In recent decades, we have witnessed radical changes in the use of permanent biomaterials. The intrinsic ability of magnesium (Mg) and its alloys to degrade without releasing toxic degradation products has led to a vast range of applications in the biomedical field, including cardiovascular stents, musculoskeletal, and orthopedic applications. With the use of biodegradable Mg biomaterials, patients would not suffer second surgery and surgical pain anymore. Be that as it may, the main drawbacks of these biomaterials are the high corrosion rate and unexpected degradation in physiological environments. Since biodegradable Mg-based implants are expected to show controllable degradation and match the requirements of specific applications, various techniques, such as designing a magnesium alloy and modifying the surface characteristics, are employed to tailor the degradation rate. In this paper, some fundamentals and particular aspects of magnesium degradation in physiological environments are summarized, and approaches to control the degradation behavior of Mg-based biomaterials are presented. It has been a long time since metallic biomaterials gained clinical significance . BiomateNowadays, degradable biomaterials play a crucial role in therapeutics, as they offer a steady resorption rate and, consequently, the best healing process. After providing adequate biomechanical support, resorbable biomaterials degrade gradually with no residues ,13,14. TThe most well-known biodegradable metals are iron (Fe), zinc (Zn), and magnesium (Mg), all of which are essential nutrients for human health ,23. The 2 layer that is stable in pH values higher than 7 (Equation (2)) [2, which is slightly soluble, precipitates on the surface of Mg and causes the alkaline pH shift of the solution.As a biodegradable material, magnesium oxidizes in contact with water on the grounds that the standard electrode potential of −2.372 V contributes to low corrosion resistance compared to other metals . In the ion (2)) . Both of2+ Equation (3). As electrons are neither created nor destroyed in a chemical reaction, H2O gains these electrons to produce hydrogen gases and hydroxide ions Equation (4), resulting in the production of gas cavities and an increase in the pH of the solution in the surrounding tissues. Note that the overall reaction, Equation (5), yields one molecule of H2 for each atom of Mg dissolved. Finally, following this chemical reaction, a partially protective film forms on the surface of Mg, which limits the further migration of ions [2 precipitations from the surface and therefore prevents the formation of a uniform Mg(OH)2 film on the surface of Mg. The degradation of Mg is not, as a result, self-inhibited, and it continues until the complete degradation of the substrate [Magnesium degradation in aqueous media begins with an anodic partial reaction: Mg loses two electrons to form Mg of ions ,44. Howeubstrate ,45,46.O2O system at 25 °C, all domains of stability of Mg are below that of H2O; accordingly, Mg is a base metal and a reducing agent. This metal is significantly susceptible to corrosion in most inorganic acidic, neutral, and slightly alkaline solutions with a speed that decreases as the pH level increases [2O at different pH. At low pH levels, the corrosion potential matches the region where hydrogen is stable, resulting in the production of hydrogen gas [2 layer, which protects it from fast corrosion. In fact, the corrosion resistance of magnesium and its alloys is closely linked to the passive layer [Based on the Pourbaix diagram for the Mg–Hncreases . In otheogen gas . At a pHve layer .2 is converted into more soluble MgCl2, and the dissolution of Mg(OH)2 film accelerates the dissolution process [As mentioned above, the formed magnesium hydroxide layer cannot preserve the surface of Mg from rapid corrosion, especially in an environment that contains a considerable amount of chloride ions. The reason for this is that Mg(OH) process ,50. The 3− and HPO42−, the corrosion products also consist of Mg/Ca carbonates and phosphates that might increase the precipitations on the surface of Mg, thereby decreasing the degradation rate of Mg-based materials. The reactions are presented as follows:It is noteworthy that, in a solution containing HCO3(PO4)2 may appear preferentially, Mg3(PO4)2 may locate homogeneously at the corrosion sites. The main reason for this is that a large concentration of Mg ions avoids the nucleation of Ca3(PO4)2 [3(PO4)2 to precipitate all over the surface. Following the coverage of the Mg surface with a protective layer of Mg3(PO4)2, the nucleation of Ca3(PO4)2 occurs, and a non-uniform distribution of Ca3(PO4)2 forms at the product layer [The distribution of degradation products of Mg is hardly uniform during the degradation process. Whereas Caa3(PO4)2 ,52; it ict layer . Finallyct layer .2, and MgCO3, were formed after exposure to SBF, HBSS, and DMEM [One of the most important factors in evaluating the degradation behavior of magnesium-based biomaterials is finding a suitable physiological fluid, as the degradation rate of these biomaterials differs significantly in various types of simulated body fluids. To simulate a human body environment, different media, notably physiological saline (0.9% NaCl) solution, Ringer’s solution (RS), phosphate-buffered saline (PBS), simulated body fluid (SBF), Hank’s balanced salt solution (HBSS), Earle’s balanced salt solution (EBSS), and Dulbecco’s Modified Eagle medium (DMEM), are widely used. Each simulated body solution contains a specific amount of components that could trigger the formation of different degradation products, pathways, and mechanisms . By way and DMEM .3−, and without HCO3− [3−, Ca2+, and alkaline pH at the Mg interface, which forms CaCO3 [By and large, a suitable simulated body solution ought to consist of three main parts: inorganic salts, buffering systems, and organic elements. To measure the degradation behavior of Mg and its alloys, physiological saline (0.9% NaCl) solution was used in several studies, most of which showed a striking difference between in vitro and in vivo results , compareut HCO3− . The comut HCO3− , resultims CaCO3 .2+ can create insoluble precipitation on the surface of the metal, which can produce inaccurate results [2 gassing. The results indicated that SBF- and DMEM- based media indicated a higher buffering capacity than HBSS, and the degradation rate of Mg was highest in HBSS [Despite the fact that PBS has been extensively used as the corrosion testing medium of Mg and its alloys ,62,63,64 results ,65. Mena results  investig results . Althoug results ,69, the  results ,71. More results ,73,74,75 results . In a re in HBSS . In anot in HBSS .EBSS has been used widely for in vitro testing of Mg and its alloys ,79,80,8142−, and HCO3−, controls the pH level in the human body [3/CO2 buffer, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), and Tris-HCl (Tris Hydrochloride) are the most frequently used buffers for in vitro studies of Mg [3 buffering alone in DMEM, EBSS, and simple salt solutions under the same conditions [Another crucial factor in simulated body solutions is the buffering system. A natural buffer system, which consists of plasma protein buffers, HPOman body ,92; by tes of Mg ,84,93. Hnditions . HEPES inditions ,96. Besi3−/CO2 buffering system is preferred for in vitro assays on the grounds of the similarity to the regulation of the pH of the body. CO2 in the testing system not only promotes the formation of carbonate on the surface of Mg but also triggers a stable pH through the equilibrium of HCO3−/CO2. A carbonated film formed in the presence of CO2 under aqueous conditions is thicker than an Mg(OH)2 film formed in the absence of CO2, thereby decelerating the degradation rate [3−/CO2 on the degradation of Mg. They found out that m-SBF(HEPES) increased the corrosion rate of Mg, whereas the corrosion mechanism of Mg in m-SBF(CO2) was similar to in vivo corrosion mechanism.Unlike Tris and HEPES, the HCOion rate . Törne eion rate  compared− to a certain extent.A number of cell culture media with small molecule organic compounds and proteins have been designed to evaluate the corrosion behavior of Mg. With the appearance of these compounds in the solutions, the complexity of corrosive media increases because the corrosive media resembles the real body fluid more closely. The corrosion resistance of Mg, in most cases, could increase . Yan et 4 and Ca–P salts) during immersion; conversely, in the “outer” layer, these components assisted the precipitation of nesquehonite rather than hydromagnesite. However, the effects of many other organic compounds and proteins on the degradation behavior of Mg have yet to be explored.An investigation assessed the stress-corrosion-cracking susceptibility of Mg–1Zn alloy in PBS, bovine calf serum (BCS), modified simulated body fluid (m-SBF), and DMEM as a case in point . It was Biomaterials, ideally, ought to degrade following tissue healing, and, furthermore, the biodegradation process should have no adverse effects on human health. Magnesium as a biodegradable material can play an important role in the biomedical field. Be that as it may, the degradation of untreated Mg in the physiological environment would indicate a high degradation rate, hydrogen evolution, and an increase in the pH of local tissues, which could harm surrounding tissues ,103,104.The addition of alloying elements has a direct influence on the degradation behavior of Mg biomaterials. A case in point is the degradation rate of ZJ41 Mg alloy, which is very fast compared to AZ31 Mg alloy . By and Ca is the main part of human bones and is vital for the life of human beings . Ca is m2 evolution [2 gas accumulated by the degradation of the alloys disappeared without discernable adverse influences.Zinc is an essential trace element that people need to stay healthy. This element can help in the normal functions of many enzymes, the normal growth of gonads, the treatment of bacterial infections, the improvement of cognitive abilities, neurotransmission, and synapse formation ,139,140.volution ,143. Howvolution  implanteIn the human body, Mn is required for the normal functionality of the brain, nervous system, enzyme, and cellular homeostasis ,146,147.Strontium is considered one of the potential candidates for orthopedic applications in that this element can promote the growth of osteoblast cells ,151,152.Chen et al.  preparedAlthough lithium is not officially considered a micronutrient , it is rIn a number of studies, it has been shown that Zr presents desirable osteocompatibility, biocompatibility, corrosion resistance, and low ionic cytotoxicity ,165,166.12La phase acted as an anodic phase along the grain boundaries in the Mg–1.43La alloy and triggered severe pitting corrosion, while the formation of the Dy2O3 oxide inhibited the Mg–0.41Dy alloy from pitting corrosion and led to high corrosion resistance. In another study, Liu et al. [Extensive use of REEs is reported to impact human health ; howeveru et al.  individuWhile Al was believed to be nontoxic, recent studies indicate that this metal can negatively affect human health, such as brain diseases  ,176,177.2. In this research, the degradation rate of AZ31 uncoated control stents was higher than AZ31 coated stents. While uncoated stents in flowing Hank’s solution lost ∼27% in weight, coated stents lost only ∼9% in weight after four weeks of dynamic degradation [Surface modification is a major approach to decelerate the degradation of Mg alloys for cardiovascular applications ,183. A sradation . For carradation  applied radation . Chen etradation  applied Generally, an ideal stent needs to fulfill not only anti-restenosis and fast endothelialization but also anti-inflammation and suitable durability. By way of illustration, Ye et al.  fabricatHaving the ability to promote in vivo bone healing and regeneration and the mechanical properties similar to that of bones, Mg alloys with suitable coatings have the potential for use as biodegradable orthopedic implants ,190,191.2 based nano-layer on ZK60 Mg alloy to improve the antimicrobial activity, osteoconductivity, and corrosion resistance of the Mg alloy. The in vitro study indicated that this TiO2/MgO nano-layer could control the degradation rate of Mg alloy, and the in vivo assay showed that at eight weeks post-surgery, 94% of the implant volume was still maintained, thus proving that this nano-layer not only could regulate its implant-to-bone integration effectively but also could control the degradation of Mg alloy. To stimulate bone formation and enhance osteogenic activity, osteocompatibility, and corrosion resistance of Mg-based implants, Xiong et al. [Other ceramic coatings could effectively suppress the rapid degradation of magnesium alloys. Lin et al.  used theg et al.  introducThe biodegradability and biocompatibility of Mg-based materials make them suitable for biomedical applications. Most of the currently researched Mg-based implants, however, degraded sooner than we expected. Accordingly, is it true to mention that Mg is not the best choice as a biodegradable biomaterial and that we should possibly focus on another biodegradable metal? The major drawback in this field is the lack of accurate data. As it is well-known, numerous factors have an influence on the corrosion rate and, therefore, the degradation of magnesium. Some of these factors relate to the environment in which the corrosion resistance would be performed; as a result, it is first and foremost to mimic the real body environment for observations and measurements. The absence of organic components in most simulated body solutions used for corrosion and degradation testing but has a dramatic effect on the degradation of this metal is a case in point. It is, on the other hand, believed that designing suitable composition and surface modification can significantly control the degradation process. Concerning controlling the degradation rate, numerous Mg alloys and techniques for surface modifications have been introduced for different applications, making the field of biodegradable Mg biomaterials significantly advanced. While a great deal of research ought to show the in vivo and clinical efficacy of these modified Mg alloy biomaterials, the world is still waiting for the introduction of new methods that can control the degradation of Mg-based biomaterials and offer novel functions at the same time.


The Rivermead assessment of somatosensory performance (RASP) provides a quantitative assessment of somatosensory processing, suitable for brain-damaged patients suffering from stroke. It consists of seven subcomponents: Subtest 1 (sharp/dull discrimination), Subtest 2 (surface pressure touch), Subtest 3 , Subtest 4 (sensory extinction), Subtest 5 (2-point discrimination), Subtest 6 (temperature discrimination), and Subtest 7 (proprioception). Overall, the RASP assesses 5 bilateral body regions: face (cheek), hand , and foot (sole and back). This study aimed at providing normative data and cut-off scores for RASP subtests, for each body region, in a large Italian population sample. We present results from 300 healthy Italian individuals aged 19 to 98 years. Data represent a comprehensive set of norms that cover each subtest and each body region tested. Performance in Subtests 1, 5, and 6 decreased, for some body regions, with increasing age. Based on these results, norms were stratified for age (seven groups), with the pathological/non-pathological cut-off coinciding with the 5th percentile. Conversely, other results were not influenced by age; in such cases, a single error, in each body region, has to be considered indicative of pathological performance. This independent investigation of all subcomponents of the somatosensory system, for each body region, further confirms RASP’s potential in clinical practice, for neurological assessment, as well as in research settings. The examination of somatic sensation requires the assessment of a range of different processes, including tactile detection, acuity, pain, proprioception, vibration, temperature sensitivity, and stereognosis . SomatosSomatosensory deficits are considered a negative predictor of functional outcome after stroke : their pFugl Meyer Sensory Scale — FMSs  and the left  foot. Also, Schooling was significant for the same body regions: right  and left  foot, respectively. As no interaction Age × Schooling [P = 0.9] was found, in Table Age only are reported.The Poisson linear model revealed a significant effect of For all the other body regions  mean correct responses are reported in Table Ps < 0.05). Table For each subtest, none of the models reached significance  2-point discrimination at 3 mm; 2 = successful 2-point discrimination (at least 4 out of 6) at 4 mm; 1 = 2-point successful discrimination (at least 4 out of 6) at 5 mm; 0 = failure, less than 4 (out of 6) accurate 2-point discrimination at 5 mm.Age for both the left  and the right  index. In addition, Schooling was significant for the left  index, only. As no interaction Age × Schooling [P = 1] was found, Table Age.The Poisson linear model revealed a significant effect of Age for the left foot . Table Age.The Poisson linear model revealed an effect of For all the other body regions , the values of the mean correct responses, which corresponds to the cut-off value, are reported in Table Ps < 0.05); a single error, in each body region, reflected a pathological performance. Results are reported in Table None of the models were significant  of neurological healthy participants  and took into consideration the Age factor, provided cut-offs also for 2-point discrimination (Subtest 5), and scores for each tested body region.Compared to the original study , the preAge, Gender, and Schooling. The role of these variables was assessed in this study, both independently and in combination. Importantly, statistical analyses confirm a significant role of the factor Age, which influences performance in all the subtests assessing discrimination abilities: sharp/dull (Subtest 1), 2-point (Subtest 5), and temperature (Subtest 6). Progressive deterioration of somatosensory performance with advancing age has been reported by several investigators. For instance, tactile acuity has been shown to decrease with age, particularly over 60 years [In previous studies , 17, a s60 years –22, as w60 years , 24.Gender nor Schooling factors were found to affect somatosensory processing in healthy participants. The lack of gender effects is in keeping with previous evidence showing the absence of sex difference in the same sensory tasks used here, while it seems to influence more complex haptic tasks, but with some inconsistencies across studies [Conversely, neither  studies , 25. As The present study also provides cut-off values, for both the left and the right index fingers and separately for age group, for 2-point discrimination (Subtest 5), not previously reported in the original work . The avaN = 50) and right (N = 50) cerebral hemispheric damage; results were reported separately for the contralesional and the ipsilesional sides of the body in stroke patients, but not in healthy participants, for which normative data referred to the sum of all five regions tested .The original work  providedHowever, unilateral focal cerebral lesions may bring about body-part-specific somatosensory impairments. For instance, impairments of tactile localization have been shown to occur in more than the 50% of stroke survivors at the wrist level, but rarely present at the contralesional side of the face (~7% of incidence) . DiffereIn conclusion, the present study provides the first Italian normative data for the RASP and cut-off values that can be used to identify somatosensory impairments. The study confirmed the RASP as a valid tool capable of measuring several different aspects of somatosensory sensation. Standardized and completed with normative values, the RASP provides clinicians and researchers with a valid instrument for both assessment and follow up protocols.The data that support the findings of this study are available from the corresponding author upon reasonable request.Not applicable.


