Evidence on associations between COVID-19 vaccination or SARS-CoV-2 infection and the risk of congenital anomalies is limited. Here we report a national, population-based, matched cohort study using linked electronic health records from Scotland (May 2020-April 2022) to estimate the association between COVID-19 vaccination and, separately, SARS-CoV-2 infection between six weeks pre-conception and 19 weeks and six days gestation and the risk of [1] any major congenital anomaly and [2] any non-genetic major congenital anomaly. Mothers vaccinated in this pregnancy exposure period mostly received an mRNA vaccine (73.7% Pfizer-BioNTech BNT162b2 and 7.9% Moderna mRNA-1273). Of the 6731 babies whose mothers were vaccinated in the pregnancy exposure period, 153 had any anomaly and 120 had a non-genetic anomaly. Primary analyses find no association between any vaccination and any anomaly  or non-genetic anomalies . Primary analyses also find no association between SARS-CoV-2 infection and any anomaly  or non-genetic anomalies . Findings are robust to sensitivity analyses. These data provide reassurance on the safety of vaccination, in particular mRNA vaccines, just before or in early pregnancy. The risks of major congenital anomalies associated with SARS-CoV-2 vaccination in early pregnancy are not well understood. Here, the authors conduct a population-based cohort study using electronic health records from Scotland and find no evidence of an association, supporting vaccine safety in pregnancy. Among the barriers affecting COVID-19 vaccine uptake in pregnancy are concerns around vaccine safety7. There is evidence of the safety of COVID-19 vaccination in pregnancy with respect to perinatal outcomes such as stillbirth and early pregnancy outcomes such as miscarriage9. However, there is very limited evidence on associations between either COVID-19 vaccination or SARS-CoV-2 infection in early pregnancy and the risk of congenital anomalies.SARS-CoV-2 infection in pregnancy is associated with severe COVID-19 symptoms, and adverse maternal and perinatal outcomes15, but these all had important methodological weaknesses. Only two of these studies, for example, restricted the exposure to vaccination in the first trimester14 when the baby’s organs develop and hence the key risk period for teratogen exposure16. Furthermore, none of the studies comprehensively captured congenital anomalies, either only documenting anomalies identified on ultrasound or only looking at live births (+/− stillbirths) thus excluding terminations of pregnancy for anomalies, which are known to account for a large number of all major congenital anomalies in Europe17. The evidence on any association between maternal SARS-CoV-2 infection and offspring risk of congenital anomalies is also very sparse. The few published studies have shown no evidence of an association20, although they have similar methodological limitations to those looking at the impact of COVID-19 vaccination. By contrast, certain other viral infections in early pregnancy  are well-recognised causes of specific anomaly syndromes21. Fever associated with infections, and medicines used to treat infections, could also be associated with anomaly risk17.The few studies that have been published to date on the association between COVID-19 vaccination and the risk of congenital anomalies have found no evidence of an association23. We estimated the association between any COVID-19 vaccination and, separately, a confirmed SARS-CoV-2 infection between six weeks pre-conception and 19 weeks and six days (19 + 6) gestation and the risk of any major congenital anomaly  and the risk of any non-genetic major congenital anomaly .Maximizing COVID-19 vaccine uptake among women that are pregnant or planning to become pregnant requires that they and their healthcare providers have access to key information on the safety of these vaccines, as well as the potential harms from SARS-CoV-2 infection, to inform their decision-making. Given the paucity of high-quality data on the risk of congenital anomalies with COVID-19 vaccine and SARS-CoV-2 infection, we conducted a national, population-based, matched cohort study using data for all residents in Scotland from the COVID-19 in Pregnancy in Scotland (COPS) cohortThe study dataset included 581,370 fetuses/babies (hereafter ‘babies’) resulting from all clinically recognized pregnancies in Scotland ending at any gestation and in any outcome  from 2015 onwards. For the COVID-19 vaccination analyses, we identified 53,914 babies in the study vaccine exposure period  who had adequate follow-up time  in the model  or which adjusted for all socio-demographic and clinical covariates   (Supplementary Table The mothers vaccinated in the pregnancy exposure period mostly received an mRNA vaccine (73.7% Pfizer-BioNTech BNT162b2 and 7.9% Moderna mRNA-1273), 18.2% were exposed to the viral vector Oxford-AstraZeneca ChAdOx1-s/nCoV-19 vaccine, and 0.2% were exposed to more than one vaccine type  and who had adequate follow up time available  or when additionally adjusting for all socio-demographic and clinical covariates   .24 with women who were motivated to get COVID-19 vaccination in this early stage of pregnancy different in their health and/or health-related behaviours compared to their unvaccinated controls. The healthy vaccinee bias may also affect our other vaccination analyses, although we have adjusted for a number of maternal characteristics that should account for this to a certain extent .There remained no evidence for an elevated risk of any anomaly when we narrowed the exposure window to the key teratogenic risk period of between conception and 9 + 6 weeks gestation. The association between maternal infection in this narrower risk window and non-genetic anomalies was essentially unchanged. By contrast, maternal vaccination in this narrower risk window was associated with a slightly lower risk of non-genetic anomalies. Confidence intervals were wide due to relatively small numbers of babies exposed to maternal vaccination in the narrow window. It is plausible, however, that this reflects a particularly strong “healthy vaccinee bias”25, facility-based studies comparing outcomes in vaccinated and unvaccinated pregnancies in the UK and the US14, as well as self-reported data on vaccination status and fetal anomaly identified at ultrasound from an online survey12. The most robust evidence published previously is a population-based cohort study from Israel conducted by Goldshtein and colleagues11. They found no evidence that singleton, live births to women who were vaccinated in the first trimester had a higher risk of congenital anomalies compared with those not exposed to vaccination in pregnancy .This lack of association between vaccination in pregnancy and the risk of anomalies in babies aligns with existing evidence from a vaccine adverse event reporting system in the US26. The pregnant women in our study receiving ChAdOx1-s/nCoV-19 will therefore mainly be those identified as clinically vulnerable due to pre-existing medical conditions: this group will be at increased risk of a range of adverse pregnancy outcomes, including anomalies. It is therefore reassuring that, whilst the risk of anomalies was slightly elevated in babies from this group, the distribution of types of anomalies seen was similar to that in controls. The distribution was also in line with expectations based on whole population data from Scotland in 2019 which showed that the most common types of major congenital anomalies were congenital heart defects, nervous system, limb and/or chromosomal congenital anomalies, with ear, face, neck, eye, respiratory and abdominal wall defects the rarest anomalies27. Nevertheless, data from settings with a different profile of women receiving ChAdOx1-s/nCoV-19 would be beneficial in confirming the safety profile of this vaccine.All the studies published to-date either only included pregnancies exposed to mRNA vaccinations or looked at all vaccines overall and did not stratify by vaccine type. We conducted pre-planned subgroup analysis by the type of vaccination . The majority of mothers vaccinated in the pregnancy exposure period received an mRNA vaccine (81.6%), and we found no evidence for an association between mRNA vaccination and either any anomaly or non-genetic anomalies. However, while the confidence intervals are wide, we cannot rule out a modest increase in the risk of any anomaly  or non-genetic anomalies  with the viral-vector vaccination (Oxford-AstraZeneca ChAdOx1-s/nCoV-19). We urge caution in the interpretation of these results for two main reasons. Firstly, there was a relatively small sample size of babies whose mother received ChAdOx1-s/nCoV-19 in the pregnancy exposure period and consequently we have wide confidence intervals. Secondly, there is potential for residual confounding, with mothers of babies exposed to this vaccine having quite different characteristics compared to both their unvaccinated controls and those of babies exposed to the mRNA vaccine. These differences reflect the roll out of the vaccination programme in Scotland. The Pfizer/BioNTech BNT162b2 vaccine was used from the start of the vaccination programme on December 8, 2020. The Oxford-AstraZeneca ChAdOx1-s/nCoV-19 vaccine was introduced from January 4, 2021, and the Moderna mRNA-1273 vaccine from April 7, 2021. In the early months of the vaccine programme, BNT162b2 was mainly offered to health and social care workers at high risk of occupational exposure to SARS-CoV-2 , and ChAdOx1-s/nCoV-19 was offered to individuals at risk of severe COVID-19 disease due to pre-existing medical conditions . In mid-April 2021, prior to vaccination being rolled out to all younger adults (without pre-existing conditions) including pregnant women, the UK’s Joint Committee on Vaccination and Immunisation (JCVI) recommended that pregnant women commencing a course of vaccination from that point on should be offered an mRNA vaccine rather than ChAdOx1-s/nCoV-19. This reflected accumulating evidence on the safety of mRNA vaccines in pregnancy following their extensive use in the US rather than any specific concern about the use of viral vector vaccines in pregnancy20. We recognise that we may have misclassified some mothers who actually had SARS-CoV-2 infection as uninfected if they did not have a positive SARS-CoV-2 reverse transcription (RT) polymerase chain reaction (PCR) test result. To minimise the number of missed infections, we restricted our analysis to the period when widespread community-based testing was available, which ensured access to testing for a wide range of people, for example, anyone with symptoms and for anyone being admitted to hospital29. Studies so far have suggested that transmission of SARS-CoV-2 across the placenta is rare31, which likely explains the lack of association. There has, however, been a case report of a severe eye anomaly linked to maternal SARS-CoV-2 infection at 5-6 weeks gestation32. We did not identify any eye anomalies in babies exposed to infection in early pregnancy (or their controls), but this highlights the importance of continued monitoring of congenital anomalies following SARS-CoV-2 infection.Our study also adds to a growing body of epidemiological evidence that maternal SARS-CoV-2 infection is not associated with the risk of congenital anomaliesThe strengths of this study include that it was population-based and, compared to most previous studies, had a large sample size. Unlike many previous studies we restricted our exposure period to the relevant early pregnancy period, and we examined both a broader exposure window, between six weeks preconception and 19 + 6 weeks