Acute generalized exanthematous pustulosis (AGEP) is a rare skin reaction, commonly caused by drugs. Available evidence mostly relies on small studies or case reports. We collected published AGEP case reports and, subsequently, described the patient characteristics, suspect and concomitant drugs, time to onset, disease management, and clinical prognosis. This study included 297 AGEP patients (64.3% women) obtained from 250 published case reports or case series with individual patient data. AGEP affected patients of all ages, but the majority of patients (88.2%) were ≥25 years old. The most frequently reported suspect drugs were anti-infectives for systemic use (36.5%), particularly antibacterials for systemic use (31.0%), and especially beta-lactam antibacterials (18.3%) and macrolides (4.3%). Other frequent suspect drugs were antineoplastics (12.2%), and anti-inflammatory/anti-rheumatic products (5.2%) plus hydroxychloroquine (12.8%). Mean time to onset was 9.1 days (standard deviation SD 13.94). Some patients developed fever (64.3%) and systemic involvement (18.9%), and most patients (76.4%) received pharmacological treatment for AGEP. Seven patients died, although five of them were already critically ill prior to AGEP. In conclusion, antibiotics remain the most common suspected cause of AGEP. While case mortality rate may be up to 2.5%, disentangling the role of AGEP on the fatal outcome from the role of the preexisting health conditions remains challenging. Acute generalized exanthematous pustulosis (AGEP) is a rare and severe skin reaction. While AGEP occurs most frequently as an adverse effect of pharmacological treatment or drugs, it may also result from contact with chemicals  or dyes ,2, or asPharmacological treatments reported as suspect agents triggering AGEP include, among others, antibiotics and other anti-infectives, cardiovascular drugs, proton pump inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and hydroxychloroquine ,11,12,13The majority of the available evidence on AGEP relies on relatively small observational studies ,10,12,14A literature review in Embase and PubMed databases was conducted, aiming to collect case reports of drug-associated AGEP published before December 2021. We used keyword search terms for “acute generalized exanthematous pustulosis” or “AGEP” to identify potential articles. The study inclusion was restricted to case reports describing drug-associated AGEP in humans and providing information at the individual patient level. Only literature in English language was included. Studies of AGEP caused by insect bites, dyes, or infective agents (viruses or bacteria) were excluded. Articles describing more than one case  were only included if sufficient data at the individual patient level were provided. Cases of acute localized exanthematous pustulosis (ALEP) were included and treated as AGEP. The articles were initially scanned through the title and abstract, and when potentially relevant, a full-text review was conducted. A database was created to record and unify data from the included case reports. Collected information comprised patient characteristics , country of the event, every drug that the patient was taking at the onset of the reaction, the suspect drug(s) according to the original authors and their indication, record of patch test investigation, the treatment to address the AGEP reaction, and the outcome of the reaction . The following assumptions were taken for the data collection process: If the patient’s age was reported as, for example, ‘in their 40s’, the start of the corresponding 10-year range was chosen, thus, 40 years old in this example. Ethnicity reported as ‘white’ was recorded as ‘Caucasian’. In the absence of a clear mention of the country of the event, the country of the affiliation from the main author of the corresponding paper was used. In the absence of a mention or indication of the presence of systemic involvement, surgery, or sequelae, it was assumed that there was no systemic involvement, surgery, or sequelae, respectively. If surgery after AGEP was reported, but this surgery was the consequence of pre-AGEP circumstances , it was not recorded as surgery. If AGEP was developed in already hospitalized patients, we classified them as yes for hospitalization; likewise, patients requiring hospitalization after AGEP. Performance of a percutaneous test was recorded as a patch test. Time to onset was recorded in days. In the cases when AGEP was suspected from a drug after several administrations, time to onset was considered as the number of days from first administration to the AGEP event. When time to onset was reported as ‘less than a week’ or ‘a few days’, we recorded it as six days. Similarly, time to onset of ‘a few hours’, ‘several hours’, or ‘less than 24 h’ was recorded as 0.5 days. Sudden onset was recorded as zero days, and one month as 30 days. p ≤ 0.05.Patient characteristics, number of reported drugs, number of suspect drugs, number of patients receiving pharmacological treatment to address AGEP, and the clinical outcome of the reaction were described overall and stratified by sex. Categorical variables were presented with counts and proportions, and continuous variables were described by mean and standard deviation (SD). In the stratified analysis, findings in men were compared to the findings in women using the chi-squared test for categorical variables and t-test for continuous variables. Statistical significance was defined as Reported drugs were classified by therapeutic class, with the aid of the Anatomical Therapeutic Chemical Classification System (ATC) system and their described indication. The frequency of reporting of suspect drugs, as well as the frequency of reporting of every reported drug independently of being or not labeled as the suspect drug, were presented, providing counts and proportions, overall and stratified by sex. Subsequently, the pharmacological treatment of AGEP was similarly presented. The analyses were performed using R Statistical Software  .From the >800 identified articles in PubMed and Embase, 250 published case reports or case series were included in the analysis ,263,264,A comprehensive database with the collected information from every patient, together with a table describing every included variable, are provided in Among the 297 included patients, 102 (34.3%) patients were men, 191 (64.3%) patients were women, and 4 patients missed information on sex. These patients’ characteristics are described in p = 0.026). Across the sex strata, non-significant differences were found for the number of all and suspect reported drugs. However, a tendency of a higher number of drugs may be observed in male (24.5% with >4 drugs) versus female patients (16.8% with >4 drugs). Similarly, although there were no significant differences across the sex strata with regard to the percentage of patients developing fever, systemic involvement, or having sequalae due to AGEP, a tendency of more men (23.5%) than women (16.8%) having systemic involvement may be observed. In the men and women cohorts, 4 (3.9%) and 3 (1.6%) deaths were registered, respectively. Stratifying by sex , women’sIn the study cohort, seven deaths were recorded ,182,221.Overall, among the 297 patients, a total of 154 unique drugs were identified as suspect triggers of AGEP. The frequency of reporting of these suspect drugs is presented in Stratifying by sex, visual assessment of the findings shows a higher frequency of hydroxychloroquine and anti-inflammatory and anti-rheumatic products as suspect drugs in women than men. Conversely, a higher frequency of analgesics may be observed in the men cohort. A description of all drugs reported in patients developing AGEP, independently of the suspect label, is given in This literature case series included 297 patients with drug-associated AGEP, whose information was obtained from 250 published scientific articles. AGEP affected both women (64.3%) and men (34.3%), and while patients’ age covered a wide spectrum, a higher frequency was observed in patients 25 years or older (88.2%). Approximately half (50.5%) of the patients reported the use of more than one drug at the time of AGEP onset, but in 90.9% of cases, only one drug was reported as the suspect agent. Among the suspect drugs, the most frequently reported ones were antibacterials for systemic use (31.0%), particularly beta-lactam antibacterials (18.3%) and macrolides (4.3%). Other frequently reported suspect drugs were antineoplastic agents (12.2%), anti-inflammatory and anti-rheumatic products (5.2%), and hydroxychloroquine (12.8%). Time to onset was ≤4 days in 50% of the patients. Fever was reported in more than half of the cases (64.3%), and systemic involvement in one in every six patients (18.9%). Three-fourths of the patients received pharmacological treatment to address the AGEP reaction. Overall, seven case reports reported the death of the patient , six of which were seriously ill prior to AGEP. It remains unclear whether AGEP was the cause of every fatal outcome. The patient demographics in this case series are generally comparable to other observational studies. Indeed, the higher frequency of women patients in our study is in line with the existing evidence ,265,266,Aging is associated with increased frailty, higher disease burden, more medication use, and higher risk for adverse drug reactions . Thus, sSystemic involvement in AGEP patients has been described as abnormal hepatic and liver function ,12, as wIn the literature, the AGEP case-fatality rate has been suggested to be 2–5%, which is often due to multi-organ failure or secondary infections ,4,12,13.Our findings confirmed previous observational studies indicating the high frequency of antibiotics as drugs clinically associated with AGEP onset, especially beta-lactam antibacterials. Antibiotics are often the most prevalent drugs associated with AGEP onset ,268,269,Following antibacterials and other anti-infective agents, the anti-inflammatory and anti-rheumatic products including hydroxychloroquine were also frequent among the AGEP triggers. Hydroxychloroquine was identified as the suspect drug in one of every eight patients (12.8%). This result was higher than the 7% previously observed by the EuroSCAR case-control study . Anti-cancer drugs were also identified as a leading cause of AGEP in our case series (8.1% of cases). In a study investigating the adverse effects associated with targeted and non-targeted chemotherapy, imatinib was identified as one of the common anti-cancer drugs responsible for AGEP . Our stuWhile the medications most frequently associated with AGEP events do not always share a common pharmacological pathway, many reflect a patient profile with an “active” immune response , or abnormal cell regulation (cancer). This could also be observed across the patient comorbidities and/or health burdens prior to AGEP. This may suggest that the patient condition for which the treatment is provided may have an impact on the development of AGEP. However, the presence of other drugs also commonly associated with this reaction, such as those for cardiovascular disease, or treatments for neurological diseases , does not necessarily support this hypothesis. In our secondary analysis where we investigated all reported drugs at the moment of AGEP onset, independently of being considered the suspect drug or not, we confirmed the strong presence of antibacterials among the patients. Interestingly, the frequency of blood/cardiovascular treatments in the all-drugs analysis was two to four times higher than in the analysis where only the suspect drugs were included, and 21.9% of patients had pre-existing cardiac/cardiovascular disease/event. While this could indicate an underlying disease–drug interaction, whereby patients with cardiac/cardiovascular diseases are at a higher susceptibility to experience AGEP, it could also suggest the potential for currently unknown drug–drug interactions or additive effects in patients with polypharmacy. A previous study identified the potential for drug interactions to play a role in the onset of Stevens–Johnson syndrome . SimilarThis study is an extensive compilation of published case reports, and it provides a detailed overview of both the drug triggers of AGEP and the clinical characteristics of the reaction. Additionally, we provide a summary table and reference to the included articles , enablinThis comprehensive overview of published case reports provides a large case series of drug-associated AGEP, thereby permitting further understanding of the patient characteristics and drugs associated with this rare, and potentially fatal, adverse drug reaction. Due to the difficulties of studying rare adverse drug reactions, we expect that our study strongly contributes to the current evidence on AGEP. Among the 297 studied patients , more than half developed fever, and almost 20% had systemic involvement. The majority received pharmacological treatment to address the skin reaction. Antibacterial drugs were the most commonly reported drug class, both overall and as the identified suspect agent. Seven patients died, but the role of AGEP in the cause of death may be difficult to disentangle from the previous health condition of the corresponding patients, and the publication bias. Finally, we provide a comprehensive database with the 297 patients from the included published case reports, thereby providing the largest publicly available case-series. In particular, the generated dataset may be used by others to describe AGEP cases and address additional questions related to polypharmacy, drug–drug interactions, and drug–disease interactions. Nevertheless, additional observational data is required to further elucidate the case-fatality rates and longitudinal outcomes within the population.