People who have COVID-19 can experience symptoms for months. Studies on long COVID in the population lack representative samples and longitudinal data focusing on new-onset symptoms occurring with COVID while accounting for pre-infection symptoms. We use a sample representing the U.S. community population from the Understanding America Study COVID-19 Survey, which surveyed around 8,000 respondents bi-weekly from March 2020 to March 2021. Our final sample includes 308 infected individuals who were interviewed one month before, around the time of, and 12 weeks after infection. About 23% of the sample experienced new-onset symptoms during infection which lasted for more than 12 weeks, and thus can be considered as having long COVID. The most common persistent new-onset symptoms among those included in the study were headache (22%), runny or stuffy nose (19%), abdominal discomfort (18%), fatigue (17%), and diarrhea (13%). Long COVID was more likely among obese individuals  and those who experienced hair loss , headache , and sore throat  during infection. Risk was unrelated to age, gender, race/ethnicity, education, current smoking status, or comorbid chronic conditions. This work provides national estimates of long COVID in a representative sample after accounting for pre-infection symptoms. While SARS-CoV-2 is usually thought of as an acute disease, we now know that some people with COVID experience a variety of post-acute health problems long after their disease onset. This experience of long-term persistent symptoms has been termed “long COVID” , 2. AcutEarly evidence of long COVID was based on discharged hospitalized COVID patients in a number of countries. Since these reflected patients with worse disease outcomes than average, the estimated prevalence of long COVID was generally high, ranging from 50–90% –11. HoweOnly two population representative surveys have been conducted to-date. In December 2020, the Office for National Statistics (ONS) estimated the prevalence of long COVID in the U.K. from a survey of 8,193 non-hospitalized and non-institutionalized respondents who ever tested positive for COVID during the survey follow-up − 21% exhibited symptoms lasting longer than 5 weeks, and 10% exhibited symptoms lasting longer than 12 weeks  reportedLong COVID can affect multiple organs and body systems, and can be reflected in a wide range of long-lasting symptoms . AccordiIn addition to interest in the population prevalence of long COVID, it is important to determine if long COVID risk differs across the population. Previous studies have found older adults , 25 and In the current study, we used survey data from a nationally representative sample of community-dwelling U.S. adults, conducted from March 2020 to March 2021 to (1) estimate the baseline-symptom-adjusted prevalence of long COVID, (2) show the most commonly reported long COVID symptoms, and (3) identify the risk factors of becoming a COVID long hauler.We used data from the Understanding America Study (UAS) COVID-19 National Sample, an ongoing longitudinal national probability-based internet panel of approximately 9,000 non-institutional U.S. adults administered by the Center for Economic and Social Research (CESR), at the University of Southern California (USC). Respondents are recruited using a random selection of households from a postal service list of addresses, covering all households in the United States. They answer the survey using a computer, tablet, or smartphone; respondents were provided with a tablet and broadband internet if they did not have access to internet . The UASThe current study used the first 25 waves of the survey, which were collected from March 10, 2020 to March 31, 2021. During this period, 8,425 respondents participated in the survey, and 872 people  reported that they were diagnosed with, or tested positive for, COVID. We limited the analytic sample to 310 respondents who had COVID during the study period who also had information on self-reported symptoms at three times: 4 weeks before reporting a COVID diagnosis/positive test, at the time of the report of a COVID diagnosis/positive test, and 12 weeks after. After excluding 2 respondents with missing information on covariates, our final analytical sample consisted of 308 people. In other words, 564 were dropped due to missing data. We believe that the missingness is mostly random, since the characteristics are not significantly different at 95% confident level between our final sample and those we dropped . The onlThe COVID diagnosed population was determined based on questions about both COVID tests and diagnosis. In the early period of the survey, tests were less available than in the later part of the period. Participants were asked: “Have you been tested for coronavirus since the last time you took our coronavirus survey? If so, what was the result?” and “Whether or not you have had a coronavirus test, has a doctor or another healthcare professional diagnosed you as having or probably having the coronavirus since the last time you took our coronavirus survey?”. We considered a respondent as having COVID who either tested positive to SARS-CoV-2 or who was diagnosed with COVID by a healthcare professional.There is no official list of clinical symptoms defining long COVID. We examined the 18 self-reported symptoms included in the survey. At each wave, respondents were asked to report whether they had experienced the following symptoms in the past 7 days: (1) fever or chills, (2) runny or stuffy nose, (3) chest congestion, (4) cough, (5) sore throat, (6) sneezing, (7) muscle or body aches, (8) headaches, (9) fatigue or tiredness, (10) shortness of breath, (11) abdominal discomfort, (12) vomiting, (13) hair loss, (14) dry skin, (15) body temperature higher than 100.4 F or 38.0 C, (16) diarrhea, (17) lost sense of smell, (18) skin rash. The response options included “Yes”, “No”, and “Unsure”. We treated “Unsure” as not reporting the symptom. A symptom count variable ranging from 0 to 18 was then generated for each respondent at each wave by adding up the number of symptoms reported at a specific wave.We define long COVID as symptoms reported by the respondent at the time of diagnosis, that were not present 4 weeks prior, and that lasted 12 weeks or more. If a respondent has any of the 18 symptoms at the time of diagnosis, did not experience the symptom 4 weeks before COVID, and reported the symptom 12 weeks after, the respondent is considered as having long COVID. This definition distinguishes symptoms most likely caused by COVID from symptoms the respondent was already experiencing prior to infection.Because underlying medical conditions have been linked to elevated risk for severe illness from COVID-19 , we examOther covariates included age, gender, race/ethnicity, education level, and current smoking status. Age was categorized into three groups: ages 18 to 49, ages 50 to 64, and ages 65 and above. Race/ethnic groups included non-Hispanic White, non-Hispanic Black, Hispanic, and others. Education was classified as high school or less, some college education without a bachelor’s degree and a bachelor’s degree or more.We treated the survey wave when the respondents reported that they tested positive for, or were diagnosed with, COVID as the time of infection. By design, the survey interval was 2 weeks. So, two waves (roughly 4 weeks) prior to the infection were the pre-infection time, and 6 waves (roughly 12–13 weeks) after infection was the post-infection stage.We first summarized the sample characteristics at the time of reported infection and compared them to the profile of the COVID-infected population in the United States provided by the Centers for Disease Control  in orderNext, we estimated the prevalence of long COVID using both the reported current symptoms, to compare with estimates from previous studies, as well as new symptom onset (accounting for pre-infection symptoms). We compared our estimates to other nationally representative studies.Then, we compared the proportions of our analytical sample who reported each of the symptoms at pre-infection, infection, and post-infection stages to show the overall recovery of the infected population. And after that we further compared the proportions of those with long COVID in our sample who reported each of the symptoms at each stage to show how their symptoms changed over time, and the frequency of reported symptoms. Based on our long COVID definition, we also showed the ranking of persistent new-onset symptoms among those with long COVID.Lastly, logistic regression models were used to identify sociodemographic and health-related risk factors associated with long COVID: smoking, existing health conditions, and new-onset symptoms at the time of infection.All results were weighted to be nationally representative, adjusting for differential sampling probabilities and survey nonresponse. All analyses were performed using STATA Version 16.0. Informed consent was obtained during the response from participants. The current analysis used the STROBE  cohort reporting guidelines.In the final sample, about 41% had high school or less than high school completion, 35% reported some college, and 24% had a bachelor’s degree or higher. Almost 30% of the respondents were current smokers. In terms of existing health conditions, 18% had diabetes, 5% had cancer, 9% had heart disease, 29% had high blood pressure, 19% had asthma, 5% had chronic lung disease, 4% had kidney disease, 5% had an autoimmune disorder, and 24% were obese. Half of the sample had none of the underlying conditions.More than two fifths of the sample reported new-onset body aches (45%), fatigue (43%), cough (41%), and headache (40%) at the infection stage; in addition, more than one fourth had new-onset fever (37%), runny or stuffy nose (35%), loss of smell (33%), diarrhea (29%), sore throat (28%), shortness of breath (26%), and chest congestion (25%).At the time of infection, 80% of the respondents were symptomatic, and the average symptom count was 6. Both the proportion symptomatic and the average symptom count were fairly similar between the UAS total COVID sample . In terms of new-onset symptoms, the long haulers were more likely to experience headache (0.004), fever (0.037), and runny or stuffy nose (0.034).In our sample of 308 COVID-infected respondents, 40% experienced at least one symptom twelve weeks