and usual activities. Therefore, the scale could be used to guide follow-up procedures such as referral to expert (outpatient) clinics or rehabilitation programs. Also, this shows that the PCFS Scale could be considered as a main outcome in clinical trials as well as observational studies, as it captures symptom intensity and HrQoL in one meaningful scale. The construct validity is a first step towards the validation of the PCFS Scale and more studies assessing other measurement properties are recommended.Additional file 1. Online Supplement.


Mycobacterium tuberculosis isolates. The development of FQ resistance in multidrug-resistant TB negatively impacts patient treatment outcome and is a serious threat to control of TB.Fluoroquinolones (FQs) are potential drugs that inhibit DNA synthesis and are used in the treatment of multidrug-resistant tuberculosis (TB) and short-term anti-TB regimens. In recent years, a high proportion of FQ resistance has been observed in sl assays were performed for the molecular detection of mutations. Sequence analysis was performed for the characterization and mutational profiling of FQ-resistant isolates.The study included a total of 562 samples from patients with pulmonary TB that had been on anti-tuberculosis therapy. MTBDRgyrA), while mutations in gyrB were observed in only two isolates. Mutational analysis revealed that the mutations mostly alter codons 94  and 90 . In MDR and treatment failure cases, resistance to FQs was most commonly associated with the D94G mutation. In contract, a high proportion of A90V mutations were observed in isolates that were newly diagnosed.FQ resistance was observed in 104 samples (18.5%), most of which were previously treated and treatment failure cases. A total of 102 isolates had mutations in DNA gyrase subunit A (The findings suggest that genotypic assays for FQ resistance should be carried out at the time of initial diagnosis, before starting treatment, in order to rule out mutations that impact the potential use of FQs in treatment and to control drug resistance. Pakistan is among the thirty countries with high tuberculosis (TB) burden in which the complete elimination of TB is, unfortunately, a distant reality. Worldwide, TB is ranked as the ninth leading cause of mortality, with about one third of the world’s population having latent TB infection . AccordiMycobacterium tuberculosis (MTB). Phenotypic resistance of TB to FQ is associated with mutation in the quinolone resistance-determining region (QRDR) of DNA subunits A (gyrA) and B (gyrB), which encode a type II DNA topoisomerase. Mutations in subunit A confer high-level resistance, whereas those in subunit B confer low-level resistance , and 41(7%) were susceptible to these two drugs.In terms of treatment history, of the 562 cases, 313 (56%) were newly diagnosed, 97 (17%) were cases of treatment failure (completed treatment but still positive for MTB), 59 (10%) were cases of treatment default , and 93 (17%) had unknown treatment history.gyrA and gyrB. GenoType MTBDRsl assays were performed to determine resistance to second-line drugs.Resistance to FQ and mutational profiling was determined for the DNA gyrase genes Resistance was interpreted according to the presence and absence of wild-type and mutant probes. The presence of all wild-types was interpreted to indicate no detectable mutation. The absence of any wild-type probe indicated that probe could not bind the respective amplicon and was considered a detectable mutation.gyrA, while 2/104 cases had a mutation in gyrB (both E540V).A total of 104 samples (18.5%) were found to be resistant to FQs. Among these isolates, eight (8%) were rifampicin-sensitive, eight (8%) were mono-resistant (resistant to rifampicin and sensitive to isoniazid), and 88 (85%) were MDR. Most of the patients had been treated previously and appeared with failure of category 1; some were on category 4 treatment. In total, 102/104 of resistant samples showed resistance mutations insl assays detect some of the most common resistance-mediating mutations. Table gyrA gene and the corresponding patterns of wild-type and mutant bands. The most common failure was of the gyrA WT3 band and development of MUT3C the most common mutation. Mutational analysis revealed that these mutations mostly alter the protein at codons 94 and 90, respectively replacing aspartic acid with glycine and alanine with valine. The aspartic acid at codon 94 was also replaced with alanine, asparagine, and tyrosine in other types of mutations, and mutation at codon 91 where serine was replaced with proline was also observed.The mutation probes in the MTBDRgyrA were observed 19 isolates representing all possible patterns were selected for further mutational analysis, with H37RV (AGH06049.1) used as a reference strain. These mutations were found to result in amino acid changes. Specifically, we identified four isolates which the amino acid changes varied from the most mutation reported by Line probe assay (LPA) testing. One isolate substituted asp→ala, two isolates had ala→val, and one had a thr → ala mutation in addition to ser/ala→X (an undetermined mutation)  and isoniazid (INH) were observed. Of all samples tested, resistance to first-line drugs (INH and RIF) was identified in 92% . Among FQ-resistant isolates, eight were RIF-sensitive, eight were mono-resistant to RIF, and 88 were MDR. Isolates having resistance against rifampicin and isoniazid are termed MDR-TB, and if they also develop additional resistance against FQs, are then known as pre-XDR TB .sl assay can detect mutations in the conserved QRDR region of gyrase genes (gyrA and gyrB) which changes the structure of the drug binding pocket (QBP) and results in cross resistance to all FQs. GenoType MTBDRsl assays were used to determine the frequency of FQ resistance in our isolates. A total of 104/562 isolates (18.5%) were found to be resistant to FQs. A high prevalence of FQ resistance was also reported in other provinces of Pakistan [MTB develops resistance against FQs mainly by developing mutations in the drug-targeted proteins. The detection of gyrase mutations in particular can help in predicting the presence and level of FQ resistance . GenoTypPakistan  and in tPakistan , 15, ChiPakistan , 17, andisolates .5% were Pakistan .Short treatment regimens are used to reduce emergence of antimicrobial resistance in MTB. According to the 2019 national guidelines for the control of TB in Pakistan (adopted by the WHO), the anti-TB short regimens for drug-susceptible cases include third- or fourth -generation fluoroquinolones  for 4 months. These drugs are also given for isoniazid-resistant and previously-treated cases in the initial phase of therapy (2 months). The high proportion of FQ resistance indicates an ineligibility of patients in this population for shorter regimens.gyrA mutations