The contamination factors suggest low contamination, except for Ni, which showed moderate contamination. The average pollution load index (PLI) revealed unpolluted to low pollution of all soil samples. The ecological risk assessment (PERI) showed that all heavy metals posed a low risk, except for Cd which exhibited a high ecological risk.The Liwa area is a primary food production area in the United Arab Emirates (UAE) and has intensively been used for agriculture. This study investigates the pollution levels with heavy metals in agricultural soils from the Liwa area. Thirty-two soil samples were analyzed for Mn, Zn, Cr, Ni, Cu, Pb, Cd, Co, and As. Results revealed that heavy metal levels varied in the ranges 220.02–311.21, 42.39–66.92, 43.43–71.55, 32.86–52.12, 10.29–21.70, 2.83–8.84, 0.46–0.69, 0.03–0.37 mg/kg for Mn, Zn, Cr, Ni, Cu, Pb, Cd, Co, and As, respectively. All samples presented low As concentrations with an average of 0.01 mg/kg. The variations in bulk metal contents in the soil samples were related to multiple sources, including agrochemicals, atmospheric dust containing heavy metals, and traffic-related metals. Enrichment factor analysis indicates that Cd, Ni, Zn, and Cr were highly enriched in soils, and they could originate from non-crustal sources. Based on the geo-accumulation index (I Soil pollution with toxic heavy metals gained growing attention in recent years due to increasing human activities and expanding the industrial and transportation sectors. Urbanization has also influenced soil properties not only in the surrounding areas but also at a distance. Heavy metals are mostly toxic, persistent, and bioaccumulative. They tend to accumulate in soils ,2,3, andChemical compounds and heavy metals may lead to degradation or loss of some soil functions and services. Heavy metal pollution is largely irreversible ,18,19,20While a large number of publications have assessed heavy metals in urban soils ,33,34,35In arid regions, soil contamination with heavy metals may have different sources and pathways. Arid climates with frequent dust storms can cause heavy metals dissipation at long distances ,39. ElevLiwa is an area in the southern UAE with a major groundwater reserve. It has been used intensively for agricultural activities. The groundwater vulnerability assessment of the Liwa’s groundwater indicated that the aquifer beneath is highly vulnerable to pollution .The goal of this research is to check the hypothesis of the soil possible contamination with heavy metals in the Liwa area (Abu Dhabi Emirate). For a correct estimation of the pollution degree different indicators suggested in the literature ,41,42,43The study area is located in Liwa, south of Abu Dhabi, in the UAE . It is aAbu Dhabi has an arid climate with a highly variable and erratic rainfall of less than 100 mm/year, occurring mainly in winter. The annual evaporation rate in the study area is considerably high.This area hosts a major groundwater aquifer, with a nominal groundwater recharge rate  and no surface water resources. This shallow aquifer system in Abu Dhabi Emirate has been overused for irrigation, where the study area has one of the Emirate’s most extensive cultivated lands . In addiEvidence of groundwater quality degradation in the Liwa region has been reported and was attributed mainly to agricultural activities ,46. Shal3, 2 mL HCl and 2 mL HF were added, and the mixture was heated for 40 min on a hot plate at 120–150 °C. The mixture was filtered through Whatman filter paper No. 42 and the filtered digest was transferred to a 50 mL plastic volumetric flask and filled up to the mark by deionized water. Metal contents were measured by Agilent 700 series ICP-OES. A Certified Reference Material (CRM) (IAEA SOIL-7) was used to validate the analytical measurement methods. A total of 32 soil samples were collected during February 2019 from several farming areas located in the Liwa area in UAE . The samsample is the ratio of metal and Fe concentrations in the sample, and (M/Fe)crust is the ratio of metal and Fe concentrations in the Earth’s crust [Heavy metal pollution in soils was assessed using the Enrichment factor (EF) of Sinex and Helz , as foll’s crust ,49. Meta’s crust .geo) [nC is the measured concentration of the examined metal n in the soil, and nB is the geochemical background concentration  of the metal n. The constant 1.5 accounts for the natural fluctuations of the metal in soil. The mean contents of the global geochemical background of Cambisols (silty and loamy soils) [geo has seven grades (0 to 6), indicating various degrees of enrichment above the background values and ranging from unpolluted to very highly polluted soil quality.Heavy metals in soils were also evaluated using the geoaccumulation index (Igeo) . It is ey soils)  and the y soils)  were useThe contamination factor (CF) for soil samples were assessed to quantify the impact of each metal on the soil ,54. The n is the number of heavy metals (nine in the present study) [The pollution degree was further assessed by the pollution load index (PLI). The PLI of each metal was computed as follows:t study) ,56,57. Ti is the single ecological risk index, Ti is the toxic response factor for a given metal, i  [i is the calculated contamination factor for the metal I, Ei < 40 indicates low contamination, whereas 40 ≤ Ei < 80, 80 ≤ Ei < 160, 160 ≤ Ei < 320, and Ei ≥ 320 shows a moderate, considerable, high, or significantly high contamination risk, respectively [i indicates a low (CFi < 1), moderate (1 ≤ CFi < 3), considerable (3 ≤ CFi < 6), or very high contamination (CFi ≥ 6) [The potential ecological risk index was computed to assess the cumulative pollution effects of multiple metal on the soils. The formula developed by Håkanson  was used Cr = 2) , CFi is ectively  and CFi CFi ≥ 6) .The PERI has four grades, corresponding to values smaller than 150 (low), from 150–300 (moderate), in the range of 300–600 (considerable), and greater than or equal to 600 (very high) .The summary of the statistical analysis of heavy metal concentrations in the soil samples is presented in The highest concentration was that of Mn, with mean and median concentrations of 273.9 and 277.22 mg/kg, respectively. The concentrations of the other heavy metals, in decreasing order, are Cr > Zn > Ni > Cu > Pb > Cd > Co > As .The variations in concentrations of bulk metals in the soil samples are related to multiple sources. This region hosts the largest groundwater aquifer in the UAE and has intensively been used for agricultural production . AgrocheThe compost is frequently used in the UAE to enhance the soil properties and improve its fertility since infertile sandy soils are widespread in the UAE. The use of compost  have been reported to increase the concentration of certain metals  in soils . These mIntensive agricultural production is commonly practiced in this region, where groundwater is the sole source of irrigation water. Salinization and contamination with chemicals were observed in groundwater ,46. The The Liwa region’s vulnerability assessment indicated that the aquifer beneath the extensive agriculture area is highly vulnerable to pollution . It indiThe study area is also bordered by a major traffic highway, with impacts from vehicular emissions. Cd, Pb, and Zn in soils could originate partly from traffic activities ,68,69,70Heavy combustion of fossil fuel is another potential source contributing to heavy metals’ measured values in soil , where the study area is located near gas and oil fields in the southern UAE. Also, the Arabian Peninsula (including the UAE) hosts leading oil and petrochemical industries. These world’s industries can add metals to the ambient dust, where the northerly wind carries airborne emissions to the UAE ,3.The electric power industry is the backbone of the UAE economic sectors and is expanding rapidly. The UAE’s energy consumption rate is one of the highest globally . NaturalDust storms are common in the UAE, contributing to the transport and deposition of the metals to soil ,11. The While the composition of soils revealed generally much greater concentrations for Mn, Zn, Cr, and Ni than other metals, only the concentration of Cd and Ni in the soil samples exceeded the background levels for the continental crust and the average worldwide soils. In contrast, the remaining heavy metals were within the reported limits . Heavy mEnrichment factor (EF) analysis showed that Cd was the most enriched element followed by Ni, Zn, Cr, Mn, Co and As .According to the enrichment classification , the lowZn can be associated with vehicular emissions such as combustion of petrol, wearing of tires and brake linings. In addition to anthropogenic sources, Cr content values in soil samples (compared to world soil average content of Cr) also suggest that Cr is derived from the chemical weathering of basalt exposed in the region and carried through atmospheric dust. Cr concentration of about 170 mg/kg was measured in basalt , whereasgeo of −2.31, −1.36, −0.97, −2.17, −6.59, −8.14 and −2.57). Soils are uncontaminated to moderately contaminated with Ni (Igeo = 0.43) and moderately contaminated with Cd (Igeo = 1.94) (geo): Cd > Ni > Zn > Cr > Pb > Mn > Cu > Co > As  . Heavy m Co > As .The CF of metals in soil samples  indicatei) of heavy metals were ranked in the following order: Cd > Ni > Pb > Cu > Cr > Zn > Mn > Co > As. All heavy metals have Ei values indicating low risk, except for Cd, which possesses a high ecological risk. The PERI in soils ranged from 152.63 to 224.39 with an average of 189.28  showed values larger than 30%, suggesting that they were probably derived from different emission sources. These metals probably originated from multiple sources, of which some are common (as discussed earlier). Some metals are released from natural sources and enriched by anthropogenic activities, such as traffic-related emissions, agriculture, and fuel combustion.This study provides valuable data about heavy metal contents in soils from Liwa (Abu Dhabi). Liwa is of prime importance as it is a major food production area of the country. A previous study had shown that the major groundwater aquifer located beneath the extensive agriculture area lies within high to very high pollution vulnerability zones. This also indicates that heavy metals in soils may leach with agricultural runoff to end up in groundwater. The composition of soils revealed generally much greater concentrations for Mn, Zn, Cr, and Ni compared to other metals, but only the concentration of Cd in soil samples exceed the background levels for the continental crust and the average worldwide soils. Even if Cd, Ni, Zn, and Cr are highly enriched in soils, the pollution indices generally showed that the soils are uncontaminated with the majority of heavy metals except for Ni and Cd. The ecological risk assessment revealed a low risk to local ecosystems, except for Cd.


