The prevalence of mental distress among university students in low- and middle-income countries (LMICs) is increasing; however, the majority do not receive evidence-based psychological intervention.This calls for the provision of culturally adapted psychological therapy in higher education institutions in LMICs. The aim of this pilot study is to evaluate the feasibility and acceptability of Interpersonal Psychotherapy adapted for Ethiopia (IPT-E) among Wolaita Sodo University students and to assess the preliminary outcomes of IPT-E in reducing symptoms of mental distress and in improving functioning.We used a quasi-experimental single-group pre-post-test study design. As indicators of feasibility of IPT-E, we used consent, treatment completion and attrition. We used Client Satisfaction Questionnaire and semi-structured interview to measure the acceptability of the intervention,self-reporting IPT-E checklist to assess treatment adherence and World Health Organization Disability Assessment and Self-Reporting Questionnaire-20 tools to assess functional impairment and mental distress, respectively. We used percentage, frequency, mean and standard deviation to summarize the demographic variables, feasibility and acceptability of IPT-E. We analyzed changes from pre- to post-tests of mental distress and functioning results using paired t-test and Wilcoxon signed-rank tests. Independent sample t-test and one way-ANOVA used to assess the difference in mean score of in demographic variables at baseline and eight weeks. The qualitative data was analyzed with the support of open code 4.02.IPT-E was feasible . The total mean score of treatment satisfaction was 27.83 (SD = 4.47). After the delivery of IPT-E, symptoms of mental distress were decreased, functioning was improved and therapist adherence to the treatment model was 100% (i.e. treatment delivered according to the IPT-E guideline).IPT-E was feasible and acceptable to treat university students with mental distress in low-income country setting. The preliminary results also suggest promising viability of IPT-E in higher education institutions of low-income country setting for students with symptoms of anxiety and depression.The online version contains supplementary material available at 10.1186/s40359-021-00570-1. The prevalence of mental distress understood as the symptoms of anxiety and depression is higher among university students as compared with the general population  has incrIncreased severity of mental distress along with the lack of access to professional mental healthcare are associated with an adverse effect on students’ academic achievement, physical health, emotion, self-esteem, social relationships, cognitive development, and their overall quality of life. Evidence showed that students with mental distress and who did not receive mental healthcare timely experienced low academic performance  and suicDespite the increasing number of universities in LMICs and a growth in the proportion of students enrolled in these universities, the provision of professional mental health services for students remains underdeveloped, largely because there are insufficiently trained therapists/counselors . As a re, Egypt [Psychological interventions are effective in treating CMDs (anxiety and depression) in LMICs  and are , Egypt , and Eth, Egypt . IPT is , Egypt .Interpersonal conflict is defined as “a situation in which the patient and at least one significant other person have non-reciprocal expectations about their relationship”  informalGrief is another IPT focal area that occurs when a student loses a significant person by death . It is cHowever, the feasibility and acceptability of IPT has not been well studied in LMIC university setting, where most students’ mental distress is mainly caused by role transitions, interpersonal conflicts and grief. At the global level, some studies showed the feasibility and acceptability of IPT among adolescents. For example, a quasi-experimental study conducted in Columbia reported that brief IPT was feasible and acceptable in reducing mild to moderate symptoms of depression and improving social functioning among adolescent students . A systeThe high prevalence of mental distress and challenges encountered by university students in LMICs are a call to implement culturally appropriate evidence-based and practical psychological intervention. Although previous studies recommend the need for accessible and acceptable evidence-based mental health interventions for university students with mental distress, to our knowledge, there is no published evidence from studies conducted in Ethiopia on the feasibility and acceptability of IPT for university students with mental distress. The primary aim of this pilot study was to evaluate the feasibility and acceptability of brief individual Interpersonal Psychotherapy adapted for Ethiopia (IPT-E) among Wolaita Sodo University (WSU) students. And the secondary objective was to evaluate outcomes that include the preliminary effectiveness of IPT-E in reducing symptoms of mental distress and improving functioning.The current study was conducted at WSU, a non-profit public university in Wolaita zone, Wolaita Sodo City which is located 320 km south of Addis Ababa, the capital of Ethiopia. The University was established in 2007 with intake of 801 students in four faculties and sixteen departments. Currently, the University runs undergraduate and graduate programs in regular, weekend and summer courses in six colleges and five schools with a total student population of 30,000. The University has its own health service facilities and it has four full-time counselors with four counseling offices that provide free counseling services for students with mental health and psychosocial problems. WSU has a referral teaching hospital (named as Otona) that provides health care services, including psychiatric care for the surrounding community and students. A dedicated clinic within the university compound provides health care services for students and it has a referral system with the hospital for students with severe physical and mental illnesses. In response to the occurrence of coronavirus (COVID-19) pandemic the University has established a Mental Health and Psychosocial Support center to help students with COVID-19 related issues.We used a quasi-experimental single group pre- and post-test design with repeated measures for secondary outcomes. The data were collected from December 2019 to February 2020.Our source population is undergraduate students in WSU. We posted flyers in target areas, including: the students’ dormitories and cafeteria, the main gate of the university, the library, and student’s health clinic. In addition, we prepared three banners in collaboration with the WSU student’s Dean and counseling offices. These banners were posted in the same strategic areas as the flyers. The flyers and banners were written in Amharic, the official language of Ethiopia which most students speak. The flyers and banners encouraged those students who experienced symptoms of psychological distress to come to student services for IPT-E. The flyers and banners included the names, addresses and contact data of the counselors as well as their time of availability.The counselors registered students that came to the counseling offices requesting assistance following the distribution of the flyers and erection of the banners, and screened them based on eligible criteria for IPT-E: they were an undergraduate student; scored 8 or more on SRQ-20; they were 18 years or older; willing to attend at least 4 IPT-E sessions and able to speak the Amharic or Wolaitigna or Afan Oromo language. The exclusion criteria were: students with serious physical illnesses; suffering from cognitive impairment; severe mental illness; and already receiving psychiatric medication or psychological treatment or traditional treatment. The counselors asked the students some questions to identify these exclusion criteria. Twenty six eligible students were recruited and participated in the IPT-E sessions. See Fig. IPT has been adapted to the Ethiopian context in collaboration with Toronto Addis Ababa Psychiatry Project and the Biaber Project and named Interpersonal Psychotherapy adapted for Ethiopia (IPT-E) . This cuThe IPT-E beginning phase includes screening a client for mental distress; how to select cases appropriate for IPT-E; ensuring consent to participate in the treatment; and screening for client safety such as suicide, domestic violence, harming others and substance use. The counselors understand clients’ problems, symptoms, functioning, and explanatory model using a Treatment Tracking Form (TTF). They also conduct an interpersonal inventory, and provide tailored psycho-education for the client. Finally, the counselors formulate one or maximum two IPT-E focus area/s  for the next middle phase of the intervention.The middle phase of IPT-E is the heart of the intervention, where general techniques such as role play, psychosocial supports, brainstorming, and communication analysis were practically implemented on the selected IPT-E focus area/s. This occurred in combination with several techniques to address the focus area specifically. In this phase, symptoms and functioning are tracked at each session using the TTF. In the termination phase, the counselor reviews the client’s efforts, progress, therapeutic achievements and changes made in the beginning and middle phases. Throughout treatment the counselor has an IPT-E treatment checklist to note the various IPT-E activities used in the counseling process.The IPT-E was conducted on a weekly basis and lasted for 40–60 min per session. The number of sessions attended in the IPT-E ranged from 4 to 8. IPT-E has a screening tool which consists of 6-items used to identify participants with mental distress. Both the screening and treatment were given by four counselors under the close supervision of the principal investigator in their own counseling offices, which were well furnished, ventilated, and attractive. All the counseling offices are situated in the same building as the student’s clinic, which promoted a robust referral system and avoided stigma of student clients having separate mental health services. The sessions were not audio-recorded because clients were not comfortable with this. However, the delivery of IPT-E in every session was documented by the counselors using the IPT-E treatment checklist. All counselors had their clients’ cell phone numbers to remind them of the time of their appointment. Clients who had to miss a session due to unexpected events agreed in advance to communicate his/her counselor via cell phone and then rebook for the next appropriate day. The first author of the article supervised the counselors’ work every week.The intensive IPT-E training was given for four consecutive days and included practical sessions on the clinical skills required. Initially, five counselors participated in the training, but four completed the training. The two women counselors had a Bachelor degree in Public Health, one male counselor had a Master’s degree in Public Health and the