Background: Post-operative pain management for patients undergoing thoracoscopy surgery is challenging for clinicians which increase both health and economic burden. The non-selective NMDA receptor antagonist esketamine possesses an analgesic effect twice that of ketamine. The application of esketamine might be beneficial in alleviating acute and chronic pain after thoracic surgery. The current study describes the protocol aiming to evaluate the analgesic effect of esketamine after pulmonary surgery via visual analog scale (VAS) score for acute and chronic pain.Methods: A multi-center, prospective, randomized, controlled, double-blind study is designed to explore the analgesic effect of esketamine in randomized patients undergoing video-assisted thoracoscopic surgery (VATS) with general anesthesia. Patients will be randomly assigned to Esketamine Group (Group K) and Control Group (Group C) in a ratio of 1:1. Group K patients will receive esketamine with a bolus of 0.1 mg/kg after anesthesia induction, 0.1 mg/kg/h throughout the operation and 0.015 mg/kg/h in PCIA after surgery while Group C patients will receive the same volume of normal saline. The primary outcome is to measure the pain intensity through the VAS score at 3 months after the operation. The secondary outcome includes VAS score at 1, 4, 8, 24, and 48 h and on the 7th day and 1 month after the operation, complications, ketamine-related neurological side effects, recovery time of bowel function, and total amount of supplemental analgesics.Discussion: The results of the current study might illustrate the analgesic effect of esketamine for patients undergoing thoracoscopy pulmonary surgery and provide evidence and insight for perioperative pain management.Study Registration: The trial was registered with Chinese Clinical Trial Registry (CHICTR) on Nov 18th, 2020 (ChiCTR2000040012). Despite of the wide spread of minimally invasive video-assisted thoracoscopic surgery (VATS), post-operative pain after thoracotomy is still a challenge for anesthesiologists , 2. ThorNon-opioids and analgesic interventions that aim to reduce opioids consumption for patients undergoing thoracotomy improve recovery and alleviate opioid-related side effects. Ketamine, a non-selective NMDA receptor inhibitor, possesses part of non-opioid analgesic properties. Studies have shown that low-dose intravenous infusion of ketamine can be used as an adjuvant drug to acute and chronic post-operative pain management –13. IntrEsketamine, the S (+)-isomer of ketamine, has an analgesic effect twice that of racemic ketamine. Esketamine possesses the advantages of a lower incidence of side effects like hallucinations, faster recovery, and the ability to lower MAC value of sevoflurane as well as protect hypoxic pulmonary vasoconstriction during one-lung ventilation . StudiesTo explore the analgesic effect of intravenous esketamine for acute and chronic pain in VATS patients, a multi-center, prospective, randomized, controlled, double-blind designed study will be launched to evaluate pain in randomized patients undergoing VATS with general anesthesia by a visual analog scale (VAS) score in the time points within 48 h and on the 7th day, 1 and 3 months after the operation. The results of this study might provide new insights for pain management in patients undergoing VATS. The flow of participants through the trial is summarized in Age 18–65 years old;ASA I~III level;Plan to perform general anesthesia with tracheal intubation for elective VATS including: lung wedge resection, lung segment resection, partial lung resection, lobectomy, and radical resection of unilateral lung cancer;Plan to be hospitalized ≥48 h after surgery;Be willing to use patient controlled intravenous analgesia (PCIA).ASA >III level;History of allergy to either anesthetics, ropivacaine, or ketamine; Allergy to or have any contra-indications to non-steroidal anti-inflammatory drugs (NSAIDs);Mental illness and chronic pain that may confuse analgesic effect;Cannot read and write Chinese, communication difficulty;Emergency surgery or trauma patients;Have a history of intraoperative awareness;Transfer to ICU after surgery;Unwilling to use PCIA or refuse to participate in this study.Reoperation during the observation period;Unconsciousness or mortality during the observation period;Discharge automatically or transferred in advance;The patient or the client refuses the informed consent or requests to withdraw from the study during the observation period;Interruption of PCIA due to severe nausea and vomiting.Patients will be divided into two groups according to a computer-generated randomized number table in a ratio of 1:1: Group K (esketamine group) and Group C (control group).n = 457), patients receive a bolus injection of 0.1 mg/kg esketamine intravenously after anesthesia induction, followed by a continuous intravenous infusion of 0.1 mg/kg/h throughout the operation. Patients will be equipped with a PCIA (sufentanil 0.03 μg/kg/h + esketamine 0.015 mg/Kg/h) in a total volume of 100 ml and continuous infusion at a rate of 1.5 mL/h for 48 h. The self-controlled capacity is 1.5 ml, and the locking time is 10 min.In group K (n = 457), patients received an injection of normal saline after anesthesia induction and followed by a continuous intravenous infusion of normal saline with the same volume as group K. After the operation, a PCIA will be used . The self-controlled capacity is 1.5 ml, and the locking time is 10 min.In group C  will be applied intravenously, and antiemetic drugs (such as ondansetron 8 mg) will be injected intravenously at the end of the operation. Use antiemetics on the first and second days post-operatively. During the operation, the systolic blood pressure and heart rate will maintain within 20% of the baseline.Before the skin incision, the anesthesiologist or surgeon will perform local infiltration anesthesia with 0.375% ropivacaine 5 ml in each incision. The number of incisions depends on the needs of the operation. An additional local infiltration of 0.375% ropivacaine 5 ml will be carried out around the drainage tube incision when requiring thoracic drainage.2O.One lung ventilation on the contralateral lung will be performed once skin incision starts. The tidal volume is set to 6–8 mL/kg of the ideal body weight, with respiratory frequency 12–16 breaths/min, and the oxygen concentration is up to 100% as needed. Set the PEEP as 3–5 cmHPCIA will be applied after the operation with continuous infusion at a rate of 1.5 mL/h for 48 h. If VAS >5, 1 mg morphine will be injected intravenously in addition to full use of PCIA. Besides, change the PCIA setting to a capacity of 2 ml for self-control and 5 min for the locking time. Patients can orally take acetaminophen (2 g/day) or tramadol (300 mg/day) or other drugs as supplemental analgesics. The type and dose of the drug should be recorded.If the VAS is found to be continuously lower than 1, and either respiratory depression, confusion, and unstable blood pressure occurs, the PCIA infusion should be suspended. Use of PCIA should be restarted until the above-mentioned manifestations improves.Each patient will be given a VAS form to record score of the most severe pain, the painful location, and the total amount of analgesics within 3 months after surgery. Mild PTPS is defined as VAS between 0 and 3 that does not affect daily activities, and a VAS between 4 and 6 that has hindered normal quality of life is defined as moderate PTPS.Researchers who are unaware of the research intervention will collect all patient data and follow up, including the following: gender, age, weight (kg), body mass index (kg/m2), FEV1%, operation time (minutes), anesthesia time (minutes), days of hospitalization, days of chest drainage, post-operative evaluation, complications, side effects , total supplemental analgesics within 48 h after surgery, recovery time of bowel function, and length of hospital stay (days) after surgery. Vital signs are measured every hour from the surgery to 24 h after the surgery, and then every 4 h from 24 to 48 h after the surgery.1) Tachycardia: When heart rate >100 beats/min, or increases by more than 20% from baseline if the baseline value is >83 beats/min, esmolol 10 mg will be given and/or adjust the dose of anesthetics;2) Hypertension: systolic blood pressure >160 mmHg, or increases from baseline 20% or more if the baseline value >133 mmHg, nicardipine 0.5 mg will be given and/or adjust the dose of anesthetics;3) Bradycardia: Heart rate <55 beats/min, or reduces by more than 20% from baseline or if the baseline value is <69 beats/min, atropine 0.3 mg and/or isoproterenol 2 μg or adjust the anesthetics dose;4) Hypotension: systolic blood pressure <95 mmHg, or drops more than 20% if the baseline value is <119 mmHg, liquid infusion, ephedrine 6 mg or norepinephrine 4 μg and/or anesthetics dose adjustment will be applied;5) Intraoperative awareness: During general anesthesia and standard treatment, patients can recall intraoperative events.Any adverse event should be recorded including type, time, duration, treatment, and sequelae and follow up until it is completely resolved or treatment is terminated. A serious adverse event is defined as any serious medical event that causes death, life-threatening, prolonged hospital stay, persistent disability or dysfunction, or other unpredictable serious medical events. If there are any serious adverse events that might cause mortality, be life-threatening, prolong hospital stay or result in persistent disability or dysfunction, the study will be terminated and treatment should start immediately.Preoperative, intraoperative and follow-up data will be recorded by researchers who are unaware of the research intervention as listed in the following .The primary outcome of this study is to assess the patient's subjective pain intensity through the VAS score at 3 months after surgery. VAS score higher than 1 will be considered positive.The secondary outcome includes VAS score at 1, 4, 8, 24, and 48 h and on 7 days and 1 month after surgery, respiratory depression, hypotension, vomiting, nausea, itching, ketamine-related neurological side effects , and recovery time of bowel function. Besides, the total amount of supplemental analgesics within 48 h and 3 months after surgery will also be documented.The study is a multi-center, prospective, double-blind, randomized, parallel controlled trial. The only person who knows which group the patients are assigned to is the research coordinator, and the anesthesiologist in charge is not informed.A statistician who is not involved in data management and statistical analysis possesses the randomized code list generated by computer. The ratio of numbers for Group K and Group C is 1:1;The results of randomization will be sealed in sequentially numbered envelopes, stored and managed by the research coordinator;The research coordinator is responsible for opening the randomization envelope, distributing experimental drugs, collecting data during the operation, and coordinating research. Anesthesiologists use the distributed experimental drugs to execute research programs;The other two researchers will be responsible for the post-operative follow-up, who are blind to the randomized allocation of patients;The anesthesiologists who carry out the research plan and the researchers who collect post-operative results data do not share any information related to patient randomization;The statistical analysis will be carried out independently by a separately appointed statistician.T-test) and figure out that each group include 388 patients. Considering ~15% dropout rate, 457 patients per group for a total of 914 patients will be recruited in this study.The literature reports that the incidence of chronic pain after thoracotomy at 3 and 6 months after surgery ranges from 47 to 80%. We assume that the incidence of chronic pain after thoracotomy in this study is about 50% at 3 months after thoracotomy in patients in the current study, and that the incidence of chronic pain after thoracoscopy will be reduced by 1/5 in the esketamine group. We calculate the required sample size with PASS software with an alpha error of 0.05 and power 80%  guidelines is presented in The two-sided test will be used for all statistical analysis, and the The trial was registered with Chinese Clinical Trial Registry (CHICTR) on Nov 18th, 2020 (ChiCTR2000040012). We started recruit participants after receiving the registration number.To our best knowledge, the analgesic effect and clinical value of esketamine in patients undergoing lung surgery remains elusive. To explore this issue, we design a multi-center, prospective, randomized, controlled, double-blind study, which aims to illustrate the hypothesis that perioperative application of esketamine alleviates acute and chronic pain in patients undergoing VATS and reduces the incidence of PTPS.As the S(+)-isomer of ketamine, esketamine possesses a mighty analgesic effect in theory. Nonetheless, the practical analgesic effect of esketamine still remains controversial. Previous studies have demonstrated that esketamine 0.5 mg/kg as a pre-incisional bolus followed by a continuous infusion 400 μg/kg/h reduced pain scores within 48 h after thoracotomy and reduced morphine consumption . In a chEven though the application of multimodal analgesia for VATS patients, PTPS is still a formidable challenge for clinicians as its prevalence generally up to 47–80% with a duration of 6 months or longer. The high incidence of PTPS might partly ascribe to its elusive mechanism. According to neuropathic symptoms complained by patients and that nerve damage might accompany thoracic surgeries, neuropathic pain might be possible mechanism of PTPS which contains complex interaction of central and peripheral insults . PreviouThe studies involving human participants were reviewed and approved by Chinese Clinical Trial Registry. The patients/participants provided their written informed consent to participate in this study.YL, HL, and FX designed the protocol and completed the manuscript. SG, YW, and WH contributed to the study design, registration and table, and figure preparation. FJ and QW designed the study and modified the manuscript. All authors contributed to the article and approved the submitted version.This study will be supported by Youth Science and Sanitary Foundation of Suzhou (kjxw2018005) and National Natural Science Foundation of China (81873925).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.