The likelihood of admission and/or presentation to an intensive care unit (ICU) versus non-ICU inpatient unit, emergency department, and outpatient services, which reflects the severity of the clinical course, was also modified by race and ethnicity. Females were less likely to be tested , and males had a higher case prevalence . Compared to other major ethnic groups, Whites experienced a higher prevalence of mortality (p<0.05). Males experienced a higher risk of mortality  at relatively younger ages (70.58±11.75) compared to females (73.02±11.46) (p = 0.0004). There was an increased severity of disease in older patient populations of both sexes. Although Hispanic and Black or African American race was associated with higher testing prevalence and positive testing rates, the only disparity with respect to mortality was a higher prevalence in Whites.With the continued rise of the global incidence of COVID-19 infection and emergent second wave, the need to understand characteristics that impact susceptibility to infection, clinical severity, and outcomes remains vital. The objective of this study was to assess modifying effects of demographic factors on COVID-19 testing status and outcomes in a large, diverse single health system cohort. The Mount Sinai Health System de-identified COVID-19 database contained records of 39,539 patients entering the health system from 02/28/2020 to 06/08/2020 with 7,032 laboratory-confirmed cases. The prevalence of qRT-PCR nasopharyngeal swabs (χ In late December 2019, the first cases of Coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), were reported in Wuhan, Hubei Province, China , 4. AddiMultiple studies from different countries have shown an age-associated vulnerability to CoV2 infection in older individuals. Reports from China, Korea, Italy, the United Kingdom, and New York City have presented evidence for increased risk of mortality with increase in age. This includes higher case fatality rates (CFR) and deaths per 100,000 individuals in aging populations . Based oWhile the increased risk of mortality with increased age seems unanimously apparent, the modifying effects of age on susceptibility to infection and impact on COVID-19 disease course is not well-understood. Korea’s cases per 100,000 individuals showed peaks in the 20–29 years old age range as well as a smaller second maximum in the ≥80 years old patients . In contData comparing sexes with respect to cases and CFR in China has also highlighted disparities between males and females in the context of CoV2 infections . While bRacial disparities in CoV2 infections have been widely reported. Communities of color, specifically Blacks and Hispanics, experience higher proportions of cases and hospitalizations compared to their representative portion of the general population . NYC has one of the most diverse populations in the world, that can provide a valuable data for reported differences among races. Based on earlier regularly updated news reports that should be taken with significant caution as they may not stand vigorous scientific testing, in non-hospitalized, non-fatal hospitalized, and confirmed deceased patients, when comparing cases per 100,000 by race/ethnicity, the trend is overwhelming and consistent with Blacks having the highest rates, followed by Hispanics, then Whites, and lastly Asians. The risk of mortality was also elevated compared to their White counterparts during the same period. These trends, while less severe, persisted when adjusting for age and relevant clinical as well as social variables . AdditioNYC rapidly became one of the early major epicenters of the US pandemic . The Mouth to June 8th 2020. Here, we provide detailed epidemiological and statistical analyses to determine the relationship between ethnicity, sex, and age on the clinical severity and mortality in the setting of COVID-19.In this retrospective study, we analyzed a de-identified MSHS COVID-19 patient database generated from 80,108 patients with a COVID-19 concern, including 109,000 individual service encounters in the MSHS from February 28The MSHS, with hospitals and outpatient sites throughout the metropolitan NYC area, was at the epicenter of the global COVID-19 pandemic. A de-identified MSHS COVID-19 patient database was generated from the electronic medical record  system and made available to the MSHS research community. From February 28th to June 8th, 2020, this database consisted of 80,108 masked electronic record numbers  that entered the MSHS with a COVID-19 related encounter, including 109,000 individual service encounters, including outpatient (OP) visits which entail telehealth and urgent care visits, emergency department (ED) visits, and inpatient (IP) admissions. IP admissions were further categorized into non-ICU or ICU admission. For the remainder of this manuscript, non-ICU patients will be referred to as IP. Multiple variables were featured in the database and used in stratification and characterization of the cohort’s associated COVID-19 risk. These included age, sex, race, ethnicity, SARS-CoV2 qRT-PCR testing, encounter types, location of care, admission type codes, discharge locations, and deceased indicators. Consistent with the database, only ethnic groups represented in the US Census were included in our analyses: White, Hispanic, Black or African American, Other, Asian, Native Hawaiian or Pacific Islander, and American Indian or Alaskan native. Black or African Americans will be referred to as Black for the remainder of this manuscript. A combined race and ethnicity variable defined by Mount Sinai’s COVID Disparities and Equity Taskforce was used to stratify demographic information to better capture Hispanic patients. Considering this combined variable, we will refer to race and ethnicity simply as ethnicity for the remainder of this manuscript.To reflect CoV2 infection severity, we created a scoring system based on the patient’s clinical service encounter where "unspecified" was scored as 1, OP visits represented mild cases were scored as 2, ED visits scored as 3, IP encounters scored as 4, and finally to ICU encounters, which represented the most severe clinical courses scored as 5. Unspecified service encounters, such as radio-oncology and neuropsychiatric visits (n = 67 patients), were excluded. After a severity score was calculated for each encounter, only the first encounter with the maximum severity score was selected to represent an individual patient’s clinical course. Thus, each patient was represented only once based on an encounter representing the most severe portion of their clinical score to avoid multiple representations in our analyses. We excluded encounters that included unspecified/unidentified data with respect to age, sex, and ethnicity. This filtration, in addition to the removal of patients with unidentified service encounters, limited our analysis to include 39,539 patients.Χ2) test for homogeneity to assess the association between race and testing under the null hypothesis (H0). The distribution of tested versus not tested individuals was the same among four major races—White, Hispanic, Black, and Asian. Additionally, we performed a Χ2 test under the H0 where the distribution of CoV2+ versus CoV2 individuals is the same among the four ethnicities. We looked for these associations in the cohort and conducted a separate analysis with a focus on the total deceased population . Native Hawaiian or Pacific Islander and American Indian or Alaskan Native were excluded from this analysis as their sample size was limited, making the X2 distribution potentially not valid. Furthermore, the Other ethnic population was excluded as it consists of a diverse group of ethnicities, which would limit the interpretation of our analysis. With regards to sex, two independent relative risk analyses were done to assess for a significant difference in the likelihood of females not being tested to males not being tested, and females being CoV2+ and males being CoV2+.We analyzed the associations between ethnicity and sex on CoV2 testing. With regards to CoV2 nasopharyngeal qRT-PCR testing status, the database included individuals who tested positive (CoV2+), presumed positive, negative (CoV2-), and individuals who were not tested. Presumed positive indicates that a patient’s positive qRT-PCR result has not yet been confirmed by the Center for Disease Control and Prevention (CDC). Within our cohort of 39,539 patients, 17.2% were CoV2+, which include presumed positives, 49.4% were CoV2-, and 32.8% were not tested for the SARS-CoV2 antigen. We performed a Chi-square  unknown  or 2) involved "admission to inpatient" (n = 7). The latter category represented ED patients with a single encounter at MSHS that did not end up being admitted to IP for unclear reasons. Of all patients discharged to hospice (n = 45), 18 were indicated as deceased, and 27 were indicated as still alive. Despite the poor prognosis of hospice patients, we included these patients in our analysis to avoid an assumption on the outcome—they represent 0.5% of all survivors.Further statistical analyses were performed to compare severity and mortality as stratified by sex and ethnicity. For the remainder of our analysis, we focused on patients with positive  or presumed positive (n = 495 patients) qRT-PCR results (i.e. CoV2+ patients). Additionally, we excluded all patients for which an outcome was unknown, limiting the analysis to 6,924 patients—5,629 individuals who recovered and 1,295 deceased. The count of recovered versus deceased individuals is reflective of results as of June 8Χ2 test was performed under H0. The distribution of CoV2+ individuals in all clinical services is the same among White, Hispanic, Black, and