other had a Master’s degree in Counseling Psychology. Three of them could speak Amharic and Wolaitigna languages fluently and one counselor could speak Afan Oromo and Amharic languages fluently. The training was given by the principal investigator who has a Bachelor’s degree in Psychology, a Master’s degree in Counseling psychology, had 2 years counseling experience in WSU counseling office and has attended the theoretical and practical training of IPT-E given by the manual adaptors.To evaluate the outcome of the training, the trainer administered pre- and post-tests prepared from the IPT-E manual and a training satisfaction feedback measuring tool. All counselors showed a significant change in the post-test result compared to the pre-test indicating that the counselors received the necessary knowledge to implement IPT-E in the practical session. The practical sessions also helped them to acquire the clinical skills of implementing IPT-E. Besides this, all the counselors rated the training as excellent and reported that the standard quality of the training was high and fulfilled their expectations. They reported that they received practical knowledge that enabled them to treat students with symptoms of anxiety and depression.Five instruments were used to collect the demographic and outcome data. IPT-E screening tool and TTF were used together to collect data including participants’ age, sex, marital status, perceived cause of the problem, treatment received, onset of the problem, concurrent problems, medication, substance use, experience of gender based violence, suicide ideas, plan and past attempts, and thoughts and past attempts of harming others. The second instrument was IPT-E feasibility measuring tool, which was used to evaluate the number of students who attended the intervention session, consent rate, completion rate, attrition rate, the duration of the intervention session attended, and the mean and modal number of sessions completed over 8-weeks.The third instrument was Client Satisfaction Questionnaire-8 items (CSQ), which was used to measure acceptability of IPT-E. The 8-items were rated on a Likert scale ranging from 1 to 4 that yield a minimum total score of 8 and a maximum total score of 32 . In addiThe fifth tool was World Health Organization Disability Assessment (WHODAS-2.0) . This inThe six instrument was Self-Reporting Questionnaire-20 items (SRQ-20) used to measure the extent of mental distress in the last 30 days. This tool is primarily developed by WHO and recommended to LMICs to screen positive cases of mental distress . It has See Additional file In the present study, data were collected at baseline and at eight-weeks. The data collected using SRQ-20 and WHODAS-2.0 were measured twice, whereas the data measured by CSQ, IPT-E feasibility measuring tool, and interviews of the clients were collected at eight weeks. The quantitative data were analyzed using Statistical Packages for the Social Sciences version 20 after cleaning, checking the missing values, outliers, and after checking normality assumption of the distribution of continuous variables. The demographic variables, feasibility and acceptability of IPT-E and treatment satisfaction were summarized using percentage, frequency, mean, and standard deviation.p-value was less than 0.05. The audiotaped qualitative data of the acceptability of IPT-E were transcribed verbatim and translated and then analyzed using thematic analysis approach supported with a qualitative software, open code 4.02 [The preliminary effectiveness of IPT-E measured by SRQ-20 at pre- and eight weeks were analyzed using paired t-test and the functioning data measured by WHODAS-2.0 at baseline and post-assessment were analyzed by Wilcoxon signed-rank test. Independent samples t-test and one-way ANOVA were used to compare the mean score difference of two and more categorical variables with normally distributed continuous outcomes, respectively. The effect size was interpreted based on 0.01 = small effect; 0.06 = moderate effect; and 0.14 = large effect . Statistode 4.02 .All the ethical considerations and the methodological plausibility of the current study were done according to Addis Ababa University College of Health Sciences (AAU-CHS) Institutional Review Board  guidelinThe proportion of male–female participants was equivalent (50%) and 79.2% were single. Their age ranged from 18 to 23 years with a mean age of 21 years (SD = 1.49). The majority (75%) perceived that the causes for their mental distress were disagreement . All participants were not receiving treatment from traditional healers or from other sources throughout the study period and 50% reported that their distress started before two years prior to this study. All participants reported that they did not have concurrent medical conditions such as HIV, TB, malaria, diabetes and heart disease and substance use. They were not taking any medication during the intervention period; they reported no previous experience of gender-based violence and no past attempts of suicide and harming others. The majority (62.5%) had no thoughts of suicide and 95.8% had no plan to commit suicide. In the past month the majority (75.0%) had no thoughts of harming others , which yielded in the attrition rate of 7.69%. These two participants were excluded from the data analysis. The mean, median and mode number of the intervention sessions attended were 8.The total mean score of client satisfaction received for IPT-E was 27.83 . The majority (66.7%) rated the quality of the intervention they received being excellent; they qualitatively expressed their satisfaction as follows:translated into English as changing a dried tree to a tree with wet leaf. I received my previous identity; I am confident, strong, have a good communication with my friends (my friends are surprised by my improvement) and I am also happy.” (Interviewee #07).“Ok, thank you, eh…the care that I received is likeA 21-year-old female student said:“If I am not able to get her (the counselor) care, I would be a daily laborer and below my friends, because my family cannot afford private college fees to teach me. God showed me the counselor because she saved me the whole of my life. I found it very helpful.” (Interviewee #05).Another 20-year-old male student explained that:Forty-six percent of the study participants reported that they definitely received the kind of the services they expected and almost all of their needs were met. Despite this, most students qualitatively expressed the treatment they received as it was beyond their expectations that fully addressed their mental health care needs. if somebody is ready to listen to me; however, what I was thinking was completely different from what I received. It is beyond my expectation.” (Interviewee #07).“Normally, when I came to this office, it was because of my friend’s advice. I was not expecting to get such kind of service; I just came to tell myA 21-year-old female student said:The majority (75.0%) of the participants reported that they would definitely recommend the intervention received to their friends in need of similar care. Over half (54.20%) reported that they were very satisfied with the intervention they received. They qualitatively expressed that all of them were satisfied by the treatment given to them and they would recommend for their friends with mental distress in need of similar mental health care.“If I love him (friend), why not bring him here? Because I’m satisfied with the service I received… (laugh). Our prophet said that one person is said to be not believed in Islam until he loves what he loves for his brother. Because I am satisfied with the therapy; I am happy to bring my friends who have a problem, even anyone on the street suffering from such a problem if it is not adding a burden on the counselor. Normally, I was laughing a false laugh before therapy, however, now I am normally happy even when I did not score a good exam result.” (Interviewee #01).A 23-year-old male student said:“Yes, I received important advice that not only helps me but also enables me to even advise someone else; now I can advise another person who has similar feelings of distress. The interviewer asked, you mean you can replace the counselor? Yes, laugh…laugh… I can send other people with a problem by informing them there is a counselor who provides counseling services and I can bring them here.” A 20-year-old male interviewee #04.Another participant stated:Most (70.80%) participants reported that the mental health service they received helped them effectively deal with their problem and half (50%) of them rated their overall treatment satisfaction as mostly satisfied or very satisfied.“Extremely, my face speaks; I am very happy today; my previous happiness has returned again; I started to communicate with many people. Previously even I do not know the name of the students in our class; I asked my friend who was this student in our class? You know I entered to the class before anyone and sat at the back corner and I left the class at the end when all students went out. But now, I play and communicate with the students; we go together up-to the dormitory. I have a good relationship with my dorm mates; there is a student who disturbs me in the dormitory; I tolerate him very well; if I were in my previous mental state, I would have conflict with him.” (Interviewee #01).A 23-year-old male student said:Most (62.5%) participants reported that they would definitely return to the counseling office if they need care again.