This study examined the distribution of dental caries in 12- and 15-year-olds in England, Wales and Northern Ireland, by severity threshold, at surface, tooth and child level and explored its association with socioeconomic, psychological and behavioural factors.Dental caries is the most prevalent condition globally. Despite improvements over the past few decades, there remains a significant disease burden in childhood. Epidemiological surveys provide insight to disease patterns and trends, and have traditionally focused on clinical decay [visual enamel caries (AV) and above] and obvious decay [non-cavitated dentine lesions (2V) and above]. Negative binomial regression was used to identify factors associated with dental caries experience at both thresholds.Data from 12- and 15-year-olds in the 2013 Children’s Dental Health Survey (CDHS 2013) were analysed at three levels, taking account of dental caries thresholds which involved recording both stage of caries recorded in both ages. The average number of surfaces with obvious decay experience, which has been the traditional epidemiological threshold, in 12- and 15-year-olds was 2.3 and 3.9 respectively. The corresponding values under the clinical decay threshold were higher, at 3.9 and 5.9 respectively. Visualisation of the distribution of dental caries at surface/tooth-level exhibited horizontal symmetry and to a lesser extent vertical symetry. In the adjusted models for both ages, country/region, school type, area deprivation, high frequency sugar consumption and irregular dental attendance were associated with greater caries experience in both groups. Dental anxiety was inversely associated with caries experience among 15-year-olds.The prevalence and severity of dental caries experience was higher among 15-year-olds at all levels. Visual change in enamel (AV) was by far the most common This research highlights the importance of recognising dental caries patterns by surface, tooth and child-level amongst adolescents and the value of reporting dental caries distribution by threshold in epidemiological surveys, including its relevance for clinical care. Inclusion of enamel caries reveals the extent of caries management required at a point when non-invasive care is possible, emphasising the importance of prevention through contemporary primary care, which includes supporting self-care.The online version contains supplementary material available at 10.1186/s12903-021-01507-1. Dental caries is the most common disease in the oral cavity globally . A decliSeveral studies have reported that enamel or non-cavitated caries lesions contribute much of the total caries prevalence in different populations and may be an indicator to help assess the risk status of an individual –10. Recoobvious decay experience (non-cavitated lesions into dentine and above), 57% and 63% of them respectively had clinical decay experience when early caries (non-cavitated enamel caries and above) was included [The 2013 Children’s Dental Health Survey (CDHS 2013), commissioned by the Health and Social Care Information Centre, is the fifth in a series of national surveys of children’s oral health within the UK. Informed by ICDAS, enamel caries was recorded both at visual (non-cavitated) and cavitated level for the first time in this series of national surveys in 2013. This revealed that whilst just 34% of 12-year-olds and 46% 15-year-olds had included , 18. Undincluded .The aims of this study were to examine the distribution of dental caries across a range of lesion-severity thresholds in 12- and 15-year-old children in England, Wales and Northern Ireland, at surface, tooth and individual levels, and explore its association with socioeconomic, psychological and behavioural factors.This study involved secondary analysis of cross-sectional data from the CDHS 2013, collected in line with the published methodology . Three osound ; visual change in enamel (CDHS AV): ICDAS 1 and 2; visual enamel change with cavitation (CDHS AC): ICDAS 3; visual dentine caries : ICDAS 4; cavitated dentine caries (CDHS 2C); and decay with pulpal involvement (CDHS 3): ICDAS 5 and 6. In addition, filled with recurrent decay (with/without cavitation), filling needs replacement, sound fillings (F), and extracted due to caries (M) were also recorded [clinical decay (CDHS AV and above), and obvious decay (CDHS 2V and above). Decay experience in terms of these criterion includes currently and previously decayed teeth/surfaces, and were reported as DAVMFT/S, D2VMFT/S respectively. All methods in the study were carried out in accordance with the Helsinki guidelines and declaration.Dental examinations were undertaken in school settings by 75 trained and calibrated dentists. Training included pre-learning with a dedicated e-Learning programme and intensive lecture and in vivo sessions conducted in both classroom and school survey settings. Examiner calibration was conducted in 8 groups, and measured by calculating kappa scores, resulting in moderate to very good agreement on dental caries diagnosis . Consentrecorded , 20. DenKey sociodemographic factors were included in this analysis as potential confounders , 22. SexToothbrushing frequency was reported as a binary categorical variable (twice a day or more versus once a day or less). Consideration of frequency of sugar intake—involved aggregating reported daily consumption of several common sugary foods and drinks  into a total score, which was recategorised into a binary variable (less than four times a day or four or more times a day). Because only 2.41% of participants reported having “never been to the dentist”, the reason for usual dental attendance was dichotomized into regular (for a check-up) versus all the rest which is irregular (only when have trouble)/none. The Modified Dental Anxiety Scale (MDAS) was first introduced to CDHS in 2013. It consists of 5 questions, each with a 5-category rating scale, ranging from ‘not anxious’ to ‘extremely anxious’. The self-rated dental anxiety score was grouped into three categories for analysis .clinical and obvious decay) across the permanent dentition at surface, tooth, and child level for 12- and 15-years-olds. Second, the characteristics of participants according to relevant socio-demographic factors, behavioural and psychological factors were examined. The distribution of excluded pupils was compared with research samples in relevant variables by using Chi-square test to evaluate the impact of missing data. Complex survey design (stratification and clustering) was taken into consideration by using Negative binomial regression [AV/2V index), an unadjusted model and an adjusted model were successively built using negative binomial regression. The association of toothbrushing frequency, frequency of sugar intake, usual dental attendance, and dental anxiety with dental caries experience (DAV/2VMFS) were estimated. Potential confounders including demographic status were introduced into the model to make an adjusted estimation. Rate ratios (RRs), 95% confidence intervals (95% CI) and level of significance were reported and compared in all models. All analyses were conducted using Stata/SE 15 . P < 0.05 was considered as statistically significant.First, we calculated the distribution and composition of different stages or thresholds of dental caries  up to 2.74 times higher in 12- and 15-year-olds at 2.60 and 3.18, respectively.When considering clinical decay experience (DAVMFS/T). 41% of the surfaces and 50% of teeth with decay-experience were enamel caries in 12-year-olds, while these proportions were lower in 15-year-olds at 32% and 41% respectively. Past decay experience, managed through extractions and fillings (missing or filled teeth), occupied a larger portion of decay experience in both age groups. It is important, therefore, to recognise the dramatic finding that by far the most frequent “stage” of lesions encountered in 12- and 15-year-olds was visual enamel caries (AV).The findings revealed that 3.32% of surfaces and 9.62% teeth in 12-year-olds, and 4.94% surfaces and 13.56% teeth in 15-year-olds had Dental decay prevalence by stage is presented visually by at tooth and surface in Fig. clinical decay prevalence of 35–39% across the four quadrants in 12-year-olds, rising to between 42 and 46% in 15-year-olds. There was little difference observed between upper/lower or left/right dentitions, merely more teeth extracted due to decay in 15-year-olds. Second molars in same dentition on both sides of the dental arch shared similar decay status with the prevalence of clinical decay experience whilst maxillary decay was lower and milder than mandibular in both age groups. Amongst pupils aged 12 years who had decayed lower second molars, only 47% of them had decayed upper second molars, this proportion increasing to 68% in 15-year-olds  symmetry, and to a lesser extent, vertical (upper/lower) symmetry. First molar teeth, which had been longest in the oral cavity exhibited comparable clinical and obvious decay exhibited marked differences amongst the 12- and 15-year-old populations as shown in Fig. obvious decay experience was 2.3 in 12-year-olds and 3.9 in 15-year-olds, then this rose to 3.9 in 12-year-olds and 5.9 in 15-year-olds, when the clinical decay threshold including enamel caries was considered.The distribution of clinical and obvious decay experience. The characteristics of children at both ages are presented in Table clinical and obvious decay experience in the unadjusted models at one or both ages , and irregular/no dental attendance, emerged as the leading behavioural risk factors for ot Table .clinical decay at tooth surface level, whereas reporting moderate anxiety to be a protective factor. In relation to obvious decay, similar patterns were present, the only differences being that area deprivation was statistically significant and toothbrushing was not  as the diagnostic threshold for decay [clinical and obvious decay in 15-year-olds compared with 12-year-olds, drawn from the same contexts, suggesting that there is greater potential for risk management given that enamel lesions are potentially reversible [It is very clear from these findings that the threshold of reporting dental caries in epidemiological studies requires careful consideration, as surveys which just focus on or decay , they wior decay . Althougor decay , 29. Thiversible . Therefoversible  and shouChange 4 Life programme, particularly between meals, is important [If readers consider that most lesions in 12-year-olds were in enamel, this suggests that progression of much future disease could be prevented by supporting young people to lower free sugar consumption to ensure it doesn’t exceed 5% of dietary energy in line with contemporary evidence , increasmportant . If we dobvious decay. Furthermore, the prevalence, level and intensity of decay increased by age with more surfaces, teeth and children affected in this cross-sectional survey. As expected, occlusal and buccal surfaces of first molars as well as lower second molars were most effected by dental caries and either restored or in need of dental intervention. This suggests that the surface-/tooth-level of caries prevalence exhibited overall symmetry. Horizontal (left/right) symmetry, which indicated similar propensity of decay affected for both sides of the same dentition can be observed in most tooth sites, whilst a degree of vertical symmetry (upper/lower) was present in relation to disease in posterior sextants. Whilst it has traditionally been considered that mandibular molars are more vulnerable to dental caries comparing with their maxillary counterparts as indicated by Luan et al. [clinical decay experience vertically or horizontally. Similarly, Macek et al. [Establishing health patterns of behaviour in support of oral health is an important foundation of maintaining a ‘functional dentition’ through adulthood . The pron et al.  who condn et al. . We founk et