P < 0.05). Cigarette, but not hookah, smoking was significantly associated with less severe symptoms. Vitamin D negatively predicted disease severity (P < 0.05). In conclusion, stress, age, and presence of comorbidities were the most important positive predictors of COVID-19 severity, while prophylactic vitamin D use and smoking were significant negative predictors. The use of protective measures and other prophylactic dietary supplements was not significantly associated with symptom severity.Most COVID-19 cases are treated as outpatients, while the majority of studies on COVID-19 focus on inpatients. Little is known about the self-reporting and self-rating of the disease’s symptoms, and the associations of prophylactic use of dietary supplements with COVID-19 severity have not been addressed. The aims of this study are to evaluate COVID-19 severity and to relate them to sociodemographic characteristics and prophylactic dietary supplements. An observational patient-based study conducted through an online questionnaire on recovered COVID-19 patients. The patients were assessed for several severity parameters, sociodemographic parameters, and prophylactic dietary supplement use. A total of 428 patients were evaluated. Age and presence of comorbidities had positive associations with the severity parameters. The severe infection group had the highest proportion of patients stressed about COVID-19 ( Age, body mass index (BMI), and comorbidities are among the most important demographic parameters; other factors such as sex, smoking status, place of residence, housing condition, nature of employment, and concern about COVID-19 are also believed to be associated with this infection and its severity. Regarding age, a slightly lower infection rate in young people has been reported in addition to a lower death rate (less than 1%) . MeanwhiRegarding smoking status in relation to the COVID-19 rate and severity, there is disagreement between the reported data ,11,12,13Concern and stress about COVID-19 are a significant problem that has emerged during this pandemic . Social To some extent, an individual’s place of residence  has an effect on the transmission and spread of COVID-19 ,2. The mFurthermore, an individual’s job, regular daily work, and hours spent outside have an effect on COVID-19 infection in that a particular job can put an individual at greater risk .The use of protective measures such as social distancing, wearing a face mask, washing hands with soap and water, and disinfecting hands regularly is highly encouraged by authorities during COVID-19 outbreaks ,34,35, aAlong with the use of protective measures to combat COVID-19, a number of prophylactic dietary supplements and drugs have been advised to enhance the immune system or decrease viral replication. A recently published review stated that micronutrients support the immune system and may reduce the risk of infection . Among tSimilarly, vitamin C (ascorbic acid) could play a role in the prevention and treatment of viral infections by different mechanisms such as scavenging free oxygen radicals, reducing pro-inflammatory cytokines, and enhancing the antimicrobial ability of certain cells ,44. A raThe trace mineral zinc is hypothesized to prevent viral attachment to the nasopharyngeal mucosa and inhibit viral replication. Different doses of zinc have been used in registered clinical trials for COVID-19, with a maximum dose of 50 mg twice daily , alcohol drinking status , and exercise .(b) Place of residence, work, and riskThis included three questions about the participants’ residency, housing conditions, and household and five questions about their work , regular daily work, time spent outdoors, close contact with COVID-19 patients, concern about COVID-19 infection before becoming infected, and chronic diseases/comorbidities .(c) The use of protective measuresThis included questions on whether the participants strictly and regularly implemented common protective measures  before they were infected with COVID-19.(d) Prophylactic drug and dietary supplementsThis included six questions to obtain information about their use of prophylactic dietary supplements , their dosages, and the duration of use (the number of weeks of use before COVID-19 diagnosis).(e) COVID-19 severity and symptom profileThe questionnaire contained a total of 39 questions about the following topics:This was the main part of the questionnaire and included 11 questions on whether the participants had experienced any symptoms during their COVID-19 infection (symptomatic) or whether they were asymptomatic. If they selected “yes” for symptomatic, they were directed to another section on COVID-19 severity. The COVID-19 severity questions comprised two parts, which are outlined below.2.4.1This section included five questions (2 during the time of infection (if available), followed by a question about the symptom duration of their disease (in days).In this part, the participants were also asked two separate questions: their highest recorded body temperature and lowest recorded SpO2.4.2(a) Treatment and sequelaeIn this section, the participants were asked whether they were hospitalized and asked six questions (yes/no) as to whether the disease made them seek any of the following: visiting a hospital, consulting a medical specialist, using medication, using oxygen therapy, receiving plasma from patients who had recovered from COVID-19, and using medication to help them sleep.This section covered 11 choices for the treatment/medication the participants received during their infection and 7 choices for the sequelae/complications  problem; and none) that they acquired after their recovery.2.5The participants were divided according to their age into four groups: paediatric (<18 years), adult (18–39 years), middle aged (40–64 years), and old age (≥65 years).2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2).According to BMI, the participants were divided into four groups: underweight  and the severe group (rating ≥4). Fever with or without rigour/sweating, coughing, and SOB were regarded as typical symptoms .2.6The patients’ responses were transferred into a single SPSS programme; IBM SPSS version 22 ; and the variables were coded and analysed for socio-demographics, use of protective measures, and dietary supplements. A normality test was performed using the Kolmogorov–Smirnov test, and all the continuous variables were non-parametric. A descriptive statistical analysis was done to find the median of each variable within the interquartile range (IQR).U test and Kruskal–Wallis H test. Spearman’s correlation was used to find a linear correlation between general socio-demographics and COVID-19 severity parameters. A linear regression analysis was performed to determine the degree of prediction between parameters of significant correlation. P ≤ 0.05 was regarded as significant. Multiple linear regression analysis was performed to quantify the correlation between patient characteristics and severity parameters as outcome. Stacked bar charts, box plots, and scatter plots were used to demonstrate significant data.Numerical variables were shown as frequency and percentages. A chi-square test was applied for all categorical variables, and COVID-19 severity was compared between different age groups, BMI groups, the presence or absence of chronic diseases, and the use of dietary supplements. The descriptive parameters, such as the variables in COVID-19 severity parameters (I), were compared between groups based on age, BMI, dietary supplement use, and with other parameters using the Mann–Whitney 3A total of 455 participants consented to fill in the form. Among them, 27 were excluded because of failure to meet the eligibility criteria and the case definition. After enrolment, 428 patients were entered into the final analysis of the study. The participants’ age ranged from 15 to 80 years, with a median age of 33 years (IQR = 18 years).3.1The general and socio-demographic characteristics of the studied participants are shown in 3.2Among the study participants, 406 (94.9%) were symptomatic. After analysing the parameters, the severity of COVID-19 infection in the symptomatic patients is given below.3.2.1The median (range) of each severity parameter is demonstrated in 3.2.2The frequency (percentage) of each severity parameter is summarized in The comparison of all the parameters of severity (I and II) between the mild-moderate and severe groups of patients is presented in 3.3The most common symptoms among the symptomatic patients were malaise (96.1%), myalgia (94.8%), and headache (92.4%), followed by fever and/or rigour and sweating (91.9%). Moreover, 78.4% of the patients reported having a cough, and 76.4% experienced loss of taste and/or smell with a sore throat . The symRegarding sequelae, 144 (35.4% of the symptomatic) patients had no sequelae, while the others had one complication (35.9%), two complications (18.2%), or more than two complications (10.5%). The most common sequelae among participants were malaise (56.8%) and respiratory problems (21.6%).3.4β of 0.23, 0.01, and 0.15; P < 0.001, 0.01, and 0.04, respectively), while smoking negatively predicted symptom severity .The multiple logistic regression analysis of COVID-19 severity predictors (with severity rating as an outcome variable) was performed and demonstrated in 3.5r = 0.15; P = 0.003) and negatively correlated with SpO2 . The severity of COVID-19 was compared between the four age groups, and significant results were found .The severity of COVID-19 parameters was compared between the four groups of BMI, and significant results were found with regard to body temperature, SpOduration . The mulP = 0.04), higher mean sequelae , and longer symptom duration  were recorded.Regarding sex, when female patients were compared to male patients, a higher symptom score . About 51.0% of the patients with comorbidities was within the group of severe symptoms compared to 27.1% of the patients without comorbidities .When the presence of comorbidities was analysed, a significantly higher severity rating, symptom score, and body temperature and a lower level of SpOP = 0.01), symptom score , body temperature , and symptom duration  were revealed. However, no significant differences were observed between hookah smokers and non-hookah smokers. Regarding the SpO2 level in relation to smoking, no significant results were found. In assessing the amount of cigarette smoking, it was observed that the more cigarettes an individual smoked, the shorter their symptom duration .No significant difference was found in the COVID-19 severity parameters between alcohol drinkers and non-drinkers and between participants who regularly exercised and those who did not . The number of family members and housing condition and the presence or absence of close contact had no significant relation with COVID-19 severity parameters (P > 0.05).Regarding the place of residence, the only parameter with a significant difference between the groups was the SpOP = 0.01; P = 0.03; Regarding job and times spent out, the patients who were self-employed had significantly more severe disease compared to