Asian subgroups. The same analysis was used to detect an association between sex and severity with the H0 assuming equal distribution of males and females at each severity. The risk of mortality was compared among ethnicities and then sexes via relative risk (RR) analyses. Relative risk analysis for each race was done against all other races independently with 6 comparisons.To evaluate the association between ethnicity and clinical severity, an We then looked at age as a modifier of outcomes in the overall CoV2+ population and subsequently in each encounter type corresponding to varying severities. Additionally, individuals born in the MSHS were automatically included in the database and removed from our analysis. Patients greater than 90 years of age were grouped under a single 90+ category and were also excluded from our age distribution frequency plots and statistical analysis. For the female population, this consisted of 171 individuals aged 0 and 532 individuals over 90, while for the male population, this included 182 and 252 individuals, respectively. Assessments for a significant difference in means were conducted using a one-way ANOVA test at the 95% CI using Sidak statistical hypothesis testing to correct for multiple comparisons. Comparisons were performed between varying severities for CoV2+ females, CoV2+ deceased females, CoV2+ males, and CoV2+ deceased males. Inter-sex comparisons were then made without correction for multiple comparisons (Fisher’s LSD Test) as each comparison stands alone. The mean age of females was compared to the mean age of males at every severity. This was done for CoV2+ patients and then with a focus on their deceased subgroup.All statistical analyses were conducted at the 95% confidence interval using GraphPad Prism version 7.00 for Windows. Significance was assigned at p < 0.05.We compared the patient population to the overall greater NYC catchment area based on the 2018 community survey US Census data (Table ID: B03002). Of the 39,539 patients, 38.5% of individuals identified as White , 21.4% as Hispanic , 21.0% as Black , 12.5% identified as Other , 6.4% as Asian , 0.1% as Native Hawaiian or Pacific Islander (n = 52) and 0.1% as American Indian or Alaskan Native (n = 21) .Compared to the demographic analysis of the greater NYC area, White and Other patients were overrepresented by 6.3% and 9.7%, respectively, in the MSHS COVID-19 total population  . FurtherWe also looked at testing rates within sex and race . Of the The individuals who tested negative or were not tested (82.2% of the MSHS cohort) also capture individuals with false-negative qRT-PCR results and individuals with clinical presentation, imaging, and labs consistent with COVID-19. Interestingly, there was a significant association when comparing qRT-PCR testing between the four major ethnic groups. Blacks and Hispanics had higher positive testing rates compared to other groups with 23.8%  and 22.7% , respectively .2 = 665.7, p<0.0001)  between test results and race. Within the total deceased patient population  , but there was a significant association between race and positive testing rates . The testing status in the deceased population is as follows: 67.7% were CoV2+ , 24.6% Cov2- (n = 471), and 7.6% (n = 146) were not tested (Rates of positive testing were similar between Whites (12.0%) and Asians (12.9%). Testing prevalence, defined as those who received qRT-PCR out of the entire ethnic population, by ethnicity was as follows—77.6% for Blacks, 69.4% for Hispanics, followed by 64.6% for Asians, and 61.4% for Whites (χ<0.0001) . Others,= 1,912) , there it tested . Within t tested . Only 1 t tested .Of the 39,539 COVID-19 related encounters, 20,770 (52.5%) patients were female and 18,769 (47.5%) were male . Within We evaluated the clinical severity of CoV2+ patients  by ethnic group and sex . COVID-1Mortality within each ethnic group was as follows: 20.4% of Whites, 17.3% of Hispanics, 17.1% of Blacks, 19.4% of Others, 19.0% of Asians, 16.7% of Native Hawaiian or Pacific Islander, and no mortality was reported amongst American Indians or Alaskan Natives .2 = 183.1, p<0.0001)   . In addi<0.0001) . The sma<0.0001) .We calculated the relative risk of mortality in CoV2+ patients for each ethnic group to further assess for any racial disparities with regards to mortality . We founThere was no significant change in the risk of mortality for the White population relative to the Asian population. Additionally, the risk of mortality was not significant between Black, Hispanic, and Asian populations . These fWe assessed the age distribution of patients that entered the MSHS for a COVID-19 concern by sex. Age distribution in total patients, regardless of testing status, is bimodal. Notably, the age distribution of the total CoV2+ population is, although attenuated at first maxima, still bimodal for both sexes . For femWe assessed age distributions as a function of clinical course severity using our severity scoring system described in the methods as a surrogate for the severity of clinical course . Across In the CoV2+ OP population, the average age was 46±16 with maximum peak at 29 years of age for females , and 45±The total IP female population showed a bimodal age distribution, with the early maxima being contributed primarily to females admitted for labor and delivery , as noteWithin the CoV2+ female population, patients admitted as IP or ICU were significantly older compared to females who presented to OP  or ED F p<0.000 or ICU  units. DRelatively younger aged males (67±12) were dying in the ICU compared to those in the ED  and males in the IP population  . Overallth 2020, 7,032 patients (17.9%) were positive or presumed positive for CoV2, of which 1,295 patients passed away (18.4%), and 5,737 recovered and were discharged (81.6%). Lack of testing can possibly be attributed to the shortage of nasopharyngeal swab testing kits during the peak of the pandemic in NYC.Since the initial reports of COVID-19 in early December 2019, the novel coronavirus outbreak continues to strain modern society, and its pathogenesis remains to be fully elucidated. Using one of the largest US patient populations across a range of clinical services, including OP, ED, IP, and ICU admission, we assessed the associations between various demographic factors including age, sex, ethnicity on CoV2 infection testing, clinical severity, and mortality. Of 39,539 patients who entered the MSHS with a COVID-19 concern as of June 8While major ethnic groups are well represented, the differences between census data and the MSHS patient population could be due to the catchment areas for the census data and socioeconomic stratification. Major ethnic groups are well-represented, but more detailed analyses are needed to understand the effects of ethnicity and potential disparities on COVID-19 patients entering the health system.With regards to CoV2 testing, we found that relative to other ethnic groups, Blacks and Hispanics had higher positive testing and infection rates, which is consistent with prior reports . AlthougWe also found that males tested positive more often than females and had a higher risk of mortality. In comparing case rates, the potential effect of false negatives and unconfirmed cases between both sexes should be taken into consideration. However, the impact of sex on susceptibility to CoV2 infection cannot be entirely excluded in our studies. Our findings regarding increased mortality in CoV2+ males are consistent with prior reports , suggestWe observed a bimodal age distribution in male and female CoV2+ population with maxima occurring at 33 and 61 years of age for females and 32 and 58 years of age for males. Mortality was highest in the older population for both sexes, with males dying younger (average 71 years of age) than females (average 73 years of age). This bimodal distribution was not observed in IP or ICU populations in both sexes, suggesting that a moderate to severe clinical course is observed predominantly in older patients. Interestingly, the average age of mortality is similar in both sexes for individuals captured in the ICU; however, younger males were passing away in IP compared to females. Overall, these findings suggest that aside from increased susceptibility of infection with CoV2, a more severe disease course in hospitalized males could be attributed to the sex differences noted earlier.There are several limitations to our study worth highlighting. We did not age adjust in our relative risk analysis, which may be one of the reasons for the greater risk of mortality that we found in White patients. Furthermore, we included hospice patients in our relative risk analysis. Hospice patients not indicated as deceased are included in the recovered category. However, they contain a very small portion of survivors or recovered patients (0.5%). Representing them in such a way only presents a 2.1% reduction in deceased patients. Our analysis also included all ED and OP populations. The limitations with these patients, as well as with IP and ICU patients post-discharge, is that there is a likelihood of being lost to follow-up as well as the risk of discharge proceeding death. While other studies have used hazard functions to circumvent this issue, they have focused on hospitalized populations. We believe our study allows for better assessment of looking at risks in the overall population. Risks may still be overstated as many individuals remain asymptomatic or present mild symptoms and therefore do not appear in hospital systems. Another limitation in our and many other studies is the false-negative rate of qRT-PCR tests, with studies estimating the sensitivity of most tests to be 70% .


