COVID-19 vaccinations and their side effects: a scoping systematic review

Introduction

COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was initially detected in Wuhan, China, in December 2019. As of 18 August 2024, there have been 776 million confirmed cases worldwide, with 3.0 million deaths (WHO 2024). It belongs to the same group of ribonucleic acid (RNA) viruses that cause Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) (Mahendra 2020). Corona-viruses are a large family of viruses that infect many different species, including humans. In humans, the coronavirus can cause a variety of diseases, from minor respiratory tract infections like the common cold to fatal infections (Weiss & Navas-Martin 2005).

The virus might be transferred by close touch or simply droplets, between people, when the mucosal membranes of healthy individuals are exposed to secretions generated by the carriers (Sharma 2020). Symptoms of COVID-19 might vary from person to person. Some of them may exhibit no signs or symptoms of infection, such as breathing difficulties, or they may succumb to the sickness (Sahin 2020).

Even though several therapeutic compounds and medications have been proposed and reused in the battle against COVID-19, they have remained supportive therapy choices; however, vaccines remain the most efficient and effective way to protect people from this disease (Tavilani et al. 2021).

The development of vaccinations has made significant advances; the first mass vaccination program started in early December 2020 in Europe, with priority given to individuals who are at high risk of severe COVID-19 infection, such as the elderly, and those who are at high risk of viral exposure and transmission, such as front-line medical staff (Paules et al. 2020). 7,952,750,402 vaccine doses have been provided globally through December 6, 2021 (WHO 2021c).

However, no vaccine is entirely free from complications or adverse reactions. Any vaccination can have early adverse reactions, including local ones like pain, swelling, and redness, as well as systemic ones like headache, chills, nausea, fatigue, myalgia, and fever (Al Khames et al. 2021). Following the SARS-CoV-2 vaccination, there have been several recorded occurrences of side effects; in addition, there have been a small number of deaths (Varsavsky 2021). This has been recorded with COVID-19 vaccinations, and it has been observed in people with pre-existing health conditions like diabetes and high blood pressure, as well as people who have had allergic reactions to the vaccine. The extent to which they are linked to vaccines, however, is unknown and under investigation (Hussien 2019).

In this systematic review, we aim to make reference to the wide range of possible reactions that can occur after vaccinations, so that healthcare providers can better understand these patients. The purpose of this scoping systematic review is to summarize and integrate the results of studies on the side effects of the COVID-19 vaccination and then determine the gaps in these studies. This paper is organized in the following manner: Section 1 is an introduction to COVID-19 viruses and vaccination, Section 2 is Background, section 3 is the methods, Section 4 is a review of the Conducted Studies, Section 5 the results, section 6 discusses the results & gaps in the literature studies, section 7 concludes the most important points of this paper and section 8 represent study strengths and limitations.

Background

Methods

The PRISMA guidelines for systematic reviews and meta-analyses were followed in this research (Moher et al. & PRISMA Group*. 2009). A structured and transparent approach was implemented to identify, select, and synthesize relevant studies on the side effects of COVID-19 vaccines.

Information sources

We searched through the databases of IEEE Xplore, ScienceDirect, the New England Journal of Medicine, Google Scholar, and PubMed to find studies about COVID-19 and the side effects of COVID-19 vaccinations. from 2019 to 2022 to select eligible research publications. The searches were performed without time filters, and backward snowballing was used to find articles that weren’t found in the initial search by screening relevant studies and their references (Figure 4). These databases had been selected based on several collected journals & conferences about emerging topics, including the Coronavirus disease (COVID-19) and the side effects related to the COVID-19 vaccine.

Search strategy

Our keyword search will be based on the following combination of Medical Subject Headings: (COVID-19 OR SARS-CoV-2 OR 2019-nCoV OR coronavirus OR MERS-CoV OR SARS-CoV) AND (Vaccines OR Vaccination OR COVID-19 vaccine OR SARS-CoV-2 vaccine OR MERS-CoV vaccine OR mRNA vaccine OR Moderna vaccine OR Pfizer-BioNTech COVID-19 vaccine OR mRNA-1273 vaccine OR ChAdOx1covid-19 vaccine OR AZ1222 covid-19 vaccine OR Johnson & Johnson covid-19 vaccination OR Ad26 covid-19 vaccine OR BIBP-CorV vaccine OR BIBP vaccine OR CDC-approved COVID-19 vaccines OR Sinopharm vaccine OR AstraZeneca-Oxford vaccine OR BNT162b2 COVID-19 Vaccine) AND (Toxicity OR harmful impact OR side effects OR adverse events OR negative reactions) as shown in Table 2.