the rest, while those who were unemployed had the least severe disease  and negatively predicted the SpO2 . Patients who were more concerned about COVID-19 before contracting the disease had a higher mean symptom score, severity rating, and sequelae rate compared to those who were less concerned. The values were as follows for the patients who were not concerned, somewhat concerned, moderately concerned, and greatly concerned: symptom score = 22.1, 24.0, 26.0, and 26.9, respectively (P = 0.02); severity rating = 2.75, 2.92, 3.23, and 3.53, respectively (P < 0.001); and sequelae rate = 0.78, 0.92, 1.28, and 1.38, respectively (P < 0.001). A higher percentage of those who were greatly concerned had severe symptoms compared to those who were less concerned . The comparison in the frequency of protective measure use between mild-moderate and severe groups was not significant (Table S1).In regard to the protective measures, none of the protective measures had a significant correlation with the COVID-19 severity parameters  individuals used prophylactic dietary supplements before contracting COVID-19. The percentage of use, the dosage of each dietary supplement , and the duration are summarized in P < 0.05; The proportion of hospital visits for patients who received prophylactic vitamins C and D supplements was statistically lower in comparison with patients who did not receive supplements .The effect of the prophylactic dietary supplements on sleep disturbances was observed according to their daily dosage before COVID-19 infection. Less proportion of sleep disturbances was observed in patients who received >1,000 mg prophylactic vitamin C compared to patients who received smaller doses or patients who did not receive it  and vitamin D: 30.4 vs 40.0% (P = 0.02). Frequency of sleep disturbances in patients using vitamin C or D, for more than 2 weeks versus less than 1 week was as follows: vitamin C: 40.0 vs 52.2% (P = 0.04), vitamin D: 39.1 vs 40.9% (P = 0.051), and zinc: 34.0 vs 41.4% (P = 0.02), respectively.Among the patients who received prophylactic vitamins C and D for more than 2 weeks, less proportion of hospital visit and a lower proportion of sleep disturbances were observed than patients who had been given a shorter duration of these supplements. Proportion of hospital visits in patients using vitamin C or D, for more than 2 weeks versus less than 1 week was as follow: vitamin C: 30.0 vs 56.5% (P > 0.05).No significant difference was observed between the patients with and without prophylactic use of zinc and vitamins C and D in terms of the hospitalization, use of medication, use of plasma, or use of oxygen therapy . The association of age with severity has been shown in previous studies ,60.The median symptom duration in our survey was 14 days; in other studies, a median symptom duration of 13–16.5 days was reported ,60. In t2 was recorded in the obese patients. This correlation could be explained by the tendency of obese people to develop metabolic syndrome [2 was recorded in patients over 65 years old. This result is in line with the findings of another study in which the researchers found that patients with SpO2 values of 90.0% or less were older [2 level was not correlated with sex.In our study, the lowest level of SpOsyndrome , which csyndrome ,63,64, tsyndrome . The lowre older . We founIn our study, we noted that those who had one or more comorbidities suffered a more severe form of COVID-19 in comparison with those who did not. This finding is in parallel with other studies that showed that the clinical manifestations of COVID-19 in those with underlying chronic illnesses were severe ,68,69,70Moreover, only a minority (1/7) of the participants were smokers, and the reason could be greater proportion of female patients in our study, as smoking was found to be less prevalent in women in our community . The smoThe lower severity rating among smokers was observed since the majority of our participants were outpatients in comparison with the hospitalized COVID-19 patients in the aforementioned study . Smoking2 levels were recorded among hookah smokers compared to cigarette smokers. A record of the SpO2 levels among different types of smokers could not be found, but the use of hookah among younger adults and the sharing of the mouthpiece between them could increase the risk of SARS‐CoV‐2 transmission [In the current study, lower SpOsmission . AlcoholIn the present study, concern about COVID-19 in two-fifths of the patients was to a moderate-high extent, which is in line with a local study in which about half of the Kurdish population consider COVID-19 to be a major harm to their lives , which r2 level observed in our suburban study participants could have been the result of having less access to health facilities and services. Another possibility could be poorer housing conditions and the greater number of households in the suburban areas compared to urban areas; thus, a lower capacity for of social distancing. In the current study, no significant correlation was found between COVID-19 severity and housing conditions or number of family members/household. In contrast, other studies have shown that areas with a higher proportion of poor housing conditions are associated with a higher rate of infection and COVID-19-related mortality [In our study, the disease severity was analysed among patients with different residency locations and housing condition: The lower SpOortality ,28. MoreIn this study, a large proportion (around two-thirds) of the patients did not apply social distancing from known or suspected patients with COVID-19. According to a systematic review, a physical distance of more than 1 m offers more protection in comparison to a distance of less than 1 m; and it is important to decrease the adverse outcomes, morbidity, and mortality of COVID-19 . In the Prophylactic use of vitamins C and D and zinc was observed in less than one-third of the participants. Among the three micronutrients, prophylactic vitamin D was significantly associated with less severity. The duration of taking prophylactic micronutrients varied, and less than half of the prophylactic supplement users had taken them for over 2 weeks before contracting COVID-19. Hospital visits and sleep disturbances among participants who had taken prophylactic vitamins C or D for longer than 2 weeks were significantly less recorded compared to the participants who took these vitamins for less than 2 weeks. Moreover, regardless of the duration of using these supplements, fewer participants taking prophylactic vitamins C and D had visited hospital compared to those not taking the supplements. Significant correlation of vitamin D with COVID-19 severity and other results supports their probable prophylactic benefits during the COVID-19 pandemic ,79,80,81Although there is no consistency regarding the dose of these supplements in the prevention and treatment of COVID-19 , we foun4.1The strengths of this study are that a patient-based study of COVID-19 patients without critical condition and ICU admissions are scant. This group of patients has been ignored in the literature even though they comprise a majority of COVID-19 patients. Most of these patients do not need hospitalization and the management and care of their COVID-19 infection are done at home. Thus, the study of the severity, morbidity, and symptom profile of these patients is of great importance, as are the frequency of their use of protective measures and prophylactic supplements and the rate at which they seek medical assistance. Furthermore, our information about the correlation of COVID-19 symptom severity with patients’ socio-demographic characteristics and prophylactic dietary supplement use will be current at the time of publication.However, this study also has limitations. As it is a patient-based survey, the most severe patients who required ICU could not be included, and the data are more subjective than objective and affected by the personal perspectives, feelings, and ratings of severity of patients. There could have been variations in their pain thresholds or exaggerations in their symptoms and severity, and recalling in their concern about the disease before getting infected with it, which would affect their responses. Another shortcoming could have resulted from the patients’ recall of their use of prophylactic supplements before their infection and their symptoms and the severity during the infection, as the data were collected after complete recovery from COVID-19. Although the medication, dosage, and duration options from which the patients chose were written out clearly, reporting the drug name, dosage, and duration of use could be difficult for some people among the general population and be subject to mistakes.Another limitation of this study is that the convenience sampling of the relatively small sample size did not allow for proper analysis of several parameters such as smoking condition, place of residency, and dose of supplementary medication used, especially after stratification by age and BMI. Another limitation is that few elderly and paediatric or underweight patients participated in this study. Otherwise, we could have found more reliable outcomes of COVID-19 in these groups and related them to COVID-19 severity parameters. Moreover, as it is a patient-based survey and the data were collected from outpatients, not all the patients were RT-PCR confirmed COVID-19; some patients were diagnosed based on typical HRCT findings reported by a radiologists; and a few of them based on typical symptoms, their contact history in combination with CXR finding, and/or serology by specialized physician. However, for the same purpose, serum 25-hydroxyvitamin D level could not be measured for the patients.5In this study, we concluded that several factors are associated with increased risk of COVID-19 severity. Stress, older age, and comorbidities were the most common and critical risk factors. The use of protective measures has no significant association with disease severity. Vitamin D is significantly associated with a lower severity rating. Furthermore, according to this study, exercise was not associated with COVID-19 severity, while cigarette smoking, but not hookah smoking, was associated with less severe infection among COVID-19 outpatients.As stress is among the risk factors for COVID-19 severity, the efforts by the authorities to help calm people and minimize panic spreading by social media are recommended in line with stress management.The use of prophylactic vitamin D is suggested before and during COVID-19 infection. Although cigarette smoking is associated with less severe COVID-19 among outpatients, it is not encouraged to smoke or to increase smoking during the COVID-19 pandemic, as smoker patients who were hospitalized showed a higher risk of ICU admission and ventilator use with worse ARDS.Overall, a large population-based study is recommended to relate the symptom severity in COVID-19 patients to socio-demographics and prophylactic dietary supplements and to compare patients with healthy individuals to relate these parameters with the rate of COVID-19 infection.