was much higher than that for gyrB. Hybridization pattern analysis revealed that most isolates had a mutation in the gyrA gene locus, with substitutions at amino acid 94 (D94G) and 90 (A90V) being more prevalent. Both of these mutations are associated with a high level of resistance to fluoroquinolone antibiotics . However, for most isolates that deviated from the pattern of well-known mutations, the affected amino acids mostly occurred at typical sites, i.e. codons 94 and 91. Overall, these findings suggest that mutation patterns can differ according and this can be revealed in the hybridization patterns of wild-type and mutant probes.The results of this study present a burden of fluoroquinolone resistance in MDR-TB patients regardless of FQ antibiotic therapy. However, further understanding of the relevance of genotypic and phenotypic resistance is important for the accurate prediction of FQ resistance. Although we found genotypes consistent with FQ resistance in susceptible isolates, these results do not reflect the true prevalence of resistance in these patients. The resistance might develop due to the prior use of FQ antibiotics, which information was not included in the study.The emergence of fluoroquinlone resistance in clinical isolates is alarming. We found a high proportion of MDR cases to have FQ resistant genotypes, even in mono-resistant and drug-sensitive isolates. The groups most likely to develop resistance are previously-treated and treatment-failure cases. Our findings suggest that the implementation of FQs in these patients should be carefully administered and that genotypic studies should be carried out, preferably at the time of initial diagnosis, to rule out all types of resistance-promoting mutations in order to ensure effective treatment and particularly to control resistance.


An autonomous Lagrangian float equipped with a high-resolution acoustic Doppler current profiler observed the evolution of upper-ocean stratification and velocity in the Eastern Pacific Fresh Pool for over 100 days in August–November 2016. Although convective mixing homogenized the water column to 40 m depth almost every night, the combination of diurnal warming on clear days and rainfall on cloudy days routinely produced strong stratification in the upper 10 m. Whether due to thermal or freshwater effects, the initial strong stratification was mixed downward and incorporated in the bulk of the mixed layer within a few hours. Stratification cycling was associated with pronounced variability of ocean surface boundary layer turbulence and vertical shear of wind-driven (Ekman) currents. Decoupled from the bulk of the mixed layer by strong stratification, warm and fresh near-surface waters were rapidly accelerated by wind, producing the well-known “slippery layer” effect, and leading to a strong downwind near-surface distortion of the Ekman profile. A case study illustrates the ability of the new generation of Lagrangian floats to measure rapidly evolving temperature, salinity, and velocity, including turbulent and internal wave components. Quantitative interpretation of the results remains a challenge, which can be addressed with high-resolution numerical modeling, given sufficiently accurate air-sea fluxes. The ocean’s response to wind forcing in the presence of rotation has been the subject of study for over 100 years, since the work of Wind-driven dynamics are known to be important in shaping the Eastern Pacific Fresh Pool EPFP; , a relatHowever, upper layers of the EPFP may not be well mixed all of the time. Frequent rainfall creates highly stratified shallow “lenses” that last several hours before they are incorporated into the bulk of the mixed layer , but witOne focus of the second NASA Salinity Processes in the Upper-ocean Regional Study (SPURS-2) experiment was the investigation of the role of the small-scale, transient, wind- and rain-driven dynamics in the evolution of the near-surface structure of the EPFP. Here, we present the first look at the observations and modeling of these small-scale dynamics.The SPURS-2 experiment took place in 2016–2017 in the EPFP. Nearly 200 elements of moored, self-navigating, and drifting instrumentation formed a distributed autonomous observing system around the nominal “central” mooring site at 10°N, 125°W. A mixed layer Lagrangian float MLF;  served a−1. The actual usable range of LR measurements was typically 20–25 m, depending on the varying amount of scatterers in the water. LR sampling over the course of the float’s dive can be used to infer the mean vertical profile of horizontal velocity in a manner similar to the lowered or glider-based ADCP  beam. The ADCP was set up to interleave the long-range, low-resolution (LR) and high-resolution (HR) pulse-coherent sampling on the four slanted beams; the vertical beam was LR only. Detailed description of LR and HR sampling modes and data processing techniques can be found in sed ADCP . HR sampties see .−1 vertical profiling speed. The profiles typically reached 60 m depth, slightly deeper than the 50 m maximum (March) climatological mixed layer thickness, according to Monthly Isopycnal & Mixed-layer Ocean Climatology , achieved through active control of the MLF profiling speed using precise ballasting control. During SPURS-2, the slow profiling efforts were partially frustrated by large (up to 300 g) buoyancy changes due to the nocturnal interference of fish  showed stratification due to diurnal heating, and 44 days (65%) due to rain. During 23 days (34%), periods of both thermal and freshwater stratification were present. Typical surface velocity anomalies relative to 30 m during these near-surface stratification events were 20–30 cm s−1  is the reason for the term “slippery layer” (−1 (1% of the vector-mean wind speed of 3 m s−1) or about 25 km relative to 30 m depth over 10 days , the layer was ~20 m thick, nearly reaching the bottom of the original mixed layer. This thickening diluted the freshwater lens by entraining saltier water from the underlying mixed layer so that the salinity anomaly continuously decreased, despite the rain, to only 0.05 g kg−1 by the end of the event. Freshwater input of the eight-hour rain event estimated from the upper-ocean salinity profiles observed with the MLF was 43 mm of freshwater equivalent. For comparison, integral IMERG rainfall accumulation was only 23 mm (53%) for the same period. This discrepancy is not unexpected, as the IMERG product represents a broad-scale average of precipitation that does not resolve the variability of convective rain events in the ITCZ , and also similar to the previously reported values.Decay of turbulence under temperature- and salinity-stratified capping layers is a known phenomenon, observed, among others, by Lagrangian float observations, such as those shown in Direct numerical