Classification of research articles

This section classifies articles according to criteria such as the year of publication and publishing house or journal. Figure 1 below shows the trend of article publications in various databases (i.e., IEEE Xplore, ScienceDirect, the New England Journal of Medicine, Google Scholar, and PubMed) from 2019 to 2022. Annual increases in publication rates are observed. Therefore, COVID-19 vaccines have in recent years gained increasing interest among researchers. Thus, further studies are expected to be conducted in the future.

Figure 1. Trends in publication among the five databases.

Figure 2 illustrates how research articles are distributed based on their orientation: survey or review papers, learning-based studies, and statistical and analytical studies. It is noticeable that a large portion of the papers is statistical since our paper attempts to investigate the side effects of vaccines. In the systematic literature review, there are three categories of research studies: survey and review studies, studies that apply machine learning, and studies that use statistics and analytical methods. The New England Journal of Medicine has published 14 articles in the statistics and analytical methods category. IEEE has published 12 articles. Two of them are survey and review studies, and the other 10 are about statistics and analytical methods. In ScienceDirect 11 articles have been published as follows: survey and review studies (3), statistics & analytical studies (8). In Google Scholar and PubMed, 19 articles have been published as follows: survey and review studies (3), machine learning studies (4), and statistics and analytical studies (12).

Figure 2. Articles in the different categories of published journals.

Review of the conducted studies

To gain a better understanding of COVID-19 vaccines and predict and analyze their side effects, several studies were conducted between 2020 and 2021. We highlight a few of these studies in this section, which presents the categories of relevant research papers based on their classification (see Figure 4).

Figure 3. Flow diagram of the search for eligible studies on the side effects, safety, and toxicity of the COVID-19 vaccine.

Figure 4. Methods of determining the side effects of COVID-19 Vaccines.

Prediction of the COVID-19 vaccine that is associated with a higher percentage of side effects using machine learning methods In (Abdulrahman et al. 2021) demonstrate how the clustering techniques utilized in the instance of COVID-19 vaccine side effects datasets help to give accuracy for clustering the COVID-19 vaccine side effects datasets. Using the WEKA tool, this paper compared four clustering techniques. It also describes the datasets in terms of multiple-precision factors, cluster case, number of iterations, and time, the findings of these algorithms, the clustering methods employed, and their accuracy. The clustering algorithm k-means was discovered to be frequently used in several types of COVID-19 vaccine side effects datasets with great accuracy.

Prediction of side effects associated with the COVID-19 vaccines and their severity using machine learning methods In (Ahamad 2020) the authors aim to categorize and define patients at risk of such responses using patient data and discover probable common reasons for such side effects to find treatments that lower patient risk. They examined patient medical records and data on the impacts and consequences of immunization. The data was analyzed using a collection of machine learning (ML) classification methods. In most cases, similar traits were shown to be closely connected to negative patient reactions. They included prior infections, hospitalizations, and SARS-CoV-2 reinfection. Medical history-based ML classifiers also could determine which patients were most likely to receive a vaccination with no side effects reliably. In (Hatmal et al. 2021) the authors evaluated the side effects and perceptions of the COVID-19 vaccines in Jordan. An online poll was distributed to Jordanians who had received any COVID-19 vaccines as part of a cross-sectional investigation. Data were statistically examined, and machine learning (ML) algorithms were utilized to predict the severity of side effects. Despite significant differences in the presence and severity of side effects among these vaccines, statistical analysis revealed that they provide comparable protection against COVID-19 infection. The current paper confirmed that the CDC-approved COVID-19 vaccines are safe and that vaccination makes people feel safer. However, severe cases may necessitate additional medical care or perhaps hospitalization.

Table 3 compares the results of studies based on machine learning techniques about the COVID-19 side effects. Evaluation of Machine Learning Models Eq. (1) was used to evaluate ML models by calculating their accuracies (Grandini et al. 2020).