“I hope I would not have to face the problem, but if it occurs again, I will come back.” (Interviewee #08)22-year-old male student explained:There was no statistically significant difference in any of the demographic variables in the treatment satisfaction.The majority of the participants attended 8 IPT-E sessions. Each session lasted 40 to 60 min as is recommended by the IPT-E guidelines. In addition to the provision of training for the counselors and regular supervision of the delivery of IPT-E counseling service, the accomplishment of the key activities to be done in each session were immediately evaluated. All counselors ticked “yes” for all activities, indicating that the necessary tasks were done in each of the IPT-E sessions.See Additional file p-value = 0.001) in mean score symptoms of mental distress from baseline  to eight weeks post assessment  with effect size of 0.89 (large effect). At the post-assessment, four participants (16.6%) scored above the cut-off 8 on SRQ-20 (2 participants scored 10 points and another 2 participants scored 14), even if they showed symptoms reduction in mental distress from the baseline.The IPT-E showed preliminary effectiveness in decreasing symptoms of mental distress and improving functioning among students. There was a statistically significant decrease (The data collected through Treatment Tracking Form (TTF) showed an improvement of mental distress in each session. Likewise, there was reduction in the frequency of mental distress symptoms from pre-to-post assessment in the past two months. During the pre-test a large proportion of the participants reported that they experienced symptoms such as being sad, miserable or hopeless (46%); had little pleasure in doing things (54%); felt anxious (67%); and experienced a lack of energy on several days in the past one month (50%). Of all participants, 29% felt restlessness and 38% had trouble concentrating on conversations or reading nearly every-day in the past month. Of the total participants, 33% felt bad about themselves and unable to control worrying several days or nearly every-day in the past one month and 42% had trouble sleeping nearly every-day in the last month. Furthermore, 46% of the participants felt afraid that something awful might happen without a reason and 50% experienced more than 5 physical symptoms several days in the past month.After the two months IPT-E intervention, the majority (75%) of the participants had not felt symptoms such as being sad, miserable or hopeless and 71% had pleasure in doing things. The majority (75%) reported that they had no symptoms of anxiety and 79% recovered their energy after the intervention they received. Almost all (91.70%) of the participants felt symptoms such as restlessness and feeling bad about themselves had remitted. They no longer had difficulty concentrating on conversations or reading after the intervention they received. Most (79%) participants no longer experienced problems controlling they worrying and 88% were sleeping well. Finally, the majority (75%) lost their dread of something awful happening without reason and 83% no longer had 5 or more physical symptoms. For further information see Table p-value = 0.001) from baseline  to post assessment  with effect size of 0.43, (large effect). The mean scores of WHODAS sub-scales were significantly improved from baseline to eight weeks assessment. For detail information, see Table The overall mean score of WHODAS-2 was significantly improved (A total number of days suffering from mental distress among the participants were reduced following the intervention.Change in mental distress following the intervention stratified by selected variables.Baseline mean score of SRQ-20 was significantly influenced by gender, duration of depressive symptoms and reporting thoughts of harming others in the past month. However, at the post-test, mean score of SRQ-20 was not significantly affected by any of the pre-specified characteristics of the study participants. There was no statistically significant difference in the mean score of SRQ-20 by marital status and perceived causes of mental distress both at baseline and post-assessment Table .Table 4MFindings of the current study indicated that IPT-E is feasible and acceptable for university students with mental distress in Ethiopia. All eligible students consented to participate in the intervention and only two of them did not complete the 8-session individual IPT-E intervention. Overall, participants were highly satisfied with the care they received. IPT-E provided a promising preliminary result in Ethiopian University in decreasing symptoms of mental distress and improving functioning of university students.Most of the study participants completed the 8 weekly sessions, which is comparable with the previous feasibility studies where the majority of depressed adolescents completed brief individual interpersonal counseling , 56. TheStudy participants reported that they were highly satisfied with the intervention they received, indicating that IPT-E was acceptable. A previous study reported that adolescents who received brief IPT were highly satisfied with the care they received . SimilarThe implementation of IPT-E indicated promising results demonstrating a significant decrease of the symptoms of mental distress and by improving functioning of the university students in the study. This finding is consistent with previous studies where most adolescents showed significant improvement in symptoms of depression and social functioning after receiving IPT intervention , 43, 56.The first onset of most mental health disorders occurs in the age range of 15–25 years  and mostLimitations: The present study had some limitations: first, our study did not include a comparison group which reduces our confidence in the effectiveness of IPT-E to decrease mental distress and improve functioning. However, the short 8 week time difference between the pre- and post-test in the present study may have addressed the reduction of symptoms by time alone. Second, the small sample size in the present study may limit the generalizability of the findings, so that the interpretation of the clinical outcomes should be undertaken with caution. Finally, in the present study, there were no follow-up sessions. We assessed the counselors’ adherence to the IPT-E manual, but future studies should measure the clinical competency of counselors. A randomized controlled trial of IPT-E and longer follow-up period would secure the evidence base of IPT-Es to further scale-up the service in similar settings.Despite the drawbacks, the present study has some strengths, including knowledge and skills transferred to the university health workers on how to effectively treat students with mental distress using the IPT-E guidelines. The other strength was that the close clinical supervision of the counselors’ and their adherence to the treatment model increased their knowledge and skills to deliver IPT-E, and extended the capacity of the students’ clinic to address to distress of student. We used locally adapted instruments to screen participants with mental distress and to measure disability. Lastly, we had balanced number of male and female counselors to comfort the need for study participants in a counseling session; we think this paved the way to equalize the sex ratio of participants in the present study.The present findings indicate that IPT-E is a feasible and acceptable intervention for the treatment of students with mental distress in low-income country settings. IPT-E also showed promising preliminary effectiveness in reducing symptoms of mental distress and improving functioning of University students. The present study findings provide viable information for mental health service providers in higher education institutions to use and scale-up the manualized IPT-E intervention designed to treat people with CMDs. Therefore, scaling-up of this intervention to the national level and implementing it in higher education institutions in Ethiopia would potentially address the high prevalence and burden of mental distress and reduce the mental health treatment gap among university students , althougAdditional file 1. Instruments used for data collection.Additional file 2. Treatment adherence and dose.


Nationally, adult day services (ADS) were forced to closed due to the COVID-19 pandemic. The forced closure of ADS programming consequentially impacted the services provided to clients. Many ADS continued to provide telephonic/remote services to clients, despite limited reimbursement from national and state sources for these services. Using data from ADS sites participating in the ADS-Plus Program (n= 22), this presentation examines the effects of COVID-19 on ADS closures and programming provided during the closure. About 86% (n=19) of the centers reported having to closed due to COVID-19. One-hundred percent of the sites reported offering telephone support to clients. Nearly 45% (n=10) of the centers reported not being reimbursed for this service. As ADS is a vital community-based resource for many families, it is important to demonstrate the crucial services provided by ADS to inform policymakers of the essentiality of day centers.


Chirality of pharmaceutical substances is an important aspect in drug research because it determines how enantiomers will interact with chiral biological targets. Enantiomers of a chiral drug can have different pharmacokinetic and pharmacological profiles; consequently, using a single pure enantiomer instead of a racemate can enhance the effectiveness and/or safety of the treatment. The tendencies of modern pharmaceutical industry regarding the current market of chiral drugs are divided between the chiral switch of previously used racemates and the development of new enantiopure drugs. The term chiral switch refers to the replacement on the market of a previously approved racemate with its single enantiomer version. The potential advantages of chiral switch can be related to a higher therapeutic index due to better potency, selectivity and fewer adverse effects, faster onset of action and exposure of the patient to lower drug dosages. However, chiral switch is also a strategy that permits manufacturers to keep market exclusivity for chiral pharmaceuticals that have lost their patent protection, even if the pure enantiomers have not demonstrated higher effectiveness or safety profile compared with the racemates. From the stereochemistry point of view, drugs can be divided into achiral, racemic and enantiopure. Approximately 50% of the small molecules used currently in therapy are chiral, containing at least one center of asymmetry in their structure, however their large majority are marketed as racemates and only about 25% in the form of pure enantiomers .L-absolute configuration while all carbohydrates have a D-absolute configuration. As a result, essential physiological processes are stereoselective and are using just one of all potential enantiomers propanoic acid), the fact that l switch . Howeverculation . As a renversion . In addibuprofen .R-ketoprofen into S-ketoprofen (dexketoprofen) is lower than for ibuprofen (less than 10%) -1H-benzimidazole) form the same main metabolites , however their proportion may differ . In the racemate . The difracemate .R-enantiomer reaches a higher plasma level in both slow and fast metabolizers, and the lower level of S-lansoprazole (dexlansoprazole) appears to be offset by the more pronounced binding of plasma proteins to the S-enantiomer [In the case of lansoprazole pyridin-2-yl]methylsulfinyl]-1H-benzimidazole), it was observed that the antiomer .Although other racemic PPI medications  are structurally related to omeprazole, they lack the 5-methyl substituent at the pyridine ring and consequently are not susceptible to CYP2C19 5-methyl hydroxylation; therefore, their enantiomers are less likely to exhibit polymorphism interindividual metabolic variance .S-citalopram , which is over 100-fold more potent than R-citalopram. However, S-citalopram plasma concentrations are roughly one-third of those of the total drug after racemic citalopram administration -1-(4-fluorophenyl)-3H-2-benzofuran-5-carbonitrile), the antagonism of serotonin reuptake is strongly related to the activity of stration . Citalop effects .R-fluoxetine and S-fluoxetine have similar SSRI potencies; however, in the case of active metabolites, S-norfluoxetine is a more powerful SSRI than R-norfluoxetine. Furthermore, plasma concentrations of S-norfluoxetine were shown to be higher than those of R-norfluoxetine in patients treated with racemic fluoxetine propan-1-amine). Fluoxetine is converted stereoselectively by N-demethylation to an active chiral metabolite, norfluoxetine, which