Background: Postpartum depression (PPD) is a devastating disease requiring improvements in diagnosis and prevention. Blood metabolomics identifies biological markers discriminatory between women with and those without antenatal depressive symptoms. Whether this cutting-edge method can be applied to postpartum depressive symptoms merits further investigation.Methods: As a substudy within the Biology, Affect, Stress, Imagine and Cognition Study, 24 women with PPD symptom (PPDS) assessment at 6 weeks postpartum were included. Controls were selected as having a score of ≤ 6 and PPDS cases as ≥12 on the Edinburgh Postnatal Depression Scale. Blood plasma was collected at 10 weeks postpartum and analyzed with gas chromatography–mass spectrometry metabolomics.Results: Variations of metabolomic profiles within the PPDS samples were identified. One cluster showed altered kidney function, whereas the other, a metabolic syndrome profile, both previously associated with depression. Five metabolites  showed higher abundance among women with PPDSs, indicating perturbations in the serine/threonine and glycerol lipid metabolism, suggesting oxidative stress conditions.Conclusions: Alterations in certain metabolites were associated with depressive pathophysiology postpartum, whereas diversity in PPDS physiologies was revealed. Hence, plasma metabolic profiling could be considered in diagnosis and pathophysiological investigation of PPD toward providing clues for treatment. Future studies require standardization of various subgroups with respect to symptom onset, lifestyle, and comorbidities. Postpartum depression (PPD) affects 1 of 10 women giving birth , shortenEvidence of alterations in various biomarkers associated with PPD is increasing . The draMetabolomics has emerged as a useful tool in psychiatry in recent years, providing a comprehensive view of the metabolic physiology, which combines genetic, epigenetic, and environmental effects , 24. As For perinatal depression, omic analyses in general and metabolomics in particular are very limited. A study of our group  providedIn the case of PPD, some metabolite or metabolite-class targeted analyses have been reported. From these studies, PPD has been associated with alterations in the levels of tryptophan and kynurenine , 36, allTo our knowledge, only two untargeted metabolomic studies for PPD have been reported to date, both based on urine samples , 43. OneThe aim of this explorative nested case–control study was to investigate whether blood plasma metabolic profiles could be discriminatory between women with and without PPD symptoms (PPDSs), using untargeted gas chromatography–mass spectrometry (GC-MS) metabolomics, which monitors mainly the primary metabolism.This study is a substudy conducted within the framework of the BASIC project , which started in 2009 and finished recruitment in 2018. The BASIC study has been previously described . All Swen = 12) at 6 wpp and controls as EPDS 1–8 (n = 12) at all the time points during pregnancy and postpartum included in the BASIC study. Some of the cases (n = 6) did not still score ≥12 points at the EPDS 10 wpp. Furthermore, controls were eligible if reporting no history of depressive episodes according to the MINI interview. As well-defined lifestyle and family environment are important in psychiatric and PPD research, the 24 women included were selected based on strict inclusion criteria: (a) 26–39 years of age, (b) body mass index (BMI) between 20.0 and 29.9 kg/m2, (c) non-smokers prior and during pregnancy and at time of blood sampling, (d) parity ≤ 4, (e) glucose levels <6.8 mmol/L during pregnancy, (f) no medication except antidepressants (for cases) or levothyroxine at time of invitation and sample collection, (g) breastfeeding, (h) no pregnancy complications including diabetes, (i) no twin pregnancies, (j) blood loss during delivery <1,000 mL, and (k) no unhealed lacerations at 10 wpp. These criteria were applied with the purpose of examining a very well-defined cohort with respect to PPD, based on the medical records of the subjects, any confounding factors, and the knowledge that we had gained from our previous study investigating antenatal depressive symptoms  version 6.0, sections A. Depression and N. Generalized anxiety disorder, and blood sampling. Cases were defined as EPDS scores 12–30 .Venous blood samples were collected and prepared as described by Brann et al. . Sampleshttp://miolite2.iceht.forth.gr)  . After mt-test and Mann–Whitney U-test were applied for continuous variables as suited, whereas the χ2 test was applied for categorical variables. Statistical significance threshold was set at p < 0.05.Background characteristics were analyzed using the Statistical Package for the Social Sciences version 26. For univariate analyses, Student For primary analysis, hierarchical clustering (HCL), principal component analysis (PCA), and significance analysis for microarrays (SAM) algorithms were implemented in version 4.9 of the omics data analysis TM4/MeV software . AnalysiThe standardized RPA of a metabolite M in the profile j, SDRPAM depict, respectively, the RPA of metabolite M in profile j, the mean RPA of metabolite M, and its standard deviation in all profiles.where In SAM, the threshold of significance (δ) is selected as the largest for the false discovery rate (FDR) median to be < 10% or that corresponding to the smallest FDR median, if the latter is >10%, as specified in each case.Based on previous experience, to identify discriminatory metabolites in possible subgroups within the groups, sensitivity analyses  were carried out using SAM algorithms. Selection criteria for the significance threshold were the same as described for the primary analysis.Univariate analyses of background characteristics showed only a slight difference in the number of days from parturition until the day of blood sampling between the controls and women with PPDSs  .Of the 12 women who reported depressive symptoms according to the EPDS at 6 wpp, six  did not pass the 12-point threshold in the EPDS filled at 10 wpp. However, these women were still included in the PPDS group. Nevertheless, one woman with EPDS < 12 at 10 wpp (participant 26) did meet the criteria for ongoing depression at the MINI interview.The standardized metabolomic dataset  was analBased on the heat map, the rest of the PPDS samples, including samples 17, 10, 13, 18, 33, 26, 19, and 35, showed, in controversy to the first cluster, no significant differences in the abundance of the metabolites of the “olive green” cluster, but higher abundances in the “purple” cluster metabolites, compared to the controls (excluding participant 12). In addition, this PPDS sample group shows higher abundances in the “blue” (“fatty acid”) metabolite cluster, including cholesterol, linoleic acid, stearate, myristate, putative lauric acid, 2-hydroxybutanoic acid, and glycerol, and/or the “pink” cluster, including urea, erythritol, 4-hydroxybutanoic acid, and glucose, compared to the controls (excluding participant 12).PC1 correspond to high abundances of the “olive green” cluster metabolites combined with low abundances of the “purple” cluster metabolites. Positive values on PC2 correspond to high abundances of the “blue” (fatty acid) cluster metabolites combined with low abundances of “pink” cluster metabolites. Lastly, positive values on PC3 correspond mainly to low glucose and cholesterol combined with high abundances of threonate, ornithine/arginine, and the “light blue” cluster metabolites myo-inositol, 3-methylbenzoate and phenylalanine. Accordingly, negative values in the respective axes correspond to the opposite profile discussed for each axis above. The further a profile is from the PCA graph origin, the more it tends to be associated with a PPDS participant's sample.Taking into consideration the loads of the PC axes, the observations from the HCL analysis are supported by the position of the profiles in the PCA graph. Positive values on Multivariate significance analysis based on the SAM method of the complete set of the control and PPDS profiles indicated that the total abundance of the 38 metabolites included in the analysis is on average larger in the PPDSs than in the controls. Additionally, 18 metabolites were positively significant with no metabolite identified as negatively significant in the PPDS profiles compared to the control profiles, although there was a high number of false positives . The complete list of the 18 positively significant metabolites in decreasing order of significance is shown in Two sensitivity SAM analyses were performed, comparing separately the different PPDS clusters observed in the primary analysis. Excluding control sample 12, which, based on HCL, could have a physical condition not yet aware of, comparisons of (a) the PPDS subcluster of samples 2, 9, 16, and 34 with all controls  and (b) the rest of the PPDS samples with all the controls  were performed.In the SAM analysis 2A, at the largest significance threshold for which FDR median is < 10%, 26 of the 38 metabolites were identified as statistically different between the two groups (FDR-median = 9.72% or 2.5 metabolites). It is noted that in this analysis, 15 metabolites were identified as distinctly differential at FDR-median = 0%. Among the 26 metabolites, 17 were positively and 9 negatively significant in the PPDS subcluster compared to the controls (10 and 5 were identified in the respective groups at FDR-median = 0%). The significant metabolites, shown in In the SAM analysis 2B, where the rest of the PPDS samples were compared with all controls but sample 12, 14 positively and none negatively significant metabolites were identified (with FDR-median = 16.92% or 2.4 out of the 14 metabolites). The significant metabolites of 2B analysis are shown in Five metabolites, glycerol, threonine, 2-hydroxybutanoic acid, erythritol, and phenylalanine, were identified as positively significant in both sensitivity (2A and 2B) analyses and the overall primary comparison between PPDS and control sample profiles.Metabolomic analyses indicated discriminatory differences between the metabolic profiles of most controls and PPDS samples. However, there were distinct subclusters within the PPDS samples, which need to be taken into consideration if high-risk metabolic biomarkers for PPD are to be accurately identified. It appears that multiple different metabolic profiles are associated with PPDS subtypes, supporting the need to standardize PPD molecular phenotyping with respect to time of onset, time of profiling, and/or symptom subgroups, to enable accurate and sensitive diagnosis and biomarker detection. Although further validation in a larger cohort is necessary, our findings are supported by previous studies suggesting heterogeneity within PPD –54.The two sensitivity analyses suggested two distinct PPDS clusters, one with high abundance of amino acids, fatty acids, and glycerol–phospholipid metabolism intermediates, and low abundance of sugars and sugar acids, compared to the controls. Lower abundance of sugars combined with higher of BCAAs is commonly considered as a “favorable” metabolic profile. The combination of higher ornithine+arginine to urea ratio in this cluster of PPDS samples suggests an aberrant urea cycle compared to the controls . During The second group of PPDS samples included in the second sensitivity analysis shows what is considered a typical “unfavorable” metabolic profile, with higher levels of metabolites comprising mostly fatty and sugar acids. This type of profile is seen among individuals with metabolic syndrome , which hThe control participant, who presented a pathological metabolic profile, was excluded from the sensitivity analyses as a consequence of having a very diverse profile compared to the rest of the controls. However, we