al. , reportek et al.  also sugInterestingly, symmetry of caries prevalence doesn’t illustrate these teeth/tooth surfaces necessarily suffered from same stages of caries simultaneously in a certain child, which hasn’t been emphasized before. The proportion of pupils with decayed lower second molars who’s upper second molars suffered from caries at the same time, increased from 47% in 12-years to 68% in 15-years with age cohort. It is quite possible that a tooth/surface is in a very early  stage of caries which cannot be detected by clinical visual examination, meanwhile, its asymmetrical surface already progressed to more advanced signs (white spot or cavitation). The similar pattern of caries horizontally and to an extent vertically in the same type of teeth suggests that when an effect that reduces/increases the cariogenic process of one of the teeth in children, is likely to affect their counterparts in the other three quadrants. This was supported by Batchelor and Sheiham’s findings that occlusal surfaces of second molars and buccal sites on mandibular second molars were in the same group in order of caries susceptibility when 5- to 16-year-olds were involved . Differeclinical/obvious decay thresholds was associated with similar but not identical dental behavioural and psychological factors in two age groups, albeit that not always significant. Sugar intake frequency, one of the most recognised dental caries risk factors, was shown to be related to clinical/obvious decay experience (DAV/2VMFS) in this research, which is consistent with the finding of 4th National Oral Health Survey in China [Modelling these data suggests that dental caries prevalence at surface level for ence DAV/VMFS in tin China . The WHOin China , affirmein China , 39, 40.in China . Whilst in China , 32. Thein China –43. Dentin China , but wasin China . InteresVariation in the significance of the findings of the analysis could relate to the year cohort, sampling or the instruments utilized for data collection. What is clear is that the same patterns are present across both ages. Importantly the patterns and trends were similar in relation to significant or tending towards significance in both adjusted models.The limitations of the study include the fact that it used cross-sectional data and differences between study samples and excluded samples could be found which have implications for its representativeness. None-the-less the uptake of the self-complete questionnaire survey was high and the survey was innovative in providing the opportunity to compare the data retrospectively with past surveys to document a further decline in caries , as wellobvious decay to achieve comparability with past surveys, the findings will seriously underestimate the prevalence of disease, and provide limited insight to the planning of health interventions. Reporting dental caries levels at the clinical decay threshold is increasingly important and possible, and the methodology used by the CDHS 2013 survey can be useful to other countries and should be replicated in the UK in future surveys. Second, the volume of enamel caries in both age-groups, highlights the important opportunity to recognise and arrest progression of these non-cavitation lesions—if they are controlled, many restorations and repeated restorations will be prevented with potential cost savings [The present findings have very important implications for public health policy, starting with epidemiology. First, initial stage of dental caries occupied almost half of decay-experienced surfaces/teeth in children according to information of CDHS 2013. Thus, if epidemiological surveys merely focus on  savings , 30. ActIn conclusion this research highlights the importance of recognising the dental caries patterns in epidemiological surveys, and the importance of appreciating the caries process and being clear about dental caries thresholds in the population. Secondary analysis illustrates that working with and examining different caries thresholds, including initial stage lesions, can provide better insights into dental caries staging and prevalence to inform contemporary primary care, which includes supporting self-care.Additional file 1. Appendix Figure 1. Distribution of CDHS 2013 code in each surface of 12-year-olds in England, Wales, and Northern Ireland, 2013 (n = 2532). Appendix Figure 2. Distribution of CDHS 2013 code in each surface of 15-year-olds in England, Wales, and Northern Ireland, 2013 (n = 2160).


Alterations of the other DNA damage repair genes such as DNA mismatch repair genes are also known to affect the drug effect. Together these genes have roles in the innate resistance, but are not sufficient for explaining the mechanism leading to acquired resistance. Recent identification of specific cellular subsets with features of stem-like cells may have role in this process. The glioma stem-like cells are known for its superior ability in withstanding the drug-induced cytotoxicity, and giving the chance to repopulate the tumor. The mechanism is complicated to administrate cellular protection, such as the enhancing ability against reactive oxygen species and altering energy metabolism, the important steps to survive. In this review, we discuss the possible mechanism for these specific cellular subsets to evade cancer treatment, and the possible impact to the following treatment courses. In addition, we also discuss the possibility that can overcome this obstacle.Glioblastoma is the most common primary malignant brain tumor that is usually considered fatal even with treatment. This is often a result for tumor to develop resistance. Regarding the standard chemotherapy, the alkylating agent temozolomide is effective in disease control but the recurrence will still occur eventually. The mechanism of the resistance is various, and differs in terms of innate or acquired. To date, aberrations in O Glioblastoma  is the most common primary malignant brain tumor. In the United States, the annual incidence is 5.26 per 100,000 population or 17,000 new diagnoses per year . The forComparing to the other malignancies, GBM is relatively rare but desperate. The 2-year survival rate is only 26.5 %, which has one of the worst outcomes regarding the advancement of latest treatment strategies . Even ap6- and N7-methylguanine (MeG) or N7-methyladenine (MeA). Regarding O6-MeG, when DNA mismatch repair (MMR) enzymes attempt to excise the modified nucleotide, they generate single- and double-strand breaks in the DNA that lead to activation of apoptotic pathways if no further repairment is available [6-methylguanine-DNA methyltransferase  but not the other molecular subclassification [As being the standard systemic treatment agent, TMZ is a second-generation imidazotetrazine lipophilic prodrug. Currently, it is perhaps the most important systemic drug in GBM treatment. It works by hydrolyzing into its active metabolite 5-(3-dimethyl-1-triazenyl) imidazole-4-carboxamide. The reactive methyldiazonium ion is then formed to methylation-associated residues in the DNA molecule at Ovailable . The druvailable –14. In available . In the vailable . Those wfication . Most offication . With itEven with the successful data after introduction of TMZ, the disease, however, remains far from optimal control in clinical aspect. Limited therapeutic efficacy has been a major issue due to eventual failure of the treatment. Despite of the initial response, development of resistance is almost inevitable, with 90 % of patients suffering from early disease recurrence . The rem6 position of guanine to reverse the cytotoxicity of TMZ [Understanding the resistance mechanism is necessary to help to develop potential strategies against the dilemma. To date, MGMT is the best-known factor leading to resistance of TMZ in GBM , 18 , homologous recombination (HR) for prediction of the drug response [7-MeG to relate with TMZ drug cytotoxicity, cells proficient at repairing with base excision repair (BER) enzyme, the major targeting repairing protein, was also reported to cause resistance [The general understanding of DNA repairing mechanism, derived from DNA single-strand break or double-strand break, suggests activation of the other DNA damage repair (DDR) genes may also have roles, especially in lab research, but requires more evidences to elucidate . As beinresponse . Finallysistance  Fig. 1)6-MeG areSetting up histological criteria based on the aforementioned DDRs is seemingly practicable and can contribute to personalized algorithm in guiding patients to receive the most appropriate treatment . HoweverLimitation in DDR to fully explain the resistant mechanism gives rise to other theories such as cancer stem-like cells (CSCs) model, which represents specific subsets in the heterogeneous tumors accountable for acquiring treatment resistance and turning into more aggressive form . These aCSCs in cell lines can provide validation for stem-cell features [Nevertheless, the theory often comes with controversy . Inconsifeatures .Conventionally, drug resistance of CSCs is caused by abundant ATP-binding cassette (ABC) transporters expression in the cells. These proteins enable the cells to pump out drugs before intracellular damage occurs, allowing them to withstand the drug toxicity. The associations of the ABC transporters and CSCs are close, providing basic theory for “side population (SP) assay” to identify them . This me2•−), hydrogen peroxide (H2O2), and hydroxyl radical (•OH) [Adaption of tumor cells is critical for their facing constantly fluctuating stress from internal environment or from anti-tumor treatment. With regard to TMZ, the drug itself and its analog TMZ-perillyl alcohol conjugate, were shown to up-regulate ROS production in GBM cells and non-small cell lung cancer cells, respectively , 60. ROSal (•OH) . Presencal (•OH) , 64, in al (•OH) . As thusal (•OH) –69. On tal (•OH) . Multiplal (•OH) , 72. In al (•OH) , 74, andal (•OH) . This waal (•OH) . As thus2O2) and peroxynitrite (ONOO−) [2O2, have crucial roles in promoting cellular proliferation, migration, and pathogen defensive mechanism [Cell-based regulation of ROS is critical. Extrinsic sourced and endogenously generated reactive oxidants are continually infused to cells by balancing of metabolized oxygen. This is a physiologically regulated process, with deregulation leading to oxidative stress and pathologic consequence of cells . Organel (ONOO−) . Superoxechanism  Fig. 2)2O2) and echanism .2O2 and oxygen. The process continues with the hydrogen peroxide reduced to H2O and O2. This will need the involvement of catalase or GPx , with each having different role in the different stages required to convert superoxide into water and oxygen . In regaRegarding the heterogeneity by cell-to-cell bases in tumor tissue, it is not surprising some cells have superior ability in regulating ROS. As aforementioned, the CSC subsets are with altered cellular features. Since external factors such as hypoxia plays crucial role in contribution of resistance in tumor tissue, the specific subsets can take advantage from the extreme condition . GSCs, tIn cellular level, mitochondria are one of the most important organelles in adjusting against the external stress. It is not surprising for CSCs to have invigorated mitochondrial dynamics that offers advantage in withstanding the tough environment . MitochoTo maintain in a lowered ROS and possibly to withstand the cytotoxicity of cancer treatment, altered metabolic reprogramming by mitochondrial control in cancer may play a critical role , 99. ManAs reviewed above, utilization of ROS and the altered mitochondria functioning in CSCs are critical for these specific subsets to survive and thrive from TMZ toxicity. This may also affect the effect of re-applying the current treatment or changing to the next-line treatment since many of the current therapy relied on ROS induction. For example, the ionizing radiation achieves