gestation, and a narrower window reflecting the key teratogenic risk period of between conception and 9 + 6 weeks. Critically, we included babies regardless of pregnancy outcome in our analyses, hence babies with an anomaly will be included whether the pregnancy ends in a termination or a live or stillbirth. The presence or absence of an anomaly is usually unknown in babies where the pregnancy ends in an early miscarriage or social termination. We therefore restricted our primary analyses to only include babies from pregnancies reaching at least 12 weeks gestation but undertook sensitivity analyses including babies from pregnancies of all duration.27. Secondly, while we used robust methods for the ascertainment and classification of anomalies based on international (EUROCAT) standards33, we are unlikely to have identified all congenital anomalies in our study population. Specifically, we will have under-ascertained anomalies among live births (particularly those that are not evident shortly after birth) as we curtailed follow-up for congenital anomalies to 28 days, rather than the usual 12 months, after birth to allow timely analyses. We also were not able to integrate data on the measurement of the occipito-frontal circumference at birth for comprehensive assessment of microcephaly, originally proposed in our study protocol as an outcome of interest, as these data were too incomplete. In primary analyses, we will have additionally excluded a small number of babies with anomalies that were subject to termination of pregnancy before 12 weeks gestation, although our sensitivity analyses retaining all babies regardless of gestation indicated that this had negligible impact. More speculatively, it is possible that pandemic-related changes in maternity and neonatal care, and associated national data quality, may have influenced the ascertainment of anomalies, however this would be unlikely to impact our exposed and controls groups differentially. Finally, and common to all observational studies, is the challenge of ensuring adequate adjustment for potential confounders. We included a number of potentially important confounders, including clinical vulnerability and smoking, but found that adjustment had little impact on the OR. We did not have data on some potential confounders, for example, parity and other major teratogenic exposures such as use of teratogenic medications or infections known to increase the risk of congenital anomalies , but this is unlikely to explain the absence of association that we observed in this study. We were also unable to match on pregnancy start date or season of conception when selecting unvaccinated controls due to the relatively small available pool of unvaccinated women who were the same maternal age and had the same pregnancy start date; additional exploratory analyses matching on season of conception and using fewer unvaccinated controls did not change our conclusions.There are, however, also some important limitations. Firstly, there were only small numbers of specific types of congenital anomalies preventing any subgroup analyses by type of anomaly. We have, however, presented descriptive data for more specific types of congenital anomalies and these were in line with the numbers expected based on previously published data from Scotland35, and that vaccination remains the best way for women to protect themselves and their babies from the known risks of SARS-CoV-2 infection in late pregnancy.In summary, this study provides some of the most robust evidence to date that there is no association between COVID-19 vaccination or SARS-CoV-2 infection and the risk of major congenital anomalies. However, even using national, population-based data, we were not able to look at specific types of congenital anomalies, highlighting the importance of continued monitoring of major congenital anomalies and pooling of data from different settings to look at these rarer events. More generally, our study adds to a growing body of evidence on the safety of COVID-19 vaccination (in particular using mRNA vaccines) in pregnancy and provides important reassurance on safety of vaccination just before or in early pregnancy, although more data are required from other settings on viral vector vaccines. This supports current policy and clinical advice that vaccination can be given at any stage of pregnancy and to women planning to become pregnant36, with our results reported and recorded according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines37.This population-based, matched cohort study was conducted according to a pre-specified study protocol and statistical analysis planThe National Research Ethics Service Committee, South East Scotland 02 provided ethical approval (REC 12/SS/0201: SA 2). The Public Benefit and Privacy Panel for Health and Social Care (PBPP-HSC) provided information governance approval (2021-0116). Under the terms of our PBPP-HSC approval, patient consent was not required for use of routine health records for the COPS study.N = 581,370). Pregnancies ending at any gestation and in any outcome  were included. Information on pregnancies, including estimated date of conception, pregnancy outcome, and gestational age at end of pregnancy, were extracted from: antenatal care (ANC) booking records; General Practitioner (GP) records; general acute hospital discharge records (Scottish Morbidity Record (SMR) 01); maternity hospital discharge records (SMR 02); statutory termination of pregnancy notifications (AAS); National Records of Scotland (NRS) statutory live birth and stillbirth registrations; and NHS Scotland live birth notifications. Further details on the creation of the COPS dataset have been published elsewhere23. In general, date of conception was estimated from the date and recorded gestation at the end of pregnancy ). Recorded gestation at the end of pregnancy is highly complete and accurate on national records relating to pregnancies ending in termination, late miscarriage, or delivery, but is usually missing for pregnancies ending in early miscarriage occurring before antenatal booking. Imputed gestation at the end of pregnancy was therefore used for any completed pregnancy with unknown gestation, with the imputed gestation based on pregnancy outcome, for example 10 + 0 weeks for miscarriages managed in non-maternity settings (and hence likely to be early losses).We used the COVID-19 in Pregnancy in Scotland (COPS) cohort as updated in mid-July, 2022. The COPS cohort includes information on all completed and ongoing pregnancies (and the resulting fetuses/babies - hereafter ‘babies’ for brevity) in Scotland from January 1, 2015 onwards .For this study, we included babies with an estimated conception date before June 2, 2021. This ensures that all babies could be followed up to 40 weeks and six days (40 + 6) gestation by the end of February 2022, with sufficient time then allowed for return of national health records relating to care provided at the end of pregnancy or (for live births) during the subsequent 28-day neonatal period, and their incorporation into the COPS dataset update in mid-July 2022. A small number of completed pregnancies with an unknown pregnancy outcome were excluded from this analysis  and confirmed SARS-CoV-2 infections were incorporated into the COPS study cohort using unique identifiers to identify exposures of interest.39 was updated in July 2022 and linked to the COPS study cohort using unique identifiers to identify babies with major congenital anomalies. The SLiCCD is usually updated on an annual basis by Public Health Scotland (PHS) to enable surveillance of the occurrence of anomalies in the Scottish population27. Production of the SLiCCD involves linkage and analysis of a range of national health datasets held by PHS ; statutory termination of pregnancy notifications (AAS); NRS statutory stillbirth registrations; hospital neonatal care (Scottish Birth Record), general including paediatric acute discharge records (SMR 01), and NRS statutory death registration records for babies; and MBRRACE perinatal death enhanced surveillance records)40. Diagnostic codes on the source records are used to identify babies with a major structural or chromosomal anomaly or recognised syndrome meeting EUROCAT inclusion criteria41, specifically EUROCAT Guide 1.4 which was in place at the time this study started33. In line with EUROCAT guidance, babies are included in SLiCCD if the pregnancy ends in a termination of pregnancy at any gestation, a spontaneous pregnancy loss at 20 weeks gestation or over, or a live birth. Usually, SLiCCD includes live born babies diagnosed at any point up to their first birthday. To allow more timely analyses, the modified version of SLiCCD produced for this study included babies diagnosed at any point up to end of the 28-day neonatal period. In addition, MBRRACE perinatal death enhanced surveillance records were not used due to long data lags.A modified version of the Scottish Linked Congenital Condition database (SLiCCD)In a deviation from our study protocol, we did not assess whether there was any association between either COVID-19 vaccination or SARS-CoV-2 infection and the risk of microcephaly, as the data on the measurement of the occipito-frontal circumference at birth were too incomplete to support these analyses.16). As noted by The Brighton Collaboration Congenital Anomalies Working Group, this exposure window allows for potential errors in assigning a date of conception, while focusing on exposure within the most plausible gestational period for development of congenital anomalies 16. Babies were categorized as having been exposed to vaccination if their mother received any vaccine type available in Scotland , any dose  and any number of doses (one dose or two doses) in this pregnancy exposure period.Our primary exposure was receipt of any COVID-19 vaccine from six weeks before conception to 19 + 6 weeks gestation or end of pregnancy if earlier  or not. The group with no major anomaly identified will include a small number of babies (from miscarriages at 12–19 weeks gestation inclusive) where anomaly status is unknowable/unknown. Following SLiCCD usual practice, we allocated each anomaly present in an affected baby to the relevant EUROCAT anomaly group . One baby could therefore be allocated to multiple groups, and the number of anomalies allocated to each group will sum to more than the total number of affected babies. Finally, we identified the subset of babies who had no known genetic basis for their anomaly groups), as anomalies with a genetic basis are not caused by environmental exposures such as medicines/vaccines.For our primary analyses, all fetuses/babies from pregnancies that reached at least 12 weeks gestation were categorized as having a major congenital anomaly  and gestational week of first maternal vaccination in the exposed baby . Maternal age is particularly strongly associated with both the likelihood of being vaccinated and the risk of certain congenital anomalies. Gestational age at exposure is also associated with the risk of certain congenital anomalies . The number of potential controls was too small to allow additional matching by calendar time or season of conception for our primary analyses.Given our focus on the safety of COVID-19 vaccination, all babies in whom the mother had SARS-CoV-2 infection between six weeks preconception and 19 + 6 weeks gestation (or the end of pregnancy if earlier) were excluded before the matching was conducted. As such, we were only able to capture the direct association between COVID-19 vaccination and congenital anomalies and not any impact of COVID-19 vaccination mediated through reducing the