Functionally graded material (FGM) based on Inconel 625 and AISI 431 stainless steel powders was produced by applying the direct laser deposition (DLD) process. The FGM starts with layers of Inconel 625 and ends with layers of 431 stainless steel having three intermediate zones with the composition (100-X)% Inconel 625-X% 431 stainless steel, X = 25, 50, and 75, in that order. This FGM was deposited on a 42CrMo4 steel substrate, with and without preheating. Microstructures of these FGMs were evaluated, while considering the distribution of chemical composition and grain structure. Microstructures mainly consisted of columnar grains independent of preheating condition; epitaxial growth was observed. The application of a non-preheated substrate caused the formation of planar grains in the vicinity of the substrate. In addition, hardness maps were produced. The hardness distribution across these FGMs confirmed a smooth transition between deposited layers; however, the heat-affected zone was greatly influenced by the preheating condition. This study suggests that an optimum Inconel 625/AISI 431 FGM obtained by DLD should not exceed 50% AISI 431 stainless steel. Functionally graded materials (FGMs) can be considered as a particular class of composites with a spatial variation of composition/microstructure along a specific direction. However, FGMs may not encompass sharp distinguishable interfaces as observed in traditional composite materials . The appThe Functionally Graded Additive Manufacturing (FGAM) concept can be developed, i.e., the production of FGMs that are different in distribution or composition through a layer-by-layer approach ,5. RegarRegarding the DLD process, the laser/substrate relative velocity, laser scanning pattern, laser power, laser beam diameter, hatch spacing, powder feed rate, powders composition, powder gradient variation, and preheating conditions are vital parameters that must be considered ,8. MoreoThe production of FGM by DLD has been the subject of study by several research groups. However, these products are currently limited to small samples. The construction of a component with functional gradient properties depends not only on the position of materials but also on optimizing process parameters required to control the microstructure and improve the mechanical properties in multi-material with functional gradient. High-performance and versatility FGMs can meet performance requirements and have been widely used in the fields of aerospace, biological, electromagnetic, nuclear, and photoelectric engineering ,11.This process uses a deposition system equipped with two or more powder feeders and can create dissimilar gradients traditionally difficult to reach. The ability to mix two or more types of powders and control the feed rate of each flow makes DLD a flexible process for manufacturing complex components for the innovative development of alloys and formation of materials with a gradient of functionality ,12,13. TRegarding the production of FGM by the DLD technique, some studies mentioned the use of different systems. For the SS316/Inconel 625 system, there was an increase of mechanical and wear resistance due to the formation of secondary phases with the increase of Inconel 625 alloy content ,14,15,16Recognizing the importance of metallic FGM and its complexity, this article explores the deposition of Inconel 625 superalloy powder gradually mixed with 431 stainless steel alloy, evaluating the influence of compositional variation, as well as preheating, on the microstructure and mechanical proprieties. The former condition was performed by preheating the substrate metal used for deposition. Although several investigations allocated the production of gradient materials by using Inconel 625 superalloy with other alloys ,15,16, tThis study included the production of compositional gradients as functionally graded material (FGM), using Inconel 625 powder , so-called M625 in this study) mixed with AISI 431 stainless steel powder  in gradient. According to the supplier’s data sheets, M625 has a particle size range of 45–90 µm, and M42C is in a size range of 45–106 µm; the chemical composition of these alloys is presented in In this study, the substrate used for deposition was 42CrMo4 steel, machined plates in 100 × 120 × 15 mm, supplied in quenched and tempered condition. This steel is widely used for manufacturing industrial components, such as gears, automotive components, and drilling joints ,22. In tThe consolidation of powders, required for the FGM production, was achieved by direct laser deposition (DLD) technique, using a six-axis robot KUKA KR90 R3100 model  connected to robotic and laser control units. This system was equipped with a laser system (LDF 3000–100), a fiber-coupled laser diode providing a wavelength range of 900–1030 nm, reaching a nominal beam power of 6000 W.The depositions started with 100% M625 on the 42CrMo4 substrates (without PHT and PHT conditions), followed by depositing layers of 75% M625–25% M42C, 50% M625–50% M42C, 25% M625–75% M42C, and ended to 100% M42C. Feeding of powder mixtures was performed in a coaxially delivering mode for constructing compositional gradients. Moreover, argon shield gas, with 99.99% purity, was used as protection gas with a flow rate equal to 5.5 L/min to minimize contamination and oxidation of the melt pool during the DLD process. For the deposition of M625 layers, the following processing conditions were used: laser power (LP) = 2000 W, scanning speed (SS) = 6 mm/s, and feeding rate (FR) = 15 g/min. The last layers (100% M42C) were deposited with the following conditions: LP = 1500 W, SS = 10 mm/s, and FR = 15 g/min. These procedures were carried out by applying a spot size equal to 2.5 mm; the trajectory of depositions involved continuously parallel depositing, applying a 40% overlapping between tracks, followed by depositing successive layers rotated in 90° in each layer. Afterwards, printed specimens, without PHT and PHT conditions, were cooled down to room temperature. The application of these conditions was based on previous studies ,24. ProcRegarding microscopic and mechanical characterizations, FGM specimens with and without PHT were prepared by using conventional metallographic techniques. Samples from each deposition were cut by using a metallographic cutoff machine with refrigeration to avoid substrate and cladding overheating. Samples were mounted in resin and polished down to 1 μm diamond suspension. However, an additional polishing step, using a 0.06 μm silica colloidal suspension mixed with ammonium hydroxide solution 25%, was needed for EBSD analysis, allowing us to obtain Kikuchi patterns [Similar FGM specimens were used for the microhardness test, using a fully automated DURASCAN 70 microindenter—EMCO TEST . The HV hardness maps were produced by 700 indentations, applying a load of 300 g, considering 0.1 mm as the distance between the centers of every two adjacent indentations. This procedure scanned an area of 5.7 × 1.1 mm.The microstructure of a FGM without PHT, from 100% M625 to 100% M42C, is illustrated in M42C deposits are prone to cracking, and strict control of processing conditions is mandatory ,26. The The inclusions (round black spots) are mainly complex oxides formed along the FGM, and the irregular porosities are likely caused by elemental segregation ,28.This second phase can be the Laves phase, resulting from the microstructural segregation of Nb and Mo elements from the liquid due to rapid solidification during deposition. The formation of the Laves phase, or even of carbides, in the austenitic matrix has been observed in several studies ,32,33,34The formation of secondary phases in FGM depends on the processing history , being pDuring the deposition of several layers of the same material, each new layer remelts the surface of the last deposited, replacing the zone of equiaxed grains with columnar ones. As a result, the equiaxed region is limited to the upper surface of the cladding. However, SEM images of The presence of Fe from the substrate in the first M625 layers is more pronounced in the PHT condition. This difference is caused by the thermal energy having caused a higher dilution of the preheated substrate, with more Fe incorporating the melt pool, as observed in other studies . As showThe microstructural evolution in the FGM was evaluated in detail through localized chemical analysis, using EDS. The EDS analysis of the zones illustrated in xOy. The microstructures also reveal the presence of lighter (white and gray) regions. The results of The PHT effect on the segregation for the interdendritic zones of Nb and Mo elements, which are the main compositional elements of the Laves phase, is not apparent throughout the FGM. However, close to the interface, this variation seems evident due to the decrease of the Laves phase by the PHT effect, as observed by comparing the representations of zone Z1 in Typically, in the DLD process, the interface and heat-affected zone (HAZ) are critical regions. In fact, the heat input in these regions is much smaller than in conventional welding processes due to the localized molten region created by the laser. Consequently, the cooling rate is very high at the beginning of cladding solidification, promoting a significant microstructural change in the HAZ. This change can increase the hardness and decrease the toughness in the substrate HAZ.In this study, preheating the substrate to a temperature of 300 °C promoted not only a microstructural change at the interface, inhibiting the formation of the planar grain layer , but alsPrevious studies confirmed that PHT positively influenced the microstructure and the mechanical properties in substrates processed by DLD . In addiAn EBSD analysis was performed to observe the morphology and grain distribution of the FGMs, as illustrated in In the layers deposited with the 50% M625 + 50% M42C powder mixture, there is a zone with equiaxed grains, probably formed by the complex chemical composition and the heat accumulation, which induced a partial reduction of the high thermal gradient. However, this localized microstructural alteration is again replaced by columnar grains, not being maintained until the last deposited layers, contrary to what has been seen in other studies . It shouFor the first two compositions (100% M625 and 75% M625 + 25% M42C), the grains of the FGM without PHT A are thiEBSD images also show that some grains form in one region and spread to the next, with different compositions. This indicates epitaxial growth in successive layers. This type of growth, which favors the bonding between layers, occurs because the deposition of a new layer remelts the surface of the previous one. This remelting/solidification process allows the grains from the previous deposition to act as nucleation sites for the solidification of new grains.The images in In this study, the composition gradient from the substrates to the upper layers, with a continuous increase in the amount of martensitic steel, should show an evolution of hardness along with the deposited layers. In fact, previous studies on the deposition of monolayers of these materials indicate average hardness values greater than 500 HV for M42C  and apprThe relatively low hardness of the M42C-rich layers is explained by a slower cooling rate in these layers, which are the last to be deposited, inhibiting an extensive martensitic transformation, and by these layers having about 10 wt.