is likewise a powerful SSRI . R-fluoxuoxetine . The useccessful .R-albuterol , which exhibits an over 60-fold higher potency than S-albuterol; while S-albuterol indirectly antagonizes the effects of R-albuterol and may have proinflammatory effects -2-(hydroxymethyl)phenol), also known under the name salbutamol, is a β2-receptor agonist used as a bronchodilator in asthma. Its bronchodilator effect resides mainly in  effects . Furtherferences .R,R- and S,S-stereoisomers ethyl]phenyl]formamide) is another β2-receptor agonist bronchodilator; it has 2 chiral centers in its structure, which generates the existence of 4 stereoisomers, and was used initially as a mixture of oisomers . As in teceptors .S-bupivacaine (levobupivacaine) proved to be less cardiotoxic than R-bupivacaine or racemic bupivacaine, while maintaining a similar anesthetic effect, with longer duration of action and less vasodilatation piperazin-1-yl]ethoxy]acetic acid) is a H1 antihistaminic drug used as an antiallergic; its effect resides mainly in its stration .S-ketamine (esketamine), which is more efficient as an analgesic and anesthetic through N-methyl-D-aspartate (NMDA) receptor antagonism, leads to shorter recovery after administration, increased tolerance and diminished side-effects . Currently both racemic ketamine and especially esketamine are used at lower sub-anesthetic doses and are considered promising options in the treatment of chronic pain and treatment-resistant depression trideca-5(13),6,8,11-tetraene-11-carboxylic acid) is a 2nd generation fluoroquinolone antibacterial with a broad spectrum of action against Gram-positive and Gram-negative bacteria. inactive ,41.S-fenfluramine (dexfenfluramine) enantiomer. Both the racemic mixture and its pure enantiomer dexfenfluramine were used in therapy; as it was hoped that the use of the single enantiomer will increase potency and tolerance, but they were both withdrawn in 1997 due to cardiovascular side effects; being associated with valvular heart lesions and pulmonary hypertension [Fenfluramine (N-ethyl-1-[3-(trifluoromethyl)phenyl]propan-2-amine) is a sympathomimetic stimulant with appetite suppressing properties deriving from amphetamine used in the short-term treatment of obesity (combination with phentermine); its anorectic effect being linked mainly to rtension .S-timolol) benzamide) a non-selective β-adrenergic blocker with associated α effects  44]. A . A 1-adrnistered .R-sotalol has both a β-blocker and a potassium channel blocker effect, while S-sotalol has potassium channel blocking activity, its affinity towards β receptors being low. The results of the SWORD  study showed that administration of optically pure S-sotalol increased mortality  in patients with myocardial infarction compared with placebo [Sotalol (N-[4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl]methanesulfonamide) is a nonselective β-adrenergic blocker used as a class III antiarrhythmic, with a chiral carbon atom in its structure.  placebo ,47.Examples of racemate drugs that have been switched successfully to the single-enantiomer version are presented in Taking into consideration the current FDA and EMA regulations, the current tendency of the pharmaceutical industry favors the development of new enantiomerically pure compounds to the detriment of the chiral switch practice to single enantiomers from already registered racemates . A revieThe single enantiomer introduced in therapy as a result of chiral switch has a similar profile and indications as the “parent” racemate but can present several therapeutic advantages: more predictable pharmacodynamic profile, improved therapeutic index and safety, reduced possibility for drug–drug interactions, faster onset of action and patient exposure to lower dosages ,12,51.Patients have benefited from a single-enantiomer chiral switch in several circumstances, especially when the pharmacological action is concentrated in one of the two enantiomers , or when the single enantiomer is less toxic than its racemate (bupivacaine—levobupivacaine).However, there have been cases in which single-enantiomer medications generated from blockbuster racemates had minimal clinical benefit over the racemate , and their release onto the market was likely used by pharmaceutical corporations as a patent-protection tactic against generic competition.Another interesting example is the one of fenfluramine, which was switched successfully to dexfenfluramine but later withdrawn from therapy due to an unfavorable safety profile.Not all of the attempted switches have been successful, and sometimes unanticipated adverse effects were reported, and the chiral switch process was stopped .Regardless of why a single-enantiomer medicine is being developed, the FDA and EMA review and approval process remains identical; as regulatory agencies normally approve new pharmaceuticals based on their efficacy in achieving a specific goal, and an improvement in action over placebo is commonly recognized. To obtain FDA or EMA approval, manufacturers of single-enantiomer medications are not obliged to undertake randomized clinical studies to compare their products to racemates. An interesting investigation was published in 2021 by Long et al. in which randomized clinical trials directly comparing single-enantiomer drugs to a previously used racemic precursors for efficacy or safety differences were evaluated. Fifteen drugs subject to a chiral switch were evaluated, and for nine of them, no randomized clinical trials that showed enhanced effectiveness or safety when compared to their racemic predecessors were found . It is iHowever, there have been situations when the innovator company neglected to patent the single enantiomers when the medications were first developed, and this allowed other companies to produce the single isomer and, as a result, engage into license arrangements with the racemate’s inventors. However, usually, enantiomer patents are issued by the innovator company with priority dates that are much later than those of the equivalent racemic patents . It is cThere are several examples of well-timed switches of racemic pharmaceuticals  with patents due to expire, in which quick and cost-effective procedures have been designed to allow efficient development and regulatory licensing of switched single enantiomer pure medications ,49.The launch of a single-enantiomer medicine is frequently timed to coincide with the launch of generic competition for its racemic counterpart, as many single-enantiomer medications have become commercial blockbusters, displacing generic versions of racemic predecessors from the market .The increased development of individual isomers at the cost of racemates has been aided by this understanding of the implication of stereochemistry in the pharmacological effect of a chiral drug, combined with developments in chemical technology and further forced by regulatory requirements. In modern chiral drug development, there are two main variants: development of an enantiomerically pure drug or switching from a racemic molecule to its eutomer in a pure form .Chiral switch is a controversial practice, as in some cases the use of the pure enantiomer does not provide enough clinical evidence for its benefit and is used by pharmaceutical companies to maintain sales as the initial racemate reaches the end of its patent on the market. Despite the increasing tendency of switching racemates to pure enantiomers in therapy, most of these enantiomeric pure drugs approved by the FDA and EMA were not specifically compared with their racemic counterpart, and there is not always indication of positive changes in treatment outcome.When the pharmacological effects of the enantiomers of a chiral drug differ sufficiently from each other and from the racemate, it is feasible to get a patent for one or both enantiomers in addition to the racemate’s patent. Several blockbuster medications were synthesized and registered initially as racemates, and their replacement with single isomers might be considered as an excellent approach of prolonging patent franchise and safeguarding against generic competition.Nonetheless, in many situations, the use of the pure enantiomer instead of the racemate may be in the benefit of patients, especially in the cases when the distomer is responsible for undesirable effects, when manufactures may seek single enantiomer production to improve safety and effectiveness.In the current review, we have presented how the chiral switch’s basic notion has evolved over the last 25 years. The original hypothesis on which chiral switch strategies were built, that existing racemates would offer a plentiful supply of new single enantiomer drugs, has proven difficult to realize; however, in some individual cases, the chiral switch presented a valuable alternative for existing racemate owners to obtain line extensions, particularly if the switch was marketed before the racemate’s patent expires.The goal of development of novel therapeutic alternatives is to improve efficacy and/or safety; the choice between homochiral drugs and racemates should be based on therapeutic benefits, potential undesirable side effects, and development costs.


The highly infectious coronavirus disease 2019 (COVID-19) associated with the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to become a global pandemic. At present, the world is relying mainly on containment and hygiene-related measures, as well as repurposed drugs to control the outbreak. The development of COVID-19 vaccines is crucial for the world to return to pre-pandemic normalcy, and a collective global effort has been invested into protection against SARS-CoV-2. As of March 2021, thirteen vaccines have been approved for application whilst over 90 vaccine candidates are under clinical trials. This review focuses on the development of COVID-19 vaccines and highlights the efficacy and vaccination reactions of the authorised vaccines. The mechanisms, storage, and dosage specification of vaccine candidates at the advanced stage of development are also critically reviewed together with considerations for potential challenges. Whilst the development of a vaccine is, in general, in its infancy, current progress is promising. However, the world population will have to continue to adapt to the “new normal” and practice social distancing and hygienic measures, at least until effective vaccines are available to the general public. D), i.e., SARS-CoV-2-S1 and SARS-CoV-2-CTD were recorded as 94.6 ± 6.5 nM and 133.3 ± 5.6 nM, respectively. Meanwhile, SARS-RBD engaging the same receptor was recorded as 408.7 ± 11.1 nM [The ongoing pandemic of coronavirus disease COVID-19) has impacted the world socially and economically on many different levels. COVID-19 is caused by a new strain of coronavirus known as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), with a much higher transmission rate of around 2.2 per patient within China 9 has imp. Though The SARS-CoV-2 is a betacoronavirus, and current research infers that the natural host may be bats . This viEpidemiological studies have shown that the main transmission route of SARS-CoV-2 is through