A variety of statistical methods have been used to assess the side effects after vaccinations (Jayadevan 2021) aim to evaluate the initial reaction to the COVID-19 vaccine’s first dosage and to investigate the range of post-vaccination symptom profiles for different vaccinations. A cross-sectional online survey was conducted in India that included questions about the immediate post-vaccination experience. Over a week, from January 29 to February 4, 5396 persons replied to the poll. Overall, 65.9% of respondents said they had had one post-vaccination symptom. 79% of those who reported symptoms did so within the first 12 hours. 472 people reported COVID-19 out of 5396 (or 8.7%). Their symptom profile was similar to those who had no prior experience. In (El-Shitany 2021) the authors obtained their data using a Google Form questionnaire (online survey). The results were based on the responses of 455 people, all of whom live in Saudi Arabia. After the first and second doses, the vaccine’s side effects were documented. The most common complaints were injection site pain, headaches, flu-like symptoms, fever, and tiredness. Fast heartbeat, generalized aches, difficulty breathing, joint discomfort, cold, and exhaustion whereas some of the less common side effects. Lymph node enlargement and pain, as well as Bell’s palsy, are uncommon side effects. Recipients who had previously been infected reported more difficulty breathing than those who had never been infected with the coronavirus.

Zahid (2021) looked into the most common side effects associated with these four vaccines’ first and second doses. 311 people who had two doses of one of these four vaccinations completed an online questionnaire, which was used to collect data. The findings of this paper demonstrated that the second dose of the vaccine caused higher side effects, independent of the vaccine’s identification. Overall, vaccination recipients (Sinopharm) experienced the fewest side effects among the four vaccines examined. The most important conclusion of the paper is that the post-vaccination side effects of the first and second doses were modest and predictable, with no hospitalizations; this information can help reduce vaccine fear.

As for comparing the side effects of the COVID-19 vaccines (Andrzejczak-Grządko et al. 2021) compared the AstraZeneca and Pfizer vaccines’ side effects. The survey results suggest that side effects from the AstraZeneca vaccine’s first dose are more common than those from the Pfizer vaccine’s first and second doses. In this survey, most respondents reported at least one side effect after receiving the AstraZeneca and Pfizer vaccines, but these reactions were less common after receiving the Pfizer vaccine. A survey was made available on the internet. It was done on patients who had been immunized with Pfizer or AstraZeneca vaccines. The respondents were asked about the side effects of the vaccines after the first and second doses. In (Almufty et al. 2021) the authors highlighted probable side effects from covid19 vaccines, a comparison of the three COVID-19 vaccines now available in Iraq, and risk factors for severe side effects (Sinopharm, AstraZeneca-Oxford, and Pfizer- BioNTech). A standardized questionnaire platform was used to collect information about the Iraqi people. The majority of the symptoms ranged from mild to moderate in severity. With P values less than 0.0001, both residencies in Iraq’s Kurdistan Region and the AstraZeneca vaccine were statistically significant risk factors for experiencing severe symptoms.

In regards to young age groups and side effects Alamer et al. (2021) looked into the early side effects of the Pfizer-BioNTech (BNT162b2) mRNA vaccine in Saudi Arabian youngsters aged 12 to 18. A cross-sectional study using a self-administered online survey was done to examine the side effects in children in this age range after receiving one or two doses of the Pfizer-BioNTech (BNT162b2) mRNA vaccine. After vaccination, general and demographic information was acquired, and vaccine-related side effects were examined.

As the safety assessment of the COVID-19 vaccines is necessary, in Dziedzic et al. (2021). The goal was to see if the ChAdOx1 n-COV-19 vaccine was safe in terms of systemic and local side effects on patients 48 hours after injection. This paper report has three (3) particular aims. First, the paper report assesses and analyzes the safety of the first and second doses of the ChAdOx1 n-COV-19 vaccinations 48 hours after administration. Second, the paper examines the side effects of the ChAdOx1 n-COV-19 vaccination among people younger than 40 years and people older than 40 years following delivery over a two-day (48-hour) period to evaluate and compare the vaccine’s safety by age and sex.