tumor control by inducing oxidizing events that is harmful for DNA. Multiple chemotherapy agents achieve to control the disease by association with eliciting ROS reaction . It was Strategies should be made to avoid the cross-resistance. Bevacizumab, which is an approved targeting therapy against VEGF, can be chosen with less impact in ROS. The other methods are active studying for tumor markers associated with anti-oxidant factors, such as Nrf-2 or SOD2. Direct modulation of ROS may also avoid the resistance or enhance the treatment . Down-reLimited breakthrough has been achieved in GBM treatment in the past few years. Before the major leap to happen, inspection of the tumor biology is potentially contributable in optimizing treatment to improve the disease outcome and in developing novel therapeutic strategies. Regarding the underlying resistant mechanism of TMZ, rationales were suggested to combine the first-line drug along with simultaneous suppression over the higher protection mechanisms of the stem-like cells to seek for opportunity to enhance the drug efficacy. This can possibly be achieved by modulating selective factors related to these specific subsets, such as enhancement of antioxidant enzymes, energy metabolism, and adaptation in the microenvironment. Though the inhibition may not be straightforward, the rationale suggests a potential framework to benefit cancer treatment.Abbreviations.2O2: hydrogen peroxide; GPx: glutathione peroxidase, MGMT: O6-methylguanine-DNA methyltransferase; TCGA: The Cancer Genome Atlas; MSI: microsatellite instability; CSC: cancer stem-like cell; GSC: glioma stem-like cell; SP: side population; ABC: ATP-binding cassette; DDR: DNA damage repair; NER: nucleotide excision repair; HR: homologous recombination; BER: base excision repair; RTK: receptor tyrosine kinase; EGFR: epidermal growth factor receptor; VEGFR: vascular endothelial growth factor receptor.GBM: glioblastoma multiforme; TMZ: temozolomide; BCNU: carmustine; TTFields: tumor-treating fields device; IDH: isocitrate dehydrogenase; Nrf-2: nuclear factor-erythroid-2–related factor 2; Sp1: specific protein 1; SOD2: superoxide dismutase 2; ROS: reactive oxygen species; H


While it is well established that skin disease places significant psychosocial burden on a patient’s wellbeing, its effects have rarely been examined in Asian populations.Evaluate the psychosocial burden of skin disease among community-dwelling adults in Singapore.This cross-sectional study included 1510 participants interviewed on their history of thirteen skin diseases. The Patient Health Questionnaire (PHQ-9), Lubben Social Network Scale-6 (LSNS-6), University of California Los Angeles (UCLA) Loneliness Scale, and European Quality of Life-5 Dimensions- 5 Level (EQ-5D-5L) were used as measures for depressive symptoms, social isolation, loneliness and quality of life respectively. Multiple linear regression analysis was used to examine the association of skin diseases with each of the four measured outcomes.Participants with skin diseases reported significantly higher PHQ-9 and UCLA Loneliness scale scores, and lower LSNS-6 and EQ-5D-5L scores when compared to their healthy counterparts. The presence of skin disease was positively associated with depressive symptoms , and negatively associated with quality of life . As disease severity was not evaluated in this study, we were unable to ascertain the associations between disease severity and measured outcomes.Participants with skin diseases were more likely to have depressive symptoms, social isolation, loneliness and lower quality of life. Unemployed, single and elderly patients were at higher risk of developing depressive symptoms. More emphasis should be placed on the psychosocial aspect of care to reduce the burden of skin disease. Some considerations include monitoring patients for mood-related changes and implementing early psychosocial interventions. Skin disease contributes 1.79% to the global burden of disease and is the fourth leading cause of non-fatal disease burden . PatientThis cross-sectional study included 1510 participants who took part in the first-year follow-up survey of the Population Health Survey between November 2016—February 2018. This was a longitudinal health survey on the health of a representative sample of community-dwelling adult population living in the central region of Singapore. The details of the study methodology have been described elsewhere . The eliThe medical history of skin diseases was obtained by asking the participants a specific question: “Have you ever had any of the following skin conditions [a list of 13 skin conditions]?” This included eczema, acne vulgaris, psoriasis, vitiligo, viral warts, scabies, fungal skin infections, chronic urticaria, bacterial skin infections, chronic ulcers or wounds, skin cancers, alopecia areata, and pruritus; and participants were offered an option of “Others” to specify any other skin diseases not listed. This list was modified from the 15 categories of skin diseases included in the Global Burden of Disease Study 2010 [The outcomes measured in this study were depression, social isolation, loneliness and health-related quality of life (HRQOL).Depressive symptoms were assessed using the 9-item Patient Health Questionnaire (PHQ-9), a well validated and widely used measure of depression. Each item of PHQ-9 is assessed on a 4-point scale  and the total depressive symptom score for the 9 items ranges from 0 to 27. The scale demonstrated good internal consistency reliability  in this study.Social isolation was assessed using the Lubben Social Network Scale-6 (LSNS- 6). The LSNS-6 measures the size, closeness and frequency of contacts of a participant’s social network with reference to the level of perceived support they receive from relatives and friends [How often do you feel that you lack companionship?”, “How often do you feel left out?” and “How often do you feel isolated from others?”, using a 3-point scale . The scores for each item were added up to produce a score ranging from 3 to 9, with higher scores indicating higher loneliness levels. The internal reliability of the UCLA Loneliness Scale in this study was good, with Cronbach’s alpha = 0.88.Loneliness was assessed using the three-item University of California Los Angeles (UCLA) Loneliness Scale . The thrHRQOL was assessed using the EQ-5D descriptive system of the European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) . The des2) tests or one-way analysis of variance (ANOVA) were used to assess group differences in socio-demographic characteristics, diagnosis of individual skin diseases, number of chronic diseases, and the measured outcomes, specifically depression, social isolation, loneliness, and HRQOL.Independent-samples t-tests, Chi-square  version 18.0  and multiple linear regression was computed using Stata/SE 12 for Windows. The result was considered significant if p-value was <0.05.The average age of the 1510 participants was 54.3 years  and 56.2% were women. The majority of participants were Chinese (78.7%), followed by Indians (10.7%) and Malays (7.8%).The demographics of participants with and without history of any listed skin diseases were compared and described in The most common skin conditions amongst our participants were eczema (8.8%), followed by bacterial skin infections (7.6%) and fungal skin infections (3.9%). The distributions of the thirteen skin conditions by gender and age are presented in Participants were interviewed on their comorbidities, with the three most common conditions being hypertension (29.6%), dyslipidaemia (29.1%) and diabetes (14.0%) . Table 3Participants with skin diseases reported significantly higher PHQ-9 and UCLA Loneliness scale scores, and lower LSNS-6 and EQ-5D-5L scores compared to those without any skin diseases .Linear regression showed that history of skin diseases had a positive correlation with depressive symptoms , and a negative correlation with HRQOL , adjusted for age group, gender, marital status, employment status, highest education level, self-reported money sufficiency, and diagnosis of any chronic diseases . ParticiThis study explores the impact of skin diseases on psychosocial measures of well-being and HROQL. In this study, participants with history of any skin diseases had a mean EQ-5D index score of 0.89. This is equivalent to people suffering from migraine headaches and is lower than the mean score (0.95) obtained from a large representative sample of community-dwelling residents aged 18 years and above [Our findings also demonstrated that participants with history of any skin diseases were more likely to have depressive symptoms, social isolation and loneliness. We examine some reasons explaining this observed phenomenon below.This study observed that participants with skin diseases were less likely to be employed and more likely to have financial constraints . Across Patients with severe skin conditions are more likely to be unfit for work, while those with mild to moderate disease may be able to work but often require time off to attend consultations or take sick leave during flares. A study in Netherlands showed that 64% of patients with atopic dermatitis took sick leave in a year, as compared to 50% of their healthy counterparts . FrequenParticipants with skin diseases were more likely to be single, including those who were widowed or divorced . StudiesTo cope with depression and loneliness, some may turn to maladaptive coping mechanisms such as alcohol. Participants with skin diseases are more likely to have alcohol misuse (28.2%) compared to their healthy counterparts (21%) . This isWith a clearer understanding of the psychosocial burden skin diseases have on our patients, we considered a few areas for improvement.Firstly, more attention should be paid towards patients with a higher risk of developing depressive symptoms, such as those who are not working, single and elderly. Some studies have suggested monitoring patients with a short instrument like PHQ-9 regularly, to detect depression early and refer them to appropriate care accordingly. The early detection of depression is important for patients with any chronic disease, including skin conditions, as studies have shown that patients with depression are three times more likely to be non-adherent to medical treatment as compared to patients without depression .In addition, more emphasis should be placed on psychosocial interventions when managing patients with skin diseases. Existing studies have demonstrated the effectiveness of psychosocial interventions such as cognitive behavioural therapy, both in-person and online , mindfulThere are several limitations of this study. Firstly, as this was a cross-sectional study, we were unable to clearly ascertain the temporal relationship between skin disease and certain outcomes such as alcoholism. Also, some participants might not have been suffering from skin disease at the point of enrolment, which may have resulted in underestimation of the measured outcomes. Secondly, our study did not evaluate the severity of skin diseases, and hence we were unable to determine the association between severity of skin diseases and measured outcomes. Thirdly, while skin specific quality of life instruments like Dermatology Life Quality Index (DLQI) were not used, EQ-5D has allowed us to compare the impact of skin diseases with other chronic diseases.Skin diseases have an adverse impact on psychosocial well-being and can lead to more depressive symptoms, social isolation, loneliness and decreased quality of life. The psychological impact of skin diseases is often underestimated compared to that of other chronic diseases. Moving forward, a more holistic approach should be taken to optimise patient care and reduce the burden of skin disease. Some considerations include monitoring patients for mood-related changes regularly and implementing psychosocial interventions early.