risk and severity of SARS-CoV-2 infection.42, confirmed infection was defined as a positive SARS-CoV-2 reverse transcription (RT) polymerase chain reaction (PCR) test result, and date of onset was taken as the date of the first positive test within the pregnancy exposure period. If a woman had multiple positive tests, these were considered separate infections if they were >90 days apart. To minimize the risk of misclassifying babies as unexposed to infection in the pregnancy exposure period due to lack of SARS-CoV-2 testing, we restricted the study population for this analysis to babies that had not yet reached 19 + 6 weeks gestation or were conceived after the date when widespread community testing became available in Scotland . Three babies not exposed to infection in the pregnancy exposure period were matched to each infected baby on maternal age at conception (+/− 1 year), gestational week of first maternal infection in the exposed baby, and season of conception. All babies in which the mother had COVID-19 vaccination between six weeks preconception and 19 + 6 weeks gestation (or the end of pregnancy if earlier) were excluded before the matching was conducted.We took a similar approach to prepare the COPS dataset to assess whether there was any association between confirmed SARS-CoV-2 infection between six weeks preconception and 19 + 6 weeks gestation (or end of pregnancy if earlier) and the risk of congenital anomalies. In line with national guidance in place over the study period43), maternal ethnicity , maternal rural urban status , maternal clinical vulnerability  or clinically extremely vulnerable), maternal diabetes , maternal smoking status , maternal body mass index (BMI)  and whether the baby was from a singleton or multiple pregnancy. Maternal area-level deprivation was based on postcode of residence and derived according to the standard measure used by the Scottish Government (Scottish Index of Multiple Deprivation [SIMD]) which ranks areas by deprivation on the basis of seven domains: income, employment, education, health, access to services, crime and housing43. Women were classified as clinically extremely vulnerable if they were identified on the national highest risk/shielding list maintained by Public Health Scotland46 and, of those not extremely vulnerable, were classified as clinically vulnerable if they were in any Q-COVID risk group47 (excluding diabetes) or had hypertension according to cross-sectional GP/primary care data available from June 2020 and January 2021. Data on maternal diabetes, and BMI at antenatal booking, were extracted from delivery records where possible, then from GP records if available. Similarly, smoking status at antenatal booking was extracted from delivery records then GP records, but with one exception. If it was documented that a woman was a non-smoker at antenatal booking, but they were recorded as either a smoker or ex-smoker on a GP record, then we categorized the woman as an ex-smoker.Data on potential sociodemographic and clinical confounders of the association between both COVID-19 vaccination and SARS-CoV-2 infection with congenital anomalies were available in the COPS data. Specifically, data were available on maternal area-level deprivation , looking at the distribution and prevalence of congenital anomalies by cohort and, for our exposed groups only, looking at further descriptive information about the exposures. For the babies exposed to vaccination, for example, we looked at the number and type of vaccinations administered to the mother in the pregnancy exposure period.To assess whether there was any evidence of an association between our exposures and any anomaly, we used conditional logistic regression to account firstly for only the matching factors , and then adjusting for all the sociodemographic and clinical covariates. For the few covariates with missing data, we included “unknown” groups in our main models so these babies were not dropped from the analysis. The same approach was taken to look at the non-genetic anomalies outcome.Analyses were conducted in R 3.6.1.We conducted pre-specified subgroup analyses, stratifying our analysis of the association between vaccination and congenital anomalies by whether the mother received mRNA vaccination  or a viral vector vaccination . Babies where the mother received different vaccinations between six weeks conception and 19 + 6 weeks gestation, and their controls, were excluded from these subgroup analyses.We conducted two sensitivity analyses for the analysis of the association between both vaccination or SARS-CoV-2 infection and congenital anomalies. Firstly, we assessed the impact of including babies from pregnancies of any duration (not just those reaching at least 12 weeks). Secondly, we restricted our pregnancy exposure period to the key teratogenic risk window from conception to 9 + 6 weeks gestation inclusive.Further information on research design is available in the Supplementary InformationPeer Review FileReporting Summary


BackgroundThe acceptance of vaccines among pregnant and breastfeeding women is vital to alleviate the risk of contracting and transmitting coronavirus disease 2019 (COVID-19). Therefore, we aimed to assess the COVID-19 vaccine acceptance among pregnant and breastfeeding/lactating women and the factors associated with the acceptance of the COVID-19 vaccine in Saudi Arabia.MethodologyA cross-sectional survey was conducted among pregnant and breastfeeding women living in Saudi Arabia. A 23-item, self-administered questionnaire was used to assess the COVID-19 vaccine acceptance among pregnant or lactating women.ResultsA total of 160 (53.3%) pregnant women and 140 (46.7%) breastfeeding/lactating mothers participated in the study. When the participants were asked, “Have you been vaccinated or are you planning to take the vaccine during pregnancy or breastfeeding/lactation?” 164 (54.7%) responded with “Yes.” When compared with breastfeeding/lactating mothers , pregnant women had more concerns about the efficacy and safety of COVID-19 vaccination (77 (48.1%); p = 0.043). The probability of rejecting COVID-19 vaccination was higher among breastfeeding/lactating women with a lower education level than those with a tertiary education level .ConclusionsThis study reported high acceptance of COVID-19 vaccination in a sample of breastfeeding/lactating women. Concern about vaccine safety among many pregnant women was the major reason for hesitancy. Factors such as low education, concerns regarding the efficacy and safety of the vaccine, and doctors’  recommendations for the COVID-19 vaccine were associated with vaccine acceptance. Coronavirus disease 2019 (COVID-19) was identified in December 2019 in Wuhan City, China . VaccinaPeople are always more inclined toward safe and effective vaccines . In addiThe risk of severe disease and emergency presentations is relatively more in pregnant women than in non-pregnant women -16. TherA cross-sectional survey using an anonymous questionnaire was conducted between November 2021 and February 2022. We included pregnant or lactating women aged 18 years and over and excluded women who were not pregnant and were not breastfeeding. The study was approved by King Saud Medical City, Ministry of Health .A non-probability snowball sampling technique was used to recruit the study participants from the maternity department of the tertiary care setting. A 23-item, self-administered questionnaire after face and content validation was distributed to the pregnant or lactating women currently living in the KSA. We prepared the initial draft of the questionnaire after adopting questions from previous reports , expert To elicit a response from 50% of respondents, with a 95% confidence level and a 5% margin of error, a sample size of 377 was estimated. The sample size was calculated by an online sample size calculator . DescripOut of the 377 questionnaires distributed among the target population, 300 were completed and returned: 160 (53.3%) pregnant women and 140 (46.7%) breastfeeding/lactating mothers. The response rate was 80%. The majority of the respondents  were between the age of 25-29 years, mostly pregnant women . While breastfeeding/lactating mothers were predominantly 30-34 years old . Moreover, the highest proportion of the participants had a university education  and did not have chronic diseases such as hypertension and diabetes mellitus  responded with “Yes.” Among these respondents, the proportion of breastfeeding/lactating women who said yes to the question was statistically higher  than that of the pregnant women group  (p = 0.0046).The participants were also asked questions related to the potential benefits and safety of receiving COVID-19 vaccines. A high proportion  of the overall participants remained neutral when they were asked the question about the potential of COVID-19 to cause harm. A higher proportion of this number were pregnant women , and 54 (38.6%) were breastfeeding/lactating mothers, with a p-value of 0.007. When compared with breastfeeding/lactating mothers , pregnant women had more concerns about the efficacy and safety of COVID-19 vaccination  (p = 0.043). Moreover, over half of the total number of participants  did not feel safe due to the absence of data about COVID-19 vaccine safety. A higher proportion of this cohort were pregnant women  than breastfeeding/lactating mothers , with a p-value of 0.017.A total number of 127 (42.4%) respondents agreed that the possible side effects of COVID-19 could interfere with their usual activities, and most of these participants were pregnant women (76 (47.5%), p = 0.014). However, 60 (42.9%) of those who are breastfeeding/lactating disagreed. With regard to a preference for using alternative remedies, the majority of pregnant women  preferred traditional medicines compared to orthodox vaccines. In contrast, 56 (40%) breastfeeding/lactating mothers believed in synthetic vaccines. The participant’s responses to the survey questions are presented in Table The results of the univariate analysis are illustrated in Table Pregnant women who agreed with the statement “I do not need vaccination because I am young and healthy” were approximately three times more likely not to accept COVID-19 vaccination than those who disagreed . Further, those who believed that “I would only take the COVID-19 vaccine if the vaccine is taken by many of the population ” are 61% less likely to accept the COVID-19 vaccination compared to pregnant women who did not agree with the statement .The probability of rejecting COVID-19 vaccination was higher among breastfeeding/lactating women with a lower education level than those with a tertiary education level . Further, breastfeeding/lactating women who were concerned about the efficacy and safety of COVID-19 vaccination are nearly three times more likely not to accept COVID-19 than those who were not . The results of the final model are illustrated in Table This study reports the first data on the rate and factors associated with accepting COVID-19 vaccination among pregnant and breastfeeding/lactating women in the KSA. We found that the COVID-19 vaccination was accepted by over half of the total participants. Specifically, we observed pregnant women were more willing to receive the vaccination compared with breastfeeding/lactating mothers. Factors associated with accepting the COVID-19 vaccination among pregnant women were having a belief that someone does not need it because she is young and healthy, and the feeling that a person would only receive the vaccine if it was taken by many pregnant women. Similarly, three factors were found to be associated with the willingness to receive COVID-19 