close contact and human-to-human transmission which occurs through droplets, aerosols, and contact . Hence, Nucleic acid testing is required to identify if a patient is infected by SARS-CoV-2. The positive result from the new highly specific coronavirus nucleic acid test confirms the diagnosis of COVID-19 ,15. ImpoAntibody-based and genome-based detection methods are used to identify infections caused by SARS-CoV-2. The genome detection method provides a preliminary diagnosis, that is, identification by nasal swabs and throat swabs sampling. However, the sensitivity of such a detection method is relatively low. Antibody-based detection is a more sensitive approach performed by extracting and amplifying the viral RNA collected from the plasma of patients with abnormal body temperature, followed by qualitative and quantitative real-time determination if virus RNA is present in the patient . In addiCurrently, there are no specific treatments for COVID-19 disease but clinical guidance for the management of suspected and confirmed COVID-19 patients are available for healthcare providers. However, these guidelines are not meant to replace clinical judgment or specialist consultation and are updated from time to time as new treatment options are available and approved based on research and clinical trial outcomes.The pharmacological therapies generally administered in the management of COVID-19 patients are discussed.WHO recommends that patients with suspected or confirmed mild to moderate COVID-19 symptoms be isolated to prevent virus transmission and they are given symptomatic treatment such as antipyretics for fever and pain, adequate nutrition, and appropriate rehydration [The National Institutes of Health (NIH) of Unites States of America mentions the use of SARS-CoV-2-neutralising-antibodies (bamlanivimab or casirivimab plus imdevimab) in outpatients who are at high risk for disease progression . Anti-SAPatients being treated at home who developed symptoms with complications  should seek emergency help while patients in hospital should have close monitoring to recognise signs and symptoms of disease progression .2) < 90%, to regulate the SpO2 to a normal level of ≥94% [2 of pregnant patients is ≥92–95% whilst non-pregnant adults and child patients are >90%.WHO recommends immediate administration of supplemental oxygen therapy and emergency airway management to any patient with emergency signs  and to any patient without emergency signs but with oxygen saturation  [The only anti-viral drug approved or authorised for temporary use in over 50 countries for the treatment of COVID-19 in severe hospitalised patients is remdesivir, the RNA-dependent RNA-polymerase (RdRp) inhibitor of the Ebola virus and is expected to have broad-spectrum antiviral effects . It is a 0.0001) . This suAnother anti-viral drug widely used is favipiravir, a nucleoside analog and is metabolised in cells to a ribosyl triphosphate form (favipiravir RTP) that selectively inhibits RNA polymerase involved in influenza viral replication. It is used as an antiviral treatment for influenza A and B . There wIt is well known that the immunity of the human body decreases with age . With thMost of the recommendations for the management of critically ill patients with COVID-19 are extrapolated from experiences with other causes of sepsis . There iThe main structure of coronavirus includes a single-strand positive-strand nucleic acid (ssRNA), S protein, membrane protein (M), an envelope protein (E), and nucleocapsid protein (N). Amongst them, the S protein is responsible for recognising and binding to receptors on the surface of host cells and plays an important role in the first step of viral infection. Viral cell entry is facilitated by the fusion of viral and host cell membranes after the RBD of S protein binds to cellular ACE2. Studies have reported that the mechanical stability of SARS-CoV-2 RBD (250 pN) plays a vital role in increasing the spread of COVID-19 due to stronger intermolecular interactions as compared to RBD of SARS-COV (200 pN) . The eneAs the genome sequences of SARS-CoV-2 and SARS-CoV are highly similar, and they have the same cellular receptor ACE2, knowledge from the development of the SARS-CoV vaccine is important and served as the basis to outline the development of SARS-CoV-2 vaccines . StudiesOn 24 January 2020, the Chinese Center for Disease Control and Prevention successfully isolated China’s first strain of new coronavirus . Up to dLive virus and inactivated vaccines with high immunogenicity that provide excellent stimulation to the immune system for antibody generation have been widely applied in the biomedical industry. Live virus vaccine is synthesised by the virus with reduced virulence or even non-virulence; whilst inactivated vaccines contain non-infectious intact virus with low- or non-pathogenicity, and thus, would not proliferate in vivo. Whilst live virus vaccines are developed with reduced virulence, they are closely monitored to ensure the reduced virulence is not restored  for the Subunit vaccines are composed primarily of non-genetic viral proteins or peptide fragments to trigger strong immune responses. The absence of an entire infectious virus in subunit vaccines increases the safety and eliminates the problem of virus inactivation or reversal of toxicity . StudiesThe vector-based vaccine is a live attenuated vaccine that uses a modified safe virus such as adenovirus, measles, and influenza as a vector to express coronavirus proteins during the immunisation process. Vector vaccines are categorised into replicating and non-replicating vectors based on their replicating potential. Many of these viral vectors could not, or can only perform limited replication in human cells, and thus, have minimum safety concerns upon application. Viral vectors generally can perform quick synthesis of recombinants, verify protein expression, and accelerate the development of the immune system . HoweverNucleic acid vaccines can be produced in bulk and at a low cost without utilising live viruses. As these are not virus-containing vaccines, there is relatively low or no risk associated with virulence or infection upon application . HoweverUnder normal circumstances, the development of a new vaccine from pre-clinical trials until approval and licensing takes an average of 10 to 15 years. According to Amanat and Krammer (2020) , two sigUp to 20 March 2021, there are over 90 vaccine candidates in clinical development, with 22 of them undergoing Phase III clinical trials, 32 in Phase II trials, and 44 in Phase I trials ,64,65. WBy March 2021, thirteen vaccines   report tApart from the efficacy, the accompanying adverse reactions also play an important role in evaluating the availability of these vaccines. Generally, there were no severe adverse reactions reported for people who have taken these vaccines and the mild side effects normally include headache, muscle/joint pain, fatigue, and so forth ,106,107.More than 100 vaccines are being developed in various countries , and theVariants of coronavirus have been detected in recent months due to virus mutation and adaption to increase its survival . B.1.1.7A vaccine escape must not happen in the coming months in which the infection rate would increase due to ineffective vaccines against mutated viruses. If this were to occur, the vaccines will have to be updated or redesigned regularly and yearly vaccine immunisation against the coronavirus is expected.The frontrunners in late-stage vaccine development, with reported interim analysis results of the vaccine being 95% effective in preventing COVID-19, is from the phase III clinical trials of the BNT162b2 mRNA-based vaccine candidate from Pfizer and BioNTech. The vaccine requires storage at −70 °C throughout the distribution process from the manufacturer’s store to its intended destination . Whilst The Moderna vaccine candidate reported their preliminary trial results of a 94% effectiveness of the vaccine in preventing COVID-19 . The vacWhilst the development of vaccines for COVID-19 is a long and tedious, yet urgent process, promising progress has been made in recent months. Multiple vaccines have been prepared and extensive preclinical research has been conducted. It begins with animal model verification and those successful proceeding to clinical trials in humans. Under normal circumstances, these vaccines can be approved for marketing only after the phase III clinical trials have fully confirmed that the vaccines are safe and effective. However, due to the urgency of this pandemic, COVID-19 vaccines have been given conditional, emergency, or temporary use authorisation with high surveillance on their efficacy and safety profile post-authorisation. Whilst such progress is promising, it is necessary to strengthen the popularisation of prevention knowledge and containment measures to collectively control the spread of the pandemic with measures such as social distancing, frequent hand washing, and mask-wearing in public areas. The world population will have to adapt to these new preventive measures in order to flatten the pandemic curve, at least until safe and effective vaccines are made available to the general public, particularly those most vulnerable.


Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation  is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT. Allogeneic hematopoietic cell transplantation  continues to serve as a potentially curative step in the management of intermediate- and high-risk acute myeloid leukemia (AML) . NowadayAML relapse post allo-HCT poses a serious challenge to clinicians, as despite increasing survival rates of younger patients relapsing post allo-HCT, their 2-year OS didn’t exceed 26% , 10, 11.Understanding the factors that led to disease relapse will help in developing and exploring rationally designed combination therapies. First, relapsing leukemia cells showed resistance to preparative chemotherapy either during induction/consolidation or within the conditioning regimen, but most importantly, they had definitely an immune escape mechanism to evade the donor-derived T cells. With the advent of new sequencing technologies, many oncogenic targets have been discovered and served as an additional tool in the armamentarium of AML management. The main goal of treatment is first to eradicate leukemia cells using effective anti-leukemia therapies, and then activate the donor alloreactive T cells toward a graft-versus-leukemia (GVL) direction. This review will discuss current therapeutic options including those directed against leukemia cells, in addition to other strategies aiming at enhancing the GVL effect of immune cells Figure 1FLT3 mutation, the absence of NPM1 mutation, the time from achieving remission to allo-HCT, the absence of GVHD and the in-vivo T-cell depletion  Class II genes , the downregulation of NK cell targets, the loss of expression of an HLA haplotype, and the increased expression of inhibitory checkpoint ligands –20.The initial goal in treating AML relapse post allo-HCT is to decrease the leukemia burden and ultimately achieve a deep complete remission (CR) that is