simulations of upper-ocean boundary layer turbulence would need to account for the very large range in spatial scales, from about 100 m, or several times the boundary layer thickness, to a few millimeters or less, the smallest Kolmogorov dissipation scale, and extend for many integral timescales of the surface boundary layer flow to study the response to such unsteady forcing. This cannot be presently done directly with even the largest computers. Instead, a large-eddy simulation (LES) approach is taken, where only the larger-scale physics are explicitly simulated and the smaller scales are modeled using turbulence closure methods. The overall evolution of salinity and velocity structure during the October 8–9, 2016, rain event  is reproThe LES may also provide insight into new potentially relevant dynamics. Patterns of upward-propagating shear layers in the marginally stratified sheared surface boundary layer immediately preceding formation of the fresh surface layer, and throughout the deepening process , where tThese preliminary analyses show the roles of alternating heat and freshwater fluxes in forming strong yet intermittent near-surface stratification in the EPFP. Despite the very different dynamics of these mechanisms, their overall impacts on the density structure and its evolution are quite similar. Together, they create stratification in the top 50 m on a large fraction (>60%) of the days, so that typical mixing depths are a few meters to a few tens of meters, clearly shallower than the 25–40 m climatological mixed layer depth. Accordingly, the changes in the upper ocean due to air-sea fluxes, sea surface temperature, and salinity anomalies caused by heat flux and rainfall, as well as the Ekman velocities caused by wind stress, will be larger than those predicted by using climatological mixed layer depth. This difference will enhance oceanic feedback to atmospheric forcing.The observations described here demonstrate the rapid advances in autonomous ocean observations. The combination of the Lagrangian float, which provided measurements in a reference frame that minimizes advective effects, and the Wave Glider, which provided local meteorological forcing information, demonstrates the potential to collect detailed observations entirely autonomously. The addition of the new generation ADCPs to the float demonstrates the ability to autonomously make detailed velocity observations of both the overall upper-ocean boundary layer velocity structure and the smaller-scale turbulence. We anticipate that additional processing will allow these fine-scale velocity measurements to be quantitatively interpreted . Numeric


This study explored the associations of individual factors , and self-rated physical and mental health) and environmental factors  with worry toward COVID-19 and general anxiety among people in Taiwan. The Chi-square was used to compare difference for worry and anxiety among categorical variables. The logistic regression was used to examine the associations between worry as well as anxiety and individual as well as environmental factors. In total, 1970 respondents were recruited and completed an online survey on worry regarding COVID-19, general anxiety during the pandemic, and individual and environmental factors. In total, 51.7% and 43.4% of respondents reported high levels of worry toward COVID-19 and general anxiety, respectively. Exhibited worse self-rated mental health, lower self-confidence in COVID-19 management, and insufficient mental health resources were significantly associated with high levels of both worry toward COVID-19 and general anxiety. Lower perceived confidence in COVID-19 management by the regional government was associated with a higher level of worry toward COVID-19. Lower perceived social support was associated with a higher level of general anxiety during the COVID-19 pandemic. The results showed that high levels of worry toward COVID-19 and general anxiety were prevalent during the outbreak. This suggests health care providers need additional surveillance of worry and anxiety during the pandemic. Multiple individual and environmental factors related to worry toward COVID-19 and general anxiety were identified. Factors found in the present study can be used for the development of intervention programs, supportive services, and government policy to reduce worry and anxiety during the COVID-19 pandemic At the end of December 2019, people developed life-threatening pneumonia in Wuhan, China. A novel coronavirus, coronavirus disease 2019 (COVID-19), was identified as the source of the infection. The number of reported cases has subsequently increased rapidly across the world. On 30 January 2020, the World Health Organization (WHO) declared the disease a public health emergency of international concern [The neuropsychiatric link between the outbreak of acute respiratory infections and mental disorders can be traced back to the influenza and severe acute respiratory syndrome (SARS) pandemics that occurred years ago . One corDisease-related worry is the another common affective reaction to an illness . A studyMany factors, including demographic, psychosocial, and environmental factors, may influence people’s worry and anxiety. Tahmassian et al. reported self-confidence is a factor that can predict the level of worry and anxiety . Shah etThis study explored the associations of individual factors  and environmental factors  with worry toward COVID-19 and general anxiety among people in Taiwan.Participants were enrolled through a Facebook advertisement between April 10 and April 20, 2020. The inclusion criteria were age ≥20 years and residence in Taiwan. The Facebook advertisement included a headline, main text, pop-up banner, and link to the research questionnaire website. We designed the advertisement to appear in the Facebook users’ “news feeds,” which are continually updated lists of updates from advertisers and users’ connections (such as friends and the Facebook groups that they have joined). Our advertisement targeted only users’ news feeds as opposed to other Facebook advertising locations , because news feed advertisements are the most effective approach for the recruitment of research participants . We targThe Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-EXEMPT (I) 20200011) approved this research and waived the need for informed consent because participation was voluntary and survey responses were anonymous. No incentive was provided for participation. Links to information on COVID-19 from the Taiwan Center for Disease Control, Kaohsiung Medical University Hospital, and the Medical College of National Cheng Kung University were prepared for participants to learn more about COVID-19.Data on respondents’ sex , age, and education level were collected. Respondents with qualifications of high school level or