by breastfeeding/lactating women. The first was education level, followed by concerns about COVID-19 safety and efficacy, and the third factor was the willingness to receive the vaccine based on the recommendation of a specialist as it could be because of breastfeeding/lactating women’s trust in their doctors. Our findings can guide interventions for promoting COVID-19 vaccination among this population.The acceptance rate of COVID-19 vaccination among pregnant and breastfeeding women is widely reported in the literature -29. WhatIdentifying factors that could be barriers to receiving COVID-19 vaccinations can guide the development and implementation of interventions for enhancing the vaccination rate in the community. In this study, we found that pregnant women who agree that they do not need vaccination because they are young and healthy are three times more likely to reject COVID-19 vaccination. This finding could be due to the lack of adequate public knowledge about the vaccine in the KSA. This poor knowledge is evident in a recent study conducted among the general population in KSA, which shows that 30-40% of people lacked information about COVID-19 vaccination among the young population and pregnant women . Thus, mWe found that having a lower education level is a predictor of rejecting COVID-19 vaccination among breastfeeding/lactating mothers in the KSA. Lower education level has been widely reported as one of the barriers to receiving COVID-19 vaccination among the public in the KSA ,33. PromThis study identified gaps that can prevent the actualization of the WHO COVID-19 immunization target of 70% . TargetiThis is the first study of its kind that assessed factors associated with the acceptance of the COVID-19 vaccine among Saudi pregnant and breastfeeding/lactating women. Nonetheless, this study also has certain limitations. One of the important study limitations is that the sample of 377 females  was not possible due to limited visits of this population, particularly during the COVID-19 period at our maternity department. Further, this was a cross-sectional survey performed at a single tertiary care setting, and, therefore, cannot inform about causality, and the findings may not be generalized to the entire group of pregnant and lactating women in Saudi Arabia. Therefore, there is a need for conducting a national cross-sectional study with a large sample size via probability sampling among Saudi pregnant and breastfeeding/lactating women regarding their perception and attitude toward COVID-19 vaccine acceptance. In addition, future research can investigate the impact of the provision of education regarding the efficacy and safety of the COVID-19 vaccine on the acceptance of vaccines among pregnant and breastfeeding/lactating women.This study reported high acceptance of COVID-19 vaccination in a sample of breastfeeding/lactating women. Concerns about vaccine safety among many pregnant women were the major reason for hesitancy. Factors such as low education, concerns regarding the efficacy and safety of the vaccine, and doctors’  recommendations for COVID-vaccine were associated with the COVID-19 vaccine acceptance. Due to the low acceptance rate among pregnant women, it is crucial to address concerns among hesitant cohorts by building trust in vaccine safety and effectiveness through the provision of evidence-based information about the COVID-19 vaccine.


Bombyx mori carotenoid-binding protein (BmCBP-ZEA) suppresses the photoinducible oxidative stress in RPE cells caused by irradiation of lipofuscin with intense white light. We implemented fluorescence lifetime imaging of the RPE cell culture ARPE-19 fed with lipofuscin granules and then irradiated by white light with and without the addition of BmCBP-ZEA. We demonstrate that after irradiation the mean fluorescence lifetime of lipofuscin significantly increases, while the presence of BmCBP-ZEA at 200 nM concentration suppresses the increase in the average lifetime of lipofuscin fluorescence, indicating an approx. 35% inhibition of the oxidative stress. This phenomenon serves as indirect yet important evidence of the efficiency of the protein-mediated carotenoid delivery into pigment epithelium cells.Lipofuscin of retinal pigment epithelium (RPE) cells is a complex heterogeneous system of chromophores which accumulates as granules during the cell’s lifespan. Lipofuscin serves as a source of various cytotoxic effects linked with oxidative stress. Several age-related eye diseases such as macular degeneration of the retina, as well as some severe inherited eye pathologies, are accompanied by a significant increase in lipofuscin granule concentration. The accumulation of carotenoids in the RPE could provide an effective antioxidant protection against lipofuscin cytotoxic manifestations. Given the highly lipophilic nature of carotenoids, their targeted delivery to the vulnerable tissues can potentially be assisted by special proteins. In this study, we demonstrate how protein-mediated delivery of zeaxanthin using water-soluble  The accumulation of lipofuscin granules inside retinal pigment epithelial (RPE) cells is generally described as an age-related pathology. The occurrence of lipofuscin granules is suggested to be the result of an incomplete lysosomal degradation of the fragments of the outer segments of photoreceptors during RPE cells’ lifespan . For somThe structure and composition of lipofuscin granules inside RPE cells is not yet understood completely. In contrast to the lipofuscin of other tissue cells, RPE lipofuscin consists mainly of retinal derivatives with some presence of proteins specific to the outer segments of the rods, for example, recoverin . Proteomtrans-retinal and membrane phospholipid phosphatidylethanolamine. The exact localization of this reaction is debatable 44], it wBombyx mori cocoons (BmCBP), was reconstituted, and its capability of concentration-dependent binding of LUT and ZEA was demonstrated. The potential of BmCBP for delivering carotenoids to model membranes was clearly demonstrated, as well as its ability to deliver ZEA to fibroblasts promoting their growth [Cyanobacterial water-soluble carotenoid-binding proteins, such as orange carotenoid protein (OCP) , are evor growth .The aim of the present study was to investigate the efficiency of the protein-mediated delivery of ZEA into RPE cells by assessing the effects of BmCBP carotenoprotein in holoform on the photo-oxidation of lipofuscin granules. We utilized fluorescence microscopy, including fluorescence lifetime imaging (FLIM), to assess the changes in the state of lipofuscin granules inside RPE cells photo-oxidized after sufficiently intense white light irradiation. This allowed us to show that protein-mediated delivery of antioxidants is promising for protecting cells from lipofuscin-induced photodamage.9 granules/mL.Lipofuscin granules (LG) were isolated from the RPE cells from 85 human cadaver eyes without ophthalmologic pathologies according to the protocol described in . Cadaver6 (cells/dishes) was cultured in supplemented culture media DMEM/F12  containing 10% fetal bovine serum , 2 mM L-glutamine, and 15 µg/mL gentamicin . ARPE-19 cells were cultivated at 37 °C in a humidified 5% CO2 incubator, tested for mycoplasma contamination, and grown in t-25 flasks.Spontaneously arising retinal pigment epithelial cell line culture ARPE-19 was obtained from the Cell Culture Collection of the Koltzov Institute of Developmental Biology of Russian Academy of Sciences . ARPE-19 cell suspension at a concentration of 0.5 × 10To feed the ARPE-19 cell culture with lipofuscin, the cells in suspension were seeded on 35 mm cell culture imaging dishes  with a concentration of 100,000 cells per dish and cultured there for 2 days. Then, 20 µL of the stock solution of lipofuscin granules (LG) was added to the Petri dish with the cells to achieve a concentration of approx. 300 granules per cell. The control sample was the ARPE-19 cells without the addition of LG. Afterward, cells were cultivated under standard conditions for 24 h.2 incubator under standard cultivation conditions in complete darkness. The second group of samples was irradiated for 18 h using a custom-made LED illumination box located inside the CO2 incubator. A photograph of the box and the spectrum of the illumination are provided in 2.Two groups of ARPE-19 cell samples, consisting of a control sample (ARPE-19 cells without LG) and LG-fed ARPE-19 cells, were used in experiments. The first group of samples was stored in a COA cell viability assay was carried out by direct counting of cells (live/dead) based on the laser confocal observations performed in FluoroBrite™ DMEM  media. Calculations were made by direct observations, and images were captured and processed using NIS Elements software . Live cells were visualized by fluorescein diacetate , and dead cells were visualized by nuclei labeling using Sytox Deep Red .For the MTT test, cells were placed in a 96-well plate (~1500 cells per well) and incubated under standard conditions for 3 days. Lipofuscin loading and irradiation were performed as described in t-test using Prism software .The statistical analysis of the data on cell viability was performed by two-way ANOVA with Tukey’s multiple comparison 6-tagged carotenoid-binding domain of Bombyx mori carotenoid-binding protein  was obtained earlier [crtY, crtI, crtB, crtZ, and crtE sequences from Erwinia uredovora allowing for constitutive ZEA production [The construct of the His earlier . Using toduction . More deoduction ,52,57.C41(DE3) cells with the overexpressed protein were then lysed, and the BmCBP holoform was purified using a combination of subtractive immobilized metal-affinity and size-exclusion chromatography, followed by hydroxyapatite chromatography for the apoform removal . The resAfter incorporation with lipofuscin granules (LG) and prior to irradiation, ARPE-19 cells in a Petri dish with a glass bottom were supplemented with DMEM containing BmCBP-ZEA at 200 nM final concentration and afterwards were maintained in accordance with the cell cultivation protocol described above. According to our previous studies , BmCBP-ZThe laser confocal microscopy imaging was performed using an Eclipse Ti-E microscope with confocal module A1  with a 532 nm excitation and detection in the 570–620 nm spectral channel. The cell samples were measured in the chamber under controlled standard cultivation conditions. Data were visualized using Nikon proprietary software.Fluorescence lifetime imaging (FLIM) was performed in the time-correlated single-photon-counting (TCSPC) mode using the confocal system DCS-120  installed on the Eclipse Ti2  microscope. Excitation was performed with a 473 nm picosecond laser BDS-SM-473-LS-101  with a 30 ps duration impulse driven at 50 MHz repetition rate synchronized with hybrid detector HMP-100-40  via board SPC-150 . The detection was performed using a 485 nm long-pass filter  or cutting-band filter at 530 nm with 40 nm band width . The choice of the detection window was made according to the spectral characteristics of lipofuscin fluorescence emission at blue light excitation .Raw FLIM data were collected using SPCM software and processed via SPCImage . The image size was 512 × 512 pixels. In each In total, eight sets of parameters were obtained: {N = 3 is the number of obtained images. Errors in the calculations of the mean values correspond to standard deviations.To characterize the results of the whole experiment considering the data of each image, the mean values were calculated:First, we performed tests of the viability of LG-fed ARPE-19 cells. The results are presented in Since a long 48 h incubation