COVID-19 has been shown to present with varied clinical course, necessitating a need for more specific diagnostic tools that could identify severe cases and predict outcomes during COVID-19 infection. Recent evidence has shown an expanded potential role for calprotectin, both as a diagnostic tool and also as a tool in stratifying COVID-19 patients in terms of severity. Therefore, this systematic review and meta-analysis aims to evaluate the levels of calprotectin in severe and non-severe COVID-19 and also identify the implication of raised calprotectin levels. MEDLINE, EMBASE, The Cochrane Library, Web of science and MedRxiv were searched. Meta-analysis was done to compare the serum/fecal levels of calprotectin between severe and non-severe COVID-19 infections. A total of ten studies included in the review . A pooled analysis of the eight studies from 613 patients who were RT-PCR positive for COVID-19  showed an overall estimate as 1.34 . In conclusion, calprotectin levels have been demonstrated to be significantly elevated in COVID-19 patients who develop the severe form of the disease, and it also has prognostic importance. Wuhan city in Hubei province of China, in December 2019, became the epicenter of an epidemic that turned into a pandemic within three months after spreading to 114 countries . Varied Calprotectin  is a 36.5 small calcium and zinc-binding heterodimer, derived from neutrophils and macrophages that often associates with its main receptor, TLR4 (Toll-like receptor 4) via a non-covalent bond to mediate downstream signaling with active involvement in inflammation , during Zhou et al. had earlier reported the raised markers of cytokine storm  in COVID-19, and also described IL-6 as the best predictor of death in their case control study on COVID-19 ,14. ReceThis study is a systematic review, and a literature search was conducted to identify recent papers on this subject. MEDLINE, EMBASE, The Cochrane library  I2 = 93% with a p-value = 0.03. Owing to the small number of included studies, a meta-regression may not be justifiable  ,25,26,27tifiable .p-value = 0.45). The fecal subgroup had some evidence of publication bias as shown by funnel plot with some asymmetry . The total cohort of studies showed some evidence of publication bias, with funnel plot showing some asymmetry .Substantial heterogeneity was further explored for bias . For thesymmetry  and Eggesymmetry C and Eggn et al. , Effenben et al.  and Britn et al. ), showedOur meta-analysis addressed heterogeneity among the included studies. It is worth noting that the total cohort, serum cohort and fecal cohort of studies, all showed substantial heterogeneity. This high level of heterogeneity in these cohorts seems to be explained by three “outlier” studies: Chen et al. , Effenben = 94) was able to select patients who needed mechanical ventilation  as opposed to those who did not need intubation  [Shi et al. reported that plasma calprotectin among those hospitalized ( 0.0001) . Silvin  0.0001) . This re 0.0001)  and Baue 0.0001) . However 0.0001)  did not r = 0.359; p = 0.003), CRP  and D-Dimer  [A marked difference in the serum calprotectin levels between COVID-19 survivors and non-survivors has been demonstrated by de Guadiana et al. . They fu= 0.007) . Silvin = 0.007) . Hence, Two clinical parameters have been identified to have a predictive value that correlated well with calprotectin levels viz diarrhea and comorbidities ,18. TherTo support the predictive capacity of calprotectin demonstrated by earlier studies, an exposition by Chen et al. showed that very high levels of calprotectin was associated with poor overall survival. This is supported by some recent works that showed elevated serum calprotectin correlates strongly with risk of death in COVID-19 often due to thrombotic issues ,37. WhenSignificant elevation of acute phase reactants such as CRP, ferritin and D-dimer have been shown to be good predictors of poor survival in COVID-19 patients . EvidencDe Guadiana et al. also showed that calprotectin has a predictive capacity  similar to that of D-Dimer and CRP, but much better than that of ferritin . This stFurthermore, several studies demonstrated the predictive capacity of calprotectin in different prognostic scenarios: Shi et al. compared AUC for calprotectin on the need for invasive ventilation  ; Silvin As a biomarker for COVID-19, serum calprotectin is unique due to the following intrinsic properties: (1) it is easy to quantify; (2) its small size makes it a more sensitive and active marker—as it diffuses easily between the blood and tissue. Hence, it is the most abundant inflammatory marker seen in the plasma of patients with severe COVID-19; (3) its results are simple to interpret; (4) it has a strong correlation with qSOFA and oxygen demand; (5) it is powerful on its own either in selecting patients with severe COVID-19 or in predicting poor outcome. Hence, it is an important single parameter biomarker model ; (6) it has a much better AUC ROC than CRP, ferritin and LDH; (7) it has the capacity to indicate early COVID-19 patients who will either end up in the ICU or die ,14,18,26To our knowledge, this is the first comprehensive and extensive systematic review and meta-analysis to assess the prognostic value of calprotectin in distinguishing between COVID-19 severity in patients and its impact on clinical outcomes, since the outbreak over 12 months ago. The meta-analysis had a pooled population size of 613 patients  who were RT-PCR positive for COVID-19. The overall pooled estimate presents with enhanced accuracy, a better picture of calprotectin’s diagnostic and prognostic significance. Further, despite being observational in nature, most of the studies were of good quality overall. Lastly, the included studies overlapped fairly well in terms of their description of severe and non-severe forms of COVID-19.This review has the following limitations. Firstly, some of the individual studies of the meta-analysis were underpowered by small number of study participants. Secondly, huge variations in the populations and clinical attributes contributed to some substantial heterogeneity in the pooled estimate of the study. Further, the study is limited by existing variations in calprotectin  normal range across different laboratories in these studies. Owing to the high heterogeneity, there is a need to be cautious in interpreting our result. Lastly, there is lack of adequate data since most of COVID-19 research is still in the infancy stage, and we continue to learn more every day on how the virus operates both within the human system and the environment. Such paucity of data warrants that we exercise some caution in generalizing our findings while we wait for more data. Hence, one cannot overemphasize the need for more data  on this subject which is relatively a novel field in COVID-19 research, as such will help to further expand our understanding of calprotectin in COVID-19 and strongly establish calprotectin’s role in COVID-19.We identified a systematic review on the use of fecal calprotectin in COVID-19 that demonstrated that COVID-19 could lead to raised fecal calprotectin mostly in the presence of GI symptoms . It inclCOVID-19 continues to spread rapidly leading to massive rates of infection across the globe, with rising death rates most especially in the USA and across Europe. Given the rapidly evolving clinical understanding of COVID-19, it remains crucial to identify biomarkers that can help predict both severity and outcomes associated with COVID-19. Such will facilitate the formulation of efficient management guidelines, geared towards improved outcomes.Our review and pooled analysis demonstrate that circulating calprotectin levels are elevated in COVID-19 infections. More importantly, these higher calprotectin levels could select severe COVID-19 from non-severe forms, predict poor outcome as well as predict gut inflammation in COVID-19 patients. Therefore, calprotectin is demonstrably a foremost candidate biomarker for COVID-19 infections with both diagnostic and prognostic significance. Recent evidence suggests that calprotectin offers a potential therapeutic strategy in severe COVID-19 as well as other inflammatory diseases. Further studies should explore its role as a druggable target with several molecules such as the oral quinoline-3-carboxamide , where it blocks the binding of calprotectin to TLR4 or RAGE (ACTRN12621000016831p). Such strategic therapeutic intervention could help decrease tissue damage, control pulmonary inflammation and thus halt the functional exhaustion seen in COVID-19. Other therapeutic strategies include lenzilumab (NCT04351152), a recombinant anti-human granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody and preclinical antiCD33 monoclonal antibodies. Despite existing data, there is still a need for further functional studies on the heterodimer to facilitate a more detailed characterization of calprotectin [


Coronavirus disease 2019 (COVID-19) has infected people in many countries worldwide. Discovering an effective treatment for this disease, particularly in severe cases, has become the subject of intense scientific investigation. Therefore, the objective of this study was to evaluate the efficacy of intravenous immunoglobulin (IVIg) in patients with severe COVID-19 infection.This study was conducted as a randomized placebo-controlled double-blind clinical trial. Fifty-nine patients with severe COVID-19 infection who did not respond to initial treatments were randomly assigned into two groups. One group received IVIg (human)—four vials daily for 3 days , while the other group received a placebo. Patients’ demographic, clinical, and select laboratory test results, as well as the occurrence of in-hospital mortality, were recorded.P > 0.05) between the two groups. The in-hospital mortality rate was significantly lower in the IVIg group compared to the control group . Multivariate regression analysis demonstrated that administration of IVIg did indeed have a significant impact on mortality rate .Among total study subjects, 30 patients received IVIg and 29 patients received a placebo. Demographics, clinical characteristics, and laboratory tests were not statistically different , number IRCT20200501047259N1. It was registered retrospectively on May 17th, 2020.A study protocol was registered at the Iranian Registry of Clinical Trials (Supplementary information accompanies this paper at 10.1186/s12879-020-05507-4. Coronavirus disease 2019 (COVID-19) was declared to be a pandemic by the World Health Organization on March 11th, 2020 . Jalili Currently, no vaccine for COVID-19 is widely available for the general population. It is estimated that it would be available by early 2021. About 78 projects have been developed for vaccine production, mostly by private industries. Although, the