To analyze the side effects from different aspects in Azimi et al. (2021), the authors aimed to determine the frequency, intensity, and degree of side effects linked with the COVID-19 vaccination (ChAdOx1 nCoV-19 vaccine or AstraZeneca) among Kabul University of Medical Sciences employees. A retrospective observational, interview-based study was undertaken among the Kabul University of Medical Science’s faculty and instructors in Kabul, Afghanistan, from April 4 to April 20, 2021, to examine the COVID-19 vaccine’s side responses (ChAdOx1 nCoV-19 vaccine or AstraZeneca). Participants were questioned after the first AstraZeneca vaccination dosage was given out. They were instructed to report any negative reactions to the vaccination within 8–10 days of getting it. Klugar et al. (2021) aimed to assess the post-vaccination side effects of the various vaccines approved in Germany. An online questionnaire that has been validated and evaluated for a priori dependability was used in a cross-sectional survey. Demographic information, medical and COVID-19-related anamneses, and local, systemic, oral, and skin-related side effects following COVID-19 immunization were all asked about in the survey. Additionally, (Riad et al. 2021) conducted a cross-sectional survey-based study in the Czech Republic to gather data on the COVID-19 vaccine’s side effects among healthcare workers. The researchers used a validated questionnaire containing twenty-eight multiple-choice items about demographics, medical anamneses, COVID-19-related, and general, oral, and skin-related side effects. The most often used drugs with side effects were antihistamines, demanding a greater investigation. Overall, people who took two doses experienced more side effects. The manufacturer’s figures matched the distribution of side effects among Czech healthcare personnel, especially their link with younger age groups and the second dosage.

Also, Kitagawa et al. (2022) conducted an online survey of people who had self-reported side effects after receiving two doses of BNT162b2 or mRNA-1273 immunization. The incidence of adverse effects was investigated after each dose of vaccination. The incidence of side effects following the second dose of the BNT162b2 and mRNA-1273 vaccines was compared using propensity score matching.

To examine the duration of side effects’ appearances, a study conducted by Alhazmi et al. (2021) aimed to see how long it took for post-vaccination adverse effects to appear. An online questionnaire was used to perform cross-sectional, retrospective research among COVID-19 immunization participants in Saudi Arabia. General and demographic data were collected after at least one immunization dose, and vaccine-related side effects were examined. The side effects described by their paper participants after receiving the Oxford-AstraZeneca and Pfizer-BioNTech vaccines are similar to those reported in clinical trials, showing that both vaccines have safe profiles.

In terms of reducing vaccine hesitancy Saeed et al. (2021) aimed to gather data on Sinopharm’s COVID-19 vaccine’s side effects. Between January and April 2021, a cross-sectional survey paper was done to gather data on the effects of the COVID-19 vaccine among UAE residents. The response of persons who refused to take the COVID-19 vaccine was reported, as demographic data, vaccination, and the reasons people did not want to take the COVID-19 vaccine. The post-vaccination side effects of the first and second doses were modest and predictable, with no hospitalizations; this knowledge can assist in reducing vaccine fear. Moreover, Kadali et al. (2021) looked at the side effects of the mRNA 1273 vaccine by going over all of the organ systems in depth an impartial online survey tool was used in a randomized, cross-sectional investigation to collect responses from HCWs. The bulk of the symptoms did not appear to be life-threatening. This vaccination appears to have a better level of acceptability, despite the wide variety of self-reported effects.

Results

According to the search strategy, 391 papers were identified. A total of 170 papers were screened for eligibility by full-text review after titles and abstracts were screened. Following a thorough full-text screening, 114 papers were deemed unacceptable for the reasons listed in (Figure 3). The remaining 17 papers (Table 5) were included in this scoping systematic review as they fulfilled the criteria specified. The majority of studies were designed as randomized cross-sectional studies (n = 2), survey-based studies (n = 3), retrospective cross-sectional studies (n = 5), cross-sectional studies (n = 5), and research article studies (n = 2) (Figure 5A).

Figure 5. A: The types of research studies that were evaluated. B: The incidence and severity of post-vaccination symptoms with age. C: Post-vaccination symptoms among males vs. females. D: Comparison of the side effects and it can be seen that injection site pain ranked highest in side effects, followed by tiredness.