of LG-fed ARPE-19 cells after exposure to white light demonstrated a significant decrease in the cell number, we visualized the intracellular localization of lipofuscin granules and characterized the mechanisms of its cytotoxic manifestations in our experimental model by laser scanning confocal microscopy. Cell images are presented in The results of the FLIM of the LG, phagocytized by ARPE-19 cells, are presented in When FLIM was performed right after the irradiation, the fluorescence lifetime distribution of either non-irradiated or irradiated lipofuscin was characterized with homogeneous single-modal straight narrow peaks D. Approxmponents . The incSimilar results were observed when FLIM was performed after 48 h of incubation after LG-fed cells were irradiated . In the  ± 36 ps D. The inca. 1–3% . At the To assess the efficiency of the ZEA delivery into the RPE cells by the BmCBP carotenoprotein, we performed an experiment to investigate how its addition to lipofuscin-fed ARPE-19 cells affects the lipofuscin fluorescence lifetime. The cytotoxic mechanism of lipofuscin photo-oxidation includes both a direct interaction between an activated sensitizer and the cell components, and the indirect formation of ROS, which, in turn, interact and damage cellular nucleic acids, proteins, and lipids . It is kIn contrast to the fluorescence intensity, the lifetime does not depend on the concentration and directly reflects changes in the quantum yield of fluorescence, which is determined by the functional properties of the fluorophore . Thus, FHaving tested the method of functional imaging of lipofuscin with FLIM on ARPE-19 cells, we examined the effects of the natural antioxidant zeaxanthin (ZEA) delivered by the water-soluble carotenoprotein BmCBP to pigment epithelium cells containing lipofuscin granules with and without exposure to white-light-inducing photo-oxidation. Our experiments show that the addition of the carotenoprotein to the culture medium leads to changes in the fluorescence lifetime distributions of lipofuscin: when BmCBP-ZEA was added, the photoinduced increase in the lipofuscin average lifetime was significantly suppressed . This obThe subsequent redistribution of the carotenoid throughout the cell upon protein-mediated delivery is probably carried out by endocytosis and vesicular transport mechanisms . We haveGiven the overlap of the fluorescence spectrum of lipofuscin and the carotenoid absorption, we assume that the electronic excitation energy of lipofuscin can be transferred to the carotenoid and, as a result, converted into heat due to vibrational relaxation. We speculate that the multichromophore structure of the lipofuscin granule promotes delocalization of electron excitation between neighboring chromophores, and the multistep energy transfer leads to the possibility of a single quencher molecule capturing excitation. Thus, this constitutes the most likely mechanism of the shortening of lipofuscin lifetime driven by carotenoid delivery. The subsequent irradiation of cells containing lipofuscin granules with carotenoid leads to an increase in the average lifetime of fluorescence, but in this case the effect does not exceed the level of the control sample before irradiation . As the Our study also demonstrated that the FLIM of lipofuscin granules can be utilized as an additional tool in advance fluorescence diagnostics of retinal pathologies characterized by lipofuscin accumulation. Previous experimental research demonstrated that fundus autofluorescence (FAF) imaging based on the probing of lipofuscin granule fluorescence quantitative and qualitative properties was an effective approach for the diagnosis of the pathological development of the RPE ,70,71,72In this study, we demonstrated that the fluorescence lifetime of lipofuscin granules, phagocytized by ARPE-19 cells, increased after white-light-induced photo-oxidation. Using time-resolved fluorescence imaging (FLIM), we observed that protein-mediated zeaxanthin delivery had an effect on the state of lipofuscin by reducing its pigment excited-state lifetime. We propose that carotenoids delivered into the cell can not only shield lipofuscin, preventing its excitation and interaction with the products of its oxidation, but also act as quenchers of excited states due to the energy coupling between the molecules.E. coli strains allows the reconstitution of water-soluble carotenoproteins [The recent advances in the use of genetically modified proteins ,52,53,57


Social media platform is one way to share online information regarding pandemic prevention. However, there is no study regarding the attitude of health professionals toward social media use for the COVID-19-related information. This study aimed to assess health professionals' attitudes toward using social media for COVID-19-related information.OR) and a p-value with a 95% CI were calculated to measure the strength of the association and assess statistical significance.An institution-based cross-sectional study was conducted among 355 health professionals in Bahir Dar city public health centers, Northwest Ethiopia. A pretested self-administered questionnaire was used to collect the data. The data were entered by EPI-data version 4.6 and analyzed using SPSS version 23 software. Descriptive statistics, bivariable, and multivariable logistic regression analysis were used to describe respondents' attitudes toward using social media for COVID-19 information and identify associated factors. An adjusted odds ratio (< 24  and age group 25–34 years , computer training , usefulness of social media , and trustworthiness  were enabling factors for attitude toward the use of social media for COVID-19 related information.Out of 341 participants, about 73% of the participants had a good attitude toward the use of social media for COVID-19 information. Age Health professionals had a moderate attitude toward using social media for accessing COVID-19-related information. This implies that after considering positive attitude predictors, such as providing basic computer training, emphasizing the usefulness of social media, and building trusted social media pages, social media platforms can be used as a source of COVID-19-related information for health professionals. The World Health Organization (WHO) declared coronavirus diseases 2019 (COVID−19) as a public health emergency of international concern on 11 March 2020 , 4. As aSocial media is defined as automated communication through mobile and web-based technologies . EvidencThe use of social media in the era of pandemics warrants greater scrutiny because of its consequences for public understanding of COVID-19 issues. The internet and social media are used as reference guides for accessing COVID-19-related information for health professionals .Evidence suggests that social media platforms encourage the exchange of current information to improve community and healthcare workers' knowledge, practice, and attitude . In a prAccording to the study, issues, such as a lack of training, a negative perception of social media sites' usefulness, and a lack of access to the internet and electronic devices contribute to a negative attitude about using social media to receive health information , 17. BesHealth practitioners were recognized to be on the front lines of raising community awareness and preventing the spread of the COVID-19 pandemics. It is difficult for healthcare providers to teach patients face to face and offer them accurate information about COVID-19 transmission and preventative strategies because of the nature of COVID-19 transmission. The lack of a well-integrated system to combat COVID-19 makes prevention challenging in developing nations . AccordiAs we have seen in different countries of the world, a few studies have explored health professionals' behavior in using social networking sites for accessing COVID-19-related information . SimilarA cross-sectional study was carried out among health professionals from 25 January to 20 February 2021, to assess the attitude of health professionals toward the use of social media for accessing COVID-19 related information in Bahir Dar town health centers, which is the objective of this research. Bahir Dar is the capital of the Amhara Region and is situated in the northwestern part of Ethiopia, which is 490 km far from the capital, Addis Ababa . In the The population included in this study consisted of all health professionals who had at least one social media account in Bahir Dar town health centers. This population had experience in social media practices and could give adequate data on the research questions. However, health professionals who were severely sick and on annual leave during the data collection period were excluded.The calculated sample size for this study using the single population proportion formula was 423, while the total number of health professionals in Bahir Dar town health centers who had at least one social media account was only 355. Therefore, all health professionals meeting the eligibility criteria were included.The study's primary outcome variable was health professionals' attitudes toward using social media for COVID-19-related information. This study's tools were adapted from a review of related studies , 17. SomAttitudes toward social media usage for COVID-19-related information were measured by using a 5-point Likert scale from “strongly disagree” (score 1) to “strongly agree” (score 5) (score 5) . The itescore 5) , 26. As score 5) .A self-administered, structured, and pre-tested questionnaire in English was used to collect data from the study population. The data were collected by ten health informatics technicians with excellent communication skills, with two health informatics professionals with prior study experience in supervising the data collection process. In addition, 1 day of training was given to data collectors. A pre-test was done out of the study area, at Gondar town in Gondar health center with 10% of the study population to avoid unclarity before actual data collection. The researchers attempted to reduce response bias based on survey replies during the pre-test. This was done by looking over the questions and making sure they were balanced, avoiding any that would provoke a strong emotional response in one direction or the other. The pre-test results were also used to evaluate the data collection instrument's validity and reliability. Cronbach's alpha result was used to assess the data collection instrument's internal consistency, and the score on attitude toward social media usage for COVID-19 was 0.86.p-value of <0.2 were included in the multivariable regression analysis. The odds ratio (OR) with 95% CI and p-value were calculated to evaluate statistical significance. For all statistical significance tests, the cut-off value was p <0.05. Multicollinearity assumptions were evaluated before running the logistic regression model, and all the variance inflation factor (VIF) values were <3, indicating no multicollinearity between variables. Since our outcome variable is not normally distributed, we have fitted a multivariable binary logistic regression. The model fitness was assessed by Hosmer and Lemeshow test, which indicates that it was well-fitted where the p-value was >5% .The data entry and cleaning were performed by using Epi-data version 4.6. After that, the data were exported to SPSS version 25 software for analysis. Descriptive statistics and percentages were computed to describe the socio-demographic variables and attitudes toward social media usage for COVID-19 information. Bivariable and multivariable binary logistic regression analyses were used to measure the association between the dependent and independent variables. In the bivariable regression analysis, factors having a The questionnaire was completed by 341 (96%) of the 355 participants. The respondents' average age was 31.49 (SD ± 6.42) years. As shown in , 235 (68CI: 67–77%) had a good attitude toward using social media for accessing COVID-19-related information. via social media is valuable and engaging. Furthermore, 47.2% of them thought using social media to stay up to date on COVID-19 was a good idea.Of the total respondents, 248 (72.7%)  healthcare providers were daily users of social media. As shown in While using social media to access COVID-19-related information, about 74.5% of health professionals concluded that COVID-19-related information released on SMNs was trustworthy. Furthermore, 81.8% of health professionals argued that COVID-19-related information published on SMNs was useful, and 194 (56.9%) had privacy concerns while using SMNs for COVID-19-related information.In both bivariable and multivariable analysis age, basic computer training, the usefulness of SMN to seek COVID-19-related information, and the trustworthiness of COVID-19 information posted on SMN were significant variables in the attitude of health professionals toward the use of social media for COVID-19 related information .