proposed mechanism of action of these vaccines varies greatly among the ongoing projects, using neutralizing antibodies against the viral spikes and its S protein is the main goal of most of them .Intravenous immunoglobulin (IVIg) is a blood product that is obtained from healthy donors and contains polyclonal immunoglobulin gamma. Since its discovery as an effective treatment 30 years ago, it has been administered as an immunomodulatory therapy in autoimmune and inflammatory diseases such as immune thrombocytopenic purpura, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy . Signifin = 59) among patients with severe COVID-19 who did not respond to initial treatments. The research was conducted in accordance with the Declaration of Helsinki protocol. Informed consent was obtained from patients or their guardians. The study protocol was approved by the medical ethics committee of the Urmia University of Medical Sciences (IR.UMSU.REC.1399.025), and was registered at the Iranian Registry of Clinical Trials with the registration number IRCT20200501047259N1 (www.IRCT.ir).This study was a randomized double-blind placebo-controlled clinical trial (2 saturation (satO2) of < 90%, and a lack of adequate response to initial treatment including at least both one antiviral and one chloroquine-class drug. Exclusion criteria, in addition to an age of less than 18 years, included pregnancy, coagulation disorders , history of hypersensitivity to IVIg, advanced heart failure (defined as a left ventricular ejection fraction less than 35%), pulmonary fibrosis/history of lung surgery, and the presence of either sarcoidosis or tuberculosis (that may interfere with an accurate estimation of the severity of pulmonary interference by COVID-19).Patients were included if they had acute respiratory syndrome and a definitive diagnosis of COVID-19, made based on real-time reverse transcription-polymerase chain reaction (RT-PCR) and chest computed tomography scan findings from an undisclosed teaching hospital. The name of the teaching hospital was hidden due to blind peer-review protocol. Patients consecutively were recruited between May 9th, 2020 and June 9th, 2020. Inclusion criteria included being over 18 years of age, possessing a PCR-confirmed COVID-19 diagnosis, involvement of > than 30% of both lungs (ground-glass opacity) in high-resolution computed tomography (HRCT) (confirmed by two radiologists), Oand hypoxemia (satO2 less than 90%), as well as the need for oxygenation to maintain satO2 above 90% after 48 h of commencing treatment.Inadequate response to initial treatment was defined as the lack of improvement of dyspnea, fever, Study subjects were randomly assigned into two approximately equal groups: IVIg treatment and placebo control using a computer-generated randomization schedule. The IVIg group received IVIg (human) flebogamma 5% DIF GRIFOLS, in addition to their prior initial treatment . Treatment group patients received four vials of 5 gm5 IVIg daily for three consecutive days. Those patients who died before 72 h after the distribution of IVIg and placebos were excluded from our study due to an incomplete course of treatment. The control group continued to receive the same treatments as were introduced initially, in addition to a placebo. Neither patients nor physicians nor data analysts were aware of treatment versus placebo membership. The only individual that did was the pharmacist of the study center. Placebo and IVIg vials were similar in appearance and contained a similar volume of solution. Placebo vials contained saline solution.Normal distribution of all continuous variables was evaluated using a Kolmogorov-Smirnov test. The majority of continuous variables  did not possess a normal distribution; therefore, the median and interquartile range  of all continuous variables was reported. The frequency and percentage of categorical variables” were reported. Continuous variables were compared using a Mann-Whitney U test. Categorical variables were compared using a chi-square or Fisher exact test. Univariate logistic regression was used to model mortality rates based on all investigated variables. Statistically significant variables  in univariable logistic regression  were entered into multivariable logistic regression. All statistical analyses were conducted using SPSS version 22  .P = 0.001), (2) white blood cell (WBC) count (1000/mm3), which was also higher in the control group , and (3) the overall duration of hospitalization (days) was longer in the treatment group .The investigated characteristics of the subjects are described in Table P = 0.025; Table P = 0.042). Moreover, increasing age, lower diastolic blood pressure, and increasing serum lactate dehydrogenase (LDH) were other determinants of elevated mortality in patients with severe COVID-19 infection  [Our results provide evidence to support the administration of IVIg for improving clinical outcomes in COVID-19 patients with severe respiratory system involvement. Prohaska et al. previously conducted research to suggest that IVIg could not be used effectively to reduce the mortality of patients with the acute respiratory distress syndrome (ARDS) undergoing extracorporeal membrane oxygenation (ECMO) therapy . The stu= 0.009) . The mor= 0.009) . Thereup= 0.009) . Cao et = 0.009) . Our resp = 0.009), and in the IVIg group, 41% of patients had the critical type of disease. In the non-IVIg group, the critical type of disease incidence was 21%. The study reported a 28-day mortality rate of 13% among both groups. The primary analysis showed no statistically significant difference between the treatment group and the control group in reducing in-hospital mortality. After adjusting the outcomes of the two groups based on the severity of illness, however, results demonstrated that administration of IVIg did significantly decrease 60-day mortality rates. The same study also showed that both IVIg dosage (> 15 g/d) and administration period  could improve efficacy [Shao et al. conducted a multicenter retrospective cohort study on 325 COVID-19 patients, 222 (68%) with severe COVID-19 and 103 (32%) with critical COVID-19. Among 174 patients, IVIg was administered (treatment group), while 151 patients did not take IVIg (control group). The cohorts had significantly different baseline characteristics. The age of the IVIg group was significantly higher (efficacy .Our study demonstrated that increasing age, decreasing diastolic blood pressure, and increasing LDH were also statistically associated with higher mortality in COVID-19 patients with severe disease. Correspondingly, Du et al. postulated that a reported age of ≥65 years is associated with higher mortality in patients with COVID-19-related pneumonia . FurtherTo the best of our knowledge, our study is the first randomized placebo-controlled double-blind trial that suggests the effectiveness of IVIg in reducing in-hospital mortality in patients with severe COVID-19 pneumonia. Nonetheless, some limitations affected our study. Research was conducted as a pilot and thus included a relatively small sample size. A further multicenter study with larger samples size should be conducted in this regard. Moreover, the study would be improved if we were to follow patients to assess the intermediate and long-term effects of IVIg treatment on mortality. Due to the current pressing concerns for recommending evidence-based medications for COVID-19 patients, we decided to report follow-up data in future reports. It should also be noted that the cost of IVIg treatment is relatively high, and therefore may not be widely available in World Bank-defined low- and middle-income countries .The patients were consecutively included in our study, and there was no tendency towards including male patients. However, a larger proportion of our sample consisted of male patients. This inequity could be due to the higher prevalence of male sex among COVID-19 cases, which is reported in the majority of studies worldwide . This seDespite the randomized allocation of patients, some parameters were significantly different between the two groups, including WBC, serum creatinine, and duration of hospitalization. Although the difference in creatinine was statistically significant, it was not clinically meaningful. Moreover, the longer duration of hospitalization in the IVIg group could be due to the longer survival of patients in the IVIg group. In other words, those patients with critical status died in the control group, but those with similar critical conditions in the IVIg group survived and stayed longer in the hospital.The results of our study suggest that the administration of IVIg in patients with severe COVID-19 infection who did not respond to initial treatments could improve clinical outcomes and thus reduce mortality rates. Regarding high price of IVIg, we suggest that it should be considered in patients with > 30% involvement of lungs in lung CT scan, whom their dyspnea do not improve with standard treatment, those with persistent satO2 under 90%, and those who develop aggravation of lung involvement in serial lung CT scans, especially in younger adults.Additional file 1: Supplementary Table 1. Demographic characteristics of patients.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019. It was first reported in Wuhan, China and has since become a global health concern. Keeping in view, the magnitude of the problem, scientists around the globe are working to develop effective therapeutic strategies. This review focuses on previous findings regarding SARS-CoV, which may prove helpful in future research on SARS-CoV-2. In addition, it also highlights recent developments in medicine and biotechnology toward developing effective drugs and vaccines against SARS-CoV-2. This review will analyze available data on this topic and will help researchers develop new thoughts using information already available as a step toward developing novel therapeutic strategies against SARS-CoV-2. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also known as 2019 novel coronavirus (2019-nCoV) is the causative agent of COVID-19. COVID-19 is a severe respiratory disease which was initially noticed in Wuhan, China in December 2019 .Over 3.1 million COVID-19 cases have been confirmed among which 224,172 deaths occurred till 1 May 2020 .Initially, the virus spread across different countries, mainly because of travelling of the infected individual from China to other countries. Precautionary measures have been taken worldwide on airports and borders. Healthcare experts also advised that those who traveled from outside the country should be tested for COVID-19. If tested positive, the person must observe a 14-day quarantine. Some of the countries have not paid attention to precautionary measures especially for immigrants, which resulted in the global spread of the virus. The world is fighting continuously to combat COVID-19. Therefore, many companies and laboratories across the globe are working to develop different vaccines or drug to explore possible ways to treat this infection. This review will focus on the global prevalence and possible treatment strategies for COVID-19.According to latest reports by the WHO, as of 1 May 2020, total cases of COVID-19 worldwide were 3,175,207 accounting for 224,172 deaths. In Africa, 26,663 confirmed cases and 973 deaths were reported, while in America, 1,291,917 confirmed cases and 69,087 deaths have been reported. In Eastern Mediterranean, 188,585 confirmed cases and 7598 deaths were confirmed. In Europe, 1,461,404 confirmed cases were reported among which 138,200 died because of COVID-19. In South East Asia, 57,088 cases have been confirmed among which 2174 died, while in the Western Pacific, 148,838 confirmed cases have been reported with 6127 deaths  [3].Currently, no specific antiviral agent is available against SARS-CoV-2 infection, with clinically proven efficacy as in case of MERS-CoV and SARS-CoV ,7. To unVirus initially binds to a host cell through targeted receptors. Previous studies on SARS-CoV revealed that the primary targets of this virus are epithelial cells, macrophages and other cells in the lungs. All these cells have ACE2 which is used by SARS-CoV for attachment and entry . AnotherIt was hypothesized that one way to stop SARS-CoV-2 infection is to saturate or block the ACE2 receptors or TMPRSS2 by using different molecules and antibiotic, which resultantly restrict virus from binding to the host cell and ultimately control the replication cycle . DiffereFor TMPRSS2 inhibition, no clinical drug has yet been specifically tested in case of COVID-19 except for the camostat mesylate which stopped virus entry into the lung cells ,37. On tAntiviral drugs are designed in such a way that they identify the viral proteins and stop the replication of virus instead of killing them as antimicrobials do. By stopping the replication cycle, they tend to reduce the number of pathogens to a certain level where they are unable to induce pathogenesis and allow the body’s own immune response to neutralize the virus .in vitro as inhibitors of SARS-CoV-2 infection are: IFN-α, previously used to treat hepatitis infection and has shown to inhibit the replication of SARS-CoV [In vitro as well as clinical studies have documented that Lopinavir/ritonavir, an HIV drug has anti coronavirus activity [WHO, US FDA, European Medicines Agency (EMA) and the Chinese government and drug manufacturers have coordinated with different institutes and industrial scientists to develop antiviral drugs. The International Clinical Trials Registry Platform of the WHO approved hundreds of the clinical studies to carry out and test postinfection therapies for COVID-19 infections ,44 with SARS-CoV . Hence, activity ,48. Antiactivity . Favipiractivity ,50.in vitro [According to one study, it was suggested that remdesivir and chloroquine can be used to treat COVID-19 infected patients because they showed promising effects in vitro ,51. Basein vitro . Preventin vitro [Ivermectin, an antiparasitic drug has also been approved recently by the FDA against COVID-19 after successful inhibition of replication of SARS-CoV-2 in vitro .All these drugs can be good choices to treat COVID-19 infections. No specific antivirals have yet been reported which may be fully effective against COVID-19. Scientists are working hard to find out the potential drugs but there is a need to do more clinical and preclinical trials of these drugs to test the efficacy and safety in COVID-19 treatment. Different drugs targeting viral replication at different steps have been shown in The complement system is one of the vital components of the innate defence system of the human body which acts as a bridge between innate and adaptive immunity. It consists of more than 35 proteins and regulators. The research on the complement system is progressing rapidly after the establishment of its role in inflammation and a potential therapeutic effect against certain diseases. There are two main types of complement immunotherapy: one in which immune response is enhanced  while in other type, body's immune responses are suppressed to control the disease by different inhibitors and biomolecules ,55. In cIn vivo infection model studies of AMY-101 (C3 inhibitor) showed that it interferes with IL-6 release [This clearly indicates that inhibition of C3 can be utilized as an effective treatment in case of SARS-CoV-2.  release . Data on release . All theBesides boosting antibody responses, enhancing cell mediated immunity is also under consideration. Natural killer cells, also known as K or killer cells, are components of the innate immune system, which play a major role in controlling tumours and rejection of virus-hijacked cells, hence restricting the pace of replication and subsequent tissue damage. Recently, the FDA approved investigational new drug CYNK-001 for Phase I/II clinical studies in COVID-19 patients. Initially, CYNK-001 was developed from placental hematopoietic stem cells and was suggested for the treatment of various haemolytic cancers and solid tumours such as multiple myeloma, myeloid leukaemia and glioblastoma multiforme. Different studies revealed that during viral infection, there is vigorous activation of natural killer cells and CYNK-001 has the potential to express natural cytotoxic receptors as well as activating receptors which bind with viral antigen on infected cells. Due to these functions, it was suggested that CYNK-001 may be used in inhibiting the replication of SARS-CoV-2 and progression of COVID-19 by eradicating the infected cells [ClinicalTrials.gov identifier NCT04315298 and NCT04331808). Few other anti-inflammatory therapeutic agents, for example, Janus kinase inhibitors, glucocorticoids and chloroquine/hydroxychloroquine have also been suggested for comparatively early recovery of SARS-CoV-2 infected patients [A couple of recent studies have suggested the effectiveness of tocilizumab in critical patients infected with corona virus. A significant improvement in these patients was observed after its use which ultimately reduced the dependence of patients on artificial oxygen support ,21. A lipatients .In SARS-CoV-2 infection, several altered pathways, for example, ‘IL-17 signalling pathway’, ‘cytokine-mediated signalling pathway’ and ‘defense response to other individuals’ were identified using gene term enrichment analysis . A cytokScientists are seeking the novel therapeutic strategies to combat COVID-19 infection. One such novel strategy is to exploit the mTOR for controlling infection. mTOR1, mTOR2 and AMPK are the associated pathways of mTOR ,62. The + effector T cell and promotion of Treg [A recent study has speculated that at an early stage of COVID-19, cross-reactive antibodies production against SARS-CoV-2 can be reduced if memory B cells are inhibited selectively, which ultimately reduce the antibody dependant enhancement process, which may contribute toward initiating cytokine storm and make the symptoms worse. mTOR pathway inhibitors, such as rapamycin, have the potential to selectively inhibit the memory B cells leading to a reduction in early-stage crossreactive antibodies against SARS-CoV-2 and resultantly less antibody dependant enhancement . Another of Treg ,66. Rapa of Treg .One of the most effective ways to prevent a disease is vaccination. Vaccine helps the immune system of the body to identify and fight infectious pathogens by inducing acquired immunity. The vaccine contains an inactive or attenuated pathogen, or one of its surface proteins or its toxins, which activate the immune system of the body and keeps us protected from the disease they cause . To contThere are numerous strategies of vaccinations for SARS-CoV-2 such as RNA vaccines, DNA vaccines, Recombinant protein vaccines, live attenuated vaccines, killed/inactivated vaccines and viral vector-based vaccines. In all these vaccines, target is S protein except the live-attenuated and killed vaccine for which the whole virion is the target. Along with many advantages, they have several disadvantages. Against MERS-CoV and SARS-CoV, these strategies have already been tested using animal models ,74 and mCurrently, more than 115 vaccines are under investigation against SARS-CoV-2 in different universities, research institutes, drug companies, biotechnology firms, health organizations and several research groups . Even ifet al.). It has a beneficial off-target/nonspecific positive effect on the immune system which may help in an early recovery of COVID-19 patients, as found previously against several respiratory infections [ClinicalTrials.gov identifier NCT04327206, NCT04328441, NCT04384549, NCT04348370 and NCT04414267) [Bacille Calmette-Guérin (BCG) vaccine is also thought to reduce the COVID-19 impact, thus could play an important role against SARS-CoV-2  .Plasma therapy is another therapeutic strategy used against COVID-19 patients just like SARS-CoV  and MERsPlants have been used for centuries as therapeutic agents against several diseases, including viral infections. Several medicinal plants have been studied in past against different viral diseases due to the presence of a repository of antiviral metabolites like alkaloids, flavonoids, terpenoids and phenols . Many Chin vitro, yet there is a need to confirm their efficacy and safety in preclinical and clinical trials. It is hoped that by using these strategies, scientists will develop new, fast, accurate, effective, cheap and safe therapeutic compound against SARS-CoV-2.This review has presented various strategies which can be used to control COVID-19 infection. COVID-19 pandemic has infected millions of people worldwide and claimed several thousand deaths. Scientists and researches around the globe are working to explore potential therapies against this deadly virus. Different strategies like controlling of replication of the virus, inhibiting the binding of the virus to host cells, use of molecules and compounds to boost innate as well as passive immunity or to screen drugs effective against other viruses can be effective and quick ways to treat COVID-19. Until now there is no approved drug available against SARS-CoV-2 and hundreds of the vaccines and antiviral drugs are under clinical trials which will take several months to be made available in the market. Some antiviral drugs and strategies have shown significant effects COVID-19 emerged at the global scene very recently and rapidly spread across the globe in a couple of months giving scientists very limited time to respond. New drugs and vaccines development usually take years if not decades. The sudden outbreak of COVID-19 caused by a virus, new to the human race, created panic in the