could not confirm any pathology recorded in her medical records. Along with the two metabolically different subgroups of PPDS samples, two “metabolically healthy” depression-positive cases  or at other location (6 wpp)], or whether the symptoms were mild and mostly resolved within 10 wpp. These findings highlight the importance of standardization of the time of diagnosis and sample collection.Five metabolites, glycerol, threonine, 2-hydroxybutanoic acid, erythritol, and phenylalanine, were identified as positively significant in both PPDS clusters and the overall comparison between PPDS and control profiles. These five were not included in neither the panel of metabolites previously identified by Lin et al.  nor the The strict inclusion criteria implemented in this study provide a homogenous, generally healthy (apart from depression) study group with no extremes concerning age or BMI. Analyses of background characteristics showed no differences between the controls and the PPDS group aside from days from parturition until blood collection, EPDS scores, and use of antidepressants, suggesting otherwise comparable study groups. Time of blood sample collection (10 wpp) is considered as a stable time period in terms of hormonal levels . As timeOur results further support multivariate statistical and data mining methods as a state-of-the-art approach to analyze the omic profiles of complex pathophysiologies, such as PPD , 80, andThere are some limitations to the current study. Because of strict inclusion criteria, the sample size was relatively small. Furthermore, sampling has been limited to older than average and more educated women. The generalizability of the conclusions requires broader sampling.In this exploratory metabolomics study, we were not able to define a unique metabolic profile of women with PPDSs. However, we identified two clusters of women within the PPDSs presenting different profiles. One cluster appeared to have altered kidney function, whereas the other showed a metabolic syndrome–related profile, both previously associated with depression. These findings need to be further validated in future larger studies. As depression is a heterogeneous diagnosis with different symptoms associated with different metabolic pathways, our results support the need to continue examining potential distinct patient groups within the PPD spectrum.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Regional Ethical Review Board of Uppsala, Sweden (Dnr 2009/171). The patients/participants provided their written informed consent to participate in this study.AS and MK conceptualized and designed the study. EB, CM, M-KI, AS, and MK performed the analyses and interpreted the results together with EF, FP, and GC. EB and HH were responsible for data acquisition from participants. EB, EF, AS, and MK wrote the draft of the manuscript. HH, CM, M-KI, FP, and GC revised the manuscript critically for important intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We report a previously healthy 82-year-old male with cryptococcal meningitis (CM) who represented neurological deterioration due to post-infectious inflammatory response syndrome (PIIRS) occurring in 4 months after initial antifungal therapy. He was treated with corticosteroids for 2 months and recovered clinically. However, the clinical manifestation, cerebrospinal fluid (CSF), and brain magnetic resonance imaging (MRI) results got worse again on the next day after corticosteroid withdrawal. The analysis of inflammatory cytokines and culture on CSF, as well as brain MRI, still suggested a diagnosis of PIIRS. Therefore, corticosteroid therapy was used again and he subsequently obtained a complete resolution of symptoms. Cryptococcal meningitis (CM) is the most common adult fungal meningitis in large parts of the world with high morbidity and mortality –3. An ex2O, protein of 0.85 g/l, glucose of 2.64 mmol/l, and white blood cell (WBC) counts of 60 × 106/l (with 30% neutrophils and 70% lymphocytes). Cerebrospinal fluid (CSF) India ink stain and culture were positive for Cryptococcus neoformans, and cryptococcal antigen titer (CRAG) in CSF was 1:2,560. Therefore, he was diagnosed with CM and treated immediately with amphotericin B deoxycholate plus 5-flucytosine. Due to the high intracranial pressure, a ventriculoperitoneal shunt (VPS) was placed on day 4 (note: day 1 represented admission day). After VPS, his CSF OP returned to 208 mmH2O and mental status improved (GCS score of 15). Three weeks after the initial antifungal therapy, his headache and neck stiffness disappeared, CSF culture was sterile, and CSF CRAG decreased to 1:160. Moreover, he was discharged with oral voriconazole and 5-flucytosine on day 26.An 82-year-old man sought treatment for a 1-month history of headache and a 1-day history of altered mental status. He had a 10-year history of hypertension with irregular medication and no histories of head trauma, or surgery. Moreover, he had no histories of contacting with pigeons and other birds. On admission, his temperature was 36.5°C. Physical examination showed drowsiness, Glasgow score of 12, neck stiffness, and positive Kernig’s sign. Furthermore, he did not have gait abnormalities, cranial nerve deficits, or visual or hearing deficits. Serum HIV antibody was negative. Lumbar puncture (LP) , glucose of 1.70 mmol/l, protein of 5.62 g/l, and CRAG of 1:40. CSF India ink stain and culture were negative for Cryptococcus neoformans. Chest CT was unremarkable. Brain MRI on day 123 revealed meningeal enhancement, and new lesions in the bilateral occipital lobe, insular lobe, hippocampus, and paraventricular appeared . LP (see Two months later (day 205), his methylprednisolone tablets reduced to 4 mg per day and he was asymptomatic, and the repeated brain MRI improved significantly . Repeated brain MRI (day 221) showed the lesions that disappeared after corticosteroid treatment reappeared (see Thirteen days later (day 219), he was readmitted to our hospital for intractable headache and fatigue. A repeated LP showed OP of 100 mmHTo the best of our knowledge, this is the oldest patient reported for CM-PIIRS. He developed PIIRS in 4 months after initial antifungal therapy. Then, he was treated with corticosteroids for 2 months and recovered clinically. However, the clinical manifestation, CSF, and brain MRI results got worse again on the next day after corticosteroid withdrawal. He received corticosteroids again and subsequently obtained a complete resolution of symptoms.PIIRS is defined as a deterioration in neurological status in a previously healthy patient with CM after CSF fungal culture converting to negative following optimal therapy , 8. UnliUS guidelines suggested that 0.5–1.0 mg/kg per day of prednisone equivalent and 2–6 weeks of corticosteroid treatment were a reasonable method for patients with severe CM-IRIS , while iOur case showed the CM-PIIRS patient who got worse in clinical manifestation and brain imaging again just one day after corticosteroid withdrawal. The phenomenon seen in our case was also similar to previous studies , 20. OneDue to the decline of immune function, the elderly individuals are often more susceptible to infectious diseases including central nervous system (CNS) infections –24. In aPIIRS is an important cause of poor outcome in CM patients. Therefore, it is very important to recognize and actively treat in these patients. Even in elderly patients, corticosteroid treatment is still beneficial. Moreover, 2 months of corticosteroid treatment may be not enough to treat CM-PIIRS.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The study involving human participants was reviewed and approved by the Medical Ethics Committee of the Third Affiliated Hospital of Sun Yat-sen University. Informed consent was obtained from the individual participant included in the study.YJ and FP were involved in the literature review, planning, and writing of the manuscript. JyL, JL, B-eQ, SY, AW, LY, ZS, and XX collected the data. YJ and FP were involved in the case identification, literature review, and planning and editing of the manuscript. YJ, FP, JyL, and JL were involved in the planning, writing, and editing of the manuscript. All authors contributed to the article and approved the submitted version.This work is supported by grants from the Natural Science Foundation of China (82071265) and Guangzhou Science and Technology Planning Project (202102010288).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: To explore the effects of anxiety and depression on the self-management ability and endogenous creatinine clearance rate of renal transplant patients.Method: Eighty-eight renal transplant recipients who were followed up in the outpatient clinic of the Affiliated Hospital of Zunyi Medical University were selected using convenient sampling. The self-made general data sheet, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and Self-Management Scale for Kidney Transplant Recipients were used. Correlation analysis was used to find factors related to endogenous creatinine clearance, while multiple linear regression was used to identify factors influencing endogenous creatinine clearance. Patients with or without anxiety and depression were divided into groups, and the indexes of the groups were compared using the independent samples t test, rank-sum test, or chi-squared test.Results: Anxiety was present in 12.5% of patients, depression in 25%, and a moderate level of self-management in 34.1%. Only 9.1% of renal transplant recipients had endogenous creatinine clearance within the normal range, and 34.1% had a body mass index not in the normal range . The endogenous creatinine clearance rate was negatively correlated with age and degree of depression, and positively correlated with body mass index, treatment management score, and psychosocial management score. The main influencing factors of endogenous creatinine clearance rate were age, sex, depression, body mass index, and treatment management score. The endogenous creatinine clearance rate and psychosocial management ability were significantly higher in patients without anxiety and depression than in patients with anxiety and depression .Conclusions: Anxiety and depression showed significant negative effects on the psychosocial self-management ability and endogenous creatinine clearance rate of renal transplant recipients and thus should be given more attention. Renal transplantation is currently recognized by the international medical community as the best treatment for patients with end-stage renal disease that can significantly improve survival and quality of life , 2. HoweThus, anxiety and depression can severely affect the recovery of renal function of renal transplant recipients, and adequate self-management is critical for renal survival and long-term quality of life of renal transplant recipients. To date, we have not found research on the relationship between anxiety, depression, self-management, and endogenous creatinine clearance in renal transplant recipients.This study therefore aimed to explore the correlations of anxiety and depression with self-management and endogenous creatinine clearance in renal transplant recipients. Our findings could faciliate future interventions to better improve postoperative quality of life and achieve optimal health outcomes in these recipients.Renal transplant recipients from the outpatient department of the Affiliated Hospital of Zunyi Medical University were selected using convenience sampling between June 2020 and December 2020. The inclusion criteria were as follows: patients who received their first allogeneic kidney transplant; age of ≥18 years; kidney transplantat time of ≥1 month; patients with communication and reading comprehension abilities. Patients with previous mental