<24 and 25–34 years) were approximately  and  times more likely to have a good attitude toward using social media for COVID-19-related information when compared with those who are >35 years of age. Health professionals taking basic computer training were  times more likely to have a good attitude toward using social media for COVID-19-related information. Similarly, health professionals who perceived social media as helpful in seeking COVID-19 information were  times more likely to have a good attitude toward using social media for COVID-19-related information than those who perceived it not helpful. Respondents argued that COVID-19 information posted on SMN trustworthy were  times more likely to show a good attitude toward using social media for COVID-19 related information than their counterparts.Health professionals who were younger  in the attitude of health professionals toward using social media for accessing COVID-19-related information  of health professionals had a favorable attitude toward using social media for accessing COVID-19-related information in this study. The possible explanation for the high attitude level in this study may be COVID-19 pandemic makes health professionals have a good attitude toward the technology . FurtherThis study showed that Facebook and Telegram were the most frequently used social media platforms for accessing COVID-19-related information. This finding supports previous research , 32 thatThe multivariable model revealed that respondents' age, basic computer training, the usefulness of social media for accessing COVID-19 information, and the trustworthiness of COVID-19 information posted on social media were all significant factors associated with health professionals' attitudes toward using social media to access COVID-19 related information.Among the factors, younger health professionals were more likely to have a good attitude toward using social media for COVID-19 information. This conclusion has been supported by previous research on the subject , 33. YouThis study also indicated that taking basic computer training was found to have a significant association with the attitude of health professionals toward the use of electronic health information sources, such as social media. This may be justified that computer-related training was more likely to increase health professionals' familiarity with using digital media, including social media platforms for accessing health information. Study findings from Ethiopia , 35, SauThe findings also showed that the perceived usefulness of social media networking sites was positively associated with health professionals' attitudes toward using social media to seek COVID-19-related information. This result is consistent with other studies where health professionals who did not believe in the possible advantages of social media were less inclined to use social media for accessing health information , 36, 37.In this study, respondents who trusted COVID-19 information on SMN were more likely to have a positive attitude toward using social media to seek COVID-19-related information. This finding is consistent with other studies . This imAs a result, interventions to improve health professionals' basic computer skills, such as training on how to access and use electronic health information sources and emphasizing individual factors, such as usefulness and trustworthiness, may have a positive impact on health professionals' use of social media in combating the COVID-19 pandemic.In general, health professionals had a moderate attitude toward using social media for accessing COVID-19-related information. Being young, having computer training, perceived usefulness, and trustworthiness of SMN contributes to a positive attitude toward using social media for COVID-19 information.Providing comprehensive digital platform training, improving health professionals' expectations of the usefulness of social media networking sites, and implementing more trusted information sources are necessary measures to increase the health professionals' attitude toward using social media for accessing pandemic-related information.Since this study was an institution-based cross-sectional survey, only health professionals who came during the data collection period were interviewed, thus excluding those who were absent during data collection time. Additionally, the information collected was self-perceived, which might have reporting bias.The ethical clearance and approval letter for this study was obtained from the Institutional Review Board (IRB) of the University of Gondar. Communication with officials was made through a formal letter received from the University of Gondar. A supporting letter was also obtained from the Amhara Regional Health bureau. All additional explanations about the research's objective and method were given with the assurance that any information contributed by study participants would be kept private. Written consent was obtained from each study participant. Participation was voluntary, and participants could withdraw from the study if they were not comfortable with the questionnaire.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethical Considerations. The ethical clearance and approval letter for this study was obtained from the Institutional Review Board (IRB) of the University of Gondar. At all level communication with officials was made through a formal letter obtained from the University of Gondar. A supporting letter was also obtained from the Amhara Regional Health bureau. All additional explanations about the purpose of the research and its procedure were explained with the assurance of confidentiality of any information provided by study subjects. Written consent was obtained from each study participant. Participation was voluntary and participants can withdraw from the study at any time if they were not comfortable with the questionnaire. The patients/participants provided their written informed consent to participate in this study.MT made significant contributions in conception, design, data collection supervision, data analysis, interpretation, and write up of the manuscript. TY, BE, and HG have contributed in extensively revising the manuscript, analysis, and interpretation. All authors have approved the final version of this 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.


Prehabilitation appears to be an effective strategy to reduce postoperative complications and enhance recovery after colorectal surgery. Although many patients prefer (unsupervised) home-based prehabilitation, adherence can be problematic. Combining home-based prehabilitation with tele-monitoring might demonstrate a higher adherence than unsupervised prehabilitation; however, evidence on its feasibility and effectiveness in patients with colorectal cancer scheduled for elective surgery who are at high risk for postoperative complications is lacking. The aim of this study was to assess the feasibility of a bimodal tele-prehabilitation program in patients with colorectal cancer at high risk for postoperative complications.High-risk patients (oxygen uptake at the ventilatory anaerobic threshold ≤11 mL/kg/min or oxygen uptake at peak exercise ≤ 18 mL/kg/min) with colorectal cancer were included in a home-based bimodal tele-prehabilitation program. The program consisted of a personalized tele-monitored moderate to high-intensity interval training intervention and nutritional counseling. Feasibility was measured by participation rate, dropout rate, adherence to the physical exercise training session’s frequency, intensity, and time, and retention rate. Patient appreciation was measured by a patient appreciation questionnaire. Changes in preoperative physical fitness as secondary outcomes were quantified by time to exhaustion on a constant work rate (cycle) test, number of repetitions on the 30-s chair-stand test, and walking speed on the 4-m gait speed test.p = 0.24). Median number of repetitions on the 30-s chair-stand test improved from 12 to 16 (p = 0.01).The participation rate was 81%, there were no adverse events, and all participants managed to complete the tele-prehabilitation program (retention rate of 100%). Adherence with regard to the exercise program’s frequency, intensity, and time was respectively 91%, 84%, and 100%. All participants appreciated the tele-prehabilitation program. Time to exhaustion on the constant work rate test improved  from a pre-prehabilitation median score of 317 seconds to a post-prehabilitation median score of 412 seconds effectiveness of tele-prehabilitation regarding preoperative improvements in preoperative aerobic fitness and postoperative reduction of complications.ISRCTN64482109. Registered 09 November 2021 - Retrospectively registered.ISRCTN,  There is a growing amount of evidence showing that prehabilitation can effectively improve preoperative aerobic fitness and reduce the incidence of postoperative complications in patients who are referred for abdominal surgery  home-based prehabilitation as opposed to supervised hospital-based prehabilitation is that adherence can be problematic without supervision  the benefits of home-based and supervised prehabilitation might be combined. This way, adherence can be measured objectively and accurately, and patients can be coached, motivated, and encouraged via tele-monitoring while performing their home-based individualized training sessions at a time and place of their preference. Evidence in patients with musculoskeletal conditions suggests that, compared to classic unsupervised home-based programs, tele-monitoring can improve adherence  is feasible in high-risk patients scheduled for colorectal cancer surgery. Secondary aims were to evaluate patient experiences and changes in preoperative aerobic fitness before and after the tele-prehabilitation program.The current pragmatic one-arm pilot feasibility study was carried out at VieCuri Medical Center, a large teaching hospital in Venlo, the Netherlands. The study was approved by the Medical Ethics Review Committee – Zuyderland/Zuyd  under reference number METCZ20190150. Initially, the trial started in February 2020; however, due to restrictions caused by the worldwide COVID-19 pandemic, inclusion could only start in July 2020 and ended in September 2021. Reporting was done in accordance with the CONSORT statement extension to randomized pilot and