later, and this would have been the estimated prevalence of long COVID if pre-infection symptoms were not considered. However, after accounting for pre-infection symptoms, only 23% of the infected experienced at least one new-onset COVID symptom that lasted for at least 12 weeks. These estimates can be compared to the other nationally representative prevalence of long COVID estimated for UK by ONS and England by Whitaker et al. of 10% and 38% respectively. Our long COVID prevalence (40%) among the U.S. population without accounting for pre-infection symptom level, is very similar to that made by Whitaker et al. of 38%. and after controlling for pre-infection symptoms, our estimate is between the other two.Similarly, To account for the pre-infection prevalence of the symptoms, Our results indicate that the estimated prevalence of long COVID in a population representative sample differs depending on whether pre-infection symptoms are accounted for. In the U.S. population, most people with COVID return to their pre-infection symptom level after the acute phase of the disease. However, more than one-fifth (23%) experience long COVID, with at least one symptom originating around the time of SARS-CoV-2 infection lasting for more than 12 weeks. Without adjusting for pre-infection symptoms, the prevalence is estimated to be 40%, which suggests the potential for a significant over-estimation of long COVID in previous studies.The most frequently experienced persistent new-onset symptoms among those with long COVID include headache (22%), runny or stuffy nose (19%), abdominal discomfort (18%), fatigue (17%), and diarrhea (13%). The fully adjusted logistic regression model indicates that the likelihood of experiencing long COVID is not significantly associated with sociodemographic or behavioral factors including age, gender, race/ethnicity, education, current smoking status or the presence of chronic conditions. COVID long haulers are more likely to experience hair loss, headache, and sore throat at the time of infection compared to their counterparts whose symptoms reduce more quickly. Also, those who are obese are at higher risk of experiencing persistent new-onset symptoms.To our knowledge, this is the first study that defined long COVID accounting for pre-infection baseline symptoms. Even before SARS-CoV-2 infection, more than two-fifths (44%) of our sample experienced at least one symptom that can be potentially linked to COVID. Also, among the infected, the prevalence of most symptoms returned to the pre-infection level at the post-infection stage. It means that people report many symptoms both before and after COVID that may be due to other conditions. So, while around 40% of the COVID-infected persons have at least one symptom 12 weeks after COVID diagnosis, this may overestimate the prevalence of long COVID if these persons are all classified as long COVID. The longitudinal nature of data, from pre-infection to post-infection stage, made it possible to distinguish new onset symptoms from the symptoms that might be experienced by someone without SARS-CoV-2 infection. Admittedly, the current approach only picks up on new-onset symptoms and not the changing severity of symptoms. But still, due to the relatively high prevalence of symptoms in our sample even before COVID, our longitudinal and conservative approach can help avoid possible overestimation.Compared to the estimates of long COVID prevalence based on other nationally representative studies, our final estimate (23%) based on UAS data is between the U.K. ONS estimate (10%) , and theOur estimated prevalence is also similar to the estimate of 27% based on never-hospitalized COVID symptomatic Californians , and theThe significant association between long COVID and obesity is consistent with previous studies , 25, 26.We differ from some existing studies, in that we did not find a significant association between long COVID and any sociodemographic factors included in this study. It is probably because the analytic approaches used by the ONS , WhitakeBy limiting our sample to those who had complete data at the pre-infection stage, the time of infection, and post-infection stage, we excluded those who were diagnosed in the last 5 waves of the survey. It means that for the respondents in our sample, the latest possible date of diagnosis was between November 25 to December 23, 2020 (the 19th survey wave). Since COVID vaccines were available for only a small number of health care workers at that time, we do not think the vaccination would change our estimate in any meaningful way, so we did not include information on vaccination status.Our study has limitations. We are likely to have missed some severe COVID cases since they likely would not have answered the survey while suffering from severe illness. Information on hospitalization is not available in the UAS. Since hospitalized COVID patients generally experience moderate or severe disease outcomes, it is reasonable to assume that they are more likely to have missing data in the UAS and to be excluded from our final sample. This would lead to an underestimate of the prevalence of long COVID. Given that around 5% of the SARS-CoV-2 infected population are hospitalized , and sinWith the availability of vaccines and the onset of new variants, the nation has moved into new stages of the pandemic. The vaccinated population has tripled since the last wave of data used in the current study, and by March 2022, more than 65% of the total US population have been fully vaccinated . The OmiSupplement 1


Coronavirus disease 2019 (COVID-19) in many countries is still very serious. At present, there is no specific and effective drug for this disease. Traditional Chinese medicine (TCM) has played a great role in fighting against COVID-19. However, their effectiveness and safety are still obscure and deserve further investigation. The aim of the study was to evaluate the efficacy and safety of TCM assisted in conventional treatment in the treatment of mild and common COVID-19.PubMed, EMbase, MEDLINE, China National Knowledge Infrastructure Database, WANFANG DATA, and VIP Chinese Science and Technology Periodical Database were searched for randomized controlled trials (RCTs) and non-randomized controlled trials of TCM assisted in conventional treatment. The RCT research quality was evaluated by Cochrane 5.1.0 bias risk scale and the non-randomized controlled trial research quality was evaluated by Newcastle Ottawa scale, and the statistical analysis was conducted by Revman 5.3 and R software. The bias and sensitivity of the statistical results were analyzed by STATA 14.0. Registration number: CRD42020210619.P < .00001). The results of Begg test (Pr > z = 0.266) and sensitivity analysis showed that the results were relatively stable. Toujie Quwen , Shufeng Jiedu , and Lianhua Qingwen  were with the best. It can also improve the main clinical symptoms , severe conversion rate, and computed tomography improvement rate. Its safety was not significantly compared with conventional treatment. However, in terms of safety of a single TCM, Shufeng Jiedu  and Lianhua Qingwen  were lower than those of conventional treatment.Fifteen studies were included with 7 RCT studies and 8 retrospective cohort studies, involving a total of 1623 patients. Compared with the control group, TCM can improve the main index clinical effective rate  , TCM as an adjuvant therapy combined with conventional treatment has good curative effect on mild and common type of COVID-19 patients. Its advantages lie in clinical efficacy and improvement of symptom group, and can prevent patients from transforming to severe disease. In terms of clinical efficacy and safety, Shufeng Jiedu and Lianhua Qingwen have obvious advantages, which are worthy of clinical promotion. Novel coronavirus pneumonia is characterized by fever, cough, fatigue, expectoration, chest distress, dyspnea, muscle soreness, diarrhea, and so on. It can be classified as “epidemic disease” and “plague” in Chinese medicine.–3 At present, there is no specific and effective drug for this disease, and the main clinical treatment is the symptomatic treatment. In China's experience in fighting against COVID-19, traditional Chinese medicine (TCM) has played a great role. In the process of novel coronavirus pneumonia, the therapeutic effect of Chinese medicine assisting western medicine has attracted wide attention, and related research reports are emerging. A large number of epidemiological studies have shown that the proportion of mild and common type of the disease is the largest. In China, “medical observation period” in the Novel Coronavirus Pneumonia Diagnosis and Treatment Plan  also recommended the Chinese medicine “Huoxiang Zhengqi capsule” , Jinhua Qinggan granule, Lianhua Qingwen capsule, Shufeng Jiedu capsule, and so on. However, TCM treatment has the characteristics of “individualization”, so it is difficult to formulate standard treatment details, which makes the evidence quality of clinical efficacy of TCM relatively weak. Therefore, it is necessary to carry out rigorous and objective quality evaluation for different types of clinical research, and the effectiveness analysis results obtained on this basis would be more convincing. Based on the published clinical research literature in China and abroad, this study conducted a systematic evaluation and network meta-analysis to understand the efficacy of TCM assisted western medicine in the treatment of COVID-19 more intuitively and evaluate the quality of evidence in current clinical trials of TCM to find potential problems and provide reference for the design and follow-up work of clinical trials of TCM.A number of patients with unexplained pneumonia have been found in Wuhan, Hubei Province, China in December 2019. And later it was confirmed to be the result of a new coronavirus infection. On February 11, 2020, the International Committee on Classification of Viruses named the virus as severe acute respiratory syndrome coronavirus 2. Meanwhile, the World Health Organization named disease caused by it as the coronavirus disease 2019 (COVID-19).2https://www.crd.york.ac.uk/prospero/), registration number: CRD42020210619. The procedure of this protocol is based on PRISMA-P guidance.This study has been registered in PROSPERO  improvement rate; severe conversion rate; negative conversion rate of viral nucleic