illness, patients who were taking antidepressants, patients who were experiencing other diseases affecting self-care, and patients with multiple organ transplants were excluded. All patients enrolled in this study volunteered to participate.General information: The general data sheet of kidney transplant recipients was designed by the researchers according to the purpose of the study and mainly included the patients' height, weight, marital status, educational level, occupation, economic status, payment method for treatment, and serum creatinine value.Anxiety level: We used the Self-rating Anxiety scale (SAS) (le (SAS) , which cDepression level: The Self-Rating Depression Scale (SDS) (le (SDS) , has 20 Self-management ability: We used the Self-Management for renal transplant recipients  = {[140 − age (years)] × body mass (kg)}/[0.818 × serum creatinine (Scr) (μ mol/L)], and the calculation result for women × 0.85. In adults, if the endogenous creatinine clearance rate is below 80 ml/min, the glomerular filtration function is decreased; reduced to 70~51 ml/min, mild damage; reduced to 50~31 ml/min, moderate damage; reduced to below 30 ml/minute, severe damage; reduced to 20~10 ml/min, early renal insufficiency; reduced to 10~5 ml/min, late renal insufficiency; and less than 5 ml/min, end-stage renal insufficiency. To obtain the BMI, the following equation is used: BMI = weight (kg)/(height × height) (m). According to the national standard for judging adult weight , BMI was divided into four groups: thin (BMI < 18.5), normal (18.5 ≤ BMI < 24), overweight (24 ≤ BMI < 28), and obese (BMI ≥ 28).This study was approved by the Ethics Committee of the Affiliated Hospital of Zunyi Medical University . Trained renal transplantation follow-up nurses conducted an on-the-spot questionnaire survey of renal transplant recipients who met the inclusion criteria. The patients were informed about the purpose and content of this study in an anonymous, confidential, and voluntary manner. The questionnaire was distributed on the spot and recycled on the spot. A total of 88 questionnaires were sent out, and all of them were collected (effective recovery rate of 100%).t-tests, Measurement data with a normal distribution were expressed as M , and the rank-sum test was used for intergroup comparison. The classified variables were expressed by frequency and percentage, and the chi-squared test was used for comparison between groups. The difference was statistically significant when P < 0.05. All statistical analyses were performed using SPSS 18.0 .Count data were expressed as frequencies and percentages, and measurement data as means and standard deviations. Rank variables were analyzed with Spearman's correlation analysis, and continuous variables with Pearson's correlation analysis. We analyzed factors related to endogenous creatinine clearance using multiple linear regression to identify the factors influencing endogenous creatinine clearance. At the same time, differences in the endogenous creatinine clearance rate and self-management ability between the anxiety non-anxiety groups, and between depression and non-depression groups were compared. Measurement data with a normal distribution were compared using the independent samples A total of 88 participants were enrolled in this study. The SAS, SDS, and self-management ability scale scores of the renal transplant patients indicated the following: 11 (12.5%) participants experienced anxiety [10 (11.4%) with mild anxiety and 1 (1.1%) with moderate anxiety] and 22 (25%) experienced depression [16 (18.2%) with mild depression and 6 (6.8%) with moderate depression]. Furthermore, there were 30 (34.1%) participants with a medium level of self-management. The self-management scores for diet, treatment, physical activity, and social psychology were 3.36 ± 0.42, 3.56 ± 0.32, 3.31 ± 0.42, and 3.10 ± 0.49, respectively. The specific scores of each scale are shown in The average endogenous creatinine clearance rate of the included patients was 64.79 ± 22.55, among which, only 8 (9.1%) patients had normal creatinine clearance rate, 12 (13.6%) had CCR < 80 ml/min, 35 (39.8%) had CCR = 50–70 ml/min, 30 (34.1%) had CCR = 31–50 ml/min, and 3 (3.4%) had CCR < 30 ml/min. The average BMI was 21.96 ± 3.13, in which 58 (65.9%) patients had a body weight within the normal range. Among the patients, 22 (25%) were overweight, of whom 2 (2.2%) were obese. There were 8 (9.1%) patients who were underweight.The results of the correlation analysis showed that there was no correlation between endogenous creatinine clearance and degree of anxiety in patients. Endogenous creatinine clearance was negatively correlated with age and degree of depression, and positively correlated with body mass index, treatment management score, and psychosocial management score. The point-two-column correlation coefficient with sex was −0.255 .Endogenous creatinine clearance was taken as the dependent variable, and six statistically significant variables  in the correlation analysis and univariate analysis were taken as independent variables. The results of the multiple linear regression analysis showed that age, sex, depression, body mass index, and treatment management scores were the main influencing factors of endogenous creatinine clearance which accounted for 33.3% of the total variation .t-test, we found that the age and body mass index of patients with anxiety and depression were higher than those without anxiety and depression; however, the difference was not statistically significant (P > 0.05). The endogenous creatinine clearance rate in the anxiety and depression groups was significantly lower than that in the non-anxiety group and depression groups, and the difference was statistically significant (P < 0.05) ((P < 0.05). Sex, payment method for treatment, educational level, and monthly income were expressed in terms of frequency and percentage. When the groups were compared using the chi-square test, the results showed that the proportion of patients with high school education and above in the non-anxiety group (71.3%) was significantly higher than that in the anxiety group (36.2%), and the proportion of patients with health insurance payments in the non-anxiety group (94.8%) was significantly higher than that in the anxiety group (72.7%). The proportion of patients with high school education and above in the non-depression group (75.7%) was significantly higher than that in the depression group (40.8%), and the difference was statistically significant   . The tot < 0.05) .Studies have confirmed that after organ transplantation, 20–60% of recipients experience anxiety, depression, or psychosocial pain . In our Our research showed that both anxiety and depression could lead to a significant decrease in the patients' self-management ability, especially in the psychosocial aspect. In our study, 34.1% of the renal transplant recipients had a medium level of self-management, and among the four dimensions of self management, psychosocial management scored the lowest. This finding is consistent with the results of Xie et al. . PsycholIn this study, we analyzed the general data of patients and the relationships of anxiety and depression with self-management ability and endogenous creatinine clearance. We found that endogenous creatinine clearance was negatively correlated with age and degree of depression and positively correlated with body mass index, treatment management score and psychosocial management score, but it showed no correlation with the degree of anxiety of the patient. In other words, the higher the degree of depression, the lower the endogenous creatinine clearance rate, but the higher the level of self-management in treatment and psychosocial aspects, the higher the endogenous creatinine clearance rate.We further analyzed the factors affecting the endogenous creatinine clearance rate and found that sex, age, body mass index, treatment management ability, and depression were the main influencing factors of endogenous creatinine clearance, which could explain 33.3% of the total variation. Although age and sex are factors that we cannot modify, we can guide patients to maintain a good body mass index through reasonable diet and exercise, and improve their physical function .Aside from the same influencing factors found in our and previous studies, self-management ability and depression were also independent influencing factors of endogenous creatinine clearance found in this study. The self-management of treatment among renal transplant recipients mainly includes taking drugs according to doctor's advice, getting used to the effects and side effects of the drugs, self-monitoring body temperature, blood pressure, and urine volume, and paying regular revisit to the docyor . The levCreatinine clearance is the most important index for evaluating renal function. To our knowledge, this study is the first to analyze the correlations of anxiety and depression with self-management and creatinine clearance in renal transplant recipients. We compared the general data, endogenous creatinine clearance rate, and self-management ability of patients with or without anxiety and depression, and found that patients with a higher educational level and health insurance payment support had a lower incidence of anxiety and depression. Patients without anxiety or depression had a higher psychosocial management ability and higher endogenous creatinine clearance. These findings suggests that for patients with a lower level of education, we should adopt health education and communication methods that are easier and more acceptable to them, and strengthen their knowledge and understanding of renal transplantation and self-management. As mentioned by Schmid-Mohler et al. , health t-tests were used, potential confounding of age and gender on the association of pyschological factors and clearance cannot be determined. Nevertheless, the findings of this study have an important practical significance because they showed the negative effects of anxiety and depression on self-management, and the negative effects of depression on creatinine clearance. Therefore, we should screen renal transplant recipients for anxiety and depression and comprehensively evaluate factors such as the patient's age, cultural background, socioeconomic status, and family relationships before surgery. A psychological service team with a professional knowledge of transplantation should be established to provide more-comprehensive health management services for transplant patients.Our study has some limitations. We only investigated renal transplant recipients in one hospital, and the sample size was limited. This setup may not provide a complete picture of the correlations of anxiety and depression with self-management and creatinine clearance in renal transplant recipients. Another limitation is that because The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of Affiliated Hospital of Zunyi Medical University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The Education Department Fund Project of Guizhou Province, Grant No. KY (2017) 045.