feasibility trials  at the ventilatory anaerobic threshold (VAT) ≤ 11 mL/kg/min or a valid VO2 at peak exercise (VO2peak) ≤ 18 mL/kg/min during CPET in combination with confirmed diagnosis of colon or rectal cancer  requiring elective resection with or without neoadjuvant treatment.A consecutive sample of potentially high-risk patients was recruited at the moment of suspected colorectal cancer by endoscopy. A few days after the endoscopy, patients were contacted by telephone to check for potential eligibility and willingness to participate. Patients were potentially eligible when they were ≥ 18 years of age, were able to operate a mobile phone, and had a score ≤ 7 metabolic equivalents of task (METs) on the veterans-specific activity questionnaire (VSAQ). These eligibility criteria were used as a pre-screening. Final eligibility was determined after CPET and final diagnosis, which was defined as an oxygen uptake (VOT0) were planned on the day of the appointment with the surgeon, approximately 2–5 days after final inclusion. In patients receiving neoadjuvant treatment, pre-prehabilitation measurements were performed concurrent with the first appointment with the surgeon after completing neoadjuvant treatment (approximately 4 weeks before surgery). Pre-prehabilitation (T0) assessments consisted of evaluating aerobic fitness by time to exhaustion on a continuous work rate test at 80% of the peak work rate achieved during CPET. Additionally, lower limb muscle power and endurance was assessed by the number of repetitions on the 30-s chair-stand test and gait speed was measured using the 4-m gait speed test. Post-prehabilitation (T1), reassessment of the continuous work rate test, 30-s chair-stand test, and the 4-m gait speed test took place 1 or 2 days prior to surgery. In addition, participants filled out a patient appreciation questionnaire, based on the questionnaire of Dronkers et al.  score ≤ 11, interspersed by 3 min of high-intensity exercise at a heart rate just below the heart rate at the respiratory compensation point (approximately 70–85% of the heart rate at VO2peak) or a Borg RPE score of 14–16. In-between training days, patients were advised to retain relative rest but still comply with the Dutch physical activity guidelines . The abovementioned training protocol was used as a blueprint, which means that training frequency, intensity, time, type, volume, and progression were personalized according to CPET results , training heart rate, training Borg RPE score, recovery after training, and participant experiences and preferences. After the first face-to-face physical exercise training at home, which was supervised by a physical therapist specialized in physical exercise training in clinical populations, participants continued the home-based physical exercise training sessions independently. Involvement of a family member or  caregiver during exercising was encouraged to promote motivation. The first face-to-face session was used to validate training zones and familiarize participants with the exercises and equipment. Performed training session’s frequency, intensity, and time were automatically uploaded to an online platform, at which they could be reviewed by the physical therapist. A weekly phone call took place to monitor training progression and adjust the physical exercise program accordingly.The tele-monitored physical exercise training module was delivered by using the mobile phone application of HC@Home  on a dedicated mobile phone (delivered to the patients for the duration of the tele-prehabilitation program) to which a heart rate monitor  was connected. Personalized training zones were set based on the heart rate at the VAT and the respiratory compensation point as determined by CPET. Ideally, training sessions took place every other day and consisted of 30 min of aerobic moderate- to high-intensity interval training by a patient’s preferred activity . Intervals consisted of 3 min of low-intensity exercise at a heart rate below the heart rate at the VAT and/or a 6Participants were screened for malnutrition using the patient-generated subjective global assessment short form (PG-SGA-SF) in combination with a comprehensive nutritional screening by a registered dietician. Preoperative nutritional counseling consisted of optimization of basic nutritional needs, as well as ensuring the recommended intake of protein, defined as 1.2–2.0 g/kg body mass  study participation rate combined with reasons for non-willingness or inability to participate, (2) the number and severity of adverse events related to the physical exercise training program, (3) adherence to the physical exercise training program, (4) study dropout rate and reasons for dropouts, and (5) retention rate. Secondary outcomes were (1) participant experiences as measured by the patient appreciation questionnaire, (2) user-friendliness of the mobile phone application that was used for tele-prehabilitation assessed using the systems usability questionnaire . Participation rates were reported descriptively as numbers and percentages of the potentially eligible patients that were willing to participate in the current study. Dropout rates and adverse events were reported as numbers and as a proportion of participants enrolled in the study. Retention rate was expressed as a percentage and defined as the proportion of enrolled participants that completed the program. Adherence to the physical exercise training program with regard to training frequency, training intensity, and training time was determined as follows. For training frequency, observed training frequency was divided by the prescribed frequency and expressed as a percentage. Regarding training intensity, an exercise training session was designated as performed at an adequate intensity when, based on heart rate, at least 3 of the 5 prescribed high-intensity exercise bouts complied with the prescribed intensity, or when the training session intensity reported on the Borg RPE score was equal or higher than prescribed. The number of attended sessions in which the prescribed intensity was accomplished (based on either heart rate or Borg RPE score) was divided by the total number of attended sessions and presented as a percentage. For training time, the observed duration of the sessions was divided by the prescribed duration of the sessions and presented as a percentage. Adherence was deemed adequate if ≥ 80% as assessed individually for training frequency, training intensity, and training time. Participant appreciation of the tele-prehabilitation program, as scored by the patient appreciation questionnaire, and user-friendliness of the mobile phone application of HC@Home, as scored by the systems usability questionnaire, were reported descriptively. A systems usability questionnaire score ≥ 73 was considered good, and a score of ≥ 85 excellent user-friendliness . Median time between start of the physical exercise training program and surgery was 23 days (range 6–30) (Table The median time that elapsed between diagnosis (date of endoscopy) and surgery was 34 days range 20–51) for participants with surgery as their first treatment (0–51 for Participant appreciation of the tele-prehabilitation program is depicted in Table Median systems usability questionnaire score was 85 (IQR 78–100). All 11 patients had a systems usability questionnaire score ≥ 73, indicating that the user-friendliness of the mobile phone application was good. Six patients had a systems usability questionnaire of ≥ 85% indicating excellent user-friendliness Fig. .Fig. 2Pap = 0.24) and from a median of 307 s to a median of 459 s (p = 0.07) with and without the participant with a general feeling of discomfort at the post-prehabilitation assessment, respectively. Following the tele-prehabilitation program, the number of repetitions at the 30-s chair-stand test significantly improved from a median of 12 to a median of 16 repetitions (p = 0.01). No significant changes were observed in walking speed as measured by means of the 4-min walk test (p = 0.33).Pre- and post-prehabilitation (preoperative) assessment of physical fitness was performed in 10 participants (91%) as shown in Fig. The current study aimed to evaluate the feasibility of a home-based tele-prehabilitation program in high-risk patients with colon or rectal cancer scheduled for surgery. Tele-prehabilitation was deemed feasible, as willingness to participate was high (81%) and adherence was good (> 80%). Patients felt the tele-prehabilitation prepared them well for surgery. Changes in physical fitness measured before and after the tele-prehabilitation program showed a trend towards improved physical fitness after tele-prehabilitation. There are no specific recommendations regarding the sample size of feasibility studies. Although only 11 participants were included in the current study, these participants were deemed representative of a larger population of patients with colorectal cancer with a high risk for postoperative complications, because participant characteristics are in line with participant characteristics in a larger randomized controlled trial in the same population  unsupervised home-based prehabilitation is the often observed low exercise session adherence  after a short introduction session. These results are in accordance with a multimodal tele-prehabilitation study in patients with abdominal cancer that used commercially available wearables to improve physical fitness prior to surgery  or being unable to perform a CPET . Although these excluded patients did not undergo CPET and therefore it is uncertain whether they would have been classified as high risk, the reasons for exclusion are specific for a tele-prehabilitation program. In addition, previous research has shown that patients that are unable to perform CPET should be treated as high-risk . Combined with a relatively long interval between diagnosis and start of the prehabilitation , this leaves limited time for a comprehensive prehabilitation program in patients who receive surgery as their first treatment. These time limitations are often caused by logistics  and time constraints. Efforts should be made to use the available time as efficiently as possible, for example by starting screening, assessment, and prehabilitation directly after colorectal cancer diagnosis by endoscopy. Nevertheless, although essential for effective prehabilitation, these strict time constraints are not strongly supported by evidence  to the physical exercise intervention. Another strength of the current study is that tele-prehabilitation was implemented within the current colorectal cancer treatment pathway and no additional study visits were required for participants.In future research, attempts should be made to optimize adherence to the exercise training intensity of the tele-monitored physical exercise program, for example by using a combination of physically supervised and tele-monitored supervision. Furthermore, a larger prospective observational study could be designed to evaluate willingness to participate, adherence, and (cost-)effectiveness of prehabilitation when different forms of multimodal prehabilitation  are presented to patients.Results of this feasibility study have shown that a home-based tele-prehabilitation program is feasible and appreciated in high-risk patients undergoing surgery for colorectal cancer. However, efforts should be made to further improve adherence towards exercise intensity. More research is needed to establish the (cost-)effectiveness of tele-prehabilitation with regard to improvements in preoperative aerobic fitness and reduction of postoperative complications before definitive conclusions can be drawn.