lower and respondents with qualifications of university level or higher were classified into low- and high-level education groups, respectively. Respondents were also asked whether they were health care workers.no) to 5 (constantly worried) were provided for this question. According to Liao et al. [We used the following question from the study of Liao et al.  to asseso et al. , particinot at all), 2 (sometimes), 3 (moderately so), or 4 (very much so) was provided. Statements reflecting positive feelings were reverse coded. A higher total score for the 10 items represents greater general anxiety. The Cronbach’s α for this section was 0.921. According to Liao et al. [General anxiety in the preceding week was measured using a previously validated state anxiety scale from the State-Trait Anxiety Inventory (STAI), wherein respondents rate their feelings in response to 10 general statements; these statements establish whether respondents feel rested, contented, comfortable, relaxed, pleasant, anxious, nervous, jittery, highly strung, or overexcited and “rattled” ,23,24. Fo et al. , particiextremely unsatisfied) to 4 (extremely satisfied) were given for each question. The total score for the three questions indicates the level of perceived social support. Higher scores represent better perceived social support.Three questions from Tardy’s study were used to assess levels of perceived social support : “How saresponding to COVID-19: “How confident are you about coping with COVID-19?” We also used a question to assess respondents’ perceived confidence in COVID-19 management by the regional government: “How confident are you regarding COVID-19 management by the government of the region where you live?” Ratings from 1  to 5 (very confident) were provided for these two questions. We used median as the cut-off point [We used the following questions from a questionnaire on the risk perception for infectious disease outbreaks  to assesff point . The medmuch worse) to 4 (much better) were provided for each question. The sum of the scores for the first and third questions indicates self-rated physical health, and the sum of the scores for the second and fourth questions indicates self-rated mental health. A higher total score indicates better physical and mental health.The Self-Perceived Health Questionnaire, developed by Ko et al. , containinsufficient and sufficient.We estimated participants’ perceptions regarding adequacy of resources and support for the COVID-19 pandemic by using four questions from the WHO Guidance Document : “Duringp value of <0.05 indicated statistical significance.Data analysis was performed using SPSS 22.0 statistical software . The chi-square was used to compare rates of high worry toward COVID-19 and high general anxiety among categorical variables. Pearson’s correlation coefficient was used to examine the correlations of worry toward COVID-19 and general anxiety with continuous variables. The associations of demographic characteristics, self-confidence in coping with COVID-19, perceived confidence in COVID-19 management by the regional government, self-rated physical and mental health, and adequacy of supplies for the COVID-19 pandemic with rates of high worry toward COVID-19 and high general anxiety were examined by using logistic regression analysis. A two-tailed In this study, 2031 respondents completed the online questionnaire. After 61 respondents with missing data were excluded, the data of 1970 respondents  were analyzed. Health care workers and participants with worse self-rated mental health, lower perceived social support, lower self-confidence in responding to COVID-19, and insufficient mental health resources showed significantly higher levels of general anxiety during the COVID-19 outbreak.High level of worry toward COVID-19 was an important mental health issue during the pandemic because more than half experienced this problem. A longitudinal study in Hong Kong during the 2009 influenza pandemic showed that between 40% and 60% of individuals exhibited significant levels of worry toward infection during the outbreak . Ro et aOur study found that the high general anxiety is also prevalent for people during the COVID-19 pandemic. A cross-sectional study showed a high level of STAI-assessed general anxiety during the 2009 influenza A (H1N1) pandemic in Turkey . ResearcIn addition to examination of psychological and behavioral responses to RID pandemics ,41, examThe results indicated that high worry toward COVID-19 and general anxiety were more prevailing among health care workers rather than among non–health care workers. Studies have reported that high levels of worry of being infected among health care workers may be associated with intended absenteeism and decreased social interaction ,43. MeanA community study showed that women have higher levels of worry and general anxiety than men across three age cohorts . In the The present study found that both worse self-rated mental health and lower self-confidence in coping with COVID-19 were associated with higher rates in high general anxiety and worry toward COVID-19. The associations might be bidirectional. Experts indicate that worse mental health may predict worse psychosocial outcomes . Hao et Regarding environmental factors, our results found that perceived confidence in COVID-19 management by the regional government was related to lower rates of the high level of worry. A study of the 2009 H1N1 pandemic in the Netherlands also found that trust in the government was associated with the public’s intention to adopt protective measures . AdoptinPerceived social support is a significant protective factor for general anxiety during COVID-19. Studies have described that perceived social support is a protective factor for anxiety , and thaThe present study has several limitations. First, although Facebook is a promising research method for recruiting participants by targeting the general public during fast-spreading infectious disease outbreaks , FacebooThis study found high anxiety and worry toward the COVID-19 among respondents in Taiwan during the pandemic were prevalent. The result highlights the urgency for enhancing health care professionals’ planning for and competence in relation to the detection and management of infectious disease outbreaks’ psychological effects. We found that poor self-rated mental health, low self-confidence in coping COVID-19, and insufficient mental health resources and heath care works were the risk factors for high worry and anxiety. Factors found in the present study can be used for the development of psychological interventions and government policy to reduce worry and anxiety during the COVID-19 pandemic. There are factors which were not examined in present study. Therefore, future lines of research could be carried out to complement this study.