% Ni, which, being one austenite stabilizer, also hinders the martensitic transformation. Finally, except for the last layer, all others undergo a self-tempering process of the martensite that may have formed.The higher hardness of the FGM with PHT (indicated by a red arrow) was measured in the M625 region, which can be attributed to compositional fluctuations leading to a local concentration of hard Laves phase/carbides.This evolution of hardness shows that, up to 50% of M42C powder, which is significantly less expensive, can be added to M625 powder without inducing significant changes in hardness and microstructure, as discussed above. Larger amounts of M42C should not be added, as they can lead to cracking.Cracking-free production of the Inconel 625/AISI 431 steel FGM, applying DLD, is only verified up to a certain composition. The addition of stainless steel cannot exceed 50 wt.%.The metallurgical bonding of deposits to substrates and between the various layers of the FGM is ensured by the diffusion in the liquid state of the alloy constituents, the remelting effect, and epitaxial growth.The grain microstructure in Inconel 625/AISI 431 FGM is essentially columnar, regardless of preheating.Preheating influenced the microstructural evolution and microhardness in the substrate and the first deposited layers; the region of planar grains observed in the vicinity of the substrate only formed without preheating. A marked increase in grain size and a reduction in martensite was observed in the preheated substrate HAZ, decreasing the hardness of this region.In this study, the production of functionally graded material (FGM) by direct laser deposition (DLD) technique was evaluated. The deposition started with layers of nickel-based superalloy (M625 powders) and ended with layers of martensitic stainless steel (M42C powders). Three mixtures of powders were used in intermediate deposits, sequentially increasing by 25 wt.% the amounts of M42C powder. Moreover, the influence of preheating the 42CrMo4 steel substrate on the microstructural and hardness evolution in FGMs were evaluated. The main conclusions of this study are as follows:


Optical microscopy, scanning electron microscopy, X-ray electron diffraction spectroscopy, and nanoindentation technique were applied to study topography, chemical composition, hardness, plastic and elastic properties. The results demonstrate that the addition of nanocopper or titanium dioxide to MWCNTs coating increases hardness, lowers Young’s modulus, improves plastic and elastic properties, wear resistance under deflection, and plastic deformation resistance. The results can be attributed to different properties, structure and geometry of applied particles, various deposition techniques, and the possible appearance of porous structures. These innovative coatings of simultaneously high strength and elasticity are promising to apply for deposition on long-term titanium implants.Titanium implants are commonly used because of several advantages, but their surface modification is necessary to enhance bioactivity. Recently, their surface coatings were developed to induce local antibacterial properties. The aim of this research was to investigate and compare mechanical properties of three coatings: multi-wall carbon nanotubes (MWCNTs), bi-layer composed of an inner MWCNTs layer and an outer TiO Carbon nanotubes (CNTs) demonstrate unique properties, such as high aspect ratio, enhanced tensile (tensile strength up to 30 GPa ) and ela2O3 ,7,8, hyd2O3 ,11,12,132O3 , titaniu2O3 [2) ,15,16, u2O3 [2) ,18, nick2O3 [2) ,20,21,222O3 [2) ,24,25, c2O3 [2) , and copAfter the reports on CNTs bioactive properties, their application in the biomedical field increased ,27. Sasa2) appears in four natural polymorphs-TiO2(B), brookite, anatase, and rutile. Most widely studied are the anatase and rutile crystalline polymorphs, but there is also an amorphous form of TiO2 [2 is a biocompatible ceramic, which can be used to achieve the antibacterial effect, corrosion resistance, and high biocompatibility in biomedical appliances [2 is widely used in many different areas, such as gas sensors, and for air purification or dye-sensitized solar cell applications [2 has some prominent properties, it is photocatalytically active, has a self-cleaning ability on surfaces, is low-toxic [2 nanoparticles sponges which proved the material to be biocompatible; the cells could proliferate well with a trend of increasing cell number with TiO2 concentration. This suggests that such a huge percentage of TiO2 nanoparticles in the material could be used for bone tissue engineering. Hsiao et al. [2 nanoparticles in terms of cytotoxicity which showed that not only the size, surface area, and shape, but also the phase of the nanoparticles played an important role. The cytotoxicity of the TiO2 nanoparticles increased in the following order: amorphous > anatase > anatase/rutile. Uboldi et al. [2 , especially the rutile, presented the most genotoxic effects. The literature showed also the induction of micronuclei by anatase TiO2 and negative results for rutile when testing genotoxicity using human cell lines [Titanium dioxide  minimized the crack problem because hydroxyl groups and carboxylic groups from CNTs bind to TiO2 particles. As a result, microcrack formation was diminished. The reinforcement effect of CNTs was also seen when the CNTs coating was synthesized by air plasma spraying [2 and CNTs/alumina (Al2O3) coatings, noticing an improvement of scratch resistance of the listed ceramic coatings. Wang et al. [2 nanocomposite coating using a ball-on-disk tribometer under dry-sliding conditions. The comparison between nanocomposite and TiO2 showed a moderate decrease in friction coefficient and a significant reduction (~93.6%) in wear volume. There were also reports about hydroxyapatite (HAp) coating with titanium and MWCNTs addition (HAp-Ti(20 wt.%)-MWCNTs (1 wt.%) [CNTs have a high surface area, which gives them the possibility to build a mesoporous structure, thus they are excellent carrier substrates for TiOi et al.  discussen et al.  used CNTspraying . The CNTspraying . Jambagispraying  tested pg et al.  verified(1 wt.%)  depositeS. aureus and E. coli were shown by Hidalgo-Robatto et al. [E. coli, S. aureus, and C. albicans by Shanmugam and Gopal [E. coli, P. aeruginosa, and S. enteritidis bacteria [Copper is an element with proved antibacterial efficiency attributed to its influence on cellular permeability, resulting in malfunction and death of bacteria . Such efo et al.  for the nd Gopal  for Cu sbacteria . Copper bacteria . The safbacteria . Howeverbacteria  high antbacteria . Moreovebacteria , Cu-dopebacteria , and Cu-bacteria .The most commonly used processing method for the production of ceramic and ceramic-based composite coatings is EPD, which is characterized by many advantages including, low cost, simplicity, low coating time and temperature, control of deposit thickness, uniformity of deposits, the ability to coat the complicated shapes, and microstructural homogeneity ,54,55,56Due to excellent physical  and cheSo far, research has shown that surface coatings are numerous as well as their properties, and different determinants for optimization of surface treatment can be chosen. In this research, we have focused only on the creation of two composite coatings which would possess greater hardness at simultaneously high elasticity than the present coatings to prevent possible damage by stresses imposed during surgery and use of an implant. To achieve this objective, we have decided to apply nanoparticles of carbon (carbon nanotubes with high surface/volume ratio), ceramic nanooxides (nanotitania) and nanocopper, in different combinations. The nanoparticles are well-known to have high mechanical properties. We have also assumed that electrophoretically deposited coatings would possess a certain porosity, resulting in lowering Young’s modulus and enlarging the elastic region. Therefore, we have prepared composite coatings as bi-layer (sandwich) deposits obtained by two consecutive processes, and the dispersion coating, formed in a one-stage process.The Ti13Nb13Zr alloy  of the composition shown in 2), rutile structure,  possessed an extremely small grain size in the range of 1 to 2 nm.The multi-wall carbon nanotubes (MWCNTs) had an outer diameter 10–15 nm, inner diameter 2–6 nm, length 1–10 μm, number of walls 3–15 . Nanocopper (nanoCu) had a mean grain size distribution of 80 nm . Titanium dioxide (TiOThe electrophoretic deposition (EPD) method was used to prepare coatings, of which parameters of synthesis are shown in 2 bi-layer coating was prepared in two steps. First, the electrophoretic suspension comprised of 0.1 g MWCNTs suspended in 40 mL of distilled water was prepared and the EPD process on the Ti13Nb13Zr substrate was proceeded. At this stage, preparation of the MWCNTs coating was finished. The MWCNTs coated samples were then subjected to EPD in suspension consisting of 0.15 g TiO2 dispersed in 50 mL of isopropanol and 0.5 mL of surfactant Polysorbate 20 .The EPD process was conducted at parameters selected from preliminary studies and based on the Cho et al. report . The MWCTo prepare the MWCNTs_Cu dispersion coating, 0.1 g of MWCNTs, 0.005 g of nanoCu, and 0.5 mL of Polysorbate 20 were dispersed in 40 mL of distilled water and deposited using the EPD method on the Ti13Nb13Zr substrate.To study the surface topography, the optical microscope  NV/SA, Mechelen, Belgium) was used. The average roughness index Sa values were estimated based on 512 lines made in the area of approximately 150 μm × 140 μm. The specimens’ surfaces and cross-sections were observed using a high-resolution scanning electron microscope (SEM)  with a LED detector, at 5 kV acceleration voltage.The chemical composition of the coatings was investigated by the X-ray energy dispersive spectrometer (EDS) .r), plasticity index (PI), and elastic recovery index (EI) were calculated using the integrated software. Young’s modulus (E) parameter was calculated based on Er value and the Poisson’s ratio (ν). The ν of 0.25 [2 [2 and MWCNTs_Cu coatings as unidirectional composite materials, the Halpin–Tsai (H-P) model was used to evaluate their ν, E [r, νr, Er, Hr and Vm, νm, Em, Hm are volume fraction, Poisson’s ratio, Young’s modulus, and hardness of the reinforcement and matrix, respectively. The volume fraction was calculated according to [3 [3 [3 [2, and nanoCu, respectively. Nanoindentation tests were performed with the NanoTest™ Vantage  using a Berkovich three-sided pyramidal diamond. The twenty-five measurements were carried out on each sample. The maximum applied force was 10 mN, the loading and unloading rate were set up at 20 s, and the dwell period at maximum load was 10 s. The distances between the subsequent indents were 20 μm. During the indent, the load–displacement curves were determined by the Oliver and Pharr method. Based on the load–penetration curves, surface hardness (H), reduced Young’s modulus , the ν values of 0.254 and 0.251 were assessed for the MWCNTs/TiO2 bi-layer coating, and MWCNTs_Cu dispersion coating. The coating surface roughness increased after composition modification with both metal and oxide particles, as proven by the results presented in 2 bi-layer coating, and the MWCNTs_Cu dispersion coating deposited on the Ti13Nb13Zr alloy. 