sustainable. Among therapies with direct anti-leukemia effect, is the use of intensive cytotoxic chemotherapy. Despite the rapid debulking effect, a minority of patients can tolerate such treatment especially in the early post-transplant phase. In addition, the use of chemotherapy alone is generally not sufficient with a 2-year OS not exceeding 7% , 22.The best results to date have been achieved after donor cell therapies either with donor lymphocyte infusion (DLI) or a second allo-HCT with 2-year OS rate between 20 and 40% , 23. BetHypomethylating agents (HMAs) such as azacitidine and decitabine are effective anti-leukemia drugs with a proven efficacy in the frontline treatment of AML in older patients. Their use as single agents resulted in improvements in clinical outcomes of older AML patients with a median OS of 8-10 months , 25. DueDespite the excitement regarding the use of HMAs in the post-transplant relapse, limited number of patients responded, and long-term survival was not possible. Craddock et al. reported the outcomes of patients with AML or high-risk myelodysplastic syndrome (MDS) treated with azacitidine +/- DLI for post-transplant relapse . The CR With the purpose of enhancing the effect of azacitidine, multiple combination therapies were assessed. The combination of azacitidine with lenalidomide might have an additive anti-leukemic effect, while azacitidine decreases the risk of acute GVHD from lenalidomide . In the The treatment of AML with novel agents is fast evolving, with multiple targeted agents already FDA approved in different settings. Currently, many new targeted agents are effective in AML, and can be used in the post-transplant relapse setting . HMAs caVenetoclax is an orally available selective BCL2 inhibitor, that competitively combines to BH3 domain and induces apoptosis of leukemia stem cells. It is currently approved by the Food and Drug Administration (FDA) in combination with azacitidine or low dose cytarabine in newly diagnosed AML patients older than 75 years or unfit for intensive chemotherapy , 36. HMAFurther ways to overcome venetoclax resistance and enhance its efficacy is by targeting MCL1, an anti-apoptotic protein. A recently reported study combined actinomycin D, with azacitidine and venetoclax for the treatment of AML relapse post allo-HCT. The rationale of adding actinomycin D was based on preclinical data suggesting a synergistic anti-leukemic effect through MCL1 degradation, in addition to mitochondrial activity yielding to senescence through PML-nuclear body biogenesis –43. TwenIDH1 or IDH2 mutations. Enasidenib monotherapy yielded an ORR of 40% with a median OS of 9.3 months, reaching 19.7 months in patients attaining CR in the R/R setting  1 and 2 occur in up to 20% of AML patients . Targete setting , 46. In asidenib . Similarotherapy . The repFLT3 internal tandem duplication (ITD) mutation that is usually associated with poor outcomes. Sorafenib is a first generation tyrosine kinase inhibitor that targets FLT3-ITD mutation. In addition to its anti-FLT3 activity, sorafenib has been shown to induce interleukin-15 production by FLT3-positive leukemia cells, thereby activating the donor CD8+ T cells and promoting the GVL effect  receptor, inhibiting the Hedgedog signaling pathway. Glasdegib was tested in combination with low dose cytarabine in the frontline treatment of AML in patients who are ineligibile for intensive chemotherapy . It was DLI is an adoptive immunotherapy treatment defined as transfusion of non-stimulated lymphocyte concentrate from the original stem cell donor. It was first introduced in the early 1990s and showed high efficacy in patients with relapsed chronic myeloid leukemia after allo-HCT , 58. ThePatients with relapsed AML after allo-HCT who are eligible for intensive treatment are usually offered a second allo-HCT. However, there is currently no standard of care regarding the donor selection and the type of conditioning regimen used in this setting. In a registry-based study of 418 patients with AML comparing survival at first relapse after allo-HCT, there was no significant difference in OS between the two groups regardless of the disease status at time of treatment. The 2- year and 5-year OS was 25% and 15% respectively in the DLI group compared to 26% and 19% in the allo-HCT group. However, the incidence of NRM was significantly higher in patients who received a second allo-HCT compared to those who received DLI including all patients and those who received treatment with active disease . NRM was not significantly different in patients who were in CR at the time of intervention. The rate of grade 2 to 4 acute GVHD was significantly higher in the allo-HCT group (37%) compared to DLI group (20%). Interestingly, there was no difference in the 2-year OS and NRM in patients who received a second allo-HCT by donor type . The impOther immune strategies to enhance the T cell activity in AML, especially in the post-transplant setting involve the use of immune checkpoint inhibitors. Although these compounds are not yet approved in the management of AML, however they are gaining more clinical interest especially after a phase 1/1b clinical trial reporting a promising anti-leukemia efficacy of high dose ipilimumab, an anti-CTLA4 antibody, in a subset of AML patients relapsing post allo-HCT . In factThe field of cellular therapy is fast evolving in the management of hematologic malignancies, especially with the approval of CAR T cells for B-cell acute lymphoblastic lymphoma and non-Hodgkin’s lymphoma. In AML, the development of CAR T cells remain problematic, mainly because many myeloid surface antigens on AML cells, are also expressed on normal hematopoietic or progenitors cells, causing severe bone marrow suppression. Currently, many CAR T cells products are being investigated in AML targeting CD33, CD123, and CLL1 that are predominately expressed on AML blasts , 69.Despite all advances in the field of allo-HCT in AML, disease relapse still represents a major challenge with very limited treatment options. Many factors contribute to disease relapse including clonal evolution with acquisition of new oncogenic mutations, immune escape mechanisms such as downregulation of MHC genes, loss of expression of HLA haplotype, downregulation of NK cells targets, and increased expression of immune inhibitory checkpoint ligands. This progress in our understanding of the biology of disease relapse post allo-HCT is being translated in new therapeutic strategies. Epigenetic regulation using HMAs showed to be effective either alone or with DLI. Immune checkpoint blockade by ipilimumab was also feasible post allo-HCT relapse, particularly in patients with extramedullary involvement . More taIA, AA, and AB reviewed the literature and wrote the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.


Patients recovering from COVID-19 may have persistent debilitating symptoms requiring long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help. Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the hypothalamo-pituitary-adrenal (HPA) axis, adrenal and thyroid function. We here review the literature and potential pathophysiological mechanisms involved in and related to post COVID-19 symptoms with an emphasis on endocrine function. At the end of 2019, a novel coronavirus termed severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) was identified as the cause of a cluster of pneumonia cases in Wuhan, China. Since then, this virus has spread rapidly and caused a pandemic that wreaked havoc at a global level. In 2015, Menachery and colleagues already (pre-SARS-CoV-2) presented evidence for a potential risk of SARS-CoV re-emergence from viruses circulating in bat populations COVID-19 is considered a multiorgan disease and as the complications caused by COVID-19 continue to unfold, it is becoming evident that there is a section of people who despite having recovered from acute effects of the COVID-19 illness, continue to suffer from persisting and cyclical symptoms. Based on the COVID-19 Symptom Study, a study carried-out on more than 4 million people in the United States, United Kingdom, and Sweden wherein people entered their ongoing symptoms on a smartphone app, around 10% of patients who have tested positive for SARS-CoV-2 virus remain symptomatic beyond 3 weeks, and a smaller fraction for months This spectrum of persisting symptoms, ranging from mild to debilitating, is being termed as Post-COVID syndrome or Long COVID and can have variable presentation in people irrespective of the severity of their initial disease. Davis et al. analyzed 3762 participants, from 56 countries, with confirmed (N = 1020) or suspected (N = 2742) COVID-19 and found that 91% of respondents took more than 35 weeks to recover It is unknown what causes long COVID and CFS. Whether it is continued inflammatory or autoimmune responses, or continued damage by the reactivated virus residues, yet needs to be elucidated .Fig. 1PoThe role of endocrine disorders in the causation of long-term symptoms post-COVID especially CFS is not fully understood. Since endocrinopathies are treatable it is essential to identify any contribution they may have to the persistent symptoms experienced by patients after COVID-19 infection.meta-analysis reported one in six cases of COVID-19 as asymptomatic with lower risk of transmission The spectrum of clinical presentation of COVID-19 varies from asymptomatic to severe illness. Asymptomatic cases of COVID-19 have been well documented As witnessed during previous global epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), existence of long-term complications and persisting debilitating symptoms with current COVID-19 is not a novel occurrence. Tansley et al. reported 18% of individuals (n = 117) with SARS-CoV infection had a reduced 6-minute walk test due to shortness of breath and fatigue after 1 year as well as reduced quality of life at 3 months, with improvement but not normalization after one year Post-COVID syndrome and long COVID are evolving secondary syndromes in which patients recovering from SARS-CoV-2 suffer from persistent symptoms that extend several months after their initial diagnosis. The National Institute of Clinical Excellence (NICE) differentiates the two terms: post-COVID syndrome and long COVID. It defines post-COVID syndrome as signs and symptoms that develop during or after an infection consistent with COVID–19 and continue for more than 12 weeks, that are not explained by an alternative diagnosis Knowledge about the prevalence, pathology, predictors or risk factors of developing long COVID-19 remains sparse. Based on data of the COVID-19 symptom study, the chances of developing long COVID are affected by age with rates being 1 to 2 % in patients in their twenties to about 5% in people in their sixties Several hypothesis have been suggested to understand the pathophysiology of post-COVID syndrome relating to hyperinflammatory states, oxidative stress, cytokine storm and DNA damage Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a term given to a gamut of symptoms such as fatigue, post exertional malaise, sleep disturbances, cognitive