Telemonitoring enables care providers to remotely support outpatients in self-managing chronic heart failure (CHF), but the objective assessment of patient compliance with self-management recommendations has seldom been studied.This study aimed to evaluate patient compliance with self-management recommendations of an innovative telemonitoring enhanced care program for CHF (ITEC-CHF).We conducted a multicenter randomized controlled trial with a 6-month follow-up. The ITEC-CHF program comprised the provision of Bluetooth-enabled scales linked to a call center and nurse care services to assist participants with weight monitoring compliance. Compliance was defined a priori as weighing at least 4 days per week, analyzed objectively from weight recordings on the scales. The intention-to-treat principle was used to perform the analysis.P=.06). However, the proportion of ITEC-CHF participants achieving the stricter compliance standard of at least 6 days a week was significantly higher than that in the control group .A total of 184 participants , with a mean age of 70.1 (SD 12.3) years, were randomized to receive either ITEC-CHF (n=91) or usual care , of which 67 ITEC-CHF and 81 control participants completed the intervention. For the compliance criterion of weighing at least 4 days per week, the proportion of compliant participants in the ITEC-CHF group was not significantly higher than that in the control group (ITEC-CHF: 67/91, 74% vs control: 56/91, 60%; ITEC-CHF improved participant compliance with weight monitoring, although the withdrawal rate was high. Telemonitoring is a promising method for supporting both patients and clinicians in the management of CHF. However, further refinements are required to optimize this model of care.Australian New Zealand Clinical Trial Registry ACTRN12614000916640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366691 Chronic heart failure (CHF) is a severe chronic disease that affects more than 26 million people worldwide . It signcompliant participants in the telemonitoring arm , the stvs 70.9% . In addiCTs (55%  and 55.4CTs (55% ). This hCTs  in an open multicenter RCT. The ITEC-CHF program focused on assisting patients in daily weight monitoring and engaging with nurse-supported care in the event of weight fluctuations. This study aimed to examine whether the ITEC-CHF program improved patient compliance with weight monitoring as well as other self-management behaviors and health outcomes.The protocol for the ITEC-CHF study has been previously published . Images Participants in the trial were individually randomized with an allocation ratio of 1:1 to receive either ITEC-CHF or usual care (control) for 6 months. Randomization was stratified by the 2 trial sites (VIC and WA) to ensure that the allocation ratio was consistent at each site. A block method was used to achieve a balanced number of participants between the ITEC-CHF and control groups throughout the trial. The random allocation assignments were sealed in opaque envelopes. Data analysts generated the randomization sequence and were blinded to the trial because of the use of deidentified patient data.The inclusion criteria were as follows: patients (1) with CHF with reduced ejection fraction , (2) able to weigh themselves safely, (3) aged at least 18 years, (4) having a regular personal general practitioner (GP) or agreeing to use a designated GP, (5) with a permanent residential address, and (6) without significant cognitive impairments. The exclusion criteria were as follows: (1) patients with expected survival <12 months, (2) patients with end-stage renal failure on dialysis, (3) long-term nursing home residents, or (4) patients participating in any other clinical trial.Living Well with Chronic Heart Failure booklet, produced by the Heart Foundation of Australia. They were instructed to maintain their usual CHF care, as provided by clinics specialized in CHF and primary care physicians, and to undertake CHF self-management as previously instructed. Each participant was also provided with an electronic weight scale  and asked to use the scale to measure their body weight daily, immediately after waking, following voiding, without shoes, in light clothing, and before taking medication. Approximately every 3 months, project nurses visited the participants to download the weight entries from the weight scale.At baseline, control participants were provided with a standard package of a paper-based diary and the rapid weight fluctuation (an increase or decrease of 2 kg over 2 days), (2) slow weight fluctuation (an increase or decrease of 5 kg over 28 days), (3) low-risk weight fluctuation (an increase or decrease of 1 kg over 24 hours), (4) missed weight measurement, (5) low level of tablet battery, and (6) tablet connection lost. In the event of a rapid weight fluctuation, project nurses were alerted, and they called the participant to assist him or her in assessing symptoms and activating their CHF action plan, such as attending their GP, visiting a CHF clinic, or presenting to an ED as indicated. For an alert of slow weight fluctuations, the project nurses assisted the participants in assessing CHF symptoms and arranging clinical reviews at the participants’ GP or CHF clinics as indicated. For low-risk fluctuations, a questionnaire was automatically triggered and sent to the participant’s computer tablet to help him or her determine the need for further clinical follow-up. Finally, the generated alerts were distributed to project nurses and/or the MEPACS call center in the ITEC-CHF program. Call operators at the center responded to the alerts in real time , focusing on reminding participants to weigh themselves if they had not done so before 10 AM, helping assess CHF symptoms and manage diet, and arranging a nurse follow-up if needed. The project nurses reviewed their alert requests on weekdays and followed up with the participants via a telephone call. Some participants were unable to monitor their body weight for a short