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Vaccination is an essential intervention to curb the coronavirus disease 2019 (COVID-19) pandemic. This review aimed to estimate the pooled proportion of COVID-19 vaccine acceptance worldwide.A systematic search of the MEDLINE (PubMed) database using “COVID-19,” “vaccine” and “acceptance” to obtain original research articles published between 2020 and July 2021. Only studies with full text and that were published in English were included. The Joanna Briggs Institute meta-analysis was used to assess the data quality. The meta-analysis was performed using generic inverse variance with a random-effects model using the Review Manager software.A total of 172 studies across 50 countries worldwide were included. Subgroup analyses were performed with regard to vaccine acceptance, regions, population, gender, vaccine effectiveness, and survey time. The pooled proportion of COVID-19 vaccine acceptance was 61% . It was higher in Southeast Asia, among healthcare workers, in males, for vaccines with 95% effectiveness, and during the first survey.COVID-19 vaccine acceptance needs to be increased to achieve herd immunity to protect the population from the disease. It is crucial to enhance public awareness of COVID-19 vaccination and improve access to vaccines.PROSPERO 2021, identifier CRD42021268645. The coronavirus disease 2019 (COVID-19) pandemic is a global health topic of concern. As of August 2021, nearly 216 million COVID-19 cases have been reported globally, with the cumulative number of deaths being just under 4.5 million  guidelines  were folThe criteria for inclusion include studies that report the proportion of COVID-19 vaccination acceptance. The acceptance of the vaccines included studies before or after the availability of COVID-19 vaccines. All types of COVID-19 vaccines were included in this review. Studies with cross-sectional, case-control, and cohort designs published in English from 2020 to 19 July 2021 were included. Case series/reports, conference papers, proceedings, articles available only in abstract form, editorial reviews, letters of communications, commentaries, systematic reviews, and qualitative studies were excluded. Articles in languages other than English were also be excluded.A systematic search was performed in the MEDLINE (PubMed) database for articles between 1 January 2020 and 19 July 2021.The search was done using the generic free-text search terms “COVID-19” AND “vaccine” AND “acceptance.” All studies published from 2020 to 19 July 2021 were retrieved to assess their eligibility for inclusion in this study. The search was restricted to full-text only and English language articles. To find additional potentially eligible studies, reference lists of included citations were cross-checked.All records identified by our search strategy were exported to EndNote software. Duplicate articles were removed from the list. One independent reviewer screened the titles and abstracts of the identified articles. The full texts of eligible studies were obtained and read thoroughly to assess their suitability. The second reviewer validated the records. A third reviewer was consulted in the event of a conflict between the two reviewers. The search method was presented in the PRISMA flow chart showing the included studies and excluded with reasons for exclusion.The data was extracted into Microsoft Excel . The data included the first author, year of publication, study location, study design, setting, study population, sample size, proportion, and data to calculate effect estimates.Assessment of critical appraisal for data quality was assessed using the Joanna Briggs Institute (J.B.I.). Meta-Analysis for cross-sectional, case-control, and cohort studies . Two autThe proportion of vaccines acceptance was reported in pooled estimate proportion with a 95% confidence interval. Terminology of vaccines acceptance refers to the willingness to be vaccinated, vaccines acceptability, desirability, demand, and positive attitudes toward the given vaccines.I2 statistic and used the guide as outlined: 0% to 40% might not be important; 30 to 60% may represent moderate heterogeneity; 50 to 90% may represent substantial heterogeneity; and 75 to 100% would be considerable heterogeneity  software . A generogeneity . SubgrouThe risk of bias was assessed by nine criteria : (1) appThe criteria of the risk assessment were represented by “yes,” “no,” “unclear” or “not available.” The score for yes was one (1) and zero (0) for the rest. The risk of bias was considered low when the total score was more than 70%, moderate when 50–69%, and high when up to 0–49% .The primary search through the database had identified 678 studies. One duplicated study was removed, and 677 studies were screened for the titles and the abstracts. A total of 466 studies were excluded, and 211 full-text articles were assessed for eligibility. Thirty-nine studies were excluded for systematic review articles, out of interest outcomes, not research articles, and qualitative study articles. As a result, a total of 172 studies that met the inclusion and exclusion criteria were included for the review and meta-analysis .n = 18) and in 2021 (n = 154). The studies involved 814,691 participants from 50 countries across six regions in the world represented as African region (n = 14) (n = 34) (n = 33) (n = 46) (n = 8) (n = 31) (The articles of included studies were published in 2020 ((n = 14) –30, Amer(n = 34) , 31–63, (n = 33) –95, Euro(n = 46) –141, Sou (n = 8) –148 and (n = 31) –179. The(n = 31) , 181, on(n = 31) , one stu(n = 31) , one stu(n = 31)  and one (n = 31) .n = 140), cohort studies (n = 4), descriptive studies (n = 23), longitudinal studies (n = 4) and combination of cross-sectional and longitudinal study (n = 1). A total of 28 studies applied probability sampling , 54 studies applied non-probability sampling , and 90 studies did not provide the sampling method , population , gender, vaccines effectiveness (at 90 and 95%), and survey time.The J.B.I. quality assessment showed that 60 studies were at low risk of bias, 47 studies were at moderate bias, and 65 studies were at high risk of bias . All theIn By subgroup analyses, the total proportion by regions was [0.62 ] pooled from 165 studies, and the region with the highest proportion of COVID-19 vaccines acceptance was in South-East Asia [0.74 ] which pooled from nine studies and the lowest vaccines acceptance was in Eastern Mediterranean [0.52 ]. The total proportion by population was pooled from 170 studies [0.61 ]. Population comparison showed that the proportion of COVID-19 vaccines acceptance was similar, which range 0.61 to 0.63 among college students, general adults, healthcare workers, and high-risk populations. However, the population of parents and caregivers was the lowest in the proportion of COVID-19 vaccines acceptance [0.52 ].The pooled proportion of COVID-19 vaccines acceptance by gender from 89 studies was [0.60 ] and was higher in male [0.64 ] compared to female [0.57 ]. The 95% vaccines effectiveness showed higher in proportion of COVID-19 vaccines acceptance [0.77 ] compared to 90% of vaccines effective [0.62 ] with the total proportion by vaccines effectiveness was [0.71 ] from six studies. The total pooled proportion from seven studies by survey time was 0.65 . The proportion of COVID-19 vaccines acceptance was reduced in the second survey [0.62 ] compared to the first survey [0.68 ]. In China and Australia, the surveys were repeated based on two epidemic phases, namely severe epidemic phase and well-contained phase , 172. A I2 > 99%). The heterogeneity of subgroups differences showed that the acceptance of the vaccine was with considerable heterogeneity; substantial heterogeneity for regions, moderate heterogeneity for gender and vaccines effectiveness. Heterogeneity might not be important for population and survey time . This finding was lower compared to a previous estimate of COVID-19 vaccine acceptance [73.31% ], which involved 38 studies across 36 countries with limited data from low-income countries . ConcernThe pooled proportion of COVID-19 vaccine acceptance among regions ranged from 52 to 74%, with Southeast Asia the highest and the Eastern Mediterranean the lowest. This result was supported by a review that reported vaccine acceptance of over 90% in Southeast Asia and the lowest proportions of acceptance in Middle East countries, with < 30% in Kuwait and Jordan . The lowVaccination acceptance was also higher in males than in females, which is in line with other reviews , 189. ItThe pooled proportion of COVID-19 vaccine acceptance for the population groups varied from 52 to 63%. Unsurprisingly, healthcare workers showed the highest proportion of vaccine acceptance. Since healthcare workers were among the first to receive COVID-19 vaccines, their attitude or perception toward COVID-19 vaccines would affect the other population's decisions to recommend the vaccination to friends, families, and their patients . SimilarThe decision to accept COVID-19 vaccination was also influenced by vaccine effectiveness ; this reThe time during which the survey was conducted showed that the acceptance of the COVID-19 vaccine changed over time. All the studies showed evidence that the COVID-19 vaccine acceptance changed over time. The proportion of vaccine acceptance was reduced in the second survey. A global review of vaccine acceptance also showed a similar pattern. In a review, countries such as France, Italy, and China established a decreased proportion of vaccine acceptance in their second and third surveys.Conversely, the United States showed an increased pattern of vaccine acceptance in the second and third surveys. The situation was different in the United Kingdom, which showed that the proportion was high in the first survey, increased further in the second survey, and then decreased for the third and fourth surveys before increasing again in the fifth survey. Still, in the fifth survey, the proportion of vaccine acceptance was not as high as in the first survey . It has Media and public service messaging, particularly fear appraisal-framed public service messages compared to safety benefits public service messages, influence willingness to obtain the COVID-19 vaccine. However, conspiracy theories circulated in the media by vaccination-averse people about vaccine side effects impact people's decision to get vaccinated . The hesThe search was limited to articles published in English only due to limited time, human, and financial resources to translate works published in other languages; this may have limited this review's generalizability. To have a more comprehensive assessment of the data, the authors decided to include all the available studies regardless of whether the quality of the data was low, moderate, or high, based on the assessment of the risk of bias. Furthermore, most of the research studies included in this review were cross-sectional studies, which can be thought of as visuals of vaccine hesitancy status in each country/region. They have different sampling strategies, which may explain some of the differences in vaccine acceptance rates reported in different studies from the same country. As a result, the findings should be regarded with caution, as they are unable to forecast future changes in vaccine acceptance rates. The other limitation was the sole dependence on the MEDLINE (PubMed) database in the search study. MEDLINE was reported as the best single source for retrieval of a systematic review, with an 89.7% inclusion rate that provided free-of-charge and open-access articles . HoweverThe rate of COVID-19 vaccine acceptance varied by region, population type, gender, vaccine effectiveness, and survey time, with an overall pooled proportion of 61%. A high level of acceptance of vaccination is required to achieve herd immunity for the disease. Many vaccination campaigns and programs are available globally to enhance public awareness to access and accept the COVID-19 vaccine to reach herd immunity and control the pandemic.The original contributions presented in the study are included in the article/RCY and MNN: conceptualization, methodology, and validation. RCY: software, formal analysis, data curation, and writing—original draft preparation. MNN and RCY: writing—review and editing. MNN and YMA: visualization and supervision. All authors have read and agreed to the published version of the 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.