The final analysis of the studies, included 38680 individuals who experienced at least 1 or more side effects were involved from twelve countries representing three regions of the world, representing as North America (n = 1), South & Western Asia (n = 9), and Central Eastern European region (n=2). A detailed description of the studies (Abdulrahman et al. 2021; Ahamad, 2020; Ma’mon, 2021; Grandini et al. 2020; Jayadevan, 2021; El-Shitany, 2021; Zahid, 2021; Andrzejczak-Grządko et al. 2021; Almufty et al. 2021; Alamer et al. 2021; Dziedzic et al. 2021; Azimi et al. 2021; Klugar et al. 2021; Riad et al. 2021; Kitagawa et al. 2022; Alhazmi et al. 2021; Saeed et al. 2021; Kadali et al. 2021) is provided in Table 5. Among the Vaccine platforms included in the systematic review were DNA (2), inactivated (2), and mRNA (2). There were seven (7) studies in which healthcare workers were the study population, while twelve (12) studies featured a majority of female participants. Among the cases reported, most side effects were reported in women and age groups between 20 and 30 (Figure 5B & C). The max number of participants in Kitagawa’s study was around 12109 and the min number of participants in Dziedzic’s study was only 247 participants. Participants in the studies were all adults and adolescents aged 18 or older. Except for Alamer’s study, participants were between 12 and 18 years old (Table 5).

Oral and skin side effects

A total of 533 cases of oral and skin side effects have been reported in three studies following vaccination with COVID-19. The most common oral side effects were vesicles (6.3%), bleeding gingiva (4.3%), oral paraesthesia (2.2%), dysgeusia (2.4%), blisters (36%), and halitosis (25.4%) (Figure 6). While rash and urticaria (other than at the site of the injection) were the most reported skin-related side effects (Figure 7). Three-fourths (75.1%) of the oral side effects appeared within the first week following vaccination. The most affected sites for skin-related side effects were the upper limb, face, chest (trunk), lower limb, and back.

Figure 6. The most commonly reported oral side effects.

Figure 7. The most commonly reported skin-related side effects.

Factors associated with side effects of COVID-19 vaccines

The association between patients’ medical histories and side effects was only looked at in some studies (Ahamad 2020).

According to the results, patient medical histories are strongly correlated with the incidence of side effects, some of which can be severe and even fatal. Patients with advanced age (71.47 years for deceased patients and 62.49 years for hospitalized patients), allergic conditions (19.53%), and those taking other medications (46.76%) are most likely to experience side effects after vaccination, as well as those with a history of type II diabetes (3.75%), heart disease (2.08%), hypertension (4.59%), or COVID-19 infection. Also, the study found that severe reactions are mostly associated with symptoms such as hospitalization duration, headache, dyspnea (shortness of breath), fever/pyrexia, chills, fatigue/tiredness, dizziness, different kinds of pain, rash, and physical disability.

In addition, females were associated with higher D-dimer levels (4.4%, p-value = 0.05). In which six women who received AstraZeneca vaccines, one of whom was over 50 years old, had elevated D-dimer levels, and three developed petechiae and hematomas. one of whom was hospitalized for thromboembolism treatment (Almufty et al. 2021). Figure 8 illustrates the various factors associated with the side effects of COVID-19 vaccines.

Figure 8. Factors associated with side effects of COVID-19 vaccines.

Discussion

Vaccines play a vital role in reducing global rates of infections and diseases (Lombard et al. 2007). The original assumption of vaccinations, dating back to the 11th century, was to expose a human to a small amount of disease to foster protection and immunity against exposure to a larger amount of the same pathogen. This method was 1st recorded in Chinese literature that ingesting a small amount of poison could prevent death from a larger dose of poison (Plotkin 2005).

Vaccines induce a strong immune-response that triggers a wide range of reactions, including fever, chills, fatigue, inflammation, and swelling at the site of injection (Marsa 2023). An “adverse event following immunization” (AEFI) is defined by the World Health Organization (WHO) as any unintended medical event that occurs after the vaccination, and which does not necessarily indicate a causal relationship with the vaccine. Symptoms, abnormal laboratory findings, or diseases that are not desirable or unintended are called adverse events (WHO 2023).