period, such as when they were hospitalized for medical treatment, traveled away from home, or experienced unresolved technical issues. Under such conditions, they were required to notify the call center, and weight monitoring was skipped. If a participant notified the call center to skip the monitoring for a period, the telemonitoring intervention was then switched off during the skipped period, and the call center did not receive any alerts from the participant and provide intervention until the skipped period ended. Monitoring days that were skipped were still included in the per-protocol analysis for the ITEC-CHF group (described in the Primary and Secondary Outcomes section).Participants in the ITEC-CHF group received the same resources as those in the control group, in addition to the ITEC-CHF program. The ITEC-CHF consists of 3 major components: remote body weight monitoring, structured telephone support, and nurse-led collaborative care. The service was integrated with a telephone call center  and community nurse care services at the trial sites in VIC and WA. Each participant was provided with an electronic weight scale and a computer tablet . Participants were asked to weigh themselves using the procedure described for the control group. After the measurement, the weight entry was automatically transmitted from the weight scale to the tablet via a wireless Bluetooth function. The tablet was preloaded with an Android app . This app received the weight entry and uploaded the entry to a software package called Manage My Health . A rule-based decision support system (a web app) in MMH automatically monitored the uploaded weight entries in real time. In response to the weight data generated by telemonitoring, 6 types of alerts were possible: (1) most of the time, as previously applied in questionnaire-based assessments [daily.The primary outcome was in compliance with weight monitoring. The monitoring frequency was calculated as average weight monitoring days per week during the 6-month assessment period (monitoring frequency=weight monitoring days/180 days×7 days/week [for 6 months: 6 months×30 days/month=180 days]). A weight monitoring day was determined if at least one weight entry was practically recorded on the weight scale on that day, irrespective of time. In total, 2 frequencies were employed in the examination. One was that the participant monitored their weight on at least four days per week. This frequency reflects the compliance threshold of essments ,12. The skip weight monitoring.Secondary outcomes included patient compliance with weight monitoring based on a per-protocol analysis  and an analysis of other guideline recommendations assessed by the Heart Failure Compliance Questionnaire , health-P value<.05 was considered statistically significant. The analysis was conducted using RStudio version 1.1.383 (RStudio Inc) [survival version 2.43-3. The intention-to-treat principle was applied to the analysis of the primary outcome of patient compliance with weight monitoring. It was also applied to the analysis of the hazards of hospitalization and ED. In the intention-to-treat analysis, all participants in the RCT were included. A per-protocol analysis was also applied to weight monitoring as a secondary outcome, only including participants who did not discontinue in the trial. A complete case analysis, which restricts the analysis to individuals with complete data, was used to analyze improvements in questionnaire-based assessments and 6-min walk distances.In the evaluation, a chi-square test was applied to analyze continuous variables such as age, and a Fisher exact test was used to compare categorical variables such as sex and subgroups of participants under a given weight monitoring frequency (participants who achieved a given monitoring frequency vs participants who did not achieve the monitoring frequency). The Wilcoxon signed-rank test was used to compare compliance scores from questionnaire-based assessments. An analysis of covariance model  was useddio Inc)  with theA total of 6587 patients were screened for eligibility. Among them, 6403 patients were excluded because of failure to meet the inclusion criteria (n=5998), declined (n=306), or for other reasons (n=99), such as losing contact with the patient . FinallyThere were no significant differences between the characteristics of the ITEC-CHF and control groups at baseline . The measkipped. Being away from home or traveling was the major reason for skipped monitoring, occurring on 515 participant monitoring days  in 41 participants. Technical issues (There were 1312 participant monitoring days when weight monitoring was l issues  resultedP=.06). However, ITEC-CHF was associated with significantly more participants who monitored their body weight on average for at least 6 days per week over the duration of the trial than the control , the difference in weight monitoring compliance was significant for weight monitoring at least 4 days a week  and at least 6 days a week .Applying a P<.01), medication adherence (P<.01), and diet (P<.01). No significant differences were found in the category of exercise (P=.10), smoking (P=.48), or alcohol use (P=.32).In the complete case analysis, 147 participants (ITEC-CHF: 66 and control: 81) completed the Heart Failure Compliance Questionnaire at baseline and 6-month assessments . ITEC-CHP=.44), self-care (P=.26), usual activities (P=.59), discomfort (P=.46), and anxiety or depression (P=.38). The mean change in the overall score of EQ-5D was also not significantly different .In the EQ-5D assessment, no significant differences were found in the change in category of mobility  or emergency department (ED) presentations , chronic heart failure (CHF)–related hospitalizations , CHF-related ED presentations , or unplanned hospitalizations .No significant differences were found in all-cause hospitalizations , facilitated by community nurses with call center support, we observed no significant differences in the weight