scientific community. It was impossible to develop a new drug or vaccine within months or year. Short term approach suggested by scientists for the treatment of COVID-19 patients was to investigate drugs already in practice against other diseases and check their efficacy against SARS-CoV-2. For vaccine development, scientists throughout the world responded rapidly with the help of funding from Govts and industrial sectors and conducting research at a very fast pace. Hence a large number of vaccines are under investigation with some showing promising results.in vitro and in animal models. Many have been approved for clinical trials. Hence it is hoped that the human race will be successful in discovering effective drugs for the treatment of severe COVID-19 patients. Besides, some positive news in vaccine development suggest that very soon new vaccines will be available in the market and it will become possible to create a herd immunity against this virus, limiting the spread of this deadly virus and eradicating it from the face of the earth as in case of so many viruses in past.Luckily SARS-CoV-2 is the sister strain of previously reported SARS-CoV and MERS viruses. Past studies performed against these two strains of coronaviruses are providing a strong baseline for drugs and vaccine development against SARS-CoV-2. Some of the strategies have proven very effective COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) also known as 2019 novel coronavirus.For SARS-CoV-2 infection, currently, no specific vaccine or antiviral agent is available with clinically proven efficacy. Scientists across the globe are working to develop a vaccine, drug and exploring possible ways to treat this infection.ACE2 receptors inhibitors naturally came across as the major targets of interest for scientific community because of established knowledge that the virus initially binds to a host cell through these receptors. Drugs like baricitinib, ruxolitinib, natural hesperidin and nafamostat mesylate are being investigated to inhibit ACE2 receptors.Type II transmembrane serine protease inhibition is also being considered by scientists. Nafamostat mesylate and camostat mesylate have already been approved for type II transmembrane serine protease inhibition.Antiviral drugs are usually aimed to stop the replication of virus instead of killing, allowing the body’s own immune response to neutralize the virus.The International Clinical Trials Registry Platform of the WHO-approved hundreds of clinical studies to investigate different antiviral drugs already used for treatments of other infections.Some of the examples are IFN-α, previously used to treat hepatitis infection. Lopinavir/ritonavir, HIV drugs have displayed some anti coronavirus activity. Similarly, antiviral drug arbidol, favipiravir and darunavir drugs used against HIV and influenza have exhibited some anti-SARS-CoV activity.USA FDA approved the antiviral drug remdesivir and ivermectin (an antiparasitic drug) against COVID-19.Although the major focus of therapeutic strategies is on vaccination by using the adaptive immune system, some scientists are suggesting to boost the innate immune system against SARS-CoV-2.One of these strategies is to suppress inflammation by blocking the activity of complement protein C3. Complement plays an important role in enhancing inflammation that complicates the disease at later stages leading to severe pneumonia.The second strategy is enhancing the function of natural killer cells. A drug like CYNK-001 has the potential to express natural cytotoxic receptors as well as activating receptors which bind with viral antigen on infected cells, creating more sites on virus hijacked cells to be identified by natural killer cells.Other Immunotherapeutic approaches like IL-6 and nTOR inhibitors are also under consideration.Vaccination is the best strategy to prevent a disease by facilitating indigenous immune system of the body to identify and fight against infectious pathogens.Various strategies of vaccinations for SARS-CoV-2 such as RNA vaccines, DNA vaccines, recombinant protein vaccines, live attenuated vaccines, killed/inactivated vaccines and viral vector-based vaccines are under investigation.Currently, more than 115 vaccines are under investigation. Majority of vaccine strategies are targeting S protein except the live-attenuated and killed vaccine for which the whole virion is the target.Other therapeutic strategies like plasma therapy, protease inhibitors for COVID-19 treatment, the recombinant human monoclonal antibody and medicinal plants are being studied for their efficacy to control COVID-19 infection.


N = 336). Using random intercept autoregressive analyses, we evaluated differences in stability across gender, racially minoritized student status, and first-generation student status. Results showed similar mean levels of self-efficacy across demographic groups and across time. However, there were notable differences in between-person and within-person stability over time, specifically showing higher between-person and lower within-person stability for racially minoritized and first-generation students. These findings indicate that racially minoritized and first-generation students’ research self-efficacy reports were less consistent from semester to semester. Such results may indicate that non-minoritized and continuing-generation students’ experiences from semester to semester typically reinforce their beliefs about their own abilities related to conducting research, while such is not the case for racially minoritized nor first-generation students. Future research should examine what types of experiences impact self-efficacy development across doctoral study to offer more precise insights about factors that influence these differences in within-person stability.Developing research self-efficacy is an important part of doctoral student preparation. Despite the documented importance of research self-efficacy, little is known about the progression of doctoral students’ research self-efficacy over time in general and for students from minoritized groups. This study examined both within- and between-person stability of research self-efficacy from semester to semester over 4 years, focusing on doctoral students in biological sciences ( Self-efficacy  is definresearch self-efficacy are mixed regarding mean differences in research self-efficacy levels between men and women in Ph.D. programs  and within-person stability between consecutive time points (a specific or state-like stability). Specifically, we examine differences in stability across demographic groups, comparing RM students to White and Asian students, first-generation college students to continuing-generation students, and women to men. The following questions frame this study:1.between persons?What proportion of research self-efficacy across time reflects stability 2.within persons)?To what extent does research self-efficacy from one academic semester predict research self-efficacy for the next semester . Across gender, n = 200 students identified as women, n = 134 identified as men, and n = 2 students identified as other gender identities. Across RM status, n = 59 were RM students, n = 271 were White or Asian students, and n = 6 did not report race nor ethnicity data. Across generation status, n = 96 were first-generation students, n = 235 were continuing generation students, and n = 5 did not report data on parental college education.The present study draws on data from a larger National Science Foundation-funded project on doctoral students’ research experiences and skill acquisition in the biological sciences. The sample includes 0 = majority, 1 = RM). To assess first-generation college status, students reported the highest degree obtained by their parent(s). Those who had no parent with a college degree were coded as first-generation . Students reported their gender identity . Because few students indicated a non-binary gender identity, we treat gender as a dichotomous variable in analyses that follow.Students completed demographic questions about their race, ethnicity, gender, and parents’ education level at the onset of the study. To measure race and ethnicity, students selected one or more of the following: American Indian or Alaska Native; Asian or Asian American; Black or African American; Latino/a; Native Hawaiian or Other Pacific Islander; White. Responses were aggregated to create a measure of RM status where students who selected only a White and/or Asian identity were coded as majority and all other students were coded as RM , spring semester (S2), and summer semester (S3). Reports from winter break were excluded from semester averages because winter break is between two semesters and includes a large chunk of time away from school work. A total of 12 measurement occasions were created from 100 biweekly reports of research self-efficacy.Biweekly surveys asked participants to respond to the question “On a scale of 1 to 7, how confident do you feel in your ability to perform [research]?” where 1 = not at all to 5 = a great deal. Correlations between the semester and composite Research Experience Self-Rating Survey annual measures within years were moderate, ranging from 0.51 to 0.57 across years. These correlations are similar in magnitude to correlations of the annual measures across time (range 0.36 to 0.66), lower than the correlations between the semesterly measures over time (range: 0.54 to 0.83), and higher than the annual items correlated with semesterly self-efficacy measures (range: 0.30 to 0.50).To determine the validity of the semesterly measure of research self-efficacy, correlations between the spring semester measure of research self-efficacy and an annual measure of research self-efficacy were evaluated. During the spring semester across years, participants received the Research Experience Self-Rating Survey , which aStudents were recruited in two ways: first, the research team contacted the department chairs and program directors of the largest 100 Ph.D. programs in the biological sciences as well as public flagship and minority serving universities  that had Ph.D. programs within the subfields of interest. Program directors and department chairs were given recruitment materials and asked to disperse the materials to incoming Ph.D. students. Additionally, participants were recruited by the research team sending emails to listservs, including the American Society for Cell Biology and the Center for the Integration of Researcher, Teaching, and Learning Network. This phase of recruitment approached saturation since all students who responded were entering Ph.D. programs contacted in the first phase of participant recruitment. Participants who responded to the research team were screened for study eligibility. Participants were then given informed consent