impairment, and non-provoked pain that persist for more than 6 months with substantial intensity and not completely explained by any medical condition. It is a heterogeneous condition with a multifactorial etiology involving immune, virologic, psychological, endocrine and other factors. Fatigue is known to occur after many virus infections or other infectious agents, the most prominent example being the Epstein-Barr virus An uncanny resemblance has been observed between the long-COVID syndrome and clinical features of CFS, though this is not an unfamiliar concept. Similar to ME/CFS, fatigue, myalgia, depression and poor sleep were seen in a cohort of 22 patients and a post-SARS-CoV syndrome [39]An important feature of viruses linked to ME/CFS is the ability to establish persistent and chronic infections. The symptom of chronic fatigue could be caused by damage to multiple organ systems during the COVID-19 disease leading to impairment of heart, lung, or kidney function. Of note, patients with severe COVID-19 including severe lung involvement can completely recover. An overall state of inflammation along with increase in inflammatory mediators as well as activation of cell-mediated immunity could possibly be contributing to the CFS-like state. Patients with long/post-COVID syndrome are predominantly female analogous to other autoimmune disorders and experts postulate a T- and B-cell dysregulation, possibly changes in the microbiota of the gastrointestinal tract https://www.proteinatlas.org/ENSG00000130234-ACE2/tissue) in the hypothalamus, pituitary, adrenal gland, thyroid, testes, and pancreatic islets leading to the involvement of the endocrine system during and after the recovery of the disease. Longitudinal and postmortem studies conducted on SARS-CoV patients provide some guidance on the extent of endocrine gland involvement. On postmortem examination, SARS-CoV RNA was found in the pituitary gland, parathyroid, pancreas and adrenal gland ACE2 receptors, the route of entry of the SARS-CoV-2 virus into the human body, are expressed  and thyroid stimulating hormone (TSH) were lower in COVID-19 patients than the healthy group, especially in severe cases It certainly is conceivable that the cytotoxic effects of COVID-19 affect pancreatic islet function and trigger development of diabetes mellitus. There is a paucity of mechanistic case studies on this topic but there are 2 recent excellent review articles Patients recovering from COVID-19 who continue to get affected by debilitating symptoms are likely to need long term support through individually tailored cardiopulmonary and psychological rehabilitation programs. Clinicians need to be aware about the likely long-term complications and their diagnostic assessments to help identify any occult problems requiring additional help. Endocrinological evaluations should be considered as part of the armamentarium in the management of such individuals with diligent cognizance about the involvement of the HPA axis, adrenal and thyroid function. Managing potentially worsening metabolic health is also important, considering that many individuals including patients infected with SARS-CoV-2 have gained weight during the Covid-19 pandemic The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


The COVID-19 pandemic has demonstrated the urgent need to develop vaccine strategies optimized for pregnant people and their newborns, as both populations are at risk of developing severe disease. Although not included in COVID-19 vaccine development trials, pregnant people have had access to these vaccines since their initial release in the US and abroad. The rapid development and distribution of novel COVID-19 vaccines to people at risk, including those who are pregnant and lactating, presents an unprecedented opportunity to further our understanding of vaccine-induced immunity in these populations. In this review, we aim to summarize the literature to date on COVID-19 vaccination in pregnancy and lactation and highlight opportunities for investigation that may inform future maternal vaccine development and implementation strategies. Vaccination against infectious pathogens is one of the most impactful public health interventions, reducing global morbidity and mortality related to infection . In the To date, two COVID-19 mRNA vaccines – BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna) – and one monovalent Ad26-vector vaccine (Janssen/Johnson & Johnson) have been granted Emergency Use Authorization (EUA) by the FDA for administration to prevent COVID-19 in the US. Although not included in COVID-19 vaccine development trials, pregnant people have had access to these vaccines since their initial release in the US, and more recent data supporting the safety of COVID-19 vaccines in pregnancy  have ledThe COVID-19 pandemic and the rapid development of novel vaccines to combat it present an unprecedented opportunity to decode the rules of vaccine-induced immunity in pregnant and lactating individuals. In this review, we aim to review the literature to date on COVID-19 vaccination in pregnancy and lactation and highlight opportunities for future investigation. Because pregnant and lactating people were not included in initial vaccine trials, data on the vaccine safety and efficacy in these populations has been limited , and guiExperience from other vaccines utilizing the mRNA and adenovirus-vector platforms has provided some reassurance that neither technology carries specific reproductive safety concerns. Although pregnant people were excluded from Phase 1 trials of mRNA vaccine platforms against other pathogens such as influenza, Zika HIV and rabies viruses , animal Despite the exclusion of pregnant and lactating people from COVID-19 vaccine trials, the American College of Obstetricians and Gynecologists as well as the Society for Maternal-Fetal Medicine have consistently voiced that the COVID-19 vaccine should be available to pregnant and lactating individuals, and both professional societies as well as the CDC now recommend vaccination in these populations . InclusiCiting as rationale the fact that mRNA vaccines induce an immune response through toll-like receptor 3 (TLR3) activation, and TLR3 activation has been linked to adverse placentally-mediated pregnancy outcomes in rodent models such as decidual arteriopathy, growth restriction, preterm delivery, and fetal loss , anotherThe CDC V-safe COVID-19 Pregnancy Registry team has recently published preliminary findings on the safety of mRNA COVID-19 vaccines in pregnant persons . A totalLong term vaccine safety data in pregnant people and their offspring are understandably lacking at this time, yet critically needed for counseling regarding not only the safety of the COVID-19 vaccines specifically but for mRNA vaccine platforms in general, as public perception regarding the safety of vaccines given in pregnancy hinges on providing high-quality information on neonatal and childhood outcomes, including birth defects and childhood developmental disorders. Given the longer time horizon necessary to collect these data, they are unlikely to inform current vaccine practice, but do have the opportunity to impact future mRNA and adenovirus-vector vaccine development efforts and public health campaigns.Pregnancy involves complex immunological changes, including modulation of the immune system to tolerate the fetal semi-allograft . Along wversus Moderna vaccine, including a more robust IgA immune response and higher antibody titers and functions induced by the Moderna compared to the Pfizer/BioNTech vaccine  and the Ad26-vector vaccine (Janssen) are highly immunogenic in non-pregnant populations , generat vaccine . Whether vaccine . Taken tWhether COVID-19 vaccines generate an equivalent or greater anti-SARS-CoV-2 antibody response against the SARS-CoV-2 virus compared to those antibodies generated by natural SARS-CoV-2 infection in pregnancy warrants additional investigation. In a study of 84 pregnant and 31 lactating participants, vaccine-induced anti-SARS-CoV-2-specific antibody titers were significantly higher in all participants than those induced by natural SARS-CoV-2 infection during pregnancy. In this cohort, participants with natural infection were symptomatic and known to be infected 4 to 12 weeks prior to titer quantification, so that timing of antibody quantification was comparable for the pregnant vaccinees and naturally-infected pregnant people . This siNot only antibody titer, but antibody function is a key consideration in evaluating vaccine-induced antibody protection for both mother and newborn. Two studies have evaluated antibody function in pregnant and lactating compared to non-pregnant women receiving the COVID-19 mRNA vaccines . Both haversus uninfected vaccinated healthcare workers found evidence that after the administration of a single dose of vaccine, the humoral response in individuals with a history of SARS-CoV-2 infection is greater than the response in previously uninfected participants who have received a second dose  vaccines . While irimester . In contrimester . Similarrimester . Importavs infection-elicited antibodies, transplacental transfer was comparable between individuals infected with SARS-CoV-2 earlier in pregnancy (15-30 weeks) and those vaccinated with the BNT162b2 mRNA vaccine in the third trimester  binding domain in recruiting the innate immune response in COVID-19 , as wellper se, previous reports have demonstrated that anti-SARS-CoV-2 breastmilk antibodies from natural infection do have neutralizing capacity, which correlates strongly with anti-RBD IgA titers (It is well known that breastmilk contains protective maternal immunoglobulins that contribute to the development of the infant’s immune system . AlthougA titers . SimilarA titers . The durA titers . These dInfection with SARS-CoV-2 has the ability to generate long-lasting immunological memory in non-pregnant populations , and emeComplete pregnancy outcomes data from people vaccinated in the first and early second trimesters are not yet available as most of these pregnancies are ongoing. Durability of IgG in the blood of neonates born to vaccinated mothers has not yet been defined, nor has whether the anti-SARS-CoV-2 IgG generated influences the response to other childhood vaccines. Information on postnatal outcomes and offspring development will require long term follow-up of children born to individuals who received the vaccine during pregnancy. Challenges in vaccine uptake in pregnant people persist despite evidence of benefit and lack of evidence of harm and strong recommendations from the medical and public health communities , and theLS and AE conceived of the topic of this review and drafted the manuscript. JS and PF contributed to drafting the manuscript. All authors contributed to the article and approved the submitted version.Eunice Kennedy Shriver National Institute of Child Health and Human Development: 3R01HD100022-02S2 to AE and K12HD103096-01 to LS. AE is also supported by the Claflin Award from Massachusetts General Hospital Executive Committee on Research.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.