monitoring frequency of at least 4 days a week but observed a significantly higher proportion of the intervention group achieving a weight monitoring frequency of at least 6 days per week compared with the control group receiving usual care. To our knowledge, this is the first study to use objective measures of weight monitoring and the intention-to-treat principle to comprehensively evaluate patient compliance with daily weighing in patients with CHF.most of the time (or at least 4 days per week) and was limited by a questionnaire-based assessment of compliance, which is prone to bias [The higher weight monitoring frequency of at least 6 days per week reflects better compliance with the recommendation in contemporary clinical guidelines for patients with CHF to weigh themselves daily as a self-management strategy to maintain fluid balance and identify signs of edema ,3. This  to bias .In the intention-to-treat analysis, 45% of participants randomized to ITEC-CHF achieved a monitoring frequency of at least 6 days per week over the 6-month follow-up period of the trial. This figure was influenced by the relatively high proportion of participants who discontinued the trial from the intervention group and provides valuable insight into factors that are pertinent to telemonitoring in clinical practice. In the early stages of the trial, there were relatively frequent technical issues with the telemonitoring system, which may have led to the withdrawal of some participants. It has previously been reported that learning how to use telemonitoring technology is perceived as burdensome and creates anxiety in some patients, especially those who are older . This maskipped because of technical issues, meaning that the difference in weight monitoring compliance between the ITEC-CHF and control groups is likely to be underestimated. These positive findings regarding weight monitoring compliance in participants who adhered to the program are likely to be underpinned by the multifactorial support mechanisms provided. This is further supported by a substantial number of alerts reported in this study, which included the automated generation of reminder alerts on 715 patient days when a weight recording was not received by 10 AM as well as contact made by the call center and project nurses. These findings not only demonstrated the effectiveness of ITEC-CHF in supporting weight management but also indicated a strong need for such support in ongoing CHF care.In participants who completed the trial , compliance with weight monitoring in ITEC-CHF was high; 97% of participants monitored themselves for at least 4 days a week over the 6-month duration of the trial, and 61% of participants monitored themselves at least 6 days a week. In the ITEC-CHF group, 390 participant monitoring days were teachable moments, enabling nurses to provide informal education to reinforce self-management practices. It has previously been acknowledged that patients often benefit from ongoing support in CHF care to effectively manage their health conditions through reinforcement of self-management strategies [The ITEC-CHF group experienced a significant improvement in health maintenance compared with usual care, as measured by the Heart Failure Compliance Questionnaire. This positive result was consistent with a finding of improved self-care maintenance reported in 2 other RCTs of telemonitoring in CHF ,28. Simirategies . It is arategies . NeverthThere were no significant effects of ITEC-CHF on hospitalizations and ED presentations, although it should be noted that the study was underpowered for this analysis. We observed that CHF-related events were not the major cause of hospitalizations 23/131, 17.5%) or ED presentations . CHF is a complex condition, more prevalent in older people, and associated with a range of comorbidities. Telemonitoring in the context of this study focused exclusively on daily weight recordings. This finding implies a need to extend telemonitoring intervention for comorbidity and critical non-CHF–related health conditions to more comprehensively address the range of health issues faced by patients with CHF. To date, the effectiveness of telemonitoring in improving hospitalization and mortality remains inconclusive 1, 17.5% . HoweverThere are several limitations of this study that warrant discussion. First, the study was limited to a 6-month intervention, which may have been insufficient to translate to meaningful changes in clinical characteristics of patients. In addition, a relatively high number of participants discontinued their involvement in the trial, which has the potential to bias the analysis of some secondary outcomes where the intention-to-treat principle could not be applied. High rates of discontinuation in the ITEC-CHF group suggest a potential bias in the per-protocol analysis. Participants who discontinued in the ITEC-CHF group were unlikely to be random because some were because of deteriorating health  and because some were deceased, as shown in The ITEC-CHF study is the first to report the effects of telemonitoring on weight monitoring compliance using an objective measure of weight recordings in patients with CHF. The proportion of participants in the ITEC-CHF program achieving a weight monitoring frequency of at least 6 days per week was higher than that in usual care controls. Furthermore, ITEC-CHF resulted in significant improvements in CHF self-management related to health maintenance, medication adherence, and diet. Among participants who completed the study, there was a high level of compliance with weight monitoring, underscoring the importance of telemonitoring platforms that are seamless to reduce the risk of patients disengaging with the technology. Although telemonitoring and digital health more broadly offer significant potential for supporting patients in self-managing chronic conditions such as heart failure, further research is required to refine these evolving strategies to achieve effective care outcomes.