and told of the expectations for continuing in the study. All students who participated received a $400 annual incentive.Biological sciences was selected as the single, target discipline for several reasons. First, it reduced the potential for cultural or structural differences between individual STEM disciplines to obscure or bias observed trends. Second, it represents the largest disciplinary area within the broader life sciences, with total awarded doctorates numbering 8,702 out of the 12,781 life sciences Ph.D. degrees granted in the United States in 2019 . Third, plus version 8.4 . Model fit statistics for all analyses are presented in For the third and fourth research questions, we evaluated multigroup versions of the random intercept autoregressive models. We separated groups by gender, RM status, and first-generation student status. We examined differences in β-coefficients across groups using MMeans of self-efficacy across both semester and demographic groups are shown in To first evaluate the stability between-persons, we examined the proportion of variance of each observed variable that was attributed to the random intercept component . The random intercept factor accounted for an average of 47% (range: 0.29 to 0.56) of the observed variable variance across all participants included in the sample. Thus, approximately between one-half of the variance in each observed variable is attributed to between-person stability. t have low deviations from the expected score at the subsequent time point, t + 1. Overall, when utilizing the entire sample, the predictive power of preceding deviations from one’s expected score on research self-efficacy was high, with β coefficients ranging from 0.71 to 0.92 . This finding was further reflected in the lower average proportion of variance attributable to the random intercept factor for White/Asian students (0.67) compared to RM students (0.80). A similar finding emerged when comparing random intercept variance across generational status. First-generation students had significantly more variance attributable to the random intercept factor than continuing generation students . The average proportion of variance attributable to the random intercept factor for first-generation students was 0.81 while this value for continuing-generation students was 0.49. Random intercept variance for men (0.83) compared to women (0.35) was not statistically significantly different . However, the proportion of variance due to the random intercept seems to reflect some differences, with men showing a higher average proportion of variance attributable to the random intercept factor (0.80) compared to women (0.57).We evaluated differences in variance attributed to the random intercept component across race/ethnicity, generational status, and gender see . White adiff = 0.31, t = 3.09, p = 0.002), summer of year 1 and fall of year 2 , spring and summer of year 2 , summer of year 2 and fall of year 3 , spring and summer of year 3 , and fall and spring of year 4 . Notably, between the spring and summer semesters in years 1, 2, and 3, RM students had significantly lower autoregressive values than White/Asian students. For RM students, deviations from their expected value do not predict future deviations to the same extent as White/Asian students. In two cases, deviations from expected values at time t negatively predict deviations from expected values at time t + 1.1 Thus, individuals are deviating from their expected research self-efficacy value in a way that is not (or negatively) predicted by prior deviations, suggesting a lack of within-person stability for RM students.Across race/ethnicity, autoregressive estimates differed across years see . Over tidiff = 0.37, t = 4.51, p < 0.001), summer of year 1 and fall of year 2 , fall and spring of year 2 , spring and summer of year 2 , summer of year 2 and fall of year 3 , spring of year 3 and summer of year 3 , and fall of year 4 and spring of year 4 . For first generation students, deviations from their expected value did not predict future deviations; thus, individuals were deviating from their expected trajectory of self-efficacy in a way that was not influenced by prior deviations, suggesting a lack of within-person stability.Similar to results across race/ethnicity, many differences in within-person stability were found across student generational status see . Continudiff = 0.29, t = 2.66, p = 0.01). No other gender differences were found (see Unlike race/ethnicity and generational student status, within-person stability was more similar across gender. Only one difference in the within-person stability of research self-efficacy was found. Women had higher within-person stability than men between summer of year 1 and fall of year 2 (βound see .Notably, our findings suggest that research self-efficacy was less stable within-person for RM students and first-generation college students relative to their majority and continuing-generation counterparts. However, their between-person stability was greater, indicating more robust trait level effects within minoritized groups.The present study has significant implications for understanding the ways in which the cumulative experiences of doctoral students from minoritized backgrounds have different impacts than their peers from non-minoritized groups. Specifically, non-RM and continuing-generation students demonstrate a relatively high level of within-person stability in their self-efficacy over time, suggesting that their experiences from semester to semester typically reinforce their beliefs about their own abilities related to conducting research, especially during the second and third years of graduate education. In contrast, RM and first-generation college students show a noticeable drop in the within-person stability of those beliefs on the basis of the beliefs they held in prior semesters, despite mean levels of self-efficacy being essentially equivalent compared to White/Asian and continuing-generation students. This suggests that even if these groups do not differ significantly from other demographic groups in terms of mean values within a given period of measurement, they may be substantially more influenced by recently unfolding events, whether positive or negative. In other words, exploring mean differences between groups in isolation fails to capture the entire story of how self-efficacy evolves. Taken together, these results demonstrate the importance of looking beyond mean differences at select time points to explore how self-efficacy differs across time between and among groups.This insight expands previous quantitative research that has found very few differences between the experiences of first-generation students pursuing a Ph.D. and their continuing generation counterparts when examining mean differences . Indeed,priori assumptions that individual responses to training interventions will have universal effects both among persons and at discrete time points. The findings in this study illustrate clearly that experiences during doctoral study differentially impact individuals in relation to the stability of their self-beliefs, regardless of whether or not measured values differ at a given point in time. Given the variation both within and between groups, self-efficacy may be even more malleable than previously understood.In addition to further contextualizing prior research, our findings provide new insights into the ways in which identity factors may shape self-efficacy within social cognitive theory . While sOur findings have important implications for both research and practice in doctoral education. In particular, our findings highlight the importance of collecting self-efficacy data across time in a longitudinal manner and evaluating the different facets of the stability of self-efficacy in addition to evaluating simple mean values of self-efficacy. This is particularly important when comparing self-efficacy across demographic groups or other factors. Mean differences may not be present, but that does not mean differences in research self-efficacy do not exist, and such differences may highlight issues of different types of development over time across groups, lack of measurement invariance, or true group differences. While self-efficacy is highly domain-specific, similar principles may apply to self-efficacy across other domains and populations, a topic that warrants future inquiry.Engaging a mixed methods approach to understanding these phenomena may represent an important next step in research on these issues. Future research should specifically examine the types of experiences and subsequent meanings that participants construct that occur during doctoral study for RM and first-generation students that differentiate them from their non-minoritized and continuing-generation peers. Because individuals are not always aware of which specific experiences affect their self-efficacy over time , such stIn terms of implications for practice, we identified patterns in how self-efficacy tended to be particularly unstable for first-generation and RM students, providing insight into critical points to develop self-efficacy. Specifically, providing targeted programming to support students during the summers may be important for all students, but especially for RM students and those who are first-generation to college. Structured reading groups, writing support programs, and other professional development programming may all be ways to foster community and provide additional support to students over summer months, which may go a long way in fostering self-efficacy by providing opportunities for students to demonstrate their skills and gain validation.Due, in part, to the lack of diversity within STEM doctoral programs, the present study lacked the statistical power to evaluate the intersectional nature of the dataset. Women, RM students, and first-generation college students are not mutually exclusive groups, and existing literature on self-efficacy and equity in education documents the importance of considering such intersections e.g., . Future STEM graduate education can serve as a means to enhance students’ upward economic mobility  and addrhttps://osf.io/7bk8h/.The raw data and analysis files used to support the conclusions of this article are publicly available at: The studies involving human participants were reviewed and approved by the Utah State University Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.KL, DF, and JB conceptualized and wrote sections of the manuscript. DF acquired funding and designed the study. KL performed statistical analysis and provided data visualizations. KL and JB wrote the first draft of the manuscript. All authors contributed to manuscript revision, and read and approved the submitted manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.