acid; incidence of adverse reactions.Types of studies: randomized controlled trial (RCT) and non-randomized controlled trial (NRIs) of Chinese medicine treatment of COVID-19, whether blind method and allocation concealment were used or not, the language was Chinese or English. Types of participants: patients with mild and common type of COVID-19 who met the diagnostic criteria of COVID-19 diagnosis and treatment plan issued by the general office of the Chinese Health Commission and the office of the Chinese Medicine Bureau. Their gender, age, race, and nationality were not limited, and other serious diseases were excluded. Types of intervention: the treatment group: on the basis of the control group, TCM treatment was given. The dosage, dosage form, administration route, and method of Chinese medicine were not limited; the control group: conventional treatment, including oxygen therapy, antibiotics, antiviral, nutritional support treatment and other measures, drug treatment measurement and treatment were not limited. There is no time limit for intervention. Types of outcome measures: primary outcomes: clinical effective rate2.2COVID-19 of heavy and dangerous heavy type; Self-control trial and non-control group study; Single use of conventional treatment or TCM; Summaries, case reports, experimental researches, and expert experiences; Only the one with the largest sample size and the most complete information was retained when the same study has been published for many times.2.3We searched PubMed, EMbase, MEDLINE, China National Knowledge Infrastructure Database and its COVID-19 special research results network launch platform, WANFANG DATA, and VIP Chinese Science and Technology Periodical Database. Chinese retrieval was based on subject words, keywords, literature tracing, and manual retrieval. First, “novel coronavirus pneumonia”, “2019-nCoV”, “COVID-19”, and “SARS-CoV-2” were used as the key words to search in WANFANG DATA. Then theme word “integrated Chinese and Western medicine”, “traditional Chinese medicine treatment”, “ traditional Chinese medicine”, and “prescription” were searched. The 2 searches were merged with “AND”. China National Knowledge Infrastructure Database has set up a network platform for the research results of COVID-19, thus it can be searched manually after selecting the “treatment” section in the platform. The English key words include“2019-nCoV” or “COVID-19” or “2019-nCoV pneumonia”, and “Drugs, Chinese Herbal” or “traditional Chinese herbal medicine” or “Chinese herb”. The search strategy of PubMed is presented in Table As the epidemic situation continues, there are still clinical studies in progress. Before the evaluation results of this system are published, all databases will be retrieved again. If there are newly published studies, they will be directly included in the comprehensive treatment together with the previous studies.2.4Two reviewers (Xiaozheng Wu and Wen Li) independently screened the literatures according to the inclusion and exclusion criteria. They furtherly read the full text of the studies that might meet the inclusion criteria to determine whether they could be really included after excluding the studies that obviously did not meet the inclusion criteria and then they cross checked them. In case of disagreement, they were discussed and resolved or handed over to the third party (Yunzhi Chen) for adjudication. If the report was not available or there was a lack of information, they would try to contact the author of the original text by email to obtain further relevant data. The design of data extraction table follows the principle of “PICOST” .Data extraction contents include: general information: research ID, author, title, publication status, report sources, and fund support; methodology information: design, number of arms, random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, sample size calculation, and baseline comparability; participant information: diagnostic criteria, inclusion criteria, exclusion criteria, setting, population, sample size, age, gender, and course of disease; intervention information: name of intervention and comparation, syndrome differentiation of TCM, types of Chinese herbal medicines, dosage form, comparison, duration of treatment, and patient follow-up; outcomes; and adverse events.2.52.5.1 was used as the quality evaluation standard to evaluate the included RCT literature.The modified Jadad scale2.5.2 in non-randomized trials.The bias risk assessment tool recommended by Cochrane 5.1.0 was used to evaluate the included RCT studies, the contents are: generation of random assignment scheme; hidden grouping; blind method for patients and doctors; blind method for result evaluation; incomplete result data; selective result report; and other biases. The quality of the included studies was evaluated one by one. The quality of methodology was evaluated by the Newcastle Ottawa scale2.5.32 test was conducted to evaluate the degree of heterogeneity between studies.We analyzed the subgroups determined in advance after checking the extracted data again and compared the efficacy of different subgroups directly. When heterogeneity was not easy to explain, it was included in the random effects model and I2.6P > .1, I2 < 50%), the fixed response model was used for combined analysis; the random effect model was conducted for combined analysis if the studies within the subgroups had clinical homogeneity, but there was statistical heterogeneity; the sensitivity analysis was used when the heterogeneity was originated from the low-quality research; the qualitative description and analysis were carried out for the data that could not be combined; the funnel plot analysis was used to analyze the publication bias. Revman5.3 software  provided by Cochrane Collaboration Network was used for meta-analysis; R software (R version 4.1.1 – "Kick Things"Copyright (C) 2021 The R Foundation for Statistical Computing.)was used for network meta-analysis; and Begg test was analyzed by using STATA14.0 software (Stata/SE 14.0 for Windows [64-bit x86-64].Revision 22Apr 2015.Copyright 1985-2015 StataCorp LP.).In this study, the mean difference and 95% Confidence interval (CI) were used as the efficacy analysis statistics for the included measurement data (continuous variables), and the odds ratio (OR) value and 95%CI were used as the efficacy analysis statistics for the included count data (2 category variables). Since “cured”, “markedly effective”, “effective”, and “ineffective” are the 4 levels of evaluation of curative effect generally recognized by the state or committee, and meta-analysis is a binary variable data, therefore “cure”, “significant effect”, and “effective” were combined into “effective”. Subgroup analysis was carried out according to the possible heterogeneity factors, such as different research types, different measurement indicators, different medication time, etc; when the included data among the subgroups were sufficiently similar . And the results showed that the clinical effective rate of the treatment group was higher than that of the control group . Subgroup analysis was done for RCT and non-RCT tests, respectively, and there was no significant heterogeneity between the 2 subgroups . There was no statistical heterogeneity among the studies after the combination of RCT test . The fixed effects model was conducted for merger analysis and the result showed that the clinical effective rate of treatment group was higher than that of control group . There was no statistical heterogeneity among the studies after the combination of non-RCT trials . The fixed effects model was used for merger analysis and the results showed that the clinical effective rate of the treatment was higher than that of the control group . The results are shown in Figure Among the included studies, 8 trials3.5.2Improvement rate of main symptoms; disappearance time of main symptoms; improvement rate of CT; severe conversion rate; negative conversion rate of nucleic acid; and adverse reactions.Meta-analysis was carried out on the data of 15 studies in which the same index was scored by the same or similar scoring method. The results of heterogeneity test, model, effect amount, and effect value are shown in Table 3.5.3Begg test was used to detect the bias of the statistical results of clinical efficiency. The results showed that 3.5.4Sensitivity analysis of the results of the clinical efficacy study showed that the lowest limit of all the study results was not lower than the number 1, indicating that there was no significant difference in the results after removing any study. It is proved that the sensitivity of clinical effective quantity is low, and it has good stability, reliability, and the analysis result is stable and credible. See Table 3.63.6.1 Shufeng Jiedu treatment in 2 cases,,23 Toujie Quwen treatment in 2 cases,,14 and Lianhua Qingwen in 3 cases,,15–16 as shown in Figure Among the 15 literatures included, 8 reported the effective rate of TCM in the treatment of COVID-19, of which Xuebijing treated COVID-19 in 1 case,3.6.23.6.2.1 Lianhua Qingke in 1 case, Lianhua Qingwen in 3 cases,–17,19 and Shufeng Jiedu in 1 case. According to the results of R software network meta-analysis, Jinhua Qinggan , Lianhua Qingwen , and Shufeng Jiedu  were better than conventional treatment group in the effective rate; and among the 4, Shufeng Jiedu was superior to Jinhua Qinggan  and Lianhua Qingwen ; in terms of the effective rate of the 4 kinds of TCM, they rank as follows: Shufeng Jiedu > Jinhua Qinggan > Lianhua Qingwen > Lianhua Qingke > Normal , and Shufeng Jiedu was the best. See Table Among the 15 included literatures, 6 reported the effective rate of TCM in the treatment of COVID-19, of which Jinhua Qinggan treated COVID-19 in 1 case,3.6.2.2 Lianhua Qingke in 1 case, Lianhua Qingwen in 3 cases,–17,19 and Shufeng Jiedu in 1 case. According to the results of R software network meta-analysis, Jinhua Qinggan , Lianhua Qingke , Lianhua Qingwen , and Shufeng Jiedu  were better than those of the conventional treatment group. The effective rates of Lianhua Qingke , Lianhua Qingwen , and Shufeng Jiedu  were better than Jinhua Qinggan. The effective rates of Lianhua Qingke  and Shufeng Jiedu  were better than Lianhua Qingwen. According to the rank order, Shufeng Jiedu > Lianhua Qingke > Lianhua Qingwen > Jinhua Qinggan > Normal , Shufeng