2 particles with an average aggregates surface area of about 1.5 µm2. The surface topography of the MWCNTs_Cu coating . As seen, the thickness of the coatings, shown in both images, extended roughly between 0.5 and 2 µm. The greatest values are observed for the MWCNTs/TiO2 coating which could be explained by the deposition method resulting in the bi-layer coating. What is important, all coatings possess the thickness sufficient to separate the substrate surface, with the greatest thickness of the MWCNTs/TiO2 coating being the most appropriate for application as sufficiently thick for retardation of possible penetration of liquids.The load–displacement hysteresis curve, as an example of the results of nanoindentation tests, is shown in The exact values of measured mechanical properties are listed in Such behavior, an inverse relationship between hardness and Young’s modulus, already anticipated by us , has beeAssuming that Young’s modulus values are also additive, porosity might be expressed as a ratio of real Young’s modulus to the calculated above value. However, such an approach is unjustified as it is no perfect composite. Zhang et al. tried to find a relation between porosity and mechanical properties (such as microhardness and Young’s modulus) and reported that, from the statistical trend, the coating porosity increases when microhardness decreases, the same as Young’s modulus decreases . In liteThe hardness, on the other side, has an understandable relation with the strengths of the components. The higher hardness values of layers comprising of titania or nanocopper can be explained by a specific nanohardness measurement which starts at the surface provided then that the minimal hardness is required to begin measurement (no test in the air might start). In such a case, in composite coatings, the hardness values which are means of several measurements may fulfill the relation between properties of composites, properties of each component, and fractions of individual components . DiffereEven more exciting is a comparison of real and theoretical values for Young’s modulus. For both coatings, these values are lower than those predicted by the model, and again the 3D structure is useful to understand such behavior. For the bi-layer, the nanoindenter tip likely bends the titania layer and this motion is not substantially impeded by the MWCNTs inner layer with its long tubes, random positioning and significant free space between nanotubes. For MWCNTs_Cu, the mechanism of deformation is different and related likely more to the misfit between MWCNTs and nanocopper particles creating additional free spaces. Therefore, the difference between real and anticipated values is, in the last case, distinctly lower than for the bi-layer coating.2 bi-layer coating, and the MWCNTs_Cu dispersion coating. As high fluctuations of both values can be observed depending on the specific measured area, these results are evidence that the coatings possess a highly non-uniform rough surface as already shown in topography tests and by great standard deviations in 2 agglomerates for the MWCNTs/TiO2 bi-layer coating and the presence of nanoCu aggregates, or in the aftermath of the microcracks, the probe’s contact with the substrate of the MWCNTs_Cu dispersion coating. 2O3-modified HfC-SiC coating for SiC-coated C/C composites [2O3 coatings [2 in BN sheets [Generally, when hardness decreases, Young’s modulus decreases as well, and vice versa, as shown by several examples such as for Ti-based alloys with Ta and Fe additions , MWCNTs mposites , HAp-Ti-mposites , YSZ-C-amposites , Ti-C-Timposites , MWCNTs/mposites , YSZ/Al2coatings , MWCNTs/coatings ,9,93, ancoatings , but alsN sheets  and for N sheets . MoreoveN sheets , nanoind2-based composites [3C2 ceramics, hardness increased at increasing pore size in the range 0.8 to 3.5 µm [2-Y2O3 coatings, again the same relationship between Young’s modulus and hardness on porosity was observed, but only in some side regions so that this relation was sensitive to the morphology of the coating [Among the problems that contribute to the difficulty in the application of indentation techniques to natural inhomogeneous materials is the presence of pores, microcracks, and voids . In poromposites , hardnesmposites , Young’smposites . In [101o 3.5 µm , but no  coating . It is aTwo factors in multicomponent components determine mechanical properties. The first is the presence of tough particles, such as here, rutile nanograins and nanocopper particles (tough species in nanoform). The hard particles counteract the indenter penetration through the matrix due to the accumulation of dislocations in the deformed area. Another determinant is adhesion and bond strength between components . We thin2/Er3). The EI represents the amount of energy released by the material under the influence of load. Whereas, the PI demonstrates the energy dissipated in the coating due to plastic deformation [2 bi-layer and the MWCNTs_Cu dispersion coating deposited on the Ti13Nb13Zr alloy. The highest PI is observed for the MWCNTs/TiO2 coating, indicating its highest plastic deformation during the nanoindentation test, while the PI for MWCNTs_Cu is the lowest. Nevertheless, the EI of the nanoCu and TiO2-modified coatings were 2-fold improved in the contrary to the MWCNTs sample, which demonstrates the stiffening effect of the additives. The mechanical behavior and the wear resistance of the examined coatings were further assessed from the nanoindentation results by evaluating elastic recovery index (EI), plasticity index (PI), ratio of the nanohardness to the reduced elastic modulus (H/Er) and yield pressure , used to evaluate the resistance to plastic deformation of materials under nanoindenter tip load [3/Er2 parameters for the MWCNTs sample, the MWCNTs/TiO2 bi-layer, and the MWCNTs_Cu dispersion coating, examined under indentation load of 10 mN are shown in 2 particles improves the wear resistance under surface deflections and the resistance to plastic deformation under applied load [3/Er2 parameter is, the higher the fraction of plastic work during stress applying on coating surface should be. Conversely, the diagram showed in Further crucial parameters are the ratio of the nanohardness to elastic modulus (H/Er), which shows the endurance capability of a surface coating, especially its ability to accommodate substrate deflections under load , and thetip load . The H/Eied load . This meThese results are favorable for both composite coatings. These coatings are innovative and, being able to oppose some stresses during and after implantation surgery, are plausible for clinical practice. Moreover, they potentially may express some antibacterial efficiency, all of the tested components. However, the coating composed of two layers, inner MWCNTs and rutile outer layer, is sufficiently thick and does not contain Cu, that above certain limits of content might be toxic for a biological organism. Therefore, in the next step, we are going to verify, for both coatings, their biological properties, including their wettability, bioactivity of live cells, cytotoxicity, and antibacterial efficiency.(1)The results show Young’s modulus value tends to decrease with rising nanohardness, which is a positive effect resulting from the structure of composite coatings, i.e., a simultaneous presence of elastic carbon nanotubes and tough nanoparticles of copper or rutile.(2)Both composite coatings demonstrate the mechanical properties better than the MWCNTs coating on Ti alloy. The additions of nanocopper or titanium dioxide to the MWCNTs coating-based Ti13Nb13Zr alloy substrate improve plastic and elastic recovery index, wear resistance to surface deflection, and to plastic deformation under applied load.(3)Comparing composite coatings to each other, the dispersion coating with nanocopper has distinctly higher hardness, slightly higher yield pressure and Young’s modulus, comparable endurance capability and elasticity recovery index, and substantially lower plasticity index. On the other side, the bi-layer coating has the greatest thickness combined with a satisfactory ability to accommodate the substrate under applied load, and the highest plasticity index, which indicates its best resistance to plastic deformation.(4)The yield pressure parameter is strictly related to the plasticity index, which shows the endurance of material to plastic deformation.(5)The observed stiffening effect can be attributed to dislocation strengthening under a load of the nanoindenter tip in presence of tough and hard nanoparticles.(6)The noticed decreasing Young’s modulus in both composite coatings compared to the MWCNTs coating may be explained by an appearance of porosity of coatings.In this study, the influence of titanium dioxide and nanocopper additions on the mechanical properties of the Ti13Nb13Zr substrate covered with the multi-wall carbon nanotube-based nanocomposites was investigated. The mechanical properties of the coatings were evaluated using the nanoindentation technique and the following conclusions were drawn from the investigations:


Lectures with audio were best approved (1.48), followed by practical videos (1.54), live stream lectures (1.81), treatment checklists (1.81), and virtual problem-based learning (2.1). Lectures such as .pdf files without audio, articles, or scripts were rated worse (2.15–2.30). Phantom-heads were considered the best substitute for patient treatment (59.5%), while additional methodical efforts for more realistic settings led to increased appraisal. However, students performed significantly worse in the multiple-choice test compared to the previous terms (p < 0.0001) and the OSPEs revealed deficits in the students’ communication skills. In the future, permanent available lectures with audio and efforts toward realistic treatment settings in the case of suspended patient treatment will be pursued.Modern teaching formats have not been considered necessary during the COVID-19 pandemic with uncertain acceptance by students. The study’s aim was to describe and evaluate all measures undertaken for theoretical and practical knowledge/skill transfer, which included objective structured practical examinations (OSPEs) covering a communication skills training. The students’ performance in the OSPE as well as the theoretical knowledge level were assessed, of which the latter was compared with previous terms. In conservative dentistry and periodontology (4th and 5th year courses), theoretical teaching formats were provided online and completed by a multiple-choice test. Practical education continued without patients in small groups using the phantom-head, 3D printed teeth, and objective structured practical examinations (OSPEs) including communication skills training. Formats were evaluated by a questionnaire. The organization was rated as very good/good (88.6%), besides poor Internet connection (22.8%) and Zoom On 12 March 2020, the World Health Organization announced that the Coronavirus disease-19 (COVID-19) was considered as a global pandemic , from deThe objective structured practical examination (OSPE) is an examination format primarily in medical school that is designed to assess clinical competence. This examination format consists of a course with different stations in which practical skills, theoretical knowledge, and communication skills are tested ,22. ProbThe aim of this study was to describe all measures and special formats of theoretical and practical knowledge/skills transfer within the undergraduate clinical dental education in the field of conservative dentistry and periodontology during the COVID-19 summer term in 2020. Furthermore, the students’ attitude toward this alternative teaching concept was surveyed by an electronic questionnaire. In addition, the theoretical knowledge level was assessed and compared with previous terms. We explored the following questions: Is teaching without practical patient contact as efficient as teaching with patients? Do additional digital teaching formats support knowledge transfer? In light of the present literature, the added value of this study may derive from issuing not only a theoretical, but also practical and communication skills training without patients such as a training and assessment OSPE in periodontology followed by structured feedback.From the results, conclusions can be drawn, of which the alternative education formats should be maintained in the future for a contemporary, crisis-proof, and sustainable dental education.n = 