Given the current state of COVID-19, it is crucial to reveal its evolving relationship with and effect on different body organ systems and their diseases. The severity and outcome of COVID-19 have a very complex relationship, especially to the vital organs including the kidney, either in their state of health or disease. Additionally, it is well known that diabetes affects the kidney, leading to diabetic nephropathy. The kidney is also affected by different pathological and immunopathological reactions with COVID-19 infection, leading to acute kidney injury. Therefore, this review intended to extract the recent advances, updates, and discoveries about the effects of COVID-19 on diabetic patients and the relationship between COVID-19 invasion and the diabetic kidney and to discuss the current state of knowledge that has not yet been proved or disproved, leading to numerous controversial issues in looking for the effect of COVID-19 associated with diabetes mellitus on the human kidney. In China, numerous cases of novel coronavirus pneumonia (NCP) have been observed since December 2019 . TherefoExisting research has mainly assessed the relationship between the presence of any chronic heart conditions and COVID-19 associated death, where subtypes of all heart conditions have been collectively investigated . In contMoreover, DM affects 425 million individuals globally and is predicted to increase by over 600 million by 2045 [DM is linked to a high severity of disease and a high risk of death in COVID-19 confirmed cases. It was observed that DM is related to higher disease severity and worse short-term outcomes. Additional robust personal prophylactic plans are recommended for diabetic people, and extra intensive surveillance and management should be considered if those are confirmed with COVID-19, particularly for elderly persons or those with pre-existing clinical conditions .Approximately 34.2 million of the population have diabetes in the US, in which diagnosed account for 26.9 million and undiagnosed for 7.3 million . CommonlMoreover, a study of 13,268 COVID-19 cases demonstrated that diabetes is significantly related to progression of COVID-19. Confirmed cases of COVID-19 with diabetes showed a high risk of disease severity and related mortality consequences. Considering the rapid increase in research information, future meta-analyses which systematically review the literature are necessary to elucidate the relationship between distinct comorbidities and the risk of COVID-19 progression and death .Persons with diabetes are more prone to contracting the viral infection, as observed during waves of preceding diseases. This does not appear to be the case for COVID-19; however, diabetes is more widespread amongst those with severe COVID-19 . In WuhaMany with COVID-19 do not experience cytokine storms and their symptoms. Some individuals may be more likely to receive cytokine storms from COVID-19 when they have the specific genes that elicit the immune system to respond in this way; currently, this is not definitively known. The severity of a COVID-19 infection is significantly determined by the existence of underlying health conditions .Diabetes leads to a rise in the risk of thromboembolic events, as it is linked to a prothrombotic state. Such a prothrombotic state results from a difference in clotting factors and fibrinolysis. Furthermore, COVID-19 raises coagulation activity. Intravessel coagulation through infection results from endothelial dysfunction related to hypoxia. Anticoagulation therapy in COVID-19 confirmed cases seems to improve disease prognosis . VarikasPersons with type 1 and type 2 diabetes treated with insulin, or type 2 diabetes not treated at home with insulin who have raised blood sugar in the hospital should have scheduled insulin while they are hospitalized to accommodate the need for high insulin. Before the COVID-19 outbreak, most patients in the emergency care setting were administered IV insulin infusions. However, several institutes have revised and implemented strategies such as scheduled insulin doses and the use of premixed insulin to treat severely ill cases because of staffing anxieties. It is essential to confirm that the patient is getting regular blood glucose monitoring during insulin therapy. COVID-19 cases have variable degrees of insulin requirements during their admission as a result of factors such as, for instance, concomitant drugs  and altering pathophysiologic conditions  .+ T cells. It was observed that the count of total T cells and CD4+ and CD8+ T cell subgroups were considerably decreased and functionally exhausted in confirmed COVID-19 cases, particularly among elderly and seriously ill cases requiring ICU admission. Kulcsar et al. [+ T cells. Therefore, ideal diabetes and intensive glycemic control treatment may aid in stopping the incidence of severe infections and problems associated with DM. It also fights against the enhanced vulnerability of infections resulting from weakened cellular and humoral immunity [Diabetes leads to a pro-inflammatory homeostatic immune reaction biased towards T helper cell 1 (Th1) and T17 cells and a decrease in regulatory T cells (Treg). Immune dysfunction of diabetes alone or resulting in infection has been observed for various immune cells, including monocytes, macrophages, and CD4immunity .Thus, it appears instinctive to guess that this pathogenic disorder could describe the rising drift of cases, hospitalization, and death for individuals with type 2 diabetes during COVID-19 infection. Additionally, lung infection in type 2 diabetes patients seem to be associated with both interleukin (IL)-6 pathways and hyperglycemia. Notably, supporting these concepts, a current and capable experimental intervention using a monoclonal antibody against the IL-6 receptor in Italy appears helpful in severe lung illness and prognosis in COVID-19 confirmed cases .DM and CKD are common illnesses that display a synergistic relationship with early death. CKD has an important global occurrence affecting 7.2% of the universal adult population, with the count intensely raised in older adults . It was It is well recognized that SARS-CoV-2 targets respiratory cells; however, other organs, namely the heart, ileum, and kidneys, might be damaged by the invaded virus because they have ACE2. It is acknowledged that the kidneys are more prone to damage, consistent with ACE2 expression. Additionally, SARS-CoV-2 is likely to damage the arterial smooth muscle and myocardial cells. As ACE and ACE2 are dissimilar enzymes with two diverse active sites, angiotensin-converting enzyme inhibitors (ACEi) do not impede ACE2. Furthermore, the evidence is unreliable and varies among the different ARBs, through ARBs can motivate ACE2 in experimental models . The regThough CKD is not listed as a causative factor for severe COVID-19, it has arisen as the most predominant comorbidity indicating a high risk for severe COVID-19. Moreover, CKD accounts considerably for the severity of COVID-19. This condition currently leads to intensive efforts to enhance the results for the universal CKD cases (850 million) .Furthermore, COVID-19 in diabetic patients is related to an unduly poorer prognosis. Diabetic ketoacidosis (DKA) is a severe problem resulting from diabetes that is characterized by a mortality rate of about 0.67%. A recent study has revealed the natural history of DKA in the existence of coronavirus disease. It explored the impact of COVID-19 on symptoms, clinical progress, and results in DKA patients. COVID-19 seems to impact the usual history of DKA conversely in type 1 and type 2 diabetes. COVID-19 in type 1 diabetes cases demonstrated a high level of hyperglycemia. Type 2 diabetes cases affected with COVID-19 and DKA showed a remarkably high necessity of ICU and high mortality rates. There is a prerequisite for a joint multi-center study to offer further conclusive outcomes .A study by Leon-Abarca et al. observed that DM exerts a more substantial effect on the rates of infection, intubation, ICU admission, and case fatality due to COVID-19 than CKD alone. DKD patients with COVID-19 showed a higher level of morbidity and mortality than those with only CKD and COVID-19. This variation might result from the supplementary impacts of chronic inflammation and immune dysfunction. DKD patients showed highly significant rates of infection with SARS-CoV-2, ICU admission, and case-mortality when compared to patients with CKD alone. The rates of lung infection and intubation were twice that of CKD alone in DKD cases . AnotherDiabetes treatment in COVID-19 confirmed cases poses a tremendous medical endeavor, requiring a highly cohesive team method since it is crucial to decrease the risk of clinical problems and demise. Cautious evaluation of the numerous elements that influence worse prognosis with COVID-19 in diabetic cases might help control the present circumstance and allow the health systems to prepare to meet the upcoming encounters efficiently . The sitConcerning kidney failure and kidney replacement therapy, dynamic actions should be taken to reveal the risk factors for kidney function damage in seriously ill cases . While treating cases with renal failure, the attention should be on the balance of acids, bases, electrolytes, body fluid, and diet; counting nitrogen balance; and the addition of trace rudiments and energies. Continuous renal replacement therapy (CRRT) can be done in seriously ill cases. CRRT is advised for the circumstances such as acidosis, pulmonary edema, or water overload; hyperkalemia; and fluid control in multiple organ dysfunction .Additionally, a recent study in Saudi Arabia observed the clinical features and results of hospitalized COVID-19 cases with or without DM. It observed the occurrence of DM is high among hospitalized COVID-19 cases in a university hospital in Riyadh. While DM cases have more mortality rates than their counterparts, other elements such as smoking, aging, use of β-blockers, congestive cardiac failure, lung infiltrates, high creatinine, and a severe lack of vitamin D seem to be more critical forecasters of lethal outcomes. Persons with acute metabolic dysfunctions, such as high blood glucose on admission, are more likely to receive rigorous care . This fiLastly, the interconnection between DKD and COVID-19 should initiate more investigation to reveal the degree to which the virus’ precise mechanisms can influence the deterioration of glycemic control. In certain cases, the remarkable growth of hyperglycemic hyperosmolar syndrome or DKA and perhaps, emerging new-onset DM might lead to an acute kidney injury . The rolIn diabetic patients, poor glycemic control is related to worse outcomes. Few mechanisms enhanced the ability of COVID-19 to influence patients with diabetics. Normal kidney functions affected by COVID-19 are of different forms, including acute kidney injury. The kidney of a diabetic patient will be more prone to a significant effect of COVID-19 depending on the stage of DKD. DKD cases showed higher rates of infection (SARS-CoV-2), ICU admission, and demise than cases with CKD alone, and the lung infection and intubation rates doubled. It was inferred that CKD is a crucial forecaster of death in confirmed cases of COVID-19. The significance of prioritizing confirmed COVID-19 cases with CKD in hospitalization led to close observation and kind care. Further research is essential to investigate the effect of COVID-19 on continuing renal function, existence, and quality of life.