Jiedu and Lianhua Qingke had the best efficacy. See Table Among the 15 included literatures, 6 reported the effective rate of TCM in the treatment of cough symptoms of COVID-19, including Jinhua Qinggan in the treatment of COVID-19 in 1 case,3.6.2.3 Lianhua Qingke in 1 case, Lianhua Qingwen in 3 cases,–17,19 and Shufeng Jiedu in 1 case. According to the results of R software network meta-analysis, Jinhua Qinggan , Lianhua Qingke , Lianhua Qingwen , and Shufeng Jiedu  were better than those of the conventional treatment group, and the difference was statistically significant. The effective rates of Lianhua Qingke  and Shufeng Jiedu  were better than Jinhua Qinggan. The effective rates of Lianhua Qingke  and Shufeng Jiedu  were better than those of Lianhua Qingwen. According to the rank order, Shufeng Jiedu > Lianhua Qingke > Jinhua Qinggan > Lianhua Qingwen > Normal , Shufeng Jiedu and Lianhua Qingke had the best efficacy. See Table Among the 15 included literatures, 6 reported the effective rate of TCM in the treatment of fatigue symptoms of COVID-19, among which Jinhua Qinggan treated COVID-19 in 1 case,95%CI –2.,–0.11), 95%CI –2.,–0.11), 3.6.3 Lianhua Qingwen in 3 cases,,15–16 Maxing Xuanfeijiedu in 1 case, Reyanning in 1 case, Shufeng Jiedu in 2 cases,,23 Toujie Quwen in 1 case, and Xuebijing in 1 case. According to the results of R software network meta-analysis, the CT improvement rate of 7 kinds of TCM on patients with COVID-19 was better than that of conventional treatment group, the difference was statistically significant. The CT improvement rate of Lianhua Qingke was better than that of Lianhua Qingwen , Toujie Quwen , Reyanning , and Shufeng Jiedu . The CT improvement rate of Xuebijing was better than that of Lianhua Qingwen , Toujie Quwen , and Shufeng Jiedu . In terms of ranking order, Lianhua Qingke > Xuebijing > Shufeng Jiedu > Maxing Xuanfeijiedu > Toujie Quwen > Reyanning > Lianhua Qingwen > Normal , and the CT improvement rate of Lianhua Qingke and Xuebijing was the highest. See Table Among the 15 included articles, 10 reported the improvement rate of CT in patients with COVID-19 by TCM. Among them, Lianhua Qingke treated COVID-19 in 1 case,3.6.4 Lianhua Qingke in 1 case, Lianhua Qingwen in 4 cases,,15–17 Maxing Xuanfeijiedu in 1 case, Shufeng Jiedu in 1 case, and Toujie Quwen in 1 case. According to the results of R software network meta-analysis, the severe conversion rate of the 6 kinds of TCM on patients with COVID-19 was better than that of the conventional treatment group, and the difference was statistically significant. The severe conversion rate of Lianhua Qingke was lower than that of Jinhua Qinggan , Shufeng Jiedu , Toujie Quwen , and Lianhua Qingwen . The severe conversion rate of Maxing Xuanfeijiedu  was lower than that of Lianhua Qingwen. In terms of ranking order, Normal  > Lianhua Qingwen > Jinhua Qinggan > Toujie Quwen > Shufeng Jiedu > Maxing Xuanfeijiedu > Lianhua Qingke, and Lianhua Qingke had the lowest conversion rate. See Table Among the 15 included articles, 9 reported the severe conversion rate of diseases in patients with COVID-19 treated by TCM, including Jinhua Qinggan treating COVID-19 in 1 case,–37.8,–0.), Shufen–37.8,–0.), Shufen3.6.5 1 by Reyanning, and 1 by Shufeng Jiedu. According to the results of R software network meta-analysis, Lianhua Qingwen , Reyanning , and Shufeng Jiedu  were better than those of the conventional treatment group, with statistically significant differences. The effective rate of Reyanning was better than Shufeng Jiedu  and Lianhua Qingwen . In terms of ranking order, Reyanning > Lianhua Qingwen > Shufeng Jiedu > Normal , and Reyanning had the best negative conversion rate. See Table Among the 15 included articles, 3 reported the negative conversion rate of nucleic acid in the treatment of COVID-19 by TCM, among which 1 was treated by Lianhua Qingwen,3.6.6 Lianhua Qingwen in 2 cases,,17 Shufeng Jiedu in 3 cases,–21,23 and Xuebijing in 1 case. According to the results of R software network meta-analysis, the incidence of adverse reactions of Lianhua Qingwen  and Shufeng Jiedu  were lower than those of the conventional treatment group, and the difference was statistically significant. Jinhua Qinggan  had a higher incidence of adverse reactions than the conventional treatment group and other TCM groups, and the difference was statistically significant. In terms of ranking order, Jinhua Qinggan > Xuebijing > Normal  > Lianhua Qingwen > Shufeng Jiedu. Shufeng Jiedu and Lianhua Qingwen had the lowest incidence of adverse reactions, while Jinhua Qinggan had the highest incidence of adverse reactions. See Table Among the 15 included articles, 7 reported the incidence of adverse reactions of TCM in the treatment of COVID-19, including Jinhua Qinggan in 1 case,4 were mostly used in mild, common, and clinical observation period COVID-19, so the primary outcomes were clinical efficiency (8 studies), and no mortality. The secondary outcomes were main common symptoms , improvement of lung imaging (CT), severe conversion rate, negative conversion rate of viral nucleic acid, and incidence of adverse reactions.A total of 15 studies were included in this study, including 7 RCTs and 8 retrospective studies. As the disease is caused by a novel coronavirus which was never detected before and it is highly contagious, but at the beginning, human beings did not have enough awareness about the disease, and it is still in the exploratory stage in the treatment plan now. And considering the ethical requirements, the prospective study is less than retrospective analysis. The Chinese medicines recommended by China's Novel Coronavirus Pneumonia Diagnosis and Treatment Plan 4.1The results of this study shows that Chinese medicine, as an adjuvant therapy combined with conventional treatment, is effective in the treatment of mild and common type of COVID-19 patients, which is manifested in improving the clinical efficiency, improving the main symptoms , reducing severe conversion rate, and improving lung imaging. Therefore, the advantages of Chinese medicine as adjuvant therapy lie in the improvement of clinical efficacy and symptom group, and it can prevent patients from transforming to severe disease. After subgroup analysis of RCT and retrospective cohort study, the results show that there is no significant difference between them, which proves the reliability of the results. For the publication bias of clinical efficiency, the results of Begg test analysis showed that there was no bias, and the sensitivity analysis showed that the results were relatively stable, which furtherly proved that the results of this study were reliable. Toujie Quwen, Shufeng Jiedu, and Lianhua Qingwen showed obvious advantages in improving clinical efficiency, among which Toujie Quwen was the best. In terms of improving the main symptoms , Shufeng Jiedu was the best. In terms of improving lung imaging, the CT improvement rate of Lianhua Qingke and Xuebijing was the highest. In terms of reducing the severe conversion rate, Lianhua Qingke had the lowest conversion rate. In terms of improving the negative conversion rate of nucleic acid of the virus, although the curative effect of TCM used as adjuvant therapy at the same time is not obvious compared with conventional treatment, the efficacy of a single Chinese medicine as adjuvant therapy is still higher than that of conventional treatment, and Reyanning had the best nucleic acid negative conversion rate. For the incidence of adverse reactions in this study, generally speaking, the safety of TCM as adjuvant therapy is not obvious compared with conventional treatment, but from the safety of single Chinese medicine, the incidence of adverse reactions of Shufeng Jiedu and Lianhua Qingwen is lower than that of conventional treatment while the incidence of adverse reactions of Xuebijing has no difference compared with conventional treatment. And the incidence of adverse reactions of Jinhua Qinggan is higher than that of conventional treatment.Therefore, in terms of clinical efficacy and safety, Shufeng Jiedu and Lianhua Qingwen have obvious advantages. Although Lianhua Qingke has certain advantages in improving lung imaging and reducing severe conversion rate, its safety needs to be further determined. Reyanning has the best effect on the negative conversion rate of nucleic acid, but its therapeutic effect on other indicators of this study was less reported, so its efficacy and safety need to be further clarified.4.2 who reported 21 missing cases, but did not describe the specific treatment. Therefore, the literature reports are only with average quality, which suggests that there may be a certain degree of bias in the literature included in this study. No follow-up or long-term follow-up was found in 8 retrospective studies, and the reported results were not evaluated, so the quality of the literature was medium. In most studies, only the main indicators and some secondary indicators were counted. The evaluation indexes were not complete, and the evaluation criteria were not completely the same. Therefore, the results of this study may have some clinical heterogeneity. Most studies did not report the laboratory indicators of patients, such as nucleic acid negative rate, white blood cell count, lymphocyte%, C-reactive protein, etc, which will affect the overall quality of the included statistics. The epidemic situation still continues at present, the sample size of all the included studies is not large, most of them are single center studies, and there are certain clinical heterogeneity, such as course of treatment, course of disease, medication method, drug dosage form, etc due to medical ethics and other reasons, these will affect the reliability of the results. The literatures included in this study are all domestic studies, of which only 1 study of Hu et al is English literature, so it would produce large language bias which may affect the conclusion and extrapolation of meta-analysis. In the 15 studies, the TCM treatment of 5 studies was Lianhua Qingwen, while the involvement of other 7 kinds of TCMs was limited (1 or 2 of each). Thus the results of meta-analysis might be affected by this feature of the data imbalance.According to the inclusion and exclusion criteria in the study, the 15 literatures included in this study all described the treatment group, control group, and outcome