86) attending the first and second clinical course in the Department of Conservative Dentistry and Periodontology, Ludwig-Maximilians University, Munich, from April until August 2020 . The participants  were motivated to participate in the evaluation after completing the OSPE. The questionnaire contained different parts: (1) General (two questions); (2) Digital setting (five questions), (3) Theoretical teaching (20 questions); and (4) Practical teaching (10 questions). The 5th year students also evaluated the OSPE (eight questions). The questions regarding teaching formats were rated as either very good, good, satisfactory, bad, and very bad. In terms of using the Likert scale, we considered the answer choices of fully agree, rather agree, partially agree, disagree, and fully disagree. A detailed explanation of the increased hygienic measures for clinical as well as educational settings at our department can be found in Diegritz et al. [The special teaching formats and their evaluation involved 4th and 5th year undergraduate students  together with scripts, checklists, videos, and virtual problem-based learning seminars (VHB). Within a regular term, the face-to-face lectures are available afterward as .pdf files on Moodle® throughout the entire term. Most of them were also available as .pdf files. Six additional videos regarding organizational procedures, hygiene briefing, and rules of conduct were generated, while videos showing specific treatment sequences were increased up to 64. In the Corona summer term of 2020, the theoretical education began with a systematic six-week theory module, while the practical education was postponed to avoid any social contact. The majority of lectures were either prerecorded with an audio file or broadcast as a live-stream with online chat and recorded, which were both available on Moodle® . In pediatric dentistry, the new digital competences of staff and students were valued to offer an international webinar on thee “oral pathology in children” by an Australian specialist via ZoomNormally, students are trained in practical and communication skills by treating patients supervised by Assistant Professors according to the National Competency Based Catalogue of Dental Education (NKLZ) . In the ®. In the following, an individual objective structured practical examination (OSPE) [In periodontology, the 5th year students solely received practical training at the phantom head, while the 4th year students first ran through a PBL tutorial. Each student received an exemplary patient case, which should be planned from anamnesis and diagnosis up to prognosis and treatment planning. They had to virtually present and discuss their cases in small supervised groups via Zoomn (OSPE) ,26 was in (OSPE) . The OSPn (OSPE) ,28, and n (OSPE) ,30.Regarding the difference between the 4th and 5th year courses, the 5th year students had to undertake 33.3% more practical work than the 4th year students, while the education methods were the same for both courses except in periodontology.At the end of the 2020 summer term, theoretical examinations took place for both courses, each consisting of 30 “Pick N Type” multiple-choice (MC) questions with four answer choices ,32. The ®, which anonymously evaluated the students’ acceptance regarding organization, technical requirements, and the different theoretical and practical teaching formats. It was addressed through the student’s identification number for both the 4th and 5th year students, whereby the 4th year questionnaire contained additional questions about the OSPE in periodontology.A questionnaire  was deveIn addition to site-specific questions, literature research was conducted with the search terms e-learning, remote learning, students’ acceptance of dental education, evaluation/assessment of new teaching forms in dentistry, COVID-19 dental education, and digitalization within the dental curriculum, which resulted in a pool of 143 questions after the elimination of redundancies. Based on the nominal group technique (NGT) ,34, a prd were also given for the comparisons (GPower 3.1).Data were analyzed descriptively and given graphically . Theoretical examination scores, separately for the 4th and 5th year courses, were statistically compared (Mann–Whitney U-test) between groups (2020summer term versus pooled previous four terms) after testing the normal distribution of the data (Shapiro–Wilk test). Alpha level was set at ≤0.05. The power as well as the effect size The response rate of the questionnaire was 91% , male 24 (30.4%)).® (14.2%). The organization was rated as “very good” (44.3%) or “good” (44.3%) (together 88.6%) by the majority of students . While most participants did not experience any technical problems (63.3%), the most frequent complaints were a poor Internet connection (22.8%) and problems with ZoomUsing grades from 1 (very good) to 5 (poor), lectures with audio were rated best with an average grade of 1.48 , followeRegarding the students’ wish to maintain the newly developed theoretical teaching formats in the future, lectures with audio were mostly named , followed by the videos (85%), live stream lectures (67%), and lectures provided solely as .pdf files at the end (32.91%) .Furthermore, the students were asked to compare the virtual theoretical teaching formats with the traditional face-to-face teaching regarding their efficacy of knowledge transfer . The ratMost students fully or rather agreed that the phantom head was the best possible replacement for treatment of a patient (59.5%). However, 69.4% of the students indicated, that they did not have the same respect toward the phantom head. Only 30.4% of the students stated they would appreciate additional training opportunities at the phantom head in the future. As advantages, the students primarily mentioned a relaxed working atmosphere (64.6%), equal conditions for all students (55.7%), gaining practical routine by working without complications , and no risk of infection (54.4%). As disadvantages, the lack of specific treatment parts, for example, injection (96.2%), anatomical individuality (96.2%), patient feedback such as pain perception (93.7%), and lack of communication (87.3%) were named.The practical teaching in restorative dentistry was rated as “very good” or “good” by 85.7% of the 4th year and 81.0% of the 5th year students. In endodontology, it was rated as “very good” or “good” by 83.3% (4th year) and even by 91.1% of the 5th year students. In periodontology, it was graded as “very good” or “good” by 78.6% (4th year students), however, by only 27.0% of the 5th year students. The 4th year students rated the combination of tutorial and OSPE to be more realistic due to the simulated communication (69.0%), and appreciated it as further training of the complex periodontal diagnostic process, and would welcome its maintenance in the future (71.4%). Analyzing the students’ performance within the OSPE, they achieved 79.8 ± 9.6% (mean ± SD) of the possible points .Taking the theoretical and practical education together, 95% of the students rated their progress in theoretical knowledge and practical skills equal to that in a regular term.p < 0.0001)  . This was significantly less than in the pooled examinations of the last four terms  ( 0.0001) . The comRegarding theoretical education, several approaches toward online availability were developed such as lectures with audio, live stream lectures, practical instructional videos, and introducing videos, which replaced hygienic or equipment briefings on site. The newly acquired online skills were also used for international exchange (webinar in pediatric dentistry). According to the questionnaire, lectures with audio were rated best among these approaches and should be maintained in the future, according to the opinion of most of the students. They especially emphasized the availability at any time and place via the Internet, and the possibility to repeat and pause sequences. These features would create a highly efficient and individual learning, which can be adapted to their own pace and daily routines. Interestingly, formats such as scripts, scientific articles, and lectures given solely as .pdf files without audio were rated worse, which may underline the importance of embedding content into an explaining frame. Besides, although not counted in particular, lecturers had the feeling of a higher number of attendees during their online lectures than their past face-to-face lectures. In contrast, it became clear from the free text comments within the survey that the students missed the communication between each other and the staff to eliminate uncertainties. Furthermore, they disapproved the lack of a clear separation of life and work, which would have a negative impact on their learning motivation. The mentioned findings are in accordance with recent studies from all over the world , which also evaluated the online learning possibilities during the COVID-19 pandemic ,16,38,39However, the presented study revealed no hints that students would feel insufficiently qualified for patient treatment after the 2020 summer term, as this was critically mentioned by various studies ,39 nor dTo substitute the suspended patient treatment in the 2020 summer term, several approaches were offered to fulfill the practical education in this crisis situation, which ranged from demanding preparations at the phantom head, PBL presentations in combination with root canal treatments in 3D-printed teeth  to tutorInterestingly, 4th year students rated the education in periodontology better than the 5th year students. The difference was that the 4th year course was provided with a tutorial and an OSPE including communication training with an acting patient in addition to the practical skills training at the phantom head. The 5th year course trained solely at the phantom head. Therefore, one could conclude that the more patient-centered simulation of periodontal treatment covering different aspects such as in this case, anamnesis, diagnosis, and treatment planning, taking the information of a simulated patient into account in combination with communication, found more acceptance by the students. Another aspect might have been, that the 5th year students had already treated patients in their 4th year course and therefore felt the difference to the phantom head and the associated loss of the mentioned attributes possibly even more. Communication was deemed important as a key process within the patient–doctor relationship as stressed already in the literature ,42,43,44As a welcome side effect when looking at the free text comments, the participants highlighted the better supervision relation between students and staff. Interestingly, the new approbation regulation for dentists, which becomes effective as of 2021, will provide a better relation of 1:3 for treatments of patients and of 1:6 for teaching at the patient .Regarding the theoretical education, the study especially suggests maintaining digital lectures with audio on demand in future education accompanied by Q&A sessions with staff. A stable Internet connection is a prerequisite of utmost importance. While nothing can really replace patient treatment in practical education, for a crisis proof practical training/assessment without patients, approaches toward a higher level of competence such as OSPEs should be applied including as many aspects of patient treatment as possible. Special attention should also be paid to the training of communication skills. Nevertheless, a limitation of this study is that only students from a single dental school participated in this study. Therefore, especially, in view of the high relevance of this subject, review articles are necessary to gain a comprehensive overview of the measures undertaken worldwide.