The backscattering spectra of a 500 nm thick gold film, which was excited near the 525 nm transverse localized plasmon resonance of its constituent, self-organized, vertically-aligned nanorods by normally incident 515 nm, 300 fs laser pulses with linear, radial, azimuthal and circular polarizations, revealed a few-percent conversion into Stokes and anti-Stokes side-band peaks. The investigation of these spectral features based on the nanoscale characterization of the oligomeric structure and numerical simulations of its backscattering response indicated nonlinear Fano-like plasmonic interactions, particularly the partially degenerate four-wave mixing comprised by the visible-range transverse plasmon resonance of the individual nanorods and an IR-range collective mode of the oligomeric structure. Such oligomeric structures in plasmonic films may greatly enhance inner nonlinear electromagnetic interactions and inner near-IR hotspots, paving the way for their engineered IR tunability for broad applications in chemosensing and biosensing. Assemblies of regularly arranged noble metal nanoelements, called plasmonic oligomers, are of interest for nonlinear plasmonics because of the broad spectra of optical-range eigenmodes and corresponding predictable spatial sets of plasmonic hotspots supported by their symmetry . Such olOne of the possible methods for the inner structural characterization of plasmonic films is macroscopic optical spectroscopy, which can reveal their features in the form of recurring micro and nanostructures by corresponding Fano-type features in the spectra. The advantage of this kind of method is the large analyzed surface area compared with other methods such as scanning electron microscopy. In the backscattering spectra of thick gold film, multiple peaks were found, which may indicate the manifestation of different nonlinear effects.One of the important cases of FWM ,8 is parIn plasmonic nanostructures, the local electromagnetic field enhancement of surface plasmon polaritons (SPPs) and localized surface plasmons (LSPs) increases the efficiency of nonlinear interactions ,10,11. SIn biosensing, localized surface plasmon resonances (LSPRs) are harnessed through various surface-enhanced processes and through resonance shifts (in the extinction spectra) induced by nearby molecules ,16,17. Oportance ,26.In this work, we report that the self-organized oligomeric structure of nanorods in plasmonic gold films, which were considered as the simplest and most broadly available chemo and biosensing elements for decades, exhibits nonlinear Fano-type plasmonic interactions. Visually, this results in the appearance in backscattering spectra of intense sub-eV shifted sub-bands caused by PDFWM. The intensity of these sub-bands is strongly dependent on the pump laser polarization . Meanwhile, near-IR hotspots could be present inside the plasmonic structure, which are highly beneficial for near-IR sensing, paving the way for their engineered IR tunability for broad applications in chemosensing and biosensing.+-doped fiber laser Satsuma  with a second harmonic wavelength of 515 nm was used. Laser pulses  with a 10 nJ low pulse energy and repetition rate f of 10 kHz were guided through the back entrance of an upper illumination channel of a microscope–spectrophotometer MSFU-K  through a 50% beam splitter . Then, the laser beam was focused onto the gold film in air through the microscope objective  with a numerical aperture (NA) of 0.65 (magnification 40×). The initial Gaussian beam with linear polarization was transformed into a donut-shaped (Laguerre–Gaussian) beam with radial or azimuthal polarization by using a commercial S-waveplate converter . Circular polarization was achieved using a quarter-wave plate.The experimental setup a was simA gold film with a thickness of ≈500 nm was deposited on a silica glass substrate by magnetron sputtering  in an argon atmosphere. The nanoscale characterization of the surface was performed by the scanning electron microscope JSM 7001F  at the accelerating voltage of 10 keV. The SEM side-view image of the gold film is presented on The interaction of laser radiation with the nanorod trimer was numerically calculated using the finite-difference time-domain (FDTD) method. The spatial distributions of the electromagnetic field inside the gold nanorod trimer were calculated at different wavelengths for plane electromagnetic waves with linear or circular polarizations and Laguerre–Gaussian beams with radial or azimuthal polarizations. Laser radiation propagated parallel to the long axis of the nanorods. In the cases of Laguerre–Gaussian beams, the trimeric nanorods were located in the ring-like area with maximal electric field amplitude and not in the beam center . The heiExperimental polarization-sensitive backscattering spectra of the gold film are presented in One can assume that the incident 515 nm laser radiation is coupled to the nanorods via its LSPR, occurring at 525 nm . The eleIexc ≈ 20 × 103 arb. units . For comparison, the FWM efficiency in other nanoscale systems reaches ~10−5 for gold nanotip [−4 for a metasurface made of silver nanoantennas with embedded diamond nanoparticles [In the quantitative aspect, the central peak value of the backscattering intensity (being close to saturation) in  nanotip ,34 and g nanotip  and 10−4articles .Since the FFT spectrum b shows tOur interpretation of the experimental results is based on the close analogy to the well-known phenomenon of the nonlinear optical FWM generation of side-bands in a nonlinear medium . In our −2. Even though the visual appearance of the effect was in the visible range, due to the symmetry of the involved oligomers, there were three hotspots of the broad, bright collective mode, which are promising for near-IR sensing, while also paving the way for their broad IR tunability, which can be engineered via unit cell scaling and packing for applications in chemosensing and biosensing.In this work, we experimentally observed intense visible-range Fano-type side-band features in backscattering spectra of the 500-nm gold film, presented by the self-organized oligomeric structure of nanorods, under its 515 nm 300fs laser excitation with different laser polarizations: linear, circular, radial and azimuthal. Such a partially-degenerate four-wave mixing mechanism was related to laser coupling to the transverse localized plasmon resonance in the nanorods, hybridized in the near-field with the near-IR collective mode of the nanorod trimer, as the elementary structural block. The corresponding conversion efficiency was evaluated as high as 10