A systematic evaluation of existing vaccination candidates was required to investigate their safety, effectiveness, immunogenicity, undesired events, and limitations. The review was conducted by scanning online resources, and 17 studies were ultimately chosen. Several types of vaccine candidates with different methods against the COVID-19 virus, including inactivated, mRNA-based, recombinant, and nanoparticle-based vaccines, are being developed and marketed, according to our findings. Depending on data from the literature, we compared these vaccines in terms of side effects. We discovered that mRNA vaccines looked to be more effective, Adenovirus Viral vector COVID-19 vaccines had a higher incidence of side effects, while inactivated vaccinations had fewer side effects.

Pain at the injection site was the most commonly reported side effect (59.1%; CI: 25.7% to 92.1%) , which conformed with the Fact sheets for post-vaccine trials (Pfizer-BioNTech COVID-19 vaccine side effects, 2023; Moderna COVID-19 vaccine side effects, 2023; Sinopharm COVID-19 vaccine side effects, 2023; AstraZeneca COVID-19 vaccine side effects, 2023; Bharat Biotech COVID-19 vaccine side effects, 2023); localized pain has been the most common side effect in numerous other injectable vaccine trials conducted previously (Nichol et al. 1996). In addition, tiredness (57.5%; CI: 37.7% to 86.9%), headaches (39.7%; CI: 17.8% to 90.3%), and fever (54.4%; CI: 32.6% to 69.7%) were the most commonly reported systemic side effects by the participants. In contrast, the other effects weren’t much-repeated, but it was individual states (Figure 6D).

Although there were no serious side effects reported in most of the studies, facial paralysis and Bell’s palsy were also observed in a few cases, which resulted in life-threatening adverse reactions (El-Shitany 2021; Ahamad 2020). Additionally, tachycardia, lymphadenopathy, and anaphylaxis were reported in a few patients (Riad et al. 2021; Almufty et al. 2021; Dziedzic et al. 2021). Anaphylaxis (an acute allergic reaction) following vaccinations can occur due to vaccination antigens, preservatives, and stabilizers in the vaccine formulation, or residual nonhuman proteins (Kim et al. 2021).

Among the included studies, three studies reported the incidence of oral and skin-related side effects. The most common oral side effects were vesicles (6.3%), bleeding gingiva (4.3%), oral paraesthesia (2.2%), dysgeusia (2.4%), blisters (36%), and halitosis (25.4%). While rash and urticaria (other than at the site of the injection) were the most reported skin-related side effects. There was a higher incidence of oral reactions in those who received only one vaccine dose (mRNA or viral vector-Based) and young age participants. While the prevalence was similar among males & females.

Skin-related side effects were more prevalent among females (22.6%), those who received two vaccine doses (mRNA or viral vector-Based), and participants aged ≤ 43 > 43 years. In general, the viral vector-Based vaccines were associated with the highest risk of oral and skin-related side effects, while an mRNA vaccine is associated with the lowest. Three-fourths (75.1%) of the oral side effects appeared within the first week following vaccination. The most affected sites for skin-related side effects were the upper limb, face, chest (trunk), lower limb, and back. As for oral-related side effects, the most commonly affected areas were the lips, labial, tongue, palate, and gingiva.

Most studies didn’t report delayed side effects, but Alhazmi’s study showed that delayed side effects were reported in 1% of the participants, with onset occurring at ≥ three days after vaccination (Alhazmi et al. 2021). It was observed that, in general, these reactions began on the first day after getting a vaccination, regardless of the dosage and most of these side effects resolve within one-three days. Fewer than 1% of studies participants required hospitalization. We discovered that mRNA vaccines looked to be more effective, while inactivated vaccinations had fewer side effects. The vaccine’s effectiveness far surpasses any concerns regarding side effects.

Conclusion and future works

In conclusion, this scoping systematic review investigated the side effects associated with COVID-19 approved vaccines including Pfizer BioNTech (Comirnaty), Moderna (mRNA-1273), Sinopharm (BBIP CorV), and AstraZeneca (ChAdOx1), as well as Bharat Biotech (Covaxin). Most of the side effects were mild, self-limiting, and common. Thus, they usually resolve within 1–3 days after vaccination. Currently, all types of vaccines that are approved still outweigh the possible risks of these vaccines, and the vaccinations are strongly recommended when it is available.

In future works, it is necessary to study the side effects more accurately, and that is done through the correct selection of the study community, which begins with the selection of the study population. The study sample must ensure appropriate representation of men and women, as gender bias was a major loophole in the studies we adopted and had a significant impact on the real results obtained.