The number of DRPs in the intervention group during hospitalization increased significantly with decreasing eGFR  and an increasing number of unintentional medication discrepancies at admission . At discharge, the number of DRPs per patient was 0.94 ± 1.03 and 1.96 ± 1.25 in the intervention and control groups, respectively (p < 0.001). The service had a significant effect on the reduction of the unintentional discrepancies at discharge (p < 0.001). (4) Conclusion: Hospital pharmacists play an important role in the prevention of DRPs at discharge and unintentional medication discrepancies in inpatients with CKD.(1) Background: The study aimed to analyze the effectiveness of clinical pharmacist services on drug-related problems (DRPs) and patient outcomes in inpatients with chronic kidney disease (CKD). (2) Methods: In a randomized controlled trial, the participants in the intervention group received pharmacist services, including medication reconciliation, medication evaluation and management, and discharge pharmaceutical care transition services. Participants in the control group received usual care. The primary outcome was the number of DRPs per patient at discharge. (3) Results: The baseline characteristics of 100 participants included the following: mean age, 52.5 years; median eGFR, 9.2 mL/min/1.73 m Many Suboptimal treatment has been reported in patients with CKD, and is associated with an increased risk of progression to ESRD. Most patients with CKD have comorbid conditions, such as electrolyte abnormalities, and cardiovascular and mineral bone disorders, and complex medication regimens ,7. TheseDue to the extraordinary comorbidity burden of CKD and associated medication complexity, the adequate management of patients with CKD requires the collaborative effort of a multidisciplinary team of nephrologists, endocrinologists, primary physicians, nurses, dieticians, and pharmacists ,14. StraThis was a prospective, randomized, parallel, controlled clinical trial conducted in collaboration with the nephrology team in the nephrology ward (33 beds) at Seoul National University Hospital (SNUH) in South Korea. The study participants were randomized in a 1:1 ratio to the clinical pharmacist intervention or control group using a centralized secure computer-generated program . The Ins2 or kidney damage, as shown by laboratory results in SNUH, within 3 months prior to the hospitalization, and (5) found to have one or more complications of CKD, such as hypertension, diabetes, dyslipidemia, acid-base and electrolyte disorders, anemia, mineral bone disorder, and hyperuricemia, or use one or more drugs for the treatment of these complications. Patients were excluded if they (1) were admitted for examination or procedure purposes for a short period of time, (2) did not take any medications before hospitalization, (3) had difficulties in responding to written questionnaires or interviews owing to cognitive problems, or (4) were participating in other studies. Those who met the above criteria were considered eligible and were invited to participate in the study. Consent for participation was obtained from all patients.Clinical pharmacists systematically identified potential participants by screening patients’ recent medical files daily. The clinical pharmacists had at least 2 years of experience with patients with CKD and were available on a full-time basis. Patients were eligible if they were (1) new admissions in the nephrology ward, (2) over 18 years of age, (3) diagnosed with CKD by their nephrologist previously, (4) confirmed to have either an eGFR of less than 60 mL/min/1.73 mIn the clinical pharmacist intervention group, the hospitalized participants received the collaborative multidisciplinary drug therapy evaluation and management (DrugTEAM) service based on the internal guidelines for inpatients ,19. ClinParticipants in the control group received usual care from pharmacists and physicians, without implementing DrugTEAM service model. The usual care mainly consisted of dispensing prescribed drugs and discharge education on the safe and appropriate use of the medicines. In Korea, medication review by pharmacist is neither part of the usual care nor reimbursed .The primary outcome was the average number of DRPs per patient at discharge. The DRPs were classified into the following subitems: prescription without indication, indication without prescription, duplicated prescription, inappropriate drug selection, inappropriate dosage/administration, allergy, ADR, drug interaction, nonadherence, cost issue, and others ,22. SecoBoth groups had the same assessments (including laboratory testing) at admission, discharge, the first visit after discharge, and 3 months after discharge. Prospective assessment was performed in the intervention group during hospitalization. However, the DRPs and medication discrepancies were retrospectively evaluated in the control group.In a randomized controlled trial by Lenander et al. , ambulatp-value < 0.05, and data analysis and computation were conducted using SAS version 9.4 . Patients excluded from the study were followed up until their withdrawal unless they specifically allowed longer follow-up.Data are shown as numbers and percentages for categorical variables, means and standard deviation (SD) for continuous parametric data, and medians and interquartile range (IQR) for nonparametric variables. Fisher’s exact and chi-square tests were used to compare categorical data and unpaired t and Mann–Whitney tests were used to compare continuous data. The percent change in unintentional medication discrepancies from admission to discharge in each group was compared using the Wilcoxon signed-rank test. Poisson regression analysis was used to study the risk factors for the occurrence of DRPs during hospitalization. Statistical significance was set at a two-sided Patients were recruited from 19 December 2015 to 31 May 2016, monitored until discharge , and followed up at the first outpatient visit after discharge . Of the 1793 patients screened, only 100 fulfilled the inclusion criteria and participated in the study . Five patients were excluded owing to follow-up loss, consent withdrawal, or death, and 95 participants completed the follow-up visit after discharge .2 . At baseline, 65% of patients were diagnosed with stage 5 CKD, and 50% were undergoing RRT. Patients had a median of five comorbidities  and received nine different drugs  within 24 h after the admission with an average adherence score of 4.5, as measured by MMS.The baseline characteristics of the study participants were similar in both groups . The meaParticipants in the intervention group were prescribed a median of 12.5 drugs  during hospitalization in the nephrology ward. In total, 182 DRPs were identified by the MEM service for inpatients with CKD . At leasp = 0.005). The primary outcome, the number of DRPs per patient at discharge, was significantly affected by the clinical pharmacist intervention (p < 0.001). We observed a nonsignificant difference in the types of DRP between the groups. The main problems at discharge in each group were indication without prescription (31.1% in the intervention group vs. 39.1% in the control group) and inappropriate dosage/administration (33.3% in the intervention group vs. 20.7% in the control group). The DRPs according to the pharmacotherapy indications at discharge were similar to those during hospitalization, but only 23 of 45 DRPs (51.1%) that occurred in the intervention group were resolved at discharge  than in the control group . The number of patients using acute care within 3 months of discharge was 16 (33.3%) and 12 (25.5%) in the intervention and control groups, respectively, and the difference was not statistically significant (p = 0.404). Among 50 patients who received RRT at baseline, seven patients in the intervention group (35.0%) and eight patients in the control group (26.7%) visited the emergency centers or hospitalized unexpectedly. The clinical pharmacist service for these patients did not affect the acute care utilization after discharge .The medication adherence score measured by MMS at the first outpatient visit after discharge was higher in the intervention group (5.2 ± 1.0) than in the control group (4.9 ± 1.3), but not significantly so (p = 0.195), the clinical pharmacist service for inpatients with CKD had a significant effect on the reduction of unintentional discrepancies at discharge . Most unintentional medication discrepancies  occurred as erroneous omissions of previously administered medicines or the addition of new drugs.Changes in medication discrepancies at discharge compared with during hospitalization in each group are shown in Hospitalized patients with CKD have a high risk of drug duplication, interactions, and adverse events, which could result in extended hospital stays, higher costs, and low quality of life. In this randomized controlled trial, we established that the clinical pharmacist intervention, based on comprehensive medication review, patient counselling, and interprofessional communication through MR, MEM and dPCT services, can reduce the number of DRPs, as well as unintentional medication discrepancies, in hospitalized patients with CKD longitudinally from admission to up to 3 months after discharge. The DrugTEAM service model was developed as a collaborative multidisciplinary team care model to improve the clinical outcomes of pharmacotherapy by reducing the number of DRPs and increasing medication adherence . We adop2; thus, this included more patients with advanced CKD than similar studies in outpatients or inpatients with CKD not treated by dialysis [In this study, two-thirds of the participants had stage 5 CKD with an average eGFR of 8.9 mL/min/1.73 mdialysis . It has dialysis . These pdialysis ,28. The dialysis . Considedialysis ,29.The majority of clinical pharmacy practice processes, often labeled as interventions, include medication review to identify any DRPs . A mediaThe well-known main pharmacist interventions are new pharmacotherapy recommendations, dosage adjustments according to kidney function, the monitoring of laboratory parameters, and the assessment of the appropriateness of medications prescribed at each point of care; these were mainly undertaken by pharmacists for patients in the intervention group ,14. Low In this study, the DrugTEAM service, which include patient counselling at discharge nominally, improved the medication adherence score compared with that in the control group at the first outpatient visit, but not significantly. The relatively young participants and their disease severity might give them alertness in taking medications and might demonstrate insignificant results. However, since the complicated regimen and polypharmacy are one of the detrimental factors in patient care, it is expected that medication adherence can be enhanced by multimodal, ongoing patient counselling and mapping medication routines in everyday activities, not by one-time medication education, as performed in this study ,35. MoreMedication errors can be attributed to discrepancies in medication history at the time of care transition. Therefore, the MR service is an important component of a mediation safety program for patients with advanced-stage CKD . It has As experts in medication management with a close relationship with patients with chronic diseases, pharmacists are well-positioned to identify patients with CKD, reduce the cardiovascular risk, assist in disease management, and produce substantial cost savings ,40. Due This study has some limitations that need to be considered. Firstly, this study was performed in a single tertiary hospital, although a statistically significant number of participants were recruited from the center. Multicenter studies with large sample sizes are needed to analyze the various clinical outcomes of pharmacist services in hospitalized patients. Secondly, the study could not be entirely blinded because the intervening pharmacist and patient knew the result of the allocation due to the educational nature of this study. We used a blinded randomization procedure and blinded the pharmacists who performed the assessment at admission, discharge, and post-discharge to avoid different levels of diligence in the review. Finally, because of the requirements for informed consent, patients with severe dementia and delirium were underrepresented in our study population. Cognitive disorders and dementia are prevalent among patients with stage 5 CKD, which accounted for approximately 60% of the participants in this study. Therefore, the effectiveness of our intervention in cognitively impaired inpatients with CKD is unknown.In conclusion, hospital pharmacists could play an important role in the prevention of DRPs at discharge and unintentional medication discrepancies in patients with CKD. This represents a promising approach for medication management in hospitalized patients with CKD by clinical pharmacists based on the DrugTEAM service model, which could have major public health implications.