indicators in detail, but there are still some problems: 7 RCT studies reported random methods, but 4 studies only mentioned random number table method, and did not give a clear generation of random methods and 1 study only mentioned random methods. All RCT studies did not report the use of allocation concealment and blind method. Almost all RCT studies reported no loss of follow-up cases except Duan et al5 In this study, TCM as an adjuvant therapy combined with conventional treatment has better curative effect on mild and common type of COVID-19 patients. It has obvious effect in improving clinical efficiency, improving main symptoms , reducing severe conversion rate and improving lung imaging compared with conventional treatment. Therefore, the advantages of TCM as an adjuvant therapy lie in the improvement of clinical efficacy and symptom group, and it can prevent patients from transforming into severe cases. However, further analysis and research are needed to improve the safety and adverse reactions of patients. In terms of clinical efficacy and safety, Shufeng Jiedu and Lianhua Qingwen have obvious advantages, which are worthy of clinical promotion; although Lianhua Qingke has certain advantages in improving lung imaging and reducing severe conversion rate, its safety needs to be further determined. Reyanning has the best effect on the negative conversion rate of nucleic acid, but its therapeutic effect on other indicators of this study is less reported, so its efficacy and safety need to be further clarified. In addition, Jinhua Qinggan has a high incidence of adverse reactions, which should be used according to the actual situation. As the current global epidemic situation is still very serious, the successful experience of TCM used as an adjuvant therapy of conventional treatment in China is worth promoting to the world. In the existing clinical studies of TCM as intervention treatment of COVID-19, RCTs are relatively few, and retrospective studies account for a slightly larger proportion. It seems that there are a lot of studies, but there are not many studies that can be used for integrated analysis to furtherly play its research value, and therefore the level of evidence quality is generally. Of course, it is not easy to carry out clinical research in the current tense epidemic situation and arduous anti-epidemic work environment. However, in order to improve the evidence-based value of clinical research of TCM, it is suggested that local research groups should establish a multicenter controlled clinical trial on the existing basis, expand the efficacy comparison between conventional treatment and combined treatment of TCM and conventional treatment, so as to explore the clinical efficacy evidence of Chinese medicine intervention in COVID-19.As of January 21, 2021, the COVID-19 epidemic has caused more than 97.48 million infections and over 2.08 million deaths in more than 220 countries and regions around the world. The World Health Organization listed it as a public health emergency of international concern, and global politics and economy were greatly impacted by this epidemic. It has brought great damage to the physical and mental health of people around the world, and has brought immeasurable losses to globalization. Many countries will continue to be threatened and devastated by novel coronavirus pneumonia before the vaccine can be formally put into widespread clinical use and the effectiveness of the vaccine can be confirmed. It has far surpassed severe acute respiratory syndrome and Middle East respiratory syndrome in terms of the number of infections and the spatial scope of epidemic areas, and poses a serious threat to global public health.This study is initiated by Xiaozheng Wu.Xiaozheng Wu and Wen Li were involved in the design of the study and the interventions of the protocol.Xiaozheng Wu will develop the search strategies, conduct data collection, and analyze independently.Zhong Qin, Lei Xue, Gao Huang, and Zhenliang Luo will revise it.All authors have approved the final manuscript.Conceptualization: Xiaozheng Wu.Data curation: Xiaozheng Wu.Formal analysis: Xiaozheng Wu.Funding acquisition: Xiaozheng Wu.Investigation: Xiaozheng Wu.Methodology: Xiaozheng Wu, Wen Li.Project administration: Xiaozheng Wu, Lei Xue.Resources: Xiaozheng Wu.Software: Xiaozheng Wu, Wen Li.Supervision: Yunzhi Chen.Validation: Zhenliang Luo.Visualization: Gao Huang.Writing – original draft: Xiaozheng Wu.Writing – review & editing: Xiaozheng Wu, Zhong Qin.


Coffea canephora using an additive-dominance architecture ANN and to compare it with genomic best linear unbiased prediction (GBLUP). The data used consists of 51 clones of C. canephora varietal Conilon, 32 of varietal group Robusta and 82 intervarietal hybrids. From this, 165 phenotyped individuals were genotyped for 14,387 SNPs. Due to the high computational cost of ANNs, we used Bagging decision tree to reduce the dimensionality of the data, selecting the markers that accumulated 70% of the total importance. An ANN with three hidden layers was run, each varying from 1 to 40 neurons summing 64,000 neural networks. The network architectures with the best predictive ability were selected. The best architectures were composed by 4, 15, and 33 neurons in the first, second and third hidden layers, respectively, for yield, and by 13, 20, and 24 neurons, respectively for rust resistance. The predictive ability was greater when using ANN with three hidden layers than using one hidden layer and GBLUP, with 0.72 and 0.88 for yield and coffee leaf rust resistance, respectively. The concordance rate (CR) of the 10% larger markers effects among the methods varied between 10% and 13.8%, for additive effects and between 5.4% and 11.9% for dominance effects. The narrow-sense  has advantage to not require priori assumptions about the relationships between inputs and the output allowing great flexibility to handle different types of complex non-additive effects, such as dominance and epistasis. Despite this advantage, the biological interpretability of ANNs is still limited. The aim of this research was to estimate the heritability and markers effects for two traits in  The interest in semi- and non-parametric statistical methods for genome-enabled prediction is increasing . MethodoDespite this advantage, reports about the biological interpretation from the marker effects and genetic parameter  estimates are limited to the best of our knowledge. Glória et al,  using siFor some species, for example, maize, eucalyptus, cotton, rice, pinus, and coffee –17, wherCoffea cenephora. In addition, we predicted the individual genetic merits of the traits (yield and coffee leaf rust resistance) using ANN, and compared the predictive ability obtained for ANN and GBLUP for predicting genetic merit.Against this background, we aimed to exploit SNP effects and heritability from additive-dominance genomic model by ANN of traits associated with the yield and coffee leaf rust resistance, in C. canephora varietal group Conilon, 32 varietal group Robusta and 82 intervarietal hybrids. These hybrids were originated from crosses between five Conilon genotypes  and five Robusta , obtained in a partial diallel model W* [2]W* …[j-1]. To estimate the additive and dominant SNP effect vectors (βaandβd) using RI, a linear approximation adapted from [M to obtain the additive or dominant effect, Z is a diagonal matrix composed by the RI values, the matrix M is the matrix of markers and To estimate the heritability and SNP effects, the relative importance (RI) of markers were obtained. Olden et al.  proposedted from  was usedTo estimate heritabilities, the additive and dominant variance X with 165 rows (plants) and 1302 columns (markers) for coffee leaf rust resistance. For yield, the matrix was made up of 165 rows and 1086 markers. The markers were selected using bagging. After reducing dimensionality, 64,000 neural networks were performed, with each hidden layer ranging from 1 to 40 neurons, and the ANN was chosen based on the best predictive ability. For yield, the best ANN has 4, 15, and 33 neurons for the first, second, and third hidden layers, respectively. For coffee leaf rust resistance, the best ANN has 13, 20, and 24 neurons for the first, second, and third hidden layers, respectively. In The input layer (IL) was composed of a genotype matrix The predictive ability mean was calculated  by fixinThe chosen ANNs were compared with GBLUP and with the simplest ANN containing one hidden layer with one neuron and the logistic function as activation function according to predictive ability. The most complex ANNs showed a better predictive ability, 0.72 and 0.88 for yield and coffee leaf rust resistance, respectively, indicating that the traits are complex. The ANNs with a single HL with one neuron showed the worse predictive ability, 0.18 and 0.57 for yield and coffee leaf rust resistance, respectively . The ANNFor both traits, the additive and dominance heritabilities captured by ANN with 3HL (ANN/3HL) were similar to those obtained by GBLUP . The ANNThe marker effects were estimated using linear approximation  based onThe absolute values of marker effects from the coffee leaf rust resistance trait are in Looking at the top 10% larger marker effects in each methodology , the conCoffea canephora was efficient. The ANN/3HL presented higher values of predictive ability compared with those obtained by GBLUP, a result also obtained by Glória et al. [The use of ANN for predicting the individual genetic merit of plants considering yield and coffee leaf rust resistance in a et al. , Waldmana et al.  and Malda et al. . Indeed,a et al. . Thus, ta et al. . The inta et al. , 35, ANNa et al. , 11, 36.The heritability estimated by ANN/3HL for yield (.15–0.79 ). For co.15–0.79  (0.37).Glória et al  considerA different pattern in marker effects was obtained in the two traits Figs  and 6. AAn issue related to using an ANN approach is the computational cost . Once itCoffea canephora. In addition, considering the estimates of predictive ability, ANN/3HL presented better results compared with those obtained from GBLUP and ANN/1HL.The Artificial Neural Network was able to access the marker effects and heritability estimates from additive-dominance genomic architectures by neural networks in S1 FigHistogram of yield and rust resistance.(TIF)Click here for additional data file.