From the dental records, information about repair and replacement of restorations was obtained. Patients were clinically examined after a mean follow-up time of 10.7 years (first cohort) or 5.2 years (second cohort) using United States Public Health Service (USPHS) criteria. Subjective patient satisfaction was also recorded using visual analogue scales (VAS). The overall quality of the restorations was good with predominantly ‘Alpha’ and ‘Bravo’ scores, respectively. Nanofilled composite showed less surface degradation and better margin qualities than microhybrid composite. Of the 59 restored teeth in the first cohort, 13 restorations showed unfavorable events after 10.7 years, of which ten could be repaired. In the second cohort, 23 of 105 restorations showed unfavorable events, which could all be repaired. VAS scores revealed high patient satisfaction with the treatment approach. In conclusion, direct composite restorations placed at an increased vertical dimension of occlusion show good clinical long-term performance in patients with severe tooth wear.Our aim was to evaluate the clinical performance of direct composite restorations placed in patients with severely worn dentitions at an increased vertical dimension of occlusion, after up to 11 years. One hundred and sixty-four teeth in 13 patients with severely worn dentitions had been reconstructed with either microhybrid (first cohort;  Tooth wear represents an irreversible, multifactorial, non-carious loss of dental hard tissues based on erosive, abrasive and/or attritional effects ,2. EpidePatients suffering from severe tooth wear require complex restorative care to compensate for the loss of tooth substance, particularly if the occlusal vertical dimension is affected. Traditional reconstructive concepts for the severely worn dentition basically comprise extensive prosthodontic treatment such as full or partial crown coverage of the majority of teeth ,9,10. ApIn particular, the use of direct resin composite materials allows for such conservative, non-invasive restorative treatment modalities. Moreover, resin composite restorations are relatively inexpensive, provide good overall esthetics as well as simple maintenance in the form of refurbishment and repair ,13. NumeIn order to avoid freehand shaping of the direct composite restorations and ensure optimal adjustment of the vertical dimension of occlusion, a wax-up-based template-aided placement approach has been suggested and has proven to be easily implemented by general practitioners . The 3- Therefore, the purpose of the present investigation was to re-evaluate the original restorations of this first cohort of patients after a mean service time of 10 ⅔ years. In addition, a second cohort of patients with posterior vertical bite reconstructions made of nanofilled composite material, instead of the originally used microhybrid composite, was evaluated to identify possible material-related differences in the clinical performance of the vertical bite reconstructions. The subjective patient satisfaction with the vertical bite composite reconstructions was assessed using visual analogue scales (VAS).The investigation was approved by the local ethical committee of the Canton of Zurich (KEK-ZH-Nr. 2015-0059), and written informed consent was obtained from all participants. Of the six patients of the first cohort evaluated in the 5.5-year follow-up, five returned for the present follow-up examination. One patient had moved to another city and could not be located despite several attempts. The mean observation time of this first patient cohort with a total of 59 posterior restorations was 10.7 ± 0.4 years (range: 10.2–11.2 years) at recall . In the The restorative treatment has been previously described in detail . Full-arTo enable accurate transfer of the waxed-up occlusion from the articulator into the patient’s mouth, wax-up-based templates were fabricated. These transfer aids were either full-arch vacuum-formed matrix templates (first cohort) or short quadrant templates made of transparent acrylic and relined with transparent bite registration material (second cohort). The templates revealed a hollow space between the occlusal surface of the natural teeth in the oral cavity and the inner facet of the template, in the dimension of the wax-up. This hollow space was later filled with the composite material to build up the worn teeth and copy the wax-up. Both the front teeth and the most distally located teeth, which had not been waxed up previously, assured stable support of the templates. The most distal teeth were restored using a freehand build-up technique without template. The front teeth were reconstructed at a later appointment.Before restoring the vertical dimension, all metallic or insufficient restorations were replaced with composite restorations. In the patients of the first cohort, the adhesive system Syntac Classic  and the microhybrid composite material Tetric  were used, while in the second cohort, the adhesive system Optibond FL  and the nanofilled composite Filtek Supreme  were used, each according to the manufacturers’ instructions. The vertical bite reconstruction was performed under local anesthesia and rubber dam placement. Surfaces of existing intact composite restorations were sandblasted with aluminum oxide and silanized. After conditioning the tooth surfaces with the respective adhesive system, the occlusal relief of the worn teeth was reconstructed by using the wax-up-based template. A step-by-step documentation of this TACS-technique (‘Template-Aided Composite Shaping’) is provided in During restorative treatment, every second tooth of each quadrant was first conditioned and built up. Either small strips of metal matrices were interproximally placed, or Teflon tape was used to insulate the adjacent teeth in order to avoid interproximal blocking with composite material, thus allowing interproximal passage with dental floss after the reconstruction. A small amount of composite material was applied onto the conditioned occlusal tooth surfaces. Then, the template was filled with composite and positioned on the tooth arch. In the second cohort, the uncured composite material inside the template was preheated for 5 min on a heating plate  to reduce composite viscosity and facilitate placement of the template without compromising physical properties of the composite material . The comAfter restorative treatment, all patients received acrylic splints (night guards) to protect the restorations. Regular recall appointments were agreed based on an individual periodontal and cariologic risk assessment, with a maximum interval of six months.Restorations still in place at the time of follow-up were evaluated according to modified United States Public Health Service (USPHS) criteria  by two iPatient-reported outcome measures (PROMs) were examined using visual analog scales (VAS). All patients were asked four questions about their satisfaction with the treatment in terms of functional parameters, acceptability, and cost-benefit ratio, and marked their response for each question on a 100-mm horizontal VAS. The response on each VAS was measured with a ruler to the nearest millimeter. Furthermore, patients were asked if they used the night guard as prescribed.The results of the clinical evaluation of the first cohort, based on modified USPHS criteria, are presented in At the 10.7-year follow-up, none of the restorations showed secondary caries, and all teeth were therefore rated ‘Alpha’. Likewise, none of the teeth showed any signs of hypersensitivity when provoked with air (100% ‘Alpha’ ratings). Highly predominant ‘Alpha’ ratings of the restorations were also given for the items color stability (96%), marginal inflammation (86%), and color match (77%). Marginal integrity was rated ‘Alpha’ in 55% and ‘Bravo’ in 43% of the restorations. One restoration showed a negative step (2%). Since the negative step was not removable with finishing, this restoration was rated ‘Charlie’. One restoration from the same patient showed localized, non-removable discoloration in the marginal area, which was rated ‘Charlie’ (2%). The other restorations received ‘Alpha’ (57%) and ‘Bravo’ (41%) ratings in terms of marginal discoloration. The item anatomical form was predominantly rated ‘Bravo’ (57%), due to visible loss of composite material as a result of attrition. Three restorations (5%) showed small composite defects extending to the tooth surface and were therefore rated ‘Charlie’. For 38% of the restorations the anatomic form was rated ‘Alpha’. ‘Alpha’ (52%) and ‘Bravo’ (48%) ratings were about equally present for the item surface texture.n = 6), one secondary caries lesion, one marginal gap, one marginal discoloration, and one void within the composite material. Three restorations needed replacement and were therefore considered as failures. The reasons for failure were complete debonding (n = 1), and severe wear (n = 1) and bulk fracture (n = 1) which were not repairable. The success rate of the restorations was 78.0% at 10.7 years. The functional survival of the restorations was 94.9%.During the 10.7-year follow-up period, a total of 10 restorations showed unfavorable events which could be repaired. These unfavorable events were mainly bulk fractures , one secondary caries lesion, one marginal gap, and seven marginal discolorations. The success rate of the restorations was 78.1% at 5.2 years. None of the restorations was lost or had to be replaced, resulting in a functional survival rate of 100%.During the 5.2-year follow-up period (second cohort), a total of 23 unfavorable, repairable events occurred. These unfavorable events were mainly bulk fractures  are given in Pathological tooth wear represents a major problem for both the patient and the dentist when teeth are severely damaged and the vertical dimension of occlusion is reduced. The restorative challenge is to provide reconstructions to rehabilitate the occlusion with the least loss of dental hard tissue in dentitions that have already lost a significant amount of tooth structure due to the tooth wear process. The present investigation is the first long-term follow-up of non-invasive vertical bite reconstructions with direct composite materials. In general, we found a good overall clinical performance of the restorations after a mean observation time of 10.7 years using the USPHS criteria, and an excellent patient acceptance of the treatment. When repairs were not considered as failures, the functional survival of the restorations was excellent with 94.9% surviving restorations in place, especially when taking into account the large size of the composite build-ups. Furthermore, the success rate of 78.0% after 10.7 years is comparable to findings of clinical studies on routine posterior composite restorations placed in patients without documented tooth wear ,32.Our results indicate that large direct composite restorations can be used to re-establish the vertical dimension of occlusion in patients with severely eroded teeth, even in the long-term. Thus, the presented non-invasive treatment approach may help clinicians to avoid more traditional reconstructive concepts for severely worn dentitions, which are mainly based on invasive methods, such as full or partial crown coverage. In spite of the limited number of patients enrolled in the present investigation and the retrospective cohort design, which are limitations of the study, it gives an adequate impression of the success of direct composite restorations placed on increased vertical dimension discrepancies. Previous studies with observation times up to four years also found high success rates of full rehabilitations with direct composite build-ups for treatment of severe tooth wear ,27. On tThe good clinical performance of the composite vertical bite reconstructions in the long-term cohort was confirmed in the second cohort with a functional survival of 100% at 5.2 years. All defective restorations could be repaired in this cohort. In both cohorts, the survival of the restorations could be considerably increased by repair measures, which emphasizes the importance of interventive maintenance care in the treatment of severe tooth-wear patients . In the All patients were included in a regular recall system based on their individual cariologic and periodontal risk assessment, but with a minimum of two visits per year. Special emphasis was put on their dietary and functional habits, and patients were re-instructed accordingly, if required. All patients received individualized caries prophylaxis with professional fluoridation. Restoration interfaces were thoroughly assessed during caries control; however, discolored margins were not routinely removed and polished due to the quasi-study character of the cohorts in order not to modify and alter the clinical presentation of the treated teeth in future assessments.While in the first cohort, the direct adhesive build-up restorations were made of a fine particle microhybrid composite material , which was state of the art as a restorative material for posterior teeth at the time the restorations were performed, in the second cohort, a nanofilled composite  was used. The clinical evaluation using USPHS criteria revealed considerably higher ‘Alpha’ ratings, and considerably lower ‘Bravo’ ratings, of the nanofilled composite restorations in terms of anatomical form, when compared with the microhybrid composite restorations at a similar 5-year restoration service time. Both laboratory  and clinThe superior clinical performance of the nanofilled composite restorations (second cohort) with respect to marginal integrity and marginal discoloration compared to the microhybrid composite restorations (first cohort) might also be due to the fact that the composite material used in the second cohort was preheated inside the template before placement. Preheating composites has been shown to reduce material viscosity  and decrIn patients with severely worn dentitions, full rehabilitations with direct composite restorations represent a valuable long-term treatment option to re-establish the vertical dimension of occlusion with a non-invasive and relatively inexpensive technique. Vertical bite reconstructions performed with nanofilled composite show less surface degradation and better margin qualities than microhybrid composite build-up restorations.