Multicenter studies involving patients with acute kidney injury (AKI) associated with the disease caused by the new coronavirus (COVID-19) and treated with renal replacement therapy (RRT) in developing countries are scarce. The objectives of this study were to evaluate the demographic profile, clinical picture, risk factors for mortality, and outcomes of critically ill patients with AKI requiring dialysis (AKI-RRT) and with COVID-19 in the megalopolis of São Paulo, Brazil.This multicenter, retrospective, observational study was conducted in the intensive care units of 13 public and private hospitals in the metropolitan region of the municipality of São Paulo. Patients hospitalized in an intensive care unit, aged ≥ 18 years, and treated with RRT due to COVID-19-associated AKI were included.The study group consisted of 375 patients . Most (62.1%) had two or more comorbidities: 68.8%, arterial hypertension; 45.3%, diabetes; 36.3%, anemia; 30.9%, obesity; 18.7%, chronic kidney disease; 15.7%, coronary artery disease; 10.4%, heart failure; and 8.5%, chronic obstructive pulmonary disease. Death occurred in 72.5% of the study population (272 patients). Among the 103 survivors, 22.3% (23 patients) were discharged on RRT. In a multiple regression analysis, the independent factors associated with death were the number of organ dysfunctions at admission and RRT efficiency.AKI-RRT associated with COVID-19 occurred in patients with an elevated burden of comorbidities and was associated with high mortality (72.5%). The number of organ dysfunctions during hospitalization and RRT efficiency were independent factors associated with mortality. A meaningful portion of survivors was discharged while dependent on RRT (22.3%). Approximately 20 to 25% of patients with acute kidney injury (AKI) in intensive care units (ICUs) require renal replacement therapy (RRT) ,2. The mThe frequencies of AKI and AKI-RRT reported in patients with COVID-19 range from 10 to 17% and 2.4 to 4.3%, respectively ,9. SubgrThe available information on the mortality and recovery of patients with AKI-RRT associated with COVID-19 is mostly from cohorts in high-income countries located in the Northern Hemisphere, which show a mortality rate of 63.3% to 79.3% and dependence on RRT after discharge in 22.0% to 38% of survivors –16. DataThe objectives of this study were to evaluate the demographic profile, clinical picture, risk factors for mortality, and outcomes of critically ill patients with AKI-RRT-associated COVID-19 in the megalopolis of São Paulo, Brazil.This was a multicenter, retrospective, observational study conducted in 13 hospitals (public and private) in the metropolitan region of the city of São Paulo. The choice of participating centers was made by convenience.The inclusion criteria were as follows: patients ≥ 18 years of age admitted to the ICU due to COVID-19 between 1 April 2020 and 31 August 2020 who required RRT due to AKI. The exclusion criteria were patients with chronic kidney disease (CKD) dependent on RRT before hospitalization and those in exclusive palliative care. The study was approved by the research ethics committees of the participating centers under CAAE  number n31693820.8.1001.5485.2 or if this diagnosis was reported in the medical record. A patient was considered to have anemia if the serum hemoglobin (Hb) concentration at admission was < 13.0 g/dl in men or Hb < 12.0 g/dl in women. In addition, the following variables were of interest: the severity of pulmonary involvement on chest tomography , Simplified Acute Physiology Score (SAPS) at ICU admission, the incidence of organ dysfunction other than kidney dysfunction during hospitalization  and the use of the following medications during hospitalization: azithromycin, hydroxychloroquine, corticosteroids, antibiotics (in addition to azithromycin), and heparin by continuous infusion. Pulmonary, circulatory, hepatic, and coagulation dysfunction was defined as a PaO2/FiO2 ratio < 400 or the need for mechanical ventilation, the use of vasopressors, serum levels of total bilirubin ≥ 1.2 mg/dl, and platelets < 150,000/mm3, respectively [Demographic data , profiles of comorbidities, and hospital admission parameters  were obtained. A patient was considered to have hypertension (HTN) if the diagnosis was recorded in the medical record, or the patient used antihypertensive drugs. A patient was considered to have diabetes mellitus (DM) if the diagnosis was recorded in the medical record, or the patient reported the previous use of oral antidiabetics drugs or insulin. A patient was considered to have CKD, heart failure (HF), chronic liver disease, and chronic obstructive pulmonary disease (COPD) if such diagnoses were reported in the medical record. A patient was considered to have coronary artery disease if she or he had a history of acute myocardial infarction, stent placement, or myocardial revascularization. A patient was considered obese with a body mass index > 30 kg/mectively .The RRT parameters evaluated were serum creatinine, urea, sodium, potassium, and bicarbonate up to 24 hours before the first RRT session, simple mean values of serum creatinine, urea, sodium, potassium, and bicarbonate during the period on RRT and the RRT method used: peritoneal dialysis (PD), intermittent hemodialysis (IHD), sustained low-efficiency dialysis (SLED), or continuous renal replacement therapy (CRRT). Efficient RRT was defined as the presence of two or more of the following criteria, which were evaluated during the period in which the patient underwent RRT: simple mean values of urea < 100 mg/dl, potassium < 5.0 mEq/l, and bicarbonate > 22 mEq/l. The number of RRT sessions, the total hours of CRRT, and the indications for the RRT method could not be obtained.The outcomes of interest were the length of hospital stay, death, and discharge (with or without RRT dependence). The patient follow-up time was up to 90 days of hospitalization.The diagnosis of COVID-19 was defined as a positive RT–PCR  result or as a combination of respiratory symptoms and chest tomography with typical changes  .2 or Fischer’s test as appropriate. Intergroup comparisons for quantitative variables were performed using Student’s t test and the Mann–Whitney U test for normally distributed and nonnormally distributed data, respectively.Categorical variables are presented as frequencies. Quantitative variables with a normal distribution are presented as the mean and standard deviation, and those with a no normal distribution are presented as the median and interquartile range. Frequencies were compared using the χThe analysis of independent risk factors for mortality was performed using logistic regression. Due to the occurrence of missing data and their no monotonic pattern, multiple inputs were performed using the Monte Carlo method via Markov chains, which generated 15 complete datasets. All variables included in the multiple logistic regression were used for the input of missing data, for which logistic regression was performed for categorical variables and linear regression was performed for continuous variables. Multiple logistic regression analysis was performed for each of the 15 complete datasets using a backward strategy and maintaining in the model the variables that, when removed, led to a change greater than 10% in the estimate of the betas of the variables present. The presence of multicollinearity was verified by the variance inflation factor.The initial logistic regression model included the following variables: type of hospital (public or private), age, sex, smoking, one or more comorbidities (no reference), lower tercile of platelets, upper tercile of creatinine at admission, number of organ dysfunctions during hospitalization , use of vasoactive drugs, mechanical ventilation, urea > 150 mg/dl, potassium > 5 mEq/l, bicarbonate < 22 mEq/l, upper tercile of serum creatinine levels measured on the day of the first indication for RRT, and efficient RRT. The quality of the model fit was evaluated using the Hosmer–Lemeshow test, and the significance of the variables was evaluated using the Wald test. The results obtained with the analysis of the 15 datasets were averaged . StatistBetween April and August 2020, the numbers of patients—total and ICU—admitted for COVID-19 in the participating hospitals were 7,918 and 2,937, respectively. In the same period, 462 of these 2,937 ICU patients (15.7%) underwent RRT due to AKI. The data for 375 (81.1%) of these patients  were obtained . PatientThe demographic data, comorbidities, and hospital admission parameters are summarized in Subsidiary examinations, clinical characteristics, organ dysfunction, treatments, and outcomes of the patients are shown in In the univariate analysis, nonsurvivors exhibited a shorter hospital stay than survivors  on the day of the first RRT indication. In addition, nonsurvivors had higher simple medians of creatinine , urea , and potassium , and lower serum bicarbonate  during the RRT period .3, p = 0.04) at admission.  and higher use of isolated IHD  based on the univariate analysis. They showed higher serum creatinine levels  and lower total leukocyte counts  –15,20. UThe present study showed that patients with higher potassium and urea and lower bicarbonate levels during the RRT period had higher mortality rates. These findings may suggest that an insufficient RRT dose affected patient outcomes. Another possible explanation is that more severe disease and hemodynamic instability hindered adequate metabolic control. In fact, in the present study, patients who died received fewer days of RRT and had shorter hospital stays. In previous studies, information on laboratory tests at the beginning of RRT and metabolic control for patients with AKI-RRT and COVID-19 has been scarce or absent. Oliguria at RRT initiation was reported as an independent risk factor for death in patients with these conditions, potentially indicating more severe AKI as well as a delay in the indication for RRT . UnfortuThe RRT method was likely not directly related to mortality in the present study or in other studies involving AKI in patients with COVID-19 ,19,20. TAs in our study, other authors reported that COVID-19-associated AKI-RRT occurred more frequently in men (68–83%) and in patients with a high burden of comorbidities  –15,20. AIn previous studies, among survivors of AKI-RRT associated with COVID-19, the percentage discharged from the hospital while dependent on RRT varied between 30–38% –15. The The limitations of this study are the retrospective design, the lack of data from all patients who met the inclusion criteria, and the lack of information on kidney function recovery after hospital discharge. In addition, considering the regional differences in Brazil and the fact that the global mortality of critically ill patients has a strong association with national income , the resCOVID-19-associated AKI-RRT occurred in patients with an elevated burden of comorbidities and showed high lethality. The number of organ dysfunctions during hospitalization and the efficiency of RRT were independent factors associated with mortality. A significant portion of the survivors were discharged without kidney function recovery.S1 File(XLSX)Click here for additional data file.